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Sample records for encephalomyelitis virus tc-83

  1. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  2. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  3. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Avian Encephalomyelitis Vaccine... STANDARD REQUIREMENTS Killed Virus Vaccines § 113.208 Avian Encephalomyelitis Vaccine, Killed Virus. Avian Encephalomyelitis Vaccine (Killed Virus) shall be prepared from virus-bearing tissues or fluids obtained...

  4. Morphogenesis of Venezuelan Equine Encephalomyelitis Virus

    PubMed Central

    Bykovsky, A. F.; Yershov, F. I.; Zhdanov, V. M.

    1969-01-01

    Morphogenesis of Venezuelan equine encephalomyelitis virus was studied by means of electron microscopy. Virus-specific structures (factories, viroplasts) were found at early stages of infection; these structures were composed of fibrillar and cylindrical formations, aggregates of ribosomes, and viral nucleoids. The latter emerged from fibrillar and cylindrical structures. Aggregates of viral nucleoids were found in the cytoplasm and occasionally in the nuclei of virus-infected cells. Viral envelopes and mature virions were formed on the cell membranes and on the membranes of intracellular vacuoles. Anomalous forms of virions (both polygenomic and oligogenomic) were observed. Images PMID:5823233

  5. Polyprotein processing of Theiler's murine encephalomyelitis virus.

    PubMed Central

    Roos, R P; Kong, W P; Semler, B L

    1989-01-01

    To investigate polyprotein processing of Theiler's murine encephalomyelitis viruses, we analyzed in vitro translation reactions programmed by in vitro-derived transcripts from an infectious full-length cDNA clone of the DA strain of Theiler's virus. To help identify the proteinases that carried out the processing, we modified the DA cDNA clone transcription template by linearization with different restriction endonucleases that generate templates of different lengths or by constructing linker insertion or deletion mutations or both in putative proteinase-coding regions. Protein 3C carried out most of the cleavages of the polyprotein, as is true for the other picornaviruses that have been studied. A second proteinase also appeared active at the LP12A-2B junction. A protein of slightly faster mobility than the leader protein was seen with translation of transcripts derived from DA cDNA but not GDVII cDNA. This protein may be synthesized from an alternative initiation site in the DA leader-coding region out of phase with the polyprotein reading frame. Our findings are relevant to ongoing investigations of the abnormal virus expression seen in DA virus late demyelinating disease, since polyprotein processing is critical in regulating picornaviral gene expression. Images PMID:2555559

  6. The susceptibility of the hamster to mouse encephalomyelitis virus.

    PubMed

    DEAN, D J; DALLDORF, G

    1948-12-01

    The OT strain of mouse encephalomyelitis virus induces an inapparent infection in suckling hamsters associated with lesions of the central nervous system and skeletal muscles. The virus increases in pathogenicity after alternating mouse-hamster transfers and then induces both paralysis and encephalitis. Pathogenicity is lost through serial hamster passages but is restored by a single mouse transfer.

  7. 9 CFR 113.207 - Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Encephalomyelitis Vaccine, Eastern... PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.207 Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus. Encephalomyelitis Vaccine, Eastern, Western,...

  8. 9 CFR 113.207 - Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Encephalomyelitis Vaccine, Eastern... PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.207 Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus. Encephalomyelitis Vaccine, Eastern, Western,...

  9. 9 CFR 113.207 - Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Encephalomyelitis Vaccine, Eastern... PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.207 Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus. Encephalomyelitis Vaccine, Eastern, Western,...

  10. 9 CFR 113.207 - Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 1 2010-01-01 2010-01-01 false Encephalomyelitis Vaccine, Eastern... PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.207 Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus. Encephalomyelitis Vaccine, Eastern, Western,...

  11. 9 CFR 113.207 - Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Encephalomyelitis Vaccine, Eastern... PRODUCTS; ORGANISMS AND VECTORS STANDARD REQUIREMENTS Killed Virus Vaccines § 113.207 Encephalomyelitis Vaccine, Eastern, Western, and Venezuelan, Killed Virus. Encephalomyelitis Vaccine, Eastern, Western,...

  12. 21 CFR 866.3240 - Equine encephalomyelitis virus serological reagents.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Equine encephalomyelitis virus serological reagents. 866.3240 Section 866.3240 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological...

  13. 21 CFR 866.3240 - Equine encephalomyelitis virus serological reagents.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Equine encephalomyelitis virus serological reagents. 866.3240 Section 866.3240 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological...

  14. 21 CFR 866.3240 - Equine encephalomyelitis virus serological reagents.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Equine encephalomyelitis virus serological reagents. 866.3240 Section 866.3240 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological...

  15. 21 CFR 866.3240 - Equine encephalomyelitis virus serological reagents.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Equine encephalomyelitis virus serological reagents. 866.3240 Section 866.3240 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological...

  16. 21 CFR 866.3240 - Equine encephalomyelitis virus serological reagents.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Equine encephalomyelitis virus serological reagents. 866.3240 Section 866.3240 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES IMMUNOLOGY AND MICROBIOLOGY DEVICES Serological...

  17. Multiphasic acute disseminated encephalomyelitis associated with atypical rubella virus infection.

    PubMed

    Shinoda, Koji; Asahara, Hideaki; Uehara, Taira; Miyoshi, Katsue; Suzuki, Satoshi O; Iwaki, Toru; Kira, Jun-ichi

    2015-02-01

    We report the first case of an occurrence of multiphasic acute disseminated encephalomyelitis (ADEM) associated with atypical rubella virus infection with no rash and long-term increased titers of serum anti-rubella IgM in a 17-year-old male who had no history of rubella vaccination. He suffered from at least six clinical exacerbations with disseminated hyperintense lesions on FLAIR MR images during the course of 18 months. Repeated methylprednisolone pulse therapy and intravenous immunoglobulin therapy resolved the exacerbations. In patients with multiphasic ADEM of unknown etiology, clinicians should also consider the possibility of preceding infection with rubella virus.

  18. Physio-chemical and morphological characteristics of avian encephalomyelitis virus

    USGS Publications Warehouse

    Gosting, L.H.; Grinnell, B.W.; Matsumoto, M.

    1980-01-01

    Avian encephalomyelitis virus (AEV) was purified from infected chick embryos by a gradient centrifugation in cesium chloride. The virus had a buoyant density of 1.31 to 1.32 g/ml and a sedimentation coefficient of 148 S. The purified AEV was resistant to treatments with chloroform, acid pH or trypsin. The presence of Mg++ stabilized the virus against heat inactivation (56°C, 1 h). Electron microscopic study showed the virus to be 24 to 32 nm in diameter. The surface structure of the purified virus was not easily discernable. Nevertheless, with uranyl acetate-stained particles, Markham's rotation technique revealed that AEV has five-fold symmetry with 32 or 42 capsomers. Exact classification of AEV awaits characterization of the viral nucleic acid.

  19. Varicella-zoster virus encephalomyelitis with a prominent demyelinating component.

    PubMed

    Berth, Sarah; Carbunar, Olimpia; Yang, Ning Sarah; Fredericks, Brian; Lipton, Howard L; Valyi-Nagy, Tibor

    2015-12-01

    The histopathologic presentation of varicella-zoster virus (VZV) infection of the central nervous system is varied and is not well understood. Here we report a case of VZV encephalomyelitis with prominent demyelinating pathology in a patient with a history of follicular lymphoma treated with allogeneic stem cell transplantation. The patient presented with waxing and waning bilateral limb weakness and mental status changes. MRI showed leptomeningeal, peripheral spinal cord and periventricular cerebral white matter lesions in the brain, and polymerase chain reaction on cerebrospinal fluid detected VZV DNA. The patient expired from developing atrial fibrillation that rapidly progressed to ventricular fibrillation 10 days after admission to our hospital. Autopsy revealed macrophage-rich areas of demyelination in the spinal cord and cerebrum with relative preservation of axons associated with inclusion bodies and positive immunostaining for VZV. This case represents a rare example of VZV encephalomyelitis presenting with a predominantly demyelinating, "multiple sclerosis-like" pathology. The clinical and histopathologic findings and relevant literature are presented and discussed.

  20. Serological evidence of avian encephalomyelitis virus infection associated with vertical transmission in chicks.

    PubMed

    Yu, Xiao-hui; Zhao, Jing; Qin, Xiu-hui; Zhang, Guo-zhong

    2015-11-01

    Avian encephalomyelitis virus (AEV) can be transmitted both horizontally and vertically. In the present study, we report a typical case of AEV infection in broiler breeder chickens and their progeny identified by clinical survey of the disease, antibody detection, and reverse transcription (RT)-polymerase chain reaction (PCR) assay. PMID:26493005

  1. Infectious cDNA clones of the DA strain of Theiler's murine encephalomyelitis virus.

    PubMed Central

    Roos, R P; Stein, S; Ohara, Y; Fu, J L; Semler, B L

    1989-01-01

    The DA strain and other members of the TO subgroup of Theiler's murine encephalomyelitis viruses cause a persistent demyelinating infection, whereas the GDVII strain and other GDVII subgroup strains cause an acute lethal polioencephalomyelitis. We generated an infectious DA cDNA clone inserted into a transcription vector. Virus derived from transfection of transcripts produced a demyelinating disease indistinguishable from that of wild-type virus. The infectious clone provides a critical reagent for the production of interstrain recombinant viruses to help identify genetic loci responsible for the biological activities of the strains. Images PMID:2555569

  2. INDUCED RESISTANCE OF THE CENTRAL NERVOUS SYSTEM TO EXPERIMENTAL INFECTION WITH EQUINE ENCEPHALOMYELITIS VIRUS

    PubMed Central

    Morgan, Isabel M.; Schlesinger, R. Walter; Olitsky, Peter K.

    1942-01-01

    1. Neutralizing antibody to equine encephalomyelitis virus was found in the spinal fluid of rabbits sufficiently vaccinated with active or formalin-inactivated virus. Antibody was specific for the Western or for the Eastern virus. 2. Neutralizing capacity of spinal fluid was equivalent to that of a 1/300 dilution of serum of the same animal, and was of the same order of magnitude as that of perfused brain of a vaccinated animal. 3. Vaccinated rabbits which showed antibody in the spinal fluid resisted intracerebral or intracisternal injection of active virus. This immunity was specific, i.e., there was no cross-reaction between the Eastern and Western virus after vaccination with formalin-inactivated virus. On the other hand, lack of antibody in the spinal fluid, even when antibody was demonstrable in the undiluted serum, was associated with lack of cerebral resistance. PMID:19871243

  3. Chimeric cDNA studies of Theiler's murine encephalomyelitis virus neurovirulence.

    PubMed Central

    Zhang, L; Senkowski, A; Shim, B; Roos, R P

    1993-01-01

    Strain GDVII and other members of the GDVII subgroup of Theiler's murine encephalomyelitis virus are highly neurovirulent and rapidly fatal, while strain DA and other members of the TO subgroup produce a chronic, demyelinating disease. GDVII/DA chimeric cDNA studies suggest that a major neurovirulence determinant is within the GDVII 1B through 1D capsid protein coding region, although the additional presence of upstream GDVII sequences, including the 5' untranslated region, contributes to full neurovirulence. Our studies indicate that there are limitations in precisely delineating neurovirulence determinants with chimeric cDNAs between evolutionarily diverged viruses, such as GDVII and DA. PMID:8510228

  4. Chimeric cDNA studies of Theiler's murine encephalomyelitis virus neurovirulence.

    PubMed

    Zhang, L; Senkowski, A; Shim, B; Roos, R P

    1993-07-01

    Strain GDVII and other members of the GDVII subgroup of Theiler's murine encephalomyelitis virus are highly neurovirulent and rapidly fatal, while strain DA and other members of the TO subgroup produce a chronic, demyelinating disease. GDVII/DA chimeric cDNA studies suggest that a major neurovirulence determinant is within the GDVII 1B through 1D capsid protein coding region, although the additional presence of upstream GDVII sequences, including the 5' untranslated region, contributes to full neurovirulence. Our studies indicate that there are limitations in precisely delineating neurovirulence determinants with chimeric cDNAs between evolutionarily diverged viruses, such as GDVII and DA.

  5. Theiler's murine encephalomyelitis virus neutralization escape mutants have a change in disease phenotype.

    PubMed Central

    Roos, R P; Stein, S; Routbort, M; Senkowski, A; Bodwell, T; Wollmann, R

    1989-01-01

    DA strain of Theiler's murine encephalomyelitis virus produces a persistent demyelinating infection. We previously produced escape mutant viruses that are resistant to a neutralizing monoclonal antibody and have a mutation in VP1 amino acid residue 268 in a neutralization site (Y. Ohara, A. Senkowski, J. Fu, L. Klaman, J. Goodall, M. Toth, and R.P. Roos, J. Virol. 62:3527-3529, 1988). In contrast to wild-type DA strain, these escape mutants produce little if any demyelinating disease after inoculation into weanling mice. Images PMID:2476574

  6. Protection of SJL/J mice from demyelinating disease mediated by Theiler's murine encephalomyelitis virus.

    PubMed

    Kurtz, C I; Sun, X M; Fujinami, R S

    1995-01-01

    Intracerebral infection with the DA strain of Theiler's murine encephalomyelitis virus induces a chronic demyelinating disease in SJL/J mice. Intraperitoneal inoculation with either the wild-type DA virus or an attenuated variant virus of DA, H7A6-2, results in protection from development of chronic demyelinating disease. Protective anti-viral immune responses result in reduced viral titers and decreased inflammation in the central nervous system within the first week following intracerebral challenge with virus. Development of protective immunity requires the presence of B cells and CD4+ T cells but does not require CD8+ T cells. High titers of serum anti-viral IgG and neutralizing antibodies are induced following the intraperitoneal inoculation with the DA virus or H7A6-2 virus prior to challenge. While protection could not be transferred with immune serum from DA virus-infected mice or neutralizing monoclonal antibodies, protection was correlated with increased numbers of DA virus-specific plasma cells in the central nervous system within the first week following intracerebral challenge. Protected mice also had enhanced levels of anti-DA virus IgG and neutralizing antibodies in the cerebral spinal fluid by 1 week following intracerebral challenge with DA virus. Thus, we conclude that vaccination with live virus results in protection from chronic demyelinating disease by inducing immune responses which are manifested in the central nervous system and rapidly clear infection after intracerebral challenge with DA virus.

  7. Receptors for Theiler's murine encephalomyelitis virus: characterization by using rabbit antiviral antiserum.

    PubMed Central

    Rubio, N; Cuesta, A

    1988-01-01

    An immunological assay was developed to characterize the binding of Theiler's murine encephalomyelitis virus to BHK-21 cell receptors. After absorption of the virus and formaldehyde fixation, rabbit antibodies and Staphylococcus aureus protein A labeled with 125I formed a specific complex on the surfaces of the cells. The optimal multiplicity of infection in this system was 10 PFU per cell. The virus was internalized at 33 and 37 degrees C, but internalization did not take place at 25 or 4 degrees C. The binding was proportional to the number of cells and was significant within 30 s. Cell surface receptors were still active after fixation, and only intact viruses were bound, as demonstrated by the lack of binding of the purified, isolated virion proteins VP1, VP2, and VP3. PMID:2845143

  8. Receptors for Theiler's murine encephalomyelitis virus: characterization by using rabbit antiviral antiserum.

    PubMed

    Rubio, N; Cuesta, A

    1988-11-01

    An immunological assay was developed to characterize the binding of Theiler's murine encephalomyelitis virus to BHK-21 cell receptors. After absorption of the virus and formaldehyde fixation, rabbit antibodies and Staphylococcus aureus protein A labeled with 125I formed a specific complex on the surfaces of the cells. The optimal multiplicity of infection in this system was 10 PFU per cell. The virus was internalized at 33 and 37 degrees C, but internalization did not take place at 25 or 4 degrees C. The binding was proportional to the number of cells and was significant within 30 s. Cell surface receptors were still active after fixation, and only intact viruses were bound, as demonstrated by the lack of binding of the purified, isolated virion proteins VP1, VP2, and VP3.

  9. An in vitro assay for quantifying the virus of avian encephalomyelitis.

    PubMed

    Berger, R G

    1982-01-01

    Chicken embryo brain (CEB) cell cultures support the replication of embryo-adapted strains, vaccine strains, and field isolates of avian encephalomyelitis virus. A centrifugal force of 1,500 X g was applied during virus adsorption. Viral antigen was detected in the infected cells by using the indirect fluorescent-antibody technique (IFAT). Combining the infectivity of the virus in CEB cell culture with the ability to detect viral antigen by the IFAT resulted in the development of a virus-titration method. This in vitro assay proved to be more sensitive than the standard embryo-inoculation assay. It was concluded that the in vitro assay provides a satisfactory alternative to the embryo-inoculation assay.

  10. Effect of dose on house finch infection with western equine encephalomyelitis and St. Louis encephalitis viruses.

    PubMed

    Reisen, William K; Chiles, Robert; Martinez, Vincent; Fang, Ying; Green, Emily; Clark, Sharon

    2004-09-01

    House finches, Carpodacus mexicanus, were experimentally infected with high and standard doses of western equine encephalomyelitis virus (WEEV) or St. Louis encephalitis virus (SLEV) to determine whether high doses would produce an elevated viremia response and a high frequency of chronic infections. Finches inoculated with approximately100,000 plaque forming units (PFU) of WEEV or SLEV produced viremia and antibody responses similar to those in finches inoculated with approximately 100 PFU of WEEV or 1000 PFU of SLEV, the approximate quantities of virus expectorated by blood-feeding Culex tarsalis Coquillett. Infected finches were held through winter and then necropsied. Only one finch inoculated with the high dose of SLEV developed a chronic infection. Our data indicated that elevated infectious doses of virus may not increase the viremia level or the frequency of chronic infection in house finches.

  11. Cap-independent translation by the 5' untranslated region of Theiler's murine encephalomyelitis virus.

    PubMed Central

    Bandyopadhyay, P K; Wang, C; Lipton, H L

    1992-01-01

    The RNA genome of Theiler's murine encephalomyelitis viruses, a picornavirus belonging to the genus Cardiovirus, is translated in infected cells to a polyprotein. Unlike cellular messages, the 5' end of the RNA is not capped, and the untranslated region (UTR) is quite long (1,064 nucleotides in size). In poliovirus and encephalomyocarditis virus, the 5'UTR is thought to mediate cap-independent translation. We report here experiments to determine the role of the Theiler's murine encephalomyelitis virus 5'UTR in translation. Recombinant DNAs were constructed that were transcribed into bicistronic mRNAs encoding 5' chloramphenicol acetyltransferase intercistronic sequences linked to luciferase and a poly(A) 3' tail. The sequences of the 5'UTR, either complete or with sequential 5' deletions, were inserted into the intercistronic region. Bicistronic RNA transcripts were translated in a rabbit reticulocyte lysate or used to transfect BHK-21 cells, and chloramphenicol acetyltransferase and luciferase synthesis was quantitated. The results strongly suggest that the Theiler's virus 5'UTR promotes cap-independent translation and that the 5' boundary of the relevant signals resides 3' to nucleotide 500. Monocistronic mRNAs were synthesized by using an expression vector in which the 5'UTR containing deletions at the 3' terminus was inserted 5' to the coding sequences for luciferase. Analysis of luciferase translation in a rabbit reticulocyte lysate suggests that the 3' end of the translation initiation signal lies between nucleotides 1043 and 1053. Images PMID:1404591

  12. Cap-independent translation by the 5' untranslated region of Theiler's murine encephalomyelitis virus.

    PubMed

    Bandyopadhyay, P K; Wang, C; Lipton, H L

    1992-11-01

    The RNA genome of Theiler's murine encephalomyelitis viruses, a picornavirus belonging to the genus Cardiovirus, is translated in infected cells to a polyprotein. Unlike cellular messages, the 5' end of the RNA is not capped, and the untranslated region (UTR) is quite long (1,064 nucleotides in size). In poliovirus and encephalomyocarditis virus, the 5'UTR is thought to mediate cap-independent translation. We report here experiments to determine the role of the Theiler's murine encephalomyelitis virus 5'UTR in translation. Recombinant DNAs were constructed that were transcribed into bicistronic mRNAs encoding 5' chloramphenicol acetyltransferase intercistronic sequences linked to luciferase and a poly(A) 3' tail. The sequences of the 5'UTR, either complete or with sequential 5' deletions, were inserted into the intercistronic region. Bicistronic RNA transcripts were translated in a rabbit reticulocyte lysate or used to transfect BHK-21 cells, and chloramphenicol acetyltransferase and luciferase synthesis was quantitated. The results strongly suggest that the Theiler's virus 5'UTR promotes cap-independent translation and that the 5' boundary of the relevant signals resides 3' to nucleotide 500. Monocistronic mRNAs were synthesized by using an expression vector in which the 5'UTR containing deletions at the 3' terminus was inserted 5' to the coding sequences for luciferase. Analysis of luciferase translation in a rabbit reticulocyte lysate suggests that the 3' end of the translation initiation signal lies between nucleotides 1043 and 1053.

  13. [The vaccines based on the replicon of the venezuelan equine encephalomyelitis virus against viral hemorrhagic fevers].

    PubMed

    Petrov, A A; Plekhanova, T M; Sidorova, O N; Borisevich, S V; Makhlay, A A

    2015-01-01

    The status of the various recombinant DNA and RNA-derived candidate vaccines, as well as the Venezuelan equine encephalomyelitis virus (VEEV) replicon vaccine system against extremely hazardous viral hemorrhagic fevers, were reviewed. The VEEV-based replication-incompetent vectors offer attractive features in terms of safety, high expression levels of the heterologous viral antigen, tropism to dendritic cells, robust immune responses, protection efficacy, low potential for pre-existing anti-vector immunity and possibility of engineering multivalent vaccines were tested. These features of the VEEV replicon system hold much promise for the development of new generation vaccine candidates against viral hemorrhagic fevers.

  14. A prospective field evaluation of an enzyme immunoassay: Detection of eastern equine encephalomyelitis virus antigen in pools of Culiseta melanura

    USGS Publications Warehouse

    Scott, T.W.; Olson, J.G.; Lewis, T.E.; Carpenter, J.W.; Lorenz, L.H.; Lembeck, L.A.; Joseph, S.R.; Pagac, B.B.

    1987-01-01

    A prospective field study was conducted to determine the sensitivity and specificity of an enzyme immunoassay (EIA) compared to virus isolation in cell culture for the detection of eastern equine encephalomyelitis (EEE) virus in naturally infected mosquitoes. A total of 10,811 adult female Culiseta melanura were collected in light traps during 1985 from four locations in Maryland. Eastern equine encephalomyelitis virus was isolated from 5 of 495 mosquito pools in African green monkey kidney and baby hamster kidney cell cultures. All five virus-infected pools were detected by the EIA, and all 490 uninfected pools were correctly scored as not containing virus. The EIA did not produce false positive or false negative results. Results support the assertion of previous researchers that the antigen detection EIA is a rapid, sensitive, specific, and simple alternative to traditional bioassays for the detection of EEE virus in mosquitoes.

  15. Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain).

    PubMed

    Luo, M; He, C; Toth, K S; Zhang, C X; Lipton, H L

    1992-03-15

    Depending on the strain, Theiler murine encephalomyelitis virus (TMEV) may cause acute encephalitis or chronic demyelinating disease, which is associated with viral persistence in mice. Persistent central nervous system infection and demyelination by the less-virulent TMEV has provided a useful animal model for the human demyelinating disease multiple sclerosis. The less-virulent BeAn strain of TMEV was crystallized and its atomic structure was determined by x-ray crystallography. The alpha-carbon coordinates of the closely related Mengo virus were used to calculate the initial phases to 3.5 A resolution and the interpretable electron density map was produced by 10 cycles of 30-fold noncrystallographic molecular replacement averaging. The structure revealed a high degree of overall structural similarity to Mengo virus as well as substantial differences in the surface loops. These structural changes might be correlated with TMEV host-specific recognition, pH-related stability, and neurovirulence.

  16. Three-dimensional structure of Theiler murine encephalomyelitis virus (BeAn strain).

    PubMed Central

    Luo, M; He, C; Toth, K S; Zhang, C X; Lipton, H L

    1992-01-01

    Depending on the strain, Theiler murine encephalomyelitis virus (TMEV) may cause acute encephalitis or chronic demyelinating disease, which is associated with viral persistence in mice. Persistent central nervous system infection and demyelination by the less-virulent TMEV has provided a useful animal model for the human demyelinating disease multiple sclerosis. The less-virulent BeAn strain of TMEV was crystallized and its atomic structure was determined by x-ray crystallography. The alpha-carbon coordinates of the closely related Mengo virus were used to calculate the initial phases to 3.5 A resolution and the interpretable electron density map was produced by 10 cycles of 30-fold noncrystallographic molecular replacement averaging. The structure revealed a high degree of overall structural similarity to Mengo virus as well as substantial differences in the surface loops. These structural changes might be correlated with TMEV host-specific recognition, pH-related stability, and neurovirulence. Images PMID:1312722

  17. Identification of cardioviruses related to Theiler's murine encephalomyelitis virus in human infections

    PubMed Central

    Chiu, Charles Y.; Greninger, Alexander L.; Kanada, Kimberly; Kwok, Thomas; Fischer, Kael F.; Runckel, Charles; Louie, Janice K.; Glaser, Carol A.; Yagi, Shigeo; Schnurr, David P.; Haggerty, Tom D.; Parsonnet, Julie; Ganem, Don; DeRisi, Joseph L.

    2008-01-01

    Cardioviruses comprise a genus of picornaviruses that cause severe illnesses in rodents, but little is known about the prevalence, diversity, or spectrum of disease of such agents among humans. A single cardiovirus isolate, Saffold virus, was cultured in 1981 in stool from an infant with fever. Here, we describe the identification of a group of human cardioviruses that have been cloned directly from patient specimens, the first of which was detected using a pan-viral microarray in respiratory secretions from a child with influenza-like illness. Phylogenetic analysis of the nearly complete viral genome (7961 bp) revealed that this virus belongs to the Theiler's murine encephalomyelitis virus (TMEV) subgroup of cardioviruses and is most closely related to Saffold virus. Subsequent screening by RT-PCR of 719 additional respiratory specimens [637 (89%) from patients with acute respiratory illness] and 400 cerebrospinal fluid specimens from patients with neurological disease (aseptic meningitis, encephalitis, and multiple sclerosis) revealed no evidence of cardiovirus infection. However, screening of 751 stool specimens from 498 individuals in a gastroenteritis cohort resulted in the detection of 6 additional cardioviruses (1.2%). Although all 8 human cardioviruses (including Saffold virus) clustered together by phylogenetic analysis, significant sequence diversity was observed in the VP1 gene (66.9%–100% pairwise amino acid identities). These findings suggest that there exists a diverse group of novel human Theiler's murine encephalomyelitis virus-like cardioviruses that hitherto have gone largely undetected, are found primarily in the gastrointestinal tract, can be shed asymptomatically, and have potential links to enteric and extraintestinal disease. PMID:18768820

  18. Theiler's murine encephalomyelitis: a model of demyelination and persistence of virus.

    PubMed

    Rodriguez, M; Oleszak, E; Leibowitz, J

    1987-01-01

    Theiler's murine encephalomyelitis virus (TMEV) causes immune-mediated demyelination in susceptible mice which is similar to human demyelinating disorders such as multiple sclerosis. In addition, the picornavirus persists within the central nervous system throughout the course of the chronic demyelinating disease. This article reviews the neuropathology, virology, immunology, and molecular biology of the model system. We analyze the possible mechanisms by which this virus induces demyelination and persists in the nervous system. Finally, we provide a hypothesis that the specificity of primary white matter destruction in the TMEV model depends on immune-sensitized cells which interact with viral antigen plus major histocompatibility complex (MHC) antigens on the surfaces of oligodendrocytes or myelin sheaths.

  19. Detection of eastern equine encephalomyelitis virus RNA in North American snakes.

    PubMed

    Bingham, Andrea M; Graham, Sean P; Burkett-Cadena, Nathan D; White, Gregory S; Hassan, Hassan K; Unnasch, Thomas R

    2012-12-01

    The role of non-avian vertebrates in the ecology of eastern equine encephalomyelitis virus (EEEV) is unresolved, but mounting evidence supports a potential role for snakes in the EEEV transmission cycle, especially as over-wintering hosts. To determine rates of exposure and infection, we examined serum samples from wild snakes at a focus of EEEV in Alabama for viral RNA using quantitative reverse transcription polymerase chain reaction. Two species of vipers, the copperhead (Agkistrodon contortrix) and the cottonmouth (Agkistrodon piscivorus), were found to be positive for EEEV RNA using this assay. Prevalence of EEEV RNA was more frequent in seropositive snakes than seronegative snakes. Positivity for the quantitative reverse transcription polymerase chain reaction in cottonmouths peaked in April and September. Body size and sex ratios were not significantly different between infected and uninfected snakes. These results support the hypothesis that snakes are involved in the ecology of EEEV in North America, possibly as over-wintering hosts for the virus.

  20. A MURINE VIRUS (JHM) CAUSING DISSEMINATED ENCEPHALOMYELITIS WITH EXTENSIVE DESTRUCTION OF MYELIN

    PubMed Central

    Bailey, Orville T.; Pappenheimer, Alwin M.; Cheever, F. Sargent; Daniels, Joan B.

    1949-01-01

    A description has been given of the pathologic changes produced experimentally in animals by the inoculation of a virus material obtained from a mouse with spontaneous encephalomyelitis. The most distinctive feature of the lesions in the central nervous system is the widespread destruction of myelin. Giant cells derived from a variety of tissue elements characterize the early lesions. The liver in the majority of cases is the seat of focal necrosis. In some mice, infected with large doses by the intravenous route, there is produced massive necrosis of the liver, with fat infiltration and calcification. Giant cells are occasionally found in lymphatic tissue, but no significant changes were noted in other organs. Inclusions or elementary bodies were not demonstrated in the lesions. Similar lesions were produced by the inoculation of mouse virus into hamsters. In rats, the lesions were of a more chronic character. The relation of this disease to other demyelinating diseases of man and animals is discussed. PMID:19871701

  1. Intranasal exposure of the Richardson's ground squirrel to Western equine encephalomyelitis virus.

    PubMed Central

    Leung, M K; McLintock, J; Iversen, J

    1978-01-01

    Adult Richardson's ground squirrels were infected with western equine encephalomyelitis virus by intranasal instillation. Mortality followed the instillation of a minimum threshold of 4.7 logs of virus while infection was produced by a dosage of 2.3 logs. The incubation period was from four to seven days, being preceded by a viremic phase. Signs were depression, ataxia and paralysis of the limbs. Highest titres of virus were recovered from the brain and histopathological changes involving the central nervous system included meningitis, vasculitis, perivascular cuffing, gliosis, neuronophagia and neuronal degeneration. The virus was also found in a variety of extraneural tissues. Lesions in extraneural tissues included necrosis of brown fat and an apparent increase in number of Kupffer's cells in the liver. The lymphoid tissue was involved indicating a possible source for viremia. The duration and magnitude of viremia were ample enough to provide virus source for arthropods. The potential for transmission of the virus independent of arthropods was discussed in view of the pathogenesis demonstrated in the experimental infections. PMID:667706

  2. Monoclonal antibody to Theiler's murine encephalomyelitis virus defines a determinant on myelin and oligodendrocytes, and augments demyelination in experimental allergic encephalomyelitis.

    PubMed

    Yamada, M; Zurbriggen, A; Fujinami, R S

    1990-06-01

    Theiler's murine encephalomyelitis virus (TMEV) causes a chronic demyelinating disease in mice. The mechanisms underlying the demyelination have not been fully elucidated. We have raised a mAb to TMEV (DA strain), H8, that reacts both with TMEV VP-1 and galactocerebroside (GC). In mouse brain cultures, cells positive for the mAb H8 epitope were double labeled with antibody to myelin basic protein, indicating that those cells were oligodendrocytes. Further, mAb H8 could immunostain myelin structures in frozen sections from mouse brains. When injected intravenously into mice with acute allergic encephalomyelitis, mAb H8 increased by 10-fold the size of demyelinated areas within the spinal cords. This is the first report demonstrating that an antibody to virus can enhance demyelination of a central nervous system disease. Ig fractions from the sera of mice with chronic TMEV infection had antibody(s) to GC, as well as to TMEV, as determined by ELISA. Furthermore, a competition ELISA for TMEV or GC antigen revealed that sera from these infected mice contained antibody(s) with the same specificity as mAb H8. Our results indicate that antibodies generated by immune response to TMEV can react with myelin and oligodendrocytes, and contribute to demyelination through an immune process.

  3. Monoclonal antibody to Theiler's murine encephalomyelitis virus defines a determinant on myelin and oligodendrocytes, and augments demyelination in experimental allergic encephalomyelitis

    PubMed Central

    1990-01-01

    Theiler's murine encephalomyelitis virus (TMEV) causes a chronic demyelinating disease in mice. The mechanisms underlying the demyelination have not been fully elucidated. We have raised a mAb to TMEV (DA strain), H8, that reacts both with TMEV VP-1 and galactocerebroside (GC). In mouse brain cultures, cells positive for the mAb H8 epitope were double labeled with antibody to myelin basic protein, indicating that those cells were oligodendrocytes. Further, mAb H8 could immunostain myelin structures in frozen sections from mouse brains. When injected intravenously into mice with acute allergic encephalomyelitis, mAb H8 increased by 10-fold the size of demyelinated areas within the spinal cords. This is the first report demonstrating that an antibody to virus can enhance demyelination of a central nervous system disease. Ig fractions from the sera of mice with chronic TMEV infection had antibody(s) to GC, as well as to TMEV, as determined by ELISA. Furthermore, a competition ELISA for TMEV or GC antigen revealed that sera from these infected mice contained antibody(s) with the same specificity as mAb H8. Our results indicate that antibodies generated by immune response to TMEV can react with myelin and oligodendrocytes, and contribute to demyelination through an immune process. PMID:1693653

  4. Theiler's murine encephalomyelitis virus induces tumour necrosis factor-alpha in murine astrocyte cell cultures.

    PubMed Central

    Sierra, A; Rubio, N

    1993-01-01

    Cytokines have been postulated to exert an important modulatory and recruiting role in demyelination induced by Theiler's murine encephalomyelitis virus (TMEV) in SJL/J mice. Using a cytolytic bioassay and ELISA, we have detected and quantified a cytokine, tumour necrosis factor-alpha (TNF-alpha), in supernatants from astrocyte cultures infected in vitro with TMEV. TNF was detected only after TMEV-specific infection of astrocyte cultures (approximately 200-400 U/ml). In vitro TNF synthesis appeared in a dose- and time-dependent manner and was produced by both SJL/J (a strain susceptible to TMEV-induced demyelination) and BALB/c (a resistant strain) astrocytes. The precise nature of TNF activity was further assessed by fast protein liquid chromatography (FPLC) and antibody neutralization. These results indicate an active role for astrocytes as accessory immune cells in our experimental model for multiple sclerosis. PMID:8478023

  5. Genomic regions of neurovirulence and attenuation in Theiler murine encephalomyelitis virus.

    PubMed Central

    Calenoff, M A; Faaberg, K S; Lipton, H L

    1990-01-01

    Full-length cDNA clones of two Theiler murine encephalomyelitis virus (TMEV) strains, one highly virulent and the other less virulent, were constructed in the bacterial plasmid pGEMR-3. Transfection of BHK-21 cells with RNA transcribed from these cDNAs yielded progeny viruses with the exact in vitro growth phenotype and mouse neurovirulence pattern of the respective parental virus strains. RNA transcripts derived from recombinant chimeras constructed by exchanging corresponding genomic regions [5' noncoding, leader/P1 (L/P1), P2, P3, and 3' noncoding] between the parental cDNAs were infectious and enabled analysis of the growth characteristics in vitro and mouse neurovirulence of the chimeras. A correlation was found between plaque size and temperature sensitivity and the origin of the L/P1 region. Neurovirulence mapped primarily to the L/P1 region encoding the leader and coat proteins. Depending on parental origin, the 5' noncoding region either influenced virus attenuation or augmented virulence. Images PMID:2153981

  6. A comparison of titration methods for live avian encephalomyelitis virus vaccines.

    PubMed

    Nicholas, R A; Hopkins, I G; Southern, S J; Thornton, D H

    1986-01-01

    Factors associated with the indirect fluorescent antibody test used for the titration of avian encephalomyelitis virus (AEV) in chick embryo brain cell cultures were examined for their influence on virus replication. It was found that virus should be inoculated onto semi-confluent cell cultures and adsorbed for two hours at room temperature. The cells should then be examined for fluorescence after five days' incubation. Using these conditions, the cell culture assay was compared with the embryo and chick assays for its ability to estimate the virus content of live commercial AEV vaccines. In most cases titres obtained by the chick assay were slightly, but not significantly, higher than those obtained in the cell culture assay, although the reliability of the chick assay was, at times, questionable. In all cases titres obtained in the embryo assay were low. It is recommended that the cell culture assay be adopted as the method of choice for titrating AEV vaccines because it is rapid, reproducible, specific and greatly reduces the requirement for experimental animals.

  7. Persistent Theiler's murine encephalomyelitis virus infection in mice depends on plaque size.

    PubMed

    Lipton, H L

    1980-01-01

    Theiler's murine encephalomyelitis virus (TMEV) is an enteric pathogen of mice which causes acute and chronic neurological disorders in the natural host. When brain-derived stocks of TMEV isolates are adapted to cell culture they predominantly form either large or small plaques. In this study the type of central nervous system (CNS) infection (acute versus chronic) and the associated disease occurring in mice inoculated intracerebrally with large and small plaque strains of TMEV was investigated. Large and small plaque strains of TMEV were found to vary in virulence, type of neurological disease produced and ability to establish persistent CNS infection in mice. Two large plaque strains, GDVII and FA viruses, were highly virulent, produced acute encephalitis, but were cleared from the nervous systems of surviving animals. Therefore, it appears that these large plaque variants do not cause persistent CNS infection in mice. In contrast, five small plaque strains, DA, WW, TO4, Yale and BeAn8386 viruses, were relatively avirulent, usually produced no illness during the first month after inoculation, but readily established persistent CNS infection in mice. Persistently infected mice later developed demyelinating disease. Having identified strains of TMEV that differ regarding their ability to persist, we now hope to be able to exploit this difference in elucidating the basic mechanism(s) of TMEV persistence.

  8. Alternative translation initiation site in the DA strain of Theiler's murine encephalomyelitis virus.

    PubMed Central

    Kong, W P; Roos, R P

    1991-01-01

    Polyprotein processing studies of Theiler's murine encephalomyelitis virus (TMEV), a group of mouse picornaviruses, demonstrated synthesis of a protein we have called l during in vitro translations from the RNA of DA, a demyelinating strain of TMEV, but not GDVII, an acute neurovirulent strain. We have proposed that l is synthesized from an alternative initiation site in the DA leader (L) coding area out of phase with the polyprotein reading frame (R. P. Roos, W.-P. Kong, B. L. Semler, J. Virol. 63:5344-5353, 1989). We now provide support for this proposal from experiments involving in vitro translation of three separate mutations of an infectious DA cDNA clone: DA"l"-1, which contains a base mismatch at the putative initiation codon of l, DAL-1, which contains a base mismatch at the presumed authentic initiation site of L at the beginning of the polyprotein; and DAL:NheI, which contains nucleotides coding for a four-amino-acid insertion in the L coding area with a termination codon in the l reading frame. Our results demonstrate that the DA strain uses an alternative initiation site and reading frame to in vitro synthesize l. l may have a role in the biological activity of the virus. Images PMID:2033677

  9. Isolation and characterization of two plaque size variants of Theiler's murine encephalomyelitis virus (DA strain).

    PubMed

    Oleszak, E L; Leibowitz, J L; Rodriguez, M

    1988-09-01

    We have isolated two plaque size variants of Theiler's murine encephalomyelitis virus (TMEV) strain DA. One variant, TMEV-CL (CL), produced large plaques, while the other, TMEV-DS (DS), produced small plaques in L-2 cells. The DS variant yielded a lower titre in BHK cells and had a significantly slower growth rate when compared to CL and DA. In contrast, DS replicated to a higher titre in the central nervous system (CNS) of infected mice than the large plaque counterpart and DA. Furthermore, the DS (but not CL) variant was temperature-sensitive, replicating 130- to 500-fold more at 37 degrees C than at 39 degrees C. Although DS, CL and DA were able to establish persistent CNS infections in mice, only the DS variant and DA induced demyelinating disease in SJL/J mice. Therefore persistence of TMEV in the CNS is not sufficient to produce demyelinating disease. These two variants of the DA strain of TMEV will be useful for study of the viral genetic elements important in the mechanism of virus-induced demyelination.

  10. Susceptibility of inbred mice to chronic central nervous system infection by Theiler's murine encephalomyelitis virus.

    PubMed

    Lipton, H L; Dal Canto, M C

    1979-10-01

    The present study demonstrated that the clinicopathological expression of the late demyelinating disease due to chronic central nervous system infection by Theiler's mouse encephalomyelitis virus was dependent, at least in part, on the strain of mouse used as host. A range of involvement was observed, with late disease being most severe in the SJL strain, intermediate in the CBA and C3H/He strains, and least in C57BL/6 mice. The lack of clinical signs in seven other inbred strains of mice indicates that their response to chronic infection was similar to C57BL/6 mice. SJL, CBA, C3H/He, and C57BL/6 mice all generated similar levels of neutralizing antibody. A correlation between the severity of late disease and central nervous system virus content was not demonstrated, which indirectly suggests an immunopathological rather than a cytolytic mechanism of myelin injury during the late disease period. Finally, in addition to being more extensive, SJL demyelinating lesions contained a disproportionately large number of macrophages compared with those of similar lesions in CBA and C3H/He mice.

  11. Madariaga Virus Infection Associated with a Case of Acute Disseminated Encephalomyelitis

    PubMed Central

    Luciani, Kathia; Abadía, Iván; Martínez-Torres, Alex O.; Cisneros, Julio; Guerra, Ilka; García, Mariana; Estripeaut, Dora; Carrera, Jean-Paul

    2015-01-01

    We present the first report of a pediatric case of acute disseminated encephalomyelitis (ADEM) associated with Madariaga virus infection (MADV, Alphavirus, Togaviridae; formerly known as South American variants of eastern equine encephalitis virus [EEEV]) in a patient of the 2010 alphaviral epidemic reported in Panama. The patient was admitted to the Hospital del Niño in Panama City with suspected meningitis, exhibited with decreased alertness and disorientation in space and time, hemiparesis, and left Babinski sign. The patient was transferred to the intensive care unit and treated with aciclovir and methylprednisolone. The magnetic resonance imaging (MRI) of the brain revealed multiple hyperintense lesions at T2-weighted images (T2) and fluid-attenuated inversion recovery (FLAIR) on the cortical–subcortical level. Sera samples obtained on days 6 and 12 were immunoglobulin M (IgM) positive for MADV. The findings on the clinical and cerebrospinal analyses, rapid symptom progression as well as neuroimaging, and serologic studies support our diagnosis. Our results suggest that MADV should be included in the etiologic differential diagnosis of ADEM in endemic countries. PMID:25870420

  12. Detection of eastern equine encephalomyelitis virus RNA in North American snakes.

    PubMed

    Bingham, Andrea M; Graham, Sean P; Burkett-Cadena, Nathan D; White, Gregory S; Hassan, Hassan K; Unnasch, Thomas R

    2012-12-01

    The role of non-avian vertebrates in the ecology of eastern equine encephalomyelitis virus (EEEV) is unresolved, but mounting evidence supports a potential role for snakes in the EEEV transmission cycle, especially as over-wintering hosts. To determine rates of exposure and infection, we examined serum samples from wild snakes at a focus of EEEV in Alabama for viral RNA using quantitative reverse transcription polymerase chain reaction. Two species of vipers, the copperhead (Agkistrodon contortrix) and the cottonmouth (Agkistrodon piscivorus), were found to be positive for EEEV RNA using this assay. Prevalence of EEEV RNA was more frequent in seropositive snakes than seronegative snakes. Positivity for the quantitative reverse transcription polymerase chain reaction in cottonmouths peaked in April and September. Body size and sex ratios were not significantly different between infected and uninfected snakes. These results support the hypothesis that snakes are involved in the ecology of EEEV in North America, possibly as over-wintering hosts for the virus. PMID:23033405

  13. Survival of athymic (nu/nu) mice after Theiler's murine encephalomyelitis virus infection by passive administration of neutralizing monoclonal antibody.

    PubMed Central

    Fujinami, R S; Rosenthal, A; Lampert, P W; Zurbriggen, A; Yamada, M

    1989-01-01

    Little or no antiviral immune response is mounted in athymic nude mice infected with the Daniels strain of Theiler's murine encephalomyelitis virus. In these athymic mice, increasing levels of infectious virus could be detected in the central nervous system. Seventy-five percent (9 of 12) of the nude mice were moribund or dead by 4 weeks postinfection. In contrast, treatment of Theiler's virus-infected nude mice with a neutralizing monoclonal antibody (H7-2) against the viral protein VP-1 resulted in a dramatic reduction of infectious virus within the central nervous system. All antibody-treated nude animals survived beyond 4 weeks postinfection. Monoclonal antibody titers could be maintained by passive transfer in treated nude mice at levels comparable to those of polyclonal antibody titers found in heterozygous infected nu/+ littermates. Areas of demyelination were detected in the untreated animals as early as 7 days after infection with little or no remyelination present. In approximately one-half of the antibody-treated nude animals, no demyelinating lesions were found. However, the rest of these treated mice were found to have areas of both demyelination and remyelination. Thus, anti-Theiler's murine encephalomyelitis virus antibody against VP-1 can play a dramatic role in the survival of mice, clearance of virus, limiting viral spread, and altering the pattern of disease in the absence of a functional T-cell response. Images PMID:2539504

  14. Survival of athymic (nu/nu) mice after Theiler's murine encephalomyelitis virus infection by passive administration of neutralizing monoclonal antibody.

    PubMed

    Fujinami, R S; Rosenthal, A; Lampert, P W; Zurbriggen, A; Yamada, M

    1989-05-01

    Little or no antiviral immune response is mounted in athymic nude mice infected with the Daniels strain of Theiler's murine encephalomyelitis virus. In these athymic mice, increasing levels of infectious virus could be detected in the central nervous system. Seventy-five percent (9 of 12) of the nude mice were moribund or dead by 4 weeks postinfection. In contrast, treatment of Theiler's virus-infected nude mice with a neutralizing monoclonal antibody (H7-2) against the viral protein VP-1 resulted in a dramatic reduction of infectious virus within the central nervous system. All antibody-treated nude animals survived beyond 4 weeks postinfection. Monoclonal antibody titers could be maintained by passive transfer in treated nude mice at levels comparable to those of polyclonal antibody titers found in heterozygous infected nu/+ littermates. Areas of demyelination were detected in the untreated animals as early as 7 days after infection with little or no remyelination present. In approximately one-half of the antibody-treated nude animals, no demyelinating lesions were found. However, the rest of these treated mice were found to have areas of both demyelination and remyelination. Thus, anti-Theiler's murine encephalomyelitis virus antibody against VP-1 can play a dramatic role in the survival of mice, clearance of virus, limiting viral spread, and altering the pattern of disease in the absence of a functional T-cell response.

  15. Molecular cloning and sequence determination of DA strain of Theiler's murine encephalomyelitis viruses.

    PubMed

    Ohara, Y; Stein, S; Fu, J L; Stillman, L; Klaman, L; Roos, R P

    1988-05-01

    Theiler's murine encephalomyelitis viruses (TMEV) belong to the Picornaviridae, and are divided into two subgroups. TO subgroup strains produce a persistent demyelinating central nervous system infection in mice, while GDVII subgroup strains cause acute polioencephalomyelitis. We generated three overlapping clones of the genome of DA strain, a member of TO subgroup. Sequence analysis revealed that the genome is 8093 nucleotides long with a poly(A) tail. The 5' noncoding region stretches from nucleotides 1 to 1065 and lacks a poly(C) tract. The open reading frame stretches from 1066 to 7968 and encodes 2301 amino acids. DA strain sequence is more closely related to members of the Cardiovirus genus than to members of other Picornavirus genera. Comparison with sequence of BeAn strain, another TO subgroup strain, showed that the P1 area has the greatest number of differences, while the noncoding regions are more well-conserved. The three overlapping clones will be important in recombinant infectious cDNA studies between strains of both subgroups.

  16. Influence of Theiler's murine encephalomyelitis virus 5' untranslated region on translation and neurovirulence.

    PubMed

    Stein, S B; Zhang, L; Roos, R P

    1992-07-01

    The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, causes a persistent, restricted infection and demyelinating disease in mice. In contrast, the GDVII strain causes an acute, fatal, neuronal disease and is highly neurovirulent. To investigate the role of the TMEV 5' untranslated region (UTR) in translational efficiency and the TMEV subgroup differences, we tested the translational efficiency of transcripts in vitro derived from plasmids containing DA, GDVII, or DA/GDVII chimeric 5' UTRs preceding a reporter gene or the rest of the TMEV genome. We demonstrated that GDVII RNA translates more efficiently in rabbit reticulocyte lysate than DA RNA and that this enhanced translation is mediated by multiple domains in the GDVII 5' UTR as well as a region of the genome outside of the 5' UTR. We also identified a region within DA nucleotides 14 to 395 which inhibits translation of DA RNA and could contribute to the persistent, restricted DA central nervous system infection; the predicted secondary structure of the 5' UTR demonstrates a remarkable stem-loop structure within this region that is relatively unique among picornaviruses. Data from experiments involving DA/GDVII chimeric 5' UTR full-length infectious cDNA clones suggested that sequences in the 5' UTR can affect the neurovirulence phenotype but that translational efficiency is necessary but not sufficient for neurovirulence. These studies emphasize the multigenic nature of neurovirulence and the importance of translation in the regulation of picornaviral gene expression.

  17. Influence of Theiler's murine encephalomyelitis virus 5' untranslated region on translation and neurovirulence.

    PubMed Central

    Stein, S B; Zhang, L; Roos, R P

    1992-01-01

    The DA strain of Theiler's murine encephalomyelitis virus (TMEV), a picornavirus, causes a persistent, restricted infection and demyelinating disease in mice. In contrast, the GDVII strain causes an acute, fatal, neuronal disease and is highly neurovirulent. To investigate the role of the TMEV 5' untranslated region (UTR) in translational efficiency and the TMEV subgroup differences, we tested the translational efficiency of transcripts in vitro derived from plasmids containing DA, GDVII, or DA/GDVII chimeric 5' UTRs preceding a reporter gene or the rest of the TMEV genome. We demonstrated that GDVII RNA translates more efficiently in rabbit reticulocyte lysate than DA RNA and that this enhanced translation is mediated by multiple domains in the GDVII 5' UTR as well as a region of the genome outside of the 5' UTR. We also identified a region within DA nucleotides 14 to 395 which inhibits translation of DA RNA and could contribute to the persistent, restricted DA central nervous system infection; the predicted secondary structure of the 5' UTR demonstrates a remarkable stem-loop structure within this region that is relatively unique among picornaviruses. Data from experiments involving DA/GDVII chimeric 5' UTR full-length infectious cDNA clones suggested that sequences in the 5' UTR can affect the neurovirulence phenotype but that translational efficiency is necessary but not sufficient for neurovirulence. These studies emphasize the multigenic nature of neurovirulence and the importance of translation in the regulation of picornaviral gene expression. Images PMID:1602556

  18. Recurrent demyelination in chronic central nervous system infection produced by Theiler's murine encephalomyelitis virus.

    PubMed

    Dal Canto, M C; Lipton, H L

    1979-08-01

    A morphologic study of demyelination produced by Theiler's encephalomyelitis virus (TMEV) infection in C3H/He mice was performed. Demyelination in this strain of mouse was less intense and had a milder gliomesodermal response than that observed in SJL mice. As early as 80 days after infection numerous remyelinated axons were present in C3H/He mice, and later, extensive remyelination was observed and was mainly by Schwann cells. About one-third of remyelinated plaques showed recurrent demyelinating activity at 200 days. The best evidence of recurrent demyelination was the loss of myelin by abons which had been previously remyelinated by Schwann cells. In addition, acute areas of demyelination were also seen in spinal cords which contained chronic or quiescent plaques. The demonstration of recurrent demyelination in TMEV infection is important for it increases the relevance of this model to multiple sclerosis (MS). In addition TMEV infection of C3H/He mice appears to be an excellent model for further studies of Schwann cell remyelination and recurrent demyelination in the central nervous system (CNS).

  19. Lack of effect of Theiler's murine encephalomyelitis virus infection on system xc⁻.

    PubMed

    Merckx, Ellen; Demuyser, Thomas; Bentea, Eduard; Van Liefferinge, Joeri; Albertini, Giulia; Deneyer, Lauren; Michiels, Thomas; Massie, Ann

    2015-04-23

    Changes in the expression of xCT, the specific subunit of system xc(-) or the cystine/glutamate antiporter, have been associated with several neurological disorders and system xc(-) was recently proposed as a potential target for the development of new treatment strategies for multiple sclerosis (MS). In this study we used Theiler's murine encephalomyelitis virus (TMEV) infection, both in vitro and in vivo, as a model to further evaluate the involvement of system xc(-) in MS. Protein levels of xCT, as well as activity of system xc(-) were unaffected in RAW264.7 macrophages after infection with the demyelinating DA strain of TMEV. Also, protein expression of xCT remained stable in spinal cord and brain of FVB mice 1-2 and 6 weeks after intracranial injection of the DA strain of TMEV. These results demonstrate that TMEV infection of macrophages or FVB mice has no effect on system xc(-) and as such cannot be used as a model to study the involvement of system xc(-) in MS.

  20. A Multicenter Blinded Analysis Indicates No Association between Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and either Xenotropic Murine Leukemia Virus-Related Virus or Polytropic Murine Leukemia Virus

    PubMed Central

    Alter, Harvey J.; Mikovits, Judy A.; Switzer, William M.; Ruscetti, Francis W.; Lo, Shyh-Ching; Klimas, Nancy; Komaroff, Anthony L.; Montoya, Jose G.; Bateman, Lucinda; Levine, Susan; Peterson, Daniel; Levin, Bruce; Hanson, Maureen R.; Genfi, Afia; Bhat, Meera; Zheng, HaoQiang; Wang, Richard; Li, Bingjie; Hung, Guo-Chiuan; Lee, Li Ling; Sameroff, Stephen; Heneine, Walid; Coffin, John; Hornig, Mady; Lipkin, W. Ian

    2012-01-01

    ABSTRACT The disabling disorder known as chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) has been linked in two independent studies to infection with xenotropic murine leukemia virus-related virus (XMRV) and polytropic murine leukemia virus (pMLV). Although the associations were not confirmed in subsequent studies by other investigators, patients continue to question the consensus of the scientific community in rejecting the validity of the association. Here we report blinded analysis of peripheral blood from a rigorously characterized, geographically diverse population of 147 patients with CFS/ME and 146 healthy subjects by the investigators describing the original association. This analysis reveals no evidence of either XMRV or pMLV infection. PMID:22991430

  1. Biological characteristics of an enzootic subtype of western equine encephalomyelitis virus from Argentina.

    PubMed

    Bianchi, T I; Avilés, G; Sabattini, M S

    1997-02-01

    In order to expand our knowledge on the biological characteristics of an enzootic South American subtype of western equine encephalomyelitis (WEE) virus, strain AG80-646, we inoculated guinea pigs, rabbits, newborn chickens and Vero and chick embryo cell cultures with this and other WEE and Wee-related viruses. AG80-646 was found apathogenic for guinea pigs even when inoculated intracranially (i.e.) or intraperitoneally (i.p.), and the animals did not develop viraemia. AG80-646 killed rabbits and the animals developed high viraemia (peak titer was 7.0 log PFU/0.1 ml). These data and previous serological evidence led us to look for a mammal as a natural host. AG80-646 was found lethal for newborn chickens inoculated subcutaneously (s.c.) (peak viraemia titer was 6.6 log PFU/0.1 ml). AG80-646 produced plaques (diameter 0.8-1.0 mm) in Vero and chick embryo cells 3-4 days post infection (p.i.) A comparison of AG80-646 with other WEE complex virus strains led to the following observations: (1) The lethality for guinea pigs was high for the two epizootic Argentinian strains, Cba 87 and Cba CIV 180, zero for the two enzootic strains, AG80-646 and BeAr 10315 (virus Aura), and intermediate for the Russian strain Y62-33 (low by i.c. route and zero by i.p. route); (2) AG80-646 was more virulent for rabbits inoculated i.p. than the three epizootic strains Cba 87, Cba CIV 180 and McMillan; (3) AG80-646 was less virulent for new-born chickens than the Argentinian epizootic strain Cba CIV 180; (4) The viraemia level correlated always with the strain virulence in each animal host. This study provides tools for the differentiation of WEE complex viruses and strains in the future ecological work on WEE in South America. PMID:9199709

  2. Biological characteristics of an enzootic subtype of western equine encephalomyelitis virus from Argentina.

    PubMed

    Bianchi, T I; Avilés, G; Sabattini, M S

    1997-02-01

    In order to expand our knowledge on the biological characteristics of an enzootic South American subtype of western equine encephalomyelitis (WEE) virus, strain AG80-646, we inoculated guinea pigs, rabbits, newborn chickens and Vero and chick embryo cell cultures with this and other WEE and Wee-related viruses. AG80-646 was found apathogenic for guinea pigs even when inoculated intracranially (i.e.) or intraperitoneally (i.p.), and the animals did not develop viraemia. AG80-646 killed rabbits and the animals developed high viraemia (peak titer was 7.0 log PFU/0.1 ml). These data and previous serological evidence led us to look for a mammal as a natural host. AG80-646 was found lethal for newborn chickens inoculated subcutaneously (s.c.) (peak viraemia titer was 6.6 log PFU/0.1 ml). AG80-646 produced plaques (diameter 0.8-1.0 mm) in Vero and chick embryo cells 3-4 days post infection (p.i.) A comparison of AG80-646 with other WEE complex virus strains led to the following observations: (1) The lethality for guinea pigs was high for the two epizootic Argentinian strains, Cba 87 and Cba CIV 180, zero for the two enzootic strains, AG80-646 and BeAr 10315 (virus Aura), and intermediate for the Russian strain Y62-33 (low by i.c. route and zero by i.p. route); (2) AG80-646 was more virulent for rabbits inoculated i.p. than the three epizootic strains Cba 87, Cba CIV 180 and McMillan; (3) AG80-646 was less virulent for new-born chickens than the Argentinian epizootic strain Cba CIV 180; (4) The viraemia level correlated always with the strain virulence in each animal host. This study provides tools for the differentiation of WEE complex viruses and strains in the future ecological work on WEE in South America.

  3. Enzyme-linked immunosorbent assay for detection of antibody to avian encephalomyelitis virus in chickens.

    PubMed

    Garrett, J K; Davis, R B; Ragland, W L

    1984-01-01

    An enzyme-linked immunosorbent assay (ELISA) for the detection of antibody to avian encephalomyelitis virus (AEV) has been developed for determining whether existing AEV control programs adequately protect breeder hens. A partially purified AEV antigen was bound to microcuvettes for reaction with specific primary antibody. A second antibody, rabbit anti-chicken immunoglobulin G (IgG) conjugated with horseradish peroxidase, was employed to react with bound primary IgG. The relative amount of bound primary IgG was detected using ortho-phenylenediamine as a substrate for enzymatic production of a chromogen by horseradish peroxidase. Intensity of absorbance of the chromogen at 490 nm was related to the bound primary antibody by the titration method. Negative antisera were surveyed to establish an appropriate positive/negative cutoff level at twice the mean absorbance of negative sera at a 1:100 dilution. The test reagents for the ELISA were optimized by reagent titrations utilizing known positive and negative antisera for discrimination. The optimized ELISA had a coefficient of variation of from 1.2 to 3.3 for within-assay titer and of 2.4 for between-assay mean titer. Even though the ELISA detected only specific IgG, it was as accurate as the virus-neutralization test for evaluating the immune status of hens to AEV. Moreover, the ELISA was more economical in the use of reagents, time, and personnel and was free from dependence on susceptible embryos. Since ELISAs can be standardized and measured with manual or automated instruments, the derived ELISA can be easily and economically used to evaluate the immune status of breeder hens in commercial poultry operations.

  4. Differential IL-1 synthesis by astrocytes from Theiler's murine encephalomyelitis virus-susceptible and -resistant strains of mice.

    PubMed

    Rubio, N; Capa, L

    1993-07-01

    Increasing evidence shows that interleukin-1 (IL-1) contributes to inflammatory processes, such as experimental allergic encephalomyelitis (EAE) and virus-induced demyelination, inside the central nervous system (CNS). Using primary cultures of mouse astrocytes, we show that these glial cells can be induced to produce IL-1 alpha when infected with Theiler's murine encephalomyelitis virus (TMEV). This was true for astrocytes from SJL/J mice, a strain susceptible to TMEV-induced demyelination. Conversely, BALB/c astrocytes, derived from animals genetically resistant to demyelination, did not produce IL-1 alpha in detectable amounts. Therefore, a differential IL-1 gene expression, which is strain specific, is demonstrated after TMEV infection in astrocytes. The release of IL-1 alpha by SJL astrocytes was studied from kinetic, infectivity, and immunochemical points of view. Since IL-1 plays a critical role in the immune response, its production by astrocytes in some strains of mice may contribute to virus-induced susceptibility and to inflammation associated with this experimental model of multiple sclerosis.

  5. Patterns of avian seroprevalence to western equine encephalomyelitis and Saint Louis encephalitis viruses in California, USA.

    PubMed

    Reisen, W K; Lundstrom, J O; Scott, T W; Eldridge, B F; Chiles, R E; Cusack, R; Martinez, V M; Lothrop, H D; Gutierrez, D; Wright, S E; Boyce, K; Hill, B R

    2000-07-01

    Temporal and spatial changes in the enzootic activity of western equine encephalomyelitis (WEE) and St. Louis encephalitis (SLE) viruses were monitored at representative wetland study sites in the Coachella, San Joaquin, and Sacramento valleys of California from 1996 to 1998 using three methods: (1) virus isolation from pools of 50 host-seeking Culex tarsalis Coquillett females, (2) seroconversions in flocks of 10 sentinel chickens, and (3) seroprevalence in wild birds collected by mist nets and grain baited traps. Overall, 74 WEE and one SLE isolates were obtained from 222,455 Cx. tarsalis females tested in 4,988 pools. In addition, 133 and 40 seroconversions were detected in 28 chicken flocks, and 143 and 27 of 20,192 sera tested from 149 species of wild birds were positive for antibodies to WEE and SLE, respectively. WEE was active in all three valleys, whereas SLE only was detected in Coachella Valley. Seroconversions in sentinel chickens provided the most sensitive indication of enzootic activity and were correlated with seroprevalence rates in wild birds. Avian seroprevalence rates did not provide an early warning of pending enzootic activity in chickens, because positive sera from after hatching year birds collected during spring most probably were the result of infections acquired during the previous season. Few seroconversions were detected among banded recaptured birds collected during spring and early summer. Age and resident status, but not sex, were significant risk factors for wild bird infection, with the highest seroprevalence rates among after hatching year individuals of permanent resident species. Migrants (with the exception of mourning doves) and winter resident species rarely were positive. House finches, house sparrows, Gambel's quail, California quail, common ground doves, and mourning doves were most frequently positive for antibodies. The initial detection of enzootic activity each summer coincided closely with the appearance of hatching

  6. Serologic survey of wild turkeys (Meleagris gallopavo) and evidence of exposure to avian encephalomyelitis virus in Georgia and Florida, USA.

    PubMed

    Ingram, Dallas R; Miller, Debra L; Baldwin, Charles A; Turco, Jenifer; Lockhart, J Mitchell

    2015-04-01

    Wild Turkeys (Meleagris gallopavo) are susceptible to many of the same diseases as domestic turkeys. Before 2005, most Wild Turkeys in southern Georgia, US, had little or no exposure to commercial poultry operations. As part of a pathogen survey examining the effects of commercial poultry on Wild Turkeys, samples were collected from Wild Turkeys from March 2005 through May 2008. The turkeys were collected from 13 counties in southern Georgia and Madison County, Florida, and tested for antibodies to various pathogens of poultry. Three (13%) of the turkeys were positive for antibodies to Salmonella. Thirteen turkeys (54%) were positive for Newcastle disease virus antibodies, and 15 turkeys (63%) were positive for antibodies to reticuloendotheliosis virus. One turkey (4%) from Madison County was positive for avian encephalomyelitis virus antibodies.

  7. Rural cases of equine West Nile virus encephalomyelitis and the normalized difference vegetation index

    USGS Publications Warehouse

    Ward, M.P.; Ramsay, B.H.; Gallo, K.

    2005-01-01

    Data from an outbreak (August to October, 2002) of West Nile virus (WNV) encephalomyelitis in a population of horses located in northern Indiana was scanned for clusters in time and space. One significant (p = 0.04) cluster of case premises was detected, occurring between September 4 and 10 in the south-west part of the study area (85.70??N, 45.50??W). It included 10 case premises (3.67 case premises expected) within a radius of 2264 m. Image data were acquired by the Advanced Very High Resolution Radiometer (AVHRR) sensor onboard a National Oceanic and Atmospheric Administration polar-orbiting satellite. The Normalized Difference Vegetation Index (NDVI) was calculated from visible and near-infrared data of daily observations, which were composited to produce a weekly-1km2 resolution raster image product. During the epidemic, a significant (p<0.01) decrease (0.025 per week) in estimated NDVI was observed at all case and control premise sites. The median estimated NDVI (0.659) for case premises within the cluster identified was significantly (p<0.01) greater than the median estimated NDVI for other case (0.571) and control (0.596) premises during the same period. The difference in median estimated NDVI for case premises within this cluster, compared to cases not included in this cluster, was greatest (5.3% and 5.1%, respectively) at 1 and 5 weeks preceding occurrence of the cluster. The NDVI may be useful for identifying foci of WNV transmission. ?? Mary Ann Liebert, Inc.

  8. Rural cases of equine West Nile virus encephalomyelitis and the normalized difference vegetation index.

    PubMed

    Ward, Michael P; Ramsay, Bruce H; Gallo, Kevin

    2005-01-01

    Data from an outbreak (August to October, 2002) of West Nile virus (WNV) encephalomyelitis in a population of horses located in northern Indiana was scanned for clusters in time and space. One significant (p = 0.04) cluster of case premises was detected, occurring between September 4 and 10 in the south-west part of the study area (85.70 degrees N, 45.50 degrees W). It included 10 case premises (3.67 case premises expected) within a radius of 2264 m. Image data were acquired by the Advanced Very High Resolution Radiometer (AVHRR) sensor onboard a National Oceanic and Atmospheric Administration polar-orbiting satellite. The Normalized Difference Vegetation Index (NDVI) was calculated from visible and near-infrared data of daily observations, which were composited to produce a weekly-1km(2) resolution raster image product. During the epidemic, a significant (p < 0.01) decrease (0.025 per week) in estimated NDVI was observed at all case and control premise sites. The median estimated NDVI (0.659) for case premises within the cluster identified was significantly (p < 0.01) greater than the median estimated NDVI for other case (0.571) and control (0.596) premises during the same period. The difference in median estimated NDVI for case premises within this cluster, compared to cases not included in this cluster, was greatest (5.3% and 5.1%, respectively) at 1 and 5 weeks preceding occurrence of the cluster. The NDVI may be useful for identifying foci of WNV transmission.

  9. Alteration of amino acid 101 within capsid protein VP-1 changes the pathogenicity of Theiler's murine encephalomyelitis virus

    PubMed Central

    1989-01-01

    Chronic Theiler's murine encephalomyelitis virus infection of susceptible mice is an animal model for human demyelinating diseases. Previously we described an altered and diminished pattern of central nervous system disease in immunocompetent SJL/J mice infected with a variant virus. This variant virus H7A6-2 was selected with a neutralizing mAb recognizing the capsid protein VP-1 of Theiler's virus. Here we characterize the variant virus by ELISA and neutralization assays and by sequencing selected regions of the viral RNA genome and relate the alteration to disease. The variant virus contains one single point mutation within a neutralizing epitope of VP- 1. This nucleotide change lead to an amino acid replacement at amino acid 101 of VP-1, a threonine (wild type) to an isoleucine (variant). Model building based on sequence alignments and the known structure of the related Mengo virus indicates that the altered amino acid is located in an exposed loop on the surface of the virus at the periphery of a site that has been proposed to be the receptor binding site. The results of ELISA, neutralization assay, and direct RNA sequencing provide for the first time an opportunity to precisely map an important structural determinant of neurovirulence. PMID:2479706

  10. Alteration of amino acid 101 within capsid protein VP-1 changes the pathogenicity of Theiler's murine encephalomyelitis virus.

    PubMed

    Zurbriggen, A; Hogle, J M; Fujinami, R S

    1989-12-01

    Chronic Theiler's murine encephalomyelitis virus infection of susceptible mice is an animal model for human demyelinating diseases. Previously we described an altered and diminished pattern of central nervous system disease in immunocompetent SJL/J mice infected with a variant virus. This variant virus H7A6-2 was selected with a neutralizing mAb recognizing the capsid protein VP-1 of Theiler's virus. Here we characterize the variant virus by ELISA and neutralization assays and by sequencing selected regions of the viral RNA genome and relate the alteration to disease. The variant virus contains one single point mutation within a neutralizing epitope of VP-1. This nucleotide change lead to an amino acid replacement at amino acid 101 of VP-1, a threonine (wild type) to an isoleucine (variant). Model building based on sequence alignments and the known structure of the related Mengo virus indicates that the altered amino acid is located in an exposed loop on the surface of the virus at the periphery of a site that has been proposed to be the receptor binding site. The results of ELISA, neutralization assay, and direct RNA sequencing provide for the first time an opportunity to precisely map an important structural determinant of neurovirulence.

  11. Prolonged gray matter disease without demyelination caused by Theiler's murine encephalomyelitis virus with a mutation in VP2 puff B.

    PubMed

    Tsunoda, I; Wada, Y; Libbey, J E; Cannon, T S; Whitby, F G; Fujinami, R S

    2001-08-01

    Theiler's murine encephalomyelitis virus (TMEV) is divided into two subgroups based on neurovirulence. During the acute phase, DA virus infects cells in the gray matter of the central nervous system (CNS). Throughout the chronic phase, DA virus infects glial cells in the white matter, causing demyelinating disease. Although GDVII virus also infects neurons in the gray matter, infected mice developed a severe polioencephalomyelitis, and no virus is detected in the white matter or other areas in the CNS in rare survivors. Several sequence differences between the two viruses are located in VP2 puff B and VP1 loop II, which are located near each other, close to the proposed receptor binding site. We constructed a DA virus mutant, DApBL2M, which has the VP1 loop II of GDVII virus and a mutation at position 171 in VP2 puff B. While DApBL2M virus replicated less efficiently than DA virus during the acute phase, DApBL2M-induced acute polioencephalitis was comparable to that in DA virus infection. Interestingly, during the chronic phase, DApBL2M caused prolonged gray matter disease in the brain without white matter involvement in the spinal cord. This is opposite what is observed during wild-type DA virus infection. Our study is the first to demonstrate that conformational differences via interaction of VP2 puff B and VP1 loop II between GDVII and DA viruses can play an important role in making the transition of infection from the gray matter in the brain to the spinal cord white matter during TMEV infection. PMID:11462022

  12. Ecology of Aedes dorsalis (Diptera: Culicidae) in relation to western equine encephalomyelitis virus in the Coachella Valley of California.

    PubMed

    Reisen, W K; Lothrop, H D; Chiles, R E

    1998-07-01

    The ecology of western equine encephalomyelitis virus (WEE) was studies during 1994-1996 along a portion of the north shore of the Salton Sea in Coachella Valley, California, known to support a focal Aedes dorsalis (Meigen) population. WEE was detected during 1995 by the seroconversion of sentinel chickens concurrently at sites within and outside of the area supporting Ae. dorsalis. WEE was not detected during 1994 or 1996; neither was WEE detected by seroconversion of sentinel rabbits nor by isolation from host-seeking females of either the primary vector, Culex tarsalis Coquillett (42,083 females tested in 913 pools), or Ae. dorsalis (10,804 females tested in 245 pools and 1,940 adults reared from field-collected immatures tested in 72 pools). Collectively, the results of this and previous investigations indicate that Ae. dorsalis may not be essential for the maintenance or amplification of WEE virus in southeastern California. PMID:9701945

  13. Monocytes/macrophages isolated from the mouse central nervous system contain infectious Theiler's murine encephalomyelitis virus (TMEV).

    PubMed

    Clatch, R J; Miller, S D; Metzner, R; Dal Canto, M C; Lipton, H L

    1990-05-01

    Knowledge of the cells in which Theiler's murine encephalomyelitis virus (TMEV) persists is crucial to understanding the pathogenesis of TMEV-induced demyelinating disease; however, it is still uncertain whether oligodendrocytes or macrophages are the primary target for persistence. In this study, mononuclear cells (MNC) isolated directly from central nervous system (CNS) inflammatory infiltrates of TMEV-infected mice on discontinuous Percoll gradients were found to contain infectious TMEV. Macrophages appeared to be the principal MNC infected as determined by two-color immunofluorescence. Infectious center assay and double immunostaining together indicated the presence and possible synthesis of TMEV in approximately 1 in 225 to 1 in 1000 CNS macrophages, with 1 to 7 PFU produced per macrophage. On the basis of these findings, limited replication in macrophages is consistent with the total CNS virus content detected at any time during the persistent phase of the infection as well as the slow pace of the infection.

  14. Dimethyl fumarate suppresses Theiler's murine encephalomyelitis virus-induced demyelinating disease by modifying the Nrf2-Keap1 pathway.

    PubMed

    Kobayashi, Kunitoshi; Tomiki, Hiroki; Inaba, Yuji; Ichikawa, Motoki; Kim, Byung S; Koh, Chang-Sung

    2015-07-01

    Dimethyl fumarate (DMF) is a modifier of the nuclear factor (erythroid-derived 2)-2 (Nrf2)-kelch-like ECH-associated protein 1 (Keap1) pathway. DMF treatment in the effector phase significantly suppressed the development of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) both clinically and histologically. DMF treatment leads to an enhanced Nrf2 antioxidant response in TMEV-IDD mice. DMF treatment in the effector phase significantly suppressed the level of IL-17A mRNA. DMF is known to inhibit differentiation of T helper 17 (Th17) cells via suppressing NF-κB. Taken together, our data suggest that DMF treatment in the effector phase may suppress TMEV-IDD not only via enhancing the antioxidant response but also via suppressing IL-17A. PMID:25721871

  15. Genetic analysis of South American eastern equine encephalomyelitis viruses isolated from mosquitoes collected in the Amazon Basin region of Peru.

    PubMed

    Kondig, John P; Turell, Michael J; Lee, John S; O'Guinn, Monica L; Wasieloski, Leonard P

    2007-03-01

    Identifying viral isolates from field-collected mosquitoes can be difficult and time-consuming, particularly in regions of the world where numerous closely related viruses are co-circulating (e.g., the Amazon Basin region of Peru). The use of molecular techniques may provide rapid and efficient methods for identifying these viruses in the laboratory. Therefore, we determined the complete nucleotide sequence of two South American eastern equine encephalomyelitis viruses (EEEVs): one member from the Peru-Brazil (Lineage II) clade and one member from the Argentina-Panama (Lineage III) clade. In addition, we determined the nucleotide sequence for the nonstructural P3 protein (nsP3) and envelope 2 (E2) protein genes of 36 additional isolates of EEEV from mosquitoes captured in Peru between 1996 and 2001. The 38 isolates were evenly distributed between lineages II and III virus groupings. However, analysis of the nsP3 gene for lineage III strongly suggested that the 19 isolates from this lineage could be divided into two sub-clades, designated as lineages III and IIIA. Compared with North American EEEV (lineage I, GA97 strain), we found that the length of the nsP3 gene was shorter in the strains isolated from South America. A total of 60 nucleotides was deleted in lineage II, 69 in lineage III, and 72 in lineage IIIA. On the basis of the sequences we determined for South American EEEVs and those for other viruses detected in the same area, we developed a series of primers for characterizing these viruses.

  16. Persistent and acute central nervous system infections are caused by Theiler's murine encephalomyelitis viruses which differ in RNA composition but code for only slightly different proteins.

    PubMed

    Lorch, Y; Kotler, M; Friedmann, A

    1984-12-01

    The RNA and proteins for four representatives of the two subgroups of Theiler's murine encephalomyelitis viruses were studied. The large RNase T1-resistant oligonucleotides, when mapped along the RNA molecules, were found to be differently distributed in the two subgroups. Replicative form RNAs of two representatives were partially denatured, and the denaturation maps obtained were found to be similar but not identical. In addition, the analysis of the tryptic maps of the capsid proteins of all four isolates revealed that only small differences in the peptide map patterns exist among these viruses. The correlation of these findings with the pathogenicity of Theiler's viruses is discussed.

  17. Landscape ecology of arboviruses in southern California: patterns in the epizootic dissemination of western equine encephalomyelitis and St. Louis encephalitis viruses in Coachella Valley, 1991-1992.

    PubMed

    Reisen, W K; Hardy, J L; Lothrop, H D

    1995-05-01

    Temporal and spatial patterns in the initiation and dissemination of western equine encephalomyelitis and St. Louis encephalitis virus activity in Coachella Valley during 1991 and 1992 were detected by testing pools of host-seeking Culex tarsalis Coquillett for virus infection and sentinel chickens for seroconversions. Both viruses repeatedly were detected first at a salt marsh adjacent to the Salton Sea in the southeastern corner of the study area and then disseminated to the northwest to freshwater marsh, agricultural, and residential habitats. Virus dissemination was relatively slow (< 1 km/d) and may have been accomplished by dispersive host-seeking mosquitoes. Repeated early-season recovery of virus activity indicated that both viruses may persist interseasonally in salt marsh habitat. PMID:7616516

  18. A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus.

    PubMed

    Hunt, Ann R; Frederickson, Shana; Hinkel, Christopher; Bowdish, Katherine S; Roehrig, John T

    2006-09-01

    A humanized monoclonal antibody (mAb) has been developed and its potential to protect from or cure a Venezuelan equine encephalomyelitis virus (VEEV) infection was evaluated. The VEEV-neutralizing, protective murine mAb 3B4C-4 was humanized using combinatorial antibody libraries and phage-display technology. Humanized VEEV-binding Fabs were evaluated for virus-neutralizing capacity, then selected Fabs were converted to whole immunoglobulin (Ig) G1, and stable cell lines were generated. The humanized mAb Hy4-26C, designated Hy4 IgG, had virus-neutralizing capacity similar to that of 3B4C-4. Passive antibody protection studies with purified Hy4 IgG were performed in adult Swiss Webster mice. As little as 100 ng Hy4 IgG protected 90 % of mice challenged with 100 intraperitoneal (i.p.) mean morbidity (MD(50)) doses of virulent VEEV (Trinidad donkey) 24 h after antibody transfer; also, 500 mug Hy4 IgG protected 80 % of mice inoculated with 100 intranasal MD(50) doses of VEEV. Moreover, 10 mug passive Hy4 IgG protected 70 % of mice from a VEEV challenge dose as great as 10(7) i.p. MD(50). Hy4 IgG also protected mice from challenge with another epizootic VEEV variety, 1C (P676). Importantly, therapeutic administration of the humanized mAb to mice already infected with VEEV cured 90 % of mice treated with Hy4 IgG within 1 h of VEEV inoculation and 75 % of mice treated 24 h after virus infection. PMID:16894184

  19. 9 CFR 113.308 - Encephalomyelitis Vaccine, Venezuelan.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 1 2012-01-01 2012-01-01 false Encephalomyelitis Vaccine, Venezuelan... REQUIREMENTS Live Virus Vaccines § 113.308 Encephalomyelitis Vaccine, Venezuelan. Encephalomyelitis Vaccine... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  20. 9 CFR 113.308 - Encephalomyelitis Vaccine, Venezuelan.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 1 2011-01-01 2011-01-01 false Encephalomyelitis Vaccine, Venezuelan... REQUIREMENTS Live Virus Vaccines § 113.308 Encephalomyelitis Vaccine, Venezuelan. Encephalomyelitis Vaccine... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  1. 9 CFR 113.308 - Encephalomyelitis Vaccine, Venezuelan.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 1 2014-01-01 2014-01-01 false Encephalomyelitis Vaccine, Venezuelan... REQUIREMENTS Live Virus Vaccines § 113.308 Encephalomyelitis Vaccine, Venezuelan. Encephalomyelitis Vaccine... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  2. 9 CFR 113.308 - Encephalomyelitis Vaccine, Venezuelan.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 1 2013-01-01 2013-01-01 false Encephalomyelitis Vaccine, Venezuelan... REQUIREMENTS Live Virus Vaccines § 113.308 Encephalomyelitis Vaccine, Venezuelan. Encephalomyelitis Vaccine... established as pure, safe, and immunogenic shall be used for preparing seeds for vaccine production....

  3. Purification of Theiler's murine encephalomyelitis virus and analysis of the structural virion polypeptides: correlation of the polypeptide profile with virulence.

    PubMed

    Lipton, H L; Friedmann, A

    1980-03-01

    Theiler's murine encephalomyelitis viruses (TMEV) are separable into two groups based on their biological behavior: those highly virulent isolates which are unable to cause persistent infection and the less virulent isolates which regularly produce persistent central nervous system infection in mice. Two highly virulent and five less virulent TMEV were found to have the same buoyant density (1.34 g/ml) on isopycnic centrifugation and virion structure by electron microscopy. Negatively stained virus particles purified in Cs(2)SO(4) gradients appeared to have icosahedral symmetry and measured 28 nm in diameter. Mature virions were found to possess three major structural polypeptides, VP1, VP2 and VP3, in the range of 25,000 to 35,000 daltons, and a smaller fourth major polypeptide, VP4, of 6,000 daltons on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The precursor of VP2 and VP4, VP0, which is a minor polypeptide of mature picornavirus particles, was also identified. However, a slight but consistent difference in several of the capsid polypeptides between the highly virulent and less virulent TMEV was found. VP1 was slightly larger (34,000 versus 33,500 daltons) and VP2 was slightly smaller (31,000 versus 32,000 daltons) for the highly virulent strains compared to the same polypeptide species in the less virulent viruses. VP0 was also slightly smaller (35,500 versus 36,000 daltons) for the highly virulent isolates compared to their less virulent counterparts. Finally, trypsin which was used initially in our purification procedure resulted in preferential cleavage of a 2,000-molecular-weight fragment or fragments from VP1 of only the less virulent isolates.

  4. Purification of Theiler's Murine Encephalomyelitis Virus and Analysis of the Structural Virion Polypeptides: Correlation of the Polypeptide Profile with Virulence

    PubMed Central

    Lipton, Howard L.; Friedmann, Adam

    1980-01-01

    Theiler's murine encephalomyelitis viruses (TMEV) are separable into two groups based on their biological behavior: those highly virulent isolates which are unable to cause persistent infection and the less virulent isolates which regularly produce persistent central nervous system infection in mice. Two highly virulent and five less virulent TMEV were found to have the same buoyant density (1.34 g/ml) on isopycnic centrifugation and virion structure by electron microscopy. Negatively stained virus particles purified in Cs2SO4 gradients appeared to have icosahedral symmetry and measured 28 nm in diameter. Mature virions were found to possess three major structural polypeptides, VP1, VP2 and VP3, in the range of 25,000 to 35,000 daltons, and a smaller fourth major polypeptide, VP4, of 6,000 daltons on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The precursor of VP2 and VP4, VP0, which is a minor polypeptide of mature picornavirus particles, was also identified. However, a slight but consistent difference in several of the capsid polypeptides between the highly virulent and less virulent TMEV was found. VP1 was slightly larger (34,000 versus 33,500 daltons) and VP2 was slightly smaller (31,000 versus 32,000 daltons) for the highly virulent strains compared to the same polypeptide species in the less virulent viruses. VP0 was also slightly smaller (35,500 versus 36,000 daltons) for the highly virulent isolates compared to their less virulent counterparts. Finally, trypsin which was used initially in our purification procedure resulted in preferential cleavage of a 2,000-molecular-weight fragment or fragments from VP1 of only the less virulent isolates. Images PMID:6245266

  5. Spatial epidemiological analysis of bovine encephalomyelitis outbreaks caused by Akabane virus infection in western Japan in 2011.

    PubMed

    Hayama, Yoko; Moriguchi, Sachiko; Yanase, Tohru; Ishikura, Youji; Abe, Shigeki; Higashi, Tomoko; Ishikawa, Hajime; Yamamoto, Takehisa; Kobayashi, Sota; Murai, Kiyokazu; Tsutsui, Toshiyuki

    2016-04-01

    Akabane disease, which is distributed in temperate and tropical regions in the world, is a vector-borne disease of ruminants caused by the Akabane virus, transmitted by Culicoides biting midges. In 2011, outbreaks of Akabane viral encephalomyelitis occurred in the Shimane Prefecture in western Japan. In this study, a spatial epidemiological analysis was conducted to understand environmental factors associated with the spread of Akabane disease. By applying a conditional autoregressive model, the relationship between infection and environmental variables was explored. The results showed that the dominance of farmlands and the presence of infected farms within a 3-km radius had a significant effect on infection. This result implies that land use, which would relate with the vector habitat, and the presence of neighboring infected farms as a source of infection may have influenced the spread of the disease in this region. These findings provide basic insights into the spread of Akabane disease and useful suggestions for developing a surveillance program and preventive measures against the disease. PMID:26898692

  6. The evidence of porcine hemagglutinating encephalomyelitis virus induced nonsuppurative encephalitis as the cause of death in piglets

    PubMed Central

    Lan, Yungang; Zhao, Kui; Lv, Xiaoling; Lu, Huijun; Ding, Ning; Zhang, Jing; Shi, Junchao; Shan, Changjian

    2016-01-01

    An acute outbreak of porcine hemagglutinating encephalomyelitis virus (PHEV) infection in piglets, characterized with neurological symptoms, vomiting, diarrhea, and wasting, occurred in China. Coronavirus-like particles were observed in the homogenized tissue suspensions of the brain of dead piglets by electron microscopy, and a wild PHEV strain was isolated, characterized, and designated as PHEV-CC14. Histopathologic examinations of the dead piglets showed characteristics of non-suppurative encephalitis, and some neurons in the cerebral cortex were degenerated and necrotic, and neuronophagia. Similarly, mice inoculated with PHEV-CC14 were found to have central nervous system (CNS) dysfunction, with symptoms of depression, arched waists, standing and vellicating front claws. Furthmore, PHEV-positive labeling of neurons in cortices of dead piglets and infected mice supported the viral infections of the nervous system. Then, the major structural genes of PHEV-CC14 were sequenced and phylogenetically analyzed, and the strain shared 95%–99.2% nt identity with the other PHEV strains available in GenBank. Phylogenetic analysis clearly proved that the wild strain clustered into a subclass with a HEV-JT06 strain. These findings suggested that the virus had a strong tropism for CNS, in this way, inducing nonsuppurative encephalitis as the cause of death in piglets. Simultaneously, the predicted risk of widespread transmission showed a certain variation among the PHEV strains currently circulating around the world. Above all, the information presented in this study can not only provide good reference for the experimental diagnosis of PHEV infection for pig breeding, but also promote its new effective vaccine development.

  7. The evidence of porcine hemagglutinating encephalomyelitis virus induced nonsuppurative encephalitis as the cause of death in piglets.

    PubMed

    Li, Zi; He, Wenqi; Lan, Yungang; Zhao, Kui; Lv, Xiaoling; Lu, Huijun; Ding, Ning; Zhang, Jing; Shi, Junchao; Shan, Changjian; Gao, Feng

    2016-01-01

    An acute outbreak of porcine hemagglutinating encephalomyelitis virus (PHEV) infection in piglets, characterized with neurological symptoms, vomiting, diarrhea, and wasting, occurred in China. Coronavirus-like particles were observed in the homogenized tissue suspensions of the brain of dead piglets by electron microscopy, and a wild PHEV strain was isolated, characterized, and designated as PHEV-CC14. Histopathologic examinations of the dead piglets showed characteristics of non-suppurative encephalitis, and some neurons in the cerebral cortex were degenerated and necrotic, and neuronophagia. Similarly, mice inoculated with PHEV-CC14 were found to have central nervous system (CNS) dysfunction, with symptoms of depression, arched waists, standing and vellicating front claws. Furthmore, PHEV-positive labeling of neurons in cortices of dead piglets and infected mice supported the viral infections of the nervous system. Then, the major structural genes of PHEV-CC14 were sequenced and phylogenetically analyzed, and the strain shared 95%-99.2% nt identity with the other PHEV strains available in GenBank. Phylogenetic analysis clearly proved that the wild strain clustered into a subclass with a HEV-JT06 strain. These findings suggested that the virus had a strong tropism for CNS, in this way, inducing nonsuppurative encephalitis as the cause of death in piglets. Simultaneously, the predicted risk of widespread transmission showed a certain variation among the PHEV strains currently circulating around the world. Above all, the information presented in this study can not only provide good reference for the experimental diagnosis of PHEV infection for pig breeding, but also promote its new effective vaccine development. PMID:27672502

  8. The evidence of porcine hemagglutinating encephalomyelitis virus induced nonsuppurative encephalitis as the cause of death in piglets

    PubMed Central

    Lan, Yungang; Zhao, Kui; Lv, Xiaoling; Lu, Huijun; Ding, Ning; Zhang, Jing; Shi, Junchao; Shan, Changjian

    2016-01-01

    An acute outbreak of porcine hemagglutinating encephalomyelitis virus (PHEV) infection in piglets, characterized with neurological symptoms, vomiting, diarrhea, and wasting, occurred in China. Coronavirus-like particles were observed in the homogenized tissue suspensions of the brain of dead piglets by electron microscopy, and a wild PHEV strain was isolated, characterized, and designated as PHEV-CC14. Histopathologic examinations of the dead piglets showed characteristics of non-suppurative encephalitis, and some neurons in the cerebral cortex were degenerated and necrotic, and neuronophagia. Similarly, mice inoculated with PHEV-CC14 were found to have central nervous system (CNS) dysfunction, with symptoms of depression, arched waists, standing and vellicating front claws. Furthmore, PHEV-positive labeling of neurons in cortices of dead piglets and infected mice supported the viral infections of the nervous system. Then, the major structural genes of PHEV-CC14 were sequenced and phylogenetically analyzed, and the strain shared 95%–99.2% nt identity with the other PHEV strains available in GenBank. Phylogenetic analysis clearly proved that the wild strain clustered into a subclass with a HEV-JT06 strain. These findings suggested that the virus had a strong tropism for CNS, in this way, inducing nonsuppurative encephalitis as the cause of death in piglets. Simultaneously, the predicted risk of widespread transmission showed a certain variation among the PHEV strains currently circulating around the world. Above all, the information presented in this study can not only provide good reference for the experimental diagnosis of PHEV infection for pig breeding, but also promote its new effective vaccine development. PMID:27672502

  9. The role of CD8+T cells in the acute and chronic phases of Theiler's murine encephalomyelitis virus-induced disease in mice.

    PubMed

    Borrow, P; Tonks, P; Welsh, C J; Nash, A A

    1992-07-01

    The technique of in vivo depletion with T cell subset-specific monoclonal antibodies was used to study the involvement of CD8+T cells in protection/pathogenesis during the acute and chronic demyelinating phases of Theiler's murine encephalomyelitis virus (TMEV)-induced disease. Mice rendered CD8-deficient prior to infection with TMEV were less efficient at clearing virus from the central nervous system compared to intact animals and also suffered demyelinating disease of earlier onset and increased severity. This indicates that CD8+ cells have a protective role in virus clearance at early times post-infection, and may also be involved in downregulating the severity of the chronic demyelinating disease. How CD8+ T cells function to produce these effects is discussed.

  10. Chronic encephalomyelitis caused by canine distemper virus in a Bengal tiger.

    PubMed

    Blythe, L L; Schmitz, J A; Roelke, M; Skinner, S

    1983-12-01

    A chronic progressive neurologic disease was observed and monitored for 18 months in a young, tamed Bengal tiger. Clinical, serologic, and neuropathologic evidence of canine distemper virus infection was seen. Clinical signs included convulsions, myoclonus, and slowly progressive ataxia. Marked increases in neutralizing antibodies against canine distemper virus were seen in the serum and cerebrospinal fluid. Neuropathologic findings were nonsuppurative meningoencephalomyelitis, with perivascular cuffing, demyelination, and inclusion bodies typical of canine distemper virus. It was concluded that, in light of this case and an earlier report of canine distemper in lion cubs, vaccination of this subgroup of carnivores with a killed vaccine may be beneficial if exposure to other animals susceptible to canine distemper is anticipated.

  11. Chronic encephalomyelitis caused by canine distemper virus in a Bengal tiger.

    PubMed

    Blythe, L L; Schmitz, J A; Roelke, M; Skinner, S

    1983-12-01

    A chronic progressive neurologic disease was observed and monitored for 18 months in a young, tamed Bengal tiger. Clinical, serologic, and neuropathologic evidence of canine distemper virus infection was seen. Clinical signs included convulsions, myoclonus, and slowly progressive ataxia. Marked increases in neutralizing antibodies against canine distemper virus were seen in the serum and cerebrospinal fluid. Neuropathologic findings were nonsuppurative meningoencephalomyelitis, with perivascular cuffing, demyelination, and inclusion bodies typical of canine distemper virus. It was concluded that, in light of this case and an earlier report of canine distemper in lion cubs, vaccination of this subgroup of carnivores with a killed vaccine may be beneficial if exposure to other animals susceptible to canine distemper is anticipated. PMID:6685717

  12. Kunjin flaviviral encephalomyelitis in an Arabian gelding in New South Wales, Australia.

    PubMed

    Tee, S Y; Horadagoda, N; Mogg, T D

    2012-08-01

    Flaviviruses, including Kunjin virus, are arboviruses that cause encephalomyelitis in humans and horses. This case report describes an Arabian gelding exhibiting neurological signs of flavivirus encephalomyelitis, the diagnostic investigation and confirmation of an unreported case of Kunjin virus equine encephalomyelitis in Australia.

  13. Kunjin flaviviral encephalomyelitis in an Arabian gelding in New South Wales, Australia.

    PubMed

    Tee, S Y; Horadagoda, N; Mogg, T D

    2012-08-01

    Flaviviruses, including Kunjin virus, are arboviruses that cause encephalomyelitis in humans and horses. This case report describes an Arabian gelding exhibiting neurological signs of flavivirus encephalomyelitis, the diagnostic investigation and confirmation of an unreported case of Kunjin virus equine encephalomyelitis in Australia. PMID:22827627

  14. Analysis of viral protein-2 encoding gene of avian encephalomyelitis virus from field specimens in Central Java region, Indonesia

    PubMed Central

    Haryanto, Aris; Ermawati, Ratna; Wati, Vera; Irianingsih, Sri Handayani; Wijayanti, Nastiti

    2016-01-01

    Aim: Avian encephalomyelitis (AE) is a viral disease which can infect various types of poultry, especially chicken. In Indonesia, the incidence of AE infection in chicken has been reported since 2009, the AE incidence tends to increase from year to year. The objective of this study was to analyze viral protein 2 (VP-2) encoding gene of AE virus (AEV) from various species of birds in field specimen by reverse transcription polymerase chain reaction (RT-PCR) amplification using specific nucleotides primer for confirmation of AE diagnosis. Materials and Methods: A total of 13 AEV samples are isolated from various species of poultry which are serologically diagnosed infected by AEV from some areas in central Java, Indonesia. Research stage consists of virus samples collection from field specimens, extraction of AEV RNA, amplification of VP-2 protein encoding gene by RT-PCR, separation of RT-PCR product by agarose gel electrophoresis, DNA sequencing and data analysis. Results: Amplification products of the VP-2 encoding gene of AEV by RT-PCR methods of various types of poultry from field specimens showed a positive results on sample code 499/4/12 which generated DNA fragment in the size of 619 bp. Sensitivity test of RT-PCR amplification showed that the minimum concentration of RNA template is 127.75 ng/µl. The multiple alignments of DNA sequencing product indicated that positive sample with code 499/4/12 has 92% nucleotide homology compared with AEV with accession number AV1775/07 and 85% nucleotide homology with accession number ZCHP2/0912695 from Genbank database. Analysis of VP-2 gene sequence showed that it found 46 nucleotides difference between isolate 499/4/12 compared with accession number AV1775/07 and 93 nucleotides different with accession number ZCHP2/0912695. Conclusions: Analyses of the VP-2 encoding gene of AEV with RT-PCR method from 13 samples from field specimen generated the DNA fragment in the size of 619 bp from one sample with sample code 499

  15. Characterization of murine hepatitis virus (JHM) RNA from rats with experimental encephalomyelitis.

    PubMed

    Jackson, D P; Percy, D H; Morris, V L

    1984-09-01

    When Wistar Furth rats are inoculated intracerebrally with the murine hepatitis virus JHM they often develop a demyelinating disease with resulting hind leg paralysis. Using an RNA transfer procedure and hybridization kinetic analysis, the virus-specific RNA in these rats was characterized. The pattern of JHM-specific RNA varied with individual infections of Wistar Furth rats. However, two species of JHM-specific RNA, the nucleocapsid and a 2.1-2.4 X 10(6)-Da RNA species were generally present. A general decrease in JHM-specific RNA in brains and spinal cord samples taken later than 20 days postinoculation was observed; however, JHM-specific RNA persisted in the spinal cord longer than in the brain of these rats.

  16. Vector competence of Peruvian mosquitoes (Diptera: Culicidae) for a subtype IIIC virus in the Venezuelan equine encephalomyelitis complex isolated from mosquitoes captured in Peru.

    PubMed

    Turell, M J; Dohm, D J; Fernandez, R; Calampa, C; O'Guinn, M L

    2006-03-01

    We evaluated mosquitoes collected in the Amazon Basin, near Iquitos, Peru, for their susceptibility to a subtype IIIC strain of the Venezuelan equine encephalomyelitis complex. This virus had been previously isolated from a pool of mixed Culex vomerifer and Cx. gnomatos captured near Iquitos, Peru, in 1997. After feeding on hamsters with viremias of about 10(8) plaque-forming units of virus per ml, Cx. gnomatos was the most efficient vector. Other species, such as Ochlerotatus fulvus and Psorophora cingulata, although highly susceptible to infection, were not efficient laboratory vectors of this virus due to a significant salivary gland barrier. The Cx. (Culex) species, consisting mostly of Cx. (Cux.) coronator, were nearly refractory to subtype IIIC virus and exhibited both midgut infection as well as salivary gland barriers. Additional studies on biting behavior, mosquito population densities, and vertebrate reservoir hosts of subtype IIIC virus are needed to determine the role that these species play in the maintenance and spread of this virus in the Amazon Basin region.

  17. Varicella zoster virus encephalomyelitis as a late complication following haematopoietic stem cell transplantation.

    PubMed

    Shahani, Lokesh

    2014-12-19

    Varicella zoster virus (VZV) causes the primary infection manifesting as varicella or chickenpox, with possibility of reactivation later in life. A 71-year-old man presented with headache and lower extremity weakness. There was no evidence of skin lesions to suggest a recent zoster infection. The patient had a history of multiple myeloma diagnosed 2 years earlier, treated with chemotherapy and autologous stem cell transplant. Antimicrobial prophylaxis was discontinued 12 months after the transplant. MRI of the brain demonstrated areas of T2/fluid-attenuated inversion recovery hyperintensity in bilateral cerebral white matter and MRI of the spine demonstrated enhancement along the cauda equine. Cerebrospinal fluid (CSF) analysis showed lymphocytic pleocytosis and VZV DNA was detected by PCR in the CSF. The patient was treated with 8 weeks of antiviral therapy with complete resolution of symptoms. VZV should be considered in patients with haematopoietic stem cell transplantation presenting with similar neurological manifestations even in the absence of dermatological signs.

  18. Mumps encephalomyelitis.

    PubMed

    Tan, K K; Manickam, W D; Cardosa, M J

    1992-10-01

    A 7-year-old Indian girl developed complete paralysis of her lower limbs and acute urinary retention 10 days after suffering from mumps. Encephalomyelitis due to mumps was not suspected initially since it is a rare complication of mumps, although relatively well-documented. However, the preceding history of parotitis and the presence of mumps-specific IgM in both blood and cerebrospinal fluid led to the diagnosis. The initially severe acute neurological deficits resolved completely three months after onset of her illness. Serological investigations were helpful in diagnosing neurological complications of mumps in this case, and especially where there is no preceding parotitis.

  19. Risk of Exposure to Eastern Equine Encephalomyelitis Virus Increases with the Density of Northern Cardinals

    PubMed Central

    Estep, Laura K.; McClure, Christopher J. W.; Vander Kelen, Patrick; Burkett-Cadena, Nathan D.; Sickerman, Stephen; Hernandez, José; Jinright, Joseph; Hunt, Brenda; Lusk, John; Hoover, Victor; Armstrong, Keith; Stark, Lillian M.; Hill, Geoffrey E.; Unnasch, Thomas R.

    2013-01-01

    For a variety of infectious diseases, the richness of the community of potential host species has emerged as an important factor in pathogen transmission, whereby a higher richness of host species is associated with a lowered disease risk. The proposed mechanism driving this pattern is an increased likelihood in species-rich communities that infectious individuals will encounter dead-end hosts. Mosquito-borne pathogen systems potentially are exceptions to such “dilution effects” because mosquitoes vary their rates of use of vertebrate host species as bloodmeal sources relative to host availabilities. Such preferences may violate basic assumptions underlying the hypothesis of a dilution effect in pathogen systems. Here, we describe development of a model to predict exposure risk of sentinel chickens to eastern equine encephalitis virus (EEEV) in Walton County, Florida between 2009 and 2010 using avian species richness as well as densities of individual host species potentially important to EEEV transmission as candidate predictor variables. We found the highest support for the model that included the density of northern cardinals, a highly preferred host of mosquito vectors of EEEV, as a predictor variable. The highest-ranking model also included Culiseta melanura abundance as a predictor variable. These results suggest that mosquito preferences for vertebrate hosts influence pathogen transmission. PMID:23469095

  20. Eastern equine encephalomyelitis virus infection in six captive southern cassowaries (Casuarius casuarius).

    PubMed

    Guthrie, Amanda; Citino, Scott; Rooker, Leah; Zelazo-Kessler, Alexandra; Lim, Ailam; Myers, Carl; Bolin, Steven R; Trainor, Karen

    2016-08-01

    CASE DESCRIPTION Within a 2-week period, 4 southern cassowaries (Casuarius casuarius) at an exhibit at a Virginia zoo died acutely subsequent to eastern equine encephalitis virus (EEEV) infection. This prompted a search for other EEEV outbreaks in cassowaries, which resulted in the identification of 2 additional cassowaries that died of EEEV infection at a conservation center in Florida. CLINICAL FINDINGS Both juvenile and adult birds were affected. Three of the 6 birds died acutely with no premonitory signs. Clinical disease in the other 3 birds was characterized by lethargy and ataxia. Clinicopathologic findings typically included leukocytosis, hyperuricemia, abnormally high liver enzyme activities, and hyper-β globulinemia, which was indicative of acute inflammation. TREATMENT AND OUTCOME The 3 birds with clinical disease died despite supportive treatment. Gross abnormalities commonly observed during necropsy included coelomitis and evidence of diarrhea. Frequently observed histologic abnormalities were encephalitis, vasculitis, hepatitis, nephritis, and splenitis. The diagnosis of EEEV infection was confirmed by detection of serum anti-EEEV antibodies or detection of viral RNA in brain tissue by use of a reverse-transcriptase PCR assay. CLINICAL RELEVANCE Findings suggested that EEEV can cause high morbidity and mortality rates in southern cassowaries. Clinical disease might be reduced or prevented by vaccination, isolation of ill birds, and mosquito control strategies. PMID:27439350

  1. Vector competence of Mexican and Honduran mosquitoes (Diptera: Culicidae) for enzootic (IE) and epizootic (IC) strains of Venezuelan equine encephalomyelitis virus.

    PubMed

    Turell, Michael J; O'Guinn, Monica L; Navarro, Roberto; Romero, Guadeloupe; Estrada-Franco, José G

    2003-05-01

    Experimental studies evaluated the vector competence of Ochlerotatus taeniorhynchus (Wiedemann), Culex cancer Theobald, Culex pseudes (Dyar and Knab), Culex taeniopus Dyar and Knab, and a Culex (Culex) species, probably Culex quinquefasciatus Say, and Culex nigripalpus Theobald from Chiapas, Mexico, and Tocoa, Honduras, for epizootic (IC) and enzootic (IE) strains of Venezuelan equine encephalomyelitis (VEE) virus. Culex pseudes was highly susceptible to infection with both the IC and IE strains of VEE (infection rates >78%). Patterns of susceptibility to VEE were similar for Oc. taeniorhynchus collected in Mexico and Honduras. Although Oc. taeniorhynchus was highly susceptible to the epizootic IC strains (infection rates > or = 95%, n = 190), this species was less susceptible to the enzootic IE strain (infection rates < or = 35%, n = 233). The Culex (Culex) species were refractory to both subtypes of VEE, and none of 166 contained evidence of a disseminated infection. Virus-exposed Cx. pseudes that refed on susceptible hamsters readily transmitted virus, confirming that this species was an efficient vector of VEE. Although Oc. taeniorhynchus that fed on hamsters infected with the epizootic IC strain transmitted VEE efficiently, only one of six of those with a disseminated infection with the enzootic IE virus that fed on hamsters transmitted virus by bite. These data indicate that Cx. pseudes is an efficient laboratory vector of both epizootic and enzootic strains of VEE and that Oc. taeniorhynchus could be an important vector of epizootic subtypes of VEE.

  2. Detection of restricted predominant epitopes of Theiler's murine encephalomyelitis virus capsid proteins expressed in the lambda gt11 system: differential patterns of antibody reactivity among different mouse strains.

    PubMed

    Crane, M A; Jue, C; Mitchell, M; Lipton, H; Kim, B S

    1990-05-01

    Intracerebral injection of mice with Theiler's murine encephalomyelitis virus results in chronic demyelination in susceptible strains, and serves as a model system for the study of multiple sclerosis. The role of individual epitopes in the disease process remains to be elucidated. Random fragments of DNA from the viral capsid protein genome covering the coding regions from VP1, VP2, and VP3 have been expressed in the lambda gt11 vector system. Fusion proteins from the clones were expressed and probed with antibodies from both resistant and susceptible strains of mice. Each strain displays a distinctive pattern with certain fusion proteins recognized by all of the strains and others recognized uniquely by either the susceptible or the resistant strains.

  3. Acute disseminated encephalomyelitis (ADEM) following a H3N3 parainfluenza virus infection in a pregnant asthmatic woman with respiratory failure.

    PubMed

    Zeb, Qaiser; Alegria, Ana

    2014-01-01

    This case report relates to a 31-year-old pregnant woman, asthmatic, admitted to the intensive care unit with respiratory failure, secondary to a viral community-acquired pneumonia. A type 3 (H3N3) parainfluenza virus RNA was isolated in her throat swab. The patient developed neurological symptoms (behavioural changes, irritability, agitation and impaired consciousness) while being weaned off sedation and ventilatory support. Cerebrospinal fluid was clear with an opening pressure of 26 cm H2O. Brain MRI showed features compatible with acute disseminated encephalomyelitis. Immune screen and EEG were normal. She was treated with intravenous methylprednisolone followed by oral prednisolone. The patient made an almost full neurological recovery within 4 weeks after starting on steroids. The patient delivered a healthy baby at 38 weeks gestation. This case highlights the importance to keep in mind rare conditions that need early recognition and prompt treatment. Brain MRI is the key to early diagnosis and treatment. PMID:25281245

  4. Acute disseminated encephalomyelitis (ADEM) following a H3N3 parainfluenza virus infection in a pregnant asthmatic woman with respiratory failure.

    PubMed

    Zeb, Qaiser; Alegria, Ana

    2014-01-01

    This case report relates to a 31-year-old pregnant woman, asthmatic, admitted to the intensive care unit with respiratory failure, secondary to a viral community-acquired pneumonia. A type 3 (H3N3) parainfluenza virus RNA was isolated in her throat swab. The patient developed neurological symptoms (behavioural changes, irritability, agitation and impaired consciousness) while being weaned off sedation and ventilatory support. Cerebrospinal fluid was clear with an opening pressure of 26 cm H2O. Brain MRI showed features compatible with acute disseminated encephalomyelitis. Immune screen and EEG were normal. She was treated with intravenous methylprednisolone followed by oral prednisolone. The patient made an almost full neurological recovery within 4 weeks after starting on steroids. The patient delivered a healthy baby at 38 weeks gestation. This case highlights the importance to keep in mind rare conditions that need early recognition and prompt treatment. Brain MRI is the key to early diagnosis and treatment.

  5. The Theiler's murine encephalomyelitis virus (TMEV) model for multiple sclerosis shows a strong influence of the murine equivalents of HLA-A, B, and C.

    PubMed

    Clatch, R J; Melvold, R W; Dal Canto, M C; Miller, S D; Lipton, H L

    1987-06-01

    Following intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV), susceptible mouse strains develop a chronic demyelinating disease characterized histologically by mononuclear cell-rich infiltrates in the central nervous system (CNS). An immune-mediated basis for this disease is strongly supported by previous studies demonstrating a correlation between clinical disease susceptibility, the presence of particular H-2 region genotypes, and the development of chronically elevated levels of TMEV-specific, MHC class II-restricted delayed-type hypersensitivity (DTH). The present study compared disease susceptibility in (B10.S X SJL)F1 and (B10.S(26R) X SJL)F1 mice which differ only at the D region of the H-2 complex. The data conclusively demonstrates a major influence for homozygosity of H-2s alleles at the H-2D region (the murine equivalent of the human class I HLA-A, B, and C genes) in determining disease susceptibility, as measured by either clinical or histopathological endpoints. In addition, disease susceptibility strongly correlated with the development of high levels of TMEV-specific DTH in the susceptible (B10.S X SJL)F1 strain. However, disease susceptibility did not appear to correlate with TMEV titers in the CNS, TMEV-specific humoral (ELISA and neutralizing) immune responses, or virus-specific splenic T cell proliferative responses. These findings lend additional support to our hypothesis that CNS myelin damage is mediated by a TMEV-specific DTH response. The possible role of class I-restricted responses in the demyelinating process is discussed and murine TMEV-induced demyelinating disease is compared with experimental allergic encephalomyelitis as relevant animal models for human multiple sclerosis.

  6. Temporal variations in the susceptibility of a semi-isolated population of Culex tarsalis to peroral infection with western equine encephalomyelitis and St. Louis encephalitis viruses.

    PubMed

    Hardy, J L; Meyer, R P; Presser, S B; Milby, M M

    1990-05-01

    A semi-isolated population of Culex tarsalis in Kern County, CA was found to vary significantly in its seasonal and yearly susceptibility to peroral infection with western equine encephalomyelitis (WEE) and St. Louis encephalitis (SLE) viruses during the breeding seasons of 1975-1981. Female cohorts of the population were significantly more resistant to WEE virus from 1975 through 1977 than from 1978 through 1981. On the average, females were 40 times more susceptible to WEE virus during May than during August. Increases in resistance correlated significantly with the number of days accrued from April through June, when daily ambient air temperatures equaled or exceeded 26.7 degrees C or 32.2 degrees C, respectively. Analyses of data on WEE viral susceptibility, temperature, and rainfall for the 7 year period suggested that Cx. tarsalis should be most susceptible to infection in years with wet winter-early spring periods followed by cool springs. However, inconsistencies in the expression of WEE viral susceptibility during mid- to late summer of some years indicated that other unidentified extrinsic factors, in addition to temperature and rainfall, may induce changes during preimaginal development that affect the peroral susceptibility of adult females. Seasonal and yearly changes in the susceptibility of the Cx. tarsalis population to per os infection with SLE virus did not necessarily occur at the same time as those observed with WEE virus and did not appear to correlate with changes in ambient air temperature. Thus, extrinsic factors that affect the expression of viral susceptibility of Cx. tarsalis, and perhaps the genetic basis of viral susceptibility, apparently differ for WEE and SLE viruses. PMID:2160200

  7. Phylogeny-Directed Search for Murine Leukemia Virus-Like Retroviruses in Vertebrate Genomes and in Patients Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Prostate Cancer

    PubMed Central

    Blomberg, Jonas; Sheikholvaezin, Ali; Elfaitouri, Amal; Blomberg, Fredrik; Sjösten, Anna; Mattson Ulfstedt, Johan; Pipkorn, Rüdiger; Källander, Clas; Öhrmalm, Christina; Sperber, Göran

    2011-01-01

    Gammaretrovirus-like sequences occur in most vertebrate genomes. Murine Leukemia Virus (MLV) like retroviruses (MLLVs) are a subset, which may be pathogenic and spread cross-species. Retroviruses highly similar to MLLVs (xenotropic murine retrovirus related virus (XMRV) and Human Mouse retrovirus-like RetroViruses (HMRVs)) reported from patients suffering from prostate cancer (PC) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) raise the possibility that also humans have been infected. Structurally intact, potentially infectious MLLVs occur in the genomes of some mammals, especially mouse. Mouse MLLVs contain three major groups. One, MERV G3, contained MLVs and XMRV/HMRV. Its presence in mouse DNA, and the abundance of xenotropic MLVs in biologicals, is a source of false positivity. Theoretically, XMRV/HMRV could be one of several MLLV transspecies infections. MLLV pathobiology and diversity indicate optimal strategies for investigating XMRV/HMRV in humans and raise ethical concerns. The alternatives that XMRV/HMRV may give a hard-to-detect “stealth” infection, or that XMRV/HMRV never reached humans, have to be considered. PMID:22315600

  8. Analysis of the complete nucleotide sequence of the picornavirus Theiler's murine encephalomyelitis virus indicates that it is closely related to cardioviruses.

    PubMed Central

    Pevear, D C; Calenoff, M; Rozhon, E; Lipton, H L

    1987-01-01

    Theiler's murine encephalomyelitis viruses (TMEV) are naturally occurring enteric pathogens of mice which constitute a separate serological group within the picornavirus family. Persistent TMEV infection in mice provides a relevant experimental animal model for the human demyelinating disease multiple sclerosis. To provide information about the TMEV classification, genome organization, and protein processing map, we determined the complete nucleotide sequence of the TMEV genome and deduced the amino acid sequence of the polyprotein coding region. The RNA genome, which is typical of the picornavirus family, is 8,098 nucleotides long. The 5' untranslated region is 1,064 nucleotides long (making it the longest in the picornavirus family after the aphthoviruses) and lacks a poly(C) tract. Computer-generated comparison of the 5' and 3' noncoding regions and polyprotein revealed the highest level of nucleotide and predicted amino acid identity between the TMEV and the cardioviruses encephalomyocarditis virus (EMCV) and Mengo virus. The TMEV polyprotein, which appears to be processed like EMCV since the amino acids flanking the putative proteolytic cleavage sites have been conserved, begins with a short leader peptide followed by 11 other gene products in the standard L-4-3-4 picornavirus arrangement. Because of these similarities, we propose that the TMEV be grouped with the cardioviruses. However, since TMEV and EMCV have different biophysical properties and show no cross-neutralization, they most likely belong in a separate cardiovirus subgroup. PMID:3033278

  9. Development of a duplex real-time RT-PCR for the simultaneous detection and differentiation of Theiler's murine encephalomyelitis virus and rat theilovirus.

    PubMed

    Yuan, Wen; Wang, Jing; Xu, Fengjiao; Huang, Bihong; Lian, Yuexiao; Rao, Dan; Yin, Xueqin; Wu, Miaoli; Zhu, Yujun; Zhang, Yu; Huang, Ren; Guo, Pengju

    2016-10-01

    Theiler's murine encephalomyelitis virus (TMEV) and rat theilovirus (RTV), the member of the genus Cardiovirus, are widespread in laboratory mice and rats, and are potential contaminants of biological materials. Cardioviruses infection may cause serious complications in biomedical research. To improve the efficiency of routine screening for Cardioviruses infection, a duplex real-time reverse transcriptase polymerase chain reaction (RT-PCR) assay was developed for simultaneous detection and differentiation of TMEV and RTV. The duplex assay was specific for reference strains of TMEV and RTV, and no cross-reaction was found with seven other rodent viruses. The limits of detection of both TMEV and RTV were 4×10(1) copies RNA/reaction. Reproducibility was estimated using standard dilutions, with coefficients of variation <3.1%. 439 clinical samples were evaluated by both duplex real-time RT-PCR and conventional RT-PCR. For 439 clinical samples,95 samples were positive for TMEV and 72 samples were positive for RTV using duplex real-time RT-PCR approach, whereas only 77 samples were positive for TMEV and 66 samples were positive for RTV when conventional RT-PCR was applied. Mixed infections were found in 20 samples when analyzed by conventional RT-PCR whereas 30 samples were found to be mixed infection when duplex real-time RT-PCR was applied. This duplex assay provides a useful tool for routine health monitoring and screening of contaminated biological materials of these two viruses.

  10. The effect of L3T4 T cell depletion on the pathogenesis of Theiler's murine encephalomyelitis virus infection in CBA mice.

    PubMed

    Welsh, C J; Tonks, P; Nash, A A; Blakemore, W F

    1987-06-01

    Theiler's murine encephalomyelitis virus (TMEV) gives rise to a biphasic disease of the central nervous system (CNS) following intracranial inoculation of susceptible strains of mice. The early phase, during the first month, resembles poliomyelitis and in the late phase the mice suffer from inflammatory demyelination reminiscent of multiple sclerosis. In order to investigate the role of helper T cells in the acute and chronic phases of the disease we depleted mice of their L3T4 T cells in vivo with rat monoclonal antibodies, prior to infection and prior to the onset of clinical signs of demyelination. Mice depleted of their helper cells failed to produce antibodies to TMEV and consequently were unable to clear virus from the CNS and died within the first month of infection. Depletion of T cells before the demyelinating phase of the disease resulted in a marked decrease in the incidence of disease from 77% of the immunocompetent animals with clinical signs of paralysis to 36%. Immunocompetent TMEV-infected mice also developed antibodies against myelin suggesting that autoimmune mechanisms may play a role in TMEV-induced demyelination.

  11. Activation of tumor suppressor protein p53 is required for Theiler's murine encephalomyelitis virus-induced apoptosis in M1-D macrophages.

    PubMed

    Son, Kyung-No; Pugazhenthi, Subbiah; Lipton, Howard L

    2009-10-01

    Theiler's murine encephalomyelitis virus (TMEV) is a highly cytolytic picornavirus that persists in the mouse central nervous system (CNS) largely in macrophages with infection maintained by macrophage-to-macrophage spread. Infected macrophages in the CNS undergo apoptosis. We recently showed that M1-D macrophages infected with the low-neurovirulence TMEV BeAn virus became apoptotic through the mitochondrial pathway that is Bax mediated. Our present analyses of the molecular events and signaling pathway(s) culminating in the mitochondrial outer membrane permeabilization that initiates the caspase cascade and apoptosis of BeAn virus-infected M1-D macrophages revealed activation of p38 mitogen-activated protein kinase by 2 to 3 h postinfection (p.i.), followed by phosphorylation of tumor suppressor protein p53 Ser 15 at 3 to 6 h p.i., stabilizing p53 levels until 6 h p.i. Activated p53 upregulated the transcription of proapoptotic puma and noxa genes at 2 to 4 h p.i. and their BH3-only protein expression, followed by the loss of detectable prosurvival Mcl-1 and A1 proteins at 4 to 10 h p.i. Degradation of the prosurvival proteins is known to release Bax, which forms homo-oligomers and translocates into and permeabilizes the mitochondrial outer membrane. Inhibition of phospho-p38 by two specific inhibitors, SB203580 and BIRB796, led to a significant decrease in apoptosis at 10 h p.i., with no effect on virus titers (only SB203580 tested). Together, these data indicate that p53 activation is required for the induction of apoptosis in infected M1-D cells.

  12. Decreased spinal cord opioid receptor mRNA expression and antinociception in a Theiler’s murine encephalomyelitis virus model of multiple sclerosis

    PubMed Central

    Lynch, Jessica L.; Alley, Jeremy F.; Wellman, Lori; Beitz, Alvin J.

    2008-01-01

    Multiple sclerosis patients typically experience increased pain that is relatively insensitive to opiate treatment. The mechanistic basis for this increased nociception is currently poorly understood. In the present study, we utilized the Theiler’s murine encephalomyelitis virus (TMEV) model of MS to examine possible changes in spinal cord opioid receptor mRNA over the course of disease progression. TMEV infection led to significantly decreased mu, delta and kappa opioid receptor mRNA expression as analyzed by quantitative Real-Time PCR in both male and female mice at days 90, 150 and 180 post-infection (PI). Since opioid receptor mRNA expression decreased in TMEV mice, we examined whether opiate analgesia is also altered. TMEV infected female mice had significantly decreased opiate analgesia in thermal nociceptive tests beginning at day 90 PI, while TMEV-infected male mice did not display significantly decreased opiate analgesia until day 120 PI. The novel finding that opioid receptor expression is significantly decreased in the spinal cord of TMEV mice could explain the increased nociception and loss of opiate analgesia observed in both TMEV mice and multiple sclerosis patients. PMID:18096140

  13. Acute disseminated encephalomyelitis (ADEM) following a H3N3 parainfluenza virus infection in a pregnant asthmatic woman with respiratory failure

    PubMed Central

    Zeb, Qaiser; Alegria, Ana

    2014-01-01

    This case report relates to a 31-year-old pregnant woman, asthmatic, admitted to the intensive care unit with respiratory failure, secondary to a viral community-acquired pneumonia. A type 3 (H3N3) parainfluenza virus RNA was isolated in her throat swab. The patient developed neurological symptoms (behavioural changes, irritability, agitation and impaired consciousness) while being weaned off sedation and ventilatory support. Cerebrospinal fluid was clear with an opening pressure of 26 cm H2O. Brain MRI showed features compatible with acute disseminated encephalomyelitis. Immune screen and EEG were normal. She was treated with intravenous methylprednisolone followed by oral prednisolone. The patient made an almost full neurological recovery within 4 weeks after starting on steroids. The patient delivered a healthy baby at 38 weeks gestation. This case highlights the importance to keep in mind rare conditions that need early recognition and prompt treatment. Brain MRI is the key to early diagnosis and treatment. PMID:25281245

  14. IgG subclass responses to Theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains.

    PubMed Central

    Peterson, J D; Waltenbaugh, C; Miller, S D

    1992-01-01

    Inbred mouse strains differ in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. A strong correlation between disease susceptibility and delayed-type hypersensitivity (DTH) has been previously demonstrated, but no strong correlation between disease susceptibility and total anti-TMEV ELISA titres was shown. Since both DTH and IgG2a antibody production are regulated by CD4+ Th1 cells, we investigated three strains of mice to determine whether antivirus IgG2a antibody levels, like DTH in previous studies, correlated with disease susceptibility. Susceptible SJL/J, intermediately susceptible C3H/HeJ, and resistant C57BL/6 mice were infected intracerebrally (i.c.) with the BeAn strain of TMEV and monitored for clinical signs of demyelination and for levels of TMEV-specific antibody of different IgG subclasses using a particle concentration fluorescence immunoassay (PCFIA). Resistant C57BL/6 mice were found to have significantly lower concentrations of total anti-TMEV antibody than susceptible SJL/J mice and intermediately susceptible C3H/HeJ mice show variable antibody responses. A predominance of anti-TMEV IgG2a (Th1 regulated) antibody was seen in susceptible and intermediately susceptible mice, whereas resistant mice displayed a predominant anti-TMEV IgG1 (Th2 regulated) response accompanied by a marked deficiency of IgG2a. In contrast, immunization of C57BL/6 mice with UV-inactivated TMEV in adjuvant revealed that this strain was not defective either in its ability to generate high levels of anti-TMEV antibody or in its ability to produce IgG2a antibody. These results suggest that the antivirus IgG subclass profile is dependent upon the immunization route, virus viability and/or the use of adjuvant and that the levels of antivirus subclasses may be predictive of disease susceptibility. PMID:1350571

  15. Nonsuppurative Encephalomyelitis in a Calf in Japan and Isolation of Japanese Encephalitis Virus Genotype 1 from the Affected Calf

    PubMed Central

    Katayama, Takashi; Saito, Sachie; Horiuchi, Sanae; Maruta, Tetsuya; Kato, Tomoko; Yanase, Tohru; Yamakawa, Makoto

    2013-01-01

    Japanese encephalitis virus (JEV) was isolated from the cerebrum of a calf which showed severe neurological symptoms in late September 2009, and the JEV isolate was revealed to be of genotype 1. This is the first report describing the isolation of genotype 1 JEV from cattle. PMID:23885004

  16. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. II. Survey of host immune responses and central nervous system virus titers in inbred mouse strains.

    PubMed

    Clatch, R J; Lipton, H L; Miller, S D

    1987-11-01

    Previous studies using mouse strains with limited genetic differences and H-2 haplotypes demonstrated that susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease strongly correlated with chronically high levels of TMEV-specific delayed-type hypersensitivity (DTH), but not with TMEV-specific T cell proliferation (Tprlf), serum antibody responses, or with CNS virus titers. To determine if this correlation would be supported by analysis of these parameters in a more thorough genetic survey, ten inbred mouse strains, representing a wide variety of genetic backgrounds and H-2 haplotypes, were inoculated intracerebrally (i.c.) with the BeAn strain of TMEV. Significant TMEV-specific DTH was observed in all highly susceptible strains, but was not detectable in intermediate and resistant strains. TMEV-specific serum antibody titers also appeared to correlate with susceptibility to demyelinating disease, however even resistant strains had high antibody responses. Significant differences in CNS TMEV titers existed between strains, but did not correlate with disease susceptibility. DTH and Tprlf responses were observed in 3/4 resistant strains following peripheral immunization with UV-inactivated TMEV indicating that most resistant strains are genetically capable of mounting virus-specific cell-mediated immune (CMI) responses. The data extends our knowledge of host immune responses and virus titers in many different inbred mouse strains persistently infected with TMEV, supports the hypothesis that the demyelination in highly susceptible mice involves a TMEV-specific DTH response, and suggests that the genetic ability to mount specific DTH responses is necessary, but not sufficient for development of the demyelinating disease.

  17. Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. III. Failure of neuroantigen-specific immune tolerance to affect the clinical course of demyelination.

    PubMed

    Miller, S D; Gerety, S J; Kennedy, M K; Peterson, J D; Trotter, J L; Tuohy, V K; Waltenbaugh, C; Dal Canto, M C; Lipton, H L

    1990-01-01

    Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) into susceptible mouse strains produces a chronic demyelinating disease in which mononuclear cell-rich infiltrates in the central nervous system (CNS) are prominent. Current evidence strongly supports an immune-mediated basis for myelin breakdown, with an effector role proposed for TMEV-specific, major histocompatibility complex (MHC) class II-restricted delayed-type hypersensitivity (DTH) responses in which lymphokine-activated macrophages mediate bystander demyelination. The present study examined the possibility that concomitant or later-appearing neuroantigen-specific autoimmune T cell responses, such as those demonstrated in chronic-relapsing experimental allergic encephalomyelitis (R-EAE), may contribute to the demyelinating process following TMEV infection. T cell responses against intact, purified major myelin proteins (myelin basic protein (MBP) and proteolipid protein (PLP], and against altered myelin constituents were readily demonstrable in SJL/J mice with R-EAE, but were not detectable in SJL/J mice with TMEV-induced demyelinating disease. TMEV-infected mice also did not display T cell responses against the peptide fragments of MBP(91-104) and PLP(139-151) recently shown to be encephalitogenic in SJL/J mice. In addition, induction of neuroantigen-specific tolerance to a heterogeneous mixture of CNS antigens, via the i.v. injection of syngeneic SJL/J splenocytes covalently coupled with mouse spinal cord homogenate, resulted in significant suppression of clinical and histologic signs of R-EAE and the accompanying MBP- and PLP-specific DTH responses. In contrast, neuroantigen-specific tolerance failed to alter the development of clinical and histologic signs of TMEV-induced demyelinating disease or the accompanying virus-specific DTH and humoral immune responses. These findings demonstrate that TMEV-induced demyelinating disease can occur in the apparent absence of neuroantigen

  18. Equine Viral Encephalomyelitis in Canada: A Review of Known and Potential Causes

    PubMed Central

    Keane, Delwyn P.; Little, Peter B.

    1987-01-01

    Rabies, equine herpesvirus type I, and eastern and western encephalomyelitis viruses, known causes of equine neurological disease, are reviewed with emphasis on epidemiology, pathogenesis, clinical signs, and diagnosis. Several arboviruses known to be active in Canada and capable of producing neurological disease in humans (Powassan, St. Louis encephalitis, snowshoe hare, and Jamestown Canyon viruses) are discussed as potential causes of encephalomyelitis in horses. PMID:17422841

  19. Immunohistochemical diagnosis of eastern equine encephalomyelitis.

    PubMed

    Patterson, J S; Maes, R K; Mullaney, T P; Benson, C L

    1996-04-01

    An immunohistochemical (IHC) assay was developed for the detection of eastern equine encephalomyelitis (EEE) virus antigen in formalin-fixed, paraffin-embedded tissues. All cases of EEE diagnosed at the Michigan State University Animal Health Diagnostic Laboratory from 1991 through 1994 were evaluated. The diagnosis was based on histopathologic examination of the brain and confirmatory virus, isolation. Sections of cerebrum from 26 equids and 5 birds were assessed by IHC. Histologically normal brain tissues from 2 horses and 1 pheasant and brain tissues from 2 cases of equine neurologic disease with diagnoses other than EEE served as negative controls. The IHC assay was based on standard streptavidin-biotin technology, using a commercially available kit and a monospecific polyclonal primary antibody preparation derived from murine ascitic fluid. Nineteen of 20 equids and all 5 birds positive by histopathology and virus isolation were positive for EEE virus antigen by IHC. Three equids with histologic lesions compatible with a diagnosis of EEE but negative by virus isolation also were negative for virus antigen by IHC. In 3 other equids, histopathology and IHC were positive for EEE, but virus isolation was not attempted because of contamination of the brain specimen. The IHC assay of formalin-fixed, paraffin-embedded brain tissues for EEE virus antigen is a rapid, effective test for confirming a histopathologic diagnosis of EEE, and assay results correlate well with virus isolation results.

  20. Immunohistochemical diagnosis of eastern equine encephalomyelitis.

    PubMed

    Patterson, J S; Maes, R K; Mullaney, T P; Benson, C L

    1996-04-01

    An immunohistochemical (IHC) assay was developed for the detection of eastern equine encephalomyelitis (EEE) virus antigen in formalin-fixed, paraffin-embedded tissues. All cases of EEE diagnosed at the Michigan State University Animal Health Diagnostic Laboratory from 1991 through 1994 were evaluated. The diagnosis was based on histopathologic examination of the brain and confirmatory virus, isolation. Sections of cerebrum from 26 equids and 5 birds were assessed by IHC. Histologically normal brain tissues from 2 horses and 1 pheasant and brain tissues from 2 cases of equine neurologic disease with diagnoses other than EEE served as negative controls. The IHC assay was based on standard streptavidin-biotin technology, using a commercially available kit and a monospecific polyclonal primary antibody preparation derived from murine ascitic fluid. Nineteen of 20 equids and all 5 birds positive by histopathology and virus isolation were positive for EEE virus antigen by IHC. Three equids with histologic lesions compatible with a diagnosis of EEE but negative by virus isolation also were negative for virus antigen by IHC. In 3 other equids, histopathology and IHC were positive for EEE, but virus isolation was not attempted because of contamination of the brain specimen. The IHC assay of formalin-fixed, paraffin-embedded brain tissues for EEE virus antigen is a rapid, effective test for confirming a histopathologic diagnosis of EEE, and assay results correlate well with virus isolation results. PMID:8744735

  1. Direct evidence of a role for amino acid 101 of VP-1 in central nervous system disease in Theiler's murine encephalomyelitis virus infection.

    PubMed

    Zurbriggen, A; Thomas, C; Yamada, M; Roos, R P; Fujinami, R S

    1991-04-01

    The DA virus, a member of the TO subgroup of Theiler's virus, invokes a chronic demyelinating disease in its natural host, the mouse, RNA transcripts from a cDNA clone, pDAFL3, are infectious, and the resulting virus, DAFL3, produces in mice a disease indistinguishable from that caused by the DA virus. Using oligonucleotide-directed site-specific mutagenesis, a single nucleotide, cytosine at position 3305 (viral genome), was changed in this infectious cDNA to a thymine. The mutated nucleotide is located in an area coding for a neutralizing epitope on loop II of VP-1. Virus OSM101, produced from the mutagenized plasmid pDA101, had the same growth characteristics and plaque phenotype in vitro as the virus DAFL3 produced from clone pDAFL3. However, in vivo in the mouse, virus OSM101 was markedly less neurovirulent than DAFL3. Central nervous system tissues from mice infected 4 to 6 weeks previously with the OSM101 virus contained less infectious virus and fewer infected cells than central nervous system tissues from animals infected with the control virus, DAFL3. Thus, we demonstrated that the single nucleotide change resulting in an amino acid substitution at position 101 (threonine to isoleucine) of VP-1 determines one aspect of Theiler's virus persistence and disease in mice.

  2. Direct evidence of a role for amino acid 101 of VP-1 in central nervous system disease in Theiler's murine encephalomyelitis virus infection.

    PubMed Central

    Zurbriggen, A; Thomas, C; Yamada, M; Roos, R P; Fujinami, R S

    1991-01-01

    The DA virus, a member of the TO subgroup of Theiler's virus, invokes a chronic demyelinating disease in its natural host, the mouse, RNA transcripts from a cDNA clone, pDAFL3, are infectious, and the resulting virus, DAFL3, produces in mice a disease indistinguishable from that caused by the DA virus. Using oligonucleotide-directed site-specific mutagenesis, a single nucleotide, cytosine at position 3305 (viral genome), was changed in this infectious cDNA to a thymine. The mutated nucleotide is located in an area coding for a neutralizing epitope on loop II of VP-1. Virus OSM101, produced from the mutagenized plasmid pDA101, had the same growth characteristics and plaque phenotype in vitro as the virus DAFL3 produced from clone pDAFL3. However, in vivo in the mouse, virus OSM101 was markedly less neurovirulent than DAFL3. Central nervous system tissues from mice infected 4 to 6 weeks previously with the OSM101 virus contained less infectious virus and fewer infected cells than central nervous system tissues from animals infected with the control virus, DAFL3. Thus, we demonstrated that the single nucleotide change resulting in an amino acid substitution at position 101 (threonine to isoleucine) of VP-1 determines one aspect of Theiler's virus persistence and disease in mice. Images PMID:1705992

  3. Evaluating an etiologically relevant platform for therapy development for temporal lobe epilepsy: effects of carbamazepine and valproic acid on acute seizures and chronic behavioral comorbidities in the Theiler's murine encephalomyelitis virus mouse model.

    PubMed

    Barker-Haliski, Melissa L; Dahle, E Jill; Heck, Taylor D; Pruess, Timothy H; Vanegas, Fabiola; Wilcox, Karen S; White, H Steve

    2015-05-01

    Central nervous system infections can underlie the development of epilepsy, and Theiler's murine encephalomyelitis virus (TMEV) infection in C57BL/6J mice provides a novel model of infection-induced epilepsy. Approximately 50-65% of infected mice develop acute, handling-induced seizures during the infection. Brains display acute neuropathology, and a high number of mice develop spontaneous, recurrent seizures and behavioral comorbidities weeks later. This study characterized the utility of this model for drug testing by assessing whether antiseizure drug treatment during the acute infection period attenuates handling-induced seizures, and whether such treatment modifies associated comorbidities. Male C57BL/6J mice infected with TMEV received twice-daily valproic acid (VPA; 200 mg/kg), carbamazepine (CBZ; 20 mg/kg), or vehicle during the infection (days 0-7). Mice were assessed twice daily during the infection period for handling-induced seizures. Relative to vehicle-treated mice, more CBZ-treated mice presented with acute seizures; VPA conferred no change. In mice displaying seizures, VPA, but not CBZ, reduced seizure burden. Animals were then randomly assigned to acute and long-term follow-up. VPA was associated with significant elevations in acute (day 8) glial fibrillary acidic protein (astrocytes) immunoreactivity, but did not affect NeuN (neurons) immunoreactivity. Additionally, VPA-treated mice showed improved motor performance 15 days postinfection (DPI). At 36 DPI, CBZ-treated mice traveled significantly less distance through the center of an open field, indicative of anxiety-like behavior. CBZ-treated mice also presented with significant astrogliosis 36 DPI. Neither CBZ nor VPA prevented long-term reductions in NeuN immunoreactivity. The TMEV model thus provides an etiologically relevant platform to evaluate potential treatments for acute seizures and disease modification.

  4. Identification of a locus on mouse chromosome 3 involved in differential susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease.

    PubMed Central

    Melvold, R W; Jokinen, D M; Miller, S D; Dal Canto, M C; Lipton, H L

    1990-01-01

    Theiler's virus-induced demyelinating disease results from a chronic infection in the white matter of the central nervous system and provides an excellent model for human multiple sclerosis. Like multiple sclerosis, there are genetic risk factors in disease development, including genes associated with the major histocompatibility complex and with those encoding the beta chain of the T-cell receptor. Comparisons of the susceptible DBA/2 and resistant C57BL/6 strains have indicated an important role for the H-2D locus and for a non-H-2 gene (not involving the beta chain of the T-cell receptor) in differential susceptibility. In the present report, analysis of recombinant-inbred strains (BXD) between the DBA/2 and C57BL/6 strains indicated that this non-H-2 locus is located at the centromeric end of chromosome 3 near (4 +/- 4 centimorgans) the carbonic anhydrase-2 (Car-2) enzyme locus. PMID:2296080

  5. Avian Encephalomyelitis in Layer Pullets Associated with Vaccination.

    PubMed

    Sentíes-Cué, C Gabriel; Gallardo, Rodrigo A; Reimers, Nancy; Bickford, Arthur A; Charlton, Bruce R; Shivaprasad, H L

    2016-06-01

    Avian encephalomyelitis (AE) was diagnosed in three flocks of leghorn layer pullets following AE vaccination. Ages of the birds were 11, 12, and 14 wk. The submissions came from three different companies located in two geographic areas of the Central Valley of California. The clinical signs included birds down on their legs, unilateral recumbency or sitting on their hocks, lethargy, reluctance to move, dehydration, unevenness in size, low weight, tremors of the head in a few birds, and mildly to moderately elevated mortality. The flocks had been vaccinated against fowl pox and AE with a combined product in the wing-web 2 wk prior to the onset of AE clinical signs. Histopathologic examination revealed lesions consistent with AE, including lymphocytic perivascular infiltration and neuronal central chromatolysis in the brain and spinal cord, as well as gliosis in the cerebellar molecular layer. The AE virus was detected by reverse-transcriptase PCR in the brain homogenate from three cases and peripheral nerves in one case. Additionally, the AE virus was isolated in specific-pathogen-free (SPF) embryonated eggs from brain tissue pool samples. Other avian viral infections capable of causing encephalitis, including avian paramyxoviruses, avian influenza virus (AIV), West Nile virus (WNV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), were ruled out by attempting virus isolation and molecular procedures. PMID:27309297

  6. A Rare Sequela of Acute Disseminated Encephalomyelitis

    PubMed Central

    Kodadhala, Vijay; Kurukumbi, Mohankumar; Jayam-Trouth, Annapurni

    2014-01-01

    Acute disseminated encephalomyelitis is a demyelinating disease, typically occurring in children following a febrile infection or a vaccination. Primary and secondary immune responses contribute to inflammation and subsequent demyelination, but the exact pathogenesis is still unknown. Diagnosis of acute disseminated encephalomyelitis is strongly suggested by temporal relationship between an infection or an immunization and the onset of neurological symptoms. Biopsy is definitive. In general, the disease is self-limiting and the prognostic outcome is favorable with anti-inflammatory and immunosuppressive agents. Locked-in syndrome describes patients who are awake and conscious but have no means of producing limb, speech, or facial movements. Locked-in syndrome is a rare complication of acute disseminated encephalomyelitis. We present a case of incomplete locked-in syndrome occurring in a 34-year-old male secondary to acute disseminated encephalomyelitis. Our case is unique, as acute disseminated encephalomyelitis occurred in a 34-year-old which was poorly responsive to immunosuppression resulting in severe disability. PMID:24977089

  7. Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage.

    PubMed

    Griffin, Diane E

    2016-07-01

    Mosquito-borne viruses are important causes of death and long-term neurologic disability due to encephalomyelitis. Studies of mice infected with the alphavirus Sindbis virus have shown that outcome is dependent on the age and genetic background of the mouse and virulence of the infecting virus. Age-dependent susceptibility reflects the acquisition by neurons of resistance to virus replication and virus-induced cell death with maturation. In mature mice, the populations of neurons most susceptible to infection are in the hippocampus and anterior horn of the spinal cord. Hippocampal infection leads to long-term memory deficits in mice that survive, while motor neuron infection can lead to paralysis and death. Neuronal death is immune-mediated, rather than a direct consequence of virus infection, and associated with entry and differentiation of pathogenic T helper 17 cells in the nervous system. To modulate glutamate excitotoxicity, mice were treated with an N-methyl-D-aspartate receptor antagonist, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists or a glutamine antagonist. The N-methyl-D-aspartate receptor antagonist MK-801 protected hippocampal neurons but not motor neurons, and mice still became paralyzed and died. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists GYKI-52466 and talampanel protected both hippocampal and motor neurons and prevented paralysis and death. Glutamine antagonist 6-diazo-5-l-norleucine protected hippocampal neurons and improved memory generation in mice surviving infection with an avirulent virus. Surprisingly, in all cases protection was associated with inhibition of the antiviral immune response, reduced entry of inflammatory cells into the central nervous system, and delayed virus clearance, emphasizing the importance of treatment approaches that include prevention of immunopathologic damage. PMID:27114366

  8. Myalgic Encephalomyelitis: Symptoms and Biomarkers

    PubMed Central

    Jasona, Leonard A.; Zinn, Marcie L.; Zinn, Mark A.

    2015-01-01

    Myalgic Encephalomyelitis (ME) continues to cause significant morbidity worldwide with an estimated one million cases in the United States. Hurdles to establishing consensus to achieve accurate evaluation of patients with ME continue, fueled by poor agreement about case definitions, slow progress in development of standardized diagnostic approaches, and issues surrounding research priorities. Because there are other medical problems, such as early MS and Parkinson’s Disease, which have some similar clinical presentations, it is critical to accurately diagnose ME to make a differential diagnosis. In this article, we explore and summarize advances in the physiological and neurological approaches to understanding, diagnosing, and treating ME. We identify key areas and approaches to elucidate the core and secondary symptom clusters in ME so as to provide some practical suggestions in evaluation of ME for clinicians and researchers. This review, therefore, represents a synthesis of key discussions in the literature, and has important implications for a better understanding of ME, its biological markers, and diagnostic criteria. There is a clear need for more longitudinal studies in this area with larger data sets, which correct for multiple testing. PMID:26411464

  9. Myalgic encephalomyelitis: International Consensus Criteria

    PubMed Central

    Carruthers, B M; van de Sande, M I; De Meirleir, K L; Klimas, N G; Broderick, G; Mitchell, T; Staines, D; Powles, A C P; Speight, N; Vallings, R; Bateman, L; Baumgarten-Austrheim, B; Bell, D S; Carlo-Stella, N; Chia, J; Darragh, A; Jo, D; Lewis, D; Light, A R; Marshall-Gradisbik, S; Mena, I; Mikovits, J A; Miwa, K; Murovska, M; Pall, M L; Stevens, S

    2011-01-01

    , Japan; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR; Department of Sports Sciences, University of the Pacific, Stockton, CA USA). Myalgic encephalomyelitis: International Consensus Criteria (Review). J Intern Med 2011; 270: 327–338. The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the

  10. Myalgic encephalomyelitis: International Consensus Criteria

    PubMed Central

    Carruthers, B M; van de Sande, M I; De Meirleir, K L; Klimas, N G; Broderick, G; Mitchell, T; Staines, D; Powles, A C P; Speight, N; Vallings, R; Bateman, L; Baumgarten-Austrheim, B; Bell, D S; Carlo-Stella, N; Chia, J; Darragh, A; Jo, D; Lewis, D; Light, A R; Marshall-Gradisbik, S; Mena, I; Mikovits, J A; Miwa, K; Murovska, M; Pall, M L; Stevens, S

    2011-01-01

    , Japan; A. Kirchenstein Institute of Microbiology and Virology, Riga Stradins University, Riga, Latvia; Department of Biochemistry & Basic Medical Sciences, Washington State University, Portland, OR; Department of Sports Sciences, University of the Pacific, Stockton, CA USA). Myalgic encephalomyelitis: International Consensus Criteria (Review). J Intern Med 2011; 270: 327–338. The label ‘chronic fatigue syndrome’ (CFS) has persisted for many years because of the lack of knowledge of the aetiological agents and the disease process. In view of more recent research and clinical experience that strongly point to widespread inflammation and multisystemic neuropathology, it is more appropriate and correct to use the term ‘myalgic encephalomyelitis’ (ME) because it indicates an underlying pathophysiology. It is also consistent with the neurological classification of ME in the World Health Organization’s International Classification of Diseases (ICD G93.3). Consequently, an International Consensus Panel consisting of clinicians, researchers, teaching faculty and an independent patient advocate was formed with the purpose of developing criteria based on current knowledge. Thirteen countries and a wide range of specialties were represented. Collectively, members have approximately 400 years of both clinical and teaching experience, authored hundreds of peer-reviewed publications, diagnosed or treated approximately 50 000 patients with ME, and several members coauthored previous criteria. The expertise and experience of the panel members as well as PubMed and other medical sources were utilized in a progression of suggestions/drafts/reviews/revisions. The authors, free of any sponsoring organization, achieved 100% consensus through a Delphi-type process. The scope of this paper is limited to criteria of ME and their application. Accordingly, the criteria reflect the complex symptomatology. Operational notes enhance clarity and specificity by providing guidance in the

  11. Acute disseminated encephalomyelitis after Rocky Mountain spotted fever.

    PubMed

    Wei, T Y; Baumann, R J

    1999-07-01

    Although acute disseminated encephalomyelitis has been observed after a variety of viral infections and an occasional bacterial infection, it has not been reported in association with rickettsial infections. Reported is a 7-year-old male with magnetic resonance images and clinical manifestations suggestive of acute disseminated encephalomyelitis after a tick bite and serologically proven Rocky Mountain spotted fever. PMID:10428440

  12. Myalgic encephalomyelitis--a persistent enteroviral infection?

    PubMed Central

    Dowsett, E. G.; Ramsay, A. M.; McCartney, R. A.; Bell, E. J.

    1990-01-01

    Myalgic encephalomyelitis is a common disability but frequently misinterpreted. Amongst 6,000 patients referred for general microbiological diagnosis between 1975 and 1987, 420 cases were recognized. Coxsackie B neutralization tests, in 205 of these, demonstrated significant titres in 103/205 (50%), while of 124 additionally investigated for enteroviral IgM, 38/124 (31%) were positive. This illness is distinguished from a variety of other post-viral states by an unique clinical and epidemiological pattern characteristic of enteroviral infection. Prompt recognition and advice to avoid over-exertion is mandatory. Routine diagnosis, specific therapy and prevention, await further technical advances. PMID:2170962

  13. Disseminated encephalomyelitis-like central nervous system neoplasm in childhood.

    PubMed

    Zhao, Jianhui; Bao, Xinhua; Fu, Na; Ye, Jintang; Li, Ting; Yuan, Yun; Zhang, Chunyu; Zhang, Yao; Zhang, Yuehua; Qin, Jiong; Wu, Xiru

    2014-08-01

    A malignant neoplasm in the central nervous system with diffuse white matter changes on magnetic resonance imaging (MRI) is rare in children. It could be misdiagnosed as acute disseminated encephalomyelitis. This report presents our experience based on 4 patients (3 male, 1 female; aged 7-13 years) whose MRI showed diffuse lesions in white matter and who were initially diagnosed with acute disseminated encephalomyelitis. All of the patients received corticosteroid therapy. After brain biopsy, the patients were diagnosed with gliomatosis cerebri, primitive neuroectodermal tumor and central nervous system lymphoma. We also provide literature reviews and discuss the differentiation of central nervous system neoplasm from acute disseminated encephalomyelitis.

  14. Inactivated eastern equine encephalomyelitis vaccine propagated in rolling-bottle cultures of chick embryo cells.

    PubMed

    Cole, F E

    1971-11-01

    A method was developed for the production of Eastern equine encephalomyelitis vaccine from virus grown in rolling-bottle cultures (840 cm(2) growth area) of chick embryo cells. The PE-6 strain of virus was propagated in chick embryo cell roller cultures maintained on serum-free medium 199 containing 0.25% human serum albumin and antibiotics (MM). A multiplicity of inoculum of 0.005 yielded acceptable titers of virus at a convenient harvest time of 18 to 24 hr and reduced the carry-over of extraneous material from the virus seed. Growth studies in which 100, 200, or 300 ml of MM was used showed that use of 300 ml of MM offered two advantages: (i) cytopathic effects were less at the 18- to 24-hr harvest time, thereby decreasing cellular material in the final product, and (ii) total virus yield was not substantially reduced, thus permitting large-scale production of virus for further processing. Studies on formalin inactivation at 37 C indicated that the virus was inactivated by 0.05% formalin within 12 to 16 hr and with 0.1% formalin within 6 to 8 hr. Antigen extinction tests in hamsters revealed excellent potency (e.g., median-effective-dose values of 0.069 to 0.012 ml) for both fluid and freeze-dried products. The advantages of the roller-bottle technique in vaccine production are discussed.

  15. Isolation of viruses from mosquitoes (Diptera: Culicidae) collected in the Amazon Basin region of Peru.

    PubMed

    Turell, M J; O'Guinn, M L; Jones, J W; Sardelis, M R; Dohm, D J; Watts, D M; Fernandez, R; Travassos da Rosa, A; Guzman, H; Tesh, R; Rossi, C A; Ludwig, V; Mangiafico, J A; Kondig, J; Wasieloski, L P; Pecor, J; Zyzak, M; Schoeler, G; Mores, C N; Calampa, C; Lee, J S; Klein, T A

    2005-09-01

    As part of a comprehensive study on the ecology of arthropod-borne viruses in the Amazon Basin region of Peru, we assayed 539,694 mosquitoes captured in Loreto Department, Peru, for arboviruses. Mosquitoes were captured either by dry ice-baited miniature light traps or with aspirators while mosquitoes were landing on human collectors, identified to species, and later tested on Vero cells for virus. In total, 164 virus isolations were made and included members of the Alphavirus (eastern equine encephalomyelitis, Trocara, Una, Venezuelan equine encephalomyelitis, and western equine encephalomyelitis viruses), Flavivirus (Ilheus and St. Louis encephalitis), and Orthobunyavirus (Caraparu, Itaqui, Mirim, Murutucu, and Wyeomyia viruses) genera. In addition, several viruses distinct from the above-mentioned genera were identified to the serogroup level. Eastern equine encephalomyelitis virus was associated primarily with Culex pedroi Sirivanakarn & Belkin, whereas Venezuelan equine encephalomyelitis virus was associated primarily with Culex gnomatos Sallum, Huchings & Ferreira. Most isolations of Ilheus virus were made from Psorophora ferox (Von Humboldt). Although species of the Culex subgenus Melanoconion accounted for only 45% of the mosquitoes collected, 85% of the virus isolations were made from this subgenus. Knowledge of the viruses that are being transmitted in the Amazon Basin region of Peru will enable the development of more effective diagnostic assays, more efficient and rapid diagnoses of clinical illnesses caused by these pathogens, risk analysis for military/civilian operations, and development of potential disease control measures.

  16. Contrasting Case Definitions for Chronic Fatigue Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Myalgic Encephalomyelitis

    PubMed Central

    Jason, Leonard A.; Brown, Abigail; Clyne, Erin; Bartgis, Lindsey; Evans, Meredyth; Brown, Molly

    2013-01-01

    This article uses data from patients recruited using the 1994 case definition of chronic fatigue syndrome (CFS) to contrast those meeting criteria for the Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) Canadian case definition with those that did not meet these criteria. The study also contrasts those meeting criteria for Myalgic Encephalomyelitis (ME) based on criteria from Ramsay and other theorists with those that did not meet the ME criteria. The ME/CFS case definition criteria identified a subset of patients with more functional impairments and physical, mental, and cognitive problems than the subset not meeting these criteria. The ME subset had more functional impairments, and more severe physical and cognitive symptoms than the subset not meeting ME criteria. When applied to a population meeting the 1994 CFS case definition, both ME/CFS and ME criteria appear to select a more severe subset of patients. PMID:22158691

  17. Contrasting case definitions for chronic fatigue syndrome, Myalgic Encephalomyelitis/chronic fatigue syndrome and myalgic encephalomyelitis.

    PubMed

    Jason, Leonard A; Brown, Abigail; Clyne, Erin; Bartgis, Lindsey; Evans, Meredyth; Brown, Molly

    2012-09-01

    This article uses data from patients recruited using the 1994 case definition of chronic fatigue syndrome (CFS) to contrast those meeting criteria for the Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) Canadian case definition with those that did not meet these criteria. The study also contrasts those meeting criteria for Myalgic Encephalomyelitis (ME) based on criteria from Ramsay and other theorists with those that did not meet the ME criteria. The ME/CFS case definition criteria identified a subset of patients with more functional impairments and physical, mental, and cognitive problems than the subset not meeting these criteria. The ME subset had more functional impairments, and more severe physical and cognitive symptoms than the subset not meeting ME criteria. When applied to a population meeting the 1994 CFS case definition, both ME/CFS and ME criteria appear to select a more severe subset of patients.

  18. T lymphocyte repertoire in Theiler's virus encephalomyelitis: the nonspecific infiltration of the central nervous system of infected SJL/J mice is associated with a selective local T cell expansion.

    PubMed

    Musette, P; Bureau, J F; Gachelin, G; Kourilsky, P; Brahic, M

    1995-06-01

    Theiler's virus causes, in the susceptible SJL/J mouse, a chronic demyelinating disease that resembles multiple sclerosis. Demyelination is at least in part immune mediated and coincides with the infiltration of the central nervous system by T lymphocytes. We analyzed the repertoire of the T cell receptor (TcR) beta-chain for each V beta-J beta combination, in spinal cord and spleen T cells of infected animals. All V beta families were detected in spinal cord as well as in spleen, as if the central nervous system were undiscriminantly invaded by T cells in the infected animals. Some T cells, defined by specific V beta-J beta combinations, were expanded in the spinal cord but not in the spleen, most probably because of an antigen-driven response. The TcR beta-chain repertoire of infiltrating T cells was the same at the onset of demyelination as when the disease was full-blown. These results provide the first description of the repertoire of the T cells which infiltrate the central nervous system during the course of this disease.

  19. Chronic fatigue syndrome or myalgic encephalomyelitis in children and adolescents.

    PubMed

    Chatterjee, Tapabrata

    2003-09-01

    Chronic fatigue syndrome or myalgic encephalomyelitis in children and adolescents is still poorly understood. The provisional diagnostic criteria and the concept are depicted here. The treatment modalities and prognosis for the disease are yet inconsistent. PMID:15168991

  20. Neuroborreliosis presenting as acute disseminated encephalomyelitis.

    PubMed

    Rocha, Ruben; Lisboa, Lurdes; Neves, João; García López, Milagros; Santos, Elsa; Ribeiro, Augusto

    2012-12-01

    We report a case of a 5-year-old boy with acute disseminated encephalomyelitis as the initial presentation of neuroborreliosis. Parents report an upper-airway infection a few days before the development of acute encephalopathy, mild facial palsy, and seizures. The patient needed mechanical ventilation for 10 days, and after extubation, he presented hypotonia, ataxia, dysarthria, as well as weak gag and cough reflexes. Brain magnetic resonance imaging showed hyperintense lesions on T2- and fluid-attenuated inversion recovery sequences on the right subcortical occipital and parietal region, left posterior arm of the internal capsule, and in the medulla oblongata. Borrelia burgdorferi was identified in the plasma and cerebrospinal fluid by polymerase chain reaction and in the plasma by Western blotting. He was treated with ceftriaxone, methylprednisolone, and human immunoglobulin. Recovery was partial. PMID:23222106

  1. Dynamic Changes of Microglia/Macrophage M1 and M2 Polarization in Theiler's Murine Encephalomyelitis.

    PubMed

    Herder, Vanessa; Iskandar, Cut Dahlia; Kegler, Kristel; Hansmann, Florian; Elmarabet, Suliman Ahmed; Khan, Muhammad Akram; Kalkuhl, Arno; Deschl, Ulrich; Baumgärtner, Wolfgang; Ulrich, Reiner; Beineke, Andreas

    2015-11-01

    Microglia and macrophages play a central role for demyelination in Theiler's murine encephalomyelitis (TME) virus infection, a commonly used infectious model for chronic-progressive multiple sclerosis. In order to determine the dynamic changes of microglia/macrophage polarization in TME, the spinal cord of Swiss Jim Lambert (SJL) mice was investigated by gene expression profiling and immunofluorescence. Virus persistence and demyelinating leukomyelitis were confirmed by immunohistochemistry and histology. Electron microscopy revealed continuous myelin loss together with abortive myelin repair during the late chronic infection phase indicative of incomplete remyelination. A total of 59 genes out of 151 M1- and M2-related genes were differentially expressed in TME virus-infected mice over the study period. The onset of virus-induced demyelination was associated with a dominating M1 polarization, while mounting M2 polarization of macrophages/microglia together with sustained prominent M1-related gene expression was present during the chronic-progressive phase. Molecular results were confirmed by immunofluorescence, showing an increased spinal cord accumulation of CD16/32(+) M1-, arginase-1(+) M2- and Ym1(+) M2-type cells associated with progressive demyelination. The present study provides a comprehensive database of M1-/M2-related gene expression involved in the initiation and progression of demyelination supporting the hypothesis that perpetuating interaction between virus and macrophages/microglia induces a vicious circle with persistent inflammation and impaired myelin repair in TME.

  2. Definitions and aetiology of myalgic encephalomyelitis: how the Canadian consensus clinical definition of myalgic encephalomyelitis works

    PubMed Central

    Carruthers, B M

    2007-01-01

    A perspective on the various definitions of myalgic encephalomyelitis and the process of discovering its aetiology is presented. The importance of clinical guidelines is emphasised to encourage clinicians to provide clear descriptions of their individual patients required for proper clinical activity; diagnosis, estimation of severity of effect, prognosis, treatment and rehabilitation. This individual knowledge is informed by general and (hopefully) publicly confirmed knowledge resulting from scientific research during the second‐person interaction which lies at the core of the clinical encounter. Both types of knowledge are essential. PMID:16935963

  3. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... embryonated chicken eggs. Each serial shall meet the general requirements prescribed in § 113.200 and the requirements prescribed in this section. Any serial found unsatisfactory by a prescribed test shall not be... or die due to causes attributable to the product, the serial is unsatisfactory. (2) An...

  4. 9 CFR 113.208 - Avian Encephalomyelitis Vaccine, Killed Virus.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... embryonated chicken eggs. Each serial shall meet the general requirements prescribed in § 113.200 and the requirements prescribed in this section. Any serial found unsatisfactory by a prescribed test shall not be... or die due to causes attributable to the product, the serial is unsatisfactory. (2) An...

  5. Development and application of an improved infectivity assay for the standardization of avian encephalomyelitis vaccines.

    PubMed

    Shafren, D R; Tannock, G A

    1990-06-01

    An improved infectivity assay for avian encephalomyelitis viruses (AEVs) is described in which susceptible 7-day-old chicken embryos were inoculated with dilutions of a particular AEV strain and, after incubation for 12 days, the presence of viral antigen in brains was detected by an enzyme-linked immunosorbent assay (ELISA). The assay (the brain antigen ELISA), which may be used for the titration of both egg-adapted and non-egg-adapted strains, can be completed within 12 days. For the conventional essays of non-egg-adapted vaccine strains, embryos are infected in ovo and hatched chickens examined for neurological signs after 3-4 weeks. No animal handling facilities are required with the brain antigen ELISA and results of comparable sensitivity to the hatch-out assay were obtained.

  6. Acute disseminated encephalomyelitis following 2009 H1N1 influenza vaccination.

    PubMed

    Maeda, Kengo; Idehara, Ryo

    2012-01-01

    Since the worldwide spread of the novel influenza type A virus in 2009, trivalent vaccines against H1N1 (pandemic) 09 and seasonal influenza have been used. We describe a 33-year-old woman who presented with hypoesthesia below the Th7 level fifteen days after vaccination without any preceding infection. Cerebrospinal fluid showed an increased level of myelin basic protein and positive oligoclonal IgG bands. Magnetic resonance imaging revealed disseminated lesions in the brain and thoracic cord. Steroid therapy improved her symptoms. She was diagnosed as having acute disseminated encephalomyelitis (ADEM) possibly related to the vaccination. As a potential adverse effect of the influenza vaccine, in addition to Guillain-Barré syndrome, ADEM should also be recognized. PMID:22821116

  7. Are Myalgic Encephalomyelitis and chronic fatigue syndrome different illnesses? A preliminary analysis.

    PubMed

    Jason, Leonard A; Sunnquist, Madison; Brown, Abigail; Evans, Meredyth; Newton, Julia L

    2016-01-01

    Considerable discussion has transpired regarding whether chronic fatigue syndrome is a distinct illness from Myalgic Encephalomyelitis. A prior study contrasted the Myalgic Encephalomyelitis International Consensus Criteria with the Fukuda and colleagues' chronic fatigue syndrome criteria and found that the Myalgic Encephalomyelitis International Consensus Criteria identified a subset of patients with greater functional impairment and physical, mental, and cognitive problems than the larger group who met Fukuda and colleagues' criteria. The current study analyzed two discrete data sets and found that the Myalgic Encephalomyelitis International Consensus Criteria identified more impaired individuals with more severe symptomatology.

  8. Encephalomyelitis by Toxoplasma gondii in a captive fossa (Cryptoprocta ferox).

    PubMed

    Corpa, J M; García-Quirós, A; Casares, M; Gerique, A C; Carbonell, M D; Gómez-Muñoz, M T; Uzal, F A; Ortega, J

    2013-03-31

    Encephalomyelitis due to Toxoplasma gondii was diagnosed in a fossa (Cryptoprocta ferox). The animal had ataxia, atrophy of hind limb muscles and progressive wasting before dying 12 months after the onset of clinical signs. Toxoplasmosis was suspected antemortem based on clinical signs and the detection of T. gondii DNA by PCR on EDTA-blood from live animal. Necropsy revealed necrotizing gastritis and severe emaciation. The main histological lesions included non-suppurative encephalomyelitis, with dilation of myelin sheaths and swollen axons in the spinal cord, and multifocal gliosis in the brain with intralesional protozoan cysts that stained positive for T. gondii immunohistochemistry. To the authors' knowledge, this is the first report of toxoplasmosis in a fossa, and a new host record.

  9. The role of IKKβ in Venezuelan equine encephalitis virus infection.

    PubMed

    Amaya, Moushimi; Voss, Kelsey; Sampey, Gavin; Senina, Svetlana; de la Fuente, Cynthia; Mueller, Claudius; Calvert, Valerie; Kehn-Hall, Kylene; Carpenter, Calvin; Kashanchi, Fatah; Bailey, Charles; Mogelsvang, Soren; Petricoin, Emanuel; Narayanan, Aarthi

    2014-01-01

    Venezuelan equine encephalitis virus (VEEV) belongs to the genus Alphavirus, family Togaviridae. VEEV infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the NF-κB cascade in the in vivo pathology. Initial studies indicated that at early time points of VEEV infection, the NF-κB complex was activated in cells infected with the TC-83 strain of VEEV. One upstream kinase that contributes to the phosphorylation of p65 is the IKKβ component of the IKK complex. Our previous studies with Rift valley fever virus, which exhibited early activation of the NF-κB cascade in infected cells, had indicated that the IKKβ component underwent macromolecular reorganization to form a novel low molecular weight form unique to infected cells. This prompted us to investigate if the IKK complex undergoes a comparable macromolecular reorganization in VEEV infection. Size-fractionated VEEV infected cell extracts indicated a macromolecular reorganization of IKKβ in VEEV infected cells that resulted in formation of lower molecular weight complexes. Well-documented inhibitors of IKKβ function, BAY-11-7082, BAY-11-7085 and IKK2 compound IV, were employed to determine whether IKKβ function was required for the production of infectious progeny virus. A decrease in infectious viral particles and viral RNA copies was observed with inhibitor treatment in the attenuated and virulent strains of VEEV infection. In order to further validate the requirement of IKKβ for VEEV replication, we over-expressed IKKβ in cells and observed an increase in viral titers. In contrast, studies carried out using IKKβ(-/-) cells demonstrated a decrease in VEEV replication. In vivo studies demonstrated that inhibitor treatment of TC-83 infected mice increased their survival. Finally, proteomics studies have revealed that IKKβ may interact with the viral protein nsP3. In conclusion, our studies have revealed that the host IKKβ protein may be

  10. The Role of IKKβ in Venezuelan Equine Encephalitis Virus Infection

    PubMed Central

    Amaya, Moushimi; Voss, Kelsey; Sampey, Gavin; Senina, Svetlana; de la Fuente, Cynthia; Mueller, Claudius; Calvert, Valerie; Kehn-Hall, Kylene; Carpenter, Calvin; Kashanchi, Fatah; Bailey, Charles; Mogelsvang, Soren; Petricoin, Emanuel; Narayanan, Aarthi

    2014-01-01

    Venezuelan equine encephalitis virus (VEEV) belongs to the genus Alphavirus, family Togaviridae. VEEV infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the NF-κB cascade in the in vivo pathology. Initial studies indicated that at early time points of VEEV infection, the NF-κB complex was activated in cells infected with the TC-83 strain of VEEV. One upstream kinase that contributes to the phosphorylation of p65 is the IKKβ component of the IKK complex. Our previous studies with Rift valley fever virus, which exhibited early activation of the NF-κB cascade in infected cells, had indicated that the IKKβ component underwent macromolecular reorganization to form a novel low molecular weight form unique to infected cells. This prompted us to investigate if the IKK complex undergoes a comparable macromolecular reorganization in VEEV infection. Size-fractionated VEEV infected cell extracts indicated a macromolecular reorganization of IKKβ in VEEV infected cells that resulted in formation of lower molecular weight complexes. Well-documented inhibitors of IKKβ function, BAY-11-7082, BAY-11-7085 and IKK2 compound IV, were employed to determine whether IKKβ function was required for the production of infectious progeny virus. A decrease in infectious viral particles and viral RNA copies was observed with inhibitor treatment in the attenuated and virulent strains of VEEV infection. In order to further validate the requirement of IKKβ for VEEV replication, we over-expressed IKKβ in cells and observed an increase in viral titers. In contrast, studies carried out using IKKβ−/− cells demonstrated a decrease in VEEV replication. In vivo studies demonstrated that inhibitor treatment of TC-83 infected mice increased their survival. Finally, proteomics studies have revealed that IKKβ may interact with the viral protein nsP3. In conclusion, our studies have revealed that the host IKKβ protein may be

  11. The role of IKKβ in Venezuelan equine encephalitis virus infection.

    PubMed

    Amaya, Moushimi; Voss, Kelsey; Sampey, Gavin; Senina, Svetlana; de la Fuente, Cynthia; Mueller, Claudius; Calvert, Valerie; Kehn-Hall, Kylene; Carpenter, Calvin; Kashanchi, Fatah; Bailey, Charles; Mogelsvang, Soren; Petricoin, Emanuel; Narayanan, Aarthi

    2014-01-01

    Venezuelan equine encephalitis virus (VEEV) belongs to the genus Alphavirus, family Togaviridae. VEEV infection is characterized by extensive inflammation and studies from other laboratories implicated an involvement of the NF-κB cascade in the in vivo pathology. Initial studies indicated that at early time points of VEEV infection, the NF-κB complex was activated in cells infected with the TC-83 strain of VEEV. One upstream kinase that contributes to the phosphorylation of p65 is the IKKβ component of the IKK complex. Our previous studies with Rift valley fever virus, which exhibited early activation of the NF-κB cascade in infected cells, had indicated that the IKKβ component underwent macromolecular reorganization to form a novel low molecular weight form unique to infected cells. This prompted us to investigate if the IKK complex undergoes a comparable macromolecular reorganization in VEEV infection. Size-fractionated VEEV infected cell extracts indicated a macromolecular reorganization of IKKβ in VEEV infected cells that resulted in formation of lower molecular weight complexes. Well-documented inhibitors of IKKβ function, BAY-11-7082, BAY-11-7085 and IKK2 compound IV, were employed to determine whether IKKβ function was required for the production of infectious progeny virus. A decrease in infectious viral particles and viral RNA copies was observed with inhibitor treatment in the attenuated and virulent strains of VEEV infection. In order to further validate the requirement of IKKβ for VEEV replication, we over-expressed IKKβ in cells and observed an increase in viral titers. In contrast, studies carried out using IKKβ(-/-) cells demonstrated a decrease in VEEV replication. In vivo studies demonstrated that inhibitor treatment of TC-83 infected mice increased their survival. Finally, proteomics studies have revealed that IKKβ may interact with the viral protein nsP3. In conclusion, our studies have revealed that the host IKKβ protein may be

  12. Mitigation of experimental allergic encephalomyelitis by cathepsin D inhibition.

    PubMed

    Boehme, D H; Marks, N

    1979-01-01

    Intraperitoneal treatment with the enzyme inhibitor, pepstatin, of BSVS mice, guinea pigs and Lewis rats which were sensitized with guinea pig spinal cord and pertussis vaccine resulted in complete or partial suppression of paralysis dependent on the species studied and alterations of histological signs of experimental allergic encephalomyelitis (EAE). The effect was dose-dependent but had no relationship to the age of the experimental animal at the time of the experiment.

  13. Immunopathology of Japanese macaque encephalomyelitis is similar to multiple sclerosis.

    PubMed

    Blair, Tiffany C; Manoharan, Minsha; Rawlings-Rhea, Stephanie D; Tagge, Ian; Kohama, Steven G; Hollister-Smith, Julie; Ferguson, Betsy; Woltjer, Randall L; Frederick, Meredith C; Pollaro, James; Rooney, William D; Sherman, Larry S; Bourdette, Dennis N; Wong, Scott W

    2016-02-15

    Japanese macaque encephalomyelitis (JME) is an inflammatory demyelinating disease that occurs spontaneously in a colony of Japanese macaques (JM) at the Oregon National Primate Research Center. Animals with JME display clinical signs resembling multiple sclerosis (MS), and magnetic resonance imaging reveals multiple T2-weighted hyperintensities and gadolinium-enhancing lesions in the central nervous system (CNS). Here we undertook studies to determine if JME possesses features of an immune-mediated disease in the CNS. Comparable to MS, the CNS of animals with JME contain active lesions positive for IL-17, CD4+ T cells with Th1 and Th17 phenotypes, CD8+ T cells, and positive CSF findings.

  14. Vaccination against Experimental Allergic Encephalomyelitis with T Cell Receptor Peptides

    NASA Astrophysics Data System (ADS)

    Howell, Mark D.; Winters, Steven T.; Olee, Tsaiwei; Powell, Henry C.; Carlo, Dennis J.; Brostoff, Steven W.

    1989-11-01

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system mediated by CD4+ T cells reactive with myelin basic protein (MBP). Rats were rendered resistant to the induction of EAE by vaccination with synthetic peptides corresponding to idiotypic determinants of the β chain VDJ region and Jα regions of the T cell receptor (TCR) that are conserved among encephalitogenic T cells. These findings demonstrate the utility of TCR peptide vaccination for modulating the activity of autoreactive T cells and represent a general therapeutic approach for T cell--mediated pathogenesis.

  15. Central Nervous System Demyelination and Remyelination is Independent from Systemic Cholesterol Level in Theiler's Murine Encephalomyelitis.

    PubMed

    Raddatz, Barbara B; Sun, Wenhui; Brogden, Graham; Sun, Yanyong; Kammeyer, Patricia; Kalkuhl, Arno; Colbatzky, Florian; Deschl, Ulrich; Naim, Hassan Y; Baumgärtner, Wolfgang; Ulrich, Reiner

    2016-01-01

    High dietary fat and/or cholesterol intake is a risk factor for multiple diseases and has been debated for multiple sclerosis. However, cholesterol biosynthesis is a key pathway during myelination and disturbances are described in demyelinating diseases. To address the possible interaction of dyslipidemia and demyelination, cholesterol biosynthesis gene expression, composition of the body's major lipid repositories and Paigen diet-induced, systemic hypercholesterolemia were examined in Theiler's murine encephalomyelitis (TME) using histology, immunohistochemistry, serum clinical chemistry, microarrays and high-performance thin layer chromatography. TME-virus (TMEV)-infected mice showed progressive loss of motor performance and demyelinating leukomyelitis. Gene expression associated with cholesterol biosynthesis was overall down-regulated in the spinal cord of TMEV-infected animals. Spinal cord levels of galactocerebroside and sphingomyelin were reduced on day 196 post TMEV infection. Paigen diet induced serum hypercholesterolemia and hepatic lipidosis. However, high dietary fat and cholesterol intake led to no significant differences in clinical course, inflammatory response, astrocytosis, and the amount of demyelination and remyelination in the spinal cord of TMEV-infected animals. The results suggest that down-regulation of cholesterol biosynthesis is a transcriptional marker for demyelination, quantitative loss of myelin-specific lipids, but not cholesterol occurs late in chronic demyelination, and serum hypercholesterolemia exhibited no significant effect on TMEV infection.

  16. Mitoprotective dietary approaches for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Caloric restriction, fasting, and ketogenic diets.

    PubMed

    Craig, Courtney

    2015-11-01

    Myalgic Encephalomyelitis/Chronic Fatigue Syndrome is an idiopathic illness characterized by debilitating fatigue and neuro-immune abnormalities. A growing body of evidence proposes mitochondrial dysfunction as a central perpetrator of the illness due to activation of immune-inflammatory pathways that burden the mitochondria. Under a model of mitochondrial dysfunction, this paper explores dietary strategies that are mitoprotective. Studied for decades, the cellular mechanisms of ketogenic diets, fasting, and caloric restriction now reveal mitochondria-specific mechanisms which could play a role in symptom reduction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Future research should examine the physiological effects of these dietary strategies in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

  17. Enlargement of cerebral ventricles as an early indicator of encephalomyelitis.

    PubMed

    Lepore, Stefano; Waiczies, Helmar; Hentschel, Jan; Ji, Yiyi; Skodowski, Julia; Pohlmann, Andreas; Millward, Jason M; Paul, Friedemann; Wuerfel, Jens; Niendorf, Thoralf; Waiczies, Sonia

    2013-01-01

    Inflammatory disorders of the central nervous system such as multiple sclerosis and acute disseminated encephalomyelitis involve an invasion of immune cells that ultimately leads to white matter demyelination, neurodegeneration and development of neurological symptoms. A clinical diagnosis is often made when neurodegenerative processes are already ongoing. In an attempt to seek early indicators of disease, we studied the temporal and spatial distribution of brain modifications in experimental autoimmune encephalomyelitis (EAE). In a thorough magnetic resonance imaging study performed with EAE mice, we observed significant enlargement of the ventricles prior to disease clinical manifestation and an increase in free water content within the cerebrospinal fluid as demonstrated by changes in T2 relaxation times. The increase in ventricle size was seen in the lateral, third and fourth ventricles. In some EAE mice the ventricle size started returning to normal values during disease remission. In parallel to this macroscopic phenomenon, we studied the temporal evolution of microscopic lesions commonly observed in the cerebellum also starting prior to disease onset. Our data suggest that changes in ventricle size during the early stages of brain inflammation could be an early indicator of the events preceding neurological disease and warrant further exploration in preclinical and clinical studies. PMID:23991157

  18. Adeno-Associated Viral-Mediated Catalase Expression Suppresses Optic Neuritis in Experimental Allergic Encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Guy, John; Qi, Xiaoping; Hauswirth, William W.

    1998-11-01

    Suppression of oxidative injury by viral-mediated transfer of the human catalase gene was tested in the optic nerves of animals with experimental allergic encephalomyelitis (EAE). EAE is an inflammatory autoimmune disorder of primary central nervous system demyelination that has been frequently used as an animal model for the human disease multiple sclerosis (MS). The optic nerve is a frequent site of involvement common to both EAE and MS. Recombinant adeno-associated virus containing the human gene for catalase was injected over the right optic nerve heads of SJL/J mice that were simultaneously sensitized for EAE. After 1 month, cell-specific catalase activity, evaluated by quantitation of catalase immunogold, was increased approximately 2-fold each in endothelia, oligodendroglia, astrocytes, and axons of the optic nerve. Effects of catalase on the histologic lesions of EAE were measured by computerized analysis of the myelin sheath area (for demyelination), optic disc area (for optic nerve head swelling), extent of the cellular infiltrate, extravasated serum albumin labeled by immunogold (for blood-brain barrier disruption), and in vivo H2O2 reaction product. Relative to control, contralateral optic nerves injected with the recombinant virus without a therapeutic gene, catalase gene inoculation reduced demyelination by 38%, optic nerve head swelling by 29%, cellular infiltration by 34%, disruption of the blood-brain barrier by 64%, and in vivo levels of H2O2 by 61%. Because the efficacy of potential treatments for MS are usually initially tested in the EAE animal model, this study suggests that catalase gene delivery by using viral vectors may be a therapeutic strategy for suppression of MS.

  19. Multiplex qRT-PCR for the Detection of Western Equine Encephalomyelitis, St. Louis Encephalitis, and West Nile Viral RNA in Mosquito Pools (Diptera: Culicidae).

    PubMed

    Brault, Aaron C; Fang, Ying; Reisen, William K

    2015-05-01

    Following the introduction of West Nile virus into California during the summer of 2003, public health and vector control programs expanded surveillance efforts and were in need of diagnostics capable of rapid, sensitive, and specific detection of arbovirus infections of mosquitoes to inform decision support for intervention. Development of a multiplex TaqMan or real-time semiquantitative reverse transcription polymerase chain reaction (RT-PCR) assay in which three virus specific primer-probe sets were used in the same reaction is described herein for the detection of western equine encephalomyelitis, St. Louis encephalitis and West Nile viral RNA. Laboratory validation and field data from 10 transmission seasons are reported. The comparative sensitivity and specificity of this multiplex assay to singleplex RT-PCR as well as an antigen detection (rapid analyte measurement platform) and standard plaque assays indicate this assay to be rapid and useful in providing mosquito infection data to estimate outbreak risk. PMID:26334826

  20. Multiplex qRT-PCR for the Detection of Western Equine Encephalomyelitis, St. Louis Encephalitis, and West Nile Viral RNA in Mosquito Pools (Diptera: Culicidae).

    PubMed

    Brault, Aaron C; Fang, Ying; Reisen, William K

    2015-05-01

    Following the introduction of West Nile virus into California during the summer of 2003, public health and vector control programs expanded surveillance efforts and were in need of diagnostics capable of rapid, sensitive, and specific detection of arbovirus infections of mosquitoes to inform decision support for intervention. Development of a multiplex TaqMan or real-time semiquantitative reverse transcription polymerase chain reaction (RT-PCR) assay in which three virus specific primer-probe sets were used in the same reaction is described herein for the detection of western equine encephalomyelitis, St. Louis encephalitis and West Nile viral RNA. Laboratory validation and field data from 10 transmission seasons are reported. The comparative sensitivity and specificity of this multiplex assay to singleplex RT-PCR as well as an antigen detection (rapid analyte measurement platform) and standard plaque assays indicate this assay to be rapid and useful in providing mosquito infection data to estimate outbreak risk.

  1. Myd88 Initiates Early Innate Immune Responses and Promotes CD4 T Cells during Coronavirus Encephalomyelitis

    PubMed Central

    Butchi, Niranjan; Kapil, Parul; Puntambekar, Shweta; Stohlman, Stephen A.; Hinton, David R.

    2015-01-01

    ABSTRACT Myd88 signaling is critical to the control of numerous central nervous system (CNS) infections by promoting both innate and adaptive immune responses. Nevertheless, the extent to which Myd88 regulates type I interferon (IFN) versus proinflammatory factors and T cell function, as well as the anatomical site of action, varies extensively with the pathogen. CNS infection by neurotropic coronavirus with replication confined to the brain and spinal cord induces protective IFN-α/β via Myd88-independent activation of melanoma differentiation-associated gene 5 (MDA5). However, a contribution of Myd88-dependent signals to CNS pathogenesis has not been assessed. Infected Myd88−/− mice failed to control virus, exhibited enhanced clinical disease coincident with increased demyelination, and succumbed to infection within 3 weeks. The induction of IFN-α/β, as well as of proinflammatory cytokines and chemokines, was impaired early during infection. However, defects in both IFN-α/β and select proinflammatory factors were rapidly overcome prior to T cell recruitment. Myd88 deficiency also specifically blunted myeloid and CD4 T cell recruitment into the CNS without affecting CD8 T cells. Moreover, CD4 T cells but not CD8 T cells were impaired in IFN-γ production. Ineffective virus control indeed correlated most prominently with reduced antiviral IFN-γ in the CNS of Myd88−/− mice. The results demonstrate a crucial role for Myd88 both in early induction of innate immune responses during coronavirus-induced encephalomyelitis and in specifically promoting protective CD4 T cell activation. In the absence of these responses, functional CD8 T cells are insufficient to control viral spread within the CNS, resulting in severe demyelination. IMPORTANCE During central nervous system (CNS) infections, signaling through the adaptor protein Myd88 promotes both innate and adaptive immune responses. The extent to which Myd88 regulates antiviral type I IFN, proinflammatory

  2. A rationally designed CD4 analogue inhibits experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jameson, Bradford A.; McDonnell, James M.; Marini, Joseph C.; Korngold, Robert

    1994-04-01

    EXPERIMENTAL allergic encephalomyelitis (EAE) is an acute inflammatory autoimmune disease of the central nervous system that can be elicited in rodents and is the major animal model for the study of multiple sclerosis (MS)1,2. The pathogenesis of both EAE and MS directly involves the CD4+ helper T-cell subset3-5. Anti-CD4 monoclonal antibodies inhibit the development of EAE in rodents6-9, and are currently being used in human clinical trials for MS. We report here that similar therapeutic effects can be achieved in mice using a small (rationally designed) synthetic analogue of the CD4 protein surface. It greatly inhibits both clinical incidence and severity of EAE with a single injection, but does so without depletion of the CD4+ subset and without the inherent immunogenicity of an antibody. Furthermore, this analogue is capable of exerting its effects on disease even after the onset of symptoms.

  3. Chronic fatigue syndrome versus sudden onset myalgic encephalomyelitis.

    PubMed

    Jason, Leonard A; Evans, Meredyth; Brown, Abigail; Sunnquist, Madison; Newton, Julia L

    2015-01-01

    A revised sudden onset case definition for Myalgic Encephalomyelitis (ME) has been developed (Jason, Damrongvachiraphan, et al., 2012 ) based on past case definitions. In a prior study, Jason, Brown, and colleagues ( 2012 ) compared patients recruited using the 1994 case definition of chronic fatigue syndrome (CFS) to contrast those meeting criteria for the revised ME criteria. They found that this revised ME case definition identified patients with more functional impairments and physical, mental, and cognitive problems than those meeting the CFS criteria. The study by Jason, Brown, et al. ( 2012 ) only selected individuals who first met the CFS criteria, and it only relied on one Chicago-based data set. The current study replicated this comparison with two distinct data sets with different case ascertainment methods. Results indicate that the ME criteria identified a group of patients with more functional disabilities as well as more severe post-exertional malaise symptoms.

  4. Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome.

    PubMed

    Pohl, Daniela; Alper, Gulay; Van Haren, Keith; Kornberg, Andrew J; Lucchinetti, Claudia F; Tenembaum, Silvia; Belman, Anita L

    2016-08-30

    Acute disseminated encephalomyelitis (ADEM) is an immune-mediated demyelinating CNS disorder with predilection to early childhood. ADEM is generally considered a monophasic disease. However, recurrent ADEM has been described and defined as multiphasic disseminated encephalomyelitis. ADEM often occurs postinfectiously, although a causal relationship has never been established. ADEM and multiple sclerosis are currently viewed as distinct entities, generally distinguishable even at disease onset. However, pathologic studies have demonstrated transitional cases of yet unclear significance. ADEM is clinically defined by acute polyfocal neurologic deficits including encephalopathy. MRI typically demonstrates reversible, ill-defined white matter lesions of the brain and often also the spinal cord, along with frequent involvement of thalami and basal ganglia. CSF analysis may reveal a mild pleocytosis and elevated protein, but is generally negative for intrathecal oligoclonal immunoglobulin G synthesis. In the absence of a specific diagnostic test, ADEM is considered a diagnosis of exclusion, and ADEM mimics, especially those requiring a different treatment approach, have to be carefully ruled out. The role of biomarkers, including autoantibodies like anti-myelin oligodendrocyte glycoprotein, in the pathogenesis and diagnosis of ADEM is currently under debate. Based on the presumed autoimmune etiology of ADEM, the current treatment approach consists of early immunotherapy. Outcome of ADEM in pediatric patients is generally favorable, but cognitive deficits have been reported even in the absence of other neurologic sequelae. This review summarizes the current knowledge on epidemiology, pathology, clinical presentation, neuroimaging features, CSF findings, differential diagnosis, therapy, and outcome, with a focus on recent advances and controversies. PMID:27572859

  5. 9 CFR 113.325 - Avian Encephalomyelitis Vaccine.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... predetermined quantity of vaccine virus. Five replicate virus titrations shall be conducted on an aliquot of the... ataxic chickens as positive evidence of viral infection. (iv) A satisfactory titration shall have at... samples of completed product shall be tested for virus titer using the titration method used in...

  6. 9 CFR 113.325 - Avian Encephalomyelitis Vaccine.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... predetermined quantity of vaccine virus. Five replicate virus titrations shall be conducted on an aliquot of the... ataxic chickens as positive evidence of viral infection. (iv) A satisfactory titration shall have at... samples of completed product shall be tested for virus titer using the titration method used in...

  7. 9 CFR 113.325 - Avian Encephalomyelitis Vaccine.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... predetermined quantity of vaccine virus. Five replicate virus titrations shall be conducted on an aliquot of the... ataxic chickens as positive evidence of viral infection. (iv) A satisfactory titration shall have at... samples of completed product shall be tested for virus titer using the titration method used in...

  8. 9 CFR 113.325 - Avian Encephalomyelitis Vaccine.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... predetermined quantity of vaccine virus. Five replicate virus titrations shall be conducted on an aliquot of the... ataxic chickens as positive evidence of viral infection. (iv) A satisfactory titration shall have at... samples of completed product shall be tested for virus titer using the titration method used in...

  9. 9 CFR 113.325 - Avian Encephalomyelitis Vaccine.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... predetermined quantity of vaccine virus. Five replicate virus titrations shall be conducted on an aliquot of the... ataxic chickens as positive evidence of viral infection. (iv) A satisfactory titration shall have at... samples of completed product shall be tested for virus titer using the titration method used in...

  10. Viruses and Multiple Sclerosis

    PubMed Central

    Owens, Gregory P.; Gilden, Don; Burgoon, Mark P.; Yu, Xiaoli; Bennett, Jeffrey L.

    2012-01-01

    Multiple sclerosis (MS) is a chronic demyelinating disorder of unknown etiology, possibly caused by a virus or virus-triggered immunopathology. The virus might reactivate after years of latency and lyse oligodendrocytes, as in progressive multifocal leukoencephalopathy, or initiate immunopathological demyelination, as in animals infected with Theiler’s murine encephalomyelitis virus or coronaviruses. The argument for a viral cause of MS is supported by epidemiological analyses and studies of MS in identical twins, indicating that disease is acquired. However, the most important evidence is the presence of bands of oligoclonal IgG (OCBs) in MS brain and CSF that persist throughout the lifetime of the patient. OCBs are found almost exclusively in infectious CNS disorders, and antigenic targets of OCBs represent the agent that causes disease. Here, the authors review past attempts to identify an infectious agent in MS brain cells and discuss the promise of using recombinant antibodies generated from clonally expanded plasma cells in brain and CSF to identify disease-relevant antigens. They show how this strategy has been used successfully to analyze antigen specificity in subacute sclerosing panencephalitis, a chronic encephalitis caused by measles virus, and in neuromyelitis optica, a chronic autoimmune demyelinating disease produced by antibodies directed against the aquaporin-4 water channel. PMID:22130640

  11. Viruses and multiple sclerosis.

    PubMed

    Owens, Gregory P; Gilden, Don; Burgoon, Mark P; Yu, Xiaoli; Bennett, Jeffrey L

    2011-12-01

    Multiple sclerosis (MS) is a chronic demyelinating disorder of unknown etiology, possibly caused by a virus or virus-triggered immunopathology. The virus might reactivate after years of latency and lyse oligodendrocytes, as in progressive multifocal leukoencephalopathy, or initiate immunopathological demyelination, as in animals infected with Theiler's murine encephalomyelitis virus or coronaviruses. The argument for a viral cause of MS is supported by epidemiological analyses and studies of MS in identical twins, indicating that disease is acquired. However, the most important evidence is the presence of bands of oligoclonal IgG (OCBs) in MS brain and CSF that persist throughout the lifetime of the patient. OCBs are found almost exclusively in infectious CNS disorders, and antigenic targets of OCBs represent the agent that causes disease. Here, the authors review past attempts to identify an infectious agent in MS brain cells and discuss the promise of using recombinant antibodies generated from clonally expanded plasma cells in brain and CSF to identify disease-relevant antigens. They show how this strategy has been used successfully to analyze antigen specificity in subacute sclerosing panencephalitis, a chronic encephalitis caused by measles virus, and in neuromyelitis optica, a chronic autoimmune demyelinating disease produced by antibodies directed against the aquaporin-4 water channel. PMID:22130640

  12. Tanshinone IIA attenuates experimental autoimmune encephalomyelitis in rats

    PubMed Central

    Yan, Jun; Yang, Xue; Han, Dong; Feng, Juan

    2016-01-01

    Multiple sclerosis (MS) is an inflammatory autoimmune neurodegenerative disease, which features focal demyelination and inflammatory cell infiltration of the brain and the spinal cord. Tanshinone IIA (TSIIA), one of the major fat-soluble components of Salvia miltiorrhiza (Danshen), has anti-inflammatory, immunoregulatory and neuroprotective activity; however, its efficacy in MS remains unknown. The current study was designed to investigate the potential therapeutic function of TSIIA on MS in the experimental autoimmune encephalomyelitis (EAE) rat model. In comparison to the vehicle control group, the TSIIA-treated groups showed notably improved clinical symptoms and pathological changes, including central nervous system inflammatory cell infiltration and demyelination. Following administration of TSIIA, the quantity of CD4+ T cells, CD8+ T cells and macrophages/microglia in the spinal cord were reduced to different extents. Furthermore, TSIIA was also shown to downregulate interleukin (IL)-17 and IL-23 levels in the brain and serum of EAE rats. The results collectively provide evidence that TSIIA alleviates EAE and support its utility as a novel therapy for MS. PMID:27357729

  13. Translational utility of experimental autoimmune encephalomyelitis: recent developments

    PubMed Central

    Guerreiro-Cacais, Andre Ortlieb; Laaksonen, Hannes; Flytzani, Sevasti; N’diaye, Marie; Olsson, Tomas; Jagodic, Maja

    2015-01-01

    Multiple sclerosis (MS) is a complex autoimmune condition with firmly established genetic and environmental components. Genome-wide association studies (GWAS) have revealed a large number of genetic polymorphisms in the vicinity of, and within, genes that associate to disease. However, the significance of these single-nucleotide polymorphisms in disease and possible mechanisms of action remain, with a few exceptions, to be established. While the animal model for MS, experimental autoimmune encephalomyelitis (EAE), has been instrumental in understanding immunity in general and mechanisms of MS disease in particular, much of the translational information gathered from the model in terms of treatment development (glatiramer acetate and natalizumab) has been extensively summarized. In this review, we would thus like to cover the work done in EAE from a GWAS perspective, highlighting the research that has addressed the role of different GWAS genes and their pathways in EAE pathogenesis. Understanding the contribution of these pathways to disease might allow for the stratification of disease subphenotypes in patients and in turn open the possibility for new and individualized treatment approaches in the future. PMID:26622189

  14. Chronic exercise confers neuroprotection in experimental autoimmune encephalomyelitis.

    PubMed

    Pryor, William M; Freeman, Kimberly G; Larson, Rebecca D; Edwards, Gaylen L; White, Lesley J

    2015-05-01

    Multiple sclerosis (MS) is an autoimmune disease that affects the CNS, resulting in accumulated loss of cognitive, sensory, and motor function. This study evaluates the neuropathological effects of voluntary exercise in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Two groups of C57BL/6J mice were injected with an emulsion containing myelin oligodendrocyte glycoprotein and then randomized to housing with a running wheel or a locked wheel. Exercising EAE mice exhibited a less severe neurological disease score and later onset of disease compared with sedentary EAE animals. Immune cell infiltration and demyelination in the ventral white matter tracts of the lumbar spinal cord were significantly reduced in the EAE exercise group compared with sedentary EAE animals. Neurofilament immunolabeling in the ventral pyramidal and extrapyramidal motor tracts displayed a more random distribution of axons and an apparent loss of smaller diameter axons, with a greater loss of fluorescence immunolabeling in the sedentary EAE animals. In lamina IX gray matter regions of the lumbar spinal cord, sedentary animals with EAE displayed a greater loss of α-motor neurons compared with EAE animals exposed to exercise. These findings provide evidence that voluntary exercise results in reduced and attenuated disability, reductions in autoimmune cell infiltration, and preservation of axons and motor neurons in the lumbar spinal cord of mice with EAE.

  15. Beneficial effects of blueberries in experimental autoimmune encephalomyelitis.

    PubMed

    Xin, Junping; Feinstein, Douglas L; Hejna, Matthew J; Lorens, Stanley A; McGuire, Susan O

    2012-06-13

    Experimental autoimmune encephalomyelitis (EAE) is an animal model of autoimmune disease that presents with pathological and clinical features similar to those of multiple sclerosis (MS) including inflammation and neurodegeneration. This study investigated whether blueberries, which possess immunomodulatory, anti-inflammatory, and neuroprotective properties, could provide protection in EAE. Dietary supplementation with 1% whole, freeze-dried blueberries reduced disease incidence by >50% in a chronic EAE model (p < 0.01). When blueberry-fed mice with EAE were compared with control-fed mice with EAE, blueberry-fed mice had significantly lower motor disability scores (p = 0.03) as well as significantly greater myelin preservation in the lumbar spinal cord (p = 0.04). In a relapsing-remitting EAE model, blueberry-supplemented mice showed improved cumulative and final motor scores compared to control diet-fed mice (p = 0.01 and 0.03, respectively). These data demonstrate that blueberry supplementation is beneficial in multiple EAE models, suggesting that blueberries, which are easily administered orally and well-tolerated, may provide benefit to MS patients. PMID:22243431

  16. R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice

    PubMed Central

    Schmitz, Katja; de Bruin, Natasja; Bishay, Philipp; Männich, Julia; Häussler, Annett; Altmann, Christine; Ferreirós, Nerea; Lötsch, Jörn; Ultsch, Alfred; Parnham, Michael J; Geisslinger, Gerd; Tegeder, Irmgard

    2014-01-01

    R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4+CD25+FoxP3+ regulatory T cells, CTLA4+ inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial. PMID:25269445

  17. R-flurbiprofen attenuates experimental autoimmune encephalomyelitis in mice.

    PubMed

    Schmitz, Katja; de Bruin, Natasja; Bishay, Philipp; Männich, Julia; Häussler, Annett; Altmann, Christine; Ferreirós, Nerea; Lötsch, Jörn; Ultsch, Alfred; Parnham, Michael J; Geisslinger, Gerd; Tegeder, Irmgard

    2014-11-01

    R-flurbiprofen is the non-cyclooxygenase inhibiting R-enantiomer of the non-steroidal anti-inflammatory drug flurbiprofen, which was assessed as a remedy for Alzheimer's disease. Because of its anti-inflammatory, endocannabinoid-modulating and antioxidative properties, combined with low toxicity, the present study assessed R-flurbiprofen in experimental autoimmune encephalomyelitis (EAE) models of multiple sclerosis in mice. Oral R-flurbiprofen prevented and attenuated primary progressive EAE in C57BL6/J mice and relapsing-remitting EAE in SJL mice, even if the treatment was initiated on or after the first flare of the disease. R-flurbiprofen reduced immune cell infiltration and microglia activation and inflammation in the spinal cord, brain and optic nerve and attenuated myelin destruction and EAE-evoked hyperalgesia. R-flurbiprofen treatment increased CD4(+)CD25(+)FoxP3(+) regulatory T cells, CTLA4(+) inhibitory T cells and interleukin-10, whereas the EAE-evoked upregulation of pro-inflammatory genes in the spinal cord was strongly reduced. The effects were associated with an increase of plasma and cortical endocannabinoids but decreased spinal prostaglandins, the latter likely due to R to S inversion. The promising results suggest potential efficacy of R-flurbiprofen in human MS, and its low toxicity may justify a clinical trial.

  18. Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Zhu, Bing; Luo, Liqing; Moore, G. R. Wayne; Paty, Donald W.; Cynader, Max S.

    2003-01-01

    Evidence has shown that excitotoxicity may contribute to the loss of central nervous system axons and oligodendrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Because dendrites and synapses are vulnerable to excitotoxicity, we examined these structures in acute and chronic models of EAE. Immunostaining for microtubule-associated protein-2 showed that extensive dendritic beading occurred in the white matter of the lumbosacral spinal cord (LSSC) during acute EAE episodes and EAE relapses. Retrograde labeling confirmed that most motoneuron dendrites were beaded in the white matter of the LSSC in acute EAE. In contrast, only mild swelling was observed in the gray matter of the LSSC. Dendritic beading showed marked recovery during EAE remission and after EAE recovery. In addition, synaptophysin, synapsin I, and PSD-95 immunoreactivities were significantly reduced in both the gray and white matter of the LSSC during acute EAE episodes and EAE relapses, but showed partial recovery during EAE remission and after EAE recovery. Pathologically, both dendritic beading and the reduction in synaptic protein immunoreactivity were well correlated with inflammatory cell infiltration in the LSSC at different EAE stages. We propose that dendritic and synaptic damage in the spinal cord may contribute to the neurological deficits in EAE. PMID:12707048

  19. Genetic analysis of experimental allergic encephalomyelitis in mice

    SciTech Connect

    Baker, D.; Rosenwasser, O.A.; O`Neill, J.K.; Turk, J.L.

    1995-10-15

    Experimental allergic encephalomyelitis (EAE) is an autoimmune disease of the central nervous system that exhibits many pathologic similarities with multiple sclerosis. While products of the MHC are known to control the development of EAE, it is clear that non-MHC products also influence susceptibility. The chromosomal locations of these were investigated in selective crosses between MHC class II-compatible, EAE-susceptible Biozzi ABH, and low responder nonobese diabetic (NOD) mice. The disease was dominant and highly influenced by gender in the backcross one (BC{sub 1}) generation. Female mice were significantly more susceptible than male mice. Segregation of disease frequency of female animals in this cross suggested that EAE was controlled by a major locus. Although microsatellite-based exclusion mapping indicated that a number of regions on chromosomes 5, 6, 7, 8, 9, 10, 11, 12, 13, and 18 showed evidence of linkage (p<0.05) compared with expected random distributions of alleles, disease susceptibility was most strongly linked (p<0.05) to chromosome 7. However, by selectively analyzing animals that were either severely affected or almost normal, additional susceptibility loci were mapped on chromosomes 18 and 11 that were linked (p<0.001) to resistance and the development of severe disease, respectively. The data indicate a major locus on chromosome 7, affecting initiation and severity of EAE that is probably modified by several other unlinked loci. These localizations may provide candidate loci for the analysis of human autoimmune-demyelinating disease. 30 refs., 5 tabs.

  20. Coincidence of spinal tumor (astrocytoma) and non-specific encephalomyelitis.

    PubMed

    Burgetova, Andrea; Vaneckova, Manuela; Nytrova, Petra; Matej, Radoslav; Seidl, Zdenek

    2012-01-01

    The aim of this paper is to demonstrate that differential diagnostics of intra-medullary spinal lesions can sometimes be very difficult, even when the latest complement examinations are used, including magnetic resonance imaging. The particular case dealt with here was complicated by the presence of two different pathological processes. We present the case report, where the case history, clinical course and results of the paraclinical examinations, including the magnetic resonance imaging, suggested an intra-medullary inflammatory/demyelinating process. The post-mortem histological finding was a surprise, because besides signs of non-specific encephalomyelitis, it also displayed signs of a spinal tumor (histological character of diffuse astrocytoma grade II-III). We would like to emphasize some important facts in our discussion, especially from the perspective of the magnetic resonance imaging. Finally, we would like to ask if the presence of both pathologies (astrocytoma and nonspecific myelitis) was coincidental, or if the myelitis had an iatrogenic etiology (by therapy, by infection during the lumbar punctions). PMID:23391981

  1. Coincidence of spinal tumor (astrocytoma) and non-specific encephalomyelitis.

    PubMed

    Burgetova, Andrea; Vaneckova, Manuela; Nytrova, Petra; Matej, Radoslav; Seidl, Zdenek

    2012-12-01

    The aim of this paper is to demonstrate that differential diagnostics of intra-medullary spinal lesions can sometimes be very difficult, even when the latest complement examinations are used, including magnetic resonance imaging. The particular case dealt with here was complicated by the presence of two different pathological processes. We present the case report, where the case history, clinical course and results of the paraclinical examinations, including the magnetic resonance imaging, suggested an intra-medullary inflammatory/demyelinating process. The post-mortem histological finding was a surprise, because besides signs of non-specific encephalomyelitis, it also displayed signs of a spinal tumor (histological character of diffuse astrocytoma grade II-III). We would like to emphasize some important facts in our discussion, especially from the perspective of the magnetic resonance imaging. Finally, we would like to ask if the presence of both pathologies (astrocytoma and nonspecific myelitis) was coincidental, or if the myelitis had an iatrogenic etiology (by therapy, by infection during the lumbar punctions). PMID:23391883

  2. Suppression of experimental autoimmune encephalomyelitis by intravenously administered polyclonal immunoglobulins.

    PubMed

    Achiron, A; Mor, F; Margalit, R; Cohen, I R; Lider, O; Miron, S

    2000-11-01

    Experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats either by active immunization with myelin basic protein (MBP) or by adoptive transfer using anti-MBP specific CD4(+)T cells. Treatment with human polyclonal immunoglobulins (IgG) effectively suppressed active EAE. Time-dependent experiments demonstrated that the effect of IgG was manifested only when treatment was given immediately after immunization; administration from day 7 after disease induction did not suppress the disease. In the adoptive transfer model of EAE, IgG had no effect in vivo. However, pretreatment in vitro of the antigen-specific T-cells with IgG inhibited their ability to mediate adoptive EAE, as it did in active EAE. Similarly, in vitro IgG pretreatment of the antigen-specific T-cells suppressed the proliferative response to MBP. Fluorescent Activated Cell Sorter (FACS) analysis demonstrated the binding of IgG to activated T-cell lines that was inhibited by soluble Fc molecules. The differential effects of IgG on active EAE and on the adoptive transfer of EAE suggest that IgG in vivo can suppress disease by acting during the early phase of the immune response which involves naive T cells. The inhibition of T-cell proliferation and adoptive transfer of EAE by incubation of T cells in vitro appears to require higher concentrations of IgG than those obtained in vivo. PMID:11040073

  3. Tuftsin-driven experimental autoimmune encephalomyelitis recovery requires neuropilin-1.

    PubMed

    Nissen, Jillian C; Tsirka, Stella E

    2016-06-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model of demyelinating autoimmune disease, such as multiple sclerosis (MS), which is characterized by central nervous system white matter lesions, microglial activation, and peripheral T-cell infiltration secondary to blood-brain barrier disruption. We have previously shown that treatment with tuftsin, a tetrapeptide generated from IgG proteolysis, dramatically improves disease symptoms in EAE. Here, we report that microglial expression of Neuropilin-1 (Nrp1) is required for tuftsin-driven amelioration of EAE symptoms. Nrp1 ablation in microglia blocks microglial signaling and polarization to the anti-inflammatory M2 phenotype, and ablation in either the microglia or immunosuppressive regulatory T cells (Tregs) reduces extended functional contacts between them and Treg activation, implicating a role for microglia in the activation process, and more generally, how immune surveillance is conducted in the CNS. Taken together, our findings delineate the mechanistic action of tuftsin as a candidate therapeutic against immune-mediated demyelinating lesions. PMID:26880314

  4. Augmenting DAF levels in vivo ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Li, Qing; Huang, Danping; Nacion, Kristine; Bu, Hong; Lin, Feng

    2009-09-01

    Recent studies in experimental autoimmune encephalomyelitis (EAE) have found that CNS injury in Daf1(-/-) mice is much greater than in wild types (WTs), suggesting that upregulating DAF levels in vivo might ameliorate disease. To test this, we generated a Daf1 transgenic (Tg) mouse which had elevated DAF levels on its cell surfaces. In by-stand C3b uptake assays, Daf1 Tg mouse erythrocytes took up less C3b on their surfaces than WT erythrocytes. When co-cultured with OT-II CD4(+) T cells together with OVA(323-339) peptide, Daf1 Tg mouse bone marrow derived dendritic cells (BM-DCs) produced less C5a and C3a than WT BM-DCs and stimulated a lesser T cell response. In MOG(35-55) immunization induced EAE model, Daf1 Tg mice exhibited delayed disease onset and decreased clinical scores compared to WTs. Histological analyses showed that there were less inflammation and demyelination in spinal cords in Daf1 Tg mice than those in WTs. In accordance with these results, Daf1 Tg mice had decreased MOG(35-55) specific Th1 and Th17 responses. These data provide further evidence that DAF suppresses autoreactive T cell responses in EAE, and indicate that augmenting its expression levels could be effective therapeutically in treating multiple sclerosis as well as other T cell mediated diseases. PMID:19660813

  5. Persistent pseudobulbar affect secondary to acute disseminated encephalomyelitis

    PubMed Central

    Li, Zhendong; Luo, Shijian; Ou, Jianying; Huang, Rihe; Wang, Ying

    2015-01-01

    Pseudobulbar affect (PBA) is a common complication of central nervous system diseases such as stroke, multiple sclerosis, and other neurological diseases, but it remains under-recognized and under-treated in the clinic. PBA caused by acute disseminated encephalomyelitis (ADEM) has rarely been reported. Here, we report a 30-year-old Chinese woman who has experienced PBA from ADEM for 7 years. The patient's principal manifestations were extreme emotions or tears when she saw, heard, or spoke about sad news or other sad things; the durations of these unmanageable emotions were often less than 30 sec, and they occurred at frequencies that ranged from one to several times a day. Occasionally, she laughed uncontrollably while people were talking despite a lack of funny or sad stimuli in the conversation or the surrounding environment. Thus, her social functioning was impaired. This case indicates that the long-term PBA can occur secondarily to ADEM, and this possibility should be considered clinically to ensure timely identification and treatment. PMID:25792370

  6. An Etiological Model for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

    PubMed Central

    Jason, Leonard A.; Sorenson, Matthew; Porter, Nicole; Belkairous, Natalie

    2011-01-01

    Kindling might represent a heuristic model for understanding the etiology of Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Kindling occurs when an organism is exposed repeatedly to an initially sub-threshold stimulus resulting in hypersensitivity and spontaneous seizure-like activity. Among patients with ME/CFS, chronically repeated low-intensity stimulation due to an infectious illness might cause kindling of the limbic-hypothalamic-pituitary axis. Kindling might also occur by high-intensity stimulation (e.g., brain trauma) of the limbic-hypothalamic-pituitary axis. Once this system is charged or kindled, it can sustain a high level of arousal with little or no external stimulus and eventually this could lead to hypocortisolism. Seizure activity may spread to adjacent structures of the limbic-hypothalamic-pituitary axis in the brain, which might be responsible for the varied symptoms that occur among patients with ME/CFS. In addition, kindling may also be responsible for high levels of oxidative stress, which has been found in patients with ME/CFS. PMID:21892413

  7. Bladder Dysfunction in Mice with Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Altuntas, Cengiz Z.; Daneshgari, Firouz; Liu, Guiming; Fabiyi, Adebola; Kavran, Michael; Johnson, Justin M.; Gulen, M. Fatih; Jaini, Ritika; Li, Xiaoxia; Frenkl, Tara L.; Tuohy, Vincent K.

    2009-01-01

    The vast majority of patients with multiple sclerosis (MS) develop bladder control problems including urgency to urinate, urinary incontinence, frequency of urination, and retention of urine. Over 60% of MS patients show detrusor-sphincter dyssynergia, an abnormality characterized by obstruction of urinary outflow as a result of discoordinated contraction of the urethral sphincter muscle and the bladder detrusor muscle. In the current study we examined bladder function in female SWXJ mice with different defined levels of neurological impairment following induction of experimental autoimmune encephalomyelitis (EAE), an animal model of central nervous system inflammation widely used in MS research. We found that EAE mice develop profound bladder dysfunction characterized by significantly increased micturition frequencies and significantly decreased urine output per micturition. Moreover, we found that the severity of bladder abnormalities in EAE mice was directly related to the severity of clinical EAE and neurologic disability. Our study is the first to show and characterize micturition abnormalities in EAE mice thereby providing a most useful model system for understanding and treating neurogenic bladder. PMID:18703233

  8. Specific Binding of Peroxidase-Labeled Myelin Basic Protein in Allergic Encephalomyelitis

    PubMed Central

    Johnson, Anne B.; Wiśniewski, Henryk M.; Raine, Cedric S.; Eylar, E. H.; Terry, Robert D.

    1971-01-01

    A conjugate of horseradish peroxidase and the encephalitogenic basic protein from myelin has been used to study the antigen reactivity of tissue in the autoimmune disease, experimental allergic encephalomyelitis. Control conjugates were also prepared of peroxidase and bovine serum albumin and of peroxidase and lysozyme, another basic protein. The basic protein from myelin conjugate was specifically bound by lymph node cells from rabbits immunized against the basic protein. Some of these cells appeared to be plasma cells. The conjugate was also specifically bound by occasional cells in the spinal-cord infiltrates of animals with early signs of allergic encephalomyelitis. These cells resembled large lymphocytes and plasma cells. There was no difference between the binding of basic protein of bovine and rabbit origin. The findings suggest the possibility that a local release of antibody within the target organ may play a role in the pathogenesis of allergic encephalomyelitis. Images PMID:5288245

  9. Specific binding of peroxidase-labeled myelin basic protein in allergic encephalomyelitis.

    PubMed

    Johnson, A B; Wiśniewski, H M; Raine, C S; Eylar, E H; Terry, R D

    1971-11-01

    A conjugate of horseradish peroxidase and the encephalitogenic basic protein from myelin has been used to study the antigen reactivity of tissue in the autoimmune disease, experimental allergic encephalomyelitis. Control conjugates were also prepared of peroxidase and bovine serum albumin and of peroxidase and lysozyme, another basic protein. The basic protein from myelin conjugate was specifically bound by lymph node cells from rabbits immunized against the basic protein. Some of these cells appeared to be plasma cells. The conjugate was also specifically bound by occasional cells in the spinal-cord infiltrates of animals with early signs of allergic encephalomyelitis. These cells resembled large lymphocytes and plasma cells. There was no difference between the binding of basic protein of bovine and rabbit origin. The findings suggest the possibility that a local release of antibody within the target organ may play a role in the pathogenesis of allergic encephalomyelitis.

  10. IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development.

    PubMed

    Kavrochorianou, Nadia; Evangelidou, Maria; Markogiannaki, Melina; Tovey, Michael; Thyphronitis, George; Haralambous, Sylva

    2016-01-01

    Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis.

  11. IFNAR signaling directly modulates T lymphocyte activity, resulting in milder experimental autoimmune encephalomyelitis development.

    PubMed

    Kavrochorianou, Nadia; Evangelidou, Maria; Markogiannaki, Melina; Tovey, Michael; Thyphronitis, George; Haralambous, Sylva

    2016-01-01

    Although interferon-β is used as first-line therapy for multiple sclerosis, the cell type-specific activity of type I interferons in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis, remains obscure. In this study, we have elucidated the in vivo immunomodulatory role of type I interferon signaling in T cells during experimental autoimmune encephalomyelitis by use of a novel transgenic mouse, carrying a cd2-ifnar1 transgene on a interferon-α/β receptor 1 null genetic background, thus allowing expression of the interferon-α/β receptor 1 and hence, a functional type I interferon receptor exclusively on T cells. These transgenic mice exhibited milder experimental autoimmune encephalomyelitis with reduced T cell infiltration, demyelination, and axonal damage in the central nervous system. It is noteworthy that interferon-β administration in transgenic mice generated a more pronounced, protective effect against experimental autoimmune encephalomyelitis compared with untreated littermates. In vivo studies demonstrated that before experimental autoimmune encephalomyelitis onset, endogenous type I interferon receptor signaling in T cells led to impaired T-helper 17 responses, with a reduced fraction of CCR6(+) CD4(+) T cells in the periphery. At the acute phase, an increased proportion of interleukin-10- and interferon-γ-producing CD4(+) T cells was detected in the periphery of the transgenic mice, accompanied by up-regulation of the interferon-γ-induced gene Irgm1 in peripheral T cells. Together, these results reveal a hitherto unknown T cell-associated protective role of type I interferon in experimental autoimmune encephalomyelitis that may provide valuable clues for designing novel therapeutic strategies for multiple sclerosis. PMID:26232452

  12. An in vivo proton neurospectroscopy study of cerebral oxidative stress in myalgic encephalomyelitis (chronic fatigue syndrome).

    PubMed

    Puri, B K; Agour, M; Gunatilake, K D R; Fernando, K A C; Gurusinghe, A I; Treasaden, I H

    2009-01-01

    A particularly important family of antioxidant defence enzymes in the body are the glutathione peroxidases, which remove H(2)O(2) by coupling its reduction to H(2)O with oxidation of reduced glutathione (GSH) to oxidised glutathione (GSSG). There are suggestions that GSH in the peripheral blood may be reduced in myalgic encephalomyelitis, which is a highly disabling neurological disease of unknown aetiology. Since many of the symptoms relate to cerebral functioning, it would seem probable that peripheral blood GSH findings would be reflected in lower cerebral GSH levels. The aim of this study was to carry out the first direct assessment of cerebral GSH levels in myalgic encephalomyelitis; the hypothesis being tested was that cerebral GSH levels would be reduced in myalgic encephalomyelitis. Cerebral proton neurospectroscopy was carried out at a magnetic field strength of 3T in 26 subjects; spectra were obtained from 20x20x20mm(3) voxels using a point-resolved spectroscopy pulse sequence. The mean cerebral GSH level in the myalgic encephalomyelitis patients was 2.703 (SD 2.311) which did not differ significantly from that in age- and gender-matched normal controls who did not have any history of neurological or other major medical disorder (5.191, SD 8.984; NS). Therefore our study does not suggest that GSH is reduced in the brain in myalgic encephalomyelitis. At the present time, based on the results of this study, there is no evidence to support the suggestion that, by taking glutathione supplements, an improvement in the brain-related symptomatology of myalgic encephalomyelitis may occur.

  13. A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

    PubMed Central

    Navaneetharaja, Navena; Griffiths, Verity; Wileman, Tom; Carding, Simon R.

    2016-01-01

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest. This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the “infectious” trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing much-needed approaches in preventing and managing a disease desperately in need of confronting. PMID:27275835

  14. A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

    PubMed

    Navaneetharaja, Navena; Griffiths, Verity; Wileman, Tom; Carding, Simon R

    2016-06-06

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest. This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the "infectious" trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing much-needed approaches in preventing and managing a disease desperately in need of confronting.

  15. A Role for the Intestinal Microbiota and Virome in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)?

    PubMed

    Navaneetharaja, Navena; Griffiths, Verity; Wileman, Tom; Carding, Simon R

    2016-01-01

    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous disorder of significant societal impact that is proposed to involve both host and environmentally derived aetiologies that may be autoimmune in nature. Immune-related symptoms of at least moderate severity persisting for prolonged periods of time are common in ME/CFS patients and B cell depletion therapy is of significant therapeutic benefit. The origin of these symptoms and whether it is infectious or inflammatory in nature is not clear, with seeking evidence of acute or chronic virus infections contributing to the induction of autoimmune processes in ME/CFS being an area of recent interest. This article provides a comprehensive review of the current evidence supporting an infectious aetiology for ME/CFS leading us to propose the novel concept that the intestinal microbiota and in particular members of the virome are a source of the "infectious" trigger of the disease. Such an approach has the potential to identify disease biomarkers and influence therapeutics, providing much-needed approaches in preventing and managing a disease desperately in need of confronting. PMID:27275835

  16. CD44 Deficiency Contributes to Enhanced Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Flynn, Kelly M.; Michaud, Michael; Madri, Joseph A.

    2014-01-01

    Adhesion molecule CD44 is expressed by multiple cell types and is implicated in various cellular and immunological processes. In this study, we examined the effect of global CD44 deficiency on myelin oligodendrocyte glycoprotein peptide (MOG)-induced experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Compared to C57BL/6 wild-type mice, CD44-deficient mice presented with greater disease severity, increased immune cell numbers in the central nervous system, and increased anti-MOG antibody and proinflammatory cytokine production, especially those associated with T helper 17 (Th17) cells. Further, decreased numbers of peripheral CD4+CD25+FoxP3+ regulatory T cells (Tregs) were observed in CD44-knockout mice throughout the disease course. CD44-knockout CD4 T cells exhibited reduced transforming growth factor-β receptor type I (TGF-β RI) expression that did not impart a defect in Treg polarization in vitro, but did correlate with enhanced Th17 polarization in vitro. Further, EAE in bone marrow–chimeric animals suggested CD44 expression on both circulating and noncirculating cells limited disease severity. Endothelial expression of CD44 limited T-cell adhesion to and transmigration through murine endothelial monolayers in vitro. Importantly, we also identified increased permeability of the blood–brain barrier in vivo in CD44-deficient mice before and following immunization. These data suggest that CD44 has multiple protective roles in EAE, with effects on cytokine production, T-cell differentiation, T-cell–endothelial cell interactions, and blood–brain barrier integrity. PMID:23416161

  17. Chondroitin 6-O-sulfate ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Miyamoto, Katsuichi; Tanaka, Noriko; Moriguchi, Kota; Ueno, Rino; Kadomatsu, Kenji; Kitagawa, Hiroshi; Kusunoki, Susumu

    2014-05-01

    Chondroitin sulfate proteoglycans (CSPGs) are the main component of the extracellular matrix in the central nervous system (CNS) and influence neuroplasticity. Although CSPG is considered an inhibitory factor for nerve repair in spinal cord injury, it is unclear whether CSPG influences the pathogenetic mechanisms of neuroimmunological diseases. We induced experimental autoimmune encephalomyelitis (EAE) in chondroitin 6-O-sulfate transferase 1-deficient (C6st1(-/-)) mice. C6ST1 is the enzyme that transfers sulfate residues to position 6 of N-acetylgalactosamine in the sugar chain of CSPG. The phenotypes of EAE in C6st1(-/-) mice were more severe than those in wild-type (WT) mice were. In adoptive-transfer EAE, in which antigen-reactive T cells from WT mice were transferred to C6st1(-/-) and WT mice, phenotypes were significantly more severe in C6st1(-/-) than in WT mice. The recall response of antigen-reactive T cells was not significantly different among the groups. Furthermore, the number of pathogenic T cells within the CNS was also not considerably different. When EAE was induced in C6ST1 transgenic mice with C6ST1 overexpression, the mice showed considerably milder symptoms compared with those in WT mice. In conclusion, the presence of sulfate at position 6 of N-acetylgalactosamine of CSPG may influence the effecter phase of EAE to prevent the progression of pathogenesis. Thus, modification of the carbohydrate residue of CSPG may be a novel therapeutic strategy for neuroimmunological diseases such as multiple sclerosis.

  18. Role of orexin-A in experimental autoimmune encephalomyelitis.

    PubMed

    Fatemi, Iman; Shamsizadeh, Ali; Ayoobi, Fatemeh; Taghipour, Zahra; Sanati, Mohammad Hossein; Roohbakhsh, Ali; Motevalian, Manijeh

    2016-02-15

    The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35-55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis.

  19. Role of orexin-A in experimental autoimmune encephalomyelitis.

    PubMed

    Fatemi, Iman; Shamsizadeh, Ali; Ayoobi, Fatemeh; Taghipour, Zahra; Sanati, Mohammad Hossein; Roohbakhsh, Ali; Motevalian, Manijeh

    2016-02-15

    The aim of this study was to evaluate the effects of orexin-A (OX-A) on behavioral and pathological parameters and on gene expression of some multiple sclerosis-related peptides in a model of experimental autoimmune encephalomyelitis (EAE). EAE was induced by subcutaneous administration of MOG 35-55. Following immunization, the treatment was initiated by using SB.334867 (orexin-1 receptor antagonist) and/or OX-A. Locomotor activity and exploratory behaviors were monitored using open field and T-maze continuous alternation task (T-CAT) respectively. Pain sensitivity was assessed by hot-plate test. Histopathological assessments were performed by H&E staining. The expression of TGF-β, MBP, MMP-9, IL-12, iNOS and MCP-1 were measured using real-time PCR method in lumbar spinal cord. OX-A administration in EAE mice remarkably attenuated the clinical symptoms, increased latency response in hot plate test, inhibited infiltration of inflammatory cells, up-regulated mRNA expression of TGF-β as well as MBP and down-regulated mRNA expression of iNOS, MMP-9 and IL-12. In contrast SB.334867 administration in EAE mice deteriorated the clinical symptoms, decreased the alternation in T-CAT, increased infiltration of inflammatory cells, down-regulated mRNA expression of TGF-β and MBP and up-regulated mRNA expression of iNOS. Results of this study suggest that the orexinergic system might be involved in pathological development of EAE. These findings suggest orexinergic system as a potential target for treatment of multiple sclerosis. PMID:26857503

  20. Sensitivity and specificity of the fluorescent antibody technique for detection of infectious laryngotracheitis virus.

    PubMed Central

    Ide, P R

    1978-01-01

    The specificity of a fluorescent conjugate to infectious laryngotracheitis virus was examined using chick trachea organ culture or tissue sections infected with other avian viruses (adenovirus, infectious bronchitis, poxvirus, reovirus, Newcastle disease virus, Marek's disease virus, avian encephalomyelitis and infectious bursal agent) or Mycoplasma gallisepticum. Confirmation of virus replication in these preparations was obtained by either 1) demonstration of virus titre increase or 2) demonstration of fluorescence when using the homologous conjugate. Once either of these criteria had been satisfied, negative results with the infectious laryngotracheitis conjugate were taken to indicate that the conjugate would not present false positive results in differentiated cells infected with these heterologous viruses. The spectrum of reactivity of the infectious laryngotracheitis conjugate was then examined on organ cultures infected with several infectious laryngotracheitis isolates from across Canada. Finally, the conjugate was applied to experimental and natural cases of infectious laryngotracheitis and its efficiency was compared to routine virus isolation methods. Images Fig. 1. Fig. 2. PMID:206327

  1. Polymerase I pathway inhibitor ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Achiron, Anat; Mashiach, Roi; Zilkha-Falb, Rina; Meijler, Michael M; Gurevich, Michael

    2013-10-15

    Applying high throughput gene expression microarrays we identified that the suppression of polymerase 1 (POL1) pathway is associated with benign course of multiple sclerosis (MS). This finding supports the rationale for direct targeting of the POL1 transcription machinery as an innovative strategy to suppress MS. To evaluate the effects of a specific polymerase I inhibitor (POL1-I) on experimental autoimmune encephalomyelitis (EAE), we immunized female C57BL/6J mice (8 weeks) with MOG35-55/CFA. A new POL1-I was administered at a daily dose of 12.5mg/kg body weight by oral gavage either from the day of immunization until disease onset (EAE score 1.0, immunization model), at disease onset (EAE score=1.0) for the following 14 days (treatment model), or by alternate daily dose of 25.0mg/kg body weight, by oral gavage from the day of immunization for the following 25 days (combined model). POL1-I remarkably suppressed EAE in the immunization model; while in the Vehicle group the onset of EAE occurred on day 10.0±0.4 with maximal clinical score of 3.2±0.2, in the POL1-I treated mice onset was significantly delayed and occurred on day 16.9±1.1 (p=0.001), and maximal disease score 2.0±0.1 was reduced (p=0.004). In the treatment model POL1-I treatment significantly reduced disease activity; maximal score was 2.0±0.5 while in the Vehicle group it reached a mean maximal score of 3.9±0.1, (p=0.0008). In the combined model, POL1-I treatment completely inhibited disease activity. The effect of POL1-I treatment was modulated through decreased expression of POL1 pathway key-related genes LRPPRC, pre-RNA, POLR1D and RRN3 together with activation of P53 dependent apoptosis of CD4+ splenocytes. Our findings demonstrate that POL1 pathway inhibition delayed and suppressed the development of EAE and ameliorated the disease in mice with persistent clinical signs.

  2. Myalgic encephalomyelitis, chronic fatigue syndrome: An infectious disease.

    PubMed

    Underhill, R A

    2015-12-01

    The etiology of myalgic encephalomyelitis also known as chronic fatigue syndrome or ME/CFS has not been established. Controversies exist over whether it is an organic disease or a psychological disorder and even the existence of ME/CFS as a disease entity is sometimes denied. Suggested causal hypotheses have included psychosomatic disorders, infectious agents, immune dysfunctions, autoimmunity, metabolic disturbances, toxins and inherited genetic factors. Clinical, immunological and epidemiological evidence supports the hypothesis that: ME/CFS is an infectious disease; the causal pathogen persists in patients; the pathogen can be transmitted by casual contact; host factors determine susceptibility to the illness; and there is a population of healthy carriers, who may be able to shed the pathogen. ME/CFS is endemic globally as sporadic cases and occasional cluster outbreaks (epidemics). Cluster outbreaks imply an infectious agent. An abrupt flu-like onset resembling an infectious illness occurs in outbreak patients and many sporadic patients. Immune responses in sporadic patients resemble immune responses in other infectious diseases. Contagion is shown by finding secondary cases in outbreaks, and suggested by a higher prevalence of ME/CFS in sporadic patients' genetically unrelated close contacts (spouses/partners) than the community. Abortive cases, sub-clinical cases, and carrier state individuals were found in outbreaks. The chronic phase of ME/CFS does not appear to be particularly infective. Some healthy patient-contacts show immune responses similar to patients' immune responses, suggesting exposure to the same antigen (a pathogen). The chronicity of symptoms and of immune system changes and the occurrence of secondary cases suggest persistence of a causal pathogen. Risk factors which predispose to developing ME/CFS are: a close family member with ME/CFS; inherited genetic factors; female gender; age; rest/activity; previous exposure to stress or toxins

  3. Atypical porcine enterovirus encephalomyelitis: possible interraction between enteroviruses and arsenicals.

    PubMed

    Pass, D A; Forman, A J; Connaughton, I D; Gillick, J C; Cutler, R S

    1979-10-01

    Porcine enteroviruses were isolated from weaner pigs that had nervous signs and mild non-suppurative meningoencephalomyelitis and ganglioneuritis. The clinical signs and lesions were not typical of enterovirus infection and it is believed that an organic arsenical present in feed enhanced pathogenicity of enteroviruses. Severe non-suppurative polioencephalomyelitis and ganglioneuritis were produced in gnotobiotic pigs by oral inoculation of the viruses.

  4. [Production and titration of a vaccine against the infectious encephalomyelitis of poultry].

    PubMed

    Shishkov, N; Enchev, S; Ribarov, B; Stoĭchev, S; Kalaĭdzhiĭski, A

    1978-01-01

    A vaccine was produced against infectious encephalomyelitis of day-old chicks infected cerebrally with strain Calnek 1143. It is a brain suspension from killed birds that have shown disease symptoms, treated with penicillin and streptomycin and stored at -20 degrees C. Experiments were carried out to titrate the vaccine through determining the minimum infective dose for day-old chicks treated with 0.1 cm3 each of it, orally, as obtained from tenfold dilutions. It was found that birds do not manifest clinically the disease, however, with birds killed 20--25 days following infection there have been characteristic histologic changes speaking of infectious encephalomyelitis. The minimum infective dose of the various batches of vaccine have been found to range from 10(-3) to 10(-5)/cm3. Applied under the conditions of the practice the vaccine has proved harmless, contributing to eradication of the disease on the infected farms.

  5. Myalgic encephalomyelitis: a review with emphasis on key findings in biomedical research

    PubMed Central

    Hooper, M

    2007-01-01

    This review examines research findings in patients with myalgic encephalomyelitis in light of the current debate about this chronic multiple‐symptom, multiorgan, multisystem illness and the conflicting views in medicine. These issues cannot be separated from the political opinions and assertions that conflict with science and medicine, and will be part of this review as they have enormous consequences for scientific and medical research, patients, clinicians, carers and policy makers. PMID:16935967

  6. A Case Report of Post Rabipur (Purified Chick Embryo Rabies Vaccine) Acute Disseminated Encephalomyelitis.

    PubMed

    Kumar, Rajesh; Singh, A K Bishorjit; Pradhan, R N; Pathak, Vipin Kumar

    2015-01-01

    Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease that typically occurs following a viral infection or vaccination. The incidence of ADEM following vaccination has become very low since introduction of non-neural rabies vaccine and only few cases had been reported due to pure chick embryo derived rabies vaccine (PCERV). Here we are reporting a rare case of delayed post vaccinal ADEM. PMID:26591130

  7. Microadaption of hemadsorption inhibition for neutralization tests with pig hemagglutinating encephalomyelitis virus.

    PubMed

    Sorensen, K J

    1974-10-01

    A microneutralization test is described, in which secondary pig thyroid cells are used and end points are determined by hemadsorption with hamster erythrocytes. The method is evaluated and compared with a macromethod, in which the fluorescent-antibody staining technique is applied for reading titers. The micromethod was found to be useful because of its sensitivity and rapidity. PMID:4608721

  8. A Consistent Orally-Infected Hamster Model for Enterovirus A71 Encephalomyelitis Demonstrates Squamous Lesions in the Paws, Skin and Oral Cavity Reminiscent of Hand-Foot-and-Mouth Disease.

    PubMed

    Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

    2016-01-01

    Enterovirus A71 (EV-A71) causes self-limiting, hand-foot-and-mouth disease (HFMD) that may rarely be complicated by encephalomyelitis. Person-to-person transmission is usually by fecal-oral or oral-oral routes. To study viral replication sites in the oral cavity and other tissues, and to gain further insights into virus shedding and neuropathogenesis, we developed a consistent, orally-infected, 2-week-old hamster model of HFMD and EV-A71 encephalomyelitis. Tissues from orally-infected, 2-week-old hamsters were studied by light microscopy, immunohistochemistry and in situ hybridization to detect viral antigens and RNA, respectively, and by virus titration. Hamsters developed the disease and died after 4-8 days post infection; LD50 was 25 CCID50. Macroscopic cutaneous lesions around the oral cavity and paws were observed. Squamous epithelium in the lip, oral cavity, paw, skin, and esophagus, showed multiple small inflammatory foci around squamous cells that demonstrated viral antigens/RNA. Neurons (brainstem, spinal cord, sensory ganglia), acinar cells (salivary gland, lacrimal gland), lymphoid cells (lymph node, spleen), and muscle fibres (skeletal, cardiac and smooth muscles), liver and gastric epithelium also showed varying amounts of viral antigens/RNA. Intestinal epithelium, Peyer's patches, thymus, pancreas, lung and kidney were negative. Virus was isolated from oral washes, feces, brain, spinal cord, skeletal muscle, serum, and other tissues. Our animal model should be useful to study squamous epitheliotropism, neuropathogenesis, oral/fecal shedding in EV-A71 infection, person-to-person transmission, and to test anti-viral drugs and vaccines.

  9. A Consistent Orally-Infected Hamster Model for Enterovirus A71 Encephalomyelitis Demonstrates Squamous Lesions in the Paws, Skin and Oral Cavity Reminiscent of Hand-Foot-and-Mouth Disease.

    PubMed

    Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

    2016-01-01

    Enterovirus A71 (EV-A71) causes self-limiting, hand-foot-and-mouth disease (HFMD) that may rarely be complicated by encephalomyelitis. Person-to-person transmission is usually by fecal-oral or oral-oral routes. To study viral replication sites in the oral cavity and other tissues, and to gain further insights into virus shedding and neuropathogenesis, we developed a consistent, orally-infected, 2-week-old hamster model of HFMD and EV-A71 encephalomyelitis. Tissues from orally-infected, 2-week-old hamsters were studied by light microscopy, immunohistochemistry and in situ hybridization to detect viral antigens and RNA, respectively, and by virus titration. Hamsters developed the disease and died after 4-8 days post infection; LD50 was 25 CCID50. Macroscopic cutaneous lesions around the oral cavity and paws were observed. Squamous epithelium in the lip, oral cavity, paw, skin, and esophagus, showed multiple small inflammatory foci around squamous cells that demonstrated viral antigens/RNA. Neurons (brainstem, spinal cord, sensory ganglia), acinar cells (salivary gland, lacrimal gland), lymphoid cells (lymph node, spleen), and muscle fibres (skeletal, cardiac and smooth muscles), liver and gastric epithelium also showed varying amounts of viral antigens/RNA. Intestinal epithelium, Peyer's patches, thymus, pancreas, lung and kidney were negative. Virus was isolated from oral washes, feces, brain, spinal cord, skeletal muscle, serum, and other tissues. Our animal model should be useful to study squamous epitheliotropism, neuropathogenesis, oral/fecal shedding in EV-A71 infection, person-to-person transmission, and to test anti-viral drugs and vaccines. PMID:26815859

  10. A Consistent Orally-Infected Hamster Model for Enterovirus A71 Encephalomyelitis Demonstrates Squamous Lesions in the Paws, Skin and Oral Cavity Reminiscent of Hand-Foot-and-Mouth Disease

    PubMed Central

    Phyu, Win Kyaw; Ong, Kien Chai; Wong, Kum Thong

    2016-01-01

    Enterovirus A71 (EV-A71) causes self-limiting, hand-foot-and-mouth disease (HFMD) that may rarely be complicated by encephalomyelitis. Person-to-person transmission is usually by fecal-oral or oral-oral routes. To study viral replication sites in the oral cavity and other tissues, and to gain further insights into virus shedding and neuropathogenesis, we developed a consistent, orally-infected, 2-week-old hamster model of HFMD and EV-A71 encephalomyelitis. Tissues from orally-infected, 2-week-old hamsters were studied by light microscopy, immunohistochemistry and in situ hybridization to detect viral antigens and RNA, respectively, and by virus titration. Hamsters developed the disease and died after 4–8 days post infection; LD50 was 25 CCID50. Macroscopic cutaneous lesions around the oral cavity and paws were observed. Squamous epithelium in the lip, oral cavity, paw, skin, and esophagus, showed multiple small inflammatory foci around squamous cells that demonstrated viral antigens/RNA. Neurons (brainstem, spinal cord, sensory ganglia), acinar cells (salivary gland, lacrimal gland), lymphoid cells (lymph node, spleen), and muscle fibres (skeletal, cardiac and smooth muscles), liver and gastric epithelium also showed varying amounts of viral antigens/RNA. Intestinal epithelium, Peyer’s patches, thymus, pancreas, lung and kidney were negative. Virus was isolated from oral washes, feces, brain, spinal cord, skeletal muscle, serum, and other tissues. Our animal model should be useful to study squamous epitheliotropism, neuropathogenesis, oral/fecal shedding in EV-A71 infection, person-to-person transmission, and to test anti-viral drugs and vaccines. PMID:26815859

  11. Solubilization of glycoproteins of envelope viruses by detergents

    SciTech Connect

    Berezin, V.E.; Zaides, V.M.; Artamsnov, A.F.; Isaeva, E.S.; Zhdanov, V.M.

    1986-11-20

    The action of a number of known ionic and nonionic detergents, as well as the new nonionic detergent MESK, on envelope viruses was investigated. It was shown that the nonionic detergents MESK, Triton X-100, and octyl-..beta..-D-glucopyranoside selectively solubilize the outer glycoproteins of the virus particles. The nonionic detergent MESK has the mildest action. Using MESK, purified glycoproteins of influenza, parainfluenza, Venezuelan equine encephalomyelitis, vesicular stomatitis, rabies, and herpes viruses were obtained. The procedure for obtaining glycoproteins includes incubation of the virus suspension with the detergent MESK, removal of subvirus structures by centrifuging, and purification of glycoproteins from detergents by dialysis. Isolated glycoproteins retain a native structure and biological activity and possess high immunogenicity. The detergent MESK is promising for laboratory tests and with respect to the production of subunit vaccines.

  12. Carbon nanospheres mediated delivery of nuclear matrix protein SMAR1 to direct experimental autoimmune encephalomyelitis in mice

    PubMed Central

    Chemmannur, Sijo V; Bhagat, Prasad; Mirlekar, Bhalchandra; Paknikar, Kishore M; Chattopadhyay, Samit

    2016-01-01

    Owing to the suppression of immune responses and associated side effects, steroid based treatments for inflammatory encephalitis disease can be detrimental. Here, we demonstrate a novel carbon nanosphere (CNP) based treatment regime for encephalomyelitis in mice by exploiting the functional property of the nuclear matrix binding protein SMAR1. A truncated part of SMAR1 ie, the DNA binding domain was conjugated with hydrothermally synthesized CNPs. When administered intravenously, the conjugate suppressed experimental animal encephalomyelitis in T cell specific conditional SMAR1 knockout mice (SMAR−/−). Further, CNP-SMAR1 conjugate delayed the onset of the disease and reduced the demyelination significantly. There was a significant decrease in the production of IL-17 after re-stimulation with MOG. Altogether, our findings suggest a potential carbon nanomaterial based therapeutic intervention to combat Th17 mediated autoimmune diseases including experimental autoimmune encephalomyelitis. PMID:27274234

  13. Molecular cloning of the complete genome of strain GDVII of Theiler's virus and production of infectious transcripts.

    PubMed Central

    Tangy, F; McAllister, A; Brahic, M

    1989-01-01

    We constructed a complete cDNA clone of strain GDVII of Theiler's virus in Bluescript plasmid. This recombinant plasmid, called pTMGDVII, was used to synthesize full-length RNA transcripts of the viral insert. This RNA was infectious for BHK cells. Virus R1-GDVII, obtained from transfected BHK cells, caused rapidly fatal encephalomyelitis in BALB/c mice. High amounts of viral antigens were present in neurons. No antigens were found in white matter. Therefore, the phenotype of R1-GDVII was indistinguishable from that of genuine GDVII Theiler's virus. Images PMID:2536823

  14. Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection.

    PubMed Central

    Dal Canto, M. C.; Lipton, H. L.

    1982-01-01

    Mice experimentally infected with Theiler's murine encephalomyelitis virus (TMEV) develop a persistent infection of the central nervous system (CNS). The most striking feature of this infection is the occurrence of inflammatory primary demyelination in the spinal cord white matter. The pathogenesis of myelin degeneration in this model has not been clarified, but morphologic and immunologic data suggest that the host immune response plays a major role in the production of myelin injury. Because of low virus titers in infected adult mice and of the small size of TMEV, virus particles have never been observed in this demyelinating model. Yet elucidation of the types of cells in the CNS supporting virus replication would be important for a better understanding of both virus persistence and virus-induced demyelinating pathology. The present paper is a sequential study of the localization of TMEV in the spinal cord in infected mice by ultrastructural immunohistochemical techniques. Results indicate that virus replication is mainly in neurons during the acute phase of the disease, while in the chronic phase viral inclusions are mainly found in macrophages in and around demyelinating lesions. Other cells are also infected, but to a lesser degree. In the neuronal system both axoplasmic and dendritic flow appear to facilitate the spread of virus in the CNS. In macrophages, the presence of virus particles and the association of virus with altered components of the cytoskeleton support active virus production rather than simple internalization. The macrophage appears to play an important role in both the establishment of virus persistence and in the process of demyelination in this animal model. Images Figure 1 and 2 Figure 3 and 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10-12 Figure 13 Figure 14 Figure 15 and 16 PMID:6275708

  15. Ultrastructural immunohistochemical localization of virus in acute and chronic demyelinating Theiler's virus infection.

    PubMed

    Dal Canto, M C; Lipton, H L

    1982-01-01

    Mice experimentally infected with Theiler's murine encephalomyelitis virus (TMEV) develop a persistent infection of the central nervous system (CNS). The most striking feature of this infection is the occurrence of inflammatory primary demyelination in the spinal cord white matter. The pathogenesis of myelin degeneration in this model has not been clarified, but morphologic and immunologic data suggest that the host immune response plays a major role in the production of myelin injury. Because of low virus titers in infected adult mice and of the small size of TMEV, virus particles have never been observed in this demyelinating model. Yet elucidation of the types of cells in the CNS supporting virus replication would be important for a better understanding of both virus persistence and virus-induced demyelinating pathology. The present paper is a sequential study of the localization of TMEV in the spinal cord in infected mice by ultrastructural immunohistochemical techniques. Results indicate that virus replication is mainly in neurons during the acute phase of the disease, while in the chronic phase viral inclusions are mainly found in macrophages in and around demyelinating lesions. Other cells are also infected, but to a lesser degree. In the neuronal system both axoplasmic and dendritic flow appear to facilitate the spread of virus in the CNS. In macrophages, the presence of virus particles and the association of virus with altered components of the cytoskeleton support active virus production rather than simple internalization. The macrophage appears to play an important role in both the establishment of virus persistence and in the process of demyelination in this animal model.

  16. Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics

    PubMed Central

    2013-01-01

    Background ‘Encephalomyelitis disseminata’ (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS. Discussion There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels. Summary This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to

  17. New type of encephalomyelitis responsive to trimethoprim/sulfamethoxazole treatment in Japan

    PubMed Central

    Sakiyama, Yusuke; Kanda, Naoaki; Higuchi, Yujiro; Yoshimura, Michiyoshi; Wakaguri, Hiroyuki; Takata, Yoshiharu; Watanabe, Osamu; Yuan, Junhui; Tashiro, Yuichi; Saigo, Ryuji; Nozuma, Satoshi; Yoshimura, Akiko; Arishima, Shiho; Ikeda, Kenichi; Shinohara, Kazuya; Arata, Hitoshi; Michizono, Kumiko; Higashi, Keiko; Hashiguchi, Akihiro; Okamoto, Yuji; Hirano, Ryuki; Shiraishi, Tadafumi; Matsuura, Eiji; Okubo, Ryuichi; Higuchi, Itsuro; Goto, Masamichi; Hirano, Hirofumi; Sano, Akira; Iwasaki, Takuya; Matsuda, Fumihiko; Izumo, Shuji

    2015-01-01

    Objective: To determine the causative pathogen and investigate the effective treatment of a new type of encephalomyelitis with an unknown pathogen in Japan and report the preliminary ultrastructural and genomic characterization of the causative agent. Methods: From 2005 to 2012, we treated 4 Japanese patients with geographic clustering and comparable clinical features, serum/CSF cytology, and radiologic findings. Brain biopsy was conducted in all patients to analyze neuropathologic changes by histology, and electron microscopy was applied to reveal the features of the putative pathogen. Genomic DNA was obtained from the affected brain tissues and CSF, and an unbiased high-throughput sequencing approach was used to screen for specific genomic sequences indicative of the pathogen origin. Results: All patients exhibited progressive dementia with involuntary tongue movements. Cytologic examination of CSF revealed elevated mononuclear cells. Abnormal MRI signals were observed in temporal lobes, subcortical white matter, and spinal cord. Biopsied brain tissue exhibited aggregated periodic acid-Schiff–positive macrophages and 2–7 μm diameter round/oval bodies without nuclei or cell walls scattered around the vessels. Unbiased high-throughput sequencing identified more than 100 archaea-specific DNA fragments. All patients were responsive to trimethoprim/sulfamethoxazole (TMP-SMX) plus corticosteroid therapy. Conclusions: We report 4 cases of encephalomyelitis due to an unknown pathogen. On the basis of ultrastructural and genomic studies, we propose a new disease entity resulting from a causative pathogen having archaeal features. TMP-SMX therapy was effective against this new type of encephalomyelitis. PMID:26309903

  18. The complement inhibitor FUT-175 suppresses T cell autoreactivity in experimental autoimmune encephalomyelitis.

    PubMed

    Li, Qing; Nacion, Kristine; Bu, Hong; Lin, Feng

    2009-08-01

    Several recent studies have shown that interacting antigen presenting cells and/or T cells produced complement activation products C5a and C3a, are integrally involved in T-cell activation, and promote the generation of myelin oligodendrocyte glycoprotein (MOG(35-55))-specific interferon-gamma and interleukin-17-producing T cells in experimental autoimmune encephalomyelitis, a rodent model of multiple sclerosis. In this study, we tested whether FUT-175, a clinical pharmaceutical that has been shown to inhibit the formation of C3/C5 convertases, can attenuate myelin-specific T-cell responses, as well as disease severity in experimental autoimmune encephalomyelitis. In vitro, FUT-175 inhibited local C5a/C3a production by antigen presenting cell-T-cell complexes and attenuated MOG(35-55)-specific Th1 and Th17 responses with little nonspecific cytotoxicity. In vivo administration of FUT-175 delayed experimental autoimmune encephalomyelitis disease onset, lowered clinical scores, decreased central nervous system inflammation, and reduced demyelination. The FUT-175-treated mice exhibited decreased numbers of MOG(35-55)-specific interferon-gamma- and interleukin-17-producing T cells. In addition, results from the FUT-175 treatment of naive recipients of adoptively transferred splenocytes from MOG(35-55)-immunized mice suggested that the effect of FUT-175 was on MOG-specific cellular responses and not on anti-MOG antibodies. These results argue that complement regulators, which inhibit C5a/C3a production, may have therapeutic efficacy in multiple sclerosis and in other clinical conditions in which T cells drive disease pathogenesis. PMID:19608865

  19. Development of human antibody fragments using antibody phage display for the detection and diagnosis of Venezuelan equine encephalitis virus (VEEV)

    PubMed Central

    Kirsch, Martina Inga; Hülseweh, Birgit; Nacke, Christoph; Rülker, Torsten; Schirrmann, Thomas; Marschall, Hans-Jürgen; Hust, Michael; Dübel, Stefan

    2008-01-01

    Background Venezuelan equine encephalitis virus (VEEV) belongs to the Alphavirus group. Several species of this family are also pathogenic to humans and are recognized as potential agents of biological warfare and terrorism. The objective of this work was the generation of recombinant antibodies for the detection of VEEV after a potential bioterrorism assault or an natural outbreak of VEEV. Results In this work, human anti-VEEV single chain Fragments variable (scFv) were isolated for the first time from a human naïve antibody gene library using optimized selection processes. In total eleven different scFvs were identified and their immunological specificity was assessed. The specific detection of the VEEV strains TC83, H12/93 and 230 by the selected antibody fragments was proved. Active as well as formalin inactivated virus particles were recognized by the selected antibody fragments which could be also used for Western blot analysis of VEEV proteins and immunohistochemistry of VEEV infected cells. The anti-VEEV scFv phage clones did not show any cross-reactivity with Alphavirus species of the Western equine encephalitis virus (WEEV) and Eastern equine encephalitis virus (EEEV) antigenic complex, nor did they react with Chikungunya virus (CHIKV), if they were used as detection reagent. Conclusion For the first time, this study describes the selection of antibodies against a human pathogenic virus from a human naïve scFv antibody gene library using complete, active virus particles as antigen. The broad and sensitive applicability of scFv-presenting phage for the immunological detection and diagnosis of Alphavirus species was demonstrated. The selected antibody fragments will improve the fast identification of VEEV in case of a biological warfare or terroristic attack or a natural outbreak. PMID:18764933

  20. Lethal acute demyelinization with encephalo-myelitis as a complication of cured Cushing's disease.

    PubMed

    Chevalier, N; Hieronimus, S; Vandenbos, F; Delmont, E; Cua, E; Cherick, F; Paquis, P; Michiels, J-F; Fenichel, P; Brucker-Davis, F

    2010-12-01

    Cushing's disease is usually associated with higher mortality rate, especially from cardiovascular causes. Development or exacerbation of autoimmune or inflammatory diseases is known to occur in patients with hypercortisolism after cure. We report for the first time a 34-year old woman with a psychiatric background, who developed four months after the surgical cure of Cushing's disease an acute disseminated encephalomyelitis (ADEM) presenting initially as a psychiatric illness. We hypothesize that the recent correction of hypercortisolism triggered ADEM and that the atypical presentation, responsible for diagnosis delay, led to the death of this patient. PMID:20850107

  1. Total glucosides of peony attenuates experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Huang, Qiling; Ma, Xiaomeng; Zhu, Dong Liang; Chen, Li; Jiang, Ying; Zhou, Linli; Cen, Lei; Pi, Rongbiao; Chen, Xiaohong

    2015-07-15

    Total glucosides of peony (TGP), an active compound extracted from the roots of Paeonia lactiflora Pall, has wide pharmacological effects on nervous system. Here we examined the effects of TGP on experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). The results showed that TGP can reduce the severity and progression of EAE in C57 BL/6 mice. In addition, TGP also down-regulated the Th1/Th17 inflammatory response and prevented the reduced expression of brain-derived neurotrophic factor and 2',3'-cyclic nucleotide 3'-phosphodiesterase of EAE. These findings suggest that TGP could be a potential therapeutic agent for MS.

  2. Effects of exercise in experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis)

    PubMed Central

    Klaren, Rachel E.; Motl, Robert W.; Woods, Jeffrey A.; Miller, Stephen D.

    2015-01-01

    Exercise training has improved many outcomes in “clinical” research involving persons with multiple sclerosis (MS), but there is limited understanding of the underlying “basic” pathophysiological mechanisms. The animal model of MS, experimental autoimmune encephalomyelitis (EAE), seems ideal for examining the effects of exercise training on MS-disease pathophysiology. EAE is an autoimmune T-helper cell-mediated disease characterized by T-cell and monocyte infiltration and inflammation in the CNS. To that end, this paper briefly describes common models of EAE, reviews existing research on exercise and EAE, and then identifies future research directions for understanding the consequences of exercise training using EAE. PMID:24999244

  3. A monoclonal antibody to alpha 4 integrin suppresses and reverses active experimental allergic encephalomyelitis.

    PubMed

    Kent, S J; Karlik, S J; Cannon, C; Hines, D K; Yednock, T A; Fritz, L C; Horner, H C

    1995-04-01

    In experimental allergic encephalomyelitis (EAE), circulating leukocytes enter the central nervous system (CNS) producing inflammation, myelin damage and paralysis. Prevention of leukocyte infiltration by an antibody against alpha 4 integrin suppressed clinical and pathological features of EAE in the guinea pig. Rapid clearance of leukocytes from the CNS and reversal of clinical findings were observed when anti-alpha 4 treatment was administered during active disease. Clinical improvement was accompanied by a marked decrease in abnormal pathological findings, including demyelination. Therefore anti-alpha 4 is an effective treatment of EAE and may be similarly useful in the treatment of autoimmune diseases such as multiple sclerosis.

  4. Teriflunomide attenuates immunopathological changes in the dark agouti rat model of experimental autoimmune encephalomyelitis.

    PubMed

    Ringheim, Garth E; Lee, Lan; Laws-Ricker, Lynn; Delohery, Tomas; Liu, Li; Zhang, Donghui; Colletti, Nicholas; Soos, Timothy J; Schroeder, Kendra; Fanelli, Barbara; Tian, Nian; Arendt, Christopher W; Iglesias-Bregna, Deborah; Petty, Margaret; Ji, Zhongqi; Qian, George; Gaur, Rajula; Weinstock, Daniel; Cavallo, Jean; Telsinskas, Juventas; McMonagle-Strucko, Kathleen

    2013-01-01

    Teriflunomide is an oral disease-modifying therapy recently approved in several locations for relapsing-remitting multiple sclerosis. To gain insight into the effects of teriflunomide, immunocyte population changes were measured during progression of experimental autoimmune encephalomyelitis in Dark Agouti rats. Treatment with teriflunomide attenuated levels of spinal cord-infiltrating T cells, natural killer cells, macrophages, and neutrophils. Teriflunomide also mitigated the disease-induced changes in immune cell populations in the blood and spleen suggesting an inhibitory effect on pathogenic immune responses. PMID:24198809

  5. Role of CD8^+ T Cells in Murine Experimental Allergic Encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Jiang, Hong; Zhang, Sheng-Le; Pernis, Benvenuto

    1992-05-01

    The course of experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis, is affected by immunoregulatory T lymphocytes. When animals are immunized with encephalitogenic peptide of myelin basic protein and recover from the first episode of EAE, they become resistant to a second induction of this disease. Animals depleted of CD8^+ T cells by antibody-mediated clearance were used to examine the role of CD8^+ T cells in EAE. These cells were found to be major participants in the resistance to a second induction of EAE but were not essential for spontaneous recovery from the first episode of the disease.

  6. Total glucosides of peony attenuates experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Huang, Qiling; Ma, Xiaomeng; Zhu, Dong Liang; Chen, Li; Jiang, Ying; Zhou, Linli; Cen, Lei; Pi, Rongbiao; Chen, Xiaohong

    2015-07-15

    Total glucosides of peony (TGP), an active compound extracted from the roots of Paeonia lactiflora Pall, has wide pharmacological effects on nervous system. Here we examined the effects of TGP on experimental autoimmune encephalomyelitis (EAE), an established model of multiple sclerosis (MS). The results showed that TGP can reduce the severity and progression of EAE in C57 BL/6 mice. In addition, TGP also down-regulated the Th1/Th17 inflammatory response and prevented the reduced expression of brain-derived neurotrophic factor and 2',3'-cyclic nucleotide 3'-phosphodiesterase of EAE. These findings suggest that TGP could be a potential therapeutic agent for MS. PMID:26025060

  7. Distribution of eastern equine encephalomyelitis viral protein and nucleic acid within central nervous tissue lesions in white-tailed deer (Odocoileus virginianus).

    PubMed

    Kiupel, M; Fitzgerald, S D; Pennick, K E; Cooley, T M; O'Brien, D J; Bolin, S R; Maes, R K; Del Piero, F

    2013-11-01

    An outbreak of eastern equine encephalomyelitis (EEE) occurred in Michigan free-ranging white-tailed deer (Odocoileus virginianus) during late summer and fall of 2005. Brain tissue from 7 deer with EEE, as confirmed by reverse transcriptase polymerase chain reaction, was studied. Detailed microscopic examination, indirect immunohistochemistry (IHC), and in situ hybridization (ISH) were used to characterize the lesions and distribution of the EEE virus within the brain. The main lesion in all 7 deer was a polioencephalomyelitis with leptomeningitis, which was more prominent within the cerebral cortex, thalamus, hypothalamus, and brainstem. In 3 deer, multifocal microhemorrhages surrounded smaller vessels with or without perivascular cuffing, although vasculitis was not observed. Neuronal necrosis, associated with perineuronal satellitosis and neutrophilic neuronophagia, was most prominent in the thalamus and the brainstem. Positive IHC labeling was mainly observed in the perikaryon, axons, and dendrites of necrotic and intact neurons and, to a much lesser degree, in glial cells, a few neutrophils in the thalamus and the brainstem, and occasionally the cerebral cortex of the 7 deer. There was minimal IHC-based labeling in the cerebellum and hippocampus. ISH labeling was exclusively observed in the cytoplasm of neurons, with a distribution similar to IHC-positive neurons. Neurons positive by IHC and ISH were most prominent in the thalamus and brainstem. The neuropathology of EEE in deer is compared with other species. Based on our findings, EEE has to be considered a differential diagnosis for neurologic disease and meningoencephalitis in white-tailed deer.

  8. The Ubiquitin Proteasome System Plays a Role in Venezuelan Equine Encephalitis Virus Infection

    PubMed Central

    Amaya, Moushimi; Keck, Forrest; Lindquist, Michael; Voss, Kelsey; Scavone, Lauren; Kehn-Hall, Kylene; Roberts, Brian; Bailey, Charles; Schmaljohn, Connie; Narayanan, Aarthi

    2015-01-01

    Many viruses have been implicated in utilizing or modulating the Ubiquitin Proteasome System (UPS) to enhance viral multiplication and/or to sustain a persistent infection. The mosquito-borne Venezuelan equine encephalitis virus (VEEV) belongs to the Togaviridae family and is an important biodefense pathogen and select agent. There are currently no approved vaccines or therapies for VEEV infections; therefore, it is imperative to identify novel targets for therapeutic development. We hypothesized that a functional UPS is required for efficient VEEV multiplication. We have shown that at non-toxic concentrations Bortezomib, a FDA-approved inhibitor of the proteasome, proved to be a potent inhibitor of VEEV multiplication in the human astrocytoma cell line U87MG. Bortezomib inhibited the virulent Trinidad donkey (TrD) strain and the attenuated TC-83 strain of VEEV. Additional studies with virulent strains of Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV) demonstrated that Bortezomib is a broad spectrum inhibitor of the New World alphaviruses. Time-of-addition assays showed that Bortezomib was an effective inhibitor of viral multiplication even when the drug was introduced many hours post exposure to the virus. Mass spectrometry analyses indicated that the VEEV capsid protein is ubiquitinated in infected cells, which was validated by confocal microscopy and immunoprecipitation assays. Subsequent studies revealed that capsid is ubiquitinated on K48 during early stages of infection which was affected by Bortezomib treatment. This study will aid future investigations in identifying host proteins as potential broad spectrum therapeutic targets for treating alphavirus infections. PMID:25927990

  9. Experimental models of virus-induced demyelination of the central nervous system.

    PubMed

    Dal Canto, M C; Rabinowitz, S G

    1982-02-01

    One of the arguments in favor of a viral pathogenesis for multiple sclerosis is the existence of several experimental and natural animal models of virus-induced primary demyelination. This review deals comprehensively with such models. Well-known examples of demyelinating viral infections in their natural host are JHM, Theiler, visna, and canine distemper encephalomyelitides. Recent reports of experimental murine infections with pathogens such as vesicular stomatitis, Chandipura, herpes simplex, Venezuelan equine encephalomyelitis, and Semliki Forest viruses are also discussed. The thrust of the review is to include viral models suspected of producing primary demyelination on an immunopathological basis.

  10. Chikungunya virus infection amongst the acute encephalitis syndrome cases in West Bengal, India.

    PubMed

    Taraphdar, D; Roy, B K; Chatterjee, S

    2015-02-01

    Chikungunya virus (CHIKV) infection from the acute encephalitis syndrome cases is an uncommon form and has been observed in the year 2010-11 from West Bengal, India. The case-1 and case-2 had the acute encephalitis syndrome; case-3 was of acute disseminated encephalomyelitis whereas the case-4 had the symptoms of meningo-encephalopathy with bulbar involvement. We are reporting four cases with neurological complications involving central nervous system (CNS) due to CHIKV infection from this state for the first time. The virus has spread almost every districts of this state rapidly. At this stage, these cases are public health threat.

  11. In vivo administration of interleukin-2 protects susceptible mice from Theiler's virus persistence.

    PubMed Central

    Larsson-Sciard, E L; Dethlefs, S; Brahic, M

    1997-01-01

    In vivo administration of interleukin-2 (IL-2)-secreting tumor cells results in complete protection against persistent infection by Theiler's murine encephalomyelitis virus (TMEV) in susceptible DBA/2 mice. The IL-2-mediated protection was found to depend on the inoculum size as well as the timing of IL-2 administration. IL-2-treated and TMEV-infected mice displayed a three- to fourfold relative increase in virus-specific cytotoxic T-lymphocyte (CTL) precursors. Thus, we postulate that the persistence of TMEV infection in susceptible mice reflects limited numbers of relevant CTL precursors and their time course of induction and activation. PMID:8985419

  12. Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant.

    PubMed

    Zurbriggen, A; Yamada, M; Thomas, C; Fujinami, R S

    1991-02-01

    The Daniels strain of Theiler's murine encephalomyelitis produces a chronic disease which is an animal model for human demyelinating disorders. Previously, we selected a neutralization-resistant virus variant producing an altered and diminished central nervous system disease in immunocompetent mice which was evident during the later stage of infection (after 4 weeks) (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). The exact epitope determining neurovirulence was precisely mapped to a capsid protein, VP-1, and represents a neutralizing region (A. Zurbriggen, J. M. Hogle, and R. S. Fujinami, J. Exp. Med. 170:2037-2049, 1989). Here, we present experiments with immunoincompetent animals to determine viral replication, spread, and targeting to the central nervous system in the absence of detectable antibodies or functional T cells. Nude mice were infected orally, and the virus was monitored by plaque assay, immunohistochemistry, and in situ hybridization. Early during the infection (1 week), the variant virus induced an acute disease comparable to that induced by the wild-type virus in these nude mice. Alterations in tropism in the central nervous system were not apparent when wild-type parental Daniels strain virus was compared with the variant virus. Moreover, variant virus replicated in tissue culture (BHK-21 cells) to similarly high titers in a time course identical to that of the wild-type virus (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). However, replication of the variant virus versus the wild-type virus within the spinal cord of athymic nude mice infected per os was substantially restricted by 6 weeks postinfection. Therefore, the reduced neurovirulence in the later stage (6 weeks) of the disease is most likely due to a diminished growth rate or spread of the variant virus in the central nervous system rather than to marked differences in viral tropism.

  13. Restricted virus replication in the spinal cords of nude mice infected with a Theiler's virus variant.

    PubMed Central

    Zurbriggen, A; Yamada, M; Thomas, C; Fujinami, R S

    1991-01-01

    The Daniels strain of Theiler's murine encephalomyelitis produces a chronic disease which is an animal model for human demyelinating disorders. Previously, we selected a neutralization-resistant virus variant producing an altered and diminished central nervous system disease in immunocompetent mice which was evident during the later stage of infection (after 4 weeks) (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). The exact epitope determining neurovirulence was precisely mapped to a capsid protein, VP-1, and represents a neutralizing region (A. Zurbriggen, J. M. Hogle, and R. S. Fujinami, J. Exp. Med. 170:2037-2049, 1989). Here, we present experiments with immunoincompetent animals to determine viral replication, spread, and targeting to the central nervous system in the absence of detectable antibodies or functional T cells. Nude mice were infected orally, and the virus was monitored by plaque assay, immunohistochemistry, and in situ hybridization. Early during the infection (1 week), the variant virus induced an acute disease comparable to that induced by the wild-type virus in these nude mice. Alterations in tropism in the central nervous system were not apparent when wild-type parental Daniels strain virus was compared with the variant virus. Moreover, variant virus replicated in tissue culture (BHK-21 cells) to similarly high titers in a time course identical to that of the wild-type virus (A. Zurbriggen and R. S. Fujinami, J. Virol. 63:1505-1513, 1989). However, replication of the variant virus versus the wild-type virus within the spinal cord of athymic nude mice infected per os was substantially restricted by 6 weeks postinfection. Therefore, the reduced neurovirulence in the later stage (6 weeks) of the disease is most likely due to a diminished growth rate or spread of the variant virus in the central nervous system rather than to marked differences in viral tropism. Images PMID:1987366

  14. Effects of immunosuppression on encephalitis virus infection in the house finch, Carpodacus mexicanus.

    PubMed

    Reisen, William K; Chiles, Robert E; Green, Emily N; Fang, Ying; Mahmood, Farida; Martinez, Vincent M; Laver, Thomas

    2003-03-01

    Immunosuppression of house finches was attempted by blood feeding Culex tarsalis Coquillett mosquitoes or by injecting birds with the corticosteroid dexamethasone or the immunosuppressant drug cyclophosphamide before and after inoculation with western equine encephalomyelitis or St. Louis encephalitis viruses. Mosquito bites (8-37 females blood feeding on each bird over a 3-d period) did not enhance the viremia response or increase the frequency of chronic infection. In contrast, dexamethasone and cyclophosphamide enhanced the amplitude and duration of the viremia response, but had no consistent effect on the antibody responses as measured by enzyme immunoassay or plaque reduction neutralization assay. Elevated viremias were followed by increases in the frequency of chronic infections with St. Louis encephalitis, but not western equine encephalomyelitis. Immunosuppression may provide a useful tool to study the chronic infection process of flaviviruses in vertebrates. PMID:12693850

  15. Monoclonal anti-I-A antibody reverses chronic paralysis and demyelination in Theiler's virus-infected mice: critical importance of timing of treatment.

    PubMed

    Friedmann, A; Frankel, G; Lorch, Y; Steinman, L

    1987-03-01

    Susceptibility to demyelination caused by the WW isolate of Theiler's murine encephalomyelitis viruses is linked to class II genes of the major histocompatibility complex. SJL/J (H-2s) mice, expressing only I-As class II gene products of the major histocompatibility complex, are highly susceptible to Theiler's murine encephalomyelitis virus infection with the WW virus isolate, with chronic paralysis and severe inflammation and demyelination in the central nervous system. The effect of in vivo administration of anti-I-As monoclonal antibodies on Theiler's murine encephalomyelitis virus infection was observed. SJL/J mice were treated in various protocols pre- or postinfection. Anti-I-As monoclonal antibody reversed chronic paralysis and reduced inflammation and demyelination when given after the establishment of persistent infection. The effect was long lasting, but clinical signs, inflammation, and demyelination recurred 2 months after treatment ceased. Anti-I-As antibodies had no effect on viral titers within the central nervous system. The timing of the administration of monoclonal antibodies was critical. Administration of anti-I-As before the establishment of the persistent infection resulted in fatal encephalitis.

  16. Monoclonal anti-I-A antibody reverses chronic paralysis and demyelination in Theiler's virus-infected mice: critical importance of timing of treatment.

    PubMed Central

    Friedmann, A; Frankel, G; Lorch, Y; Steinman, L

    1987-01-01

    Susceptibility to demyelination caused by the WW isolate of Theiler's murine encephalomyelitis viruses is linked to class II genes of the major histocompatibility complex. SJL/J (H-2s) mice, expressing only I-As class II gene products of the major histocompatibility complex, are highly susceptible to Theiler's murine encephalomyelitis virus infection with the WW virus isolate, with chronic paralysis and severe inflammation and demyelination in the central nervous system. The effect of in vivo administration of anti-I-As monoclonal antibodies on Theiler's murine encephalomyelitis virus infection was observed. SJL/J mice were treated in various protocols pre- or postinfection. Anti-I-As monoclonal antibody reversed chronic paralysis and reduced inflammation and demyelination when given after the establishment of persistent infection. The effect was long lasting, but clinical signs, inflammation, and demyelination recurred 2 months after treatment ceased. Anti-I-As antibodies had no effect on viral titers within the central nervous system. The timing of the administration of monoclonal antibodies was critical. Administration of anti-I-As before the establishment of the persistent infection resulted in fatal encephalitis. Images PMID:3492612

  17. The Brain Proteome of the Ubiquitin Ligase Peli1 Knock-Out Mouse during Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Lereim, Ragnhild Reehorst; Oveland, Eystein; Xiao, Yichuan; Torkildsen, Øivind; Wergeland, Stig; Myhr, Kjell-Morten; Sun, Shao-Cong; Berven, Frode S

    2016-01-01

    The ubiquitin ligase Peli1 has previously been suggested as a potential treatment target in multiple sclerosis. In the multiple sclerosis disease model, experimental autoimmune encephalomyelitis, Peli1 knock-out led to less activated microglia and less inflammation in the central nervous system. Despite being important in microglia, Peli1 expression has also been detected in glial and neuronal cells. In the present study the overall brain proteomes of Peli1 knock-out mice and wild-type mice were compared prior to experimental autoimmune encephalomyelitis induction, at onset of the disease and at disease peak. Brain samples from the frontal hemisphere, peripheral from the extensive inflammatory foci, were analyzed using TMT-labeling of sample pools, and the discovered proteins were verified in individual mice using label-free proteomics. The greatest proteomic differences between Peli1 knock-out and wild-type mice were observed at the disease peak. In Peli1 knock-out a higher degree of antigen presentation, increased activity of adaptive and innate immune cells and alterations to proteins involved in iron metabolism were observed during experimental autoimmune encephalomyelitis. These results unravel global effects to the brain proteome when abrogating Peli1 expression, underlining the importance of Peli1 as a regulator of the immune response also peripheral to inflammatory foci during experimental autoimmune encephalomyelitis. The proteomics data is available in PRIDE with accession PXD003710. PMID:27746629

  18. Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis.

    PubMed

    Bernardes, Danielle; Brambilla, Roberta; Bracchi-Ricard, Valerie; Karmally, Shaffiat; Dellarole, Anna; Carvalho-Tavares, Juliana; Bethea, John R

    2016-01-01

    Although previous studies have shown that forced exercise modulates inflammation and is therapeutic acutely for experimental autoimmune encephalomyelitis (EAE), the long-term benefits have not been evaluated. In this study, we investigated the effects of preconditioning exercise on the clinical and pathological progression of EAE. Female C57BL/6 mice were randomly assigned to either an exercised (Ex) or unexercised (UEx) group and all of them were induced for EAE. Mice in the Ex group had an attenuated clinical score relative to UEx mice throughout the study. At 42 dpi, flow cytometry analysis showed a significant reduction in B cells, CD4(+) T cells, and CD8(+) T cells infiltrating into the spinal cord in the Ex group compared to UEx. Ex mice also had a significant reduction in myelin damage with a corresponding increase in proteolipid protein expression. Finally, Ex mice had a significant reduction in axonal damage. Collectively, our study demonstrates for the first time that a prolonged and forced preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease. In this study, we show that a program of 6 weeks of preconditioning exercise promoted a significant reduction of cells infiltrating into the spinal cord, a significant reduction in myelin damage and a significant reduction in axonal damage in experimental autoimmune encephalomyelitis (EAE) mice at 42 dpi. Collectively, our study demonstrates for the first time that a preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease.

  19. Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis*

    PubMed Central

    Kurnellas, Michael P.; Brownell, Sara E.; Su, Leon; Malkovskiy, Andrey V.; Rajadas, Jayakumar; Dolganov, Gregory; Chopra, Sidharth; Schoolnik, Gary K.; Sobel, Raymond A.; Webster, Jonathan; Ousman, Shalina S.; Becker, Rachel A.; Steinman, Lawrence; Rothbard, Jonathan B.

    2012-01-01

    To determine whether the therapeutic activity of αB crystallin, small heat shock protein B5 (HspB5), was shared with other human sHsps, a set of seven human family members, a mutant of HspB5 G120 known to exhibit reduced chaperone activity, and a mycobacterial sHsp were expressed and purified from bacteria. Each of the recombinant proteins was shown to be a functional chaperone, capable of inhibiting aggregation of denatured insulin with varying efficiency. When injected into mice at the peak of disease, they were all effective in reducing the paralysis in experimental autoimmune encephalomyelitis. Additional structure activity correlations between chaperone activity and therapeutic function were established when linear regions within HspB5 were examined. A single region, corresponding to residues 73–92 of HspB5, forms amyloid fibrils, exhibited chaperone activity, and was an effective therapeutic for encephalomyelitis. The linkage of the three activities was further established by demonstrating individual substitutions of critical hydrophobic amino acids in the peptide resulted in the loss of all of the functions. PMID:22955287

  20. Anti-Hu--associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients.

    PubMed

    Dalmau, J; Graus, F; Rosenblum, M K; Posner, J B

    1992-03-01

    We studied 71 patients with "paraneoplastic" encephalomyelitis, sensory neuronopathy, or both associated with the presence of the anti-Hu antibody in their serum. Most (78%) had small-cell lung cancer. In 9 patients no tumor was detected. Fifty-two patients (73%) had signs and symptoms of multifocal involvement of the nervous system; in 28 (39%), 2 areas, and in 24 (34%), 3 or more areas were clinically affected. Sensory neuronopathy was present in 52 patients (74%), but in only 44 (62%) did it dominate the course of the disease. Other predominant findings were: motor neuron dysfunction (14 patients, 20%), limbic encephalopathy (14, 20%), cerebellar symptoms (11, 15%), brainstem encephalopathy (10, 14%), and autonomic nervous system dysfunction (7, 10%). The presence of the anti-Hu antibody prompted a search for the tumor in 60% of the patients; the tumor when found was usually small and remained localized until death, or was demonstrated only at autopsy. Treatment using steroids and plasmapheresis, immunosuppressants, or both, did not improve the paraneoplastic symptoms. Autonomic and respiratory failure, either of central origin or secondary to neuromuscular weakness, were the principal causes of death. Patients with rapidly developing sensory neuropathy or symptoms of encephalomyelitis should be studied for the presence of the anti-Hu antibody; if the antibody is found, the possibility of small-cell lung cancer should be investigated. If a tumor is not found in the initial search, one may become evident in several months. PMID:1312211

  1. Von-Willebrand Factor Influences Blood Brain Barrier Permeability and Brain Inflammation in Experimental Allergic Encephalomyelitis

    PubMed Central

    Noubade, Rajkumar; del Rio, Roxana; McElvany, Benjamin; Zachary, James F.; Millward, Jason M.; Wagner, Denisa D.; Offner, Halina; Blankenhorn, Elizabeth P.; Teuscher, Cory

    2008-01-01

    Weibel-Palade bodies within endothelial cells are secretory granules known to release von Willebrand Factor (VWF), P-selectin, chemokines, and other stored molecules following histamine exposure. Mice with a disrupted VWF gene (VWFKO) have endothelial cells that are deficient in Weibel-Palade bodies. These mice were used to evaluate the role of VWF and/or Weibel-Palade bodies in Bordetella pertussis toxin-induced hypersensitivity to histamine, a subphenotype of experimental allergic encephalomyelitis, the principal autoimmune model of multiple sclerosis. No significant differences in susceptibility to histamine between wild-type and VWFKO mice were detected after 3 days; however, histamine sensitivity persisted significantly longer in VWFKO mice. Correspondingly, encephalomyelitis onset was earlier, disease was more severe, and blood brain barrier (BBB) permeability was significantly increased in VWFKO mice, as compared with wild-type mice. Moreover, inflammation was selectively increased in the brains, but not spinal cords, of VWFKO mice as compared with wild-type mice. Early increases in BBB permeability in VWFKO mice were not due to increased encephalitogenic T-cell activity since BBB permeability did not differ in adjuvant-treated VWFKO mice as compared with littermates immunized with encephalitogenic peptide plus adjuvant. Taken together, these data indicate that VWF and/or Weibel-Palade bodies negatively regulate BBB permeability changes and autoimmune inflammatory lesion formation within the brain elicited by peripheral inflammatory stimuli. PMID:18688020

  2. Location and distribution of virus antigen in the central nervous system of mice persistently infected with Theiler's virus.

    PubMed

    Sethi, P; Lipton, H L

    1983-02-01

    The present study has shown that virus can be readily detected by immunofluorescent staining in the central nervous system (CNS) of SJL mice persistently infected with Theiler's murine encephalomyelitis virus (TMEV). Considering the low CNS virus content, large amounts of virus antigen were found in the white matter, the site of demyelinating lesions. Virus antigen was detected in all animals killed after post-infection (PI) Day 21, a time which can be considered as the beginning of the persistent phase of this infection, and the appearance of virus antigen in white matter corresponded closely in time with the onset of demyelination. The pathogensis of this persistent infection can now be reasonably well reconstructed from the temporal observations made in this study. It would appear that between the second and third week PI, virus replication largely shifts from neurons in spinal cord gray matter to other cell types located in white matter. While a lower-grade persistent infection (in terms of the relative number of cells containing virus antigen) is established and maintained in cells in the gray matter and inflammatory and leptomeningeal infiltrates, cells in white matter appear to be mainly responsible for perpetuating the infection. Why these cells should supplant neurons as the most susceptible host cell during the chronic phase of the infection is discussed.

  3. Theiler's virus infection in nude mice: viral RNA in vascular endothelial cells.

    PubMed Central

    Zurbriggen, A; Fujinami, R S

    1988-01-01

    Infection of athymic (nu/nu) mice with Theiler's murine encephalomyelitis virus results in an acute encephalitis which resembles poliomyelitis. Immunohistochemistry and in situ hybridization were used to delineate the presence of viral proteins and RNA in the nervous systems of nude mice infected with the Daniels strain of Theiler's virus. This system permits the analysis of a viral infection in the absence of an effective immune response. By immunohistochemistry, viral antigen was found in the processes and cell bodies of neurons and glial cells. Besides the presence of viral antigen in these cell types, by in situ hybridization, Theiler's virus RNA was also found in cells associated with vascular endothelium in the brains and spinal cords of these infected mice. Theiler's virus RNA-positive endothelial cells were observed not only near the primary lesions but also away from demonstrable lesions in normal-appearing regions in the central nervous system. Earlier work had suggested an intra-axonal dissemination for this virus (M. C. Dal Canto and H. L. Lipton, Am. J. Pathol. 106:20-29, 1982). Our findings are consistent with this model but also suggest an additional mechanism for virus spread within the central nervous system, i.e., by infecting vascular cells and crossing the blood-brain barrier. Lastly, after Theiler's murine encephalomyelitis virus infection, not only glial cells but also endothelial cells express major histocompatibility complex class II (la) antigen on their surface (M. Rodriguez, M. L. Pierce, and E. A. Howie, J. Immunol. 138:3438-3442, 1987). Our demonstration of Theiler's virus-infected endotheliumlike cells may explain interactions of virus products in stimulating antigen presentation. Images PMID:2843661

  4. Theiler's virus infection in nude mice: viral RNA in vascular endothelial cells.

    PubMed

    Zurbriggen, A; Fujinami, R S

    1988-10-01

    Infection of athymic (nu/nu) mice with Theiler's murine encephalomyelitis virus results in an acute encephalitis which resembles poliomyelitis. Immunohistochemistry and in situ hybridization were used to delineate the presence of viral proteins and RNA in the nervous systems of nude mice infected with the Daniels strain of Theiler's virus. This system permits the analysis of a viral infection in the absence of an effective immune response. By immunohistochemistry, viral antigen was found in the processes and cell bodies of neurons and glial cells. Besides the presence of viral antigen in these cell types, by in situ hybridization, Theiler's virus RNA was also found in cells associated with vascular endothelium in the brains and spinal cords of these infected mice. Theiler's virus RNA-positive endothelial cells were observed not only near the primary lesions but also away from demonstrable lesions in normal-appearing regions in the central nervous system. Earlier work had suggested an intra-axonal dissemination for this virus (M. C. Dal Canto and H. L. Lipton, Am. J. Pathol. 106:20-29, 1982). Our findings are consistent with this model but also suggest an additional mechanism for virus spread within the central nervous system, i.e., by infecting vascular cells and crossing the blood-brain barrier. Lastly, after Theiler's murine encephalomyelitis virus infection, not only glial cells but also endothelial cells express major histocompatibility complex class II (la) antigen on their surface (M. Rodriguez, M. L. Pierce, and E. A. Howie, J. Immunol. 138:3438-3442, 1987). Our demonstration of Theiler's virus-infected endotheliumlike cells may explain interactions of virus products in stimulating antigen presentation.

  5. Cellular microRNAs Repress Vesicular Stomatitis Virus but Not Theiler’s Virus Replication

    PubMed Central

    De Cock, Aurélie; Michiels, Thomas

    2016-01-01

    Picornavirus’ genomic RNA is a positive-stranded RNA sequence that also serves as a template for translation and replication. Cellular microRNAs were reported to interfere to different extents with the replication of specific picornaviruses, mostly acting as inhibitors. However, owing to the high error rate of their RNA-dependent RNA-polymerases, picornavirus quasi-species are expected to evolve rapidly in order to lose any detrimental microRNA target sequence. We examined the genome of Theiler’s murine encephalomyelitis virus (TMEV) for the presence of under-represented microRNA target sequences that could have been selected against during virus evolution. However, little evidence for such sequences was found in the genome of TMEV and introduction of the most under-represented microRNA target (miR-770-3p) in TMEV did not significantly affect viral replication in cells expressing this microRNA. To test the global impact of cellular microRNAs on viral replication, we designed a strategy based on short-term Dicer inactivation in mouse embryonic fibroblasts. Short-term Dicer inactivation led to a >10-fold decrease in microRNA abundance and strongly increased replication of Vesicular stomatitis virus (VSV), which was used as a microRNA-sensitive control virus. In contrast, Dicer inactivation did not increase TMEV replication. In conclusion, cellular microRNAs appear to exert little influence on Theiler’s virus fitness. PMID:26978386

  6. Cellular microRNAs Repress Vesicular Stomatitis Virus but Not Theiler's Virus Replication.

    PubMed

    De Cock, Aurélie; Michiels, Thomas

    2016-03-01

    Picornavirus' genomic RNA is a positive-stranded RNA sequence that also serves as a template for translation and replication. Cellular microRNAs were reported to interfere to different extents with the replication of specific picornaviruses, mostly acting as inhibitors. However, owing to the high error rate of their RNA-dependent RNA-polymerases, picornavirus quasi-species are expected to evolve rapidly in order to lose any detrimental microRNA target sequence. We examined the genome of Theiler's murine encephalomyelitis virus (TMEV) for the presence of under-represented microRNA target sequences that could have been selected against during virus evolution. However, little evidence for such sequences was found in the genome of TMEV and introduction of the most under-represented microRNA target (miR-770-3p) in TMEV did not significantly affect viral replication in cells expressing this microRNA. To test the global impact of cellular microRNAs on viral replication, we designed a strategy based on short-term Dicer inactivation in mouse embryonic fibroblasts. Short-term Dicer inactivation led to a >10-fold decrease in microRNA abundance and strongly increased replication of Vesicular stomatitis virus (VSV), which was used as a microRNA-sensitive control virus. In contrast, Dicer inactivation did not increase TMEV replication. In conclusion, cellular microRNAs appear to exert little influence on Theiler's virus fitness. PMID:26978386

  7. Neurovirulence determinants of genetically engineered Theiler viruses.

    PubMed

    Fu, J L; Stein, S; Rosenstein, L; Bodwell, T; Routbort, M; Semler, B L; Roos, R P

    1990-06-01

    Theiler murine encephalomyelitis viruses (TMEVs) are picornaviruses that cause enteric and neurological disease in mice. The GDVII strain and other members of the GDVII subgroup are highly virulent and cause an acute, fatal polioencephalomyelitis following intracerebral inoculation, whereas the DA stain and other members of the TO subgroup cause a persistent, demyelinating infection. We previously produced a full-length, infectious DA cDNA clone. We now describe the generation of a full-length, infectious GDVII cDNA clone and the subsequent production of intratypic chimeric cDNAs and intratypic recombinant viruses. Inoculation of the recombinant viruses into mice demonstrated that a major determinant of TMEV neurovirulence is within the GDVII 1B (capsid protein VP2)-2C coding region, most likely in the GDVII 1B (VP2)-2A coding region. Genomic sequences 5' to this region of GDVII RNA also contribute to expression of the full neurovirulence phenotype. These data demonstrate the multigenic nature of TMEV neurovirulence, as has been reported for other viruses.

  8. Neurovirulence determinants of genetically engineered Theiler viruses.

    PubMed Central

    Fu, J L; Stein, S; Rosenstein, L; Bodwell, T; Routbort, M; Semler, B L; Roos, R P

    1990-01-01

    Theiler murine encephalomyelitis viruses (TMEVs) are picornaviruses that cause enteric and neurological disease in mice. The GDVII strain and other members of the GDVII subgroup are highly virulent and cause an acute, fatal polioencephalomyelitis following intracerebral inoculation, whereas the DA stain and other members of the TO subgroup cause a persistent, demyelinating infection. We previously produced a full-length, infectious DA cDNA clone. We now describe the generation of a full-length, infectious GDVII cDNA clone and the subsequent production of intratypic chimeric cDNAs and intratypic recombinant viruses. Inoculation of the recombinant viruses into mice demonstrated that a major determinant of TMEV neurovirulence is within the GDVII 1B (capsid protein VP2)-2C coding region, most likely in the GDVII 1B (VP2)-2A coding region. Genomic sequences 5' to this region of GDVII RNA also contribute to expression of the full neurovirulence phenotype. These data demonstrate the multigenic nature of TMEV neurovirulence, as has been reported for other viruses. Images PMID:2161533

  9. Vibsanin B preferentially targets HSP90β, inhibits interstitial leukocyte migration, and ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Ye, Bai-Xin; Deng, Xu; Shao, Li-Dong; Lu, Ying; Xiao, Run; Liu, Yi-Jie; Jin, Yi; Xie, Yin-Yin; Zhao, Yan; Luo, Liu-Fei; Ma, Shun; Gao, Ming; Zhang, Lian-Ru; He, Juan; Zhang, Wei-Na; Chen, Yi; Xia, Cheng-Feng; Deng, Min; Liu, Ting-Xi; Zhao, Qin-Shi; Chen, Sai-Juan; Chen, Zhu

    2015-05-01

    Interstitial leukocyte migration plays a critical role in inflammation and offers a therapeutic target for treating inflammation-associated diseases such as multiple sclerosis. Identifying small molecules to inhibit undesired leukocyte migration provides promise for the treatment of these disorders. In this study, we identified vibsanin B, a novel macrocyclic diterpenoid isolated from Viburnum odoratissimum Ker-Gawl, that inhibited zebrafish interstitial leukocyte migration using a transgenic zebrafish line (TG:zlyz-enhanced GFP). We found that vibsanin B preferentially binds to heat shock protein (HSP)90β. At the molecular level, inactivation of HSP90 can mimic vibsanin B's effect of inhibiting interstitial leukocyte migration. Furthermore, we demonstrated that vibsanin B ameliorates experimental autoimmune encephalomyelitis in mice with pathological manifestation of decreased leukocyte infiltration into their CNS. In summary, vibsanin B is a novel lead compound that preferentially targets HSP90β and inhibits interstitial leukocyte migration, offering a promising drug lead for treating inflammation-associated diseases.

  10. Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Chandraratna, Roshantha As; Noelle, Randolph J; Nowak, Elizabeth C

    2016-01-01

    Retinoid x receptors (RXRs) are master regulators that control cell growth, differentiation, and survival and form heterodimers with many other family members. Here we show that treatment with the RXR agonist IRX4204 enhances the differentiation of CD4(+) T cells into inducible regulatory T cells (iTreg) and suppresses the development of T helper (Th) 17 cells in vitro. Furthermore in a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)), treatment with IRX4204 profoundly attenuates both active and Th17-mediated passive disease. In the periphery, treatment with IRX4204 is associated with decreased numbers of CD4(+) T cells that produce pro-inflammatory cytokines. In addition, CD4(+) T cells express decreased levels of Ki-67 and increased expression of CTLA-4. Our findings demonstrate IRX4204 treatment during EAE results in immune modulation and profound attenuation of disease severity. PMID:27158387

  11. C-C chemokine receptor type 4 antagonist Compound 22 ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Moriguchi, Kota; Miyamoto, Katsuichi; Tanaka, Noriko; Ueno, Rino; Nakayama, Takashi; Yoshie, Osamu; Kusunoki, Susumu

    2016-02-15

    Chemokines and chemokine receptors play important roles in the immune response. We previously reported the pathogenic role of C-C chemokine receptor type 4 (CCR4) in experimental autoimmune encephalomyelitis (EAE). Here, we examined whether CCR4 antagonism modulates the disease course of EAE. Wild-type and CCR4-knockout mice were induced EAE and were administered Compound 22, an antagonist of CCR4. Compound 22 significantly ameliorated the severity of EAE in wild-type mice, but not in the CCR4-knockout mice. Compound 22 inhibited Th1 and Th17 polarization of antigen-induced T-cell responses. Therefore, CCR4 antagonists might be potential therapeutic agents for multiple sclerosis. PMID:26857495

  12. Charcot-Marie-Tooth disease masquerading as acute demyelinating encephalomyelitis-like illness.

    PubMed

    Kim, Gun-Ha; Kim, Kyoung Min; Suh, Sang-Il; Ki, Chang-Seok; Eun, Baik-Lin

    2014-07-01

    X-linked Charcot-Marie-Tooth disease (CMTX1) is a clinically heterogeneous hereditary motor and sensory neuropathy with X-linked transmission. Common clinical manifestations of CMTX1 disease, as in other forms of Charcot-Marie-Tooth (CMT) disease, are distal muscle wasting and weakness, hyporeflexia, distal sensory disturbance, and foot deformities. Mutations in the connexin-32 gene (gap junction protein β1 [GJB1]) are responsible for CMTX1 disease. In this report, we describe a patient with CMTX1 disease presenting with recurrent attacks of transient and episodic acute demyelinating encephalomyelitis (ADEM)-like symptoms without previous signs of lower extremity weakness or foot deformities; the patient, as well as his asymptomatic mother, exhibited a novel GJB1 mutation (p.Met1Ile). Differential diagnosis of recurrent and transient ADEM-like illness, if unexplained, should include the possibility of CMTX1 disease.

  13. Dysregulation of the hypothalamic-pituitary-gonadal axis in experimental autoimmune encephalomyelitis and multiple sclerosis.

    PubMed

    Foster, Scott C; Daniels, Crystal; Bourdette, Dennis N; Bebo, Bruce F

    2003-07-01

    The ability of sex hormones to regulate cytokine production is well established, but the ability of cytokines to regulate sex hormone production has only begun to be investigated. We measured sex hormones in mice with passive experimental autoimmune encephalomyelitis (EAE) and in multiple sclerosis (MS) patients with sexual dysfunction. Abnormally low serum testosterone levels were found in male mice with EAE and in male MS patients, while serum estrogen levels in female mice with EAE were normal. An inverse relationship between cytokine and testosterone levels in male mice with EAE, coupled with an increase in serum luteinizing hormone (LH) levels, suggests that inflammatory cytokines suppress testosterone production by a direct effect on testicular Leydig cells. Gender differences in the sensitivity of the hypothalamic-pituitary-gonadal (HPG) axis to inflammation may be an important factor regulating the duration and severity of central nervous system (CNS) autoimmunity.

  14. Microglia response in retina and optic nerve in chronic experimental autoimmune encephalomyelitis.

    PubMed

    Horstmann, Lioba; Kuehn, Sandra; Pedreiturria, Xiomara; Haak, Kathrin; Pfarrer, Christiane; Dick, H Burkhard; Kleiter, Ingo; Joachim, Stephanie C

    2016-09-15

    Experimental autoimmune encephalomyelitis (EAE) is a common rodent model for multiple sclerosis (MS). Yet, the long-term consequences for retina and optic nerve (ON) are unknown. C57BL/6 mice were immunized with an encephalitogenic peptide (MOG35-55) and the controls received the carriers or PBS. Clinical symptoms started at day 8, peaked at day 14, and were prevalent until day 60. They correlated with infiltration and demyelination of the ON. In MOG-immunized animals more microglia cells in the ONs and retinas were detected at day 60. Additionally, retinal ganglion cell (RGC) loss was combined with an increased macroglia response. At this late stage, an increased number of microglia was associated with axonal damage in the ON and in the retina with RGC loss. Whether glial activation contributes to repair mechanisms or adversely affects the number of RGCs is currently unclear. PMID:27609273

  15. Probenecid Application Prevents Clinical Symptoms and Inflammation in Experimental Autoimmune Encephalomyelitis.

    PubMed

    Hainz, Nadine; Wolf, Sandra; Tschernig, Thomas; Meier, Carola

    2016-02-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Neurological impairments are caused by axonal damage due to demyelination and neuroinflammation within the central nervous system. T cells mediate the neuroinflammation. The activation of T cells is induced by the release of adenosine triphosphate and involves purinergic receptors as well as pannexin (Panx) proteins. As Panx1 is expressed on T cells, we here propose that application of probenecid, a known Panx inhibitor, will prevent the onset of clinical symptoms in a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE) model. EAE-induced mice received daily injections of probenecid. Disease scores, T cell numbers, and microglia activation were compared between experimental groups. Probenecid treatment resulted in lower disease scores as compared to EAE animals. Probenecid-treated animals also displayed fewer inflammatory lesions. Microglia activation was not altered by treatment. In conclusion, probenecid prevented the onset of EAE. PMID:26276126

  16. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination.

    PubMed

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-01-01

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches.

  17. Gonadotropin-releasing hormone reduces the severity of experimental autoimmune encephalomyelitis, a model of multiple sclerosis.

    PubMed

    Quintanar, J Luis; Salinas, Eva; Quintanar-Stephano, Andrés

    2011-02-01

    It has been reported that the spinal cord possesses Gonadotropin-releasing hormone (GnRH) receptor and that GnRH has neurotrophic properties. Experimental autoimmune encephalomyelitis (EAE) causes neurodegeneration in spinal cord. Thus, the present study was designed to determine whether administration of GnRH reduces the severity of EAE. The clinical signs of locomotion, axonal morphometry and neurofilaments (NFs) expression were evaluated. Clinical signs remained significantly lower in EAE rats with GnRH administration compared to animals without treatment. Morphometric analysis, there were more axons of larger areas in the spinal cord of EAE+GnRH group compared to EAE animals. Western blot analysis demonstrated that GnRH administration significantly increased the expression of NFs of 68, 160 and 200kDa in the spinal cord of EAE animals. Our results indicate that GnRH administration reduces the severity of EAE in the rat.

  18. CD20 therapies in multiple sclerosis and experimental autoimmune encephalomyelitis - Targeting T or B cells?

    PubMed

    Agahozo, Marie Colombe; Peferoen, Laura; Baker, David; Amor, Sandra

    2016-09-01

    MS is widely considered to be a T cell-mediated disease although T cell immunotherapy has consistently failed, demonstrating distinct differences with experimental autoimmune encephalomyelitis (EAE), an animal model of MS in which T cell therapies are effective. Accumulating evidence has highlighted that B cells also play key role in MS pathogenesis. The high frequency of oligoclonal antibodies in the CSF, the localization of immunoglobulin in brain lesions and pathogenicity of antibodies originally pointed to the pathogenic role of B cells as autoantibody producing plasma cells. However, emerging evidence reveal that B cells also act as antigen presenting cells, T cell activators and cytokine producers suggesting that the strong efficacy of anti-CD20 antibody therapy observed in people with MS may reduce disease progression by several different mechanisms. Here we review the evidence and mechanisms by which B cells contribute to disease in MS compared to findings in the EAE model. PMID:27645355

  19. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination

    PubMed Central

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-01-01

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches. PMID:27040771

  20. Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome.

    PubMed

    Hornig, M; Gottschalk, G; Peterson, D L; Knox, K K; Schultz, A F; Eddy, M L; Che, X; Lipkin, W I

    2016-02-01

    Myalgic encephalomyelitis/chronic fatigue syndrome is an unexplained debilitating disorder that is frequently associated with cognitive and motor dysfunction. We analyzed cerebrospinal fluid from 32 cases, 40 subjects with multiple sclerosis and 19 normal subjects frequency-matched for age and sex using a 51-plex cytokine assay. Group-specific differences were found for the majority of analytes with an increase in cases of CCL11 (eotaxin), a chemokine involved in eosinophil recruitment. Network analysis revealed an inverse relationship between interleukin 1 receptor antagonist and colony-stimulating factor 1, colony-stimulating factor 2 and interleukin 17F, without effects on interleukin 1α or interleukin 1β, suggesting a disturbance in interleukin 1 signaling. Our results indicate a markedly disturbed immune signature in the cerebrospinal fluid of cases that is consistent with immune activation in the central nervous system, and a shift toward an allergic or T helper type-2 pattern associated with autoimmunity.

  1. Strain-related effects of fenbendazole treatment on murine experimental autoimmune encephalomyelitis.

    PubMed

    Ramp, A A; Hall, C; Orian, J M

    2010-07-01

    Parasitic infections are a concern in animal facilities, in view of their influence on physiological processes and the immune status of animals. Pinworms are effectively controlled with the anthelminthic fenbendazole (FBZ, [5-(phenylthio)-1H-benzamidazol-2-yl]carbamic acid methyl ester; C(15)H(13)N(3)O(2)S); however, questions remain as to whether prolonged FBZ exposure alters the disease course in specific experimental models, such as those pertaining to the immune system. We report that a three-month regimen of FBZ-medicated feed severely affected the onset and disease severity of murine experimental autoimmune encephalomyelitis (EAE), a disease that mimics multiple sclerosis. Differences were recorded between mouse strains used. Our data suggest that where the use of FBZ is mandatory, its full effect should be verified on the particular EAE variant adopted by the laboratory.

  2. Kindling and Oxidative Stress as Contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

    PubMed Central

    Jason, L. A.; Porter, N.; Herrington, J.; Sorenson, M.; Kubow, S.

    2010-01-01

    Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) is one of the more complex illnesses involving multiple systems within the body. Onset of ME/CFS frequently occurs quickly, and many patients report a prior exposure to a viral infection. This debilitating illness can affect the immune, neuroendocrine, autonomic, and neurologic systems. Abnormal biological findings among some patients have included aberrant ion transport and ion channel activity, cortisol deficiency, sympathetic nervous system hyperactivity, EEG spike waves, left ventricular dysfunction in the heart, low natural killer cell cytotoxicity, and a shift from Th1 to Th2 cytokines. We propose that the kindling and oxidative stress theories provide a heuristic template for better understanding the at times conflicting findings regarding the etiology and pathophysiology of this illness. PMID:21253446

  3. Kappa opioid receptor activation alleviates experimental autoimmune encephalomyelitis and promotes oligodendrocyte-mediated remyelination.

    PubMed

    Du, Changsheng; Duan, Yanhui; Wei, Wei; Cai, Yingying; Chai, Hui; Lv, Jie; Du, Xiling; Zhu, Jian; Xie, Xin

    2016-01-01

    Multiple sclerosis (MS) is characterized by autoimmune damage to the central nervous system. All the current drugs for MS target the immune system. Although effective in reducing new lesions, they have limited effects in preventing the progression of disability. Promoting oligodendrocyte-mediated remyelination and recovery of neurons are the new directions of MS therapy. The endogenous opioid system, consisting of MOR, DOR, KOR and their ligands, has been suggested to participate in the pathogenesis of MS. However, the exact receptor and mechanism remain elusive. Here we show that genetic deletion of KOR exacerbates experimental autoimmune encephalomyelitis, whereas activating KOR with agonists alleviates the symptoms. KOR does not affect immune cell differentiation and function. Instead, it promotes oligodendrocyte differentiation and myelination both in vitro and in vivo. Our study suggests that targeting KOR might be an intriguing way to develop new MS therapies that may complement the existing immunosuppressive approaches. PMID:27040771

  4. CD20 therapies in multiple sclerosis and experimental autoimmune encephalomyelitis - Targeting T or B cells?

    PubMed

    Agahozo, Marie Colombe; Peferoen, Laura; Baker, David; Amor, Sandra

    2016-09-01

    MS is widely considered to be a T cell-mediated disease although T cell immunotherapy has consistently failed, demonstrating distinct differences with experimental autoimmune encephalomyelitis (EAE), an animal model of MS in which T cell therapies are effective. Accumulating evidence has highlighted that B cells also play key role in MS pathogenesis. The high frequency of oligoclonal antibodies in the CSF, the localization of immunoglobulin in brain lesions and pathogenicity of antibodies originally pointed to the pathogenic role of B cells as autoantibody producing plasma cells. However, emerging evidence reveal that B cells also act as antigen presenting cells, T cell activators and cytokine producers suggesting that the strong efficacy of anti-CD20 antibody therapy observed in people with MS may reduce disease progression by several different mechanisms. Here we review the evidence and mechanisms by which B cells contribute to disease in MS compared to findings in the EAE model.

  5. Treatment with retinoid X receptor agonist IRX4204 ameliorates experimental autoimmune encephalomyelitis

    PubMed Central

    Chandraratna, Roshantha AS; Noelle, Randolph J; Nowak, Elizabeth C

    2016-01-01

    Retinoid x receptors (RXRs) are master regulators that control cell growth, differentiation, and survival and form heterodimers with many other family members. Here we show that treatment with the RXR agonist IRX4204 enhances the differentiation of CD4+ T cells into inducible regulatory T cells (iTreg) and suppresses the development of T helper (Th) 17 cells in vitro. Furthermore in a murine model of multiple sclerosis (experimental autoimmune encephalomyelitis (EAE)), treatment with IRX4204 profoundly attenuates both active and Th17-mediated passive disease. In the periphery, treatment with IRX4204 is associated with decreased numbers of CD4+ T cells that produce pro-inflammatory cytokines. In addition, CD4+ T cells express decreased levels of Ki-67 and increased expression of CTLA-4. Our findings demonstrate IRX4204 treatment during EAE results in immune modulation and profound attenuation of disease severity. PMID:27158387

  6. In silico analysis of exercise intolerance in myalgic encephalomyelitis/chronic fatigue syndrome.

    PubMed

    Lengert, Nicor; Drossel, Barbara

    2015-07-01

    Post-exertional malaise is commonly observed in patients with myalgic encephalomyelitis/chronic fatigue syndrome, but its mechanism is not yet well understood. A reduced capacity for mitochondrial ATP synthesis is associated with the pathogenesis of CFS and is suspected to be a major contribution to exercise intolerance in CFS patients. To demonstrate the connection between a reduced mitochondrial capacity and exercise intolerance, we present a model which simulates metabolite dynamics in skeletal muscles during exercise and recovery. CFS simulations exhibit critically low levels of ATP, where an increased rate of cell death would be expected. To stabilize the energy supply at low ATP concentrations the total adenine nucleotide pool is reduced substantially causing a prolonged recovery time even without consideration of other factors, such as immunological dysregulations and oxidative stress. Repeated exercises worsen this situation considerably. Furthermore, CFS simulations exhibited an increased acidosis and lactate accumulation consistent with experimental observations.

  7. Galectin isolated from parasite inhibits remission of experimental autoimmune encephalomyelitis by up-regulating autoantibody

    PubMed Central

    Bing, S J; Ha, D; Ahn, G; Cho, J; Kim, A; Park, S K; Yu, H S; Jee, Y

    2015-01-01

    Recently, parasite infections or parasite-derived products have been suggested as a therapeutic strategy with suppression of immunopathology, which involves the induction of regulatory T cells or/and T helper type 2 (Th2) responses. In a recent study, researchers reported that constructed recombinant galectin (rTl-gal) isolated from an adult worm of the gastrointestinal nematode parasite Toxascaris leonina attenuated clinical symptoms of inflammatory bowel disease in mice treated with dextran sulphate sodium. Noting the role of rTl-gal in inflammatory disease, we attempted to investigate the effect of the parasite via its rTl-gal on neuronal autoimmune disease using experimental autoimmune encephalomyelitis (EAE), a mouse inflammatory and demyelinating autoimmune disease model of human multiple sclerosis. In this model, rTl-gal-treated experimental autoimmune encephalomyelitis (EAE) mice failed to recover after the peak of the disease, leading to persistent central nervous system (CNS) damage, such as demyelination, gliosis and axonal damage. Further, rTl-gal-treated EAE mice markedly increased the number of CD45R/B220+ B cells in both infiltrated inflammation and the periphery, along with the increased production of autoantibody [anti-myelin oligodendrocyte glycoprotein (MOG)35–55] in serum at chronic stage. Upon antigen restimulation, rTl-gal treatment affected the release of overall cytokines, especially interferon (IFN)-γ and tumour necrosis factor (TNF)-α. Our results suggest that galectin isolated from a gastrointestinal parasite can deliver a harmful effect to EAE contrary to its beneficial effect on inflammatory bowel disease. PMID:25619397

  8. Histamine H2 receptor signaling × environment interactions determine susceptibility to experimental allergic encephalomyelitis

    PubMed Central

    Saligrama, Naresha; Case, Laure K.; Krementsov, Dimitry N.; Teuscher, Cory

    2014-01-01

    Histamine and its receptors are important in both multiple sclerosis and experimental allergic encephalomyelitis (EAE). C57BL/6J (B6) mice deficient for the histamine H2 receptor (H2RKO) are less susceptible to EAE and exhibit blunted Th1 responses. However, whether decreased antigen-specific T-cell effector responses in H2RKO mice were due to a lack of H2R signaling in CD4+ T cells or antigen-presenting cells has remained unclear. We generated transgenic mice expressing H2R specifically in T cells on the H2RKO background, and, using wild-type B6 and H2RKO mice as controls, induced EAE either in the presence or absence of the ancillary adjuvant pertussis toxin (PTX), which models the effects of infectious inflammatory stimuli on autoimmune disease. We monitored the mice for clinical signs of EAE and neuropathology, as well as effector T-cell responses using flow cytometry. EAE severity and neuropathology in H2RKO mice expressing H2R exclusively in T cells become equal to those in wild-type B6 mice only when PTX is used to elicit disease. EAE complementation was associated with frequencies of CD4+IFN-γ+ and CD4+IL-17+ cells that are equal to or greater than those in wild-type B6, respectively. Thus, the regulation of encephalitogenic T-cell responses and EAE susceptibility by H2R signaling in CD4+ T cells is dependent on gene × environment interactions.—Saligrama, N., Case, L. K., Krementsov, D. N., Teuscher, C. Histamine H2 receptor signaling × environment interactions determine susceptibility to experimental allergic encephalomyelitis. PMID:24371118

  9. Prior regular exercise improves clinical outcome and reduces demyelination and axonal injury in experimental autoimmune encephalomyelitis.

    PubMed

    Bernardes, Danielle; Brambilla, Roberta; Bracchi-Ricard, Valerie; Karmally, Shaffiat; Dellarole, Anna; Carvalho-Tavares, Juliana; Bethea, John R

    2016-01-01

    Although previous studies have shown that forced exercise modulates inflammation and is therapeutic acutely for experimental autoimmune encephalomyelitis (EAE), the long-term benefits have not been evaluated. In this study, we investigated the effects of preconditioning exercise on the clinical and pathological progression of EAE. Female C57BL/6 mice were randomly assigned to either an exercised (Ex) or unexercised (UEx) group and all of them were induced for EAE. Mice in the Ex group had an attenuated clinical score relative to UEx mice throughout the study. At 42 dpi, flow cytometry analysis showed a significant reduction in B cells, CD4(+) T cells, and CD8(+) T cells infiltrating into the spinal cord in the Ex group compared to UEx. Ex mice also had a significant reduction in myelin damage with a corresponding increase in proteolipid protein expression. Finally, Ex mice had a significant reduction in axonal damage. Collectively, our study demonstrates for the first time that a prolonged and forced preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease. In this study, we show that a program of 6 weeks of preconditioning exercise promoted a significant reduction of cells infiltrating into the spinal cord, a significant reduction in myelin damage and a significant reduction in axonal damage in experimental autoimmune encephalomyelitis (EAE) mice at 42 dpi. Collectively, our study demonstrates for the first time that a preconditioning protocol of exercise improves clinical outcome and attenuates pathological hallmarks of EAE at chronic disease. PMID:26364732

  10. Viral infection and dissemination through the olfactory pathway and the limbic system by Theiler's virus.

    PubMed

    Wada, Y; Fujinami, R S

    1993-07-01

    Theiler's murine encephalomyelitis virus (TMEV) infection of mice can produce a biphasic disease of the central nervous system (CNS). Most susceptible strains of mice survive the acute infection and develop a chronic demyelinating disease. In this report, we analyzed the routes of spread of TMEV within the CNS of nude mice and target sites eventually infected in the CNS. Compared to the immunocompetent mouse, in which an antiviral immune response is mounted but virus persists, the nude mouse develops a severe encephalomyelitis due to the lack of functional T lymphocytes and provides a useful model for the study of viral dissemination. We demonstrated, by immunohistochemistry, the presence of viral antigen in defined regions of the CNS, corresponding to various structures of the limbic system. In addition, we found a different time course for viral spread using two different sites of intracerebral inoculation, ie, via the olfactory bulb or the cortex. Limbic structures were rapidly infected following olfactory bulb infection and then showed a decrease in viral load, presumably due to loss of target neurons. Using either route of infection, the virus was able to disseminate to similar regions. These results indicate that limbic structures and their connections are very important for the spread of TMEV in the brain. In the spinal cord, not only neuronal but hematogenous pathways were suspected to be involved in the dissemination of Theiler's virus.

  11. Viral infection and dissemination through the olfactory pathway and the limbic system by Theiler's virus.

    PubMed Central

    Wada, Y.; Fujinami, R. S.

    1993-01-01

    Theiler's murine encephalomyelitis virus (TMEV) infection of mice can produce a biphasic disease of the central nervous system (CNS). Most susceptible strains of mice survive the acute infection and develop a chronic demyelinating disease. In this report, we analyzed the routes of spread of TMEV within the CNS of nude mice and target sites eventually infected in the CNS. Compared to the immunocompetent mouse, in which an antiviral immune response is mounted but virus persists, the nude mouse develops a severe encephalomyelitis due to the lack of functional T lymphocytes and provides a useful model for the study of viral dissemination. We demonstrated, by immunohistochemistry, the presence of viral antigen in defined regions of the CNS, corresponding to various structures of the limbic system. In addition, we found a different time course for viral spread using two different sites of intracerebral inoculation, ie, via the olfactory bulb or the cortex. Limbic structures were rapidly infected following olfactory bulb infection and then showed a decrease in viral load, presumably due to loss of target neurons. Using either route of infection, the virus was able to disseminate to similar regions. These results indicate that limbic structures and their connections are very important for the spread of TMEV in the brain. In the spinal cord, not only neuronal but hematogenous pathways were suspected to be involved in the dissemination of Theiler's virus. Images Figure 2 Figure 3 Figure 4 PMID:8317548

  12. National Institutes of Health Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

    PubMed

    Green, Carmen R; Cowan, Penney; Elk, Ronit; O'Neil, Kathleen M; Rasmussen, Angela L

    2015-06-16

    The National Institutes of Health (NIH) Pathways to Prevention Workshop: Advancing the Research on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome was cosponsored by the NIH Office of Disease Prevention and the Trans-NIH Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Research Working Group. A multidisciplinary working group developed the agenda, and an Evidence-based Practice Center prepared an evidence report through a contract with the Agency for Healthcare Research and Quality to facilitate the discussion. During the 1.5-day workshop, invited experts discussed the body of evidence and attendees had the opportunity to comment during open discussions. After weighing evidence from the evidence report, expert presentations, and public comments, an unbiased, independent panel prepared a draft report that identified research gaps and future research priorities. The report was posted on the NIH Office of Disease Prevention Web site for 4 weeks for public comment.

  13. Trivittatus virus infections in wild mammals and sentinel rabbits in central Iowa.

    PubMed

    Pinger, R R; Rowley, W A; Wong, Y W; Dorsey, D C

    1975-11-01

    A serological survey was conducted in Iowa to determine the prevalence rate of California group virus antibodies in sera of several vertebrate species. Serum specimens were assayed for infectivity-neutralizing antibody in a microneutralization system with baby hamster kidney cell culture. Of 77 sera assayed, 21 (27%) neutralized trivittatus (TVT) virus infectivity. The antibody prevalence rate was highest for eastern cottontail rabbits inasmuch as 46% (10/22) of the serum specimens form this species possessed neutralizing activity. Other vertebrate species having TVT virus antibody included the fox squirrel, 29% (7/24), opossum, 12% (3/25), and raccoon, 17% (1/6). One cottontail rabbit serum neutralized both TVT virus and Jamestown Canyon (JC) virus infectivity, and one opossum serum specimen neutralized JC virus. None of the vertebrate sera neutralized La Crosse, St. Louis encephalitis, or western equine encephalomyelitis virus infectivity. Trivittatus virus neutralizing antibody was detected in the sera of sentinel rabbits, and TVT virus was isolated from the blood collected from one of these sentinels shortly after the first population peak of adult Aedes trivittatus mosquitoes in 1973. The implications of these data and the possibility of trans-ovarial transmission of TVT virus in A. trivittatus are discussed.

  14. Activation of cannabinoid CB2 receptors reduces hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis.

    PubMed

    Fu, Weisi; Taylor, Bradley K

    2015-05-19

    Clinical trials investigating the analgesic efficacy of cannabinoids in multiple sclerosis have yielded mixed results, possibly due to psychotropic side effects mediated by cannabinoid CB1 receptors. We hypothesized that, a CB2-specific agonist (JWH-133) would decrease hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. Four weeks after induction of experimental autoimmune encephalomyelitis, we found that intrathecal administration of JWH-133 (10-100μg) dose-dependently reduced both mechanical and cold hypersensitivity without producing signs of sedation or ataxia. The anti-hyperalgesic effects of JWH-133 could be dose-dependently prevented by intrathecal co-administration of the CB2 antagonist, AM-630 (1-3μg). Our results suggest that JWH-133 acts at CB2 receptors, most likely within the dorsal horn of the spinal cord, to suppress the hypersensitivity associated with experimental autoimmune encephalomyelitis. These are the first pre-clinical studies to directly promote CB2 as a promising target for the treatment of central pain in an animal model of multiple sclerosis.

  15. Activation of Cannabinoid CB2 receptors Reduces Hyperalgesia in an Experimental Autoimmune Encephalomyelitis Mouse Model of Multiple Sclerosis

    PubMed Central

    Fu, Weisi; Taylor, Bradley K.

    2015-01-01

    Clinical trials investigating the analgesic efficacy of cannabinoids in multiple sclerosis have yielded mixed results, possibly due to psychotropic side effects mediated by cannabinoid CB1 receptors. We hypothesized that a CB2-specific agonist (JWH-133) would decrease hyperalgesia in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. 4 weeks after induction of experimental autoimmune encephalomyelitis, we found that intrathecal administration of JWH-133 (10–100 μg) dose-dependently reduced both mechanical and cold hypersensitivity without producing signs of sedation or ataxia. The anti-hyperalgesic effects of JWH-133 could be dose-dependently prevented by intrathecal co-administration of the CB2 antagonist, AM-630 (1–3 μg). Our results suggest that JWH-133 acts at CB2 receptors, most likely within the dorsal horn of the spinal cord, to suppress the hypersensitivity associated with experimental autoimmune encephalomyelitis. These are the first pre-clinical studies to directly promote CB2 as a promising target for the treatment of central pain in an animal model of multiple sclerosis. PMID:25849525

  16. Involvement of cardiovirus leader in host cell-restricted virus expression.

    PubMed Central

    Kong, W P; Ghadge, G D; Roos, R P

    1994-01-01

    Theiler murine encephalomyelitis virus designates a number of picornavirus strains that are classified into two subgroups on the basis of their different biological activities. DA strain and other members of the TO subgroup produce a chronic demyelinating disease in which the virus persists and manifests a restricted expression. Mutagenesis studies of the DA strain leader (L) coding region, which is located at the 5' end of the polyprotein coding region, demonstrate that L is completely dispensable for infection of some cells; in addition, nucleotides can be inserted into the L coding region with no loss in infectivity, indicating that Theiler murine encephalomyelitis virus may be used as a vector for delivering foreign sequences. In other cells, L is critical for plaque formation and efficient viral multiplication. These findings raise the possibility that L may play a role in the DA-induced demyelinating restricted infection. The functions of L, and even its presence within the genome, vary among picornaviruses, reflecting the various requirements for viral growth among different host cells. Images PMID:8127884

  17. Strains from both Theiler's virus subgroups encode a determinant for demyelination.

    PubMed Central

    Fu, J; Rodriguez, M; Roos, R P

    1990-01-01

    The GDVII strain and other members of the GDVII subgroup of Theiler's murine encephalomyelitis viruses (TMEV) cause an acute lethal neuronal infection in mice, whereas the DA strain and other members of the TO subgroup of TMEV cause a chronic demyelinating disease associated with a persistent virus infection. We used GDVII/DA chimeric infectious cDNAs to produce intratypic recombinant viruses in order to clarify reasons for the TMEV subgroup-specific difference in demyelinating activity. We found that both the GDVII and DA strains contain a genetic determinant(s) for demyelinating activity. No demyelination occurs following GDVII strain inoculation because this strain produces an early neuronal disease that kills mice before white matter disease and persistent infection can occur. Images PMID:2243399

  18. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME)

    PubMed Central

    Mitchell, William M

    2016-01-01

    ABSTRACT Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA). Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2ʹ-5ʹ adenylate synthetase, protein kinase R). Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe. The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed. PMID:27045557

  19. Acute Disseminated Encephalomyelitis after Oral Therapy with Herbal Extracts: A Case Report

    PubMed Central

    Kaymakamzade, Bahar; Karabudak, Rana; Kurne, Aslı Tuncer; Nurlu, Gülay

    2016-01-01

    Background: Acute disseminated encephalomyelitis (ADEM) is a rare demyelinating disease of the central nervous system, commonly attributed to infections or vaccinations. Toxic or allergenic compounds can also trigger a response in the immune system and may cause demyelination. We present a case with ADEM after using oral herbal medications. Case Report: A 25 year-old male developed bilateral central facial palsy and severe quadriparesis after taking herbal drugs (containing echinacea and many other herbal ingredients) for two weeks. He had used the extract to increase his potency and reproductivity. He had no past history of recent immunization or viral infection. The clinical findings, cerebrospinal fluid (CSF) analysis and brain magnetic resonance imaging (MRI) were compatible with ADEM. The neurological findings were improved after seven doses of pulse methylprednisolone treatment. To our knowledge, this is the third report in the literature that links herbal therapy and demyelinating disease. Conclusion: Most of the ADEM cases related to herbal therapy in the literature similarly used echinacea. It is our opinion that other ingredients of the herbal extract used by our case, besides echinacea, could have the potential to cause a trigger in the immune system. Further studies are needed to clarify the immunological effects of different kinds of herbal compounds, as well as the effects of different parts of the plants and the results of various dosages. Moreover, ingredients should also be tested for toxicity, adverse effects and drug interactions. PMID:27308086

  20. SAP suppresses the development of experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Ji, Zhe; Ke, Zun-Ji; Geng, Jian-Guo

    2012-04-01

    Experimental autoimmune encephalomyelitis (EAE) is a CD4(+) T cell-mediated disease of the central nervous system. Serum amyloid P component (SAP) is a highly conserved plasma protein named for its universal presence in amyloid deposits. Here we report that SAP-transgenic mice had unexpectedly attenuated EAE due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35-55 in complete Freund's adjuvant, SAP-transgenic mice showed reduced spinal cord inflammation with lower severity of EAE attacks as compared with control C57BL/6 mice. However, in SAP-Knockout mice, the severity of EAE is enhanced. Adoptive transfer of Ag-restimulated T cells from wild type to SAP-transgenic mice, or transfer of SAP-transgenic Ag-restimulated T cells to control mice, induced milder EAE. T cells from MOG-primed SAP-transgenic mice showed weak proliferative responses. Furthermore, in SAP-transgenic mice, there is little infiltration of CD45-positive cells in the spinal cord. In vitro, SAP suppressed the secretion of interleukin-2 stimulated by P-selectin and blocked P-selectin binding to T cells. Moreover, SAP could change the affinity between α4-integrin and T cells. These data suggested that SAP could antagonize the development of the acute phase of inflammation accompanying EAE by modulating the function of P-selectin.

  1. Serum Immune Proteins in Moderate and Severe Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

    PubMed Central

    Hardcastle, Sharni Lee; Brenu, Ekua Weba; Johnston, Samantha; Nguyen, Thao; Huth, Teilah; Ramos, Sandra; Staines, Donald; Marshall-Gradisnik, Sonya

    2015-01-01

    Immunological dysregulation is present in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME), with recent studies also highlighting the importance of examining symptom severity. This research addressed this relationship between CFS/ME severity subgroups, assessing serum immunoglobulins and serum cytokines in severe and moderate CFS/ME patients. Participants included healthy controls (n= 22), moderately (n = 22) and severely (n=19) affected CFS/ME patients. The 1994 Fukuda Criteria defined CFS/ME and severity scales confirmed mobile and housebound CFS/ME patients as moderate and severe respectively. IL-1β was significantly reduced in severe compared with moderate CFS/ME patients. IL-6 was significantly decreased in moderate CFS/ME patients compared with healthy controls and severe CFS/ME patients. RANTES was significantly increased in moderate CFS/ME patients compared to severe CFS/ME patients. Serum IL-7 and IL-8 were significantly higher in the severe CFS/ME group compared with healthy controls and moderate CFS/ME patients. IFN-γ was significantly increased in severe CFS/ME patients compared with moderately affected patients. This was the first study to show cytokine variation in moderate and severe CFS/ME patients, with significant differences shown between CFS/ME symptom severity groups. This research suggests that distinguishing severity subgroups in CFS/ME research settings may allow for a more stringent analysis of the heterogeneous and otherwise inconsistent illness. PMID:26516304

  2. A pain-mediated neural signal induces relapse in murine autoimmune encephalomyelitis, a multiple sclerosis model

    PubMed Central

    Arima, Yasunobu; Kamimura, Daisuke; Atsumi, Toru; Harada, Masaya; Kawamoto, Tadafumi; Nishikawa, Naoki; Stofkova, Andrea; Ohki, Takuto; Higuchi, Kotaro; Morimoto, Yuji; Wieghofer, Peter; Okada, Yuka; Mori, Yuki; Sakoda, Saburo; Saika, Shizuya; Yoshioka, Yoshichika; Komuro, Issei; Yamashita, Toshihide; Hirano, Toshio; Prinz, Marco; Murakami, Masaaki

    2015-01-01

    Although pain is a common symptom of various diseases and disorders, its contribution to disease pathogenesis is not well understood. Here we show using murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (MS), that pain induces EAE relapse. Mechanistic analysis showed that pain induction activates a sensory-sympathetic signal followed by a chemokine-mediated accumulation of MHC class II+CD11b+ cells that showed antigen-presentation activity at specific ventral vessels in the fifth lumbar cord of EAE-recovered mice. Following this accumulation, various immune cells including pathogenic CD4+ T cells recruited in the spinal cord in a manner dependent on a local chemokine inducer in endothelial cells, resulting in EAE relapse. Our results demonstrate that a pain-mediated neural signal can be transformed into an inflammation reaction at specific vessels to induce disease relapse, thus making this signal a potential therapeutic target. DOI: http://dx.doi.org/10.7554/eLife.08733.001 PMID:26193120

  3. CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis.

    PubMed

    Bao, Jianhong; Zhu, Jinying; Luo, Sheng; Cheng, Ying; Zhou, Saijun

    2016-01-01

    Multiple sclerosis (MS) is the prototypical inflammatory demyelinating disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE), widely used as an animal model of MS, classically manifests as an ascending paralysis that is characterized by extensive infiltration of the CNS by inflammatory cells. Although several studies uncover the significant role of microglia in the development of EAE, the cellular mechanisms of microglia that govern EAE pathogenesis remain unknown. In the current study, we report that CXCR7 expression is dynamic regulated in activated microglia during CNS autoimmunity and positively correlates with the clinical severity of EAE. In addition, microglial chemotaxis is mediated by CXCR7 during CNS autoimmunity, signaling through extracellular signal-regulated kinase (ERK)1/2 activation, whereas p38 mitogen-activated protein kinase (MAPK) and (c-Jun N-terminal kinase) JNK are not involved. Most importantly, CXCR7 neutralizing treatment ameliorates the clinical severity of EAE along with ERK1/2 phosphorylation reduction. Collectively, our data demonstrate that CXCR7 suppression modulates microglial chemotaxis to ameliorate EAE.

  4. Nigella sativa amliorates inflammation and demyelination in the experimental autoimmune encephalomyelitis-induced Wistar rats.

    PubMed

    Noor, Neveen A; Fahmy, Heba M; Mohammed, Faten F; Elsayed, Anwar A; Radwan, Nasr M

    2015-01-01

    Multiple sclerosis (MS) is the major, immune-mediated, demyelinating neurodegenerative disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of MS. The aim of the present study was to investigate the protective and ameliorative effects of N. sativa seeds (2.8 g/kg body weight) in EAE-induced Wistar rats. EAE-induced rats were divided into: 1- EAE-induced rats ("EAE" group). 2- "N. sativa + EAE" group received daily oral administration of N. sativa 2 weeks prior EAE induction until the end of the experiment. 3- "EAE + N. sativa" group received daily oral administration of N. sativa after the appearance of first clinical signs until the end of the experiment. All animals were decapitated at the 28th day post EAE-induction. EAE was investigated using histopathological, immunohistochemical and ultrastructural examinations in addition to determination of some oxidative stress parameters in the cerebellum and medulla. N. sativa suppressed inflammation observed in EAE-induced rats. In addition, N. sativa enhanced remyelination in the cerebellum. Moreover, N. sativa reduced the expression of transforming growth factor beta 1 (TGF β1). N. sativa seeds could provide a promising agent effective in both the protection and treatment of EAE.

  5. Nigella sativa amliorates inflammation and demyelination in the experimental autoimmune encephalomyelitis-induced Wistar rats

    PubMed Central

    Noor, Neveen A; Fahmy, Heba M; Mohammed, Faten F; Elsayed, Anwar A; Radwan, Nasr M

    2015-01-01

    Multiple sclerosis (MS) is the major, immune-mediated, demyelinating neurodegenerative disease of the central nervous system (CNS). Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of MS. The aim of the present study was to investigate the protective and ameliorative effects of N. sativa seeds (2.8 g/kg body weight) in EAE-induced Wistar rats. EAE-induced rats were divided into: 1- EAE-induced rats (“EAE” group). 2- “N. sativa + EAE” group received daily oral administration of N. sativa 2 weeks prior EAE induction until the end of the experiment. 3- “EAE + N. sativa” group received daily oral administration of N. sativa after the appearance of first clinical signs until the end of the experiment. All animals were decapitated at the 28th day post EAE-induction. EAE was investigated using histopathological, immunohistochemical and ultrastructural examinations in addition to determination of some oxidative stress parameters in the cerebellum and medulla. N. sativa suppressed inflammation observed in EAE-induced rats. In addition, N. sativa enhanced remyelination in the cerebellum. Moreover, N. sativa reduced the expression of transforming growth factor beta 1 (TGF β1). N. sativa seeds could provide a promising agent effective in both the protection and treatment of EAE. PMID:26261504

  6. Effects of Intermittent Fasting on Experimental Autoimune Encephalomyelitis in C57BL/6 Mice.

    PubMed

    Razeghi Jahromi, Soodeh; Ghaemi, Amir; Alizadeh, Akram; Sabetghadam, Fatemeh; Moradi Tabriz, Hedieh; Togha, Mansoureh

    2016-06-01

    Several religions recommend periods of fasting. One of the most frequently asked questions of MS patients before the holy month of Ramadan is weather fasting might have an unfavorable effect on their disease course. This debate became more challenging after the publication of experimental studies suggesting that calorie restriction prior to disease induction attenuates disease severity. We conducted this study to assess early and late effects of fasting on the animal model of MS, known as autoimmune encephalomyelitis. EAE was induced in the C57BL/6 mice, using Myelin Oligodendrocyte Glycopeptide  (MOG) 35-55 and they fasted every other day either after the appearance of the first clinical sign or 30 days after disease induction for ten days. Thereafter, the mice were sacrificed for further histological and immunological evaluations. Intermittent fasting after the establishment of EAE did not have any unfavorable effect on the course of disease. Moreover, fasting at the early phase of disease alleviated EAE severity by ameliorating spinal cord demyelination. Fasting suppressed the secretion of IFN-γ, TNF-α and raised IL-10 production in splenocytes. Fasting was also associated with a lower percent of cytotoxicity. Intermittent fasting not only had no unfavorable effect on EAE but also reduced EAE severity if started at early phase of disease. PMID:27424136

  7. Targeting Non-classical Myelin Epitopes to Treat Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Wang, Xiaohua; Zhang, Jintao; Baylink, David J.; Li, Chih-Huang; Watts, Douglas M.; Xu, Yi; Qin, Xuezhong; Walter, Michael H.; Tang, Xiaolei

    2016-01-01

    Qa-1 epitopes, the peptides that bind to non-classical major histocompatibility complex Ib Qa-1 molecules and are recognized by Qa-1-restricted CD8+ regulatory T (Treg) cells, have been identified in pathogenic autoimmune cells that attack myelin sheath in experimental autoimmune encephalomyelitis (EAE, an animal model for multiple sclerosis [MS]). Additionally, immunization with such epitopes ameliorates the EAE. However, identification of such epitopes requires knowledge of the pathogenic autoimmune cells which are largely unknown in MS patients. Hence, we asked whether the CD8+ Treg cells could directly target the myelin sheath to ameliorate EAE. To address this question, we analyzed Qa-1 epitopes in myelin oligodendrocyte glycoprotein (MOG that is a protein in myelin sheath). Here, we report identification of a MOG-specific Qa-1 epitope. Immunization with this epitope suppressed ongoing EAE, which was abrogated by CD8+ T cell depletion. Additionally, the epitope immunization activated the epitope-specific CD8+ T cells which specifically accumulated in the CNS-draining cervical lymph nodes. Finally, CD8+ T cells primed by the epitope immunization transferred EAE suppression. Hence, this study reveals a novel regulatory mechanism mediated by the CD8+ Treg cells. We propose that immunization with myelin-specific HLA-E epitopes (human homologues of Qa-1 epitopes) is a promising therapy for MS. PMID:27796368

  8. Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis

    PubMed Central

    Kalyvas, Athena; Baskakis, Constantinos; Magrioti, Victoria; Constantinou-Kokotou, Violetta; Stephens, Daren; López-Vales, Rubèn; Lu, Jian-Qiang; Yong, V. Wee; Dennis, Edward A.; Kokotos, George

    2009-01-01

    The phospholipase A2 (PLA2) superfamily hydrolyzes phospholipids to release free fatty acids and lysophospholipids, some of which can mediate inflammation and demyelination, hallmarks of the CNS autoimmune disease multiple sclerosis. The expression of two of the intracellular PLA2s (cPLA2 GIVA and iPLA2 GVIA) and two of the secreted PLA2s (sPLA2 GIIA and sPLA2 GV) are increased in different stages of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We show using small molecule inhibitors, that cPLA2 GIVA plays a role in the onset, and iPLA2 GVIA in the onset and progression of EAE. We also show a potential role for sPLA2 in the later remission phase. These studies demonstrate that selective inhibition of iPLA2 can ameliorate disease progression when treatment is started before or after the onset of symptoms. The effects of these inhibitors on lesion burden, chemokine and cytokine expression as well as on the lipid profile provide insights into their potential modes of action. iPLA2 is also expressed by macrophages and other immune cells in multiple sclerosis lesions. Our results therefore suggest that iPLA2 might be an excellent target to block for the treatment of CNS autoimmune diseases, such as multiple sclerosis. PMID:19218359

  9. Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Gharagozloo, Marjan; Mahmoud, Shaimaa; Gris, Denis

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG35–55 plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS. PMID:27610007

  10. Ulinastatin attenuates experimental autoimmune encephalomyelitis by enhancing anti-inflammatory responses.

    PubMed

    Feng, Ming; Shu, Yaqing; Yang, Yu; Zheng, Xueping; Li, Rui; Wang, Yuge; Dai, Yongqiang; Qiu, Wei; Lu, Zhengqi; Hu, Xueqiang

    2014-01-01

    Multiple sclerosis (MS) is a common inflammatory and demyelinating neurological disease. Experimental autoimmune encephalomyelitis (EAE), an animal model of MS, has been widely used to test MS treatment methods. Ulinastatin (UTI), a drug used to treat acute inflammatory disorders, has been tested in animal models of autoimmune inflammatory diseases, such as ulcerative colitis and crescentic glomerulonephritis. We recently found that UTI has a neuroprotective effect on EAE by reducing oligodendrocyte apoptosis and demyelination. The anti-inflammatory effects of UTI on EAE/MS, however, have never been investigated. We have therefore evaluated the anti-inflammatory effects of UTI in EAE and explored the mechanisms underlying this effect. EAE was induced in mice with and without UTI treatment. Inflammation and demyelination of spinal cords were evaluated by staining with hematoxylin and eosin and with Luxol fast blue, respectively. Inflammatory markers in serum were analyzed by the Luminex method, and spinal cords were evaluated by immunofluorescence and Western blotting. UTI significantly lowered the clinical and pathological scores and the serum concentrations of the inflammatory cytokines interleukin (IL)-1β, IL-6, and matrix metal protease-9 (MMP-9). UTI also reduced the expression of tumor necrosis factor-alpha (TNF-α)/nuclear factor kappaB (NF-κB)/inducible nitric oxide synthase (iNOS) proteins and decreased CD11b(+) cells in spinal cord lesions. UTI may protect against EAE in mice by suppressing inflammatory responses. We think that UTI might be a potential therapeutic agent for MS.

  11. Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis.

    PubMed

    Desbiens, Louisane; Lapointe, Catherine; Gharagozloo, Marjan; Mahmoud, Shaimaa; Pejler, Gunnar; Gris, Denis; D'Orléans-Juste, Pedro

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG35-55 plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS. PMID:27610007

  12. Gestational Hypothyroidism Increases the Severity of Experimental Autoimmune Encephalomyelitis in Adult Offspring

    PubMed Central

    Albornoz, Eduardo A.; Carreño, Leandro J.; Cortes, Claudia M.; Gonzalez, Pablo A.; Cisternas, Pablo A.; Cautivo, Kelly M.; Catalán, Tamara P.; Opazo, M. Cecilia; Eugenin, Eliseo A.; Berman, Joan W.; Bueno, Susan M.; Kalergis, Alexis M.

    2013-01-01

    Background: Maternal thyroid hormones play a fundamental role in appropriate fetal development during gestation. Offspring that have been gestated under maternal hypothyroidism suffer cognitive impairment. Thyroid hormone deficiency during gestation can significantly impact the central nervous system by altering the migration, differentiation, and function of neurons, oligodendrocytes, and astrocytes. Given that gestational hypothyroidism alters the immune cell ratio in offspring, it is possible that this condition could result in higher sensitivity for the development of autoimmune diseases. Methods: Adult mice gestated under hypothyroidism were induced with experimental autoimmune encephalomyelitis (EAE). Twenty-one days after EAE induction, the disease score, myelin content, immune cell infiltration, and oligodendrocyte death were evaluated. Results: We observed that mice gestated under hypothyroidism showed higher EAE scores after disease induction during adulthood compared to mice gestated in euthyroidism. In addition, spinal cord sections of mice gestated under hypothyroidism that suffered EAE in adulthood showed higher demyelination, CD4+ and CD8+ infiltration, and increased oligodendrocyte death. Conclusions: These results show for the first time that a deficiency in maternal thyroid hormones during gestation can influence the outcome of a central nervous system inflammatory disease, such as EAE, in their offspring. These data strongly support evaluating thyroid hormones in pregnant women and treating hypothyroidism during pregnancy to prevent increased susceptibility to inflammatory diseases in the central nervous system of offspring. PMID:23777566

  13. LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice.

    PubMed

    Sun, Jun-Jun; Ren, Qing-Guo; Xu, Lin; Zhang, Zhi-Jun

    2015-09-18

    More than 50% of multiple sclerosis patients develop cognitive impairment. However, the underlying mechanisms are still unclear, and there is no effective treatment. LINGO-1 (LRR and Ig domain containing NOGO receptor interacting protein 1) has been identified as an inhibitor of oligodendrocyte differentiation and myelination. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, we assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our results suggest that demyelination in the PHC and fimbria-fornix might contribute to cognitive deficits and the LINGO-1 antibody could ameliorate these deficits by promoting myelin growth in the PHC. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients.

  14. Effects of exercise in a relapsing-remitting model of experimental autoimmune encephalomyelitis.

    PubMed

    Klaren, Rachel E; Stasula, Ulana; Steelman, Andrew J; Hernandez, Jessica; Pence, Brandt D; Woods, Jeffrey A; Motl, Robert W

    2016-10-01

    Previous research has examined the effects of exercise in experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. However, all previous studies have utilized a chronic model of EAE, with exercise delivered prior to or immediately after induction of EAE. To our knowledge, no study has examined the effects of exercise delivered during a remission period after initial disease onset in a relapsing-remitting model of EAE (RR-EAE). The current study examines the effects of both voluntary wheel running and forced treadmill exercise on clinical disability and hippocampal brain-derived neurotrophic factor (BDNF) in SJL mice with RR-EAE. The results demonstrate no significant effects of exercise delivered during remission after initial disease onset on clinical disability scores or levels of hippocampal BDNF in mice with RR-EAE. Furthermore, our results demonstrate no significant increase in citrate synthase activity in the gastrocnemius and soleus muscles of mice in the running wheel or treadmill conditions compared with the sedentary condition. These results suggest that the exercise stimuli might have been insufficient to elicit differences in clinical disability or hippocampal BDNF among treatment conditions. © 2016 Wiley Periodicals, Inc. PMID:27312674

  15. Autophagy regulates the therapeutic potential of mesenchymal stem cells in experimental autoimmune encephalomyelitis.

    PubMed

    Dang, Shipeng; Xu, Huanbai; Xu, Congfeng; Cai, Wei; Li, Qian; Cheng, Yiji; Jin, Min; Wang, Ru-Xing; Peng, Yongde; Zhang, Yi; Wu, Changping; He, Xiaozhou; Wan, Bing; Zhang, Yanyun

    2014-07-01

    Mesenchymal stem cell (MSC)-based therapy is a promising approach to treat various inflammatory disorders including multiple sclerosis. However, the fate of MSCs in the inflammatory microenvironment is largely unknown. Experimental autoimmune encephalomyelitis (EAE) is a well-studied animal model of multiple sclerosis. We demonstrated that autophagy occurred in MSCs during their application for EAE treatment. Inflammatory cytokines, e.g., interferon gamma and tumor necrosis factor, induced autophagy in MSCs synergistically by inducing expression of BECN1/Beclin 1. Inhibition of autophagy by knockdown of Becn1 significantly improved the therapeutic effects of MSCs on EAE, which was mainly attributable to enhanced suppression upon activation and expansion of CD4(+) T cells. Mechanistically, inhibition of autophagy increased reactive oxygen species generation and mitogen-activated protein kinase 1/3 activation in MSCs, which were essential for PTGS2 (prostaglandin-endoperoxide synthase 2 [prostaglandin G/H synthase and cyclooxygenase]) and downstream prostaglandin E2 expression to exert immunoregulatory function. Furthermore, pharmacological treatment of MSCs to inhibit autophagy increased their immunosuppressive effects on T cell-mediated EAE. Our findings indicate that inflammatory microenvironment-induced autophagy downregulates the immunosuppressive function of MSCs. Therefore, modulation of autophagy in MSCs would provide a novel strategy to improve MSC-based immunotherapy.

  16. The experimental autoimmune encephalomyelitis (EAE) model of MS: utility for understanding disease pathophysiology and treatment

    PubMed Central

    ROBINSON, ANDREW P.; HARP, CHRISTOPHER T.; NORONHA, AVERTANO; MILLER, STEPHEN D.

    2014-01-01

    While no single model can exactly recapitulate all aspects of multiple sclerosis (MS), animal models are essential in understanding the induction and pathogenesis of the disease and to develop therapeutic strategies that limit disease progression and eventually lead to effective treatments for the human disease. Several different models of MS exist, but by far the best understood and most commonly used is the rodent model of experimental autoimmune encephalomyelitis (EAE). This model is typically induced by either active immunization with myelin-derived proteins or peptides in adjuvant or by passive transfer of activated myelin-specific CD4+ T lymphocytes. Mouse models are most frequently used because of the inbred genotype of laboratory mice, their rapid breeding capacity, the ease of genetic manipulation, and availability of transgenic and knockout mice to facilitate mechanistic studies. Although not all therapeutic strategies for MS have been developed in EAE, all of the current US Food and Drug Administration (FDA)-approved immunomodulatory drugs are effective to some degree in treating EAE, a strong indicator that EAE is an extremely useful model to study potential treatments for MS. Several therapies, such as glatiramer acetate (GA: Copaxone), and natalizumab (Tysabri), were tested first in the mouse model of EAE and then went on to clinical trials. Here we discuss the usefulness of the EAE model in understanding basic disease pathophysiology and developing treatments for MS as well as the potential drawbacks of this model. PMID:24507518

  17. C-reactive protein directly suppresses T helper 1 cell differentiation and alleviates experimental autoimmune encephalomyelitis

    PubMed Central

    Zhang, Lin; Liu, Shan-Hui; Wright, Tyler T.; Shen, Zhi-Yuan; Li, Hai-Yun; Zhu, Wei; Potempa, Lawrence A.; Ji, Shang-Rong; Szalai, Alexander J.; Wu, Yi

    2015-01-01

    Human C-reactive protein (CRP) is a serum soluble pattern recognition receptor (PRR) that serves as a marker of inflammation and directly contributes to innate immunity. Herein we show that human CRP also directly contributes to adaptive immunity, i.e. native CRP binds specifically to human Jurkat T cells and to mouse naïve CD4+ T cells and modulates their T helper (Th) 1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naïve CD4+ T cells. In vivo for human CRP transgenic (CRPtg) compared to wild type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover in both CRPtg mice and in wild type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble PRR to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease. PMID:25917100

  18. Significant Contribution of Mouse Mast Cell Protease 4 in Early Phases of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Gharagozloo, Marjan; Mahmoud, Shaimaa; Gris, Denis

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a mouse model that reproduces cardinal signs of clinical, histopathological, and immunological features found in Multiple Sclerosis (MS). Mast cells are suggested to be involved in the main inflammatory phases occurring during EAE development, possibly by secreting several autacoids and proteases. Among the latter, the chymase mouse mast cell protease 4 (mMCP-4) can contribute to the inflammatory response by producing endothelin-1 (ET-1). The aim of this study was to determine the impact of mMCP-4 on acute inflammatory stages in EAE. C57BL/6 wild type (WT) or mMCP-4 knockout (KO) mice were immunized with MOG35–55 plus complete Freund's adjuvant followed by pertussis toxin. Immunized WT mice presented an initial acute phase characterized by progressive increases in clinical score, which were significantly reduced in mMCP-4 KO mice. In addition, higher levels of spinal myelin were found in mMCP-4 KO as compared with WT mice. Finally, whereas EAE triggered significant increases in brain levels of mMCP-4 mRNA and immunoreactive ET-1 in WT mice, the latter peptide was reduced to basal levels in mMCP-4 KO congeners. Together, the present study supports a role for mMCP-4 in the early inflammatory phases of the disease in a mouse model of MS.

  19. Treatment of ongoing autoimmune encephalomyelitis with activated B-cell progenitors maturing into regulatory B cells

    PubMed Central

    Korniotis, Sarantis; Gras, Christophe; Letscher, Hélène; Montandon, Ruddy; Mégret, Jérôme; Siegert, Stefanie; Ezine, Sophie; Fallon, Padraic G.; Luther, Sanjiv A.; Fillatreau, Simon; Zavala, Flora

    2016-01-01

    The influence of signals perceived by immature B cells during their development in bone marrow on their subsequent functions as mature cells are poorly defined. Here, we show that bone marrow cells transiently stimulated in vivo or in vitro through the Toll-like receptor 9 generate proB cells (CpG-proBs) that interrupt experimental autoimmune encephalomyelitis (EAE) when transferred at the onset of clinical symptoms. Protection requires differentiation of CpG-proBs into mature B cells that home to reactive lymph nodes, where they trap T cells by releasing the CCR7 ligand, CCL19, and to inflamed central nervous system, where they locally limit immunopathogenesis through interleukin-10 production, thereby cooperatively inhibiting ongoing EAE. These data demonstrate that a transient inflammation at the environment, where proB cells develop, is sufficient to confer regulatory functions onto their mature B-cell progeny. In addition, these properties of CpG-proBs open interesting perspectives for cell therapy of autoimmune diseases. PMID:27396388

  20. Prostaglandin I2 Signaling Drives Th17 Differentiation and Exacerbates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Zhou, Weisong; Dowell, Dustin R.; Huckabee, Matthew M.; Newcomb, Dawn C.; Boswell, Madison G.; Goleniewska, Kasia; Lotz, Matthew T.; Toki, Shinji; Yin, Huiyong; Yao, Songyi; Natarajan, Chandramohan; Wu, Pingsheng; Sriram, Subramaniam; Breyer, Richard M.; FitzGerald, Garret A.; Peebles, R. Stokes

    2012-01-01

    Background Prostaglandin I2 (PGI2), a lipid mediator currently used in treatment of human disease, is a critical regulator of adaptive immune responses. Although PGI2 signaling suppressed Th1 and Th2 immune responses, the role of PGI2 in Th17 differentiation is not known. Methodology/Principal Findings In mouse CD4+CD62L+ naïve T cell culture, the PGI2 analogs iloprost and cicaprost increased IL-17A and IL-22 protein production and Th17 differentiation in vitro. This effect was augmented by IL-23 and was dependent on PGI2 receptor IP signaling. In mouse bone marrow-derived CD11c+ dendritic cells (BMDCs), PGI2 analogs increased the ratio of IL-23/IL-12, which is correlated with increased ability of BMDCs to stimulate naïve T cells for IL-17A production. Moreover, IP knockout mice had delayed onset of a Th17-associated neurological disease, experimental autoimmune encephalomyelitis (EAE), and reduced infiltration of IL-17A-expressing mononuclear cells in the spinal cords compared to wild type mice. These results suggest that PGI2 promotes in vivo Th17 responses. Conclusion The preferential stimulation of Th17 differentiation by IP signaling may have important clinical implications as PGI2 and its analogs are commonly used to treat human pulmonary hypertension. PMID:22590492

  1. Identification of gene expression patterns crucially involved in experimental autoimmune encephalomyelitis and multiple sclerosis

    PubMed Central

    Herrmann, Martin M.; Barth, Silvia; Greve, Bernhard; Schumann, Kathrin M.; Bartels, Andrea

    2016-01-01

    ABSTRACT After encounter with a central nervous system (CNS)-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS), a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1) rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J) mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions. PMID:27519689

  2. Natural Killer T Cell Activation Protects Mice Against Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Singh, Avneesh K.; Wilson, Michael T.; Hong, Seokmann; Olivares-Villagómez, Danyvid; Du, Caigan; Stanic, Aleksandar K.; Joyce, Sebastian; Sriram, Subramaniam; Koezuka, Yasuhiko; Van Kaer, Luc

    2001-01-01

    Experimental autoimmune encephalomyelitis (EAE) serves as a prototypic model for T cell–mediated autoimmunity. Vα14 natural killer T (NKT) cells are a subset of T lymphocytes that recognize glycolipid antigens presented by the nonpolymorphic major histocompatibility complex (MHC) class I–like protein CD1d. Here, we show that activation of Vα14 NKT cells by the glycosphingolipid α-galactosylceramide (α-GalCer) protects susceptible mice against EAE. β-GalCer, which binds CD1d but is not recognized by NKT cells, failed to protect mice against EAE. Furthermore, α-GalCer was unable to protect CD1d knockout (KO) mice against EAE, indicating the requirement for an intact CD1d antigen presentation pathway. Protection of disease conferred by α-GalCer correlated with its ability to suppress myelin antigen-specific Th1 responses and/or to promote myelin antigen-specific Th2 cell responses. α-GalCer was unable to protect IL-4 KO and IL-10 KO mice against EAE, indicating a critical role for both of these cytokines. Because recognition of α-GalCer by NKT cells is phylogenetically conserved, our findings have identified NKT cells as novel target cells for treatment of inflammatory diseases of the central nervous system. PMID:11748281

  3. Thiamine deficiency promotes T cell infiltration in experimental autoimmune encephalomyelitis: the involvement of CCL2.

    PubMed

    Ji, Zhe; Fan, Zhiqin; Zhang, Ying; Yu, Ronghuan; Yang, Haihua; Zhou, Chenghua; Luo, Jia; Ke, Zun-Ji

    2014-09-01

    Multiple sclerosis (MS) is a complex multifactorial disease that results from the interplay between environmental factors and a susceptible genetic background. Experimental autoimmune encephalomyelitis (EAE) has been widely used to investigate the mechanisms underlying MS pathogenesis. Chemokines, such as CCL2, are involved in the development of EAE. We have previously shown that thiamine deficiency (TD) induced CCL2 in neurons. We hypothesized that TD may affect the pathogenesis of EAE. In this study, EAE was induced in C57BL/6J mice by the injection of myelin oligodendroglial glycoprotein (MOG) peptides 35-55 with or without TD. TD aggravated the development of EAE, which was indicated by clinical scores and pathologic alterations in the spinal cord. TD also accelerated the development of EAE in an adoptive transfer EAE model. TD caused microglial activation and a drastic increase (up 140%) in leukocyte infiltration in the spinal cord of the EAE mice; specifically, TD increased Th1 and Th17 cells. TD upregulated the expression of CCL2 and its receptor CCR2 in the spinal cord of EAE mice. Cells in peripheral lymph node and spleen isolated from MOG-primed TD mice showed much stronger proliferative responses to MOG. CCL2 stimulated the proliferation and migration of T lymphocytes in vitro. Our results suggested that TD exacerbated the development of EAE through activating CCL2 and inducing pathologic inflammation.

  4. γδ T cell subsets play opposing roles in regulating experimental autoimmune encephalomyelitis.

    PubMed

    Blink, Sarah E; Caldis, Matthew W; Goings, Gwendolyn E; Harp, Christopher T; Malissen, Bernard; Prinz, Immo; Xu, Dan; Miller, Stephen D

    2014-07-01

    γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1(+) and Vγ4(+), with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4(+) subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4(+) Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS.

  5. Classification of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome by Types of Fatigue

    PubMed Central

    Jason, Leonard A.; Boulton, Aaron; Porter, Nicole S.; Jessen, Tricia; Njoku, Mary Gloria

    2016-01-01

    Persons with Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) often complain of fatigue states (e.g. post-exertional malaise, brain fog) that are qualitatively different than normal, daily fatigue. Given the heterogeneous nature of ME/CFS, it is likely that individuals with this illness experience these fatigue types differently in terms of severity and frequency. It is also possible that meaningful subgroups of patients exist regarding different patterns of the fatigue experience. The purpose of this study was to investigate whether individuals with ME/CFS can be classified in a meaningful way according to the different types of fatigue they experience. One hundred individuals with ME/CFS participated in the study. Individuals that met inclusion criteria were administered the Multiple Fatigue Types Questionnaire (MFTQ), a five-factor instrument that distinguishes between different types of fatigue. A cluster analysis was used to classify patients into various clusters based upon factor subscale scores. Using a three-factor solution, individuals were classified according to illness severity (low, moderate, severe) across the different fatigue factors. However, a 5-cluster solution enabled participants with moderate to severe fatigue levels to fall out into more differentiated clusters and demonstrate distinct fatigue state patterns. These results suggest that fatigue patterns of individuals with ME/CFS are heterogeneous and patients may be classified into meaningful subgroups. PMID:20185398

  6. Visualisation of the kinetics of macrophage infiltration during experimental autoimmune encephalomyelitis by magnetic resonance imaging.

    PubMed

    Baeten, Kurt; Hendriks, Jerome Ja; Hellings, Niels; Theunissen, Evi; Vanderlocht, Joris; Ryck, Leen De; Gelan, Jan; Stinissen, Piet; Adriaensens, Peter

    2008-03-01

    Macrophages are considered to be the predominant effector cells in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Ultra small particles of iron oxide (USPIO) can be used to detect macrophage infiltrates in the CNS with magnetic resonance imaging (MRI). Here, we investigated whether the kinetics of lesion formation in EAE can be visualised by altering the time point of USPIO injection and the time interval between particle injection and MRI. When USPIO are systemically injected 24 h before MRI, hypo intense regions are detected in different brain regions depending on the disease stage. These regions correspond to sites of macrophage infiltration. A more complete visualisation of sites of inflammation is accomplished by USPIO injection at disease onset and postponing MRI to top of disease. This study demonstrates that the distribution pattern and amount of inflammatory lesions detected with USPIO, depends on timing of USPIO administration and subsequent MRI. These findings are important for a correct application and interpretation of USPIO dependent contrast imaging of CNS inflammation.

  7. Therapeutic effect of baicalin on experimental autoimmune encephalomyelitis is mediated by SOCS3 regulatory pathway

    PubMed Central

    Zhang, Yuan; Li, Xing; Ciric, Bogoljub; Ma, Cun-Gen; Gran, Bruno; Rostami, Abdolmohamad; Zhang, Guang-Xian

    2015-01-01

    Natural compounds derived from medicinal plants have long been considered a rich source of novel therapeutic agents. Baicalin (Ba) is a bioactive flavonoid compound derived from the root of Scutellaria baicalensis, an herb widely used in traditional medicine for the treatment of various inflammatory diseases. In this study, we investigate the effects and mechanism of action of Ba in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Ba treatment effectively ameliorated clinical disease severity in myelin oligodendrocyte glycoprotein (MOG)35–55 peptide-induced EAE, and reduced inflammation and demyelination of the central nervous system (CNS). Ba reduced infiltration of immune cells into the CNS, inhibited expression of proinflammatory molecules and chemokines, and prevented Th1 and Th17 cell differentiation via STAT/NFκB signaling pathways. Further, we showed that SOCS3 induction is essential to the effects of Ba, given that the inhibitory effect of Ba on pathogenic Th17 responses was largely abolished when SOCS3 signaling was knocked down. Taken together, our findings demonstrate that Ba has significant potential as a novel anti-inflammatory agent for therapy of autoimmune diseases such as MS. PMID:26616302

  8. CCR5 knockout suppresses experimental autoimmune encephalomyelitis in C57BL/6 mice.

    PubMed

    Gu, Sun Mi; Park, Mi Hee; Yun, Hyung Mun; Han, Sang Bae; Oh, Ki Wan; Son, Dong Ju; Yun, Jae Suk; Hong, Jin Tae

    2016-03-29

    Multiple sclerosis (MS) is an inflammatory disease in which myelin in the spinal cord is damaged. C-C chemokine receptor type 5 (CCR5) is implicated in immune cell migration and cytokine release in central nervous system (CNS). We investigated whether CCR5 plays a role in MS progression using a murine model, experimental autoimmune encephalomyelitis (EAE), in CCR5 deficient (CCR5-/-) mice. CCR5-/- and CCR5+/+ (wild-type) mice were immunized with myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) followed by pertussis toxin, after which EAE paralysis was scored for 28 days. We found that clinical scoring and EAE neuropathology were lower in CCR5-/- mice than CCR5+/+ mice. Immune cells (CD3+, CD4+, CD8+, B cell, NK cell and macrophages) infiltration and astrocytes/microglial activation were attenuated in CCR5-/- mice. Moreover, levels of IL-1β, TNF-α, IFN-γ and MCP-1 cytokine levels were decreased in CCR5-/- mice spinal cord. Myelin basic protein (MBP) and CNPase were increased while NG2 and O4 were decreased in CCR5-/- mice, indicating that demyelination was suppressed by CCR5 gene deletion. These findings suggest that CCR5 is likely participating in demyelination in the spinal cord the MS development, and that it could serve as an effective therapeutic target for the treatment of MS.

  9. Prevention of experimental autoimmune encephalomyelitis by antibodies against α4βl integrin

    NASA Astrophysics Data System (ADS)

    Yednock, Ted A.; Cannon, Catherine; Fritz, Lawrence C.; Sanchez-Madrid, Francisco; Steinman, Lawrence; Karin, Nathan

    1992-03-01

    EXPERIMENTAL autoimmune encephalomyelitis (EAE) is an inflammatory condition of the central nervous system with similarities to multiple sclerosis1,2. In both diseases, circulating leukocytes penetrate the blood-brain barrier and damage myelin, resulting in impaired nerve conduction and paralysis3-5. We sought to identify the adhesion receptors that mediate the attachment of circulating leukocytes to inflamed brain endothelium in EAE, because this interaction is the first step in leukocyte entry into the central nervous system. Using an in vitro adhesion assay on tissue sections, we found that lymphocytes and monocytes bound selectively to inflamed EAE brain vessels. Binding was inhibited by antibodies against the integrin molecule α4βl, but not by antibodies against numerous other adhesion receptors. When tested in vivo, anti-α4 integrin effectively prevented the accumulation of leukocytes in the central nervous system and the development of EAE. Thus, therapies designed to interfere with α4βl integrin may be useful in treating inflammatory diseases of the central nervous system, such as multiple sclerosis.

  10. Conduction block in the peripheral nervous system in experimental allergic encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Pender, M. P.; Sears, T. A.

    1982-04-01

    Experimental allergic encephalomyelitis (EAE) has been widely studied as a model of multiple sclerosis, a central nervous system (CNS) disease of unknown aetiology. The clinical features of both EAE and multiple sclerosis provide the only guide to the progress and severity of these diseases, and are used to assess the response to treatment. In such comparisons the clinical features of EAE are assumed to be due to lesions in the CNS, but in this disease there is also histological evidence of damage to the peripheral nervous system1-8. However, the functional consequences of such peripheral lesions have been entirely ignored. To examine this we have studied nerve conduction in rabbits with EAE. We report here that most of the large diameter afferent fibres are blocked in the region of the dorsal root ganglion and at the dorsal root entry zone, thus accounting for the loss of tendon jerks and also, through the severe loss of proprioceptive information, the ataxia of these animals. We conclude that whenever clinical comparisons are made between EAE and multiple sclerosis, the pathophysiology associated with the histological damage of the peripheral nervous system must be taken into account.

  11. Critical role of activation induced cytidine deaminase in experimental autoimmune encephalomyelitis.

    PubMed

    Sun, Yonglian; Peng, Ivan; Senger, Kate; Hamidzadeh, Kajal; Reichelt, Mike; Baca, Miriam; Yeh, Ronald; Lorenzo, Maria N; Sebrell, Andrew; Dela Cruz, Christopher; Tam, Lucinda; Corpuz, Racquel; Wu, Jiansheng; Sai, Tao; Roose-Girma, Merone; Warming, Søren; Balazs, Mercedesz; Gonzalez, Lino C; Caplazi, Patrick; Martin, Flavius; Devoss, Jason; Zarrin, Ali A

    2013-03-01

    Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder caused by chronic inflammation and demyelination within the central nervous system (CNS). Clinical studies in MS patients have demonstrated efficacy with B cell targeted therapies such as anti-CD20. However, the exact role that B cells play in the disease process is unclear. Activation Induced cytidine deaminase (AID) is an essential enzyme for the processes of antibody affinity maturation and isotype switching. To evaluate the impact of affinity maturation and isotype switching, we have interrogated the effect of AID-deficiency in an animal model of MS. Here, we show that the severity of experimental autoimmune encephalomyelitis (EAE) induced by the extracellular domain of human myelin oligodendrocyte glycoprotein (MOG1-125) is significantly reduced in Aicda deficient mice, which, unlike wild-type mice, lack serum IgG to myelin associated antigens. MOG specific T cell responses are comparable between wild-type and Aicda knockout mice suggesting an active role for antigen experienced B cells. Thus affinity maturation and/or class switching are critical processes in the pathogenesis of EAE. PMID:23167594

  12. Critical role of activation induced cytidine deaminase in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    2013-01-01

    Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder caused by chronic inflammation and demyelination within the central nervous system (CNS). Clinical studies in MS patients have demonstrated efficacy with B cell targeted therapies such as anti-CD20. However, the exact role that B cells play in the disease process is unclear. Activation Induced cytidine deaminase (AID) is an essential enzyme for the processes of antibody affinity maturation and isotype switching. To evaluate the impact of affinity maturation and isotype switching, we have interrogated the effect of AID-deficiency in an animal model of MS. Here, we show that the severity of experimental autoimmune encephalomyelitis (EAE) induced by the extracellular domain of human myelin oligodendrocyte glycoprotein (MOG1-125) is significantly reduced in Aicda deficient mice, which, unlike wild-type mice, lack serum IgG to myelin associated antigens. MOG specific T cell responses are comparable between wild-type and Aicda knockout mice suggesting an active role for antigen experienced B cells. Thus affinity maturation and/or class switching are critical processes in the pathogenesis of EAE. PMID:23167594

  13. LINGO-1 antibody ameliorates myelin impairment and spatial memory deficits in experimental autoimmune encephalomyelitis mice

    PubMed Central

    Sun, Jun-Jun; Ren, Qing-Guo; Xu, Lin; Zhang, Zhi-Jun

    2015-01-01

    More than 50% of multiple sclerosis patients develop cognitive impairment. However, the underlying mechanisms are still unclear, and there is no effective treatment. LINGO-1 (LRR and Ig domain containing NOGO receptor interacting protein 1) has been identified as an inhibitor of oligodendrocyte differentiation and myelination. Using the experimental autoimmune encephalomyelitis (EAE) mouse model, we assessed cognitive function at early and late stages of EAE, determined brain expression of myelin basic protein (MBP) and investigated whether the LINGO-1 antibody could restore deficits in learning and memory and ameliorate any loss of MBP. We found that deficits in learning and memory occurred in late EAE and identified decreased expression of MBP in the parahippocampal cortex (PHC) and fimbria-fornix. Moreover, the LINGO-1 antibody significantly improved learning and memory in EAE and partially restored MBP in PHC. Furthermore, the LINGO-1 antibody activated the AKT/mTOR signaling pathway regulating myelin growth. Our results suggest that demyelination in the PHC and fimbria-fornix might contribute to cognitive deficits and the LINGO-1 antibody could ameliorate these deficits by promoting myelin growth in the PHC. Our research demonstrates that LINGO-1 antagonism may be an effective approach to the treatment of the cognitive impairment of multiple sclerosis patients. PMID:26383267

  14. Epitopes of Microbial and Human Heat Shock Protein 60 and Their Recognition in Myalgic Encephalomyelitis

    PubMed Central

    Elfaitouri, Amal; Herrmann, Björn; Bölin-Wiener, Agnes; Wang, Yilin; Gottfries, Carl-Gerhard; Zachrisson, Olof; Pipkorn, Rϋdiger; Rönnblom, Lars; Blomberg, Jonas

    2013-01-01

    Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity. PMID:24312270

  15. Experimental autoimmune encephalomyelitis is a good model of multiple sclerosis if used wisely.

    PubMed

    Baker, David; Amor, Sandra

    2014-09-01

    Although multiple sclerosis is a uniquely human disease, many pathological features can be induced in experimental autoimmune encephalomyelitis (EAE) models following induction of central nervous system-directed autoimmunity. Whilst it is an imperfect set of models, EAE can be used to identify pathogenic mechanisms and therapeutics. However, the failure to translate many treatments from EAE into human benefit has led some to question the validity of the EAE model. Whilst differences in biology between humans and other species may account for this, it is suggested here that the failure to translate may be considerably influenced by human activity. Basic science contributes to failings in aspects of experimental design and over-interpretation of results and lack of transparency and reproducibility of the studies. Importantly issues in trial design by neurologists and other actions of the pharmaceutical industry destine therapeutics to failure and terminate basic science projects. However animal, particularly mechanism-orientated, studies have increasingly identified useful treatments and provided mechanistic ideas on which most hypothesis-led clinical research is based. Without EAE and other animal studies, clinical investigations will continue to be "look-see" exercises, which will most likely provide more misses than hits and will fail the people with MS that they aim to serve.

  16. High-Throughput Sequencing of Plasma MicroRNA in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

    PubMed Central

    Brenu, Ekua W.; Ashton, Kevin J.; Batovska, Jana; Staines, Donald R.; Marshall-Gradisnik, Sonya M.

    2014-01-01

    Background MicroRNAs (miRNAs) are known to regulate many biological processes and their dysregulation has been associated with a variety of diseases including Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). The recent discovery of stable and reproducible miRNA in plasma has raised the possibility that circulating miRNAs may serve as novel diagnostic markers. The objective of this study was to determine the role of plasma miRNA in CFS/ME. Results Using Illumina high-throughput sequencing we identified 19 miRNAs that were differentially expressed in the plasma of CFS/ME patients in comparison to non-fatigued controls. Following RT-qPCR analysis, we were able to confirm the significant up-regulation of three miRNAs (hsa-miR-127-3p, hsa-miR-142-5p and hsa-miR-143-3p) in the CFS/ME patients. Conclusion Our study is the first to identify circulating miRNAs from CFS/ME patients and also to confirm three differentially expressed circulating miRNAs in CFS/ME patients, providing a basis for further study to find useful CFS/ME biomarkers. PMID:25238588

  17. IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation.

    PubMed

    Sosa, Rebecca A; Murphey, Cathi; Robinson, Rachel R; Forsthuber, Thomas G

    2015-09-01

    Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ-/-) or IFN-γ receptor knockout (IFN-γR-/-) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, "free" myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-l-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ-signaling-deficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.

  18. Efficacy of rintatolimod in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME).

    PubMed

    Mitchell, William M

    2016-06-01

    Chronic fatigue syndrome/ Myalgic encephalomyelitis (CFS/ME) is a poorly understood seriously debilitating disorder in which disabling fatigue is an universal symptom in combination with a variety of variable symptoms. The only drug in advanced clinical development is rintatolimod, a mismatched double stranded polymer of RNA (dsRNA). Rintatolimod is a restricted Toll-Like Receptor 3 (TLR3) agonist lacking activation of other primary cellular inducers of innate immunity (e.g.- cytosolic helicases). Rintatolimod also activates interferon induced proteins that require dsRNA for activity (e.g.- 2'-5' adenylate synthetase, protein kinase R). Rintatolimod has achieved statistically significant improvements in primary endpoints in Phase II and Phase III double-blind, randomized, placebo-controlled clinical trials with a generally well tolerated safety profile and supported by open-label trials in the United States and Europe. The chemistry, mechanism of action, clinical trial data, and current regulatory status of rintatolimod for CFS/ME including current evidence for etiology of the syndrome are reviewed.

  19. Increased Vulnerability to Pattern-Related Visual Stress in Myalgic Encephalomyelitis.

    PubMed

    Wilson, Rachel L; Paterson, Kevin B; Hutchinson, Claire V

    2015-12-01

    The objective of this study was to determine vulnerability to pattern-related visual stress in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A total of 20 ME/CFS patients and 20 matched (age, gender) controls were recruited to the study. Pattern-related visual stress was determined using the Pattern Glare Test. Participants viewed three patterns, the spatial frequencies (SF) of which were 0.3 (low-SF), 2.3 (mid-SF), and 9.4 (high-SF) cycles per degree (c/deg). They reported the number of distortions they experienced when viewing each pattern. ME/CFS patients exhibited significantly higher pattern glare scores than controls for the mid-SF pattern. Mid-high SF differences were also significantly higher in patients than controls. These findings provide evidence of altered visual perception in ME/CFS. Pattern-related visual stress may represent an identifiable clinical feature of ME/CFS that will prove useful in its diagnosis. However, further research is required to establish if these symptoms reflect ME/CFS-related changes in the functioning of sensory neural pathways.

  20. Epitopes of microbial and human heat shock protein 60 and their recognition in myalgic encephalomyelitis.

    PubMed

    Elfaitouri, Amal; Herrmann, Björn; Bölin-Wiener, Agnes; Wang, Yilin; Gottfries, Carl-Gerhard; Zachrisson, Olof; Pipkorn, Rϋdiger; Rönnblom, Lars; Blomberg, Jonas

    2013-01-01

    Myalgic encephalomyelitis (ME, also called Chronic Fatigue Syndrome), a common disease with chronic fatigability, cognitive dysfunction and myalgia of unknown etiology, often starts with an infection. The chaperonin human heat shock protein 60 (HSP60) occurs in mitochondria and in bacteria, is highly conserved, antigenic and a major autoantigen. The anti-HSP60 humoral (IgG and IgM) immune response was studied in 69 ME patients and 76 blood donors (BD) (the Training set) with recombinant human and E coli HSP60, and 136 30-mer overlapping and targeted peptides from HSP60 of humans, Chlamydia, Mycoplasma and 26 other species in a multiplex suspension array. Peptides from HSP60 helix I had a chaperonin-like activity, but these and other HSP60 peptides also bound IgG and IgM with an ME preference, theoretically indicating a competition between HSP60 function and antibody binding. A HSP60-based panel of 25 antigens was selected. When evaluated with 61 other ME and 399 non-ME samples (331 BD, 20 Multiple Sclerosis and 48 Systemic Lupus Erythematosus patients), a peptide from Chlamydia pneumoniae HSP60 detected IgM in 15 of 61 (24%) of ME, and in 1 of 399 non-ME at a high cutoff (p<0.0001). IgM to specific cross-reactive epitopes of human and microbial HSP60 occurs in a subset of ME, compatible with infection-induced autoimmunity.

  1. Treatment with Vitamin D/MOG Association Suppresses Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Chiuso-Minicucci, Fernanda; Ishikawa, Larissa Lumi Watanabe; Mimura, Luiza Ayumi Nishiyama; Fraga-Silva, Thais Fernanda de Campos; França, Thais Graziela Donegá; Zorzella-Pezavento, Sofia Fernanda Gonçalves; Marques, Camila; Ikoma, Maura Rosane Valerio; Sartori, Alexandrina

    2015-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model to study multiple sclerosis (MS). Considering the tolerogenic effects of active vitamin D, we evaluated the therapeutic effect of myelin oligodendrocyte glycoprotein (MOG) associated with active vitamin D in EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG emulsified with Complete Freund’s Adjuvant plus Mycobacterium tuberculosis. Animals also received two intraperitoneal doses of Bordetella pertussis toxin. One day after immunization, mice were treated with 0,1μg of 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) every other day during 15 days (on days 1, 3, 5, 7, 9, 11, 13 and 15). MOG (150μg) was co-administered on days 3 and 11. The administration of 1,25(OH) 2D3 or MOG determined significant reduction in EAE incidence and in clinical scores. When MOG was associated with 1,25(OH) 2D3 the animals did not develop EAE. Spleen and central nervous system (CNS) cell cultures from this group produced less IL-6 and IL-17 upon stimulation with MOG in comparison to the EAE control group. In addition, this treatment inhibited dendritic cells maturation in the spleen and reduced inflammatory infiltration in the CNS. The association of MOG with 1,25(OH) 2D3 was able to control EAE development. PMID:25965341

  2. Immunosuppression of experimental allergic encephalomyelitis in guinea pigs by antibrain and antithymocyte heteroantisera.

    PubMed

    Rauch, H C; Tom, B H

    1980-01-01

    Experimental allergic encephalomyelitis (EAE), induced by central nervous system (CNS) myelin basic protein (MBP) in adjuvant, is considered a thymus dependent autoimmune disease. Brain contains the thymic antigen, thy 1. The possibility that brain associated anti thy 1 immunoglobulin may be provoked in certain pathologic conditions of the CNS suggested a comparative evaluation of brain and thymocyte antisera on the development of EAE. Antisera produced in rabbits against brain from guinea pigs, rats and mice or fetal guinea pig thymus were highly reactive against thy 1 containing cells when assessed by indirect immunofluorescent staining or complement-mediated cell lysis. Treatment of guinea pigs with heteroantisera to guinea pig and mouse, but not to rat brain, for 3 days around the time of MBP sensitization markedly reduced physical signs of disease, particularly paralysis, but had little effect on the development of inflammatory lesions in the CNS. Anti-guinea pig thymocyte sera eliminated all physical signs of EAE with only residual pathology. These results establish the relative immunosuppressive effect of brain and thymocyte antisera in EAE and corroborate the thymus-dependent nature of EAE in guinea pigs.

  3. Novel sinomenine derivative 1032 improves immune suppression in experimental autoimmune encephalomyelitis.

    PubMed

    Yan, Ling-Chen; Bi, En-Guang; Lou, Yang-Tong; Wu, Xiao-Dong; Liu, Zhi-Duo; Zou, Jia; Zhou, Jia; Wang, Yuan; Ma, Zhao; Lin, Guo-Mei; Sun, Shu-Hui; Bian, Chao; Chen, Ai-Zhong; Yao, Zhu-Jun; Sun, Bing

    2010-01-01

    Sinomenine (SIN) is an alkaloid isolated from the Chinese medicinal plant Sinomenium acutum. It is widely used as an immunosuppressive drug for treating autoimmune diseases. Due to its poor efficiency, the large-dose treatment presents some side effects and limits its further applications. In this study, we used chemical modification to improve the therapeutic effect of SIN in vitro and in vivo. A new derivative of sinomenine, named 1032, demonstrates significantly improved immunosuppressive activity over that of its parent natural compound (SIN). In an experimental autoimmune encephalomyelitis (EAE) model, 1032 significantly reduced encephalitogenic T cell responses and induced amelioration of EAE, which outcome was related to its selective inhibitory effect on the production of IL-17. By contrast, SIN treatment only led to a moderate alleviation of EAE severity and the expression level of IL-17 was not significantly reduced. Furthermore, 1032 exhibited suppression of Th17, but not Treg, cell differentiation, a result probably related to its inhibitory effect on IkappaB-alpha degradation as well as on IL-6 and TNF-alpha secretion in BMDCs. We speculate that 1032 as a novel anti-inflammatory agent may target DC to block IL-6 production, which in turn would terminate Th17 cell development. Thus, SIN derivative 1032 presents considerable potential in new drug development for treating autoimmune and inflammatory disease. PMID:20004644

  4. Oral flavonoids delay recovery from experimental autoimmune encephalomyelitis in SJL mice.

    PubMed

    Verbeek, Richard; van Tol, Eric A F; van Noort, Johannes M

    2005-07-15

    Flavonoids are food components that appear to have potential beneficial health effects. There is a range of in vitro studies supporting the anti-oxidant and anti-inflammatory properties of flavonoids. Previously, we demonstrated that in vitro flavonoids, including luteolin and apigenin, inhibit proliferation and IFN-gamma production by murine and human autoimmune T cells. In the present study, we examined the effects of oral flavonoids as well as of curcumin on autoimmune T cell reactivity in mice and on the course of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis. Continuous oral administration of flavonoids significantly affected antigen-specific proliferation and IFN-gamma production by lymph node-derived T cells following immunization with an EAE-inducing peptide. Both luteolin and apigenin suppress proliferative responses as they did in vitro, whereas IFN-gamma production on the other hand was enhanced. Other flavonoids exerted differential effects on proliferation and IFN-gamma production. The effects of flavonoids and curcumin on EAE were assessed using either passive transfer of autoimmune T cells or active disease induction. In passive EAE, flavonoids led to delayed recovery of clinical symptoms rather than to any reduction in disease. In active EAE, the effects were less pronounced but also, in this case, the flavonoid hesperitin delayed recovery. Oral curcumin had overall mild but beneficial effects. Our results indicate that oral flavonoids fail to beneficially influence the course of EAE in mice but, instead, suppress recovery from acute inflammatory damage.

  5. Ncx3 gene ablation impairs oligodendrocyte precursor response and increases susceptibility to experimental autoimmune encephalomyelitis.

    PubMed

    Casamassa, Antonella; La Rocca, Claudia; Sokolow, Sophie; Herchuelz, Andre; Matarese, Giuseppe; Annunziato, Lucio; Boscia, Francesca

    2016-07-01

    The Na(+) /Ca(2+) exchanger NCX3, recently identified as a myelin membrane component, is involved in the regulation of [Ca(2+) ]i during oligodendrocyte maturation. Here NCX3 involvement was studied in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Western blotting and quantitative colocalization studies performed in wild-type ncx3(+/+) mice at different stages of EAE disease showed that NCX3 protein was intensely upregulated during the chronic stage, where it was intensely coexpressed with the oligodendrocyte precursor cells (OPC) marker NG2 and the premyelinating marker CNPase. Moreover, MOG35-55 -immunized mice lacking the ncx3 gene displayed not only a reduced diameter of axons and an intact myelin ring number but also a dramatic decrease in OPC and pre-myelinating cells in the white matter of the spinal cord when compared with ncx3(+/+) . Accordingly, ncx3(-/-) and ncx3(+/-) mutants developed early onset of EAE and more severe clinical symptoms. Interestingly, cytofluorimetric analysis revealed that during the peak stage of the disease, the number of immune T-cell subsets in ncx3(-/-) mice, was not statistically different from that measured in ncx3(+/+) . Our findings demonstrate that knocking-out NCX3 impairs oligodendrocyte response and worsens clinical symptoms in EAE without altering the immune T-cell population. GLIA 2016;64:1124-1137. PMID:27120265

  6. IL-21R signaling is critical for induction of spontaneous experimental autoimmune encephalomyelitis

    PubMed Central

    Lee, Youjin; Mitsdoerffer, Meike; Xiao, Sheng; Gu, Guangxiang; Sobel, Raymond A.; Kuchroo, Vijay K.

    2015-01-01

    IL-17–producing CD4+ T cells (Th17 cells) have well-described pathogenic roles in tissue inflammation and autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE); however, the involvement of IL-21 in these processes has remained controversial. While IL-21 is an essential autocrine amplification factor for differentiation of Th17 cells, the loss of IL-21 or IL-21 receptor (IL-21R) does not protect mice from actively induced EAE. Here, we utilized a transgenic EAE mouse model, in which T and B cells overexpress receptors for myelin oligodendrocyte glycoprotein (MOG) (referred to as 2D2xTH mice), and demonstrated that IL-21 is critical for the development of a variant form of spontaneous EAE in these animals. Il21r deletion in 2D2xTH mice reduced the incidence and severity of spontaneous EAE, which was associated with a defect in Th17 cell generation. Moreover, IL-21R deficiency limited IL-23R expression on Th17 cells and inhibited expression of key molecules involved in the generation of pathogenic Th17 cells. Conversely, loss of IL-23R in 2D2xTH mice resulted in complete resistance to the development of spontaneous EAE. Our data identify a previously unappreciated role for IL-21 in EAE and reveal that IL-21–mediated signaling supports generation and stabilization of pathogenic Th17 cells and development of spontaneous autoimmunity. PMID:26413871

  7. The expressed needs of people with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A systematic review

    PubMed Central

    2009-01-01

    Background We aimed to review systematically the needs for support in managing illness and maintaining social inclusion expressed by people with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) Methods We carried out a systematic review of primary research and personal ('own') stories expressing the needs of people with CFS/ME. Structured searches were carried out on Medline, AMED, CINAHL, EMBASE, ASSIA, CENTRAL, and other health, social and legal databases from inception to November 2007. Study inclusion, data extraction and risk of bias were assessed independently in duplicate. Expressed needs were tabulated and a conceptual framework developed through an iterative process. Results Thirty two quantitative and qualitative studies, including the views of over 2500 people with CFS/ME with mainly moderate or severe illness severity, met the inclusion criteria. The following major support needs emerged: 1) The need to make sense of symptoms and gain diagnosis, 2) for respect and empathy from service providers, 3) for positive attitudes and support from family and friends, 4) for information on CFS/ME, 5) to adjust views and priorities, 6) to develop strategies to manage impairments and activity limitations, and 7) to develop strategies to maintain/regain social participation. Conclusions Although the studies were heterogeneous, there was consistent evidence that substantial support is needed to rebuild lives. Gaining support depends - most importantly - on the ability of providers of health and social care, colleagues, friends and relatives, and those providing educational and leisure services, to understand and respond to those needs. PMID:20003363

  8. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

    PubMed Central

    Kaye, Joel; Piryatinsky, Victor; Birnberg, Tal; Hingaly, Tal; Raymond, Emanuel; Kashi, Rina; Amit-Romach, Einat; Caballero, Ignacio S.; Towfic, Fadi; Ator, Mark A.; Rubinstein, Efrat; Laifenfeld, Daphna; Orbach, Aric; Shinar, Doron; Marantz, Yael; Grossman, Iris; Knappertz, Volker; Hayden, Michael R.; Laufer, Ralph

    2016-01-01

    Laquinimod is an oral drug currently being evaluated for the treatment of relapsing, remitting, and primary progressive multiple sclerosis and Huntington’s disease. Laquinimod exerts beneficial activities on both the peripheral immune system and the CNS with distinctive changes in CNS resident cell populations, especially astrocytes and microglia. Analysis of genome-wide expression data revealed activation of the aryl hydrocarbon receptor (AhR) pathway in laquinimod-treated mice. The AhR pathway modulates the differentiation and function of several cell populations, many of which play an important role in neuroinflammation. We therefore tested the consequences of AhR activation in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) using AhR knockout mice. We demonstrate that the pronounced effect of laquinimod on clinical score, CNS inflammation, and demyelination in EAE was abolished in AhR−/− mice. Furthermore, using bone marrow chimeras we show that deletion of AhR in the immune system fully abrogates, whereas deletion within the CNS partially abrogates the effect of laquinimod in EAE. These data strongly support the idea that AhR is necessary for the efficacy of laquinimod in EAE and that laquinimod may represent a first-in-class drug targeting AhR for the treatment of multiple sclerosis and other neurodegenerative diseases. PMID:27671624

  9. Complement activation and expression during chronic relapsing experimental autoimmune encephalomyelitis in the Biozzi ABH mouse.

    PubMed

    Ramaglia, V; Jackson, S J; Hughes, T R; Neal, J W; Baker, D; Morgan, B P

    2015-06-01

    Chronic relapsing experimental autoimmune encephalomyelitis (crEAE) in mice recapitulates many of the clinical and histopathological features of human multiple sclerosis (MS), making it a preferred model for the disease. In both, adaptive immunity and anti-myelin T cells responses are thought to be important, while in MS a role for innate immunity and complement has emerged. Here we sought to test whether complement is activated in crEAE and important for disease. Disease was induced in Biozzi ABH mice that were terminated at different stages of the disease to assess complement activation and local complement expression in the central nervous system. Complement activation products were abundant in all spinal cord areas examined in acute disease during relapse and in the progressive phase, but were absent in early disease remission, despite significant residual clinical disease. Local expression of C1q and C3 was increased at all stages of disease, while C9 expression was increased only in acute disease; expression of the complement regulators CD55, complement receptor 1-related gene/protein y (Crry) and CD59a was reduced at all stages of the disease compared to naive controls. These data show that complement is activated in the central nervous system in the model and suggest that it is a suitable candidate for exploring whether anti-complement agents might be of benefit in MS.

  10. Prevention and Treatment of Experimental Autoimmune Encephalomyelitis by Soluble CD83

    PubMed Central

    Zinser, Elisabeth; Lechmann, Matthias; Golka, Antje; Lutz, Manfred B.; Steinkasserer, Alexander

    2004-01-01

    CD83 is up-regulated on the surface of dendritic cells (DCs) during maturation and has been widely used as a marker for mature DCs. Recently, we reported the recombinant expression of the extracellular immunoglobulin domain of human CD83 (hCD83ext). Using this soluble form of CD83, allogeneic as well as specific cytotoxic T lymphocyte proliferation could be blocked in vitro. Here we report the functional analysis of soluble CD83 in vivo, using murine experimental autoimmune encephalomyelitis (EAE) as a model. Strikingly, only three injections of soluble CD83 prevented the paralysis associated with EAE almost completely. In addition, even when the EAE was induced a second time, CD83-treated mice were protected, indicating a long-lasting suppressive effect. Furthermore, soluble CD83 strongly reduced the paralysis in different therapeutic settings. Most important, even when the treatment was delayed until the disease symptoms were fully established, soluble CD83 clearly reduced the paralyses. In addition, also when EAE was induced a second time, soluble CD83-treated animals showed reduced disease symptoms. Finally, hCD83ext treatment almost completely reduced leukocyte infiltration in the brain and in the spinal cord. In summary, this work strongly supports an immunosuppressive role of soluble CD83, thereby indicating its therapeutic potential in the regulation of immune disorders in vivo. PMID:15289503

  11. Breast regression protein-39 is not required for experimental autoimmune encephalomyelitis induction.

    PubMed

    Cantó, Ester; Espejo, Carmen; Costa, Carme; Montalban, Xavier; Comabella, Manuel

    2015-10-01

    Increasing evidence points to a role for chitinase 3-like 1 (CHI3L1) in multiple sclerosis (MS). Here, we aimed to explore the potential involvement of CHI3L1 in the animal model of MS, experimental autoimmune encephalomyelitis (EAE). EAE was induced by immunization with MOG 35-55 peptide in wild-type (WT) and knock-out (KO) mice for breast regression protein 39 (BRP-39), the mouse homologue of human CHI3L1. Immunological responses in splenocytes were assessed by means of polyclonal and antigen-specific proliferation assays. Central nervous system pathology and chitinase gene expression were also investigated. BRP-39 expression was increased in WT MOG 35-55-immunized mice compared to saline-immunized controls. No differences were found between WT and BRP-39 KO mice regarding EAE clinical course, day of disease onset, mortality rate, splenocyte proliferative responses or histopathological findings. These results do not support a role of BRP-39 in the pathogenesis of EAE.

  12. Contrasting effects of immunosuppression on Theiler's virus infection in mice.

    PubMed

    Lipton, H L; Canto, C D

    1977-03-01

    In the present study, cyclophosphamide and rabbit anti-mouse thymocyte serum were used to immunosuppress SJL/J mice infected with Theiler's mouse encephalomyelitis virus (TMEV) in order to delineate the potential mechanism(s) of virus-induced cellular injury in this infection. Whereas both immunosuppressive agents produced a significant increase in mortality, this treatment had differing effects on the pathological involvement of gray and white-matter structures in the central nervous system. The central nervous system of immunosuppressed TMEV-infected mice had increased microglial cell proliferation and neuronal necrosis, longer maintenance of high virus levels and spread of virus antigen to involve the neocortex and hippocampal complex. These observations indicate that TMEV causes a cytolotic infection of neurons and possibly other cells in gray matter. In contrast, immunosuppression produced a dramatic reduction in mononuclear inflammatory cells in the leptomeninges and spinal cord white matter of infected mice and prevented demyelination. Further, virus antigen was not detected in the leptomeninges and white matter of immunosuppressed and infected mice. These findings suggest that demyelination of TMEV infection is immune mediated.

  13. Inventing Viruses.

    PubMed

    Summers, William C

    2014-11-01

    In the nineteenth century, "virus" commonly meant an agent (usually unknown) that caused disease in inoculation experiments. By the 1890s, however, some disease-causing agents were found to pass through filters that retained the common bacteria. Such an agent was called "filterable virus," the best known being the virus that caused tobacco mosaic disease. By the 1920s there were many examples of filterable viruses, but no clear understanding of their nature. However, by the 1930s, the term "filterable virus" was being abandoned in favor of simply "virus," meaning an agent other than bacteria. Visualization of viruses by the electron microscope in the late 1930s finally settled their particulate nature. This article describes the ever-changing concept of "virus" and how virologists talked about viruses. These changes reflected their invention and reinvention of the concept of a virus as it was revised in light of new knowledge, new scientific values and interests, and new hegemonic technologies.

  14. Inventing Viruses.

    PubMed

    Summers, William C

    2014-11-01

    In the nineteenth century, "virus" commonly meant an agent (usually unknown) that caused disease in inoculation experiments. By the 1890s, however, some disease-causing agents were found to pass through filters that retained the common bacteria. Such an agent was called "filterable virus," the best known being the virus that caused tobacco mosaic disease. By the 1920s there were many examples of filterable viruses, but no clear understanding of their nature. However, by the 1930s, the term "filterable virus" was being abandoned in favor of simply "virus," meaning an agent other than bacteria. Visualization of viruses by the electron microscope in the late 1930s finally settled their particulate nature. This article describes the ever-changing concept of "virus" and how virologists talked about viruses. These changes reflected their invention and reinvention of the concept of a virus as it was revised in light of new knowledge, new scientific values and interests, and new hegemonic technologies. PMID:26958713

  15. Expression of human HLA-B27 transgene alters susceptibility to murine Theiler's virus-induced demyelination.

    PubMed

    Rodriguez, M; Nickerson, C; Patick, A K; David, C S

    1991-04-15

    Infection of certain strains of mice with Theiler's murine encephalomyelitis virus results in persistence of virus and an immune-mediated primary demyelination in the central nervous system that resembles multiple sclerosis. Because susceptibility/resistance to demyelination in B10 congeneic mice maps strongly to class I MHC genes (D region) we tested whether expression of a human class I MHC gene (HLA-B27) would alter susceptibility to Theiler's murine encephalomyelitis virus-induced demyelination. Transgenic HLA-B27 mice were found to co-express human and endogenous mouse class I MHC genes by flow microfluorimetry analysis of PBL. In the absence of the human transgene, H-2stf, or v mice but not H-2b mice had chronic demyelination and persistence of virus at 45 days after infection. No difference in degree of demyelination, meningeal inflammation, or virus persistence was seen between transgenic HLA-B27 and nontransgenic littermate mice of H-2f or H-2v haplotype. In contrast, H-2s (HLA-B27+) mice showed a dramatic decrease in extent of demyelination and number of virus-Ag+ cells in the spinal cord compared with H-2s (HLA-B27-) littermate mice. In addition, none of the eight H-2s mice homozygous for HLA-B27 gene had spinal cord lesions even though infectious virus was isolated chronically from their central nervous system. Expression of HLA-B27 transgene did not interfere with the resistance to demyelination normally observed in B10 (H-2b) mice. These experiments demonstrate that expression of a human class I MHC gene can modulate a virus-induced demyelinating disease process in the mouse.

  16. Rehabilitation outcomes after combined acute disseminated encephalomyelitis and Guillain-Barré syndrome in a child: a case report.

    PubMed

    Korupolu, Radha; Ngo, Thien; Hack, Nawaz; Escott, Edward; Salles, Sara

    2014-01-01

    A 5-year old female presented with acute tetraparesis and areflexia. Initial imaging and cerebrospinal fluid analysis were suggestive of acute disseminated encephalomyelitis (ADEM). Minimal clinical response with intravenous steroids prompted further work up. Limited nerve conduction studies suggested possible acute motor-sensory axonal neuropathy, a rare variant of Guillain-Barré syndrome (GBS). Repeat imaging was compatible with polyradiculopathy indicating concomitance of ADEM and GBS. The patient suffered severe motor deficits and neuropathic pain. Slow but significant functional recovery was noted after intensive inpatient rehabilitation followed by continued rehabilitation via home health services.

  17. Metformin ameliorates the development of experimental autoimmune encephalomyelitis by regulating T helper 17 and regulatory T cells in mice.

    PubMed

    Sun, Yafei; Tian, Tian; Gao, Juan; Liu, Xiaoqian; Hou, Huiqing; Cao, Runjing; Li, Bin; Quan, Moyuan; Guo, Li

    2016-03-15

    Immoderate immunoreaction of antigen-specific Th17 and Treg cell dysfunction play critical roles in the pathogenesis of multiple sclerosis. We examined Th17/Treg immune responses and the underlying mechanisms in response to metformin in C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Metformin reduced Th17 and increased Treg cell percentages along with the levels of associated cytokines. Molecules involved in cellular metabolism were altered in mice with EAE. Suppressed activation of mTOR and its downstream target, HIF-1α, likely mediated the protective effects of metformin. Our findings demonstrate that regulation of T cell metabolism represents a new therapeutic target for CNS autoimmune disorders.

  18. Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis.

    PubMed

    Benedek, Gil; Zhang, Jun; Bodhankar, Sheetal; Nguyen, Ha; Kent, Gail; Jordan, Kelley; Manning, Dustin; Vandenbark, Arthur A; Offner, Halina

    2016-04-15

    Sex hormones promote immunoregulatory effects on multiple sclerosis. The current study evaluated estrogen effects on regulatory B cells and resident CNS microglia during experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of multiple regulatory B cell markers indicative of IL-10 dependent as well as IFN-γ dependent pathways. Moreover, although estrogen pretreatment of EAE mice inhibited the infiltration of pro-inflammatory cells into the CNS, it enhanced the frequency of regulatory B cells and M2 microglia. Our study suggests that estrogen has a broad effect on the development of regulatory B cells during EAE, which in turn could promote neuroprotection. PMID:27049561

  19. Commentary on "Possible induction of acute disseminated encephalomyelitis (ADEM)-like demyelinating illness by intrathecal mesenchymal stem cell injection".

    PubMed

    Butzkueven, Helmut

    2013-02-01

    The case report that is the subject of this Commentary describes a 27-year-old woman, who, 3 months after a devastating low cervical myelitis, underwent intrathecal mesenchymal stem cell (MSC) infusions. Six hours after the third infusion, she became unconscious, febrile and cerebral MRI showed acute bitemporal and left cerebellar lesions, consistent with an acute disseminated encephalomyelitis. It is likely that this is the first reported patient with neuroinflammatory exacerbation after MSC therapy. This case suggests that, in addition to their malignant potential, autologous MSC expanded in vitro can exhibit immune-activating properties leading to autoimmune exacerbation.

  20. Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis.

    PubMed

    Benedek, Gil; Zhang, Jun; Bodhankar, Sheetal; Nguyen, Ha; Kent, Gail; Jordan, Kelley; Manning, Dustin; Vandenbark, Arthur A; Offner, Halina

    2016-04-15

    Sex hormones promote immunoregulatory effects on multiple sclerosis. The current study evaluated estrogen effects on regulatory B cells and resident CNS microglia during experimental autoimmune encephalomyelitis (EAE). Herein, we demonstrate an estrogen-dependent induction of multiple regulatory B cell markers indicative of IL-10 dependent as well as IFN-γ dependent pathways. Moreover, although estrogen pretreatment of EAE mice inhibited the infiltration of pro-inflammatory cells into the CNS, it enhanced the frequency of regulatory B cells and M2 microglia. Our study suggests that estrogen has a broad effect on the development of regulatory B cells during EAE, which in turn could promote neuroprotection.

  1. Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis

    PubMed Central

    Buhler, Lillian A; Samara, Ramsey; Guzman, Esther; Wilson, Carole L; Krizanac-Bengez, Liljana; Janigro, Damir; Ethell, Douglas W

    2009-01-01

    Background Metalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Matrix metalloproteinase-9 (MMP-9) has been implicated, but it is not clear if other MMPs are also involved, including matrilysin/MMP-7 – an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression. Results Here we report that MMP-7-deficient (mmp7-/-) mice on the C57Bl/6 background are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG). Brain sections from MOG-primed mmp7-/-mice did not show signs of immune cell infiltration of the CNS, but MOG-primed wild-type mice showed extensive vascular cuffing and mononuclear cell infiltration 15 days after vaccination. At the peak of EAE wild-type mice had MMP-7 immuno-reactive cells in vascular cuffs that also expressed the macrophage markers Iba-1 and Gr-1, as well as tomato lectin. MOG-specific proliferation of splenocytes, lymphocytes, CD4+ and CD8+ cells were reduced in cells isolated from MOG-primed mmp7-/- mice, compared with MOG-primed wild-type mice. However, the adoptive transfer of splenocytes and lymphocytes from MOG-primed mmp7-/- mice induced EAE in naïve wild-type recipients, but not naïve mmp7-/- recipients. Finally, we found that recombinant MMP-7 increased permeability between endothelial cells in an in vitro blood-brain barrier model. Conclusion Our findings suggest that MMP-7 may facilitate immune cell access or re-stimulation in perivascular areas, which are critical events in EAE and multiple sclerosis, and provide a new therapeutic target to treat this disorder. PMID:19267908

  2. GABAergic Agonists Modulate the Glutamate Release from Frontal Cortex Synaptosomes of Rats with Experimental Autoimmune Encephalomyelitis.

    PubMed

    Fernández Hurst, Nicolás; Chanaday, Natalí L; Roth, German A

    2015-01-01

    Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease that mimics many of the clinical and pathological features of multiple sclerosis. We have previously described a significant diminution in the GABAergic regulation of glutamate release from synaptosomes of EAE rats isolated during the acute stage of the disease. In order to explore the possible metabolic pathways responsible for this alteration, in this work we evaluate the direct effect of different GABAergic agonists on the glutamate release and concomitant synapsin I phosphorylation in synaptosomes from the frontal cortex of control and EAE animals. The results show that GABA as well as the GABA receptor agonists Muscimol (GABAA agonist) and Baclofen (GABAB agonist) caused a decrease in glutamate release in control rats paralleled by a similar reduction in synapsin I phosphorylation. Meanwhile synaptosomes from EAE animals are responsive only to Baclofen with respect to nontreated EAE synaptosomes, since glutamate release from the synaptosomes treated with Muscimol was similar to that observed in EAE rat synaptosomes which was already reduced as consequence of the disease. In the case of the benzodiazepines Diazepam and Clonazepam (GABAA allosteric agonists), both of them induced a reduction in glutamate release in synaptosomes from the CFA rats, effect that was only observed in synaptosomes of EAE rats treated with Clonazepam. In all cases both benzodiazepines showed a higher effect on synapsin I phosphorylation than in glutamate release. These results indicate that the extent of GABAergic modulation of presynaptic terminals depends on the type of agonist employed and this regulation is altered in the frontal cortex during the acute phase of EAE with respect to control animals. PMID:26631092

  3. Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis.

    PubMed

    Esaki, Yoshiyasu; Li, Youxian; Sakata, Daiji; Yao, Chengcan; Segi-Nishida, Eri; Matsuoka, Toshiyuki; Fukuda, Kazuhiko; Narumiya, Shuh

    2010-07-01

    Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4(-/-) mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2(-/-) mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2(-/-) mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE(2) exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.

  4. Calpain activity and expression are increased in splenic inflammatory cells associated with experimental allergic encephalomyelitis.

    PubMed

    Shields, D C; Schaecher, K E; Goust, J M; Banik, N L

    1999-09-01

    Since calcium-activated neutral proteinase (calpain) activity and expression are significantly increased in activated glial/inflammatory cells in the central nervous system of animals with autoimmune demyelinating diseases, this enzyme may also play a role in peripheral organ systems in these diseases. In this study, the activity and expression of calpain and the endogenous inhibitor, calpastatin, were evaluated at transcriptional and translational levels in spleens of Lewis rats with acute experimental allergic encephalomyelitis (EAE) prior to the onset of clinical symptoms. Calpain activity and translational expression were increased by 475.5% and 44.3% respectively, on day 4 post-induction in adjuvant controls and animals with EAE. These levels remained elevated compared to normal controls on days 8 and 12. Calpastatin translational expression was similarly increased at these time points although transcriptional expression was not significantly altered at any time following induction of EAE. Likewise, transcriptional expression of mu-calpain was unchanged following induction, while small increases in m-calpain transcriptional expression were observed on days 2 and 8. Most calpain expression was observed in activated splenic macrophages at day 8 post-induction even though activated T cells were also calpain positive. In spinal cords of animals with EAE, calpain expression was significantly increased in rats with severe disease compared to those exhibiting only mild symptoms at day 12 post-induction. Thus, prior to symptomatic EAE, increased calpain activity and expression in peripheral lymphoid organs may play an important role in T cell migration and subsequent disease progression. PMID:10496171

  5. Cinnamon ameliorates experimental allergic encephalomyelitis in mice via regulatory T cells: implications for multiple sclerosis therapy.

    PubMed

    Mondal, Susanta; Pahan, Kalipada

    2015-01-01

    Upregulation and/or maintenance of regulatory T cells (Tregs) during an autoimmune insult may have therapeutic efficacy in autoimmune diseases. Although several immunomodulatory drugs and molecules are available, most present significant side effects over long-term use. Cinnamon is a commonly used natural spice and flavoring material used for centuries throughout the world. Here, we have explored a novel use of cinnamon powder in protecting Tregs and treating the disease process of experimental allergic encephalomyelitis (EAE), an animal model of MS. Oral feeding of cinnamon (Cinnamonum verum) powder suppresses clinical symptoms of relapsing-remitting EAE in female PLP-TCR transgenic mice and adoptive transfer mouse model. Cinnamon also inhibited clinical symptoms of chronic EAE in male C57/BL6 mice. Dose-dependent study shows that cinnamon powder at a dose of 50 mg/kg body wt/d or higher significantly suppresses clinical symptoms of EAE in mice. Accordingly, oral administration of cinnamon also inhibited perivascular cuffing, maintained the integrity of blood-brain barrier and blood-spinal cord barrier, suppressed inflammation, normalized the expression of myelin genes, and blocked demyelination in the central nervous system of EAE mice. Interestingly, cinnamon treatment upregulated Tregs via reduction of nitric oxide production. Furthermore, we demonstrate that blocking of Tregs by neutralizing antibodies against CD25 abrogates cinnamon-mediated protection of EAE. Taken together, our results suggest that oral administration of cinnamon powder may be beneficial in MS patients and that no other existing anti-MS therapies could be so economical and trouble-free as this approach.

  6. Alpha-tocopherol ameliorates experimental autoimmune encephalomyelitis through the regulation of Th1 cells

    PubMed Central

    Xue, Haikuo; Ren, Huijun; Zhang, Lei; Sun, Xiaoxu; Wang, Wanhai; Zhang, Shijie; Zhao, Junwei; Ming, Liang

    2016-01-01

    Objective(s): Multiple sclerosis (MS) is a serious neurological autoimmune disease, it commonly affects young adults. Vitamin E (Vit E) is an important component of human diet with antioxidant activity, which protects the body’s biological systems. In order to assess the effect of Vit E treatment on this autoimmune disease, we established experimental autoimmune encephalomyelitis (EAE), the animal model of MS, and treated EAE with α-tocopherol (AT) which is the main content of Vit E. Materials and Methods: Twenty C57BL/6 adult female mice were used and divided into two groups randomly. EAE was induced with myelin oligodendrocyte glycoprotein (MOG), and one group was treated with AT, at a dose of 100 mg/kg on the 3th day post-immunization with MOG, the other group was treated with 1% alcohol. Mice were euthanized on day 14, post-immunization, spleens were removed for assessing splenocytes proliferation and cytokine profile, and spinal cords were dissected to assess the infiltration of inflammatory cells in spinal cord. Results: AT was able to attenuate the severity of EAE and delay the disease progression. H&E staining and fast blue staining indicated that AT reduced the inflammation and the demyelination reaction in the spinal cord. Treatment with AT significantly decreased the proliferation of splenocytes. AT also inhibited the production of IFN-γ (Th1 cytokine), though the other cytokines were only affected slightly. Conclusion: According to the results, AT ameliorated EAE, through suppressing the proliferation of T cells and the Th1 response. AT may be used as a potential treatment for MS. PMID:27403263

  7. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome.

    PubMed

    Morris, Gerwyn; Maes, Michael

    2013-12-01

    This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors. Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve. Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis. This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this

  8. Characterization of immune response to neurofilament light in experimental autoimmune encephalomyelitis

    PubMed Central

    2013-01-01

    Background Autoimmunity to neuronal proteins occurs in several neurological syndromes, where cellular and humoral responses are directed to surface as well as intracellular antigens. Similar to myelin autoimmunity, pathogenic immune response to neuroaxonal components such as neurofilaments may contribute to neurodegeneration in multiple sclerosis. Methods We studied the immune response to the axonal protein neurofilament light (NF-L) in the experimental autoimmune encephalomyelitis animal model of multiple sclerosis. To examine the association between T cells and axonal damage, pathology studies were performed on NF-L immunized mice. The interaction of T cells and axons was analyzed by confocal microscopy of central nervous system tissues and T-cell and antibody responses to immunodominant epitopes identified in ABH (H2-Ag7) and SJL/J (H2-As) mice. These epitopes, algorithm-predicted peptides and encephalitogenic motifs within NF-L were screened for encephalitogenicity. Results Confocal microscopy revealed both CD4+ and CD8+ T cells alongside damaged axons in the lesions of NF-L immunized mice. CD4+ T cells dominated the areas of axonal injury in the dorsal column of spastic mice in which the expression of granzyme B and perforin was detected. Identified NF-L epitopes induced mild neurological signs similar to the observed with the NF-L protein, yet distinct from those characteristic of neurological disease induced with myelin oligodendrocyte glycoprotein. Conclusions Our data suggest that CD4+ T cells are associated with spasticity, axonal damage and neurodegeneration in NF-L immunized mice. In addition, defined T-cell epitopes in the NF-L protein might be involved in the pathogenesis of the disease. PMID:24053384

  9. Accelerated and enhanced effect of CCR5-transduced bone marrow neural stem cells on autoimmune encephalomyelitis

    PubMed Central

    Yang, Jingxian; Yan, Yaping; Ma, Cun-Gen; Kang, Tingguo; Zhang, Nan; Gran, Bruno; Xu, Hui; Li, Ke; Ciric, Bogoljub; Zangaladze, Andro; Curtis, Mark; Rostami, Abdolmohamad; Zhang, Guang-Xian

    2013-01-01

    The suppressive effect of neural stem cells (NSCs) on experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), has been reported. However, the migration of NSCs to inflammatory sites was relatively slow as was the onset of rather limited clinical benefit. Lack of, or low expression of particular chemokine receptors on NSCs could be an important factor underlying the slow migration of NSCs. To enhance the therapeutic effect of NSCs, in the present study we transduced bone marrow (BM)-derived NSCs with CCR5, a receptor for CCL3, CCL4, and CCL5, chemokines that are abundantly produced in CNS-inflamed foci of MS/EAE. After i.v. injection, CCR5-NSCs rapidly reached EAE foci in larger numbers, and more effectively suppressed CNS inflammatory infiltration, myelin damage, and clinical EAE than GFP-NSCs used as controls. CCR5-NSC-treated mice also exhibited augmented remyelination and neuron/oligodendrocyte repopulation compared to PBS- or GFP-NSC-treated mice. We inferred that the critical mechanism underlying enhanced effect of CCR5-transduced NSCs on EAE is the early migration of chemokine receptor-transduced NSCs into the inflamed foci. Such migration at an earlier stage of inflammation enables NSCs to exert more effective immunomodulation, to reduce the extent of early myelin/neuron damage by creating a less hostile environment for remyelinating cells, and possibly to participate in the remyelination/neural re-population process. These features of BM-derived transduced NSCs, combined with their easy availability (the subject’s own BM) and autologous properties, may lay the groundwork for an innovative approach to rapid and highly effective MS therapy. PMID:22526024

  10. Implanting glass spinal cord windows in adult mice with experimental autoimmune encephalomyelitis.

    PubMed

    Fenrich, Keith K; Weber, Pascal; Rougon, Genevieve; Debarbieux, Franck

    2013-12-21

    Experimental autoimmune encephalomyelitis (EAE) in adult rodents is the standard experimental model for studying autonomic demyelinating diseases such as multiple sclerosis. Here we present a low-cost and reproducible glass window implantation protocol that is suitable for intravital microscopy and studying the dynamics of spinal cord cytoarchitecture with subcellular resolution in live adult mice with EAE. Briefly, we surgically expose the vertebrae T12-L2 and construct a chamber around the exposed vertebrae using a combination of cyanoacrylate and dental cement. A laminectomy is performed from T13 to L1, and a thin layer of transparent silicone elastomer is applied to the dorsal surface of the exposed spinal cord. A modified glass cover slip is implanted over the exposed spinal cord taking care that the glass does not directly contact the spinal cord. To reduce the infiltration of inflammatory cells between the window and spinal cord, anti-inflammatory treatment is administered every 2 days (as recommended by ethics committee) for the first 10 days after implantation. EAE is induced only 2-3 weeks after the cessation of anti-inflammatory treatment. Using this approach we successfully induced EAE in 87% of animals with implanted windows and, using Thy1-CFP-23 mice (blue axons in dorsal spinal cord), quantified axonal loss throughout EAE progression. Taken together, this protocol may be useful for studying the recruitment of various cell populations as well as their interaction dynamics, with subcellular resolution and for extended periods of time. This intravital imaging modality represents a valuable tool for developing therapeutic strategies to treat autoimmune demyelinating diseases such as EAE.

  11. Cinnamon Ameliorates Experimental Allergic Encephalomyelitis in Mice via Regulatory T Cells: Implications for Multiple Sclerosis Therapy

    PubMed Central

    Mondal, Susanta; Pahan, Kalipada

    2015-01-01

    Upregulation and/or maintenance of regulatory T cells (Tregs) during an autoimmune insult may have therapeutic efficacy in autoimmune diseases. Although several immunomodulatory drugs and molecules are available, most present significant side effects over long-term use. Cinnamon is a commonly used natural spice and flavoring material used for centuries throughout the world. Here, we have explored a novel use of cinnamon powder in protecting Tregs and treating the disease process of experimental allergic encephalomyelitis (EAE), an animal model of MS. Oral feeding of cinnamon (Cinnamonum verum) powder suppresses clinical symptoms of relapsing-remitting EAE in female PLP-TCR transgenic mice and adoptive transfer mouse model. Cinnamon also inhibited clinical symptoms of chronic EAE in male C57/BL6 mice. Dose-dependent study shows that cinnamon powder at a dose of 50 mg/kg body wt/d or higher significantly suppresses clinical symptoms of EAE in mice. Accordingly, oral administration of cinnamon also inhibited perivascular cuffing, maintained the integrity of blood-brain barrier and blood-spinal cord barrier, suppressed inflammation, normalized the expression of myelin genes, and blocked demyelination in the central nervous system of EAE mice. Interestingly, cinnamon treatment upregulated Tregs via reduction of nitric oxide production. Furthermore, we demonstrate that blocking of Tregs by neutralizing antibodies against CD25 abrogates cinnamon-mediated protection of EAE. Taken together, our results suggest that oral administration of cinnamon powder may be beneficial in MS patients and that no other existing anti-MS therapies could be so economical and trouble-free as this approach. PMID:25569428

  12. Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE).

    PubMed

    Benson, Curtis; Paylor, John W; Tenorio, Gustavo; Winship, Ian; Baker, Glen; Kerr, Bradley J

    2015-09-01

    Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression, and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1h every day. Allowing only 1h every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioral changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease. PMID:26033473

  13. Cellular basis of the genetic susceptibility of murine experimental allergic encephalomyelitis

    SciTech Connect

    Binder, T.A.; Greiner, D.L.; Goldschneider, I.

    1986-03-01

    Murine experimental allergic encephalomyelitis (EAE) is an induced autoimmune disease that resembles human multiple sclerosis. The authors have investigated the cellular basis of the genetic predisposition and resistance of inbred strains of mice to EAE using an adoptive transfer system between two H-2 compatible, Thy 1 antigen disparate strains of mice. Genetically EAE susceptible SJL/J strain mice (H-2/sup s/, Thy 1.2) and resistant B10.S Thy 1.1 (H-2/sub s/, Thy 1.1) strain mice were lethally irradiated (700R) and reconstituted with 5-10 x 10/sup 6/ bone marrow cells from either SJL/J or congenic B10.S (Thy 1.1 or Thy 1.2) donors. After 30-45 days, more than 95% of the thymocytes and 75% of the peripheral T cells in the chimeras were of donor origin. These lymphohemopoietic chimeras were then sensitized in their hind footpads with porcine myelin basic protein in complete Freund's adjuvant containing M. tuberculosis H/sub 37/RA, followed at 24 and 72 hours by i.v. injection of B. pertussis. Clinical signs of EAE developed in unirradiated SJL/J, but not B10.S, controls, and in irradiated B10.S and SJL/J recipients of SJL/J, but not B10.S, bone marrow. These results indicate that bone marrow cells can transfer the predisposition to EAE from genetically susceptible to genetically resistant mouse strains. The cellular component in the bone marrow that is responsible for the transfer of the genetic susceptibility to EAE is under investigation.

  14. Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis

    PubMed Central

    Ho, Peggy P.; Steinman, Lawrence

    2016-01-01

    Bile acids are ligands for the nuclear hormone receptor, farnesoid X receptor (FXR). The bile acid–FXR interaction regulates bile acid synthesis, transport, and cholesterol metabolism. Recently, bile acid–FXR regulation has been reported to play an integral role in both hepatic and intestinal inflammation, and in atherosclerosis. In this study, we found that FXR knockout mice had more disease severity in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Obeticholic acid (6α-ethyl-chenodeoxycholic acid, 6-ECDCA), a synthetic FXR agonist, is an orally available drug that is currently in clinical trials for the treatment of inflammatory diseases such as alcoholic hepatitis, nonalcoholic steatohepatitis, and primary biliary cirrhosis. When we treated mice exhibiting established EAE with 6-ECDCA, or the natural FXR ligand chenodeoxycholic acid (CDCA), clinical disease was ameliorated by (i) suppressing lymphocyte activation and proinflammatory cytokine production; (ii) reducing CD4+ T cells and CD19+ B cell populations and their expression of negative checkpoint regulators programmed cell death protein 1 (PD1), programmed death-ligand 1 (PD-L1), and B and T lymphocyte attenuator (BTLA); (iii) increasing CD8+ T cells and PD1, PDl-1, and BTLA expression; and (iv) reducing VLA-4 expression in both the T- and B-cell populations. Moreover, adoptive transfer of 6-ECDCA– or CDCA-treated donor cells failed to transfer disease in naive recipients. Thus, we show that FXR functions as a negative regulator in neuroinflammation and we highlight that FXR agonists represent a potential previously unidentified therapy for MS. PMID:26811456

  15. Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis.

    PubMed

    Saligrama, Naresha; Case, Laure K; del Rio, Roxana; Noubade, Rajkumar; Teuscher, Cory

    2013-07-15

    Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein-coupled receptors: H1, H2, H3, and H4 (histamine receptors; H(1-4)R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood-brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase-deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35-55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein-coupled-HRs (H(1-4)RKO mice). In this article, we report that in contrast to HDCKO mice, H(1-4)RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H(1-4)RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1-4RKO mice suggest that HA may signal independently of H1-4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.

  16. Analysis of neurogenesis during experimental autoimmune encephalomyelitis reveals pitfalls of bioluminescence imaging.

    PubMed

    Ayzenberg, Ilya; Schlevogt, Sibylle; Metzdorf, Judith; Stahlke, Sarah; Pedreitturia, Xiomara; Hunfeld, Anika; Couillard-Despres, Sebastien; Kleiter, Ingo

    2015-01-01

    Bioluminescence imaging is a sensitive approach for longitudinal neuroimaging. Transgenic mice expressing luciferase under the promoter of doublecortin (DCX-luc), a specific marker of neuronal progenitor cells (NPC), allow monitoring of neurogenesis in living mice. Since the extent and time course of neurogenesis during autoimmune brain inflammation are controversial, we investigated neurogenesis in MOG-peptide induced experimental allergic encephalomyelitis (EAE) using DCX-luc reporter mice. We observed a marked, 2- to 4-fold increase of the bioluminescence signal intensity 10 days after EAE induction and a gradual decline 1-2 weeks thereafter. In contrast, immunostaining for DCX revealed no differences between EAE and control mice 2 and 4 weeks after immunization in zones of adult murine neurogenesis such as the dentate gyrus. Ex vivo bioluminescence imaging showed similar luciferase expression in brain homogenates of EAE and control animals. Apart from complete immunization including MOG-peptide also incomplete immunization with complete Freund´s adjuvant and pertussis toxin resulted in a rapid increase of the in vivo bioluminescence signal. Blood-brain barrier (BBB) leakage was demonstrated 10 days after both complete and incomplete immunization and might explain the increased bioluminescence signal in vivo. We conclude, that acute autoimmune inflammation in EAE does not alter neurogenesis, at least at the stage of DCX-expressing NPC. Effects of immunization on the BBB integrity must be considered when luciferase is used as a reporter within the CNS during the active stage of EAE. Models with stable CNS-restricted luciferase expression could serve as technically convenient way to evaluate BBB integrity in a longitudinal manner.

  17. The tick saliva immunosuppressor, Salp15, contributes to Th17-induced pathology during Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Juncadella, Ignacio J.; Bates, Tonya C.; Suleiman, Reem; Monteagudo-Mera, Andrea; Olson, Chris M.; Navasa, Nicolás; Olivera, Elias R.; Osborne, Barbara A.; Anguita, Juan

    2010-01-01

    Summary Salp15 is a tick saliva protein that inhibits CD4+ T cell differentiation through its interaction with CD4. The protein inhibits early signaling events during T cell activation and IL-2 production. Because murine experimental autoimmune encephalomyelitis development is mediated by central nervous system-infiltrating CD4+ T cells that are specific for myelin-associated proteins, we sought to determine whether the treatment of mice with Salp15 during EAE induction would prevent the generation of proinflammatory T cell responses and the development of the disease. Surprisingly, Salp15-treated mice developed more severe EAE than control animals. The treatment of EAE-induced mice with the tick saliva protein did not result in increased infiltration of T cells to the central nervous system, indicating that Salp15 had not affected the permeability of the blood-brain barrier. Salp15 treatment did not affect the development of antibody responses against the eliciting peptide or the presence of IFNγ in the sera. The treatment with Salp15 resulted, however, in the increased differentiation of Th17 cells in vivo, as evidenced by higher IL-17 production from PLP139-151-specific CD4+ T cells isolated from the central nervous system and the periphery. In vitro, Salp15 was able to induce the differentiation of Th17 cells in the presence of IL-6 and the absence of TGFβ These results suggest that a conductive milieu for the differentiation of Th17 cells can be achieved by restriction of the production of IL-2 during T cell differentiation, a role that may be performed by TGFβ and other immunosuppressive agents. PMID:20920474

  18. Variability of postural orthostatic tachycardia in patients with myalgic encephalomyelitis and orthostatic intolerance.

    PubMed

    Miwa, Kunihisa

    2016-09-01

    Central nervous system dysfunction with myalgic encephalomyelitis (ME) has been suggested as the main cause of chronic fatigue syndrome. Fluctuation of the symptom severity and hierarchy is a characteristic feature in ME patients. The characteristics of the sympathetic activation may differ between the "good days" and "bad days" in them. Twenty-four ME patients with orthostatic intolerance underwent a conventional 10-min active standing test and echocardiography both on a "good day" and a "bad day", defined according to the severity of their symptoms. The mean heart rate at rest was significantly higher on the "bad days" than on the "good days". During the standing test on a "bad day", 5 patients (21 %) failed to maintain an upright posture for 10 min, whereas on a "good day" all the 24 patients maintained it. Postural orthostatic tachycardia (POT) (increase in heart rate ≥30 beats/min) or severe POT (heart rate ≥120 beats/min) was observed on the "bad days" in 10 patients (43 %) who did not suffer from the severe tachycardia on the "good days", suggesting the exaggerated sympathetic nervous activation. In contrast, POT did not occur or severe POT was attenuated on the "bad days" in 5 patients (21 %) who developed POT or severe POT on the "good days", suggesting the impaired sympathetic activation. Echocardiography revealed significantly lower mean values of both the left ventricular end-diastolic diameter and stroke volume index on the "bad days" compared with the "good days". In conclusion, in ME patients with orthostatic intolerance, the exaggerated activation of the sympathetic nervous system while standing appears to switch to the impaired sympathetic activation after the system is loaded with the additional accentuated stimuli associated with the preload reduction.

  19. High-mobility group box 1 protein (HMGB1) neutralization ameliorates experimental autoimmune encephalomyelitis.

    PubMed

    Robinson, Andrew P; Caldis, Matthew W; Harp, Christopher T; Goings, Gwendolyn E; Miller, Stephen D

    2013-06-01

    Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. Here we demonstrate that HMGB1 drives neuroinflammatory responses in experimental autoimmune encephalomyelitis (EAE), a murine model for MS, and that inhibition of HMGB1 signaling ameliorates disease. Specifically i.v. injection of an HMGB1 neutralizing antibody in the C57BL/6 model of chronic EAE or SJL/J model of relapsing-remitting EAE ameliorated clinical disease prophylactically or during ongoing disease, blocked T cell infiltration of the central nervous system, and inhibited systemic CD4(+) T cell responses to myelin epitopes. Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro, and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity.

  20. Application of dendritic cells stimulated with Trichinella spiralis excretory-secretory antigens alleviates experimental autoimmune encephalomyelitis.

    PubMed

    Sofronic-Milosavljevic, L J; Radovic, I; Ilic, N; Majstorovic, I; Cvetkovic, J; Gruden-Movsesijan, A

    2013-06-01

    The parasitic nematode, Trichinella spiralis (T. spiralis), exerts an immunomodulatory effect on the host immune response through excretory-secretory products (ES L1) released from encysted muscle larvae. Our model of combined T. spiralis infection and experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA) rats demonstrated a significant reduction in EAE severity in infected animals. Recently, we have created an immune status characteristic for the live infection by in vivo application of dendritic cells (DCs) stimulated with ES L1 products of T. spiralis muscle larvae. Moreover, these cells were able to ameliorate EAE when applied 7 days before EAE induction. ES L1-stimulated DCs increased production of IL-4, IL-10 and TGF-β, and decreased production of IFN-γ and IL-17, both at the systemic level and in target organs. A significant increase in the proportion of CD4+CD25+Foxp3+ T cells was found among spleen cells, and CNS infiltrates from DA rats treated with ES L1-stimulated DCs before EAE induction, compared to controls injected with unstimulated DCs. Regulatory T cells, together with elevated levels of IL-10 and TGF-β, are most likely involved in restraining the production of Th1 and Th17 cytokines responsible for autoimmunity and thus are responsible for the beneficial effect of ES L1-educated DCs on the course of EAE. Our results show that ES L1 antigen-stimulated DCs are able not only to provoke, but also to sustain anti-inflammatory and regulatory responses regardless of EAE induction, with subsequent amelioration of EAE, or even protection from the disease.

  1. High salt drives Th17 responses in experimental autoimmune encephalomyelitis without impacting myeloid dendritic cells.

    PubMed

    Jörg, Stefanie; Kissel, Jan; Manzel, Arndt; Kleinewietfeld, Markus; Haghikia, Aiden; Gold, Ralf; Müller, Dominik N; Linker, Ralf A

    2016-05-01

    Recently, we have shown that high dietary salt intake aggravates T helper cell (Th) 17 responses and neuroinflammation. Here, we employed in vitro assays for myeloid dendritic cell (mDC) maturation, DC cytokine production, T cell activation and ex vivo analyses in murine experimental autoimmune encephalomyelitis (EAE) to investigate whether the salt effect on Th17 cells is further mediated through DCs in vivo. In cell culture, an excess of 40mM sodium chloride did neither affect the generation, maturation nor the function of DCs, but, in different assays, significantly increased Th17 differentiation. During the initiation phase of MOG35-55 EAE, we did not observe altered DC frequencies or co-stimulatory capacities in lymphoid organs, while IL-17A production and Th17 cells in the spleen were significantly increased. Complementary ex vivo analyses of the spinal cord during the effector phase of EAE showed increased frequencies of Th17 cells, but did not reveal differences in phenotypes of CNS invading DCs. Finally, adaption of transgenic mice harboring a MOG specific T cell receptor to a high-salt diet led to aggravated clinical disease only after active immunization. Wild-type mice adapted to a high-salt diet in the effector phase of EAE, bypassing the priming phase of T cells, only displayed mildly aggravated disease. In summary, our data argue for a direct effect of NaCl on Th17 cells in neuroinflammation rather than an effect primarily exerted via DCs. These data may further fuel our understanding on the dietary impact on different immune cell subsets in autoimmune diseases, such as multiple sclerosis.

  2. Targeted GAS6 Delivery to the CNS Protects Axons from Damage during Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Gruber, Ross C.; Ray, Alex K.; Johndrow, Christopher T.; Guzik, Hillary; Burek, Dominika; de Frutos, Pablo García

    2014-01-01

    Growth arrest-specific protein 6 (GAS6) is a soluble agonist of the TYRO3, AXL, MERTK (TAM) family of receptor tyrosine kinases identified to have anti-inflammatory, neuroprotective, and promyelinating properties. During experimental autoimmune encephalomyelitis (EAE), wild-type (WT) mice demonstrate a significant induction of Gas6, Axl, and Mertk but not Pros1 or Tyro3 mRNA. We tested the hypothesis that intracerebroventricular delivery of GAS6 directly into the CNS of WT mice during myelin oligodendrocyte glycoprotein (MOG)-induced EAE would improve the clinical course of disease relative to artificial CSF (ACSF)-treated mice. GAS6 did not delay disease onset, but significantly reduced the clinical scores during peak and chronic EAE. Mice receiving GAS6 for 28 d had preserved SMI31+ neurofilament immunoreactivity, significantly fewer SMI32+ axonal swellings and spheroids and less demyelination relative to ACSF-treated mice. Alternate-day subcutaneous IFNβ injection did not enhance GAS6 treatment effectiveness. Gas6−/− mice sensitized with MOG35-55 peptide exhibit higher clinical scores during late peak to early chronic disease, with significantly increased SMI32+ axonal swellings and Iba1+ microglia/macrophages, enhanced expression of several proinflammatory mRNA molecules, and decreased expression of early oligodendrocyte maturation markers relative to WT mouse spinal cords with scores for 8 consecutive days. During acute EAE, flow cytometry showed significantly more macrophages but not T-cell infiltrates in Gas6−/− spinal cords than WT spinal cords. Our data are consistent with GAS6 being protective during EAE by dampening the inflammatory response, thereby preserving axonal integrity and myelination. PMID:25471571

  3. Clinical Profiles and Short-Term Outcomes of Acute Disseminated Encephalomyelitis in Adult Chinese Patients

    PubMed Central

    Yang, Hong-Qi; Zhao, Wen-Cong; Yang, Wei-Min; Li, Yong-Li; Sun, Zhi-Kun; Chen, Shuai

    2016-01-01

    Background and Purpose Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder that predominantly affects children. Previous studies have mostly involved children in Western developed countries. Methods This study retrospectively reviewed the clinical profiles of ADEM in adult Chinese patients. Results ADEM occurred during summer and autumn in about two-thirds of the 42 included patients. Prior infection was found in five patients and no preimmunization was recorded. The most frequent clinical presentations were alterations in consciousness (79%) and behavior changes (69%), followed by motor deficits (64%) and fever (50%). About one-quarter (26%) of the patients showed positive results for oligoclonal bands, and about half of them exhibited increases in the IgG index and 24-hour IgG synthesis rate. Magnetic resonance imaging showed white- and gray-matter lesions in 83% and 23% of the patients, respectively. Steroids were the main treatment, and full recovery occurred in 62% of the patients, with residual focal neurological deficits recorded in a few patients. After a mean follow-up period of 3.4 years, two patients exhibited recurrence and one patient exhibited a multiphasic course. One patient was diagnosed with multiple sclerosis (MS). Conclusions With the exception of the seasonal distribution pattern and prior vaccine rate, the clinical profiles of ADEM in adult Chinese patients are similar to those in pediatric populations. No specific markers are available for distinguishing ADEM from MS at the initial presentation. Careful clinical evaluations, cerebrospinal fluid measurements, and neuroradiological examinations with long-term follow-up will aid the correct diagnosis of ADEM. PMID:27449911

  4. Natural killer T cells in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis.

    PubMed

    Van Kaer, Luc; Wu, Lan; Parekh, Vrajesh V

    2015-09-01

    Multiple sclerosis (MS) is a chronic inflammatory disease that causes demyelination of neurons in the central nervous system. Traditional therapies for MS have involved anti-inflammatory and immunosuppressive drugs with significant side effects that often only provide short-term relief. A more desirable outcome of immunotherapy would be to protect against disease before its clinical manifestation or to halt disease after its initiation. One attractive approach to accomplish this goal would be to restore tolerance by targeting immunoregulatory cell networks. Although much of the work in this area has focused on CD4(+) Foxp3(+) regulatory T cells, other studies have investigated natural killer T (NKT) cells, a subset of T cells that recognizes glycolipid antigens in the context of the CD1d glycoprotein. Studies with human MS patients have revealed alterations in the numbers and functions of NKT cells, which have been partially supported by studies with the experimental autoimmune encephalomyelitis model of MS. Additional studies have shown that activation of NKT cells with synthetic lipid antigens can, at least under certain experimental conditions, protect mice against the development of MS-like disease. Although mechanisms of this protection remain to be fully investigated, current evidence suggests that it involves interactions with other immunoregulatory cell types such as regulatory T cells and immunosuppressive myeloid cells. These studies have provided a strong foundation for the rational design of NKT-cell-based immunotherapies for MS that induce tolerance while sparing overall immune function. Nevertheless, additional pre-clinical and clinical studies will be required to bring this goal to fruition.

  5. Immunomodulatory effects and improved prognosis of experimental autoimmune encephalomyelitis after O-tetradecanoyl-genistein treatment.

    PubMed

    Castro, Sandra B R; Junior, Celso O R; Alves, Caio C S; Dias, Alyria T; Alves, Lívia L; Mazzoccoli, Luciano; Mesquita, Felipe P; Figueiredo, Nathália S V; Juliano, Maria A; Castañon, Maria Christina M N; Gameiro, Jacy; Almeida, Mauro V; Teixeira, Henrique C; Ferreira, Ana Paula

    2012-02-01

    Experimental autoimmune encephalomyelitis (EAE) is a murine autoimmune disease used to study multiple sclerosis (MS), a human inflammatory demyelinating disease of the central nervous system. Genistein, an isoflavonoid phytoestrogenic compound found in soy, is known to reverse clinical signs of EAE. Although genistein has some potential in clinical application, it has some disadvantages related to its chemical structure, such as rapid in vivo metabolism and a fast decline in serum after oral administration. The present work investigates the treatment of EAE by using 7-O-tetradecanoyl-genistein (TDG), a more lipophilic analog of genistein obtained by esterification. The clinical course of EAE was investigated in C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG)(35-55) in complete Freund's adjuvant supplemented with Mycobacterium tuberculosis H37RA. After 14 days of MOG immunization, mice were treated with TDG for seven days. Numbers of IL-17-producing cells and Foxp3 by CD4(+) T cells and CTLA-4 expression by CD3(+) T cells from brain were determined by flow cytometry. Levels of IL-6, IFN-γ and IL-10 were evaluated by ELISA. Brain sections were stained by hematoxylin and eosin method. The data obtained indicate that TDG treatment ameliorates the clinical signs of EAE, which correlates with a decrease of IL-17-producing cells and an increase in Foxp3(+)CD4(+) cells in the brain. TDG is also shown to enhance IL-10 production and CTLA-4 expression and to reduce IFN-γ and IL-6. Altogether, these findings suggest an immunomodulatory therapeutic role for TDG in EAE and multiple sclerosis.

  6. Immunomodulation of Experimental Autoimmune Encephalomyelitis by Oral Administration of Copolymer 1

    NASA Astrophysics Data System (ADS)

    Teitelbaum, Dvora; Arnon, Ruth; Sela, Michael

    1999-03-01

    The activity of copolymer 1 (Cop 1, Copax-one, glatiramer acetate) in suppressing experimental autoimmune encephalomyelitis (EAE) and in the treatment of multiple sclerosis patients when injected parenterally has been extensively demonstrated. In the present study we addressed the question of whether Cop 1 can induce oral tolerance to EAE similar to myelin basic protein (MBP). We now have demonstrated that oral Cop 1 inhibited EAE induction in both rats and mice. Furthermore, oral Cop 1 was more effective than oral MBP in suppressing EAE in rats. The beneficial effect of oral Cop 1 was found to be associated with specific inhibition of the proliferative and Th1 cytokine secretion responses to MBP of spleen cells from Cop 1-fed mice and rats. In all of these assays, oral Cop 1 was more effective than oral MBP. The tolerance induced by Cop 1 could be adoptively transferred with spleen cells from Cop 1-fed animals. Furthermore, Cop 1-specific T cell lines, which inhibit EAE induction in vivo, could be isolated from the above spleen cells. These T cell lines secrete the anti-inflammatory cytokines IL-10 and transforming growth factor type β , but not IL-4, in response to both Cop 1 and MBP. In conclusion, oral Cop 1 has a beneficial effect on the development of EAE that is associated with down-regulation of T cell immune responses to MBP and is mediated by Th2/3 type regulatory cells. These results suggest that oral administration of Cop 1 may modulate multiple sclerosis as well.

  7. Voluntary wheel running delays disease onset and reduces pain hypersensitivity in early experimental autoimmune encephalomyelitis (EAE).

    PubMed

    Benson, Curtis; Paylor, John W; Tenorio, Gustavo; Winship, Ian; Baker, Glen; Kerr, Bradley J

    2015-09-01

    Multiple sclerosis (MS) is classically defined by motor deficits, but it is also associated with the secondary symptoms of pain, depression, and anxiety. Up to this point modifying these secondary symptoms has been difficult. There is evidence that both MS and the animal model experimental autoimmune encephalomyelitis (EAE), commonly used to study the pathophysiology of the disease, can be modulated by exercise. To examine whether limited voluntary wheel running could modulate EAE disease progression and the co-morbid symptoms of pain, mice with EAE were allowed access to running wheels for 1h every day. Allowing only 1h every day of voluntary running led to a significant delay in the onset of clinical signs of the disease. The development of mechanical allodynia was assessed using Von Frey hairs and indicated that wheel running had a modest positive effect on the pain hypersensitivity associated with EAE. These behavioral changes were associated with reduced numbers of cFOS and phosphorylated NR1 positive cells in the dorsal horn of the spinal cord compared to no-run EAE controls. In addition, within the dorsal horn, voluntary wheel running reduced the number of infiltrating CD3(+) T-cells and reduced the overall levels of Iba1 immunoreactivity. Using high performance liquid chromatography (HPLC), we observed that wheel-running lead to significant changes in the spinal cord levels of the antioxidant glutathione. Oxidative stress has separately been shown to contribute to EAE disease progression and neuropathic pain. Together these results indicate that in mice with EAE, voluntary motor activity can delay the onset of clinical signs and reduce pain symptoms associated with the disease.

  8. Hyperinducibility of Ia antigen on astrocytes correlates with strain-specific susceptibility to experimental autoimmune encephalomyelitis.

    PubMed Central

    Massa, P T; ter Meulen, V; Fontana, A

    1987-01-01

    In search of a phenotypic marker determining genetically controlled susceptibility to delayed-type hypersensitivity (DTH) reactions in the brain--in particular, experimental autoimmune encephalomyelitis (EAE)--we have compared the gamma-interferon (IFN-gamma) induction of Ia molecules on astrocytes and macrophages from rat and mouse strains that are susceptible or resistant to this disease. We focused on Ia expression because DTH reactions to self or foreign antigens are largely mediated by lymphocytes restricted by class II (Ia) antigens of the major histocompatibility complex (MHC). Our data demonstrate that Lewis (fully susceptible) and Brown Norway (BN) (fully resistant) rats are very different in that Lewis astrocytes express much higher levels of Ia than BN astrocytes. Similar data were obtained from an analysis of EAE-susceptible and -resistant mouse strains (SJL and BALB/c, respectively), which suggests that this phenomenon may be universal and not limited to only one mammalian species. At least one gene responsible for Ia hyperinduction is located outside the rat RT-1 or the mouse MHC locus. Animals congenic at the RT-1 or MHC locus of the resistant strain but with background genes of the susceptible strain exhibit intermediate levels of Ia compared to fully resistant and susceptible rodents, which fits well with the reduced EAE susceptibility of these congenic animals. Furthermore, hyperinduction of Ia is astrocyte specific, since peritoneal macrophages of susceptible and resistant strains exhibit identical profiles of Ia induction. Thus, astrocyte Ia hyperinducibility may be a major strain- and tissue-specific factor that contributes to Ia-restricted DTH reactions in the brain. Images PMID:3495802

  9. Regulation of Th1 cells and experimental autoimmune encephalomyelitis (EAE) by glycogen synthase kinase-3

    PubMed Central

    Beurel, Eléonore; Kaidanovich-Beilin, Oksana; Yeh, Wen-I; Song, Ling; Palomo, Valle; Michalek, Suzanne M.; Woodgett, James R.; Harrington, Laurie E.; Eldar-Finkelman, Hagit; Martinez, Ana; Jope, Richard S.

    2013-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis (MS), a debilitating autoimmune disease of the central nervous system, for which only limited therapeutic interventions are available. Since MS is mediated in part by autoreactive T cells, particularly Th17 and Th1 cells, in the present study, we tested if inhibitors of glycogen synthase kinase-3 (GSK3), previously reported to reduce Th17 cell generation, also alter Th1 cell production or ameliorate EAE. GSK3 inhibitors were found to impede the production of Th1 cells by reducing STAT1 activation. Molecularly reducing the expression of either of the two GSK3 isoforms demonstrated that Th17 cell production was sensitive to reduced levels of GSK3β, and Th1 cell production was inhibited in GSK3α-deficient cells. Administration of the selective GSK3 inhibitors TDZD-8, VP2.51, VP0.7, or L803-mts, significantly reduced the clinical symptoms of MOG35-55-induced EAE in mice, nearly eliminating the chronic progressive phase, and reduced the number of Th17 and Th1 cells in the spinal cord. Administration of TDZD-8 or L803-mts after the initial disease episode ameliorated clinical symptoms in a relapsing/remitting model of PLP139-151-induced EAE. Furthermore, deletion of GSK3β specifically in T cells was sufficient to ameliorate MOG35-55-induced EAE. These results demonstrate isoform-selective effects of GSK3 on T cell generation, therapeutic effects of GSK3 inhibitors in EAE, and that GSK3 inhibition in T cells is sufficient to reduce the severity of EAE, suggesting that GSK3 may be a feasible target for developing new therapeutic interventions for MS. PMID:23606540

  10. Ageing and recurrent episodes of neuroinflammation promote progressive experimental autoimmune encephalomyelitis in Biozzi ABH mice.

    PubMed

    Peferoen, Laura A N; Breur, Marjolein; van de Berg, Sarah; Peferoen-Baert, Regina; Boddeke, Erik H W G M; van der Valk, Paul; Pryce, Gareth; van Noort, Johannes M; Baker, David; Amor, Sandra

    2016-10-01

    Current therapies for multiple sclerosis (MS) reduce the frequency of relapses by modulating adaptive immune responses but fail to limit the irreversible neurodegeneration driving progressive disability. Experimental autoimmune encephalomyelitis (EAE) in Biozzi ABH mice recapitulates clinical features of MS including relapsing-remitting episodes and secondary-progressive disability. To address the contribution of recurrent inflammatory events and ageing as factors that amplify progressive neurological disease, we examined EAE in 8- to 12-week-old and 12-month-old ABH mice. Compared with the relapsing-remitting (RREAE) and secondary progressive (SPEAE) EAE observed in young mice, old mice developed progressive disease from onset (PEAE) associated with pronounced axonal damage and increased numbers of CD3(+) T cells and microglia/macrophages, but not B cells. Whereas the clinical neurological features of PEAE and SPEAE were comparable, the pathology was distinct. SPEAE was associated with significantly reduced perivascular infiltrates and T-cell numbers in the central nervous system (CNS) compared with PEAE and the acute phase of RREAE. In contrast to perivascular infiltrates that declined during progression from RREAE into SPEAE, the numbers of microglia clusters remained constant. Similar to what is observed during MS, the microglia clusters emerging during EAE were associated with axonal damage and oligodendrocytes expressing heat-shock protein B5, but not lymphocytes. Taken together, our data reveal that the course of EAE is dependent on the age of the mice. Younger mice show a relapsing-remitting phase followed by progressive disease, whereas old mice immediately show progression. This indicates that recurrent episodes of inflammation in the CNS, as well as age, contribute to progressive neurological disease.

  11. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

    PubMed

    Pryce, Gareth; Riddall, Dieter R; Selwood, David L; Giovannoni, Gavin; Baker, David

    2015-06-01

    Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer the potential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3 year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

  12. [Acute disseminated encephalomyelitis following influenza vaccination: report of a case with callosal disconnection syndrome].

    PubMed

    Arai, Motomi; Takagi, Daisuke; Nagao, Ryosuke

    2014-01-01

    We present a case of callosal disconnection syndrome as a rare manifestation of acute disseminated encephalomyelitis (ADEM). A dextral 48-year-old Japanese woman received trivalent inactivated influenza vaccine in mid-November 2011. Twenty days later, she was found to be in a daze. Subsequently, she developed abnormal behavior and gait disturbance, and she was disoriented regarding time and place. Nystagmus and abnormal ocular movements were absent. Upper limb power was normal, whereas her lower limbs were mildly weak. Tendon reflexes were normally evoked without pathological reflexes. There was no sensory impairment. Serum CRP levels were slightly elevated; other routine laboratory tests, thyroid functions, and vitamin B1 levels were within the normal range. Cerebrospinal fluid examination revealed that it was acellular with a protein level of 54 mg/dl and high myelin basic protein level. Fluid-attenuated inversion recovery MR images revealed a large hyperintense lesion in the corpus callosum, but the lower part of the splenium was spared. Flow voids were observed in the pericallosal arteries. She was diagnosed with post-vaccination ADEM and vigorously treated with an intravenous infusion of methylprednisolone (1 g/day for 6 days) and immunoglobulin (1.2 g/kg). Gait disturbance and disorientation rapidly improved; however, tactile anomia, ideomotor apraxia, ideational apraxia, and agraphia of the left hand were present one month after onset. She had no aphasia or alexia.Interestingly, the patient's left unilateral agraphia was more prominent in kana than kanji (an article in Japanese text) for polysyllabic words, whereas she could write kana characters to dictation. Changes in the sequential order of kana characters within a word were observed. These findings were similar to those observed in pure agraphia associated with lesions in the posterior part of the left middle frontal gyrus. Thus, an interhemispheric mechanism is probably involved in the selection and

  13. Epidemiological characteristics of chronic fatigue syndrome/myalgic encephalomyelitis in Australian patients

    PubMed Central

    Johnston, Samantha C; Staines, Donald R; Marshall-Gradisnik, Sonya M

    2016-01-01

    Background No epidemiological investigations have previously been conducted in Australia according to the current clinical definitions of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to describe sociodemographic and illness characteristics of Australian patients with CFS/ME. Methods A cross-sectional survey on the medical history of patients enrolled in an Australian CFS/ME research database between April 2013 and April 2015. Participants were classified according to Fukuda criteria and International Consensus Criteria. Results A total of 535 patients diagnosed with CFS/ME by a primary care physician were identified. The mean age of all patients was 46.4 years (standard deviation 12.0); the majority were female (78.61%), Caucasian, and highly educated. Of these, 30.28% met Fukuda criteria. A further 31.96% met both Fukuda criteria and International Consensus Criteria. There were 14.58% reporting chronic fatigue but did not meet criteria for CFS/ME and 23.18% were considered noncases due to exclusionary conditions. Within those meeting CFS/ME criteria, the most common events prior to illness included cold or flu, gastrointestinal illness, and periods of undue stress. Of the 60 symptoms surveyed, fatigue, cognitive, and short-term memory symptoms, headaches, muscle and joint pain, unrefreshed sleep, sensory disturbances, muscle weakness, and intolerance to extremes of temperature were the most commonly occurring symptoms (reported by more than two-thirds of patients). Significant differences in symptom occurrence between Fukuda- and International Consensus Criteria-defined cases were also identified. Conclusion This is the first study to summarize sociodemographic and illness characteristics of a cohort of Australian CFS/ME patients. This is vital for identifying potential risk factors and predictors associated with CFS/ME and for guiding decisions regarding health care provision, diagnosis, and management. PMID:27279748

  14. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis.

    PubMed

    Khaiboullina, Svetlana F; DeMeirleir, Kenny L; Rawat, Shanti; Berk, Grady S; Gaynor-Berk, Rory S; Mijatovic, Tatjana; Blatt, Natalia; Rizvanov, Albert A; Young, Sheila G; Lombardi, Vincent C

    2015-03-01

    Gulf War illness (GWI) is a chronic disease of unknown etiology characterized by persistent symptoms such as cognitive impairment, unexplained fatigue, pervasive pain, headaches, and gastrointestinal abnormalities. Current reports suggest that as many as 200,000 veterans who served in the 1990-1991 Persian Gulf War were afflicted. Several potential triggers of GWI have been proposed including chemical exposure, toxins, vaccines, and unknown infectious agents. However, a definitive cause of GWI has not been identified and a specific biological marker that can consistently delineate the disease has not been defined. Myalgic encephalomyelitis (ME) is a disease with similar and overlapping symptomology, and subjects diagnosed with GWI typically fit the diagnostic criteria for ME. For these reasons, GWI is often considered a subgroup of ME. To explore this possibility and identify immune parameters that may help to understand GWI pathophysiology, we measured 77 serum cytokines in subjects with GWI and compared these data to that of subjects with ME as well as healthy controls. Our analysis identified a group of cytokines that identified ME and GWI cases with sensitivities of 92.5% and 64.9%, respectively. The five most significant cytokines in decreasing order of importance were IL-7, IL-4, TNF-α, IL-13, and IL-17F. When delineating GWI and ME cases from healthy controls, the observed specificity was only 33.3%, suggesting that with respect to cytokine expression, GWI cases resemble control subjects to a greater extent than ME cases across a number of parameters. These results imply that serum cytokines are representative of ME pathology to a greater extent than GWI and further suggest that the two diseases have distinct immune profiles despite their overlapping symptomology.

  15. Cell Fusion along the Anterior-Posterior Neuroaxis in Mice with Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Sankavaram, Sreenivasa R.; Svensson, Mikael A.; Olsson, Tomas; Brundin, Lou; Johansson, Clas B.

    2015-01-01

    Background It is well documented that bone marrow-derived cells can fuse with a diverse range of cells, including brain cells, under normal or pathological conditions. Inflammation leads to robust fusion of bone marrow-derived cells with Purkinje cells and the formation of binucleate heterokaryons in the cerebellum. Heterokaryons form through the fusion of two developmentally differential cells and as a result contain two distinct nuclei without subsequent nuclear or chromosome loss. Aim In the brain, fusion of bone marrow-derived cells appears to be restricted to the complex and large Purkinje cells, raising the question whether the size of the recipient cell is important for cell fusion in the central nervous system. Purkinje cells are among the largest neurons in the central nervous system and accordingly can harbor two nuclei. Results Using a well-characterized model for heterokaryon formation in the cerebellum (experimental autoimmune encephalomyelitis - a mouse model of multiple sclerosis), we report for the first time that green fluorescent protein-labeled bone marrow-derived cells can fuse and form heterokaryons with spinal cord motor neurons. These spinal cord heterokaryons are predominantly located in or adjacent to an active or previously active inflammation site, demonstrating that inflammation and infiltration of immune cells are key for cell fusion in the central nervous system. While some motor neurons were found to contain two nuclei, co-expressing green fluorescent protein and the neuronal marker, neuron-specific nuclear protein, a number of small interneurons also co-expressed green fluorescent protein and the neuronal marker, neuron-specific nuclear protein. These small heterokaryons were scattered in the gray matter of the spinal cord. Conclusion This novel finding expands the repertoire of neurons that can form heterokaryons with bone marrow-derived cells in the central nervous system, albeit in low numbers, possibly leading to a novel therapy

  16. Role of ethanolamine phosphate in the hippocampus of rats with acute experimental autoimmune encephalomyelitis.

    PubMed

    Aguado-Llera, D; Puebla-Jiménez, L; Barrios, V; Hernández-Pinto, A; Arilla-Ferreiro, E

    2011-01-01

    Here, we assessed the effects of acute experimental autoimmune encephalomyelitis (EAE) on the rat hippocampal somatostatinergic system and whether administration of an ethanolamine phosphate salt could prevent the appearance of the clinical signs and the impairment of the somatostatinergic system in this pathological condition. Female Lewis rats were injected in both hindlimb footpads with myelin basic protein from guinea pig brain and complete Freund's adjuvant and were sacrificed when limp tail (grade 1 EAE) or severe hindlimb paralysis (grade 3 EAE) were observed. One group was injected daily with ethanolamine phosphate, starting two days prior to immunization and for 15 days thereafter. The animals were sacrificed 15 days post-immunization. Acute EAE in grade 3 increased anti-myelin basic protein antibodies in rat serum as well as tumor necrosis factor-α and interferon-γ levels in hippocampal extracts. In addition, it decreased the somatostatin receptor density, somatostatin receptor subtype 2 mRNA and protein content, and the inhibitory effect of somatostatin on adenylyl cyclase activity in the hippocampus. The protein levels of the inhibitory G protein subunits αi(1-3), the G protein-coupled receptor kinase isoforms 2, 5 and 6, the phosphorylated cyclic AMP-binding protein and the somatostatin-like immunoreactivity content were unaltered in this brain area. Acute EAE in grade 1 did not modify any of these parameters. Ethanolamine phosphate administration prevented the clinical expression of acute EAE as well as the decrease in the somatostatin receptor density, somatostatin receptor subtype 2 expression and the capacity of somatostatin to inhibit adenylyl cyclase activity at the time-period studied. Furthermore, it blunted the rise in serum anti-myelin basic protein antibodies and hippocampal interferon-γ and tumor necrosis factor-α levels. Altogether, these data suggest that ethanolamine phosphate might provide protection against acute EAE.

  17. Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance.

    PubMed

    Álvarez-Sánchez, Nuria; Cruz-Chamorro, Ivan; López-González, Antonio; Utrilla, José C; Fernández-Santos, José M; Martínez-López, Alicia; Lardone, Patricia J; Guerrero, Juan M; Carrillo-Vico, Antonio

    2015-11-01

    Experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS), is triggered by myelin-specific Th1 and Th17 cells. The immunomodulatory activities of melatonin have been shown to be beneficial under several conditions in which the immune system is exacerbated. Here, we sought to elucidate the basis of the melatonin protective effect on EAE by characterizing the T effector/regulatory responses, particularly those of the memory cell subsets. Melatonin was tested for its effect on Th1, Th17 and T regulatory (Treg) cells in the lymph nodes and CNS of immunodominant peptide of myelin oligodendrocyte glycoprotein (pMOG)-immunized and EAE mice, respectively. The capacity of melatonin to ameliorate EAE as well as modifying both T cell response and effector/regulatory balance was surveyed. T cell memory subsets and CD44, a key activation marker involved in the EAE pathogenesis, were also examined. Melatonin protected from EAE by decreasing peripheral and central Th1/Th17 responses and enhancing both the Treg frequency and IL-10 synthesis in the CNS. Melatonin reduced the T effector memory population and its pro-inflammatory response and regulated CD44 expression, which was decreased in T effector cells and increased in Tregs. The alterations in the T cell subpopulations were associated with a reduced mononuclear infiltration (CD4 and CD11b cells) of the melatonin-treated mice CNS. For the first time, we report that melatonin protects against EAE by controlling peripheral and central T effector/regulatory responses, effects that might be partially mediated by CD44. This immunomodulatory effect on EAE suggests that melatonin may represent an effective treatment option for MS.

  18. An aza-anthrapyrazole negatively regulates Th1 activity and suppresses experimental autoimmune encephalomyelitis.

    PubMed

    Clark, Matthew P; Leaman, Douglas W; Hazelhurst, Lori A; Hwang, Eun S; Quinn, Anthony

    2016-02-01

    Previously we showed that BBR3378, a novel analog of the anticancer drug mitoxantrone, had the ability to ameliorate ascending paralysis in MOG35-55-induced experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis, without the drug-induced cardiotoxicity or lymphopenia associated with mitoxantrone therapy. Chemotherapeutic drugs like mitoxantrone, a topoisomerase inhibitor, are thought to provide protection in inflammatory autoimmune diseases like EAE by inducing apoptosis in rapidly proliferating autoreactive lymphocytes. Here, we show that while BR3378 blocked cell division, T cells were still able to respond to antigenic stimulation and upregulate surface molecules indicative of activation. However, in contrast to mitoxantrone, BBR3378 inhibited the production of the proinflammatory cytokine IFN-γ both in recently activated T cell blasts and established Th1 effectors, while sparing the activities of IL-13-producing Th2 cells. IFN-γ is known to be regulated by the transcription factor T-bet. In addition to IFN-γ, in vitro and in vivo exposure to BBR3378 suppressed the expression of other T-bet regulated proteins, including CXCR3 and IL-2Rβ. Microarray analysis revealed BBR3378-induced suppression of additional T-bet regulated genes, suggesting that the drug might disrupt global Th1 programming. Importantly, BBR3378 antagonized ongoing Th1 autoimmune responses in vivo, modulated clinical disease and CNS inflammation in acute and relapsing forms of EAE. Therefore, BBR3378 may be a unique inhibitor of T-bet regulated genes and may have potential as a therapeutic intervention in human autoimmune disease. PMID:26709219

  19. Targeted GAS6 delivery to the CNS protects axons from damage during experimental autoimmune encephalomyelitis.

    PubMed

    Gruber, Ross C; Ray, Alex K; Johndrow, Christopher T; Guzik, Hillary; Burek, Dominika; de Frutos, Pablo García; Shafit-Zagardo, Bridget

    2014-12-01

    Growth arrest-specific protein 6 (GAS6) is a soluble agonist of the TYRO3, AXL, MERTK (TAM) family of receptor tyrosine kinases identified to have anti-inflammatory, neuroprotective, and promyelinating properties. During experimental autoimmune encephalomyelitis (EAE), wild-type (WT) mice demonstrate a significant induction of Gas6, Axl, and Mertk but not Pros1 or Tyro3 mRNA. We tested the hypothesis that intracerebroventricular delivery of GAS6 directly into the CNS of WT mice during myelin oligodendrocyte glycoprotein (MOG)-induced EAE would improve the clinical course of disease relative to artificial CSF (ACSF)-treated mice. GAS6 did not delay disease onset, but significantly reduced the clinical scores during peak and chronic EAE. Mice receiving GAS6 for 28 d had preserved SMI31(+) neurofilament immunoreactivity, significantly fewer SMI32(+) axonal swellings and spheroids and less demyelination relative to ACSF-treated mice. Alternate-day subcutaneous IFNβ injection did not enhance GAS6 treatment effectiveness. Gas6(-/-) mice sensitized with MOG35-55 peptide exhibit higher clinical scores during late peak to early chronic disease, with significantly increased SMI32(+) axonal swellings and Iba1(+) microglia/macrophages, enhanced expression of several proinflammatory mRNA molecules, and decreased expression of early oligodendrocyte maturation markers relative to WT mouse spinal cords with scores for 8 consecutive days. During acute EAE, flow cytometry showed significantly more macrophages but not T-cell infiltrates in Gas6(-/-) spinal cords than WT spinal cords. Our data are consistent with GAS6 being protective during EAE by dampening the inflammatory response, thereby preserving axonal integrity and myelination. PMID:25471571

  20. Immune response to controlled release of immunomodulating peptides in a murine experimental autoimmune encephalomyelitis (EAE) model

    PubMed Central

    Zhao, Hong; Kiptoo, Paul; Williams, Todd D.; Siahaan, Teruna J.; Topp, Elizabeth M.

    2014-01-01

    The effects of controlled release on immune response to an immunomodulating peptide were evaluated in a murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS). The peptide, Ac-PLP-BPI-NH2-2 (Ac-HSLGKWLGHPDKF-(AcpGAcpGAcp)2-ITDGEATDSG-NH2; Ac = acetyl, Acp = aminocaproic acid) was designed to suppress T-cell activation in response to PLP139–151, an antigenic peptide in MS. Poly-lactide-co-glycolide (PLGA) microparticles containing Ac-PLP-BPI-NH2-2 (8±4 μm, 1.4±0.2% (w/w)) were prepared by a powder-in oil-in water emulsion-solvent evaporation method, sterilized and administered subcutaneously (s.c.) to SJL/J (H-2s) mice in which EAE had been induced by immunization with PLP139–151. Treatment groups received Ac-PLP-BPI-NH2-2: (i) in solution by repeated i.v. or s.c. injection, (ii) in solution co-administered with blank PLGA microparticles, (iii) in solution co-administered with Ac-PLP-BPI-NH2-2 loaded microparticles, and (iv) as Ac-PLP-BPI-NH2-2 loaded microparticles. Administration of Ac-PLP-BPI-NH2-2 as an s.c. solution produced clinical scores and maintenance of body weight comparable to i.v. solution, but with reduced overall survival, presumably due to anaphylaxis. Administration as s.c. microparticles provided a somewhat less effective reduction in symptoms but with no toxicity during treatment. Thus, the results suggest that s.c. administration of Ac-PLP-BPI-NH2-2 microparticles can provide pharmacological efficacy and reduction in dosing frequency without increased toxicity. PMID:19748537

  1. Comparison of structural and nonstructural proteins of virulent and less virulent Theiler's virus isolates using two-dimensional gel electrophoresis.

    PubMed

    Rozhon, E J; Kratochvil, J D; Lipton, H L

    1985-02-01

    The Theiler's murine encephalomyelitis viruses (TMEV) are important neurotropic picornaviruses because they persist in the central nervous system (CNS) and produce an inflammatory demyelinating disease in the mouse, their natural host. Insight into the pathogenesis of this disease may come from studying the genetic and biochemical compositions of these viruses; therefore, in this report, the structural and nonstructural proteins specified by both highly and less virulent TMEV were examined. Using two-dimensional gel electrophoresis, structural and nonstructural proteins, originating from each of the three regions of the picornavirus genome (Kitamura et al., 1981; Rueckert and Wimmer, 1984), from nine TMEV isolates were compared on the basis of isoelectric points (pI). Proteins of two virulent TMEV (GDVII and FA viruses) had almost indistinguishable pI values, whereas two of the three major capsid proteins of the less virulent TMEV varied considerably. For example, the structural proteins VP1 and VP3 from seven less virulent viruses ranged from pI 6.3 to 6.9 and 6.5 to 8.3, respectively. On the other hand, the pI values of VP2 and nonstructural proteins from the less virulent TMEV varied relatively little. In general, structural proteins of each TMEV group had pI ranges unique to their respective biological group, while most nonstructural proteins were similar for all TMEV. The virus-specified proteins of Vilyuisk virus, which is serologically related to the TMEV and a possible cause of encephalomyelitis in man, had pI values similar to the less virulent TMEV. Finally, VP3 not only showed the greatest variation in pI among the less virulent TMEV, but it also was preferentially radioiodinated in intact virus from each of the two biological groups using the lactoperoxidase technique.

  2. Zika Virus

    MedlinePlus

    Zika is a virus that is spread mostly by mosquitoes. A pregnant mother can pass it to ... through blood transfusions. There have been outbreaks of Zika virus in the United States, Africa, Southeast Asia, ...

  3. Zika Virus

    MedlinePlus

    ... Search The CDC Cancel Submit Search The CDC Zika Virus Note: Javascript is disabled or is not supported ... Areas with Zika Countries and territories with active Zika virus transmission... Mosquito Control Prevent mosquito bites, integrated mosquito ...

  4. Chikungunya Virus

    MedlinePlus

    ... traveling to countries with chikungunya virus, use insect repellent, wear long sleeves and pants, and stay in ... Chikungunya Prevention is key! Prevent Infection. Use mosquito repellent. Chikungunya Virus Distribution Chikungunya in the U.S. What's ...

  5. B cells promote induction of experimental autoimmune encephalomyelitis by facilitating reactivation of T cells in the central nervous system.

    PubMed

    Pierson, Emily R; Stromnes, Ingunn M; Goverman, Joan M

    2014-02-01

    The efficacy of rituximab treatment in multiple sclerosis has renewed interest in the role of B cells in CNS autoimmunity. In this study, we show that B cells are the predominant MHC class II(+) subset in the naive CNS in mice, and they constitutively express proinflammatory cytokines. Incidence of experimental autoimmune encephalomyelitis induced by adoptive transfer was significantly reduced in C3HeB/Fej μMT (B cell-deficient) mice, suggesting an important role for CNS B cells in initiating inflammatory responses. Initial T cell infiltration of the CNS occurred normally in μMT mice; however, lack of production of T cell cytokines and other immune mediators indicated impaired T cell reactivation. Subsequent recruitment of immune cells from the periphery driven by this initial T cell reactivation did not occur in μMT mice. B cells required exogenous IL-1β to reactivate Th17 but not Th1 cells in vitro. Similarly, reactivation of Th1 cells infiltrating the CNS was selectively impaired compared with Th17 cells in μMT mice, causing an increased Th17/Th1 ratio in the CNS at experimental autoimmune encephalomyelitis onset and enhanced brain inflammation. These studies reveal an important role for B cells within the CNS in reactivating T cells and influencing the clinical manifestation of disease.

  6. Tonsillar crypt epithelium is an important extra-central nervous system site for viral replication in EV71 encephalomyelitis.

    PubMed

    He, Yaoxin; Ong, Kien Chai; Gao, Zifen; Zhao, Xishun; Anderson, Virginia M; McNutt, Michael A; Wong, Kum Thong; Lu, Min

    2014-03-01

    Enterovirus 71 (EV71; family Picornaviridae, species human Enterovirus A) usually causes hand, foot, and mouth disease, which may rarely be complicated by fatal encephalomyelitis. We investigated extra-central nervous system (extra-CNS) tissues capable of supporting EV71 infection and replication, and have correlated tissue infection with expression of putative viral entry receptors, scavenger receptor B2 (SCARB2), and P-selectin glycoprotein ligand-1 (PSGL-1). Formalin-fixed, paraffin-embedded CNS and extra-CNS tissues from seven autopsy cases were examined by IHC and in situ hybridization to evaluate viral antigens and RNA. Viral receptors were identified with IHC. In all seven cases, the CNS showed stereotypical distribution of inflammation and neuronal localization of viral antigens and RNA, confirming the clinical diagnosis of EV71 encephalomyelitis. In six cases in which tonsillar tissues were available, viral antigens and/or RNA were localized to squamous epithelium lining the tonsillar crypts. Tissues from the gastrointestinal tract, pancreas, mesenteric nodes, spleen, and skin were all negative for viral antigens/RNA. Our novel findings strongly suggest that tonsillar crypt squamous epithelium supports active viral replication and represents an important source of viral shedding that facilitates person-to-person transmission by both the fecal-oral or oral-oral routes. It may also be a portal for viral entry. A correlation between viral infection and SCARB2 expression appears to be more significant than for PSGL-1 expression.

  7. Modulation of the expression of integrins on glial cells during experimental autoimmune encephalomyelitis. A central role for TNF-alpha.

    PubMed Central

    Previtali, S. C.; Archelos, J. J.; Hartung, H. P.

    1997-01-01

    Integrins comprise a group of adhesion receptors involved in cell-cell and cell-extracellular matrix interactions. Evidence is accumulating that integrins expressed on mononuclear cells play a central role in the induction of autoimmune diseases of the central nervous system. The effects of integrins on glial cell behavior, myelination, and angiogenesis suggest that they may also have a role in resolving inflammation in the nervous system and in promoting tissue repair. We investigated the temporospatial expression of integrins in the rat central nervous system during the course of experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. A higher expression of alpha v- and beta 4-integrin subunits in astrocytes and alpha 2 integrin in oligodendrocytes was observed in active lesions of experimental autoimmune encephalomyelitis, in comparison with controls. Proinflammatory cytokines, primarily TNF-alpha, also enhanced alpha v, beta 4, and alpha 2 expression in purified glial cells ex vivo. Furthermore, we observed that the expression of some integrin subunits was modulated in the cerebral vasculature during inflammation. Our results suggest an active role for glial and vascular integrins in the regulation of autoimmune diseases of the central nervous system, opening an avenue for new potential immunotherapies. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 9 PMID:9358769

  8. Acute encephalomyelitis complicated with severe neurological sequelae after intrathecal administration of methotrexate in a patient with acute lymphoblastic leukemia.

    PubMed

    Nishikawa, Takuro; Okamoto, Yasuhiro; Maruyama, Shinsuke; Tanabe, Takayuki; Kurauchi, Koichiro; Kodama, Yuichi; Nakagawa, Shunsuke; Shinkoda, Yuichi; Kawano, Yoshifumi

    2014-11-01

    A four-year-old girl on maintenance therapy for acute lymphoblastic leukemia (ALL) complained of a headache and low back pain on the day she received her 21st intrathecal methotrexate (it-MTX) administration, and the next day experienced numbness and pain in her foot. This numbness gradually spread to her hand. She thereafter developed a fever and was hospitalized on day 8. After antibiotic therapy, the fever disappeared. However, her lower limbs became paralyzed, and she also developed urinary retention. On day 12, her paralysis progressed upwards, and she also developed paralysis of the upper limbs. Finally, she experienced convulsions with an impairment of consciousness. A magnetic resonance imaging study of the brain and spinal cord showed abnormal signals in the brain cortex and anterior horn. Accordingly, we diagnosed acute encephalomyelitis associated with it-MTX. High-dose intravenous immunoglobulin, steroid pulse therapy, plasma exchange, and dextromethorphan administration were initiated, while she received mechanical ventilation. Despite this intensive treatment, she suffered severe neurological damage and had to be maintained on mechanical ventilation due to persistent flaccid quadriplegia one year after the onset. When patients have symptoms of ascending paralysis during it-MTX treatment, clinicians should carefully consider the possibility of acute encephalomyelitis due to it-MTX. PMID:25501412

  9. Prevention and Mitigation of Experimental Autoimmune Encephalomyelitis by Murine β-Defensins via Induction of Regulatory T Cells.

    PubMed

    Bruhs, Anika; Schwarz, Thomas; Schwarz, Agatha

    2016-01-01

    The antimicrobial peptide murine β-defensin-14 (mBD14) was found to exert, in addition to its antimicrobial activity, the capacity to induce regulatory T cells as demonstrated in the model of contact hypersensitivity. Because it is induced by ultraviolet radiation, mBD14 may contribute to the antigen-specific immunosuppression by ultraviolet radiation. To prove whether this applies also for other immunologic models and because ultraviolet radiation appears to have beneficial effects on multiple sclerosis, we utilized the model of experimental autoimmune encephalomyelitis. Injection of mBD14 into mice before immunization with myelin oligodendrocyte glycoprotein caused amelioration of the disease with less central nervous system inflammation and decreased levels of proinflammatory cytokines and cytotoxic T cells. The beneficial effect was due to Foxp3(+) regulatory T cells because it was lost on in vivo depletion of regulatory T cells. mBD14, however, also acts in a therapeutic setting, because injection of mBD14 into mice with clinical features of experimental autoimmune encephalomyelitis reduced the clinical score significantly. Human β-defensin-3, the human orthologue of mBD14, induced in vitro regulatory T cell-specific markers in CD4(+)CD25(-) T cells, shifting these nonregulatory cells into a regulatory phenotype with suppressive features. Thus, defensins may represent candidates worth being further pursued for the therapy of multiple sclerosis. PMID:26763437

  10. A Pair of Identical Twins Discordant for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Differ in Physiological Parameters and Gut Microbiome Composition

    PubMed Central

    Giloteaux, Ludovic; Hanson, Maureen R.; Keller, Betsy A.

    2016-01-01

    Patient: Male, 34 Final Diagnosis: ME/CFS Symptoms: Exertion intolerance • loss of functional capacity • pain • severe fatigue Medication: — Clinical Procedure: Cardiopulmonary exercise test Specialty: Sports Medicine Objective: Unknown ethiology Background: Patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) present with profound fatigue, flu-like symptoms, pain, cognitive impairment, orthostatic intolerance, post-exertional malaise (PEM), and exacerbation of some or all of the baseline symptoms. Case Report: We report on a pair of 34-year-old monozygotic twins discordant for ME/CFS, with WELL, the non-affected twin, and ILL, the affected twin. Both twins performed a two-day cardiopulmonary exercise test (CPET), preand post-exercise blood samples were drawn, and both provided stool samples for biochemical and molecular analyses. At peak exertion for both CPETs, ILL presented lower VO2peak and peak workload compared to WELL. WELL demonstrated normal reproducibility of VO2@ventilatory/anaerobic threshold (VAT) during CPET2, whereas ILL experienced an abnormal reduction of 13% in VAT during CPET2. A normal rise in lactate dehydrogenase (LDH), creatine kinase (CK), adrenocorticotropic hormone (ACTH), cortisol, creatinine, and ferritin content was observed following exercise for both WELL and ILL at each CPET. ILL showed higher increases of resistin, soluble CD40 ligand (sCD40L), and soluble Fas ligand (sFasL) after exercise compared to WELL. The gut bacterial microbiome and virome were examined and revealed a lower microbial diversity in ILL compared to WELL, with fewer beneficial bacteria such as Faecalibacterium and Bifidobacterium, and an expansion of bacteriophages belonging to the tailed dsDNA Caudovirales order. Conclusions: Results suggest dysfunctional immune activation in ILL following exercise and that prokaryotic viruses may contribute to mucosal inflammation and bacterial dysbiosis. Therefore, a two-day CPET and molecular

  11. A three-nucleotide insertion in the H stem-loop of the 5' untranslated region of Theiler's virus attenuates neurovirulence.

    PubMed Central

    Bandyopadhyay, P K; Pritchard, A; Jensen, K; Lipton, H L

    1993-01-01

    The highly structured 5' untranslated region (5' UTR) of Theiler's murine encephalomyelitis virus is involved in cap-independent translation of the viral RNA. Previously, we reported that the bicistronic mRNA chloramphenicol acetyltransferase-5' UTR-luciferase (Luc) efficiently expressed Luc both in a rabbit reticulocyte lysate and when transfected into BHK-21 cells. Insertion of 3 nucleotides at position 665 in the 5' UTR of this bicistronic mRNA resulted in greatly reduced Luc expression in BHK-21 cells but had little effect on expression of Luc in rabbit reticulocyte lysate. This mutation was also introduced into a virulent Theiler's murine encephalomyelitis virus chimera, Chi-VL. The kinetics of viral RNA and protein synthesis and virus production in BHK-21 cells were slower for the mutant chimera [Chi-VL(IN668)] than for Chi-VL; however, the final virus yields were comparable. Intracerebral inoculation of mice with the chimeras revealed that Chi-VL(IN668) was completely attenuated in neurovirulence. The reduced neurovirulence of Chi-VL(IN668) may be ascribed to its reduced growth in the central nervous system, most likely due to an impaired ability to synthesize viral proteins. Images PMID:7684472

  12. A three-nucleotide insertion in the H stem-loop of the 5' untranslated region of Theiler's virus attenuates neurovirulence.

    PubMed

    Bandyopadhyay, P K; Pritchard, A; Jensen, K; Lipton, H L

    1993-06-01

    The highly structured 5' untranslated region (5' UTR) of Theiler's murine encephalomyelitis virus is involved in cap-independent translation of the viral RNA. Previously, we reported that the bicistronic mRNA chloramphenicol acetyltransferase-5' UTR-luciferase (Luc) efficiently expressed Luc both in a rabbit reticulocyte lysate and when transfected into BHK-21 cells. Insertion of 3 nucleotides at position 665 in the 5' UTR of this bicistronic mRNA resulted in greatly reduced Luc expression in BHK-21 cells but had little effect on expression of Luc in rabbit reticulocyte lysate. This mutation was also introduced into a virulent Theiler's murine encephalomyelitis virus chimera, Chi-VL. The kinetics of viral RNA and protein synthesis and virus production in BHK-21 cells were slower for the mutant chimera [Chi-VL(IN668)] than for Chi-VL; however, the final virus yields were comparable. Intracerebral inoculation of mice with the chimeras revealed that Chi-VL(IN668) was completely attenuated in neurovirulence. The reduced neurovirulence of Chi-VL(IN668) may be ascribed to its reduced growth in the central nervous system, most likely due to an impaired ability to synthesize viral proteins.

  13. SHP-1-dependent macrophage differentiation exacerbates virus-induced myositis

    PubMed Central

    Watson, Neva B.; Schneider, Karin M.; Massa, Paul T.

    2015-01-01

    Virus-induced myositis is an emerging global affliction that remains poorly characterized with few treatment options. Moreover, muscle-tropic viruses often spread to the central nervous system causing dramatically increased morbidity. Therefore, there is an urgent need to explore genetic factors involved in this class of human disease. This report investigates critical innate immune pathways affecting murine virus-induced myositis. Of particular importance, the key immune regulator SHP-1, which normally suppresses macrophage-mediated inflammation, is a major factor in promoting clinical disease in muscle. We show that Theiler’s murine encephalomyelitis virus infection of skeletal myofibers induces inflammation and subsequent dystrophic calcification with loss of ambulation in wild type mice. Surprisingly, although similar extensive myofiber infection and inflammation is observed in SHP-1-deficient (SHP-1−/−) mice, these mice neither accumulate dead calcified myofibers nor lose ambulation. Macrophages were the predominant effector cells infiltrating WT and SHP-1−/− muscle, and an increased infiltration of immature monocytes/macrophages correlated with absence of clinical disease in SHP-1−/− mice, while mature M1-like macrophages corresponded with increased myofiber degeneration in WT mice. Furthermore, blocking SHP-1 activation in WT macrophages blocked virus-induced myofiber degeneration, and pharmacologic ablation of macrophages inhibited muscle calcification in TMEV-infected WT animals. These data suggest that following TMEV infection of muscle, SHP-1 promotes M1 differentiation of infiltrating macrophages, and these inflammatory macrophages are likely involved in damaging muscle fibers. These findings reveal a pathological role for SHP-1 in promoting inflammatory macrophage differentiation and myofiber damage in virus-infected skeletal muscle, thus identifying SHP-1 and M1 macrophages as essential mediators of virus-induced myopathy. PMID:25681345

  14. Virus Maturation

    PubMed Central

    Veesler, David; Johnson, John E.

    2013-01-01

    We examined virus maturation of selected non-enveloped and enveloped ssRNA viruses; retroviruses; bacteriophages and herpes virus. Processes associated with maturation in the RNA viruses range from subtle (noda and picornaviruses) to dramatic (tetraviruses and togaviruses). The elaborate assembly and maturation pathway of HIV is discussed in contrast to the less sophisticated but highly efficient processes associated with togaviruses. Bacteriophage assembly and maturation are discussed in general terms with specific examples chosen for emphasis. Finally the herpes viruses are compared with bacteriophages. The data support divergent evolution of noda, picorna and tetraviruses from a common ancestor and divergent evolution of alpha and flaviviruses from a common ancestor. Likewise, bacteriophages and herpes viruses almost certainly share a common ancestor in their evolution. Comparing all the viruses, we conclude that maturation is a convergent process that is required to solve conflicting requirements in biological dynamics and function. PMID:22404678

  15. Abrogation of resistance to Theiler's virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin.

    PubMed

    Rodriguez, M; Dunkel, A J; Thiemann, R L; Leibowitz, J; Zijlstra, M; Jaenisch, R

    1993-07-01

    Intracerebral infection of susceptible strains of mice with Theiler's virus, a picornavirus, results in central nervous system demyelination, which is similar to multiple sclerosis. Immunogenetic experiments indicate that the MHC (H-2) and, in particular, the D region that controls class I-restricted immune responses, is an important determinant to development of demyelination. We tested whether disruption of beta 2-microglobulin (beta 2-m) would abrogate resistance to demyelinating disease normally observed in H-2b mice. All (C57BI/6 x 129)F3 mice transgenic for homozygous beta 2-m gene disruption (-/-) developed chronic demyelination after Theiler's murine encephalomyelitis virus infection, whereas none of the infected littermates with normal expression of class I MHC (beta 2-m, +/+) developed demyelination. Demyelinated lesions showed class II MHC expression, macrophages, and TNF but no class I MHC expression or CD8+ T cells. No correlation was observed between development of demyelination and delayed-type hypersensitivity responses to virus Ag. Despite the presence of demyelinating lesions, none of the infected beta 2-m (-/-) mice developed neurologic deficits. Infectious virus and virus Ag persisted in the central nervous systems of infected beta 2-m (-/-) mice but not in beta 2-m (+/+) mice. These experiments support the hypothesis that a class I immune response mediated by CD8+ T cells is important in resistance to Theiler's murine encephalomyelitis virus-induced demyelination. Development of chronic neurologic deficits as observed in immunocompetent susceptible strains of mice may be dependent on the presence of class I MHC and CD8+ T cells.

  16. Functional and Pathogenic Differences of Th1 and Th17 Cells in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Domingues, Helena S.; Mues, Marsilius; Lassmann, Hans; Wekerle, Hartmut; Krishnamoorthy, Gurumoorthy

    2010-01-01

    Background There is consensus that experimental autoimmune encephalomyelitis (EAE) can be mediated by myelin specific T cells of Th1 as well as of Th17 phenotype, but the contribution of either subset to the pathogenic process has remained controversial. In this report, we compare functional differences and pathogenic potential of “monoclonal” T cell lines that recognize myelin oligodendrocyte glycoprotein (MOG) with the same transgenic TCR but are distinguished by an IFN-γ producing Th1-like and IL-17 producing Th17-like cytokine signature. Methods and Findings CD4+ T cell lines were derived from the transgenic mouse strain 2D2, which expresses a TCR recognizing MOG peptide 35–55 in the context of I-Ab. Adoptive transfer of Th1 cells into lymphopenic (Rag2−/−) recipients, predominantly induced “classic” paralytic EAE, whereas Th17 cells mediated “atypical” ataxic EAE in approximately 50% of the recipient animals. Combination of Th1 and Th17 cells potentiated the encephalitogenicity inducing classical EAE exclusively. Th1 and Th17 mediated EAE lesions differed in their composition but not in their localization within the CNS. While Th1 lesions contained IFN-γ, but no IL-17 producing T cells, the T cells in Th17 lesions showed plasticity, substantially converting to IFN-γ producing Th1-like cells. Th1 and Th17 cells differed drastically by their lytic potential. Th1 but not Th17 cells lysed autoantigen presenting astrocytes and fibroblasts in vitro in a contact-dependent manner. In contrast, Th17 cells acquired cytotoxic potential only after antigenic stimulation and conversion to IFN-γ producing Th1 phenotype. Conclusions Our data demonstrate that both Th1 and Th17 lineages possess the ability to induce CNS autoimmunity but can function with complementary as well as differential pathogenic mechanisms. We propose that Th17-like cells producing IL-17 are required for the generation of atypical EAE whereas IFN-γ producing Th1 cells induce

  17. Antagonism of histamine H4 receptors exacerbates clinical and pathological signs of experimental autoimmune encephalomyelitis

    PubMed Central

    Ballerini, C; Aldinucci, A; Luccarini, I; Galante, A; Manuelli, C; Blandina, P; Katebe, M; Chazot, P L; Masini, E; Passani, M B

    2013-01-01

    Background and Purpose The histamine H4 receptor has a primary role in inflammatory functions, making it an attractive target for the treatment of asthma and refractory inflammation. These observations suggested a facilitating action on autoimmune diseases. Here we have assessed the role of H4 receptors in experimental autoimmune encephalomyelitis (EAE) a model of multiple sclerosis (MS). Experimental Approach We induced EAE with myelin oligodendrocyte glycoprotein (MOG35–55) in C57BL/6 female mice as a model of MS. The histamine H4 receptor antagonist 5-chloro-2-[(4-methylpiperazin-1-yl)carbonyl]-1H-indole (JNJ7777120) was injected i.p. daily starting at day 10 post-immunization (D10 p.i.). Disease severity was monitored by clinical and histopathological evaluation of inflammatory cells infiltrating into the spinal cord, anti-MOG35–55 antibody production, assay of T-cell proliferation by [3H]-thymidine incorporation, mononucleate cell phenotype by flow cytometry, cytokine production by elisa assay and transcription factor quantification of mRNA expression. Key Results Treatment with JNJ7777120 exacerbated EAE, increased inflammation and demyelination in the spinal cord of EAE mice and increased IFN-γ expression in lymph nodes, whereas it suppressed IL-4 and IL-10, and augmented expression of the transcription factors Tbet, FOXP3 and IL-17 mRNA in lymphocytes. JNJ7777120 did not affect proliferation of anti-MOG35–55 T-cells, anti-MOG35–55 antibody production or mononucleate cell phenotype. Conclusions and Implications H4 receptor blockade was detrimental in EAE. Given the interest in the development of H4 receptor antagonists as anti-inflammatory compounds, it is important to understand the role of H4 receptors in immune diseases to anticipate clinical benefits and also predict possible detrimental effects. Linked Articles This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http

  18. Immunomodulatory activity of polysaccharides isolated from Clerodendrum splendens: Beneficial effects in experimental autoimmune encephalomyelitis

    PubMed Central

    2013-01-01

    Background Extracts of leaves from Clerodendrum have been used for centuries to treat a variety of medicinal problems in tropical Africa. However, little is known about the high-molecular weight active components conferring therapeutic properties to these extracts. Methods Polysaccharides from the leaves of Clerodendrum splendens were extracted and fractionated by ion exchange and size-exclusion chromatography. Molecular weight determination, sugar analysis, degree of methyl esterification, and other chemical characterization of the fractions were performed. Immunomodulatory activity of the fractions was evaluated by determining their ability to induce monocyte/macrophage nitric oxide (NO), cytokine production, and mitogen-activated protein kinase (MAPK) phosphorylation. Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice, and severity of EAE was monitored in mice treated with intraperitoneal (i.p.) injections of the most active polysaccharide fraction. Lymph nodes (LN) and spleen were harvested, and levels of cytokines in supernatants from LN cells and splenocytes challenged with myelin oligodendrocyte glycoprotein peptide were determined. Results Fractions containing type II arabinogalactan had potent immunomodulatory activity. Specifically, the high-molecular weight sub-fraction CSP-AU1 (average of 38.5 kDa) induced NO and cytokine [interleukin (IL)-1α, -1β, -6, -10, tumor necrosis factor (TNF; designated previously as TNF-α), and granulocyte macrophage-colony stimulating factor (GM-CSF)] production by human peripheral blood mononuclear cells (PBMCs) and monocyte/macrophages. CSP-AU1-induced secretion of TNF was prevented by Toll-like receptor 4 (TLR4) antagonist LPS-RS, indicating a role for TLR4 signaling. Treatment with CSP-AU1 also induced phosphorylation of a number of MAPKs in human PBMC and activated AP-1/NF-κB. In vivo treatment of mice with CSP-AU1 and CSP-NU1 resulted in increased serum IL-6, IL-10, TNF, monocyte

  19. A Cannabigerol Derivative Suppresses Immune Responses and Protects Mice from Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Carrillo-Salinas, Francisco J.; Navarrete, Carmen; Mecha, Miriam; Feliú, Ana; Collado, Juan A.; Cantarero, Irene; Bellido, María L.; Muñoz, Eduardo; Guaza, Carmen

    2014-01-01

    Phytocannabinoids that do not produce psychotropic effects are considered of special interest as novel therapeutic agents in CNS diseases. A cannabigerol quinone, the compound VCE-003, has been shown to alleviate symptoms in a viral model of multiple sclerosis (MS). Hence, we studied T cells and macrophages as targets for VCE-003 and its efficacy in an autoimmune model of MS. Proliferation, cell cycle, expression of activation markers was assessed by FACs in human primary T cells, and cytokine and chemokine production was evaluated. Transcription was studied in Jurkat cells and RAW264.7 cells were used to study the effects of VCE-003 on IL-17-induced macrophage polarization to a M1 phenotype. Experimental autoimmune encephalomyelitis (EAE) was induced by myelin oligodendrocyte glycoprotein (MOG35–55) immunization and spinal cord pathology was assessed by immunohistochemistry. Neurological impairment was evaluated using disease scores. We show here that VCE-003 inhibits CD3/CD28-induced proliferation, cell cycle progression and the expression of the IL-2Rα and ICAM-1 activation markers in human primary T cells. VCE-003 inhibits the secretion of Th1/Th17 cytokines and chemokines in primary murine T cells, and it reduces the transcriptional activity of the IL-2, IL-17 and TNFα promoters induced by CD3/CD28. In addition, VCE-003 and JWH-133, a selective CB2 agonist, dampened the IL-17-induced polarization of macrophages to a pro-inflammatory M1 profile. VCE-003 also prevented LPS-induced iNOS expression in microglia. VCE-003 ameliorates the neurological defects and the severity of MOG-induced EAE in mice through CB2 and PPARγ receptor activation. A reduction in cell infiltrates, mainly CD4+ T cells, was observed, and Th1 and Th17 responses were inhibited in the spinal cord of VCE-003-treated mice, accompanied by weaker microglial activation, structural preservation of myelin sheets and reduced axonal damage. This study highlights the therapeutic potential of VCE

  20. Platelet-Activating Factor Receptors Mediate Excitatory Postsynaptic Hippocampal Injury in Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Geathers, Jasmine S.; Allan, Kevin C.; Gelbard, Harris A.

    2016-01-01

    Gray matter degeneration contributes to progressive disability in multiple sclerosis (MS) and can occur out of proportion to measures of white matter disease. Although white matter pathology, including demyelination and axon injury, can lead to secondary gray matter changes, we hypothesized that neurons can undergo direct excitatory injury within the gray matter independent of these. We tested this using a model of experimental autoimmune encephalomyelitis (EAE) with hippocampal degeneration in C57BL/6 mice, in which immunofluorescent staining showed a 28% loss of PSD95-positive excitatory postsynaptic puncta in hippocampal area CA1 compared with sham-immunized controls, despite preservation of myelin and VGLUT1-positive excitatory axon terminals. Loss of postsynaptic structures was accompanied by appearance of PSD95-positive debris that colocalized with the processes of activated microglia at 25 d after immunization, and clearance of debris was followed by persistently reduced synaptic density at 55 d. In vitro, addition of activated BV2 microglial cells to hippocampal cultures increased neuronal vulnerability to excitotoxic dendritic damage following a burst of synaptic activity in a manner dependent on platelet-activating factor receptor (PAFR) signaling. In vivo treatment with PAFR antagonist BN52021 prevented PSD95-positive synapse loss in hippocampi of mice with EAE but did not affect development of EAE or local microglial activation. These results demonstrate that postsynaptic structures can be a primary target of injury within the gray matter in autoimmune neuroinflammatory disease, and suggest that this may occur via PAFR-mediated modulation of activity-dependent synaptic physiology downstream of microglial activation. SIGNIFICANCE STATEMENT Unraveling gray matter degeneration is critical for developing treatments for progressive disability and cognitive impairment in multiple sclerosis (MS). In a mouse model of MS, we show that neurons can undergo injury

  1. Three-dimensional structure of Theiler virus.

    PubMed Central

    Grant, R A; Filman, D J; Fujinami, R S; Icenogle, J P; Hogle, J M

    1992-01-01

    Theiler murine encephalomyelitis virus strains are categorized into two groups, a neurovirulent group that rapidly kills the host, and a demyelinating group that causes a generally nonlethal infection of motor neurons followed by a persistent infection of the white matter with demyelinating lesions similar to those found in multiple sclerosis. The three-dimensional structure of the DA strain, a member of the demyelinating group, has been determined at 2.8 A resolution. As in other picornaviruses, the icosahedral capsid is formed by the packing of wedge-shaped eight-stranded antiparallel beta barrels. The surface of Theiler virus has large star-shaped plateaus at the fivefold axes and broad depressions spanning the twofold axes. Several unusual structural features are clustered near one edge of the depression. These include two finger-like loops projecting from the surface (one formed by residues 78-85 of VP1, and the other formed by residues 56-65 of VP3) and a third loop containing three cysteines (residues 87, 89, and 91 of VP3), which appear to be covalently modified. Most of the sequence differences between the demyelinating and neurovirulent groups that could play a role in determining pathogenesis map to the surface of the star-shaped plateau. The distribution of these sequence differences on the surface of the virion is consistent with models in which the differences in the pathogenesis of the two groups of Theiler viruses are the result of differences in immunological or receptor-mediated recognition processes. Images PMID:1549565

  2. Zika virus.

    PubMed

    2016-02-10

    Essential facts Zika virus disease is caused by a virus that is transmitted by the Aedes mosquito. While it generally causes a mild illness, there is increasing concern that it is harmful in pregnancy and can cause congenital abnormalities in infants born to women infected with the virus. There is no antiviral treatment or vaccine currently available. The best form of prevention is protection against mosquito bites.

  3. Ebola virus.

    PubMed

    Streether, L A

    1999-01-01

    Ebola virus was first identified as a filovirus in 1976, following epidemics of severe haemorrhagic fever in sub-Saharan Africa. Further outbreaks have occurred since, but, despite extensive and continued investigations, the natural reservoir for the virus remains unknown. The mortality rate is high and there is no cure for Ebola virus infection. Molecular technology is proving useful in extending our knowledge of the virus. Identification of the host reservoir, control and prevention of further outbreaks, rapid diagnosis of infection, and vaccine development remain areas of continued interest in the fight against this biosafety level-four pathogen.

  4. Virus Crystallography

    NASA Astrophysics Data System (ADS)

    Fry, Elizabeth; Logan, Derek; Stuart, David

    Crystallography provides a means of visualizing intact virus particles as well as their isolated constituent proteins and enzymes (1-3) at near-atomic resolution, and is thus an extraordinarily powerful tool in the pursuit of a fuller understanding of the functioning of these simple biological systems. We have already expanded our knowledge of virus evolution, assembly, antigenic variation, and host-cell interactions; further studies will no doubt reveal much more. Although the rewards are enormous, an intact virus structure determination is not a trivial undertaking and entails a significant scaling up in terms of time and resources through all stages of data collection and processing compared to a traditional protein crystallographic structure determination. It is the methodology required for such studies that will be the focus of this chapter. The computational requirements were satisfied in the late 1970s, and when combined with the introduction of phase improvement techniques utilizing the virus symmetry (4,5), the application of crystallography to these massive macromolecular assemblies became feasible. This led to the determination of the first virus structure (the small RNA plant virus, tomato bushy stunt virus), by Harrison and coworkers in 1978 (6). The structures of two other plant viruses followed rapidly (7,8). In the 1980s, a major focus of attention was a family of animal RNA viruses; the Picornaviridae.

  5. Leuprolide acetate, a GnRH agonist, improves experimental autoimmune encephalomyelitis: a possible therapy for multiple sclerosis.

    PubMed

    Guzmán-Soto, Irene; Salinas, Eva; Hernández-Jasso, Irma; Quintanar, J Luis

    2012-10-01

    Gonadotrophin-releasing hormone (GnRH), a well known hypothalamic neuropeptide, has been reported to possess neurotrophic properties. Leuprolide acetate, a synthetic analogue of GnRH is considered to be a very safe and tolerable drug and it has been used for diverse clinical applications, including the treatment of prostate cancer, endometriosis, uterine fibroids, central precocious puberty and in vitro fertilization techniques. The present study was designed to determine whether Leuprolide acetate administration, exerts neurotrophic effects on clinical signs, body weight gain, neurofilaments (NFs) and myelin basic protein (MBP) expression, axonal morphometry and cell infiltration in spinal cord of experimental autoimmune encephalomyelitis (EAE) rats. In this work, we have found that Leuprolide acetate treatment decreases the severity of clinical signs of locomotion, induces a significantly greater body weight gain, increases the MBP and NFs expression, axonal area and cell infiltration in EAE animals. These results suggest the use of this agonist as a potential therapeutic approach for multiple sclerosis.

  6. CP-10, a chemotactic peptide, is expressed in lesions of experimental autoimmune encephalomyelitis, neuritis, uveitis and in C6 gliomas.

    PubMed

    Deininger, M H; Zhao, Y; Schluesener, H J

    1999-01-01

    CP-10 (chemotactic protein of m.w. 10,000) is a member of the S100 superfamily of Ca2+ binding peptides, which has potent chemotactic activity for murine and human myeloid cells. Here we report on the generation of monoclonal antibodies against CP-10 and accumulation of CP-10+ cells during experimental autoimmune encephalomyelitis (EAE), neuritis (EAN), uveitis (EAU) and in experimentally transplanted C6 gliomas. During acute inflammation, CP-10 is mainly expressed by large ED1+ monocytic perivascular cells that accumulate at days 11-14. CP-10+ cells are predominantly located in areas of cellular infiltration but are as well found in the meninges and infiltrating the brain parenchyma. In transplanted gliomas, CP-10+ cells are located exclusively within the tumor parenchyma. Using double labeling experiments, other cells participating in the inflammatory reaction were found to express CP-10, like few lymphoblastic W3/13+ cells in the vicinity of the inflammatory infiltrate.

  7. Reg-2, A Downstream Signaling Protein in the Ciliary Neurotrophic Factor Survival Pathway, Alleviates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Jiang, Hong; Tian, Ke-Wei; Zhang, Fan; Wang, Beibei; Han, Shu

    2016-01-01

    Ciliary neurotrophic factor (CNTF), originally described as a neurocytokine that could support the survival of neurons, has been recently found to alleviate demyelination, prevent axon loss, and improve functional recovery in a rat model of acute experimental autoimmune encephalomyelitis (EAE). However, poor penetration into the brain parenchyma and unfavorable side effects limit the utility of CNTF. Here, we evaluated the therapeutic potential of a protein downstream of CNTF, regeneration gene protein 2 (Reg-2). Using multiple morphological, molecular biology, and electrophysiological methods to assess neuroinflammation, axonal loss, demyelination, and functional impairment, we observed that Reg-2 and CNTF exert similar effects in the acute phase of EAE. Both treatments attenuated axonal loss and demyelination, improved neuronal survival, and produced functional improvement. With a smaller molecular weight and improved penetration into the brain parenchyma, Reg-2 may be a useful substitute for CNTF therapy in EAE and multiple sclerosis (MS). PMID:27242448

  8. [Immunotherapy of certain acute and chronic forms of neuroinfections (tick-borne encephalitis, multiple sclerosis, disseminated encephalomyelitis)].

    PubMed

    Umanskiĭ, K G; Shishov, A S; Dekonenko, E P; Ashmarina, E E; Andreeva, L S

    1981-01-01

    The pathogenetic community of various viral neuroinfections different in their form and course points out that the use of means targeted at correction of the immune system functions is desirable. As a result of using combined immunotherapy methods the authors have obtained positive results in treating 38 patients suffering from some acute and chronic neuroinfections (grave local forms of acute tick-borne encephalitis, progredient forms of the same encephalitis, disseminated sclerosis, disseminated encephalomyelitis). Interrelations between the immunity factors are studied, and their role in the therapeutic effect obtained is discussed. The scheme and the result of the treatment, as well as general principles of dynamic observation and treatment of those patients are presented.

  9. Acute Disseminated Encephalomyelitis following Vaccination against Hepatitis B in a Child: A Case Report and Literature Review.

    PubMed

    Yuan, Jun-Liang; Wang, Shuang-Kun; Guo, Xiao-Juan; Hu, Wen-Li

    2016-01-01

    Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system, which has been associated with several vaccines such as rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, and the Hog vaccine. Here, we presented a case of 12-year-old child who suffered from ADEM three weeks after hepatitis B vaccination. He was admitted to our hospital with symptoms of weakness of limbs, high fever, and alteration of consciousness. Some abnormalities were also found in CSF. Treatment with high-dose corticosteroids and intravenous immunoglobulin had significant effect, with marked improvement of the clinical symptoms and the results of CSF. The findings of MRI also detected some abnormal lesions located in both brain and spinal cord. The clinical features, the findings of CSF and MRI, and therapeutic effect may contribute to such diagnosis of ADEM. PMID:27478662

  10. Acute Disseminated Encephalomyelitis following Vaccination against Hepatitis B in a Child: A Case Report and Literature Review

    PubMed Central

    Yuan, Jun-liang; Wang, Shuang-kun; Guo, Xiao-juan

    2016-01-01

    Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system, which has been associated with several vaccines such as rabies, diphtheria-tetanus-polio, smallpox, measles, mumps, rubella, Japanese B encephalitis, pertussis, influenza, and the Hog vaccine. Here, we presented a case of 12-year-old child who suffered from ADEM three weeks after hepatitis B vaccination. He was admitted to our hospital with symptoms of weakness of limbs, high fever, and alteration of consciousness. Some abnormalities were also found in CSF. Treatment with high-dose corticosteroids and intravenous immunoglobulin had significant effect, with marked improvement of the clinical symptoms and the results of CSF. The findings of MRI also detected some abnormal lesions located in both brain and spinal cord. The clinical features, the findings of CSF and MRI, and therapeutic effect may contribute to such diagnosis of ADEM. PMID:27478662

  11. Live Virus Smallpox Vaccine

    MedlinePlus

    ... Index SMALLPOX FACT SHEET The Live Virus Smallpox Vaccine The vaccinia virus is the "live virus" used ... cannot cause smallpox. What is a "live virus" vaccine? A "live virus" vaccine is a vaccine that ...

  12. Stone Lakes virus (family Togaviridae, genus Alphavirus), a variant of Fort Morgan virus isolated from swallow bugs (Hemiptera: Cimicidae) west of the Continental Divide.

    PubMed

    Brault, Aaron C; Armijos, M Veronica; Wheeler, Sarah; Wright, Stan; Fang, Ying; Langevin, Stanley; Reisen, William K

    2009-09-01

    Multiple isolates of an alphaviruses within the western equine encephalomyelitis-serocomplex that were related closely to Ft. Morgan and its variant Buggy Creek virus were made from swallow bugs, Oeciacus vicarius Horvath (Hemiptera: Cimicidae), collected from cliff swallow (Petrochelidon pyrrhonota) nests at the Stone Lakes National Wildlife Refuge, Sacramento County, CA, during the summers of 2005 and 2006. This virus (hereafter Stone Lakes virus, family Togaviridae, genus Alphavirus, STLV) was the first record of this viral group west of the Continental Divide. STLV replicated well in Vero and other vertebrate cell cultures but failed to replicate in C6/36 cells or infect Culex tarsalis Coquillett mosquitoes. STLV failed to produce elevated viremias in adult chickens or house sparrows and was weakly immunogenic. In addition, STLV was not isolated from cliff swallow nestlings nor was antibody detected in adults collected at mist nets. We suggest that STL and related swallow bug viruses may be primarily infections of cimicids that are maintained and amplified either by vertical or nonviremic transmission and that cliff swallows may primarily be important as a bloodmeal source for the bugs rather than as an amplification host for the viruses. PMID:19769055

  13. XY sex chromosome complement, compared with XX, in the CNS confers greater neurodegeneration during experimental autoimmune encephalomyelitis.

    PubMed

    Du, Sienmi; Itoh, Noriko; Askarinam, Sahar; Hill, Haley; Arnold, Arthur P; Voskuhl, Rhonda R

    2014-02-18

    Women are more susceptible to multiple sclerosis (MS) and have more robust immune responses than men. However, men with MS tend to demonstrate a more progressive disease course than women, suggesting a disconnect between the severity of an immune attack and the CNS response to a given immune attack. We have previously shown in an MS model, experimental autoimmune encephalomyelitis, that autoantigen-sensitized XX lymph node cells, compared with XY, are more encephalitogenic. These studies demonstrated an effect of sex chromosomes in the induction of immune responses, but did not address a potential role of sex chromosomes in the CNS response to immune-mediated injury. Here, we examined this possibility using XX versus XY bone marrow chimeras reconstituted with a common immune system of one sex chromosomal type. We found that experimental autoimmune encephalomyelitis mice with an XY sex chromosome complement in the CNS, compared with XX, demonstrated greater clinical disease severity with more neuropathology in the spinal cord, cerebellum, and cerebral cortex. A candidate gene on the X chromosome, toll-like receptor 7, was then examined. Toll-like receptor 7 expression in cortical neurons was higher in mice with XY compared with mice with XX CNS, consistent with the known neurodegenerative role for toll-like receptor 7 in neurons. These results suggest that sex chromosome effects on neurodegeneration in the CNS run counter to effects on immune responses, and may bear relevance to the clinical enigma of greater MS susceptibility in women but faster disability progression in men. This is a demonstration of a direct effect of sex chromosome complement on neurodegeneration in a neurological disease.

  14. Myelin oligodendrocyte glycoprotein (MOG35-55)-induced experimental autoimmune encephalomyelitis is ameliorated in interleukin-32 alpha transgenic mice.

    PubMed

    Yun, Jaesuk; Gu, Sun Mi; Yun, Hyung Mun; Son, Dong Ju; Park, Mi Hee; Lee, Moon Soon; Hong, Jin Tae

    2015-12-01

    Multiple sclerosis (MS), also known as disseminated sclerosis or encephalomyelitis disseminate, is an inflammatory disease in which myelin in the spinal cord and brain are damaged. IL-32α is known as a critical molecule in the pathophysiology of immune-mediated chronic inflammatory disease such as rheumatoid arthritis, chronic pulmonary disease, and cancers. However, the role of IL-32α on spinal cord injuries and demyelination is poorly understood. Recently, we reported that the release of proinflammatory cytokines were reduced in IL-32α-overexpressing transgenic mice. In this study, we investigated whether IL-32α plays a role on MS using experimental autoimmune encephalomyelitis (EAE), an experimental mouse model of MS, in human IL-32α Tg mice. The Tg mice were immunized with MOG35-55 suspended in CFA emulsion followed by pertussis toxin, and then EAE paralysis of mice was scored. We observed that the paralytic severity and neuropathology of EAE in IL-32α Tg mice were significantly decreased compared with that of non-Tg mice. The immune cells infiltration, astrocytes/microglials activation, and pro-inflammatory cytokines (IL-1β and IL-6) levels in spinal cord were suppressed in IL-32α Tg mice. Furthermore, NG2 and O4 were decreased in IL-32α Tg mice, indicating that spinal cord damaging was suppressed. In addition, in vitro assay also revealed that IL-32α has a preventive role against Con A stimulation which is evidenced by decrease in T cell proliferation and inflammatory cytokine levels in IL-32α overexpressed Jurkat cell. Taken together, our findings suggested that IL-32α may play a protective role in EAE by suppressing neuroinflammation in spinal cord. PMID:26564962

  15. A DNA Vaccine for Venezuelan Equine Encephalitis Virus Delivered by Intramuscular Electroporation Elicits High Levels of Neutralizing Antibodies in Multiple Animal Models and Provides Protective Immunity to Mice and Nonhuman Primates ▿

    PubMed Central

    Dupuy, Lesley C.; Richards, Michelle J.; Ellefsen, Barry; Chau, Lillian; Luxembourg, Alain; Hannaman, Drew; Livingston, Brian D.; Schmaljohn, Connie S.

    2011-01-01

    We evaluated the immunogenicity and protective efficacy of a DNA vaccine expressing codon-optimized envelope glycoprotein genes of Venezuelan equine encephalitis virus (VEEV) when delivered by intramuscular electroporation. Mice vaccinated with the DNA vaccine developed robust VEEV-neutralizing antibody responses that were comparable to those observed after administration of the live-attenuated VEEV vaccine TC-83 and were completely protected from a lethal aerosol VEEV challenge. The DNA vaccine also elicited strong neutralizing antibody responses in rabbits that persisted at high levels for at least 6 months and could be boosted by a single additional electroporation administration of the DNA performed approximately 6 months after the initial vaccinations. Cynomolgus macaques that received the vaccine by intramuscular electroporation developed substantial neutralizing antibody responses and after an aerosol challenge had no detectable serum viremia and had reduced febrile reactions, lymphopenia, and clinical signs of disease compared to those of negative-control macaques. Taken together, our results demonstrate that this DNA vaccine provides a potent means of protecting against VEEV infections and represents an attractive candidate for further development. PMID:21450977

  16. Attenuated rabies virus activates, while pathogenic rabies virus evades, the host innate immune responses in the central nervous system.

    PubMed

    Wang, Zhi W; Sarmento, Luciana; Wang, Yuhuan; Li, Xia-qing; Dhingra, Vikas; Tseggai, Tesfai; Jiang, Baoming; Fu, Zhen F

    2005-10-01

    Rabies virus (RV) induces encephalomyelitis in humans and animals. However, the pathogenic mechanism of rabies is not fully understood. To investigate the host responses to RV infection, we examined and compared the pathology, particularly the inflammatory responses, and the gene expression profiles in the brains of mice infected with wild-type (wt) virus silver-haired bat RV (SHBRV) or laboratory-adapted virus B2C, using a mouse genomic array (Affymetrix). Extensive inflammatory responses were observed in animals infected with the attenuated RV, but little or no inflammatory responses were found in mice infected with wt RV. Furthermore, attenuated RV induced the expression of the genes involved in the innate immune and antiviral responses, especially those related to the alpha/beta interferon (IFN-alpha/beta) signaling pathways and inflammatory chemokines. For the IFN-alpha/beta signaling pathways, many of the interferon regulatory genes, such as the signal transduction activation transducers and interferon regulatory factors, as well as the effector genes, for example, 2'-5'-oligoadenylate synthetase and myxovirus proteins, are highly induced in mice infected with attenuated RV. However, many of these genes were not up-regulated in mice infected with wt SHBRV. The data obtained by microarray analysis were confirmed by real-time PCR. Together, these data suggest that attenuated RV activates, while pathogenic RV evades, the host innate immune and antiviral responses.

  17. Analysis of genetic variation in Theiler's virus during persistent infection in the mouse central nervous system.

    PubMed

    Rozhon, E J; Kratochvil, J D; Lipton, H L

    1983-07-15

    The genetic changes occurring in the BeAn strain of Theiler's murine encephalomyelitis virus (TMEV) during persistent infection in the mouse central nervous system (CNS) were studied. RNase T1-oligonucleotide fingerprinting of the RNAs of 28 BeAn viruses isolated at various times postinfection (p.i.) demonstrated that mutation occurred throughout the infection. Although plaque-purified BeAn virus was used to inoculate mice intracerebrally, genetically different viruses were recovered from the CNS. One to three oligonucleotide changes were found up to Day 152 p.i., but all three viruses isolated at Day 180 had four to nine oligonucleotide changes. No pattern of oligonucleotide changes occurring in different virus isolates was found, yet three viruses isolated from different animals at Day 180 had the same four new oligonucleotides. Overall, the number of oligonucleotide changes represented a 0.1 to 1.2% change in the virus genome. In addition, the analytical two-dimensional gel technique of P.Z. O'Farrell, H.M. Goodman, and P.H. O'Farrell (Cell 12, 1133-1142, 1977) suggested that mutation occurred in all virus isolates. In nine isolates, one to three proteins were found to have charge changes, and in general, as many nonstructural proteins had charge changes as structural proteins. P20, a nonstructural protein probably equivalent to the protease described for encephalomyocarditis virus, was found to have shifted cathodally in six different viruses. Several virus isolates had doublet patterns, suggesting the possibility that within the CNS, subpopulations existed which had proteins of slightly different charge or that virus-specified proteins had been modified after translation. Finally, antigenic variation of neutralizing site(s) on BeAn virus isolates as a way for virus to evade immune surveillance and thereby maintain the persistent state was studied. The ability of mouse serum to neutralize persisting virus isolates was not significantly different from the

  18. Three-dimensional model of the capsid proteins of two biologically different Theiler virus strains: clustering of amino acid difference identifies possible locations of immunogenic sites on the virion.

    PubMed Central

    Pevear, D C; Luo, M; Lipton, H L

    1988-01-01

    To explore structural features of the Theiler murine encephalomyelitis virion, we have constructed a three-dimensional model of the capsid proteins (VP1, VP2, and VP3) of the BeAn strain based on the atomic coordinates of the closely related Mengo virus. By superimposition of amino acid differences between BeAn virus and another Theiler virus strain, GDVII, on the three-dimensional model, clusters of differences were found in four distinct sites; the VP1 third corner, the VP2 "puff," and the VP3 first corner and "knob." These clusters, which are found on the surface of the virion, may represent neutralizing immunogenic sites that have come under selective pressure from neutralizing antibodies. Furthermore, the putative viral receptor binding site ("pit") of the two Theiler virus strains was found to be markedly conserved. Images PMID:2454472

  19. Inflammation severely alters thyroid hormone signaling in the central nervous system during experimental allergic encephalomyelitis in rat: Direct impact on OPCs differentiation failure.

    PubMed

    Fernández, Mercedes; Baldassarro, Vito A; Sivilia, Sandra; Giardino, Luciana; Calzà, Laura

    2016-09-01

    Differentiation of oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes is severely impaired by inflammatory cytokines and this could lead to remyelination failure in inflammatory/demyelinating diseases. Due to the role of thyroid hormone in the maturation of OPCs and developmental myelination, in this study we investigated (i) the possible occurrence of dysregulation of thyroid hormone signaling in the CNS tissue during experimental neuroinflammation; (ii) the possible impact of inflammatory cytokines on thyroid hormone signaling and OPCs differentiation in vitro. The disease model is the experimental allergic encephalomyelitis in female Dark-Agouti rats, whereas in vitro experiments were carried out in OPCs derived from neural stem cells. The main results are the following: (i) a strong upregulation of cytokine mRNA expression level was found in the spinal cord during experimental allergic encephalomyelitis; (ii) thyroid hormone signaling in the spinal cord (thyroid hormone receptors; deiodinase; thyroid hormone membrane transporter) is substantially downregulated, due to the upregulation of the thyroid hormone inactivating enzyme deiodinase 3 and the downregulation of thyroid hormone receptors, as investigated at mRNA expression level; (iii) when exposed to inflammatory cytokines, deiodinase 3 is upregulated in OPCs as well, and OPCs differentiation is blocked; (iv) deiodinase 3 inhibition by iopanoic acid recovers OPCs differentiation in the presence on inflammatory cytokines. These data suggest that cellular hypothyroidism occurs during experimental allergic encephalomyelitis, possibly impacting on thyroid hormone-dependent cellular processes, including maturation of OPCs into myelinating oligodendrocytes. GLIA 2016;64:1573-1589. PMID:27404574

  20. Unimpaired Autoreactive T-Cell Traffic Within the Central Nervous System During Tumor Necrosis Factor Receptor-Mediated inhibition of Experimental Autoimmune Encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Korner, Heinrich; Goodsall, Anna L.; Lemckert, Frances A.; Scallon, Bernard J.; Ghrayeb, John; Ford, Andrew L.; Sedgwick, Jonathon D.

    1995-11-01

    The critical role of tumor necrosis factor (TNF) as a mediator in autoimmune inflammatory processes is evident from in vivo studies with TNF-blocking agents. However, the mechanisms by which TNF, and possibly also its homologue lymphotoxin α, contributes to development of pathology in rheumatoid arthritis and Crohn disease and in animal models like experimental autoimmune encephalomyelitis is unclear. Possibilities include regulation of vascular adhesion molecules enabling leukocyte movement into tissues or direct cytokine-mediated effector functions such as mediation of tissue damage. Here we show that administration of a TNF receptor (55 kDa)-IgG fusion protein prevented clinical signs of actively induced experimental autoimmune encephalomyelitis. Significantly, the total number of CD4^+ T lymphocytes isolated from the central nervous system of clinically healthy treated versus diseased control animals was comparable. By using a CD45 congenic model of passively transferred experimental autoimmune encephalomyelitis to enable tracking of myelin basic protein-specific effector T lymphocytes, prevention of clinical signs of disease was again demonstrated in treated animals but without quantitative or qualitative impediment to the movement of autoreactive T lymphocytes to and within the central nervous system. Thus, despite the uninterrupted movement of specific T lymphocytes into the target tissue, subsequent disease development was blocked. This provides compelling evidence for a direct effector role of TNF/lymphotoxin α in autoimmune tissue damage.

  1. Invariant NKT Cells Regulate the CD8 T Cell Response during Theiler's Virus Infection

    PubMed Central

    Mars, Lennart T.; Mas, Magali; Beaudoin, Lucie; Bauer, Jan; Leite-de-Moraes, Maria; Lehuen, Agnès; Bureau, Jean-Francois; Liblau, Roland S.

    2014-01-01

    Invariant NKT cells are innate lymphocytes with a broad tissue distribution. Here we demonstrate that iNKT cells reside in the central nervous system (CNS) in the absence of inflammation. Their presence in the CNS dramatically augments following inoculation of C57Bl/6 mice with the neurotropic Theiler's murine encephalomyelitis virus (TMEV). At the peak of inflammation the cellular infiltrate comprises 45 000 iNKT cells for 1 250 CD8 T cells specific for the immunodominant TMEV epitope. To study the interaction between these two T cell subsets, we infected both iNKT cell deficient Jα18-/- mice and iNKT cell enriched Vα14 transgenic mice with TMEV. The CD8 T cell response readily cleared TMEV infection in the iNKT cell deficient mice. However, in the iNKT cell enriched mice TMEV infection persisted and was associated with significant mortality. This was caused by the inhibition of the CD8 T cell response in the cervical lymph nodes and spleen after T cell priming. Taken together we demonstrate that iNKT cells reside in the CNS in the absence of inflammation and that their enrichment is associated with the inhibition of the anti-viral CD8 T cell response and an augmented mortality during acute encephalomyelitis. PMID:24498175

  2. Complete genome sequence analysis of Seneca Valley virus-001, a novel oncolytic picornavirus.

    PubMed

    Hales, Laura M; Knowles, Nick J; Reddy, P Seshidar; Xu, Ling; Hay, Carl; Hallenbeck, Paul L

    2008-05-01

    The complete genome sequence of Seneca Valley virus-001 (SVV-001), a small RNA virus, was determined and was shown to have typical picornavirus features. The 7280 nt long genome was predicted to contain a 5' untranslated region (UTR) of 666 nt, followed by a single long open reading frame consisting of 6543 nt, which encodes a 2181 aa polyprotein. This polyprotein could potentially be cleaved into 12 polypeptides in the standard picornavirus L-4-3-4 layout. A 3' UTR of 71 nt was followed by a poly(A) tail of unknown length. Comparisons with other picornaviruses showed that the P1, 2C, 3C and 3D polypeptides of SVV-001 were related most closely to those of the cardioviruses, although they were not related as closely to those of encephalomyocarditis virus and Theiler's murine encephalomyelitis virus as the latter were to each other. Most other regions of the polyprotein differed considerably from those of all other known picornaviruses. SVV-001 contains elements of an internal ribosome entry site reminiscent of that found in hepatitis C virus and a number of genetically diverse picornaviruses. SVV-001 is a novel picornavirus and it is proposed that it be classified as the prototype species in a novel genus named 'Senecavirus'.

  3. Computer viruses

    NASA Technical Reports Server (NTRS)

    Denning, Peter J.

    1988-01-01

    The worm, Trojan horse, bacterium, and virus are destructive programs that attack information stored in a computer's memory. Virus programs, which propagate by incorporating copies of themselves into other programs, are a growing menace in the late-1980s world of unprotected, networked workstations and personal computers. Limited immunity is offered by memory protection hardware, digitally authenticated object programs,and antibody programs that kill specific viruses. Additional immunity can be gained from the practice of digital hygiene, primarily the refusal to use software from untrusted sources. Full immunity requires attention in a social dimension, the accountability of programmers.

  4. Hendra virus.

    PubMed

    Middleton, Deborah

    2014-12-01

    Hendra virus infection of horses occurred sporadically between 1994 and 2010 as a result of spill-over from the viral reservoir in Australian mainland flying-foxes, and occasional onward transmission to people also followed from exposure to affected horses. An unprecedented number of outbreaks were recorded in 2011 leading to heightened community concern. Release of an inactivated subunit vaccine for horses against Hendra virus represents the first commercially available product that is focused on mitigating the impact of a Biosafety Level 4 pathogen. Through preventing the development of acute Hendra virus disease in horses, vaccine use is also expected to reduce the risk of transmission of infection to people.

  5. Hendra virus.

    PubMed

    Middleton, Deborah

    2014-12-01

    Hendra virus infection of horses occurred sporadically between 1994 and 2010 as a result of spill-over from the viral reservoir in Australian mainland flying-foxes, and occasional onward transmission to people also followed from exposure to affected horses. An unprecedented number of outbreaks were recorded in 2011 leading to heightened community concern. Release of an inactivated subunit vaccine for horses against Hendra virus represents the first commercially available product that is focused on mitigating the impact of a Biosafety Level 4 pathogen. Through preventing the development of acute Hendra virus disease in horses, vaccine use is also expected to reduce the risk of transmission of infection to people. PMID:25281398

  6. Persistent West Nile virus transmission and the apparent displacement St. Louis encephalitis virus in southeastern California, 2003-2006.

    PubMed

    Reisen, William K; Lothrop, Hugh D; Wheeler, Sarah S; Kennsington, Marc; Gutierrez, Arturo; Fang, Ying; Garcia, Sandra; Lothrop, Branka

    2008-05-01

    West Nile virus (family Flaviviridae, genus Flavivirus, WNV) invaded the Colorado Desert biome of southern California during summer 2003 and seemed to displace previously endemic St. Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV, an antigenically similar Flavivirus in the Japanese encephalitis virus serocomplex). Western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), an antigenically distinct Alphavirus, was detected during 2005 and 2006, indicating that conditions were suitable for encephalitis virus introduction and detection. Cross-protective "avian herd immunity" due to WNV infection possibly may have prevented SLEV reintroduction and/or amplification to detectable levels. During 2003-2006, WNV was consistently active at wetlands and agricultural habitats surrounding the Salton Sea where Culex tarsalis Coquillett served as the primary enzootic maintenance and amplification vector. Based on published laboratory infection studies and the current seroprevalence estimates, house sparrows, house finches, and several Ardeidae may have been important avian amplifying hosts in this region. Transmission efficiency may have been dampened by high infection rates in incompetent avian hosts, including Gamble's quail, mourning doves, common ground doves, and domestic pigeons. Early season WNV amplification and dispersal from North Shore in the southeastern portion of the Coachella Valley resulted in sporadic WNV incursions into the urbanized Upper Valley near Palm Springs, where Culex pipiens quinquefasciatus Say was the primary enzootic and bridge vector. Although relatively few human cases were detected during the 2003-2006 period, all were concentrated in the Upper Valley and were associated with high human population density and WNV infection in peridomestic populations of Cx. p. quinquefasciatus. Intensive early mosquito control during 2006 seemed to interrupt and delay transmission, perhaps setting the stage for the

  7. Persistent West Nile Virus Transmission and the Apparent Displacement St. Louis Encephalitis Virus in Southeastern California, 2003−2006

    PubMed Central

    REISEN, WILLIAM K.; LOTHROP, HUGH D.; WHEELER, SARAH S.; KENNSINGTON, MARC; GUTIERREZ, ARTURO; FANG, YING; GARCIA, SANDRA; LOTHROP, BRANKA

    2008-01-01

    West Nile virus (family Flaviviridae, genus Flavivirus, WNV) invaded the Colorado Desert biome of southern California during summer 2003 and seemed to displace previously endemic St. Louis encephalitis virus (family Flaviviridae, genus Flavivirus, SLEV, an antigenically similar Flavivirus in the Japanese encephalitis virus serocomplex). Western equine encephalomyelitis virus (family Togaviridae, genus Alphavirus, WEEV), an antigenically distinct Alphavirus, was detected during 2005 and 2006, indicating that conditions were suitable for encephalitis virus introduction and detection. Cross-protective “avian herd immunity” due to WNV infection possibly may have prevented SLEV reintroduction and/or amplification to detectable levels. During 2003−2006, WNV was consistently active at wetlands and agricultural habitats surrounding the Salton Sea where Culex tarsalis Coquillett served as the primary enzootic maintenance and amplification vector. Based on published laboratory infection studies and the current seroprevalence estimates, house sparrows, house finches, and several Ardeidae may have been important avian amplifying hosts in this region. Transmission efficiency may have been dampened by high infection rates in incompetent avian hosts, including Gamble's quail, mourning doves, common ground doves, and domestic pigeons. Early season WNV amplification and dispersal from North Shore in the southeastern portion of the Coachella Valley resulted in sporadic WNV incursions into the urbanized Upper Valley near Palm Springs, where Culex pipiens quinquefasciatus Say was the primary enzootic and bridge vector. Although relatively few human cases were detected during the 2003−2006 period, all were concentrated in the Upper Valley and were associated with high human population density and WNV infection in peridomestic populations of Cx. p. quinquefasciatus. Intensive early mosquito control during 2006 seemed to interrupt and delay transmission, perhaps setting the stage

  8. Schwann cell remyelination and recurrent demyelination in the central nervous system of mice infected with attenuated Theiler's virus.

    PubMed

    Dal Canto, M C; Lipton, H L

    1980-01-01

    Theiler's murine encephalomyelitis virus (TMEV) infection produces a chronic demyelinating disease in mice, and myelin breakdown appears to be immune-mediated. By using an attenuated TMEC strain, WW virus, to infect mice, the course of the disease was slowed and the severity of the inflammatory and glial responses were reduced. In this circumstance, most of the demyelinating lesions showed extensive remyelination, predominantly by Schwann cells. In addition, it was demonstrated that there was recurrent demyelinating activity in the central nervous system (CNS) of infected animals. It is suggested that the rapidity and intensity of demyelinating lesions may influence the potential for remyelination and that Schwann cell participation may be a more important mechanism of myelin repair than it is now thought to be. The fact that there is a recurrent demyelination in TMEV infection increases its relevance as an experimental animal model for multiple sclerosis.

  9. A neutralization-resistant Theiler's virus variant produces an altered disease pattern in the mouse central nervous system.

    PubMed Central

    Zurbriggen, A; Fujinami, R S

    1989-01-01

    Theiler's murine encephalomyelitis virus infection of mice is an animal model for human demyelinating diseases. To further define the role of this virus in the disease process, we selected a virus variant resistant to neutralization by a monoclonal antibody to VP-1. This virus variant was then injected into SJL/J mice. Central nervous system tissue was compared between variant virus- and wild-type virus-infected mice. Within the brain, no large differences were observed between the two groups as to the distribution of inflammatory infiltrates around the injection site and the number of viral antigen-positive cells during the first weeks of the observation period. In contrast, in the spinal cord major differences were found between variant virus- and wild-type virus-infected mice regarding the number of inflammatory lesions, infected cells, and the size of the areas involved with time. By immunohistochemistry, equivalent numbers of infected cells could be found in the spinal cord 1 week postinfection (p.i.): however, after that time, the number of infected cells in the wild-type virus-infected mice continued to increase, whereas the virus-positive cells from the variant virus-infected mice gradually decreased. Thus, the number of viral antigen-containing cells peaked by 1 week p.i. in the variant virus-infected animals. Conversely, the number of infected cells in the spinal cords from mice inoculated with wild-type virus steadily increased until 8 weeks p.i. At this time (8 weeks p.i.), no more variant virus antigen-positive cells could be observed within the spinal cord. Plaque assay of central nervous system tissue confirmed these differences between the two groups observed by immunohistochemistry. No infectious variant virus could be isolated after 2 weeks p.i. from the brain and 4 weeks p.i. from the spinal cord, whereas infectious wild-type virus could be detected up to the end of the observation period (12 weeks p.i.). Virus which was isolated from variant

  10. A neutralization-resistant Theiler's virus variant produces an altered disease pattern in the mouse central nervous system.

    PubMed

    Zurbriggen, A; Fujinami, R S

    1989-04-01

    Theiler's murine encephalomyelitis virus infection of mice is an animal model for human demyelinating diseases. To further define the role of this virus in the disease process, we selected a virus variant resistant to neutralization by a monoclonal antibody to VP-1. This virus variant was then injected into SJL/J mice. Central nervous system tissue was compared between variant virus- and wild-type virus-infected mice. Within the brain, no large differences were observed between the two groups as to the distribution of inflammatory infiltrates around the injection site and the number of viral antigen-positive cells during the first weeks of the observation period. In contrast, in the spinal cord major differences were found between variant virus- and wild-type virus-infected mice regarding the number of inflammatory lesions, infected cells, and the size of the areas involved with time. By immunohistochemistry, equivalent numbers of infected cells could be found in the spinal cord 1 week postinfection (p.i.): however, after that time, the number of infected cells in the wild-type virus-infected mice continued to increase, whereas the virus-positive cells from the variant virus-infected mice gradually decreased. Thus, the number of viral antigen-containing cells peaked by 1 week p.i. in the variant virus-infected animals. Conversely, the number of infected cells in the spinal cords from mice inoculated with wild-type virus steadily increased until 8 weeks p.i. At this time (8 weeks p.i.), no more variant virus antigen-positive cells could be observed within the spinal cord. Plaque assay of central nervous system tissue confirmed these differences between the two groups observed by immunohistochemistry. No infectious variant virus could be isolated after 2 weeks p.i. from the brain and 4 weeks p.i. from the spinal cord, whereas infectious wild-type virus could be detected up to the end of the observation period (12 weeks p.i.). Virus which was isolated from variant

  11. Zika Virus

    MedlinePlus

    ... be at risk for developing fetal complications. Blood, organ and tissue donor screening tests are also needed to assure the safety of transfusion and transplantation in areas of active mosquito-borne virus transmission. ...

  12. Chikungunya virus

    MedlinePlus

    ... first time in the Americas in the Caribbean Islands. In the Americas, local transmission of the disease ... in Florida, Puerto Rico, and the U.S. Virgin Islands. How Chikungunya can spread Mosquitoes spread the virus ...

  13. Zika Virus.

    PubMed

    Phillips, Jennan A; Neyland, Anavernyel

    2016-08-01

    Zika virus (ZIKV) infections are the latest global public health emergency. Occupational health nurses can protect society by educating workers, women of childbearing age, and others traveling in ZIKV-infected areas about prevention strategies.

  14. Dengue virus.

    PubMed

    Ross, Ted M

    2010-03-01

    Dengue is the most prevalent arthropod-borne virus affecting humans today. The virus group consists of 4 serotypes that manifest with similar symptoms. Dengue causes a spectrum of disease, ranging from a mild febrile illness to a life-threatening dengue hemorrhagic fever. Breeding sites for the mosquitoes that transmit dengue virus have proliferated, partly because of population growth and uncontrolled urbanization in tropical and subtropical countries. Successful vector control programs have also been eliminated, often because of lack of governmental funding. Dengue viruses have evolved rapidly as they have spread worldwide, and genotypes associated with increased virulence have spread across Asia and the Americas. This article describes the virology, epidemiology, clinical manifestations and outcomes, and treatments/vaccines associated with dengue infection.

  15. Zika Virus.

    PubMed

    Phillips, Jennan A; Neyland, Anavernyel

    2016-08-01

    Zika virus (ZIKV) infections are the latest global public health emergency. Occupational health nurses can protect society by educating workers, women of childbearing age, and others traveling in ZIKV-infected areas about prevention strategies. PMID:27411846

  16. Pattern and Outcome of Acute Disseminated Encephalomyelitis (ADEM) in Children: Experience in a Tertiary Center, Upper Egypt

    PubMed Central

    Sadek, Abdelrahim Abdrabou; Mohamed, Mostafa Ashry; Abou-Taleb, Ashraf; Mohammed, Marwa Ibrahim

    2016-01-01

    Introduction Acute disseminated encephalomyelitis (ADEM) is an immune mediated disease of the brain. Although it occurs in all ages, most reported cases are in children and adolescents. The aims of this study were to study the clinical pattern and outcome of ADEM in children in a tertiary center in Upper Egypt and to determine the effect of combined use of steroids and IVIg on outcome. Methods This observational study was carried out from January 2014 through December 2014 in the Pediatric Department of Sohag University Hospital (Egypt). All children diagnosed as ADEM during a one year period were included in this study. The treatments used were IV methylprednisolone followed by oral prednisone taper and intravenous immunoglobulin for severe cases. All studied cases were followed up and reevaluated at three months and six months. We used SPSS version 10 and Chi Square, Spearman’s test and t-test for data analysis. Results Eighteen children were included in this study (10 males and 8 females), the average age was 5.5 ± 0.9 years. Prodroma was found in 72.22% of the cases while the main complaint was encephalopathy (83.33%) followed by seizures (11.11%). The neurological findings were convulsions in 83.33%, quadriparesis (33.33%), hemiparesis (33.33), bladder involvement (both retention and incontinence) in 61.11%, and cranial nerve affection (11.11%). Demyelination patches were multifocal in 50%, mainly subcortical in 27.78%. Intelligence quotient (IQ) assessment after 6 months follow up showed that 50% were below average, 25% had mild MR while neurological evaluation showed that 75% of our patients were completely cured. The predictors of better outcome were; children related to the age group (1–4 years) (p = 0.01), children with higher GCS (6–14) (p = 0.01), and children who received steroids on the first day of symptoms and intravenous immunoglobulin in the first week (p = 0.03). Conclusion The clinical pattern of acute disseminated encephalomyelitis is

  17. Pattern and Outcome of Acute Disseminated Encephalomyelitis (ADEM) in Children: Experience in a Tertiary Center, Upper Egypt

    PubMed Central

    Sadek, Abdelrahim Abdrabou; Mohamed, Mostafa Ashry; Abou-Taleb, Ashraf; Mohammed, Marwa Ibrahim

    2016-01-01

    Introduction Acute disseminated encephalomyelitis (ADEM) is an immune mediated disease of the brain. Although it occurs in all ages, most reported cases are in children and adolescents. The aims of this study were to study the clinical pattern and outcome of ADEM in children in a tertiary center in Upper Egypt and to determine the effect of combined use of steroids and IVIg on outcome. Methods This observational study was carried out from January 2014 through December 2014 in the Pediatric Department of Sohag University Hospital (Egypt). All children diagnosed as ADEM during a one year period were included in this study. The treatments used were IV methylprednisolone followed by oral prednisone taper and intravenous immunoglobulin for severe cases. All studied cases were followed up and reevaluated at three months and six months. We used SPSS version 10 and Chi Square, Spearman’s test and t-test for data analysis. Results Eighteen children were included in this study (10 males and 8 females), the average age was 5.5 ± 0.9 years. Prodroma was found in 72.22% of the cases while the main complaint was encephalopathy (83.33%) followed by seizures (11.11%). The neurological findings were convulsions in 83.33%, quadriparesis (33.33%), hemiparesis (33.33), bladder involvement (both retention and incontinence) in 61.11%, and cranial nerve affection (11.11%). Demyelination patches were multifocal in 50%, mainly subcortical in 27.78%. Intelligence quotient (IQ) assessment after 6 months follow up showed that 50% were below average, 25% had mild MR while neurological evaluation showed that 75% of our patients were completely cured. The predictors of better outcome were; children related to the age group (1–4 years) (p = 0.01), children with higher GCS (6–14) (p = 0.01), and children who received steroids on the first day of symptoms and intravenous immunoglobulin in the first week (p = 0.03). Conclusion The clinical pattern of acute disseminated encephalomyelitis is

  18. Role of peridomestic birds in the transmission of St. Louis encephalitis virus in southern California.

    PubMed

    Gruwell, J A; Fogarty, C L; Bennett, S G; Challet, G L; Vanderpool, K S; Jozan, M; Webb, J P

    2000-01-01

    In response to the 1984 St. Louis encephalitis (SLE) epidemic in the Los Angeles Basin of southern California (USA), an investigative program was initiated to evaluate the interactive components of the SLE virus transmission cycle. From 1987 through 1996 (10 yr), 52,589 birds were bled and their sera tested for SLE and western equine encephalomyelitis (WEE) virus antibodies by the hemagglutination inhibition (HAI) test. Eighty-three percent of the birds tested were house finches (Carpodacus mexicanus) (48.7%) and house sparrows (Passer domesticus) (34.6%); 1.1% of these birds were positive for SLE antibodies. Prevalence of WEE antibodies was negligible. The analysis of 5,481 sera from rock doves (Columbia livia) yielded 3.6% SLE positives and 0.4% WEE positives. Collection sites were maintained as study sites when identified as positive bird, mosquito, and SLE virus activity localities; others were abandoned. Serial serum samples from 7,749 banded house sparrows and 9,428 banded house finches from these selected sites demonstrated year-round SLE virus transmission. One location exhibited significant numbers of house finches undergoing annual SLE seroconversion and a number of seroconversion-reversion-reconversion sequences suggesting either viral reinfection from mosquitoes or recrudescence by latent virus. A proportion of both bird species also lived for longer than 1 yr, thus, increasing the possibility of virus carry-over from autumn to spring. Assessment of concurrently collected mosquitoes indicated no correlative association between mosquito populations and SLE seroconversion and reconversion. European house sparrows introduced in the 1800's may have provided a supplemental link to the existing SLE virus enzootic cycle involving endemic house finches. Meteorological factors are reviewed as possible important correlates of SLE epidemics. The house finch/house sparrow serosurveillance system is also evaluated for use as an "Early Warning" indicator of SLE virus

  19. Mechanism of Theiler's virus-induced demyelination in nude mice.

    PubMed

    Rosenthal, A; Fujinami, R S; Lampert, P W

    1986-05-01

    In its natural murine host, infection with Theiler's murine encephalomyelitis virus (TMEV) produces a chronic, progressive demyelinating disease. To help elucidate the role of host immune mechanisms involved in demyelination, we studied TMEV infection in Nude mice. These animals demonstrated rising titers of infectious virus within the central nervous system and failed to produce anti-TMEV antibody. Neurologic signs including the development of severe hind limb paralysis were evident approximately 2 weeks postinfection with most animals succumbing within the first month. Immunoperoxidase studies demonstrated viral antigen in the cytoplasm of neurons and glial cells for the entire period of observation. Plaques of demyelination associated with scanty inflammatory infiltrates were present in the spinal cord by 14 days postinfection. Electron microscopic studies of the involved white matter revealed numerous degenerating glial cells, many of which contained paracrystalline arrays of picornavirus within their cytoplasm. Some of the infected glial cells were identified as oligodendrocytes by demonstrating their myelin-plasma membrane connections. The studies indicate that in Nude mice TMEV causes a lytic infection of oligodendrocytes producing demyelination independent of the T lymphocyte immune system.

  20. Computer Viruses. Technology Update.

    ERIC Educational Resources Information Center

    Ponder, Tim, Comp.; Ropog, Marty, Comp.; Keating, Joseph, Comp.

    This document provides general information on computer viruses, how to help protect a computer network from them, measures to take if a computer becomes infected. Highlights include the origins of computer viruses; virus contraction; a description of some common virus types (File Virus, Boot Sector/Partition Table Viruses, Trojan Horses, and…

  1. Parainfluenza Viruses

    PubMed Central

    Henrickson, Kelly J.

    2003-01-01

    Human parainfluenza viruses (HPIV) were first discovered in the late 1950s. Over the last decade, considerable knowledge about their molecular structure and function has been accumulated. This has led to significant changes in both the nomenclature and taxonomic relationships of these viruses. HPIV is genetically and antigenically divided into types 1 to 4. Further major subtypes of HPIV-4 (A and B) and subgroups/genotypes of HPIV-1 and HPIV-3 have been described. HPIV-1 to HPIV-3 are major causes of lower respiratory infections in infants, young children, the immunocompromised, the chronically ill, and the elderly. Each subtype can cause somewhat unique clinical diseases in different hosts. HPIV are enveloped and of medium size (150 to 250 nm), and their RNA genome is in the negative sense. These viruses belong to the Paramyxoviridae family, one of the largest and most rapidly growing groups of viruses causing significant human and veterinary disease. HPIV are closely related to recently discovered megamyxoviruses (Hendra and Nipah viruses) and metapneumovirus. PMID:12692097

  2. Persistent Macrophage/Microglial Activation and Myelin Disruption after Experimental Autoimmune Encephalomyelitis in Tissue Inhibitor of Metalloproteinase-1-Deficient Mice

    PubMed Central

    Crocker, Stephen J.; Whitmire, Jason K.; Frausto, Ricardo F.; Chertboonmuang, Parntip; Soloway, Paul D.; Whitton, J. Lindsay; Campbell, Iain L.

    2006-01-01

    Increased leukocyte trafficking into the parenchyma during inflammatory responses in the central nervous system (CNS) is facilitated by the extracellular proteolytic activities of matrix metalloproteinases that are regulated, in part, by the endogenous tissue inhibitors of metalloproteinases (TIMPs). In experimental autoimmune encephalomyelitis (EAE), TIMP-1 gene expression is induced in astrocytes surrounding inflammatory lesions in the CNS. The physiological importance of this temporal and spatial relationship is not clear. Herein, we have addressed the functional role of TIMP-1 in a myelin oligodendrocyte glycoprotein (MOG35-55)-induced model of EAE using TIMP-1-deficient (TIMP-1−/−) C57BL/6 mice. Although CD4+ T-cell immune responses to myelin in wild-type (WT) and TIMP-1−/− mice were similar, analysis of CNS tissues from TIMP-1−/− mice after EAE revealed more severe myelin pathology than that of WT mice. This disruption of myelin was associated with both increased lymphocyte infiltration and microglial/macrophage accumulation in the brain parenchyma. These findings suggest that induction of TIMP-1 by astrocytes during EAE in WT mice represents an inherent cytoprotective response that mitigates CNS myelin injury through the regulation of both immune cell infiltration and microglial activation. PMID:17148673

  3. Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo

    PubMed Central

    Boggio, Elena; Gigliotti, Casimiro Luca; Soluri, Maria Felicia; Clemente, Nausicaa; Toth, Erika; Raineri, Davide; Ferrara, Benedetta; Chiocchetti, Annalisa

    2016-01-01

    Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction with α4β1 integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated, in vitro, their effect on human cells and in vivo in EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects both in vitro and in vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases. PMID:27478856

  4. Intranasal delivery of FSD-C10, a novel Rho kinase inhibitor, exhibits therapeutic potential in experimental autoimmune encephalomyelitis

    PubMed Central

    Li, Yan-Hua; Yu, Jie-Zhong; Liu, Chun-Yun; Zhang, Hui; Zhang, Hai-Fei; Yang, Wan-Fang; Li, Jun-Lian; Feng, Qian-Jin; Feng, Ling; Zhang, Guang-Xian; Xiao, Bao-Guo; Ma, Cun-Gen

    2014-01-01

    Viewing multiple sclerosis (MS) as both neuroinflammation and neurodegeneration has major implications for therapy, with neuroprotection and neurorepair needed in addition to controlling neuroinflammation in the central nervous system (CNS). While Fasudil, an inhibitor of Rho kinase (ROCK), is known to suppress experimental autoimmune encephalomyelitis (EAE), an animal model of MS, it relies on multiple, short-term injections, with a narrow safety window. In this study, we explored the therapeutic effect of a novel ROCK inhibitor FSD-C10, a Fasudil derivative, on EAE. An important advantage of this derivative is that it can be used via non-injection routes; intranasal delivery is the preferred route because of its efficient CNS delivery and the much lower dose compared with oral delivery. Our results showed that intranasal delivery of FSD-C10 effectively ameliorated the clinical severity of EAE and CNS inflammatory infiltration and promoted neuroprotection. FSD-C10 effectively induced CNS production of the immunoregulatory cytokine interleukin-10 and boosted expression of nerve growth factor and brain-derived neurotrophic factor proteins, while inhibiting activation of p-nuclear factor-κB/p65 on astrocytes and production of multiple pro-inflammatory cytokines. In addition, FSD-C10 treatment effectively induced CD4+ CD25+, CD4+ FOXP3+ regulatory T cells. Together, our results demonstrate that intranasal delivery of the novel ROCK inhibitor FSD-C10 has therapeutic potential in EAE, through mechanisms that possibly involve both inhibiting CNS inflammation and promoting neuroprotection. PMID:24749492

  5. Immune cell-specific transcriptional profiling highlights distinct molecular pathways controlled by Tob1 upon experimental autoimmune encephalomyelitis

    PubMed Central

    Didonna, Alessandro; Cekanaviciute, Egle; Oksenberg, Jorge R.; Baranzini, Sergio E.

    2016-01-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system characterized by focal lymphocytic infiltration, demyelination and neurodegeneration. Despite the recent advances in understanding MS molecular basis, no reliable biomarkers have been identified yet to monitor disease progression. Our group has previously reported that low levels of TOB1 in CD4+ T cells are strongly associated with a higher risk of MS conversion in individuals experiencing an initial demyelinating event. Consistently, Tob1 ablation in mice exacerbates the clinical phenotype of the MS model experimental autoimmune encephalomyelitis (EAE). To shed light on Tob1 molecular functions in the immune system, we have conducted the first cell-based transcriptomic analysis in Tob1−/− and wildtype mice upon EAE. Next-generation sequencing was employed to characterize the changes in gene expression in T and B cells at pre- and post-symptomatic EAE stages. Remarkably, we found only modest overlap among the different genetic signatures, suggesting that Tob1 may control distinct genetic programs in the different cytotypes. This hypothesis was corroborated by gene ontology and global interactome analyses, which highlighted specific cellular pathways in each cellular subset before and after EAE induction. In summary, our work pinpoints a multifaceted activity of Tob1 in both homeostasis and disease progression. PMID:27546286

  6. Overexpression of the Dominant-Negative Form of Interferon Regulatory Factor 1 in Oligodendrocytes Protects against Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Ren, Zhihua; Wang, Yan; Tao, Duan; Liebenson, David; Liggett, Thomas; Goswami, Rajendra; Clarke, Robert; Stefoski, Dusan

    2011-01-01

    Interferon regulatory factor 1 (IRF-1) is a transcription factor that has been implicated in the pathogenesis of the human autoimmune demyelinating disease multiple sclerosis (MS) and in its animal model, experimental autoimmune encephalomyelitis (EAE). The goal of the present study was to directly examine the role of IRF-1 in oligodendrocyte injury and inflammatory demyelination. For the purpose of this study, we generated a transgenic mouse line (CNP/dnIRF-1) that overexpresses the dominant-negative form of IRF-1 (dnIRF1) specifically in oligodendrocytes. CNP/dnIRF-1 mice exhibited no phenotypic abnormalities but displayed suppressed IRF-1 signaling in oligodendrocytes. The major finding of our study was that the CNP/dnIRF-1 mice, compared with the wild-type mice, were protected against EAE, a phenomenon associated with significant reduction of inflammatory demyelination and with oligodendrocyte and axonal preservation. The observed protection was related to suppressed IRF-1 signaling and impaired expression of immune and proapoptotic genes in oligodendrocytes. No significant differences in the peripheral immune responses between the wild-type and the CNP/dnIRF-1 mice were identified throughout the experiments. This study indicates that IRF-1 plays a critical role in the pathogenesis of EAE by mediating oligodendrocyte response to inflammation and injury. It also suggests that oligodendrocytes are actively involved in the neuroimmune network, and that exploring oligodendrocyte-related pathogenic mechanisms, in addition to the conventional immune-based ones, may have important therapeutic implications in MS. PMID:21653838

  7. Effects of beta 2 adrenergic agonists on axonal injury and mitochondrial metabolism in experimental autoimmune encephalomyelitis rats.

    PubMed

    Zhang, Z W; Qin, X Y; Che, F Y; Xie, G; Shen, L; Bai, Y Y

    2015-01-01

    The primary aims of this study were to investigate mitochondrial metabolism during experimental allergic encephalomyelitis (EAE) animal model axonal injury and to determine the correlation among neurological function scores, pathological changes, and the activities of the BB isoenzyme of creatine kinase (CK-BB), catalase (CAT), and calpain in the brain tissues of EAE rats. Another goal was to preliminarily define the mechanism of mitochondrial metabolism resulting from the effect of beta 2 adrenergic agonists in the process of EAE animal model axonal damage. EAE was induced in specific pathogen free Wistar rats by guinea pig spinal cord homogenate, complete Freund's adjuvant, and pertussis vaccine. We recorded the behavioral change in EAE rats, detected pathological changes in central nervous tissue, and observed the changes of the CK-BB, CAT, and calpain in the EAE rat brain and spinal cord. The results indicated that the average neurologic function score increased in the EAE group compared to that of the controls (P < 0.01). In addition, CAT and CK-BB activities significantly decreased and the calpain activity significantly increased compared with those of the control group (P < 0.05). The decrease of the activity of central nervous CK-BB and CAT content, as well as the increase of calpain activity at the highest time point were considered to be the consequences of EAE. Furthermore, the results revealed that use of salbutamol could alleviate disease symptoms and reduce the recurrence of the EAE disease. PMID:26535670

  8. Novel Function of Extracellular Matrix Protein 1 in Suppressing Th17 Cell Development in Experimental Autoimmune Encephalomyelitis.

    PubMed

    Su, Pan; Chen, Sheng; Zheng, Yu Han; Zhou, Hai Yan; Yan, Cheng Hua; Yu, Fang; Zhang, Ya Guang; He, Lan; Zhang, Yuan; Wang, Yanming; Wu, Lei; Wu, Xiaoai; Yu, Bingke; Ma, Li Yan; Yang, Zhiru; Wang, Jianhua; Zhao, Guixian; Zhu, Jinfang; Wu, Zhi-Ying; Sun, Bing

    2016-08-15

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by demyelination and axonal damage. Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model for human MS. Although Th17 cells are important for disease induction, Th2 cells are inhibitory in this process. In this article, we report the effect of a Th2 cell product, extracellular matrix protein 1 (ECM1), on the differentiation of Th17 cells and the development of EAE. Our results demonstrated that ECM1 administration from day 1 to day 7 following the EAE induction could ameliorate the Th17 cell responses and EAE development in vivo. Further study of the mechanism revealed that ECM1 could interact with αv integrin on dendritic cells and block the αv integrin-mediated activation of latent TGF-β, resulting in an inhibition of Th17 cell differentiation at an early stage of EAE induction. Furthermore, overexpression of ECM1 in vivo significantly inhibited the Th17 cell response and EAE induction in ECM1 transgenic mice. Overall, our work has identified a novel function of ECM1 in inhibiting Th17 cell differentiation in the EAE model, suggesting that ECM1 may have the potential to be used in clinical applications for understanding the pathogenesis of MS and its diagnosis. PMID:27316685

  9. Amelioration of experimental autoimmune encephalomyelitis by probiotic mixture is mediated by a shift in T helper cell immune response.

    PubMed

    Kwon, Ho-Keun; Kim, Gi-Cheon; Kim, Young; Hwang, Won; Jash, Arijita; Sahoo, Anupama; Kim, Jung-Eun; Nam, Jong Hee; Im, Sin-Hyeog

    2013-03-01

    The immunomodulatory effect of probiotics has been shown mainly in gastro-intestinal immune disorders and little information is available on the inflammation of central nervous system. Recently we reported that IRT5 probiotics, a mixture of 5 probiotics, could suppress diverse experimental inflammatory disorders. In this study, we evaluated the prophylactic and therapeutic effects of IRT5 probiotics in experimental autoimmune encephalomyelitis (EAE), a T cell mediated inflammatory autoimmune disease of the central nervous system. Pretreatment of IRT5 probiotics before disease induction significantly suppressed EAE development. In addition, treatment with IRT5 probiotics to the ongoing EAE delayed the disease onset. Administration of IRT5 probiotics inhibited the pro-inflammatory Th1/Th17 polarization, while inducing IL10(+) producing or/and Foxp3(+) regulatory T cells, both in the peripheral immune system and at the site of inflammation. Collectively, our data suggest that IRT5 probiotics could be applicable to modulate T cell mediated neuronal autoimmune diseases, including multiple sclerosis.

  10. Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling.

    PubMed

    Li, Wen; Zhang, Zhihui; Zhang, Kai; Xue, Zhenyi; Li, Yan; Zhang, Zimu; Zhang, Lijuan; Gu, Chao; Zhang, Qi; Hao, Junwei; Da, Yurong; Yao, Zhi; Kong, Ying; Zhang, Rongxin

    2016-10-01

    Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases.

  11. Dehydrodiconiferyl alcohol (DHCA) modulates the differentiation of Th17 and Th1 cells and suppresses experimental autoimmune encephalomyelitis.

    PubMed

    Lee, Junghun; Choi, Jinyong; Lee, Wonwoo; Ko, Kyeongryang; Kim, Sunyoung

    2015-12-01

    Dehydrodiconiferyl alcohol (DHCA), originally isolated from the stems of Cucurbita moschata, has previously been shown to exhibit anti-adipogenic and anti-lipogenic effects in 3T3-L1 cells and primary mouse embryonic fibroblasts (MEFs) (Lee et al., 2012). Here, we investigated whether synthetic DHCA could suppress the CD4 T helper 17 (Th17)-mediated production of the interleukin (IL)-17 protein. The results from RT-qPCR suggest that DHCA-mediated down-regulation of IL-17 occurred at the transcriptional level by suppressing the expression of RAR-related orphan receptor (ROR)γt, the master transcription factor involved in the differentiation of Th17 cells. Furthermore, such inhibition was mediated by the suppression of NF-κB activity. DHCA also inhibited the Th1-mediated production of interferon (IFN) γ by controlling the expression of a key transcription factor known to regulate the production of this cytokine, T-bet. In the mouse experimental autoimmune encephalomyelitis (EAE) model, DHCA showed significant therapeutic effects by inhibiting the infiltration of immune cells into the spinal cords, decreasing the differentiation of pathogenic Th17 and Th1 cells, suppressing the expression of various pro-inflammatory cytokines, and eventually ameliorating the clinical symptoms of EAE mice. Taken together, our data indicate that DHCA may be a potential candidate as an agent for the control of Th17 and Th1-mediated inflammatory diseases.

  12. Comparative Effects of Human Neural Stem Cells and Oligodendrocyte Progenitor Cells on the Neurobehavioral Disorders of Experimental Autoimmune Encephalomyelitis Mice

    PubMed Central

    Bae, Dae-Kwon; Park, Dongsun; Lee, Sun Hee; Yang, Goeun; Kyung, Jangbeen; Kim, Dajeong; Shin, Kyungha; Choi, Ehn-Kyoung; Kim, Gonhyung; Hong, Jin Tae; Kim, Seung U.

    2016-01-01

    Since multiple sclerosis (MS) is featured with widespread demyelination caused by autoimmune response, we investigated the recovery effects of F3.olig2 progenitors, established by transducing human neural stem cells (F3 NSCs) with Olig2 transcription factor, in myelin oligodendrocyte glycoprotein- (MOG-) induced experimental autoimmune encephalomyelitis (EAE) model mice. Six days after EAE induction, F3 or F3.olig2 cells (1 × 106/mouse) were intravenously transplanted. MOG-injected mice displayed severe neurobehavioral deficits which were remarkably attenuated and restored by cell transplantation, in which F3.olig2 cells were superior to its parental F3 cells. Transplanted cells migrated to the injured spinal cord, matured to oligodendrocytes, and produced myelin basic proteins (MBP). The F3.olig2 cells expressed growth and neurotrophic factors including brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and leukemia inhibitory factor (LIF). In addition, the transplanted cells markedly attenuated inflammatory cell infiltration, reduced cytokine levels in the spinal cord and lymph nodes, and protected host myelins. The results indicate that F3.olig2 cells restore neurobehavioral symptoms of EAE mice by regulating autoimmune inflammatory responses as well as by stimulating remyelination and that F3.olig2 progenitors could be a candidate for the cell therapy of demyelinating diseases including MS. PMID:27429621

  13. Triterpenoid modulation of IL-17 and Nrf-2 expression ameliorates neuroinflammation and promotes remyelination in autoimmune encephalomyelitis

    PubMed Central

    Pareek, Tej K.; Belkadi, Abdelmadjid; Kesavapany, Sashi; Zaremba, Anita; Loh, Sook L.; Bai, Lianhua; Cohen, Mark L.; Meyer, Colin; Liby, Karen T.; Miller, Robert H.; Sporn, Michael B.; Letterio, John J.

    2011-01-01

    Inflammatory cytokines and endogenous anti-oxidants are variables affecting disease progression in multiple sclerosis (MS). Here we demonstrate the dual capacity of triterpenoids to simultaneously repress production of IL-17 and other pro-inflammatory mediators while exerting neuroprotective effects directly through Nrf2-dependent induction of anti-oxidant genes. Derivatives of the natural triterpene oleanolic acid, namely CDDO-trifluoroethyl-amide (CDDO-TFEA), completely suppressed disease in a murine model of MS, experimental autoimmune encephalomyelitis (EAE), by inhibiting Th1 and Th17 mRNA and cytokine production. Encephalitogenic T cells recovered from treated mice were hypo-responsive to myelin antigen and failed to adoptively transfer the disease. Microarray analyses showed significant suppression of pro-inflammatory transcripts with concomitant induction of anti-inflammatory genes including Ptgds and Hsd11b1. Finally, triterpenoids induced oligodendrocyte maturation in vitro and enhanced myelin repair in an LPC-induced non-inflammatory model of demyelination in vivo. These results demonstrate the unique potential of triterpenoid derivatives for the treatment of neuroinflammatory disorders such as MS. PMID:22355716

  14. Anti-myelin antibodies play an important role in the susceptibility to develop proteolipid protein-induced experimental autoimmune encephalomyelitis

    PubMed Central

    Marín, N; Eixarch, H; Mansilla, M J; Rodríguez-Martín, E; Mecha, M; Guaza, C; Álvarez-Cermeño, J C; Montalban, X; Villar, L M; Espejo, C

    2014-01-01

    Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is an autoimmune disorder in which activated T cells cross the blood–brain barrier (BBB) to initiate an inflammatory response that leads to demyelination and axonal damage. The key mechanisms responsible for disease initiation are still unknown. We addressed this issue in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. It is widely known that EAE manifests only in certain strains when immunized with myelin proteins or peptides. We studied the differential immune responses induced in two mouse strains that are susceptible or resistant to EAE induction when they are immunized with the 139–151 peptide of proteolipid protein, an encephalitogenic peptide capable of inducing EAE in the susceptible strain. The adequate combination of major histocompatibility complex alleles and myelin peptides triggered in susceptible mice a T helper type 17 (Th17) response capable of inducing the production of high-affinity anti-myelin immunoglobulin (Ig)G antibodies. These were not detected in resistant mice, despite immunization with the encephalitogenic peptide in junction with complete Freund's adjuvant and pertussis toxin, which mediate BBB disruption. These data show the pivotal role of Th17 responses and of high-affinity anti-myelin antibodies in EAE induction and that mechanisms that prevent their appearance can contribute to resistance to EAE. PMID:24188195

  15. Induction of regulatory T cells in Th1-/Th17-driven experimental autoimmune encephalomyelitis by zinc administration.

    PubMed

    Rosenkranz, Eva; Maywald, Martina; Hilgers, Ralf-Dieter; Brieger, Anne; Clarner, Tim; Kipp, Markus; Plümäkers, Birgit; Meyer, Sören; Schwerdtle, Tanja; Rink, Lothar

    2016-03-01

    The essential trace element zinc is indispensable for proper immune function as zinc deficiency accompanies immune defects and dysregulations like allergies, autoimmunity and an increased presence of transplant rejection. This point to the importance of the physiological and dietary control of zinc levels for a functioning immune system. This study investigates the capacity of zinc to induce immune tolerance. The beneficial impact of physiological zinc supplementation of 6 μg/day (0.3mg/kg body weight) or 30 μg/day (1.5mg/kg body weight) on murine experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis with a Th1/Th17 (Th, T helper) cell-dominated immunopathogenesis, was analyzed. Zinc administration diminished EAE scores in C57BL/6 mice in vivo (P<.05), reduced Th17 RORγT(+) cells (P<.05) and significantly increased inducible iTreg cells (P<.05). While Th17 cells decreased systemically, iTreg cells accumulated in the central nervous system. Cumulatively, zinc supplementation seems to be capable to induce tolerance in unwanted immune reactions by increasing iTreg cells. This makes zinc a promising future tool for treating autoimmune diseases without suppressing the immune system.

  16. Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

    NASA Astrophysics Data System (ADS)

    Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

    2014-09-01

    Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE.

  17. Paranodal myelin retraction in relapsing experimental autoimmune encephalomyelitis visualized by coherent anti-Stokes Raman scattering microscopy

    NASA Astrophysics Data System (ADS)

    Fu, Yan; Frederick, Terra J.; Huff, Terry B.; Goings, Gwendolyn E.; Miller, Stephen D.; Cheng, Ji-Xin

    2011-10-01

    How demyelination is initiated is a standing question for pathology of multiple sclerosis. By label-free coherent anti-Stokes Raman scattering (CARS) imaging of myelin lipids, we investigate myelin integrity in the lumbar spinal cord tissue isolated from naïve SJL mice, and from mice at the onset, peak acute, and remission stages of relapsing experimental autoimmune encephalomyelitis (EAE). Progressive demyelinating disease is initially characterized by the retraction of paranodal myelin both at the onset of disease and at the borders of acute demyelinating lesions. Myelin retraction is confirmed by elongated distribution of neurofascin proteins visualized by immunofluorescence. The disruption of paranodal myelin subsequently exposes Kv1.2 channels at the juxtaparanodes and lead to the displacement of Kv1.2 channels to the paranodal and nodal domains. Paranodal myelin is partially restored during disease remission, indicating spontaneous myelin regeneration. These findings suggest that paranodal domain injury precedes formation of internodal demyelinating lesions in relapsing EAE. Our results also demonstrate that CARS microscopy is an effective readout of myelin disease burden.

  18. Spatial reference memory deficits precede motor dysfunction in an experimental autoimmune encephalomyelitis model: the role of kallikrein-kinin system.

    PubMed

    Dutra, Rafael C; Moreira, Eduardo L G; Alberti, Thaís B; Marcon, Rodrigo; Prediger, Rui D; Calixto, João B

    2013-10-01

    Multiple sclerosis (MS) is a progressive T cell-mediated autoimmune demyelinating inflammatory disease of the central nervous system (CNS). Although it is recognized that cognitive deficits represent a manifestation of the disease, the underlying pathogenic mechanisms remain unknown. Here we provide evidence of spatial reference memory impairments during the pre-motor phase of experimental autoimmune encephalomyelitis (EAE) in mice. Specifically, these cognitive deficits were accompanied by down-regulation of choline acetyltransferase (ChAT) mRNA expression on day 5 and 11 post-immunization, and up-regulation of inflammatory cytokines in the hippocampus and prefrontal cortex. Moreover, a marked increase in B1R mRNA expression occurred selectively in the hippocampus, whereas protein level was up-regulated in both brain areas. Genetic deletion of kinin B1R attenuated cognitive deficits and cholinergic dysfunction, and blocked mRNA expression of both IL-17 and IFN-γ in the prefrontal cortex, lymph node and spleen of mice subjected to EAE. The discovery of kinin receptors, mainly B1R, as a target for controlling neuroinflammatory response, as well as the cognitive deficits induced by EAE may foster the therapeutic exploitation of the kallikrein-kinin system (KKS), in particular for the treatment of autoimmune disorders, such as MS, mainly during pre-symptomatic phase. PMID:23777652

  19. Mannosylated self-peptide inhibits the development of experimental autoimmune encephalomyelitis via expansion of nonencephalitogenic T cells.

    PubMed

    Kel, Junda M; Slütter, Bram; Drijfhout, Jan Wouter; Koning, Frits; Nagelkerken, Lex

    2008-07-01

    Tolerance to experimental autoimmune encephalomyelitis (EAE) in SJL mice can be induced by immunization with a mannosylated form of the proteolipid protein (M-PLP139-151), despite the presence of CFA. The state of tolerance is characterized by poor delayed-type hypersensitivity responses and the absence of clinical EAE symptoms. In vivo monitoring of CFSE-labeled PLP139-151-specific TCR-transgenic (5B6) T cells revealed that immunization with M-PLP139-151 increases the clonal expansion of 5B6 T cells that do not develop full effector functions. Moreover, nonfunctional T cells obtained from M-PLP139-151-immunized mice showed poor blastogenesis and were unable to transfer EAE to naïve recipients. Nevertheless, the in vitro production of cytokines and chemokines associated with EAE was unaffected. Importantly, tolerance induced by M-PLP139-151 was abrogated by the administration of pertussis toxin, resulting in EAE development. Our results suggest that M-PLP139-151 inhibits EAE development by affecting the differentiation of T cells into encephalitogenic effector cells.

  20. Interventions for the treatment, management and rehabilitation of patients with chronic fatigue syndrome/myalgic encephalomyelitis: an updated systematic review

    PubMed Central

    Chambers, Duncan; Bagnall, Anne-Marie; Hempel, Susanne; Forbes, Carol

    2006-01-01

    Objectives To determine whether any particular intervention or combination of interventions is effective in the treatment, management and rehabilitation of adults and children with a diagnosis of chronic fatigue syndrome / myalgic encephalomyelitis (CFS/ME). Design Substantive update of a systematic review published in 2002. Randomized (RCTs) and non-randomized controlled trials of any intervention or combination of interventions were eligible for inclusion. Study participants could be adults or children with a diagnosis of CFS/ME based on any criteria. We searched eleven electronic databases, reference lists of articles and reviews, and textbooks on CFS/ME. Additional references were sought by contact with experts. Results Seventy studies met the inclusion criteria. Studies on behavioural, immunological, pharmacological and complementary therapies, nutritional supplements and miscellaneous other interventions were identified. Graded exercise therapy and cognitive behaviour therapy appeared to reduce symptoms and improve function based on evidence from RCTs. For most other interventions, evidence of effectiveness was inconclusive and some interventions were associated with significant adverse effects. Conclusions Over the last five years, there has been a marked increase in the size and quality of the evidence base on interventions for CFS/ME. Some behavioural interventions have shown promising results in reducing the symptoms of CFS/ME and improving physical functioning. There is a need for research to define the characteristics of patients who would benefit from specific interventions and to develop clinically relevant objective outcome measures. PMID:17021301

  1. Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

    PubMed Central

    Chacko, Anu; Staines, Donald R.; Johnston, Samantha C.; Marshall-Gradisnik, Sonya M.

    2016-01-01

    BACKGROUND The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME. METHOD Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years). RESULTS The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls. CONCLUSIONS In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness.

  2. Replacing Myalgic Encephalomyelitis and Chronic Fatigue Syndrome with Systemic Exercise Intolerance Disease Is Not the Way forward

    PubMed Central

    Twisk, Frank N.M.

    2016-01-01

    Myalgic encephalomyelitis (ME), described in the medical literature since 1938, is characterized by distinctive muscular symptoms, neurological symptoms, and signs of circulatory impairment. The only mandatory feature of chronic fatigue syndrome (CFS), introduced in 1988 and redefined in 1994, is chronic fatigue, which should be accompanied by at least four or more out of eight “additional” symptoms. The use of the abstract, polythetic criteria of CFS, which define a heterogeneous patient population, and self-report has hampered both scientific progress and accurate diagnosis. To resolve the “diagnostic impasse” the Institute of Medicine proposes that a new clinical entity, systemic exercise intolerance disease (SEID), should replace the clinical entities ME and CFS. However, adopting SEID and its defining symptoms, does not resolve methodological and diagnostic issues. Firstly, a new diagnostic entity cannot replace two distinct, partially overlapping, clinical entities such as ME and CFS. Secondly, due to the nature of the diagnostic criteria, the employment of self-report, and the lack of criteria to exclude patients with other conditions, the SEID criteria seem to select an even more heterogeneous patient population, causing additional diagnostic confusion. This article discusses methodological and diagnostic issues related to SEID and proposes a methodological solution for the current “diagnostic impasse”. PMID:26861399

  3. Matrine downregulates IL-33/ST2 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis.

    PubMed

    Zhao, Xiaoyu; Zhang, Xiaojian; Lv, Ying; Xu, Yuming; Li, Menglong; Pan, Qingxia; Chu, Yaojuan; Liu, Nan; Zhang, Guang-Xian; Zhu, Lin

    2016-10-01

    Interleukin (IL)-33 is a recently described member of the IL-1 family and functions as a ligand for ST2, a member of the IL-1 receptor family. The role of IL-33/ST2 axis in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), remains controversial. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, the underlying immunoregulatory mechanisms have not been fully elucidated, and whether this effect of MAT is through inhibiting the function of the IL-33/ST2 axis is not known. In this study, we investigated the relationship between the therapeutic effects of MAT and IL-33/ST2 expression. MAT treatment successfully attenuated severe clinical deficit and histopathological changes, compared to untreated controls. While IL-33/ST2 mRNA expression was largely increased in spinal cord of EAE rats compared to naïve rats, this expression was significantly inhibited in rats treated with MAT. These results were further confirmed by their protein levels tested with immunohistochemistry. Together, our study demonstrates that MAT treatment regulates the inflammatory IL-33/ST2 axis, thus being a novel mechanism underlying the effect of MAT.

  4. Matrine downregulates IL-33/ST2 expression in the central nervous system of rats with experimental autoimmune encephalomyelitis.

    PubMed

    Zhao, Xiaoyu; Zhang, Xiaojian; Lv, Ying; Xu, Yuming; Li, Menglong; Pan, Qingxia; Chu, Yaojuan; Liu, Nan; Zhang, Guang-Xian; Zhu, Lin

    2016-10-01

    Interleukin (IL)-33 is a recently described member of the IL-1 family and functions as a ligand for ST2, a member of the IL-1 receptor family. The role of IL-33/ST2 axis in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an experimental model of multiple sclerosis (MS), remains controversial. Matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae Flave, has been recently found to suppress clinical EAE and CNS inflammation. However, the underlying immunoregulatory mechanisms have not been fully elucidated, and whether this effect of MAT is through inhibiting the function of the IL-33/ST2 axis is not known. In this study, we investigated the relationship between the therapeutic effects of MAT and IL-33/ST2 expression. MAT treatment successfully attenuated severe clinical deficit and histopathological changes, compared to untreated controls. While IL-33/ST2 mRNA expression was largely increased in spinal cord of EAE rats compared to naïve rats, this expression was significantly inhibited in rats treated with MAT. These results were further confirmed by their protein levels tested with immunohistochemistry. Together, our study demonstrates that MAT treatment regulates the inflammatory IL-33/ST2 axis, thus being a novel mechanism underlying the effect of MAT. PMID:27562326

  5. Differential effects of polysulfated polysaccharide on experimental encephalomyelitis, proliferation of autoimmune T cells, and inhibition of heparanase activity.

    PubMed

    Hershkoviz, R; Mor, F; Miao, H Q; Vlodavsky, I; Lider, O

    1995-10-01

    The extravasation of activated T lymphocytes through blood vessel walls and their migration to inflammatory loci are associated with secretion of extracellular matrix (ECM)-degrading enzymes, such as heparanase, which degrades heparan sulfate (HS) moieties of the ECM. The HS-degrading activity of heparanase was found to be inhibited by HS and heparin. Since induction of experimental autoimmune encephalomyelitis (EAE) requires extravasation and migration of autoimmune T cells, degradation of ECM by heparanase is expected to be involved in induction of the disease. Herein, we examined whether laminarin sulfate, a polysulfated polysaccharide (PSS) isolated from the cell walls of seaweeds and subjected to chemical sulfation, could inhibit ECM degradation by mammalian heparanase, and could prevent EAE. PSS was a more potent inhibitor of heparanase-mediated degradation of ECM than heparin. In-vivo, PSS, injected once a week, inhibited the severity of actively-induced EAE in rats. However, inhibition of EAE was not due to an overall suppression of autoimmune T cells, since PSS enhanced the proliferation of myelin basic protein (MBP)-specific, encephalitogenic T cells. PSS-activated autoimmune T cells, but not MBP-activated cells, failed to induce EAE in recipient rats. Moreover, rats injected with PSS-activated T cells were resistant to induction of EAE by anti-MBP CD4+ T cells. Thus, PSS may have potential clinical applications in the treatment of autoimmune diseases. PMID:8579728

  6. The immunomodulator AS101suppresses production of inflammatory cytokines and ameliorates the pathogenesis of experimental autoimmune encephalomyelitis

    PubMed Central

    Xie, Li; Chen, Jing; McMickle, Anthony; Awar, Nadia; Nady, Soad; Sredni, Benjamin; Drew, Paul D.; Yu, Shiguang

    2014-01-01

    We reported that AS101 (organotellurium compound, trichloro(dioxoethylene-O,O′) tellurate) inhibited the differentiation of Th17 cells and reduced the production of IL-17 and GM-CSF. In addition, AS101 promoted the production of IL-2 in activated T cells. Flow cytometric analysis showed that AS101 inhibited Th17 cell proliferation. AS101 blocked the activation of transcriptional factor NFAT, Stat3, and RORγt, and increased activation of Erk1/2, suggesting a mechanism of action of AS101. We further demonstrated that AS101 was effective in amelioration of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. Finally, by real-time PCR analysis we showed that AS101 reduces the IL-17, IFN-γ, GM-CSF, and IL-6 mRNA expression in inflammatory cells of spinal cords. Additionally, flow cytometry analysis also indicated that the CD4+ T cells and IL-17 and GM-CSF-producing cells were reduced in the spinal cords of AS101 treated mice compared to those treated with PBS. PMID:24975323

  7. Arctigenin Suppress Th17 Cells and Ameliorates Experimental Autoimmune Encephalomyelitis Through AMPK and PPAR-γ/ROR-γt Signaling.

    PubMed

    Li, Wen; Zhang, Zhihui; Zhang, Kai; Xue, Zhenyi; Li, Yan; Zhang, Zimu; Zhang, Lijuan; Gu, Chao; Zhang, Qi; Hao, Junwei; Da, Yurong; Yao, Zhi; Kong, Ying; Zhang, Rongxin

    2016-10-01

    Arctigenin is a herb compound extract from Arctium lappa and is reported to exhibit pharmacological properties, including neuronal protection and antidiabetic, antitumor, and antioxidant properties. However, the effects of arctigenin on autoimmune inflammatory diseases of the CNS, multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) are still unclear. In this study, we demonstrated that arctigenin-treated mice are resistant to EAE; the clinical scores of arctigenin-treated mice are significantly reduced. Histochemical assays of spinal cord sections also showed that arctigenin reduces inflammation and demyelination in mice with EAE. Furthermore, the Th1 and Th17 cells in peripheral immune organs are inhibited by arctigenin in vivo. In addition, the Th1 cytokine IFN-γ and transcription factor T-bet, as well as the Th17 cytokines IL-17A, IL-17F, and transcription factor ROR-γt are significantly suppressed upon arctigenin treatment in vitro and in vivo. Interestedly, Th17 cells are obviously inhibited in CNS of mice with EAE, while Th1 cells do not significantly change. Besides, arctigenin significantly restrains the differentiation of Th17 cells. We further demonstrate that arctigenin activates AMPK and inhibits phosphorylated p38, in addition, upregulates PPAR-γ, and finally suppresses ROR-γt. These findings suggest that arctigenin may have anti-inflammatory and immunosuppressive properties via inhibiting Th17 cells, indicating that it could be a potential therapeutic drug for multiple sclerosis or other autoimmune inflammatory diseases. PMID:26440666

  8. A Mushroom Extract Piwep from Phellinus igniarius Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibiting Immune Cell Infiltration in the Spinal Cord

    PubMed Central

    Li, Lan; Wu, Guang; Choi, Bo Young; Jang, Bong Geom; Kim, Jin Hee; Sung, Gi Ho; Cho, Jae Youl; Park, Hyoung Jin

    2014-01-01

    The present study aimed to evaluate the therapeutic potential of a mushroom extract from Phellinus igniarius in an animal model of multiple sclerosis. The medicinal mushroom, Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35–55) in C57BL/6 female mice. A water-ethanol extract of Phellinus igniarius (Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α4 in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γ in the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression. PMID:24592383

  9. A mushroom extract Piwep from Phellinus igniarius ameliorates experimental autoimmune encephalomyelitis by inhibiting immune cell infiltration in the spinal cord.

    PubMed

    Li, Lan; Wu, Guang; Choi, Bo Young; Jang, Bong Geom; Kim, Jin Hee; Sung, Gi Ho; Cho, Jae Youl; Suh, Sang Won; Park, Hyoung Jin

    2014-01-01

    The present study aimed to evaluate the therapeutic potential of a mushroom extract from Phellinus igniarius in an animal model of multiple sclerosis. The medicinal mushroom, Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35-55) in C57BL/6 female mice. A water-ethanol extract of Phellinus igniarius (Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α 4 in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γ in the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression. PMID:24592383

  10. Preventive and therapeutic effects of adenanthin on experimental autoimmune encephalomyelitis by inhibiting NF-κB signaling.

    PubMed

    Yin, Qian-Qian; Liu, Chuan-Xu; Wu, Ying-Li; Wu, Shao-Fang; Wang, Yan; Zhang, Xia; Hu, Xiao-Juan; Pu, Jian-Xin; Lu, Ying; Zhou, Hu-Chen; Wang, Hong-Lin; Nie, Hong; Sun, Han-Dong; Chen, Guo-Qiang

    2013-09-01

    Adenanthin, a diterpenoid isolated from the leaves of Isodon adenanthus, has been reported to possess antileukemic activity through targeting peroxiredoxin I/II. However, its other potential activities remain to be explored. Using myelin oligodendrocyte glycoprotein (MOG)35-55-induced experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, we report in this study that adenanthin exerts efficaciously preventive and therapeutic effects on EAE accompanied by significant restriction of infiltration of inflammatory cells and demyelination in CNS. Adenanthin-presented immunomodulatory effects on EAE are correlated with suppressed proliferation of MOG35-55-reactive T cells, decreased Th1 and Th17 cells, increased regulatory T cell populations, decreased production of serum proinflammatory cytokines, and reduced stimulatory capacity of APCs, which might be mediated by its inhibitory action on NF-κB signaling pathway. Our results propose that, as a novel NF-κB inhibitor, adenanthin has potent immunomodulatory activity for the treatment of multiple sclerosis and possibly other autoimmune disorders. PMID:23964105

  11. Thrombin Cleavage of Osteopontin Modulates Its Activities in Human Cells In Vitro and Mouse Experimental Autoimmune Encephalomyelitis In Vivo.

    PubMed

    Boggio, Elena; Dianzani, Chiara; Gigliotti, Casimiro Luca; Soluri, Maria Felicia; Clemente, Nausicaa; Cappellano, Giuseppe; Toth, Erika; Raineri, Davide; Ferrara, Benedetta; Comi, Cristoforo; Dianzani, Umberto; Chiocchetti, Annalisa

    2016-01-01

    Osteopontin is a proinflammatory cytokine and plays a pathogenetic role in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), by recruiting autoreactive T cells into the central nervous system. Osteopontin functions are modulated by thrombin cleavage generating N- and C-terminal fragment, whose individual roles are only partly known. Published data are difficult to compare since they have been obtained with heterogeneous approaches. Interestingly, thrombin cleavage of osteopontin unmasks a cryptic domain of interaction with α 4 β 1 integrin that is the main adhesion molecule involved in lymphocyte transmigration to the brain and is the target for natalizumab, the most potent drug preventing relapses. We produced recombinant osteopontin and its N- and C-terminal fragments in an eukaryotic system in order to allow their posttranslational modifications. We investigated, in vitro, their effect on human cells and in vivo in EAE. We found that the osteopontin cleavage plays a key role in the function of this cytokine and that the two fragments exert distinct effects both in vitro and in vivo. These findings suggest that drugs targeting each fragment may be used to fine-tune the pathological effects of osteopontin in several diseases. PMID:27478856

  12. The leukotriene B{sub 4} receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis

    SciTech Connect

    Kihara, Yasuyuki; Yokomizo, Takehiko; Kunita, Akiko; Morishita, Yasuyuki; Fukayama, Masashi; Ishii, Satoshi; Shimizu, Takao

    2010-04-09

    Leukotriene B{sub 4} (LTB{sub 4}) is a potent chemoattractant and activator of neutrophils, macrophages and T cells. These cells are a key component of inflammation and all express BLT1, a high affinity G-protein-coupled receptor for LTB{sub 4}. However, little is known about the neuroimmune functions of BLT1. In this study, we describe a distinct role for BLT1 in the pathology of experimental autoimmune encephalomyelitis (EAE) and T{sub H}1/T{sub H}17 immune responses. BLT1 mRNA was highly upregulated in the spinal cord of EAE mice, especially during the induction phase. BLT1{sup -/-} mice had delayed onset and less severe symptoms of EAE than BLT1{sup +/+} mice. Additionally, inflammatory cells were recruited to the spinal cord of asymptomatic BLT1{sup +/+}, but not BLT1{sup -/-} mice before the onset of disease. Ex vivo studies showed that both the proliferation and the production of IFN-{gamma}, TNF-{alpha}, IL-17 and IL-6 were impaired in BLT1{sup -/-} cells, as compared with BLT1{sup +/+} cells. Thus, we suggest that BLT1 exacerbates EAE by regulating the migration of inflammatory cells and T{sub H}1/T{sub H}17 immune responses. Our findings provide a novel therapeutic option for the treatment of multiple sclerosis and other T{sub H}17-mediated diseases.

  13. Microwave & Magnetic (M2) Proteomics Reveals CNS-Specific Protein Expression Waves that Precede Clinical Symptoms of Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Raphael, Itay; Mahesula, Swetha; Purkar, Anjali; Black, David; Catala, Alexis; Gelfond, Jonathon A. L.; Forsthuber, Thomas G.; Haskins, William E.

    2014-01-01

    Central nervous system-specific proteins (CSPs), transported across the damaged blood-brain-barrier (BBB) to cerebrospinal fluid (CSF) and blood (serum), might be promising diagnostic, prognostic and predictive protein biomarkers of disease in individual multiple sclerosis (MS) patients because they are not expected to be present at appreciable levels in the circulation of healthy subjects. We hypothesized that microwave & magnetic (M2) proteomics of CSPs in brain tissue might be an effective means to prioritize putative CSP biomarkers for future immunoassays in serum. To test this hypothesis, we used M2 proteomics to longitudinally assess CSP expression in brain tissue from mice during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Confirmation of central nervous system (CNS)-infiltrating inflammatory cell response and CSP expression in serum was achieved with cytokine ELISPOT and ELISA immunoassays, respectively, for selected CSPs. M2 proteomics (and ELISA) revealed characteristic CSP expression waves, including synapsin-1 and α-II-spectrin, which peaked at day 7 in brain tissue (and serum) and preceded clinical EAE symptoms that began at day 10 and peaked at day 20. Moreover, M2 proteomics supports the concept that relatively few CNS-infiltrating inflammatory cells can have a disproportionally large impact on CSP expression prior to clinical manifestation of EAE. PMID:25182730

  14. Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS)

    PubMed Central

    Morris, Gerwyn; Maes, Michael

    2014-01-01

    Myalgic Encephalomyelitis (ME) / Chronic Fatigue Syndrome (CFS) has been classified as a disease of the central nervous system by the WHO since 1969. Many patients carrying this diagnosis do demonstrate an almost bewildering array of biological abnormalities particularly the presence of oxidative and nitrosative stress (O&NS) and a chronically activated innate immune system. The proposal made herein is that once generated chronically activated O&NS and immune-inflammatory pathways conspire to generate a multitude of self-sustaining and self-amplifying pathological processes which are associated with the onset of ME/CFS. Sources of continuous activation of O&NS and immune-inflammatory pathways in ME/CFS are chronic, intermittent and opportunistic infections, bacterial translocation, autoimmune responses, mitochondrial dysfunctions, activation of the Toll-Like Receptor Radical Cycle, and decreased antioxidant levels. Consequences of chronically activated O&NS and immune-inflammatory pathways in ME/CFS are brain disorders, including neuroinflammation and brain hypometabolism / hypoperfusion, toxic effects of nitric oxide and peroxynitrite, lipid peroxidation and oxidative damage to DNA, secondary autoimmune responses directed against disrupted lipid membrane components and proteins, mitochondrial dysfunctions with a disruption of energy metabolism (e.g. compromised ATP production) and dysfunctional intracellular signaling pathways. The interplay between all of these factors leads to self-amplifying feed forward loops causing a chronic state of activated O&NS, immune-inflammatory and autoimmune pathways which may sustain the disease. PMID:24669210

  15. Sphingosine kinase 2 deficient mice exhibit reduced experimental autoimmune encephalomyelitis: Resistance to FTY720 but not ST-968 treatments.

    PubMed

    Imeri, Faik; Schwalm, Stephanie; Lyck, Ruth; Zivkovic, Aleksandra; Stark, Holger; Engelhardt, Britta; Pfeilschifter, Josef; Huwiler, Andrea

    2016-06-01

    The immunomodulatory drug FTY720 is presently approved for the treatment of relapsing-remitting multiple sclerosis. It is a prodrug that requires activation by sphingosine kinase 2 (SK-2) to induce T cell homing to secondary lymphoid tissue. In this study, we have investigated the role of SK-2 in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. We show that SK-2 deficiency reduced clinical symptoms of EAE. Furthermore, in SK-2-deficient mice, the protective effect of FTY720 on EAE was abolished, while the non-prodrug FTY720-derivative ST-968 was still fully active. Protection was paralleled by reduced numbers of T-lymphocytes in blood and a reduced blood-brain-barrier leakage. This correlated with reduced mRNA expression of ICAM-1, VCAM-1, but enhanced expression of PECAM-1. A similar regulation of permeability and of PECAM-1 was seen in primary cultures of isolated mouse brain vascular endothelial cells and in a human immortalized cell line upon SK-2 knockdown. In summary, these data demonstrated that deletion of SK-2 exerts a protective effect on the pathogenesis of EAE in C57BL/6 mice and that SK-2 is essential for the protective effect of FTY720 but not of ST-968. Thus, ST-968 is a promising novel immunomodulatory compound that may be a valuable alternative to FTY720 under conditions where SK-2 activity is limited. PMID:26808312

  16. 18β-glycyrrhetinic acid suppresses experimental autoimmune encephalomyelitis through inhibition of microglia activation and promotion of remyelination.

    PubMed

    Zhou, Jieru; Cai, Wei; Jin, Min; Xu, Jingwei; Wang, Yanan; Xiao, Yichuan; Hao, Li; Wang, Bei; Zhang, Yanyun; Han, Jie; Huang, Rui

    2015-01-01

    Microglia are intrinsic immune cells in the central nervous system (CNS). The under controlled microglia activation plays important roles in inflammatory demyelination diseases, such as multiple sclerosis (MS). However, the means to modulate microglia activation as a therapeutic modality and the underlying mechanisms remain elusive. Here we show that administration of 18β-glycyrrhetinic acid (GRA), by using both preventive and therapeutic treatment protocols, significantly suppresses disease severity of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. The treatment effect of GRA on EAE is attributed to its regulatory effect on microglia. GRA-modulated microglia significantly decreased pro-inflammatory profile in the CNS through suppression of MAPK signal pathway. The ameliorated CNS pro-inflammatory profile prevented the recruitment of encephalitogenic T cells into the CNS, which alleviated inflammation-induced demyelination. In addition, GRA treatment promoted remyelination in the CNS of EAE mice. The induced remyelination can be mediated by the overcome of inflammation-induced blockade of brain-derived neurotrophic factor expression in microglia, as well as enhancing oligodendrocyte precursor cell proliferation. Collectively, our results demonstrate that GRA-modulated microglia suppresses EAE through inhibiting microglia activation-mediated CNS inflammation, and promoting neuroprotective effect of microglia, which represents a potential therapeutic strategy for MS and maybe other neuroinflammatory diseases associated with microglia activation.

  17. A silent exonic SNP in kdm3a affects nucleic acids structure but does not regulate experimental autoimmune encephalomyelitis.

    PubMed

    Gillett, Alan; Bergman, Petra; Parsa, Roham; Bremges, Andreas; Giegerich, Robert; Jagodic, Maja

    2013-01-01

    Defining genetic variants that predispose for diseases is an important initiative that can improve biological understanding and focus therapeutic development. Genetic mapping in humans and animal models has defined genomic regions controlling a variety of phenotypes known as quantitative trait loci (QTL). Causative disease determinants, including single nucleotide polymorphisms (SNPs), lie within these regions and can often be identified through effects on gene expression. We previously identified a QTL on rat chromosome 4 regulating macrophage phenotypes and immune-mediated diseases including experimental autoimmune encephalomyelitis (EAE). Gene analysis and a literature search identified lysine-specific demethylase 3A (Kdm3a) as a potential regulator of these phenotypes. Genomic sequencing determined only two synonymous SNPs in Kdm3a. The silent synonymous SNP in exon 15 of Kdm3a caused problems with quantitative PCR detection in the susceptible strain through reduced amplification efficiency due to altered secondary cDNA structure. Shape Probability Shift analysis predicted that the SNP often affects RNA folding; thus, it may impact protein translation. Despite these differences in rats, genetic knockout of Kdm3a in mice resulted in no dramatic effect on immune system development and activation or EAE susceptibility and severity. These results provide support for tools that analyze causative SNPs that impact nucleic acid structures. PMID:24312603

  18. Anti-myelin antibodies play an important role in the susceptibility to develop proteolipid protein-induced experimental autoimmune encephalomyelitis.

    PubMed

    Marín, N; Eixarch, H; Mansilla, M J; Rodríguez-Martín, E; Mecha, M; Guaza, C; Álvarez-Cermeño, J C; Montalban, X; Villar, L M; Espejo, C

    2014-02-01

    Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system. It is an autoimmune disorder in which activated T cells cross the blood-brain barrier (BBB) to initiate an inflammatory response that leads to demyelination and axonal damage. The key mechanisms responsible for disease initiation are still unknown. We addressed this issue in experimental autoimmune encephalomyelitis (EAE), the animal model of MS. It is widely known that EAE manifests only in certain strains when immunized with myelin proteins or peptides. We studied the differential immune responses induced in two mouse strains that are susceptible or resistant to EAE induction when they are immunized with the 139-151 peptide of proteolipid protein, an encephalitogenic peptide capable of inducing EAE in the susceptible strain. The adequate combination of major histocompatibility complex alleles and myelin peptides triggered in susceptible mice a T helper type 17 (Th17) response capable of inducing the production of high-affinity anti-myelin immunoglobulin (Ig)G antibodies. These were not detected in resistant mice, despite immunization with the encephalitogenic peptide in junction with complete Freund's adjuvant and pertussis toxin, which mediate BBB disruption. These data show the pivotal role of Th17 responses and of high-affinity anti-myelin antibodies in EAE induction and that mechanisms that prevent their appearance can contribute to resistance to EAE. PMID:24188195

  19. Pain in people with chronic fatigue syndrome/myalgic encephalomyelitis: the role of traumatic stress and coping strategies.

    PubMed

    Krzeczkowska, Anna; Karatzias, Thanos; Dickson, Adele

    2015-01-01

    Pain is a significant problem for many people with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME). This exploratory study investigated the extent to which severity of pain was related to coping strategies and post-traumatic symptomatology in people with CFS/ME. Participants comprised 27 individuals with CFS/ME and 27 healthy controls. All participants completed the CFS/ME Symptom Questionnaire, the brief pain inventory, the impact of event scale-revised and the brief-COPE. It was found that CFS/ME participants present with significantly more post-traumatic stress symptoms and report significantly less emotion focused strategies and problem focused coping strategies compared with healthy controls. Severity of pain in the CFS/ME subgroup was not associated with traumatic symptomatology, although those with severe pain reported less use of self-distraction, positive re-framing and acceptance than those with mild pain. Our results suggest that the enhancement of certain coping strategies (facilitated by psychological interventions such as acceptance and commitment therapy) may be beneficial in alleviating pain in people with CFS/ME.

  20. Dysregulation of Protein Kinase Gene Expression in NK Cells from Chronic Fatigue Syndrome/Myalgic Encephalomyelitis Patients

    PubMed Central

    Chacko, Anu; Staines, Donald R.; Johnston, Samantha C.; Marshall-Gradisnik, Sonya M.

    2016-01-01

    BACKGROUND The etiology and pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) are unknown. However, natural killer (NK) cell dysfunction, in particular reduced NK cytotoxic activity, is a consistent finding in CFS/ME patients. Previous research has reported significant changes in intracellular mitogen-activated protein kinase pathways from isolated NK cells. The purpose of this present investigation was to examine whether protein kinase genes have a role in abnormal NK cell intracellular signaling in CFS/ME. METHOD Messenger RNA (mRNA) expression of 528 protein kinase genes in isolated NK cells was analyzed (nCounter GX Human Kinase Kit v2 (XT); NanoString Technologies) from moderate (n = 11; age, 54.9 ± 10.3 years) and severe (n = 12; age, 47.5 ± 8.0 years) CFS/ME patients (classified by the 2011 International Consensus Criteria) and nonfatigued controls (n = 11; age, 50.0 ± 12.3 years). RESULTS The expression of 92 protein kinase genes was significantly different in the severe CFS/ME group compared with nonfatigued controls. Among these, 37 genes were significantly upregulated and 55 genes were significantly downregulated in severe CFS/ME patients compared with nonfatigued controls. CONCLUSIONS In severe CFS/ME patients, dysfunction in protein kinase genes may contribute to impairments in NK cell intracellular signaling and effector function. Similar changes in protein kinase genes may be present in other cells, potentially contributing to the pathomechanism of this illness. PMID:27594784

  1. Intrinsic Functional Hypoconnectivity in Core Neurocognitive Networks Suggests Central Nervous System Pathology in Patients with Myalgic Encephalomyelitis: A Pilot Study.

    PubMed

    Zinn, Marcie L; Zinn, Mark A; Jason, Leonard A

    2016-09-01

    Exact low resolution electromagnetic tomography (eLORETA) was recorded from nineteen EEG channels in nine patients with myalgic encephalomyelitis (ME) and 9 healthy controls to assess current source density and functional connectivity, a physiological measure of similarity between pairs of distributed regions of interest, between groups. Current source density and functional connectivity were measured using eLORETA software. We found significantly decreased eLORETA source analysis oscillations in the occipital, parietal, posterior cingulate, and posterior temporal lobes in Alpha and Alpha-2. For connectivity analysis, we assessed functional connectivity within Menon triple network model of neuropathology. We found support for all three networks of the triple network model, namely the central executive network (CEN), salience network (SN), and the default mode network (DMN) indicating hypo-connectivity in the Delta, Alpha, and Alpha-2 frequency bands in patients with ME compared to controls. In addition to the current source density resting state dysfunction in the occipital, parietal, posterior temporal and posterior cingulate, the disrupted connectivity of the CEN, SN, and DMN appears to be involved in cognitive impairment for patients with ME. This research suggests that disruptions in these regions and networks could be a neurobiological feature of the disorder, representing underlying neural dysfunction.

  2. Genome-wide association analysis identifies genetic variations in subjects with myalgic encephalomyelitis/chronic fatigue syndrome

    PubMed Central

    Schlauch, K A; Khaiboullina, S F; De Meirleir, K L; Rawat, S; Petereit, J; Rizvanov, A A; Blatt, N; Mijatovic, T; Kulick, D; Palotás, A; Lombardi, V C

    2016-01-01

    Myalgic encephalomyelitis, also known as chronic fatigue syndrome or ME/CFS, is a multifactorial and debilitating disease that has an impact on over 4 million people in the United States alone. The pathogenesis of ME/CFS remains largely unknown; however, a genetic predisposition has been suggested. In the present study, we used a DNA single-nucleotide polymorphism (SNP) chip representing over 906,600 known SNPs to analyze DNA from ME/CFS subjects and healthy controls. To the best of our knowledge, this study represents the most comprehensive genome-wide association study (GWAS) of an ME/CFS cohort conducted to date. Here 442 SNPs were identified as candidates for association with ME/CFS (adjusted P-value<0.05). Whereas the majority of these SNPs are represented in non-coding regions of the genome, 12 SNPs were identified in the coding region of their respective gene. Among these, two candidate SNPs resulted in missense substitutions, one in a pattern recognition receptor and the other in an uncharacterized coiled-coil domain-containing protein. We also identified five SNPs that cluster in the non-coding regions of T-cell receptor loci. Further examination of these polymorphisms may help identify contributing factors to the pathophysiology of ME/CFS, as well as categorize potential targets for medical intervention strategies. PMID:26859813

  3. Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells.

    PubMed

    Rezende, Rafael M; Oliveira, Rafael P; Medeiros, Samara R; Gomes-Santos, Ana C; Alves, Andrea C; Loli, Flávia G; Guimarães, Mauro A F; Amaral, Sylvia S; da Cunha, André P; Weiner, Howard L; Azevedo, Vasco; Miyoshi, Anderson; Faria, Ana M C

    2013-02-01

    Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice. PMID:22939403

  4. Single-Step Grafting of Aminooxy-Peptides to Hyaluronan: A Simple Approach to Multifunctional Therapeutics for Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Sestak, Joshua.; Mullins, Meagan; Northrup, Laura; Thati, Shara; Siahaan, Teruna; Berkland, Cory

    2013-01-01

    The immune response to antigens is directed in part by the presence or absence of costimulatory signals. The ability to coincidently present both antigen and, for example, a peptide that inhibits or activates the costimulatory pathway, would be a valuable tool for tolerization or immunization, respectively. A simple reaction scheme utilizing oxime chemistry was identified as a means to efficiently conjugate different peptide species to hyaluronan. Peptides synthesized with an aminooxy N-terminus reacted directly to hyaluronan under slightly acidic aqueous conditions without the need for a catalyst. The resulting oxime bond was found to rapidly hydrolyze at pH 2 releasing peptide, but was stable at higher pH values (5.5 and 7). Two different peptide species, a multiple sclerosis antigen (PLP) and an ICAM-1 ligand (LABL) known to block immune cell stimulation, were functionalized with the aminooxy end group. These peptides showed similar reactivity to hyaluronan and were conjugated in an equimolar ratio. The resulting hyaluronan with grafted PLP and LABL significantly inhibited disease in mice with experimental autoimmune encephalomyelitis, a model of multiple sclerosis. Aminooxy-peptides facilitate simple synthesis of multifunctional hyaluronan graft polymers, thus enabling novel approaches to antigen-specific immune modulation. PMID:23541930

  5. Accurate diagnosis of myalgic encephalomyelitis and chronic fatigue syndrome based upon objective test methods for characteristic symptoms

    PubMed Central

    Twisk, Frank NM

    2015-01-01

    Although myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS) are considered to be synonymous, the definitional criteria for ME and CFS define two distinct, partially overlapping, clinical entities. ME, whether defined by the original criteria or by the recently proposed criteria, is not equivalent to CFS, let alone a severe variant of incapacitating chronic fatigue. Distinctive features of ME are: muscle weakness and easy muscle fatigability, cognitive impairment, circulatory deficits, a marked variability of the symptoms in presence and severity, but above all, post-exertional “malaise”: a (delayed) prolonged aggravation of symptoms after a minor exertion. In contrast, CFS is primarily defined by (unexplained) chronic fatigue, which should be accompanied by four out of a list of 8 symptoms, e.g., headaches. Due to the subjective nature of several symptoms of ME and CFS, researchers and clinicians have questioned the physiological origin of these symptoms and qualified ME and CFS as functional somatic syndromes. However, various characteristic symptoms, e.g., post-exertional “malaise” and muscle weakness, can be assessed objectively using well-accepted methods, e.g., cardiopulmonary exercise tests and cognitive tests. The objective measures acquired by these methods should be used to accurately diagnose patients, to evaluate the severity and impact of the illness objectively and to assess the positive and negative effects of proposed therapies impartially. PMID:26140274

  6. Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells

    PubMed Central

    Rezende, Rafael M.; Oliveira, Rafael P.; Medeiros, Samara R.; Gomes-Santos, Ana C.; Alves, Andrea C.; Loli, Flávia G.; Guimarães, Mauro A.F.; Amaral, Sylvia S.; da Cunha, André P.; Weiner, Howard L.; Azevedo, Vasco; Miyoshi, Anderson; Faria, Ana M.C.

    2013-01-01

    Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice. PMID:22939403

  7. Hsp65-producing Lactococcus lactis prevents experimental autoimmune encephalomyelitis in mice by inducing CD4+LAP+ regulatory T cells.

    PubMed

    Rezende, Rafael M; Oliveira, Rafael P; Medeiros, Samara R; Gomes-Santos, Ana C; Alves, Andrea C; Loli, Flávia G; Guimarães, Mauro A F; Amaral, Sylvia S; da Cunha, André P; Weiner, Howard L; Azevedo, Vasco; Miyoshi, Anderson; Faria, Ana M C

    2013-02-01

    Heat shock proteins (Hsps) participate in the cellular response to stress and they are hiperexpressed in inflammatory conditions. They are also known to play a major role in immune modulation, controlling, for instance, autoimmune responses. In this study, we showed that oral administration of a recombinant Lactococcus lactis strain that produces and releases LPS-free Hsp65 prevented the development of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice. This was confirmed by the reduced inflammatory cell infiltrate and absence of injury signs in the spinal cord. The effect was associated with reduced IL-17 and increased IL-10 production in mesenteric lymph node and spleen cell cultures. Hsp65-producing-L. lactis-fed mice had a remarkable increase in the number of natural and inducible CD4+Foxp3+ regulatory T (Treg) cells and CD4+LAP+ (Latency-associated peptide) Tregs - which express the membrane-bound TGF-β - in spleen, inguinal and mesenteric lymph nodes as well as in spinal cord. Moreover, many Tregs co-expressed Foxp3 and LAP. In vivo depletion of LAP+ cells abrogated the effect of Hsp65-producing L. lactis in EAE prevention and worsened disease in medium-fed mice. Thus, Hsp65-L.lactis seems to boost this critical regulatory circuit involved in controlling EAE development in mice.

  8. A mushroom extract Piwep from Phellinus igniarius ameliorates experimental autoimmune encephalomyelitis by inhibiting immune cell infiltration in the spinal cord.

    PubMed

    Li, Lan; Wu, Guang; Choi, Bo Young; Jang, Bong Geom; Kim, Jin Hee; Sung, Gi Ho; Cho, Jae Youl; Suh, Sang Won; Park, Hyoung Jin

    2014-01-01

    The present study aimed to evaluate the therapeutic potential of a mushroom extract from Phellinus igniarius in an animal model of multiple sclerosis. The medicinal mushroom, Phellinus igniarius, contains biologically active compounds that modulate the human immune system. Experimental autoimmune encephalomyelitis (EAE) was induced by immunization with myelin oligodendrocyte glycoprotein (MOG 35-55) in C57BL/6 female mice. A water-ethanol extract of Phellinus igniarius (Piwep) was delivered intraperitoneally every other day for the entire experimental course. Three weeks after the initial immunization, demyelination and immune cell infiltration in the spinal cord were examined. Piwep injection profoundly decreased the daily incidence rate and clinical score of EAE. The Piwep-mediated inhibition of the clinical course of EAE was accompanied by suppression of demyelination and infiltration of encephalitogenic immune cells including CD4+ T cells, CD8+ T cells, macrophages, and B cells in the spinal cord. Piwep reduced expression of vascular cell adhesion molecule-1 (VCAM-1) in the spinal cord and integrin-α 4 in the lymph node of EAE mice. Piwep also inhibited proliferation of lymphocytes and secretion of interferon-γ in the lymph node of EAE mice. The results suggest that a mushroom extract, Piwep, may have a high therapeutic potential for ameliorating multiple sclerosis progression.

  9. A method for histopathological study of the multifocal nature of spinal cord lesions in murine experimental autoimmune encephalomyelitis.

    PubMed

    Gibson-Corley, Katherine N; Boyden, Alexander W; Leidinger, Mariah R; Lambertz, Allyn M; Ofori-Amanfo, Georgina; Naumann, Paul W; Goeken, J Adam; Karandikar, Nitin J

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model for multiple sclerosis and is characterized by infiltration of mononuclear cells and demyelination within the central nervous system along with the clinical symptoms of paralysis. EAE is a multifocal and random disease, which sometimes makes histopathologic analysis of lesions difficult as it may not be possible to predict where lesions will occur, especially when evaluating cross sections of spinal cord. Consequently, lesions may be easily missed due to limited sampling in traditional approaches. To evaluate the entire length of the spinal cord while maintaining anatomic integrity, we have developed a method to section the cord within the decalcified spinal column, which allows for the study of the multifocal nature of this disease and also minimizes handling artifact. HE and Luxol fast blue staining of these spinal cord sections revealed a paucity of lesions in some areas, while others showed marked inflammation and demyelination. The percentage of spinal cord affected by EAE was evaluated at four separate areas of longitudinally sectioned cord and it varied greatly within each animal. Immunohistochemical staining of in situ spinal cords which had undergone decalcification was successful for key immuno-markers used in EAE research including CD3 for T cells, B220 for B cells and F4/80 for murine macrophages. This method will allow investigators to look at the entire spinal cord on a single slide and evaluate the spinal cord with and without classic EAE lesions. PMID:26855861

  10. Neuroprotective effects of a polyphenolic white grape juice extract in a mouse model of experimental autoimmune encephalomyelitis.

    PubMed

    Giacoppo, Sabrina; Galuppo, Maria; Lombardo, Giovanni Enrico; Ulaszewska, Maria Malgorzata; Mattivi, Fulvio; Bramanti, Placido; Mazzon, Emanuela; Navarra, Michele

    2015-06-01

    In the last 20 years, wine phenolic compounds have received increasing interest since several epidemiological studies have suggested associations between regular consumption of moderate amount of wine and prevention of certain chronic pathologies, such as neurodegenerative diseases. This study was aimed to investigate the possible neuroprotective role of a polyphenolic white grape juice extract (WGJe) in an experimental mice model of autoimmune encephalomyelitis (EAE), the most commonly used model for multiple sclerosis (MS) in vivo. EAE mimics the main features of MS, including paralysis, weight loss, demyelination, central nervous system (CNS) inflammation and blood-brain barrier (BBB) breakdown. Our study demonstrated that oral administration of WGJe (20 and 40 mg/kg/day) may exert neuroprotective effects against MS, diminishing both clinical signs and histological score typical of disease (lymphocytic infiltration and demyelination). In particular, by western blot, histological evaluations and immunolocalization of the main markers of inflammation, oxidative stress and apoptosis (TNF-α, iNOS, Nitrotyrosine, PARP, Foxp3, Bcl-2, Caspase 3 and DNA fragmentation), we documented that WGJe counteracts the alteration of all these inflammatory and oxidative pathway, without any apparent sign of toxicity. On these bases, we propose this natural product as putative novel helpful tools for the prevention of autoimmune and neurodegenerative diseases such as MS. WGJe could have considerable implication for future therapies of MS, and this study may represents the starting point for further investigation on the role of WGJe in neuroinflammation. PMID:25863350

  11. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review.

    PubMed

    Nijs, Jo; Nees, Andrea; Paul, Lorna; De Kooning, Margot; Ickmans, Kelly; Meeus, Mira; Van Oosterwijck, Jessica

    2014-01-01

    An increasing number of studies have examined how the immune system of patients with Chronic Fatigue Syndrome (CFS), or myalgic encephalomyelitis, responds to exercise. The objective of the present study was to systematically review the scientific literature addressing exercise-induced immunological changes in CFS patients compared to healthy control subjects. A systematic literature search was conducted in the PubMed and Web of science databases using different keyword combinations. We included 23 case control studies that examined whether CFS patients, compared to healthy sedentary controls, have a different immune response to exercise. The included articles were evaluated on their methodological quality. Compared to the normal response of the immune system to exercise as seen in healthy subjects, patients with CFS have a more pronounced response in the complement system (i.e. C4a split product levels), oxidative stress system (i.e. enhanced oxidative stress combined with a delayed and reduced anti-oxidant response), and an alteration in the immune cells' gene expression profile (increases in post-exercise interleukin-10 and toll-like receptor 4 gene expression), but not in circulating pro- or anti-inflammatory cytokines. Many of these immune changes relate to post-exertional malaise in CFS, a major characteristic of the illness. The literature review provides level B evidence for an altered immune response to exercise in patients with CFS.

  12. Replacing Myalgic Encephalomyelitis and Chronic Fatigue Syndrome with Systemic Exercise Intolerance Disease Is Not the Way forward.

    PubMed

    Twisk, Frank N M

    2016-02-05

    Myalgic encephalomyelitis (ME), described in the medical literature since 1938, is characterized by distinctive muscular symptoms, neurological symptoms, and signs of circulatory impairment. The only mandatory feature of chronic fatigue syndrome (CFS), introduced in 1988 and redefined in 1994, is chronic fatigue, which should be accompanied by at least four or more out of eight "additional" symptoms. The use of the abstract, polythetic criteria of CFS, which define a heterogeneous patient population, and self-report has hampered both scientific progress and accurate diagnosis. To resolve the "diagnostic impasse" the Institute of Medicine proposes that a new clinical entity, systemic exercise intolerance disease (SEID), should replace the clinical entities ME and CFS. However, adopting SEID and its defining symptoms, does not resolve methodological and diagnostic issues. Firstly, a new diagnostic entity cannot replace two distinct, partially overlapping, clinical entities such as ME and CFS. Secondly, due to the nature of the diagnostic criteria, the employment of self-report, and the lack of criteria to exclude patients with other conditions, the SEID criteria seem to select an even more heterogeneous patient population, causing additional diagnostic confusion. This article discusses methodological and diagnostic issues related to SEID and proposes a methodological solution for the current "diagnostic impasse".

  13. Detection of Theiler's virus RNA in mouse central nervous system by in situ hybridization.

    PubMed

    Stroop, W G; Baringer, J R; Brahic, M

    1981-12-01

    The location and distribution of viral RNA were examined in the central nervous system tissues of weanling mice acutely infected with the GDVII strain of Theiler's murine encephalomyelitis virus. Viral RNA was detected by autoradiography following in situ hybridization of a 3H-labeled DNA synthesized in vitro complementary to purified viral RNA. Viral RNA was detected in pyramidal neurons of the hippocampus, cerebral cortex, brainstem nuclei, thalamus, basal ganglia, and spinal cord. Autoradiographic grains could be detected in the axonal and dendritic processes of many infected neurons. No viral RNA was detected in any cell of the cerebellum or white matter. In addition to demonstrating the location of viral RNA in infected central nervous system tissues, and hence the sites of viral replication during this acute polioencephalomyelitis, they indicate that necrosis of hippocampal neurons is due to lytic infection, rather than to hypoxia.

  14. Cytotoxic T cells isolated from the central nervous systems of mice infected with Theiler's virus.

    PubMed Central

    Lindsley, M D; Thiemann, R; Rodriguez, M

    1991-01-01

    Intracerebral inoculation of resistant mice (C57BL/10SNJ) with Theiler's murine encephalomyelitis virus (TMEV) results in acute encephalitis followed by subsequent clearance of virus from the central nervous system (CNS). In contrast, infection of susceptible mice (SJL/J) results in virus persistence and chronic immune-mediated demyelination. Both resistance and susceptibility to TMEV-induced disease appear to be immune mediated, since immunosuppression results in enhanced encephalitis in resistant mice but diminished demyelination in susceptible mice. The purpose of these experiments was to determine whether anti-TMEV cytotoxic T lymphocytes (CTLs) are generated during acute and chronic TMEV infection. Nonspecific lectin-dependent cellular cytotoxicity was used initially to detect the cytolytic potential of lymphocytes infiltrating the CNS irrespective of antigen specificity. Using TMEV-infected targets, H-2-restricted TMEV-specific CTLs of the CD8+ phenotype were demonstrated in lymphocytes from the CNS of susceptible and resistant mice, arguing against the hypothesis that the ability to generate CD8+ CTLs mediates resistance. In chronically infected SJL/J mice, TMEV-specific CTL activity was detected in the CNS as late as 226 days postinfection. These experiments demonstrate that virus-specific CTLs are present in the CNS during both acute and chronic TMEV infection. Anti-TMEV CTLs in the CNS of chronically infected SJL/J mice may play a role in demyelination through their ability to lyse TMEV-infected glial cells. PMID:1658365

  15. Cytotoxic T cells isolated from the central nervous systems of mice infected with Theiler's virus.

    PubMed

    Lindsley, M D; Thiemann, R; Rodriguez, M

    1991-12-01

    Intracerebral inoculation of resistant mice (C57BL/10SNJ) with Theiler's murine encephalomyelitis virus (TMEV) results in acute encephalitis followed by subsequent clearance of virus from the central nervous system (CNS). In contrast, infection of susceptible mice (SJL/J) results in virus persistence and chronic immune-mediated demyelination. Both resistance and susceptibility to TMEV-induced disease appear to be immune mediated, since immunosuppression results in enhanced encephalitis in resistant mice but diminished demyelination in susceptible mice. The purpose of these experiments was to determine whether anti-TMEV cytotoxic T lymphocytes (CTLs) are generated during acute and chronic TMEV infection. Nonspecific lectin-dependent cellular cytotoxicity was used initially to detect the cytolytic potential of lymphocytes infiltrating the CNS irrespective of antigen specificity. Using TMEV-infected targets, H-2-restricted TMEV-specific CTLs of the CD8+ phenotype were demonstrated in lymphocytes from the CNS of susceptible and resistant mice, arguing against the hypothesis that the ability to generate CD8+ CTLs mediates resistance. In chronically infected SJL/J mice, TMEV-specific CTL activity was detected in the CNS as late as 226 days postinfection. These experiments demonstrate that virus-specific CTLs are present in the CNS during both acute and chronic TMEV infection. Anti-TMEV CTLs in the CNS of chronically infected SJL/J mice may play a role in demyelination through their ability to lyse TMEV-infected glial cells.

  16. Predominant binding of Theiler's viruses to a 34-kilodalton receptor protein on susceptible cell lines.

    PubMed Central

    Kilpatrick, D R; Lipton, H L

    1991-01-01

    Western immunoblots of BHK-21 cell lysates probed with the highly virulent GDVII and the less virulent BeAn strains of Theiler's murine encephalomyelitis virus (TMEV) revealed predominant binding to a 34-kDa membrane protein and much lower levels of binding to 100- and 18-kDa membrane proteins. Complete inhibition of virus binding to both the 34- and 18-kDa membrane species by excess unlabeled TMEV demonstrated specificity of binding. Virus binding was also blocked by wheat germ agglutinin, which specifically binds to sialic acid residues and blocks TMEV binding to whole BHK-21 cells. Radiolabeled TMEV also bound to 100-, 34-, and 18-kDa membrane proteins expressed on other TMEV permissive cell lines but not on the nonpermissive cell lines tested. These data suggest that a 34-kDa cellular protein may be the primary determinant of susceptibility to TMEV infection by mediating the binding of GDVII and BeAn viruses to susceptible cells. Images PMID:1895381

  17. Central nervous system immunity in mice infected with theiler's virus. I. Local neutralizing antibody response.

    PubMed

    Lipton, H L; Gonzalez-Scarano, F

    1978-02-01

    Experimental Theiler's mouse encephalomyelitis virus (TMEV) infection in mice is atypical of most other picornavirus infections because virus persists in the host. It was shown previously that low levels of infectious virus are readily detectable in the central nervous system (CNS) despite the presence of substantial titers of serum neutralizing antibody. In this study antibody assays were performed on CNS tissue homogenates, and neutralizing antibody was regularly found in the CNS of TMEV-infected mice. That neutralization by infected CNS extracts was due to antibody was demonstrated by the specificity of neutralization for TMEV and by elimination or marked reduction of neutralization by in vitro treatment with goat antiserum to mouse IgG. In addition, immunofluorescent staining consistently revealed IgG- but not IgM-containing cells in perivascular cuffs and parenchymal lesions of the brains of infected animals. Evidence of local antibody formation in the CNS was found in the actual reversal of the serum-CNS antibody ratio in about one-third of infected mice after three weeks. In contrast, normal mice had a mean serum-CNS antibody ratio of approximately 100:1 after passive transfer of antibody. Possible reasons for the fact that TMEV is not neutralized by antibody and chronic infection is not aborted include the formation of complexes of infectious virus and antibody in the CNS and the production of antibodies with low affinity for TMEV.

  18. Hepatitis and Jaundice Associated with Immunization against Certain Virus Diseases: (Section of Comparative Medicine).

    PubMed

    Findlay, G M; Maccallum, F O

    1938-05-01

    (1) Among 3,100 persons immunized against yellow fever with virus and immune serum over a period of five years, 89 cases of jaundice have been traced.(2) The symptoms are those of a hepatitis and closely resemble those produced by common infective hepatic jaundice, cases of which have frequently been noted as occurring in the same areas.(3) The average period between the time of inoculation and the development of hepatitis is between two and three months.(4) Attention is directed to the occurrence of hepatitis in horses, usually two to three months after immunization against the viruses of horse sickness and equine encephalomyelitis, and also after the injection of horse serum containing antitoxins against Cl. welchii toxins. Similar symptoms were observed, though to a lesser extent, in normal horses.(5) The only factor common to the inoculated horses and men was the injection of homologous proteins, either in sera or in tissue extracts.(6) The only theories which at present explain the observed facts are that either (1) a hepatotoxic virus is introduced with the virus inoculum or that (2) two factors combine to induce the hepatitis (a) a hepatotoxic substance present in the homologous sera or tissue extract injected and (b) an infective agent which, in the case at least of human beings, is probably the causal agent of common infective hepatic jaundice.

  19. [Genetic characterization of the Syr-Darya valley fever virus (SDVFV) (Picornaviridae, Cardiovirus) isolated from the blood of the patients and ticks Hyalomma as. asiaticum (Hyalomminae), Dermacentor daghestanicus (Rhipicephalinae) (Ixodidae) and Ornithodoros coniceps (Argasidae) in Kazakhstan and Turkmenistan].

    PubMed

    L'vov, D K; Al'khovskiĭ, S V; Shchelkanov, M Iu; Shchetinin, A M; Deriabin, P G; Gitel'man, A K; Aristova, V A; Botikov, A G

    2014-01-01

    The Syr-Darya valley fever virus (SDVFV) was originally isolated from the blood of the patient with fever in the Kyzylorda province, Kazakhstan, in July 1973 and was classified to the Cardiovirus genus (fam. Picornaviridae). Later, SDVFV was isolated from the ticks Hyalomma as. asiaticum Schulze et Schlottke, 1929 (Hyalomminae) (1 strain) and Dermacentor daghestanicus Olenev, 1929 (Rhipicephalinae) (7 strains), collected in the floodplains of the Syr-Darya river and the Ili river. In this paper, complet genome of the SDVFV (strain LEIV-Tur2833) was sequenced using the next-generation sequencing approach (GenBank ID: KJ191558). It was demonstrated that, phylogenetically, the SDVFV is closely related closest to the Theiler's murine encephalomyelitis virus (TMEV) and Vilyuisk human encephalomyelitis virus (VMEV). The similarity of the SDVFV with VHEV and TMEV based on P1 region of the polyprotein-precursor (structural proteins VP1-VP4), reaches 75% and 91% for nucleotide sequences and 80% and 93% for putative amino acid sequences, respectively. For nonstructural proteins regions P2 (2A-2C) and P3 (3A-3D) similarity of SDVFV with TMEV and VHEV is 96%-98%.

  20. [Genetic characterization of the Syr-Darya valley fever virus (SDVFV) (Picornaviridae, Cardiovirus) isolated from the blood of the patients and ticks Hyalomma as. asiaticum (Hyalomminae), Dermacentor daghestanicus (Rhipicephalinae) (Ixodidae) and Ornithodoros coniceps (Argasidae) in Kazakhstan and Turkmenistan].

    PubMed

    L'vov, D K; Al'khovskiĭ, S V; Shchelkanov, M Iu; Shchetinin, A M; Deriabin, P G; Gitel'man, A K; Aristova, V A; Botikov, A G

    2014-01-01

    The Syr-Darya valley fever virus (SDVFV) was originally isolated from the blood of the patient with fever in the Kyzylorda province, Kazakhstan, in July 1973 and was classified to the Cardiovirus genus (fam. Picornaviridae). Later, SDVFV was isolated from the ticks Hyalomma as. asiaticum Schulze et Schlottke, 1929 (Hyalomminae) (1 strain) and Dermacentor daghestanicus Olenev, 1929 (Rhipicephalinae) (7 strains), collected in the floodplains of the Syr-Darya river and the Ili river. In this paper, complet genome of the SDVFV (strain LEIV-Tur2833) was sequenced using the next-generation sequencing approach (GenBank ID: KJ191558). It was demonstrated that, phylogenetically, the SDVFV is closely related closest to the Theiler's murine encephalomyelitis virus (TMEV) and Vilyuisk human encephalomyelitis virus (VMEV). The similarity of the SDVFV with VHEV and TMEV based on P1 region of the polyprotein-precursor (structural proteins VP1-VP4), reaches 75% and 91% for nucleotide sequences and 80% and 93% for putative amino acid sequences, respectively. For nonstructural proteins regions P2 (2A-2C) and P3 (3A-3D) similarity of SDVFV with TMEV and VHEV is 96%-98%. PMID:25549463