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Sample records for multiple common hla

  1. Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status

    PubMed Central

    Binder, Michele D.; Fox, Andrew D.; Merlo, Daniel; Johnson, Laura J.; Giuffrida, Lauren; Calvert, Sarah E.; Akkermann, Rainer; Ma, Gerry Z. M.; Perera, Ashwyn A.; Gresle, Melissa M.; Laverick, Louise; Foo, Grace; Fabis-Pedrini, Marzena J.; Spelman, Timothy; Jordan, Margaret A.; Baxter, Alan G.; Foote, Simon; Butzkueven, Helmut; Kilpatrick, Trevor J.; Field, Judith

    2016-01-01

    Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients. PMID:26990204

  2. Common and Low Frequency Variants in MERTK Are Independently Associated with Multiple Sclerosis Susceptibility with Discordant Association Dependent upon HLA-DRB1*15:01 Status.

    PubMed

    Binder, Michele D; Fox, Andrew D; Merlo, Daniel; Johnson, Laura J; Giuffrida, Lauren; Calvert, Sarah E; Akkermann, Rainer; Ma, Gerry Z M; Perera, Ashwyn A; Gresle, Melissa M; Laverick, Louise; Foo, Grace; Fabis-Pedrini, Marzena J; Spelman, Timothy; Jordan, Margaret A; Baxter, Alan G; Foote, Simon; Butzkueven, Helmut; Kilpatrick, Trevor J; Field, Judith

    2016-03-01

    Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. The risk of developing MS is strongly influenced by genetic predisposition, and over 100 loci have been established as associated with susceptibility. However, the biologically relevant variants underlying disease risk have not been defined for the vast majority of these loci, limiting the power of these genetic studies to define new avenues of research for the development of MS therapeutics. It is therefore crucial that candidate MS susceptibility loci are carefully investigated to identify the biological mechanism linking genetic polymorphism at a given gene to the increased chance of developing MS. MERTK has been established as an MS susceptibility gene and is part of a family of receptor tyrosine kinases known to be involved in the pathogenesis of demyelinating disease. In this study we have refined the association of MERTK with MS risk to independent signals from both common and low frequency variants. One of the associated variants was also found to be linked with increased expression of MERTK in monocytes and higher expression of MERTK was associated with either increased or decreased risk of developing MS, dependent upon HLA-DRB1*15:01 status. This discordant association potentially extended beyond MS susceptibility to alterations in disease course in established MS. This study provides clear evidence that distinct polymorphisms within MERTK are associated with MS susceptibility, one of which has the potential to alter MERTK transcription, which in turn can alter both susceptibility and disease course in MS patients. PMID:26990204

  3. Class II HLA antigens in multiple sclerosis.

    PubMed Central

    Miller, D H; Hornabrook, R W; Dagger, J; Fong, R

    1989-01-01

    HLA typing in Wellington revealed a stronger association of multiple sclerosis with DR2 than with DQw1. The association with DQw1 appeared to be due to linkage disequilibrium of this antigen with DR2. These results, when considered in conjunction with other studies, are most easily explained by the hypothesis that susceptibility to multiple sclerosis is influenced by multiple risk factors, with DR2 being an important risk factor in Caucasoid populations. PMID:2732726

  4. Common antigenic structures of HL-A antigens

    PubMed Central

    Nakamuro, K.; Tanigaki, N.; Kreiter, V. P.; Pressman, D.

    1974-01-01

    Spent culture media of all the human cell lines tested have been found to contain the antigenic activity present on the 11,000-Dalton HL-A common portion fragment of the HL-A antigen molecule that appears to be a characteristic, invariant portion of HL-A antigen molecules. From the culture medium of one of these lines, RPMI 1788, a lymphoid cell line, the substance carrying HL-A common activity was isolated, which was shown to be identical to the HL-A common portion fragment with respect to molecular size, electrophoretic mobility, isoelectric focusing patterns, and certain antigenic characteristics. By an isolation procedure involving differential ultrafiltration, gel filtration, and column electrophoresis, 8 litres of the culture medium yielded 1.5–2.0 A280 units of the substance representing 15–20 per cent of the HL-A common antigenic activity originally present. A single protein band with a Rf of 0.47 was obtained by disc electrophoresis. The molecular size was shown to be about 11,000 Daltons by gel filtration and by sodium dodecyl sulphate—acrylamide gel electrophoresis. Upon isoelectric focusing two bands were obtained which corresponded exactly to those obtained with HL-A common portion fragment prepared from papain-solubilized HL-A antigen preparations by acid dissociation. The isoelectric point of the major band was 5.0. The reactions of this substance with rabbit antisera against human lymphoid cell membrane and against the substance were essentially identical to the reactions of HL-A common portion fragment with these same antisera. ImagesFIG. 3Fig. 4Fig. 5 PMID:4476726

  5. [Detection of common determinants of HLA antigens A2 and B17 by absorption using human HLA serum].

    PubMed

    Májský, A; Korínková, P

    1983-01-01

    Attempts of cross absorption where sera of anti-HLA A2 + B17, anti-HLA A2 and anti-HLA B17 with thrombocytes were absorbed from donors of HLA A2 positive, B17 negative and HLA A2 negative, B17 positive, revealed that anti-HLA A2 and anti-HLA B17 could be eliminated from the sera of both HLA types on the platelets. Thus, the findings allow the existence of a common determinant of HLA A2 and B17-antigens to be assumed. This is the first case where the evidence of a cross reaction between antigens of two different HLA loci with human sera could be established.

  6. Multiple HLA Epitopes Contribute to Type 1 Diabetes Susceptibility

    PubMed Central

    Roark, Christina L.; Anderson, Kirsten M.; Simon, Lucas J.; Schuyler, Ronald P.; Aubrey, Michael T.; Freed, Brian M.

    2014-01-01

    Disease susceptibility for type 1 diabetes is strongly associated with the inheritance of specific HLA alleles. However, conventional allele frequency analysis can miss HLA associations because many alleles are rare. In addition, disparate alleles that have similar peptide-binding sites, or shared epitopes, can be missed. To identify the HLA shared epitopes associated with diabetes, we analyzed high-resolution genotyping for class I and class II loci. The HLA epitopes most strongly associated with susceptibility for disease were DQB1 A57, DQA1 V76, DRB1 H13, and DRB1 K71, whereas DPB1 YD9,57, HLA-B C67, and HLA-C YY9,116 were more weakly associated. The HLA epitopes strongly associated with resistance were DQB1 D57, DQA1 Y80, DRB1 R13, and DRB1 A71. A dominant resistance phenotype was observed for individuals bearing a protective HLA epitope, even in the presence of a susceptibility epitope. In addition, an earlier age of disease onset correlated with significantly greater numbers of susceptibility epitopes and fewer resistance epitopes (P < 0.0001). The prevalence of both DQ and DR susceptibility epitopes was higher in patients than in control subjects and was not exclusively a result of linkage disequilibrium, suggesting that multiple HLA epitopes may work together to increase the risk of developing diabetes. PMID:24357703

  7. HLA and multiple sclerosis in south east Wales.

    PubMed Central

    Swingler, R J; Kirk, P F; Darke, C; Compston, D A

    1987-01-01

    A stronger association has been found between multiple sclerosis and HLA-DR2 than -DQwl in south east Wales (prevalence c 113/10(5)) in contrast to recent observations in north east Scotland (prevalence 178/10(5). The complex relationship between the HLA system and multiple sclerosis, demonstrated in this and other studies, is explained more easily under a polygenic model of inheritance, in which environmental events and genes interact, than by the presence of a single susceptibility gene. PMID:3499485

  8. HLA typing in families with multiple cases of rheumatoid arthritis.

    PubMed Central

    Strotzer, M; Menninger, H; Scholz, S; Albert, E D

    1991-01-01

    Thirty one white patients from 14 families with multiple cases of rheumatoid arthritis (RA) and 42 of their healthy relatives were completely HLA typed. In contrast with class I antigens, the class II antigens DR1 and DR4 were significantly more common in the patients than in a group of 200 healthy local white controls (DR1: 32% v 12%; DR4: 48% v 28%, in patients and controls respectively). Owing to the small number of cases the data from this study were combined with those of published reports. Examination of patients for DR1 and DR4 homozygosity and DR1/4 heterozygosity showed an increase of DR1 homozygous patients, which was not statistically significant. There was no striking deviation from random expectation in haplotype sharing of affected sib pairs. These results are compatible with a dominant influence of DR1 and DR4 in the mode of inheritance. The nearly random haplotype sharing and the molecular relation between DR1 and DR4 support the hypothesis of a direct influence of these antigens in the pathogenesis of RA. Only 68% of the patients in this study possessed either DR1 or DR4, possibly indicating a subtype of RA which is independent of HLA. Clinical and serological variables were measured and indicated no significant difference between DR1 (or DR4) positive and DR1 (or DR4) negative disease. In this small group of patients the clinical course of RA seemed to be determined mainly by other genetic or environmental factors. PMID:2042983

  9. Modification of Multiple Sclerosis Phenotypes by African Ancestry at HLA

    PubMed Central

    Cree, Bruce A. C.; Reich, David E.; Khan, Omar; De Jager, Philip L.; Nakashima, Ichiro; Takahashi, Toshiyuki; Bar-Or, Amit; Tong, Christine; Hauser, Stephen L.; Oksenberg, Jorge R.

    2015-01-01

    Background In those with multiple sclerosis (MS), African American individuals have a more severe disease course, an older age at onset, and more often have clinical manifestations restricted to the optic nerves and spinal cord (opticospinal MS) than white persons. Objective To determine whether genetic variation influences clinical MS patterns. Design Retrospective multicenter cohort study. Participants Six hundred seventy-three African American and 717 white patients with MS. Main Outcome Measures Patients with MS were geno-typed for HLA-DRB1 and HLA-DQB1 alleles. The proportion of European ancestry at HLA was estimated by genotyping single-nucleotide polymorphisms with known significant frequency differences in West African and European populations. These genotypes were correlated with the opticospinal disease phenotype, disability measures, and age at onset. Results Subjects with DRB1*15 alleles were twice as likely to have typical MS rather than opticospinal MS (P = .001). Of the subjects with opticospinal MS or a history of recurrent transverse myelitis who were seropositive for anti–aquaporin 4 antibodies (approximately 5%), none carried DRB1*15 alleles (P = .008). Independently of DRB1* 15, African ancestry at HLA correlated with disability as measured by the Multiple Sclerosis Severity Score (P < .001) andriskof cane dependency (hazard ratio, 1.36; P < .001); DRB1*15 alleles were associated with a 2.1-year earlier age at onset (P < .001). Conclusions These data indicate that the role of HLA in MS is not limited to disease susceptibility but that genes embedded in this locus also influence clinical outcomes. PMID:19204159

  10. Uncoupling the Roles of HLA-DRB1 and HLA-DRB5 Genes in Multiple Sclerosis1

    PubMed Central

    Caillier, Stacy J.; Briggs, Farren; Cree, Bruce A. C.; Baranzini, Sergio E.; Fernandez-Viña, Marcelo; Ramsay, Patricia P.; Khan, Omar; Royal, Walter; Hauser, Stephen L.; Barcellos, Lisa F.; Oksenberg, Jorge R.

    2015-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the MHC located on chromosome 6p21. This signal maps primarily to a 1-Mb region encompassing the HLA class II loci, and it segregates often with the HLA-DQB1*0602, -DQA1*0102, -DRB1*1501, -DRB5*0101 haplotype. However, the identification of the true predisposing gene or genes within the susceptibility haplotype has been handicapped by the strong linkage disequilibrium across the locus. African Americans have greater MHC haplotypic diversity and distinct patterns of linkage disequilibrium, which make this population particularly informative for fine mapping efforts. The purpose of this study was to establish the telomeric boundary of the HLA class II region affecting susceptibility to MS by assessing genetic association with the neighboring HLA-DRB5 gene as well as seven telomeric single nucleotide polymorphisms in a large, well-characterized African American dataset. Rare DRB5*null individuals were previously described in African populations. Although significant associations with both HLA-DRB1 and HLA-DRB5 loci were present, HLA-DRB1*1503 was associated with MS in the absence of HLA-DRB5, providing evidence for HLA-DRB1 as the primary susceptibility gene. Interestingly, the HLA-DRB5*null subjects appear to be at increased risk for developing secondary progressive MS. Thus, HLA-DRB5 attenuates MS severity, a finding consistent with HLA-DRB5’s proposed role as a modifier in experimental autoimmune encephalomyelitis. Additionally, conditional haplotype analysis revealed a susceptibility signal at the class III AGER locus independent of DRB1. The data underscore the power of the African American MS dataset to identify disease genes by association in a region of high linkage disequilibrium. PMID:18832704

  11. Common genomic HLA haplotypes contributing to successful donor search in unrelated hematopoietic transplantation.

    PubMed

    Pedron, B; Duval, M; Elbou, O M; Moskwa, M; Jambou, M; Vilmer, E; Sterkers, G

    2003-03-01

    The aim of the study was to identify the most frequent HLA haplotypes in order to optimize donor searches in unrelated hematopoietic stem cell (HSC) transplantation. Pediatric patients from the north of France who underwent initial HLA typing for donor search in our center were included. Patients and family members were broadly typed for HLA class I and II. Patients were further DNA typed at the sequence level for HLA-A, -B, -Cw, -DRB1, and -DQB1 alleles. In 200 of 207 patients HLA haplotypes were assigned by the mode of inheritance. The most common haplotypes were defined based on frequencies over 0.75%. Searches for unrelated donors were completed for 86 patients lacking a family donor. Matching criteria were either the optimal level of 10 alleles or a one-HLA class I mismatch as a second choice. Rates of successful search reach 85% for patients (n=20) who express at least one common five-allele (HLA-A/B/Cw/DRB1/DQB1) haplotype, but also 77% for more patients (n=53) who express at least one of the 20 most frequent three-allele (HLA-A/B/Cw) haplotypes. Success rates are clearly less (39%) in patients lacking these haplotypes. The use of these data to delineate search strategies is discussed.

  12. Common HLA Alleles Associated with Health, but Not with Facial Attractiveness

    PubMed Central

    Coetzee, Vinet; Barrett, Louise; Greeff, Jaco M.; Henzi, S. Peter; Perrett, David I.; Wadee, Ahmed A.

    2007-01-01

    Three adaptive hypotheses have been proposed to explain the link between the human leucocyte antigen (HLA) genes, health measures and facial attractiveness: inbreeding avoidance, heterozygote advantage and frequency-dependent selection. This paper reports findings that support a new hypothesis relating HLA to health. We suggest a new method to quantify the level of heterozygosity. HLA heterozygosity did not significantly predict health measures in women, but allele frequency did. Women with more common HLA alleles reported fewer cold and flu bouts per year, fewer illnesses in the previous year and rated themselves healthier than women with rare alleles. To our knowledge, this is the first study to show a positive correlation between HLA allele frequency and general health measures. We propose that certain common HLA alleles confer resistance to prevalent pathogens. Nevertheless, neither HLA heterozygosity nor allele frequency significantly predicted how healthy or attractive men rated the female volunteers. Three non-mutually exclusive explanations are put forward to explain this finding. PMID:17653267

  13. Common and well-documented HLA alleles: 2012 update to the CWD catalogue.

    PubMed

    Mack, S J; Cano, P; Hollenbach, J A; He, J; Hurley, C K; Middleton, D; Moraes, M E; Pereira, S E; Kempenich, J H; Reed, E F; Setterholm, M; Smith, A G; Tilanus, M G; Torres, M; Varney, M D; Voorter, C E M; Fischer, G F; Fleischhauer, K; Goodridge, D; Klitz, W; Little, A-M; Maiers, M; Marsh, S G E; Müller, C R; Noreen, H; Rozemuller, E H; Sanchez-Mazas, A; Senitzer, D; Trachtenberg, E; Fernandez-Vina, Marcelo

    2013-04-01

    We have updated the catalogue of common and well-documented (CWD) human leukocyte antigen (HLA) alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and -DPB1 loci in IMGT (IMmunoGeneTics)/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and -DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being 'common' (having known frequencies) and 707 as being 'well-documented' on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program's bioinformatics web pages. PMID:23510415

  14. Association of HLA Genetic Risk Burden With Disease Phenotypes in Multiple Sclerosis

    PubMed Central

    Isobe, Noriko; Keshavan, Anisha; Gourraud, Pierre-Antoine; Zhu, Alyssa H.; Datta, Esha; Schlaeger, Regina; Caillier, Stacy J.; Santaniello, Adam; Lizée, Antoine; Himmelstein, Daniel S.; Baranzini, Sergio E.; Hollenbach, Jill; Cree, Bruce A. C.; Hauser, Stephen L.; Oksenberg, Jorge R.; Henry, Roland G.

    2016-01-01

    IMPORTANCE Although multiple HLA alleles associated with multiple sclerosis (MS) risk have been identified, genotype-phenotype studies in the HLA region remain scarce and inconclusive. OBJECTIVES To investigate whether MS risk-associated HLA alleles also affect disease phenotypes. DESIGN, SETTING, AND PARTICIPANTS A cross-sectional, case-control study comprising 652 patients with MS who had comprehensive phenotypic information and 455 individuals of European origin serving as controls was conducted at a single academic research site. Patients evaluated at the Multiple Sclerosis Center at University of California, San Francisco between July 2004 and September 2005 were invited to participate. Spinal cord imaging in the data set was acquired between July 2013 and March 2014; analysis was performed between December 2014 and December 2015. MAIN OUTCOMES AND MEASURES Cumulative HLA genetic burden (HLAGB) calculated using the most updated MS-associated HLA alleles vs clinical and magnetic resonance imaging outcomes, including age at onset, disease severity, conversion time from clinically isolated syndrome to clinically definite MS, fractions of cortical and subcortical gray matter and cerebral white matter, brain lesion volume, spinal cord gray and white matter areas, upper cervical cord area, and the ratio of gray matter to the upper cervical cord area. Multivariate modeling was applied separately for each sex data set. RESULTS Of the 652 patients with MS, 586 had no missing genetic data and were included in the HLAGB analysis. In these 586 patients (404 women [68.9%]; mean [SD] age at disease onset, 33.6 [9.4] years), HLAGB was higher than in controls (median [IQR], 0.7 [0–1.4] and 0 [−0.3 to 0.5], respectively; P = 1.8 × 10−27). A total of 619 (95.8%) had relapsing-onset MS and 27 (4.2%) had progressive-onset MS. No significant difference was observed between relapsing-onset MS and primary progressive MS. A higher HLAGB was associated with younger age at onset

  15. Common and Well-Documented HLA Alleles: 2012 Update to the CWD Catalogue

    PubMed Central

    Mack, Steven J.; Cano, Pedro; Hollenbach, Jill A.; He, Jun; Hurley, Carolyn Katovich; Middleton, Derek; Moraes, Maria Elisa; Pereira, Shalini E.; Kempenich, Jane H.; Reed, Elaine F.; Setterholm, Michelle; Smith, AnaJane G.; Tilanus, Marcel G.; Torres, Margareth; Varney, Michael D.; Voorter, Christien E. M.; Fischer, Gottfried F.; Fleischhauer, Katharina; Goodridge, Damian; Klitz, William; Little, Ann-Margaret; Maiers, Martin; Marsh, Steven G. E.; Müller, Carlheinz R.; Noreen, Harriet; Rozemuller, Erik H.; Sanchez-Mazas, Alicia; Senitzer, David; Trachtenberg, Elizabeth; Fernandez-Vina, Marcelo

    2013-01-01

    We have updated the catalogue of common and well-documented (CWD) HLA alleles to reflect current understanding of the prevalence of specific allele sequences. The original CWD catalogue designated 721 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, and –DPB1 loci in IMGT/HLA Database release 2.15.0 as being CWD. The updated CWD catalogue designates 1122 alleles at the HLA-A, -B, -C, -DRB1, -DRB3/4/5, -DQA1, -DQB1, -DPA1 and –DPB1 loci as being CWD, and represents 14.3% of the HLA alleles in IMGT/HLA Database release 3.9.0. In particular, we identified 415 of these alleles as being “common” (having known frequencies) and 707 as being “well-documented” on the basis of ~140,000 sequence-based typing observations and available HLA haplotype data. Using these allele prevalence data, we have also assigned CWD status to specific G and P designations. We identified 147/151 G groups and 290/415 P groups as being CWD. The CWD catalogue will be updated on a regular basis moving forward, and will incorporate changes to the IMGT/HLA Database as well as empirical data from the histocompatibility and immunogenetics community. This version 2.0.0 of the CWD catalogue is available online at cwd.immunogenomics.org, and will be integrated into the Allele Frequencies Net Database, the IMGT/HLA Database and National Marrow Donor Program’s bioinformatics web pages. PMID:23510415

  16. Common Genetic Variants Found in HLA and KIR Immune Genes in Autism Spectrum Disorder

    PubMed Central

    Torres, Anthony R.; Sweeten, Thayne L.; Johnson, Randall C.; Odell, Dennis; Westover, Jonna B.; Bray-Ward, Patricia; Ward, David C.; Davies, Christopher J.; Thomas, Aaron J.; Croen, Lisa A.; Benson, Michael

    2016-01-01

    The “common variant—common disease” hypothesis was proposed to explain diseases with strong inheritance. This model suggests that a genetic disease is the result of the combination of several common genetic variants. Common genetic variants are described as a 5% frequency differential between diseased vs. matched control populations. This theory was recently supported by an epidemiology paper stating that about 50% of genetic risk for autism resides in common variants. However, rare variants, rather than common variants, have been found in numerous genome wide genetic studies and many have concluded that the “common variant—common disease” hypothesis is incorrect. One interpretation is that rare variants are major contributors to genetic diseases and autism involves the interaction of many rare variants, especially in the brain. It is obvious there is much yet to be learned about autism genetics. Evidence has been mounting over the years indicating immune involvement in autism, particularly the HLA genes on chromosome 6 and KIR genes on chromosome 19. These two large multigene complexes have important immune functions and have been shown to interact to eliminate unwanted virally infected and malignant cells. HLA proteins have important functions in antigen presentation in adaptive immunity and specific epitopes on HLA class I proteins act as cognate ligands for KIR receptors in innate immunity. Data suggests that HLA alleles and KIR activating genes/haplotypes are common variants in different autism populations. For example, class I allele (HLA-A2 and HLA-G 14 bp-indel) frequencies are significantly increased by more than 5% over control populations (Table 2). The HLA-DR4 Class II and shared epitope frequencies are significantly above the control populations (Table 2). Three activating KIR genes: 3DS1, 2DS1, and 2DS2 have increased frequencies of 15, 22, and 14% in autism populations, respectively. There is a 6% increase in total activating KIR genes in

  17. Identification of HLA-A*0201-Restricted Cytotoxic T Lymphocyte Epitopes Derived from HLA-DOβ as a Novel Target for Multiple Myeloma

    PubMed Central

    Kang, Yoon Joong; Zeng, Wanyong; Song, Weihua; Reinhold, Bruce; Choi, Jaewon; Brusic, Vladimir; Yamashita, Takuto; Munshi, Aditya; Li, Cheng; Minvielle, Stephane; Anderson, Kenneth C.; Munshi, Nikhil; Reinherz, Ellis L.; Sasada, Tetsuro

    2014-01-01

    Summary Despite the recent development of effective therapeutic agents against multiple myeloma (MM), new therapeutic approaches, including immunotherapies, remain to be developed. Here we identified novel human leucocyte antigen (HLA)-A*0201 (HLAA2)-restricted cytotoxic T lymphocyte (CTL) epitopes from a B cell specific molecule HLA-DOβ (DOB) as a potential target for MM. By DNA microarray analysis, the HLADOB expression in MM cells was significantly higher than that in normal plasma cells. Twenty-five peptides were predicted to bind to HLA-A2 from the amino acid sequence of HLA-DOB. When screened for the immunogenicity in HLA-A2-transgenic mice immunized with HLA-DOB cDNA, 4 peptides were substantially immunogenic. By mass spectrometry analysis of peptides eluted from HLA-A2-immunoprecipitates of MM cell lines, only two epitopes, HLA-DOB232-240 (FLLGLIFLL) and HLA-DOB185-193 (VMLEMTPEL), were confirmed for their physical presence on cell surface. When healthy donor blood was repeatedly stimulated in vitro with these two peptides and assessed by antigen-specific γ-interferon secretion, HLA-DOB232-240 was more immunogenic than HLA-DOB185-193. Additionally, the HLA-DOB232-240-specific CTLs, but not the HLA-DOB185-193-specific CTLs, displayed an major histocompatibility complex class I-restricted reactivity against MM cell lines expressing both HLA-A2 and HLA-DOB. Taken together, based on the physical presence on tumour cell surface and high immunogenicity, HLA-DOB232-240 might be useful for developing a novel immunotherapy against MM. PMID:24032635

  18. Multiple order common path spectrometer

    NASA Technical Reports Server (NTRS)

    Newbury, Amy B. (Inventor)

    2010-01-01

    The present invention relates to a dispersive spectrometer. The spectrometer allows detection of multiple orders of light on a single focal plane array by splitting the orders spatially using a dichroic assembly. A conventional dispersion mechanism such as a defraction grating disperses the light spectrally. As a result, multiple wavelength orders can be imaged on a single focal plane array of limited spectral extent, doubling (or more) the number of spectral channels as compared to a conventional spectrometer. In addition, this is achieved in a common path device.

  19. Five HLA-DP Molecules Frequently Expressed in the Worldwide Human Population Share a Common HLA Supertypic Binding Specificity

    PubMed Central

    Sidney, John; Steen, Amiyah; Moore, Carrie; Ngo, Sandy; Chung, Jolan; Peters, Bjoern; Sette, Alessandro

    2010-01-01

    Compared with DR and DQ, knowledge of the binding repertoires and specificities of HLA-DP alleles is somewhat limited. However, a growing body of literature has indicated the importance of DP-restricted responses in the context of cancer, allergy, and infectious disease. In the current study, we developed high-throughput binding assays for the five most common HLA-DPB1 alleles in the general worldwide population. Using these assays on a comprehensive panel of single-substitution analogs and large peptide libraries, we derived novel detailed binding motifs for DPB1*0101 and DPB1*0501. We also derived more detailed quantitative motifs for DPB1*0201, DPB1*0401, and DPB1*0402, which were previously characterized on the basis of sets of eluted ligands and/or limited sets of substituted peptides. Unexpectedly, all five DP molecules, originally selected only on the basis of their frequency in human populations, were found to share largely overlapping peptide motifs. Testing panels of known DP epitopes and a panel of peptides spanning a set of Phleum pratense Ags revealed that these molecules also share largely overlapping peptide-binding repertoires. This demonstrates that a previously hypothesized DP supertype extends far beyond what was originally envisioned and includes at least three additional very common DP specificities. Taken together, these DP supertype molecules are found in >90% of the human population. Thus, these findings have important implications for epitope-identification studies and monitoring of human class II-restricted immune responses. PMID:20139279

  20. Empirical evaluations of analytical issues arising from predicting HLA alleles using multiple SNPs

    PubMed Central

    2011-01-01

    Background Numerous immune-mediated diseases have been associated with the class I and II HLA genes located within the major histocompatibility complex (MHC) consisting of highly polymorphic alleles encoded by the HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1 loci. Genotyping for HLA alleles is complex and relatively expensive. Recent studies have demonstrated the feasibility of predicting HLA alleles, using MHC SNPs inside and outside of HLA that are typically included in SNP arrays and are commonly available in genome-wide association studies (GWAS). We have recently described a novel method that is complementary to the previous methods, for accurately predicting HLA alleles using unphased flanking SNPs genotypes. In this manuscript, we address several practical issues relevant to the application of this methodology. Results Applying this new methodology to three large independent study cohorts, we have evaluated the performance of the predictive models in ethnically diverse populations. Specifically, we have found that utilizing imputed in addition to genotyped SNPs generally yields comparable if not better performance in prediction accuracies. Our evaluation also supports the idea that predictive models trained on one population are transferable to other populations of the same ethnicity. Further, when the training set includes multi-ethnic populations, the resulting models are reliable and perform well for the same subpopulations across all HLA genes. In contrast, the predictive models built from single ethnic populations have superior performance within the same ethnic population, but are not likely to perform well in other ethnic populations. Conclusions The empirical explorations reported here provide further evidence in support of the application of this approach for predicting HLA alleles with GWAS-derived SNP data. Utilizing all available samples, we have built "state of the art" predictive models for HLA-A, -B, -C, -DRB1, -DQB1 and -DPB1. The HLA allele

  1. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

    PubMed Central

    Salier, J P; Sesboüé, R; Martin-Mondière, C; Daveau, M; Cesaro, P; Cavelier, B; Coquerel, A; Legrand, L; Goust, J M; Degos, J D

    1986-01-01

    In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease. PMID:3461005

  2. Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

    PubMed

    Salier, J P; Sesboüé, R; Martin-Mondière, C; Daveau, M; Cesaro, P; Cavelier, B; Coquerel, A; Legrand, L; Goust, J M; Degos, J D

    1986-08-01

    In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for major histocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226 geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and G1m(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 4.3) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gm1/Gm3 heterozygous patients, but not in Gm3/Gm3 homozygous patients. Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease. PMID:3461005

  3. Unraveling Multiple MHC Gene Associations with Systemic Lupus Erythematosus: Model Choice Indicates a Role for HLA Alleles and Non-HLA Genes in Europeans

    PubMed Central

    Morris, David L.; Taylor, Kimberly E.; Fernando, Michelle M.A.; Nititham, Joanne; Alarcón-Riquelme, Marta E.; Barcellos, Lisa F.; Behrens, Timothy W.; Cotsapas, Chris; Gaffney, Patrick M.; Graham, Robert R.; Pons-Estel, Bernardo A.; Gregersen, Peter K.; Harley, John B.; Hauser, Stephen L.; Hom, Geoffrey; Langefeld, Carl D.; Noble, Janelle A.; Rioux, John D.; Seldin, Michael F.; Criswell, Lindsey A.; Vyse, Timothy J.

    2012-01-01

    We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1∗03:01, HLA-DRB1∗08:01, and HLA-DQA1∗01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000). PMID:23084292

  4. Molecular analysis of HLA-DQB1 alleles in childhood common acute lymphoblastic leukaemia.

    PubMed Central

    Dearden, S. P.; Taylor, G. M.; Gokhale, D. A.; Robinson, M. D.; Thompson, W.; Ollier, W.; Binchy, A.; Birch, J. M.; Stevens, R. F.; Carr, T.; Bardsley, W. G.

    1996-01-01

    Epidemiological studies suggest that childhood common acute lymphoblastic leukaemia (c-ALL) may be the rare outcome of early post-natal infection with a common infectious agent. One of the factors that may determine whether a child succumbs to c-ALL is how it responds to the candidate infection. Since immune responses to infection are under the partial control of (human leucocyte antigen) HLA genes, an association between an HLA allele and c-ALL could provide support for an infectious aetiology. To define the limit of c-ALL susceptibility within the HLA region, we have compared HLA-DQB1 allele frequencies in a cohort of 62 children with c-ALL with 76 newborn controls, using group-specific polymerase chain reaction (PCR) amplification, and single-strand conformation polymorphism (SSCP) analysis. We find that a significant excess of children with c-ALL type for DQB1*05 [relative risk (RR): 2.54, uncorrected P=0.038], and a marginal excess with DQB1*0501 (RR: 2.18; P=0.095). Only 3 of the 62 children with c-ALL have the other susceptibility allele, DPB1*0201 as well as DQB1*0501, whereas 15 had one or the other allele. This suggests that HLA-associated susceptibility may be determined independently by at least two loci, and is not due to linkage disequilibrium. The combined relative risk of the two groups of children with DPB1*0201 and/or DQB1*0501 is 2.76 (P=0.0076). Analysis of amino acids encoded by exon 2 of DQB1 reveal additional complexity, with significant (P<0.05) or borderline-significant increases in Gly26, His30, Val57, Glu66-Val67 encoding motifs in c-ALL compared with controls. Since these amino acids are not restricted to DQB1*0501, our results suggest that, as with DPB1, the increased risk of c-ALL associated with DQB1 is determined by specific amino acid encoding motifs rather than by an individual allele. These results also suggest that HLA-associated susceptibility to c-ALL may not be restricted to the region bounded by DPB1 and DQB1. Images Figure 2

  5. Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis

    SciTech Connect

    McMahon, Róisín M.; Friis, Lone; Siebold, Christian; Friese, Manuel A.; Fugger, Lars; Jones, E. Yvonne

    2011-05-01

    The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease.

  6. Interaction between passive smoking and two HLA genes with regard to multiple sclerosis risk

    PubMed Central

    Hedström, Anna Karin; Bomfim, Izaura Lima; Barcellos, Lisa F; Briggs, Farren; Schaefer, Catherine; Kockum, Ingrid; Olsson, Tomas; Alfredsson, Lars

    2014-01-01

    Background: The recently described interaction between smoking, human leukocyte antigen (HLA) DRB1*15 and absence of HLA-A*02 with regard to multiple sclerosis (MS) risk shows that the risk conveyed by smoking differs depending on genetic background. We aimed to investigate whether a similar interaction exists between passive smoking and HLA genotype. Methods: We used one case-control study with incident cases of MS (736 cases, 1195 controls) and one with prevalent cases (575 cases, 373 controls). Never-smokers with different genotypes and passive smoking status were compared with regard to occurrence of MS, by calculating odds ratios (ORs) with 95% confidence intervals (CIs). The potential interaction between different genotypes and passive smoking was evaluated by calculating the attributable proportion (AP) due to interaction. Results: An interaction was observed between passive smoking and carriage of HLA-DRB1*15 (AP 0.3, 95% CI 0.02–0.5 in the incident study, and AP 0.4, 95% CI 0.1–0.7 in the prevalent study), as well as between passive smoking and absence of HLA-A*02. Compared with non-smokers without any of these two genetic risk factors, non-exposed subjects with the two risk genotypes displayed an OR of 4.5 (95% CI 3.3–6.1) whereas the same genotype for subjects exposed to passive smoking rendered an OR of 7.7 (95% CI 5.5–10.8). Conclusions: The risk of developing MS associated with different HLA genotypes may be influenced by exposure to passive smoking. The finding supports our hypothesis that priming of the immune response in the lungs may subsequently lead to MS in people with a genetic susceptibility to the disease. PMID:25324153

  7. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis

    PubMed Central

    Lima Bomfim, Izaura; Barcellos, Lisa; Gianfrancesco, Milena; Schaefer, Catherine; Kockum, Ingrid; Olsson, Tomas; Alfredsson, Lars

    2014-01-01

    Objective: We investigated potential interactions between human leukocyte antigen (HLA) genotype and body mass index (BMI) status in relation to the risk of developing multiple sclerosis (MS). Methods: We used 2 case-control studies, one with incident cases (1,510 cases, 2,017 controls) and one with prevalent cases (937 cases, 609 controls). Subjects with different genotypes and BMI were compared with regard to incidence of MS by calculating odds ratios (ORs) with 95% confidence intervals (CIs) employing logistic regression. Potential interactions between genotypes and BMI were evaluated by calculating the attributable proportion due to interaction. Results: In both cohorts, a significant interaction was observed between HLA-DRB1*15 and obesity, regardless of HLA-A*02 status. Similarly, there was a significant interaction between absence of A*02 and obesity, regardless of DRB1*15 status. In the incident cohort, obese subjects with the most susceptible genotype (carriage of DRB1*15 and absence of A*02) had an OR of 16.2 (95% CI 7.5–35.2) compared to nonobese subjects without the genetic risk factors. The corresponding OR in the prevalent study was 13.8 (95% CI 4.1–46.8). Conclusions: We observed striking interactions between BMI status and HLA genotype with regard to MS risk. Hypothetically, a low-grade inflammatory response inherent to obesity synergizes with the adaptive, HLA molecule–restricted arm of the immune system, causing MS. Prevention of adolescent obesity may thus lower the risk of developing MS, predominantly among people with a genetic susceptibility to the disease. PMID:24500647

  8. HLA-DR-dependent variation of intrathecal IgG1 (Gm) allotype synthesis in multiple sclerosis.

    PubMed

    Salier, J P; Martin-Mondiere, C; Sesboüé, R; Daveau, M; Goust, J M; Govaerts, A; Schuller, E; Degos, J D

    1985-03-01

    Genetic susceptibility to multiple sclerosis (MS) in Caucasians was previously shown to be correlated to the presence of given alleles at the HLA-DR and Gm loci. We now demonstrate that the humoral immune response in MS central nervous system (CNS) is modulated by both loci: the levels of IgG1 subclass and IgG1 allotypes in cerebrospinal fluid of MS patients depend on both their Gm genotype and their HLA-DR2 or HLA-DR7 phenotype. That HLA-DR molecules may either participate in a preferential recruitment of IgG1 allotype-producing B cells in MS CNS or act after such a selective homing is discussed. These results demonstrate that both HLA and Gm loci are synergistically involved in the modulation of the humoral immune response. PMID:3855432

  9. HLA-DRB1*14 is a protective allele for multiple sclerosis in an admixed Colombian population

    PubMed Central

    Cuellar-Giraldo, David; Díaz-Cruz, Camilo; Burbano, Lisseth-Estefania; Guío, Claudia-Marcela; Reyes, Saúl; Cortes, Fabián; Cárdenas-Robledo, Simón; Narváez, Diana M.; Cárdenas, Wilmer; Porras, Alexandra; Lattig, María-Claudia; Groot de Restrepo, Helena

    2015-01-01

    Objective: The aim of this study was to determine ancestry informative markers, mitochondrial DNA haplogroups, and the association between HLA-DRB1 alleles and multiple sclerosis (MS) in a group of patients from Bogotá, Colombia. Methods: In this case-control study, genomic DNA was isolated and purified from blood samples. HLA-DRB1 allele genotyping was done using PCR. Mitochondrial hypervariable region 1 was amplified and haplogroups were determined using HaploGrep software. Genomic ancestry was estimated by genotyping a panel of ancestry informative markers. To test the association of HLA polymorphisms and MS, we ran separate multivariate logistic regression models. Bonferroni correction was used to account for multiple regression tests. Results: A total of 100 patients with MS (mean age 40.4 ± 12 years; 70% females) and 200 healthy controls (mean age 37.6 ± 11 years; 83.5% females) were included in the analysis. Ancestry proportions and haplogroup frequencies did not differ between patients and controls. HLA-DRB1*15 was present in 31% of cases and 13.5% of controls, whereas HLA-DRB1*14 was present in 5% of cases and 15.5% of controls. In the multivariate model, HLA-DRB1*15 was significantly associated with MS (odds ratio [OR] = 3.05, p < 0.001), whereas HLA-DRB1*14 was confirmed as a protective factor in our population (OR = 0.16, p = 0.001). Conclusions: This study provides evidence indicating that HLA-DRB1*15 allele confers susceptibility to MS and HLA-DRB1*14 allele exerts resistance to MS in a highly admixed population. This latter finding could partially explain the low prevalence of MS in Bogotá, Colombia. PMID:26740965

  10. Multiple sclerosis risk markers in HLA-DRA, HLA-C, and IFNG genes are associated with sex-specific childhood leukemia risk.

    PubMed

    Morrison, Brittany A; Ucisik-Akkaya, Esma; Flores, Hilario; Alaez, Carmen; Gorodezky, Clara; Dorak, M Tevfik

    2010-12-01

    Previous epidemiologic studies showed four times increased risk of acute lymphoblastic leukemia (ALL) in children of women with multiple sclerosis (MS). MS shows a risk association with Human leukocyte antigens (HLA)-DRA single nucleotide polymorphism (SNP) rs3135388, which is a proxy marker for DRB1*1501. We examined the relevance of rs3135388 in childhood ALL risk along with two other HLA-DRA SNPs in two case-control groups: 114 cases and 388 controls from South Wales (UK) and 100 Mexican Mestizo cases and 253 controls. We first confirmed the correlation between rs3135388 and DRB1*1501 in HLA-typed reference cell lines. We noted a female-specific risk association in childhood ALL (pooled odds ratio (OR) = 2.6, 95% confidence interval (CI) = 1.5-4.5, Mantel-Haenszel P = 0.0009) similar to the stronger association of DRB1*1501 in females with MS. Examination of an HLA-C 5' flanking region SNP rs9264942, known to correlate with HLA-C expression, showed a protective association in girls (OR = 0.4, 95% CI = 0.2-0.7, Mantel-Haenszel P = 0.0003) similar to the protective HLA-Cw*05 association in MS. In a reference cell line panel, HLA-Cw5 homozygous samples (n = 8) were also homozygous for the minor allele of the SNP. Likewise, the male-specific protective association of interferon-gamma (IFNG) SNP rs2069727 in MS was replicated with the same sex specificity in childhood ALL (OR = 0.6, 95% CI = 0.4-1.0, Mantel-Haenszel P = 0.03). Two other SNPs in superkiller viralicidic activity 2-like and tenascin XB that are markers for systemic lupus erythematosus susceptibility showed female-specific associations but due to linkage disequilibrium with HLA-DRB1*15. Our observations supported the epidemiologic link between MS and childhood ALL and added the sex effect to this connection. It appears that only girls born to mothers with MS may have an increased risk of ALL. Investigating the mechanism of these sex-specific associations may help understand the pathogenesis of MS and ALL.

  11. Prevalence of HLA-B27 in Moroccan healthy subjects and patients with ankylosing spondylitis and mapping construction of several factors influencing AS diagnosis by using multiple correspondence analysis.

    PubMed

    Akassou, Amal; Yacoubi, Hanae; Jamil, Afaf; Dakka, Nadia; Amzazi, Saaïd; Sadki, Khalid; Niamane, Redouane; Elhassani, Selma; Bakri, Youssef

    2015-11-01

    The aim of the present study was to determine the prevalence of human leukocyte antigen HLA-B27 in Moroccan healthy controls and in patients with ankylosing spondylitis (AS), and to analyze the correlation between HLA-B27 and AS in Moroccan patients. The prevalence of HLA-B27 was determined by evaluating the number of HLA-B27-positive samples in 128 healthy subjects and in 53 patients diagnosed with AS according to the ESSG and AMOR criteria. HLA-B27 was determined by the polymerase chain reaction using sequence-specific primers. Multivariate analysis of our data (HLA-B27, age, sex, and family history) for AS and healthy controls was performed by multiple correspondence analysis (MCA). The frequency of HLA-B27 was significantly greater in AS patients (45.3 %) than in healthy controls (4.7 %) [p < 0.0001, OR 16.8, and CI 95 % (5.83-51.03)]. In addition, HLA-B27 was more common in male patients than in female ones (p < 0.05). 100 % of the AS patients reported a family history of AS, whereas only 20 % of the healthy controls reported a family history of AS. The graphical interpretation of MCA showed a significant relation between the presence of HLA-B27 and AS. This study strengthens the link between HLA-B27 and AS and represents a very valuable informative diagnostic tool, especially in regard to male patients who have a family history of AS.

  12. Month of birth, HLA-DRB1*15 locus and risk of multiple sclerosis in offspring.

    PubMed

    Guijarro-Castro, C; Sanchez-Zapardiel, E; Munoz, D; Fernandez, O; Leyva, L; Castro-Panete, M J; Picon-Munoz, C; Talise, M; Martinez-Feito, A; Paz-Artal, E

    2016-09-01

    Introduccion. El haplotipo HLA-DRB1*1501 es el marcador genetico que se ha asociado con un riesgo tres veces mayor de padecer esclerosis multiple (EM) en caucasicos occidentales. Recientemente se ha sabido que hay una asociacion entre el mes de nacimiento en abril, el genotipo HLA-DRB1 y el riesgo de EM en paises del norte de Europa y Canada. Esto apoya la teoria de que debe haber una interaccion entre un factor de riesgo estacional con un locus cercano al HLA-DRB1*15 durante la gestacion o cerca del posparto. Sujetos y metodos. Se realizo el genotipado de la presencia y subtipo de HLA-DRB1*1501 en 326 pacientes de dos centros espa˜oles y en 226 controles sin patologia neurologica. Se compararon los meses de nacimiento de la muestra de pacientes con los nacimientos mensuales locales en los mismos periodos. Resultados. Comparados los pacientes con EM que eran portadores del alelo HLA-DRB1*15 (10,3%) frente a los pacientes no portadores (3,8%), significativamente mas pacientes nacian en diciembre (p = 0,0185). Tambien se confirmaba el mismo mes de nacimiento de diciembre entre sanos portadores frente a no portadores de HLA-DRB1*15 y entre pacientes portadores de HLA-DRB1*15 frente a sanos. Conclusiones. El mes de nacimiento, el genotipo HLA-DRB1*15 y el riesgo de presentar EM estan asociados. A diferencia de los resultados obtenidos en paises del norte de Europa, donde esta asociacion se ha encontrado en el mes de abril, en Espa˜a es en diciembre. Se demuestra la interaccion de un factor de riesgo estacional en invierno en el locus HLA-DRB1*15 o cercano a este durante la gestacion o tras el nacimiento.

  13. Identification of multiple independent susceptibility loci in the HLA region in Behçet's disease.

    PubMed

    Hughes, Travis; Coit, Patrick; Adler, Adam; Yilmaz, Vuslat; Aksu, Kenan; Düzgün, Nursen; Keser, Gokhan; Cefle, Ayse; Yazici, Ayten; Ergen, Andac; Alpsoy, Erkan; Salvarani, Carlo; Casali, Bruno; Kötter, Ina; Gutierrez-Achury, Javier; Wijmenga, Cisca; Direskeneli, Haner; Saruhan-Direskeneli, Güher; Sawalha, Amr H

    2013-03-01

    Behçet's disease is an inflammatory disease characterized by recurrent oral and genital ulcers and significant organ involvement. Localizing the genetic association between HLA-B*51 and Behçet's disease and exploring additional susceptibility loci in the human leukocyte antigen (HLA) region are complicated by the strong linkage disequilibrium in this region. We genotyped 8,572 variants in the extended HLA locus and carried out imputation and meta-analysis of 24,834 variants in 2 independent Behçet's disease cohorts from 2 ancestry groups. Genotyped SNPs were used to infer classical HLA alleles in the HLA-A, HLA-B, HLA-C, HLA-DQA1, HLA-DQB1 and HLA-DRB1 loci. Our data suggest that the robust HLA-B*51 association in Behçet's disease is explained by a variant located between the HLA-B and MICA genes (rs116799036: odds ratio (OR) = 3.88, P = 9.42 × 10(-50)). Three additional independent genetic associations within PSORS1C1 (rs12525170: OR = 3.01, P = 3.01 × 10(-26)), upstream of HLA-F-AS1 (rs114854070: OR = 1.95, P = 7.84 × 10(-14)) and with HLA-Cw*1602 (OR = 5.38, P = 6.07 × 10(-18)) were also identified and replicated.

  14. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses

    PubMed Central

    Hammer, Christian; Begemann, Martin; McLaren, Paul J.; Bartha, István; Michel, Angelika; Klose, Beate; Schmitt, Corinna; Waterboer, Tim; Pawlita, Michael; Schulz, Thomas F.; Ehrenreich, Hannelore; Fellay, Jacques

    2015-01-01

    The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans. PMID:26456283

  15. Contribution of HLA-A/B/C/DRB1/DQB1 common haplotypes to donor search outcome in unrelated hematopoietic stem cell transplantation.

    PubMed

    Pédron, Béatrice; Guérin-El Khourouj, Valérie; Dalle, Jean-Hugues; Ouachée-Chardin, Marie; Yakouben, Karima; Corroyez, France; Auvrignon, Anne; Petit, Arnaud; Landman-Parker, Judith; Leverger, Guy; Baruchel, André; Sterkers, Ghislaine

    2011-11-01

    In unrelated hematopoietic stem cell transplantation (HSCT), the prediction of donor search outcome at the time of search initiation is of great value for the physicians to delineate the strategy of patient care. The probability of finding an unrelated donor is high for patients who carry at least 1 of the 10 most common HLA haplotypes in Caucasians. As only 10% to 20% patients respond to this criterion, here we aimed at finding additional common haplotypes to improve the prediction of a successful search. HLA broad HLA-A/B/DRB1 haplotypes that were observed with frequencies ≥0.19% in patient families of European origin and that split into ≤2 predominant 4-digit HLA-A/B/C/DRB1/DQB1 haplotypes were considered as common. Carriage of at least 1 of those in 168 patients of various geographic areas with no family donor was confronted to the chance of finding ≥9/10 HLA-matched unrelated donors. Fifty common 4-digit haplotypes were identified. A higher (P < 5 × 10(-6)) chance of finding a suitable donor was found for 55 of 170 (32%) recipients that carried at least 1 of these common haplotypes. Up to now, estimates classified patients into ≥3 groups of probability with ≥1 intermediate group of poor utility for the clinicians. Considering carriage of these common haplotypes together with the frequencies of alleles and of B/C and DRB1/DQB1 associations, which are carried by patient HLA haplotypes, we could classify the patients into 2 groups of probability with a 98% and 26% chance of finding a donor, respectively. Prediction of search outcome could be improved by including the 50 most common HLA haplotypes in the current approaches.

  16. Cell surface expression level variation between two common Human Leukocyte Antigen alleles, HLA-A2 and HLA-B8, is dependent on the structure of the C terminal part of the alpha 2 and the alpha 3 domains.

    PubMed

    Dellgren, Christoffer; Nehlin, Jan O; Barington, Torben

    2015-01-01

    Constitutive cell surface expression of Human Leukocyte Antigen (HLA) class I antigens vary extremely from tissue to tissue and individual antigens may differ widely in expression levels. Down-regulation of class I expression is a known immune evasive mechanism used by cancer cells and viruses. Moreover, recent observations suggest that even minor differences in expression levels may influence the course of viral infections and the frequency of complications to stem cell transplantation. We have shown that some human multipotent stem cells have high expression of HLA-A while HLA-B is only weakly expressed, and demonstrate here that this is also the case for the human embryonic kidney cell line HEK293T. Using quantitative flow cytometry and quantitative polymerase chain reaction we found expression levels of endogenous HLA-A3 (median 71,204 molecules per cell) 9.2-fold higher than the expression of-B7 (P = 0.002). Transfection experiments with full-length HLA-A2 and -B8 encoding plasmids confirmed this (54,031 molecules per cell vs. 2,466, respectively, P = 0.001) independently of transcript levels suggesting a post-transcriptional regulation. Using chimeric constructs we found that the cytoplasmic tail and the transmembrane region had no impact on the differential cell surface expression. In contrast, ~65% of the difference could be mapped to the six C-terminal amino acids of the alpha 2 domain and the alpha 3 domain (amino acids 176-284), i.e. amino acids not previously shown to be of importance for differential expression levels of HLA class I molecules. We suggest that the differential cell surface expression of two common HLA-A and-B alleles is regulated by a post-translational mechanism that may involve hitherto unrecognized molecules. PMID:26258424

  17. Adaptive interactions between HLA and HIV-1: Highly divergent selection imposed by HLA class I molecules with common supertype motifs1

    PubMed Central

    John, Mina; Heckerman, David; James, Ian; Park, Lawrence P.; Carlson, Jonathan M.; Chopra, Abha; Gaudieri, Silvana; Nolan, David; Haas, David W.; Riddler, Sharon A.; Haubrich, Richard; Mallal, Simon

    2010-01-01

    Currently 1.1 million individuals in the United States of America are living with HIV-1 infection. While this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the U.S.A, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic diversity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes which are determined by the human leukocyte antigen (HLA) class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically diverse, national U.S cohort of HIV-1 infected individuals. We found a striking divergence in the immunoselection patterns associated with HLA variants which have very similar or identical peptide binding specificities but are differentially distributed among racial/ethnic groups. Though their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide binding groove contributes to ‘race-specific’ selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the T cell receptor (TCR) varies significantly within HLA supertype groups, which in turn, influences HIV-1 evolution. PMID:20231689

  18. Complex relation of HLA-DRB1*1501, age at menarche, and age at multiple sclerosis onset

    PubMed Central

    Chua, Alicia S.; Xia, Zongqi; Chibnik, Lori; De Jager, Philip L.; Chitnis, Tanuja

    2016-01-01

    Objective: To examine the relationship between 2 markers of early multiple sclerosis (MS) onset, 1 genetic (HLA-DRB1*1501) and 1 experiential (early menarche), in 2 cohorts. Methods: We included 540 white women with MS or clinically isolated syndrome (N = 156 with genetic data available) and 1,390 white women without MS but with a first-degree relative with MS (Genes and Environment in Multiple Sclerosis [GEMS]). Age at menarche, HLA-DRB1*1501 status, and age at MS onset were analyzed. Results: In both cohorts, participants with at least 1 HLA-DRB1*1501 allele had a later age at menarche than did participants with no risk alleles (MS: mean difference = 0.49, 95% confidence interval [CI] = [0.03–0.95], p = 0.036; GEMS: mean difference = 0.159, 95% CI = [0.012–0.305], p = 0.034). This association remained after we adjusted for body mass index at age 18 (available in GEMS) and for other MS risk alleles, as well as a single nucleotide polymorphism near the HLA-A region previously associated with age of menarche (available in MS cohort). Confirming previously reported associations, in our MS cohort, every year decrease in age at menarche was associated with a 0.65-year earlier MS onset (95% CI = [0.07–1.22], p = 0.027, N = 540). Earlier MS onset was also found in individuals with at least 1 HLA-DRB1*1501 risk allele (mean difference = −3.40 years, 95% CI = [−6.42 to −0.37], p = 0.028, N = 156). Conclusions: In 2 cohorts, a genetic marker for earlier MS onset (HLA-DRB1*1501) was inversely related to earlier menarche, an experiential marker for earlier symptom onset. This finding warrants broader investigations into the association between the HLA region and hormonal regulation in determining the onset of autoimmune disease. PMID:27504495

  19. HLA class II genotypes in Mexican Mestizos with familial and nonfamilial multiple sclerosis.

    PubMed

    Alvarado-de la Barrera, C; Zúñiga-Ramos, J; Ruíz-Morales, J A; Estañol, B; Granados, J; Llorente, L

    2000-12-26

    Predisposition to MS is associated with the HLA-DR2 antigen in white patients. The authors investigated the genetic factors behind the increasing frequency of MS in the Mexican population. HLA-DR and DQ were analyzed in 17 patients with MS, 15 of their first-degree relatives, and 99 healthy ethnically matched controls. DR2 or DR3 was found in 15 of 17 patients. In controls, both alleles had frequencies less than 0.05. MS in Mexican patients was associated with HLA-DR2 and DR3.

  20. Interaction between HLA-DRB1-DQB1 haplotypes in Sardinian multiple sclerosis population.

    PubMed

    Cocco, Eleonora; Murru, Raffaele; Costa, Gianna; Kumar, Amit; Pieroni, Enrico; Melis, Cristina; Barberini, Luigi; Sardu, Claudia; Lorefice, Lorena; Fenu, Giuseppe; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Marrosu, Maria Giovanna

    2013-01-01

    We performed a case-control study in 2,555 multiple sclerosis (MS) Sardinian patients and 1,365 healthy ethnically matched controls, analyzing the interactions between HLA-DRB1-DQB1 haplotypes and defining a rank of genotypes conferring a variable degree of risk to the disease. Four haplotypes were found to confer susceptibility (*13:03-*03:01 OR = 3.3, Pc 5.1 × 10(-5), *04:05-*03:01 OR = 2.1, Pc 9.7 × 10(-8), *15:01-*06:02 OR = 2.0, Pc = 9.1 × 10(-3), *03:01-*02:01 OR = 1.7 Pc = 7.9 × 10(-22)) and protection (*11, OR = 0.8, Pc = 2.7 × 10(-2), *16:01-*05:02 OR = 0.6, Pc = 4.8 × 10(-16), *14:01-4-*05:031 = OR = 0.5, Pc = 9.8 × 10(-4) and *15:02-*06:01 OR = 0.4, Pc = 5.1 × 10(-4)). The relative predispositional effect method confirms all the positively associated haplotypes and showed that also *08 and *04 haplotypes confers susceptibility, while the *11 was excluded as protective haplotype. Genotypic ORs highlighted two typologies of interaction between haplotypes: i) a neutral interaction, in which the global risk is coherent with the sum of the single haplotype risks; ii) a negative interaction, in which the genotypic OR observed is lower than the sum of the OR of the two haplotypes. The phylogenic tree of the MS-associated DRB1 alleles found in Sardinian patients revealed a cluster represented by *14:01, *04:05, *13∶03, *08:01 and *03:01 alleles. Sequence alignment analysis showed that amino acids near pocket P4 and pocket P9 differentiated protective from predisposing alleles under investigation. Furthermore, molecular dynamics simulation performed on alleles revealed that position 70 is crucial in binding of MBP 85-99 peptide. All together, these data suggest that propensity to MS observed in Sardinian population carried by the various HLA-DRB1-DQB1 molecules can be due to functional peculiarity in the antigen presentation mechanisms.

  1. Presence of CSF oligoclonal bands (OCB) is associated with the HLA-DRB1 genotype in a West Australian multiple sclerosis cohort.

    PubMed

    Wu, Jing-Shan; Qiu, Wei; Castley, Alison; James, Ian; Joseph, Joyce; Christiansen, Frank T; Carroll, William M; Mastaglia, Frank L; Kermode, Allan G

    2010-01-15

    High-resolution HLA-DRB1 genotyping was performed in 97 OCB-positive and 68 OCB-negative cases with demyelinating disease to determine the influence of HLA-DRB1 alleles on the presence of OCB in a West Australian multiple sclerosis (MS) cohort. Carriage of the HLA-DRB1*1501 allele was associated with both OCB-positive and OCB-negative MS compared with controls, but more strongly with the OCB-positive group, and increased the likelihood of having OCB 2.1-fold with evidence of a dominant dose-effect. The HLA-DRB1*0301 allele was negatively correlated with OCB, with all homozygotes OCB-negative, suggesting a possible recessive protective effect of HLA-DRB1*0301. There was no significant correlation between OCB and the DRB1*04 alleles which have been associated with OCB-negative MS in previous Swedish and Japanese studies. Evidence of allelic interactions was found with HLA-DRB1*1501/*1301 heterozygotes having a reduced frequency of OCB and HLA-DRB1*0301/*0401 heterozygotes all being OCB-negative. These findings confirm the strong association between HLA-DRB1*1501 and OCB which has been found in other populations but indicate that the influence of other HLA-DRB1 alleles varies in different populations. Our study is the first to show that HLA-DRB1 allele interactions and dose-effects influence the frequency of OCB. PMID:19879597

  2. Common coding variants in the HLA-DQB1 region confer susceptibility to age-related macular degeneration.

    PubMed

    Jorgenson, Eric; Melles, Ronald B; Hoffmann, Thomas J; Jia, Xiaoming; Sakoda, Lori C; Kvale, Mark N; Banda, Yambazi; Schaefer, Catherine; Risch, Neil; Shen, Ling

    2016-07-01

    Age-related macular degeneration (AMD) risk variants in the complement system point to the important role of immune response and inflammation in the pathogenesis of AMD. Although the human leukocyte antigen (HLA) region has a central role in regulating immune response, previous studies of genetic variation in HLA genes and AMD have been limited by sample size or incomplete coverage of the HLA region by first-generation genotyping arrays and imputation panels. Here, we conducted a large-scale HLA fine-mapping study with 4841 AMD cases and 23 790 controls of non-Hispanic white ancestry from the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Genotyping was conducted using custom Affymetrix Axiom arrays, with dense coverage of the HLA region. Classic HLA polymorphisms were imputed using SNP2HLA, which utilizes a large reference panel to provide improved imputation accuracy of variants in this region. We examined a total of 6937 SNPs and 172 classical HLA alleles, conditioning on established AMD risk variants, which revealed novel associations with two non-synonymous SNPs in perfect linkage disequilibrium, rs9274390 and rs41563814 (odds ratio (OR)=1.21; P=1.4 × 10(-11)) corresponding to amino-acid changes at position 66 and 67 in HLA-DQB1, respectively, and the DQB1*02 classical HLA allele (OR=1.22; P=3.9 × 10(-10)) with the risk of AMD. We confirmed these association signals, again conditioning on established risk variants, in the MMAP data set of subjects with advanced AMD (rs9274390/rs41563814: OR=1.28; P=1.30 × 10(-3), DQB1*02: OR=1.32; P=9.00 × 10(-4)). These findings support a role of HLA class II alleles in the risk of AMD. PMID:26733291

  3. HLA-DRB1-DQB1 Haplotypes Confer Susceptibility and Resistance to Multiple Sclerosis in Sardinia

    PubMed Central

    Cocco, Eleonora; Sardu, Claudia; Pieroni, Enrico; Valentini, Maria; Murru, Raffaele; Costa, Gianna; Tranquilli, Stefania; Frau, Jessica; Coghe, Giancarlo; Carboni, Nicola; Floris, Matteo; Contu, Paolo; Marrosu, Maria Giovanna

    2012-01-01

    Introduction Genetic predisposition to multiple sclerosis (MS) in Sardinia (Italy) has been associated with five DRB1*-DQB1* haplotypes of the human leukocyte antigen (HLA). Given the complexity of these associations, an in-depth re-analysis was performed with the specific aims of confirming the haplotype associations; establishing the independence of the associated haplotypes; and assessing patients' genotypic risk of developing MS. Methods and Results A transmission disequilibrium test (TDT) of the DRB1*-DQB1* haplotypes in 943 trio families, confirmed a higher than expected transmission rate (over-transmission) of the *13:03-*03:01 (OR = 2.9, P = 7.6×10−3), *04:05-*03:01 (OR = 2.4, P = 4.4×10−6) and *03:01-*02:01 (OR = 2.1, P = 1.0×10−15) haplotype. In contrast, the *16:01-*05:02 (OR = 0.5, P = 5.4×10−11) and the *15:02-*06:01 (OR = 0.3, P = 1.5×10−3) haplotypes exhibited a lower than expected transmission rate (under-transmission). The independence of the transmission of each positively and negatively associated haplotype was confirmed relative to all positively associated haplotypes, and to the negatively associated *16:01-*05:02 haplotype. In patients, carriage of two predisposing haplotypes, or of protective haplotypes, respectively increased or decreased the patient's risk of developing MS. The risk of MS followed a multiplicative model of genotypes, which was, in order of decreasing ORs: *04:05-*0301/*03:01-*02:01 (OR = 4.5); *03:01-*02:01/*03:01-*02:01 (OR = 4.1); and the *16:01-*05:02/*16:01-*0502 (OR = 0.2) genotypes. Analysis of DRB1 and DQB1 protein chain residues showed that the Val/Gly residue at position 86 of the DRB1 chain was the only difference between the protective *16:01- *15:02 alleles and the predisposing *15:01 one. Similarly, the Ala/Val residue at position 38 of the DQB1 chain differentiated the positively associated *06:02 allele and the negatively associated *05

  4. Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development.

    PubMed

    Yu, Lei; Cheng, Yi-ju; Cheng, Ming-liang; Yao, Yu-mei; Zhang, Quan; Zhao, Xue-ke; Liu, Hua-juan; Hu, Ya-xin; Mu, Mao; Wang, Bi; Yang, Guo-zhen; Zhu, Li-li; Zhang, Shuai

    2015-01-01

    Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance. PMID:26462556

  5. Quantitative assessment of common genetic variations in HLA-DP with hepatitis B virus infection, clearance and hepatocellular carcinoma development

    PubMed Central

    Yu, Lei; Cheng, Yi-ju; Cheng, Ming-liang; Yao, Yu-mei; Zhang, Quan; Zhao, Xue-ke; Liu, Hua-juan; Hu, Ya-xin; Mu, Mao; Wang, Bi; Yang, Guo-zhen; Zhu, Li-li; Zhang, Shuai

    2015-01-01

    Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB), liver cirrhosis (LC) and hepatocellular carcinoma (HCC). Recently, genome-wide association studies have identified human leukocyte antigen (HLA)-DP polymorphisms (rs3077 and rs9277535) as a new chronic HBV infection susceptibility locus. Since then, the relationship between HLA-DP polymorphisms and various outcomes of HBV infection has been reported. However, the results have been inconclusive. To derive a more precise estimation of the relationship between HLA-DP polymorphisms and various outcomes of HBV infection, a meta-analysis of 62,050 subjects from 29 case-control studies was performed. We found that rs3077 and rs9277535 in HLA-DP significantly decreased HBV infection risks and increased HBV clearance possibility in a dose-dependent manner. In the subgroup analysis by ethnicity, study design and sample size, significant associations were found for these polymorphisms in almost all comparisons. Meanwhile, haplotype analyses of the two polymorphisms revealed a significant association between the combination of these alleles and HBV infection outcomes. However, no significant results were observed in HCC development. Our results further confirm that genetic variants in the HLA-DP locus are strongly associated with reduced HBV infection and increased the likelihood of spontaneous viral clearance. PMID:26462556

  6. Genotype-Phenotype Correlations in Multiple Sclerosis: "HLA" Genes Influence Disease Severity Inferred by [superscript 1]HMR Spectroscopy and MRI Measures

    ERIC Educational Resources Information Center

    Okuda, D. T.; Srinivasan, R.; Oksenberg, J. R.; Goodin, D. S.; Baranzini, S. E.; Beheshtian, A.; Waubant, E.; Zamvil, S. S.; Leppert, D.; Qualley, P.; Lincoln, R.; Gomez, R.; Caillier, S.; George, M.; Wang, J.; Nelson, S. J.; Cree, B. A. C.; Hauser, S. L.; Pelletier, D.

    2009-01-01

    Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) "DRB1*1501" allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated…

  7. Multiple Sclerosis Risk Variant HLA-DRB1*1501 Associates with High Expression of DRB1 Gene in Different Human Populations

    PubMed Central

    Abad-Grau, María del Mar; Fedetz, María; Izquierdo, Guillermo; Lucas, Miguel; Fernández, Óscar; Ndagire, Dorothy; Catalá-Rabasa, Antonio; Ruiz, Agustín; Gayán, Javier; Delgado, Concepción; Arnal, Carmen

    2012-01-01

    The human leukocyte antigen (HLA) DRB1*1501 has been consistently associated with multiple sclerosis (MS) in nearly all populations tested. This points to a specific antigen presentation as the pathogenic mechanism though this does not fully explain the disease association. The identification of expression quantitative trait loci (eQTL) for genes in the HLA locus poses the question of the role of gene expression in MS susceptibility. We analyzed the eQTLs in the HLA region with respect to MS-associated HLA-variants obtained from genome-wide association studies (GWAS). We found that the Tag of DRB1*1501, rs3135388 A allele, correlated with high expression of DRB1, DRB5 and DQB1 genes in a Caucasian population. In quantitative terms, the MS-risk AA genotype carriers of rs3135388 were associated with 15.7-, 5.2- and 8.3-fold higher expression of DQB1, DRB5 and DRB1, respectively, than the non-risk GG carriers. The haplotype analysis of expression-associated variants in a Spanish MS cohort revealed that high expression of DRB1 and DQB1 alone did not contribute to the disease. However, in Caucasian, Asian and African American populations, the DRB1*1501 allele was always highly expressed. In other immune related diseases such as type 1 diabetes, inflammatory bowel disease, ulcerative colitis, asthma and IgA deficiency, the best GWAS-associated HLA SNPs were also eQTLs for different HLA Class II genes. Our data suggest that the DR/DQ expression levels, together with specific structural properties of alleles, seem to be the causal effect in MS and in other immunopathologies rather than specific antigen presentation alone. PMID:22253788

  8. Uncommon HLA alleles identified by hemizygous ultra-high Sanger sequencing: haplotype associations and reconsideration of their assignment in the Common and Well-Documented catalogue.

    PubMed

    Voorter, Christina E M; Groeneweg, Mathijs; Groeneveld, Lisette; Tilanus, Marcel G J

    2016-02-01

    Although the number of HLA alleles still increases, many of them have been reported being uncommon. This is partly due to lack of full length gene sequencing, especially for those alleles belonging to an allele ambiguity in which the first discovered allele has been assigned as the most frequent one. As members of the working group on Common and Well Documented (CWD) alleles and since we implemented full length group-specific sequencing as standard method routinely, we have investigated the presence of presumably rare alleles in our collection of HLA typing data. We identified 50 alleles, that were not previously encountered as Common or Well Documented. Sixteen of them should be added to the CWD catalogue, since we encountered them in 5 or more unrelated individuals. Another 11 could be added, based upon our results and the data present in the IMGT database and the rare allele section of the allele frequencies database. Furthermore, tight associations were observed between several different alleles even at the level of synonymous and non-coding sequences. In addition, in several cases the uncommon allele was found to be more frequent than its common counterpart.

  9. Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis.

    PubMed

    van Luijn, Marvin M; Kreft, Karim L; Jongsma, Marlieke L; Mes, Steven W; Wierenga-Wolf, Annet F; van Meurs, Marjan; Melief, Marie-José; der Kant, Rik van; Janssen, Lennert; Janssen, Hans; Tan, Rusung; Priatel, John J; Neefjes, Jacques; Laman, Jon D; Hintzen, Rogier Q

    2015-06-01

    C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis

  10. Multiple sclerosis-associated CLEC16A controls HLA class II expression via late endosome biogenesis

    PubMed Central

    van Luijn, Marvin M.; Kreft, Karim L.; Jongsma, Marlieke L.; Mes, Steven W.; Wierenga-Wolf, Annet F.; van Meurs, Marjan; Melief, Marie-José; van der Kant, Rik; Janssen, Lennert; Janssen, Hans; Tan, Rusung; Priatel, John J.; Neefjes, Jacques; Laman, Jon D.

    2015-01-01

    C-type lectins are key players in immune regulation by driving distinct functions of antigen-presenting cells. The C-type lectin CLEC16A gene is located at 16p13, a susceptibility locus for several autoimmune diseases, including multiple sclerosis. However, the function of this gene and its potential contribution to these diseases in humans are poorly understood. In this study, we found a strong upregulation of CLEC16A expression in the white matter of multiple sclerosis patients (n = 14) compared to non-demented controls (n = 11), mainly in perivascular leukocyte infiltrates. Moreover, CLEC16A levels were significantly enhanced in peripheral blood mononuclear cells of multiple sclerosis patients (n = 69) versus healthy controls (n = 46). In peripheral blood mononuclear cells, CLEC16A was most abundant in monocyte-derived dendritic cells, in which it strongly co-localized with human leukocyte antigen class II. Treatment of these professional antigen-presenting cells with vitamin D, a key protective environmental factor in multiple sclerosis, downmodulated CLEC16A in parallel with human leukocyte antigen class II. Knockdown of CLEC16A in distinct types of model and primary antigen-presenting cells resulted in severely impaired cytoplasmic distribution and formation of human leucocyte antigen class II-positive late endosomes, as determined by immunofluorescence and electron microscopy. Mechanistically, CLEC16A participated in the molecular machinery of human leukocyte antigen class II-positive late endosome formation and trafficking to perinuclear regions, involving the dynein motor complex. By performing co-immunoprecipitations, we found that CLEC16A directly binds to two critical members of this complex, RILP and the HOPS complex. CLEC16A silencing in antigen-presenting cells disturbed RILP-mediated recruitment of human leukocyte antigen class II-positive late endosomes to perinuclear regions. Together, we identify CLEC16A as a pivotal gene in multiple sclerosis

  11. PLA2R-associated membranous glomerulopathy is modulated by common variants in PLA2R1 and HLA-DQA1 genes.

    PubMed

    Saeed, M; Beggs, M L; Walker, P D; Larsen, C P

    2014-12-01

    Membranous glomerulopathy (MG) is most commonly caused by autoantibodies directed against the podocyte phospholipase A2 receptor (PLA2R1) and common variants in this gene are associated with MG. Here for the first time, we carried out a large case-control association study (n=1512) of PLA2R-positive and -negative MG to determine the extent of association in these pathologic subtypes. We performed four separate sets of analyses to determine significance of the single-nucleotide polymorphisms (SNPs) and their haplotypes followed by joint analysis and trans-ethnic mapping to increase power. The PLA2R1 SNP rs35771982 was most strongly associated with PLA2R-positive MG (P=1.4 × 10(-14), odds ratio (ORGG)=1.98). The associations of other SNPs in PLA2R1 could be explained because of linkage disequilibrium with the G-allele. Haplotypes in PLA2R1 did not exceed the significance of rs35771982 even after 10 000 permutations. PLA2R1 variants were only associated with PLA2R-positive MG and predominantly in Caucasians. PLA2R1 variants did not associate with MG in African Americans (AA). There was strong epistasis between HLA-DQA1 SNP rs2187668 and the PLA2R1 variant rs35771982. Thus, common variants in the PLA2R1, particularly rs35771982, modulate PLA2R-positive MG with HLA-DQA1 in Caucasians. PLA2R-negative MG especially in AA, may provide a novel opportunity to discover new genes underlying MG.

  12. Congenital multiple clustered dermatofibroma and multiple eruptive dermatofibromas - unusual presentations of a common entity*

    PubMed Central

    Pinto-Almeida, Teresa; Caetano, Mónica; Alves, Rosário; Selores, Manuela

    2013-01-01

    Dermatofibroma is one of the most common entities seen in dermatology clinical practice. Several clinical subtypes have nevertheless been described, all of them of uncommon occurrence. The authors present two rare clinical variants of dermatofibromas: congenital multiple clustered dermatofibroma (the presented case is the 4th congenital case to be reported so far) and multiple eruptive dermatofibromas developing in the setting of a Sjögren's syndrome. Since the uncommon subtypes may not be clinically evident, dermatologists should familiarize themselves with their main features and we advise a high level of clinical suspicion in order to reach the correct diagnosis. PMID:24346882

  13. Associations of HLA-A, -B and -DRB1 Types with Oral Diseases in Swiss Adults

    PubMed Central

    Mauramo, Matti; Ramseier, Adrian Markus; Buser, Andreas; Tiercy, Jean-Marie; Weiger, Roland; Waltimo, Tuomas

    2014-01-01

    Human leukocyte antigens (HLA) are crucial components of host defense against microbial challenge but the associations of HLA types with oral infectious diseases have not been studied in detail. This prospective cross-sectional study examined associations of HLA-A, -B and -DRB1 types with common oral diseases in a healthy Swiss adult population. 257 subjects (107 m, 150 f, mean age: 43.5 yr; range: 21–58 yr) with known HLA-A, -B and -DRB1 profiles and comprehensive medical records were included. A thorough anamnesis was followed by oral examinations including saliva flow measurements, the DMFT score for cariological status, complete periodontal status with plaque and bleeding indexes as well as assessment of mucosal alterations and temporomandibular dysfunction (TMD). Student’s t-test and Pearson chi-square test were utilized to compare the oral diseases between HLA positive and negative subjects. Bonferroni correction for multiple comparisons was used and PBonf<0.05 was considered statistically significant. HLA types -B15 (PBonf = 0.002), -B51 (PBonf = 0.02) and -DRB1*12 (PBonf = 0.02) were associated with less periodontal disease manifestations. HLA-A32 had a positive association with TMD dysfunction (PBonf = 0.012). No other statistically significant associations were observed. In conclusion, HLA types may contribute to the development of oral diseases in generally healthy Caucasian adults. PMID:25072155

  14. Combined effects of smoking, anti-EBNA antibodies, and HLA-DRB1*1501 on multiple sclerosis risk(e–Pub ahead of print)

    PubMed Central

    Simon, K.C.; van der Mei, I.A.F.; Munger, K.L.; Ponsonby, A.; Dickinson, J.; Dwyer, T.; Sundström, P.; Ascherio, A.

    2010-01-01

    Objective: To examine the interplay between smoking, serum antibody titers to the Epstein-Barr virus nuclear antigens (anti-EBNA), and HLA-DR15 on multiple sclerosis (MS) risk. Methods: Individual and pooled analyses were conducted among 442 cases and 865 controls from 3 MS case-control studies—a nested case-control study in the Nurses' Health Study/Nurses' Health Study II, the Tasmanian MS Study, and a Swedish MS Study. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% CIs for the association between smoking, anti-EBNA titers, HLA-DR15, and MS risk. Study estimates were pooled using inverse variance weights to determine a combined effect and p value. Results: Among MS cases, anti-EBNA titers were significantly higher in ever smokers compared to never smokers. The increased risk of MS associated with high anti-EBNA Ab titers was stronger among ever smokers (OR = 3.9, 95% CI = 2.7–5.7) compared to never smokers (OR = 1.8, 95% CI = 1.4–2.3; p for interaction = 0.001). The increased risk of MS associated with a history of smoking was no longer evident after adjustment for anti-EBNA Ab titers. No modification or confounding by HLA-DR15 was observed. The increased risk of MS associated with ever smoking was only observed among those who had high anti-EBNA titers (OR = 1.7, 95% CI = 1.1–2.6). Conclusions: Smoking appears to enhance the association between high anti-EBNA titer and increased multiple sclerosis (MS) risk. The association between HLA-DR15 and MS risk is independent of smoking. Further work is necessary to elucidate possible biologic mechanisms to explain this finding. GLOSSARY anti-EBNA = antibody titers to the Epstein-Barr virus nuclear antigens; EBV = Epstein-Barr virus; MS = multiple sclerosis; NHS = Nurses' Health Study; NHSII = Nurses' Health Study II; NSHDS = Northern Sweden Health and Disease Study Cohort; OR = odds ratio. PMID:20375311

  15. Frequencies of allele groups HLA-A, HLA-B and HLA-DRB1 in a population from the northwestern region of São Paulo State, Brazil.

    PubMed

    Ayo, C M; da Silveira Camargo, A V; Xavier, D H; Batista, M F; Carneiro, O A; Brandão de Mattos, C C; Ricci, O; de Mattos, L C

    2015-02-01

    The aim of this study was to estimate the HLA-A, HLA-B and HLA-DRB1 allele groups frequencies in a population of 1559 volunteer bone marrow donors from the northwestern region of São Paulo State grouped according to ethnicity. An additional objective was to compare the allele frequencies of the current study with data published for other Brazilian populations. The allele groups were characterized by the PCR-rSSO method using Luminex(®) technology. Twenty HLA-A, 32 HLA-B and 13 HLA-DRB1 allele groups were identified. The most common allele groups in European descent and mixed African and European descent samples were HLA-A*02, HLA-B*35 and HLA-DRB1*13, while HLA-A*02, HLA-B*35 and HLA-DRB1*11 were more common in African descent samples. The HLA-A*23, HLA-A*36, HLA-B*58 and HLA-B*81 allele groups were more common in sample from African descent than European descent, and the HLA-DRB1*08 was more common in mixed African and European descent than in European descent. Allele group frequencies were compared with samples from other Brazilian regions. The HLA-A*30 and HLA-A*23 were more common in this study than in the populations of Rio Grande do Sul and Paraná; and the HLA-A*01, HLA-B*18, HLA-B*57 and HLA-DRB1*11 were more common in this study than in the population of Piauí. The least frequent allele groups were HLA-A*31, HLA-B*15, HLA-B*40 and HLA-DRB1*08 for the population of Piauí, HLA-A*01 and HLA-A*11 for Parana, HLA-A*02 and -A*03 for Rio Grande do Sul and HLA-DRB1*04 for Paraná, Rio Grande do Sul and Piauí. These data provide an overview on the knowledge on HLA diversity in the population of the northwestern region of São Paulo State and show that the genes of this system are useful to distinguish different ethnic groups.

  16. The HLA-A2-supermotif: a QSAR definition.

    PubMed

    Doytchinova, Irini; Flower, Darren

    2003-08-01

    Identification of epitopes capable of binding multiple HLA types will significantly rationalise the development of epitope-based vaccines. A quantitative method assessing the contribution of each amino acid at each position was applied to over 500 nonamer peptides binding to 5 MHC alleles--A*0201, A*0202, A*0203, A*0206 and A*6802--which together define the HLA-A2-like supertype. FXIGXI (L)IFV was identified as a supermotif for the A2-supertype based on the contributions of the common preferred amino acids at each of the nine positions. The results indicate that HLA-A*6802 is an intermediate allele standing between A2 and A3 supertypes: at anchor position 2 it is closer to A3 and at anchor position 9 it is nearer to A2. Models are available free on-line at http://www.jenner.ac.uk/MHCPred and can be used for binding affinity prediction. PMID:12948188

  17. Myelin autoreactivity in multiple sclerosis: recognition of myelin basic protein in the context of HLA-DR2 products by T lymphocytes of multiple-sclerosis patients and healthy donors.

    PubMed Central

    Pette, M; Fujita, K; Wilkinson, D; Altmann, D M; Trowsdale, J; Giegerich, G; Hinkkanen, A; Epplen, J T; Kappos, L; Wekerle, H

    1990-01-01

    A panel of 20 human myelin basic protein (hMBP)-specific T-lymphocyte lines was generated from the peripheral blood of eight multiple sclerosis (MS) patients and two healthy donors, most of them expressing the HLA-DR2 haplotype, which is associated with an increased susceptibility to MS. Using HLA-DR gene-transfected mouse L-cell lines as antigen-presenting cells, we established that of the 20 hMBP-specific T-lymphocyte lines, 7 were restricted by the DR2a gene products of the DR2Dw2 haplotype. Four T-cell lines recognized hMBP in the context of the DR2b products of the DR2Dw2 haplotype. DR2b-restricted T-cell responses were demonstrable only in T-cell lines derived from MS patients. The hMBP epitopes presented by the DR2a heterodimer were mapped to peptides covering amino acid residues 1-44, 76-91, 131-145, or 139-153 and to a region spanning the thrombin-cleaved bond at Arg130-Ala131. DR2b-restricted T-cell lines recognized epitopes within amino acids 80-99 and 148-162. Peptide 139-153 was also presented in the context of HLA-DR1 molecules. Our data show that (i) in MS patients both the DR2a and DR2b products of the DR2Dw2 haplotype function as restriction elements for the myelin autoantigen hMBP, (ii) the DR2a molecule presents at least five different epitopes to hMBP-specific T lymphocytes, and (iii) anti-hMBP T-cell lines derived from individual donors can differ in their antigen fine specificity as well as in their HLA restriction. Images PMID:1700423

  18. Common Language Effect Size for Multiple Treatment Comparisons

    ERIC Educational Resources Information Center

    Liu, Xiaofeng Steven

    2015-01-01

    Researchers who need to explain treatment effects to laypeople can translate Cohen's effect size (standardized mean difference) to a common language effect size--a probability of a random observation from one population being larger than a random observation from the other population. This common language effect size can be extended to represent…

  19. Common Genetic Variant Association with Altered HLA Expression, Synergy with Pyrethroid Exposure, and Risk for Parkinson’s Disease: An Observational and Case–Control Study

    PubMed Central

    Kannarkat, G. T.; Cook, D. A.; Lee, J-K.; Chang, J.; Chung, J.; Sandy, E.; Paul, K. C.; Ritz, B.; Bronstein, J.; Factor, S. A.; Boss, J. M.; Tansey, M. G.

    2016-01-01

    Background/Objectives The common non-coding single nucleotide polymorphism (SNP) rs3129882 in HLA-DRA is associated with risk for idiopathic Parkinson’s disease (PD). The location of the SNP in the major histocompatibility complex class II (MHC-II) locus implicates regulation of antigen presentation as a potential mechanism by which immune responses link genetic susceptibility to environmental factors in conferring lifetime risk for PD. Methods For immunophenotyping, blood cells from 81 subjects were analyzed by qRT-PCR and flow cytometry. A case-control study was performed on a separate cohort of 962 subjects to determine association of pesticide exposure and the SNP with risk of PD. Results Homozygosity for G at this SNP was associated with heightened baseline expression and inducibility of MHC class II molecules in B cells and monocytes from peripheral blood of healthy controls and PD patients. In addition, exposure to a commonly used class of insecticide, pyrethroids, synergized with the risk conferred by this SNP (OR = 2.48, p = 0.007), thereby identifying a novel gene-environment interaction that promotes risk for PD via alterations in immune responses. Conclusions In sum, these novel findings suggest that the MHC-II locus may increase susceptibility to PD through presentation of pathogenic, immunodominant antigens and/or a shift toward a more pro-inflammatory CD4+ T cell response in response to specific environmental exposures, such as pyrethroid exposure through genetic or epigenetic mechanisms that modulate MHC-II gene expression. PMID:27148593

  20. MICA, MICB Polymorphisms and Linkage Disequilibrium with HLA-B in a Chinese Mongolian Population.

    PubMed

    Wang, W Y; Tian, W; Zhu, F M; Liu, X X; Li, L X; Wang, F

    2016-06-01

    In this study, polymorphisms of major histocompatibility complex class I chain-related genes A and B (MICA and MICB) and human leucocyte antigen (HLA)-B gene were investigated for 158 unrelated Chinese Mongolian subjects recruited from central Inner Mongolia Autonomous Region, northern China, by polymerase chain reaction-sequence-based typing (PCR-SBT) and cloning. Collectively, 79 alleles, including 20 MICA, 12 MICB and 47 HLA-B alleles, were identified. MICA*008:01 (21.2%), MICB*005:02 (48.1%) and HLA-B*51:01 (7.91%) were the most common alleles. Significant global linkage disequilibrium (LD) was detected between HLA-B and MICA, HLA-B and MICB, and MICA and MICB loci (all P < 0.000001). The most frequent haplotypes were HLA-B*51:01-MICA*009:01 (7.28%), HLA-B*58:01-MICB*008 (6.96%), MICA*010-MICB*005:02 (13.92%) and HLA-B*58:01-MICA*002:01-MICB*008 (6.96%). HLA-B-MICA haplotypes such as HLA-B*50:01-MICA*009:02 were associated with single MICB allele. Some HLA-B-MICA haplotypes were associated with multiple MICB alleles, including HLA-B*51:01-MICA*009:01. One novel MICB allele, MICB*031, was identified, which has possibly arisen from MICB*002:01 through single mutation event. We also confirmed the existence of a recently recognized MICA allele, MICA*073, whose ethnic origin has not been previously described. Genotype distributions at MICA, MICB and HLA-B were consistent with a neutrality model. Our results provide new insight into MIC genetic polymorphisms in Chinese ethnic groups. Findings shown here are important from an anthropologic perspective and will inform future studies of the potential role of MIC genes in allogeneic organ transplantation and HLA-linked disease association in populations of related ancestry.

  1. MICA, MICB Polymorphisms and Linkage Disequilibrium with HLA-B in a Chinese Mongolian Population.

    PubMed

    Wang, W Y; Tian, W; Zhu, F M; Liu, X X; Li, L X; Wang, F

    2016-06-01

    In this study, polymorphisms of major histocompatibility complex class I chain-related genes A and B (MICA and MICB) and human leucocyte antigen (HLA)-B gene were investigated for 158 unrelated Chinese Mongolian subjects recruited from central Inner Mongolia Autonomous Region, northern China, by polymerase chain reaction-sequence-based typing (PCR-SBT) and cloning. Collectively, 79 alleles, including 20 MICA, 12 MICB and 47 HLA-B alleles, were identified. MICA*008:01 (21.2%), MICB*005:02 (48.1%) and HLA-B*51:01 (7.91%) were the most common alleles. Significant global linkage disequilibrium (LD) was detected between HLA-B and MICA, HLA-B and MICB, and MICA and MICB loci (all P < 0.000001). The most frequent haplotypes were HLA-B*51:01-MICA*009:01 (7.28%), HLA-B*58:01-MICB*008 (6.96%), MICA*010-MICB*005:02 (13.92%) and HLA-B*58:01-MICA*002:01-MICB*008 (6.96%). HLA-B-MICA haplotypes such as HLA-B*50:01-MICA*009:02 were associated with single MICB allele. Some HLA-B-MICA haplotypes were associated with multiple MICB alleles, including HLA-B*51:01-MICA*009:01. One novel MICB allele, MICB*031, was identified, which has possibly arisen from MICB*002:01 through single mutation event. We also confirmed the existence of a recently recognized MICA allele, MICA*073, whose ethnic origin has not been previously described. Genotype distributions at MICA, MICB and HLA-B were consistent with a neutrality model. Our results provide new insight into MIC genetic polymorphisms in Chinese ethnic groups. Findings shown here are important from an anthropologic perspective and will inform future studies of the potential role of MIC genes in allogeneic organ transplantation and HLA-linked disease association in populations of related ancestry. PMID:27028549

  2. HLA-A, -B and -DR allele and haplotype frequencies in Malays.

    PubMed

    Dhaliwal, J S; Shahnaz, M; Too, C L; Azrena, A; Maiselamah, L; Lee, Y Y; Irda, Y A; Salawati, M

    2007-03-01

    One thousand four hundreds and forty-five Malays registered with the Malaysian Marrow Donor Registry were typed for HLA-A, HLA-B and HLA-DR. Fifteen HLA-A, twenty nine HLA-B and fourteen HLA-DR alleles were detected. The most common HLA-A alleles and their frequencies were HLA-A24 (0.35), HLA-A11 (0.21) and HLA-A2 (0.15). The most common HLA-B alleles were HLA-B15 (0.26), HLA-B35 (0.11) and HLA-B18 (0.10) while the most common HLA-DR alleles were HLA-DR15 (0.28), HLA-DR12 (0.27) and HLA-DR7 (0.10). A24-B15-DR12 (0.047), A24-B15-DR15 (0.03) and the A24-B35-DR12 (0.03) were the most frequent haplotypes. This data may be useful in determining the probability of finding a matched donor and for estimating the incidence of HLA associated diseases.

  3. Improving coeliac disease risk prediction by testing non-HLA variants additional to HLA variants

    PubMed Central

    Romanos, Jihane; Rosén, Anna; Kumar, Vinod; Trynka, Gosia; Franke, Lude; Szperl, Agata; Gutierrez-Achury, Javier; van Diemen, Cleo C; Kanninga, Roan; Jankipersadsing, Soesma A; Steck, Andrea; Eisenbarth, Georges; van Heel, David A; Cukrowska, Bozena; Bruno, Valentina; Mazzilli, Maria Cristina; Núñez, Concepcion; Bilbao, Jose Ramon; Mearin, M Luisa; Barisani, Donatella; Rewers, Marian; Norris, Jill M; Ivarsson, Anneli; Boezen, H Marieke; Liu, Edwin; Wijmenga, Cisca

    2014-01-01

    Background The majority of coeliac disease (CD) patients are not being properly diagnosed and therefore remain untreated, leading to a greater risk of developing CD-associated complications. The major genetic risk heterodimer, HLA-DQ2 and DQ8, is already used clinically to help exclude disease. However, approximately 40% of the population carry these alleles and the majority never develop CD. Objective We explored whether CD risk prediction can be improved by adding non-HLA-susceptible variants to common HLA testing. Design We developed an average weighted genetic risk score with 10, 26 and 57 single nucleotide polymorphisms (SNP) in 2675 cases and 2815 controls and assessed the improvement in risk prediction provided by the non-HLA SNP. Moreover, we assessed the transferability of the genetic risk model with 26 non-HLA variants to a nested case–control population (n=1709) and a prospective cohort (n=1245) and then tested how well this model predicted CD outcome for 985 independent individuals. Results Adding 57 non-HLA variants to HLA testing showed a statistically significant improvement compared to scores from models based on HLA only, HLA plus 10 SNP and HLA plus 26 SNP. With 57 non-HLA variants, the area under the receiver operator characteristic curve reached 0.854 compared to 0.823 for HLA only, and 11.1% of individuals were reclassified to a more accurate risk group. We show that the risk model with HLA plus 26 SNP is useful in independent populations. Conclusions Predicting risk with 57 additional non-HLA variants improved the identification of potential CD patients. This demonstrates a possible role for combined HLA and non-HLA genetic testing in diagnostic work for CD. PMID:23704318

  4. Measles Virus Epitope Presentation by HLA: Novel Insights into Epitope Selection, Dominance, and Microvariation

    PubMed Central

    Schellens, Ingrid M.; Meiring, Hugo D.; Hoof, Ilka; Spijkers, Sanne N.; Poelen, Martien C. M.; van Gaans-van den Brink, Jacqueline A. M.; Costa, Ana I.; Vennema, Harry; Keşmir, Can; van Baarle, Debbie; van Els, Cécile A. C. M.

    2015-01-01

    Immunity to infections with measles virus (MV) can involve vigorous human leukocyte antigen (HLA) class I-restricted CD8+ cytotoxic T cell (CTL) responses. MV, albeit regarded monotypic, is known to undergo molecular evolution across its RNA genome. To address which regions of the MV proteome are eligible for recognition by CD8+ CTLs and how different HLA class I loci contribute to the epitope display, we interrogated the naturally processed and presented MV peptidome extracted from cell lines expressing in total a broad panel of 16 different common HLA-A, -B, and -C molecules. The repertoire and abundance of MV peptides were bona fide identified by nanoHPLC–MS/MS. ­Eighty-nine MV peptides were discovered and assignment to an HLA-A, -B, or -C allele, based on HLA-peptide affinity prediction, was in most cases successful. Length variation and presentation by multiple HLA class I molecules was common in the MV peptidome. More than twice as many unique MV epitopes were found to be restricted by HLA-B than by HLA-A, while MV peptides with supra-abundant expression rates (>5,000 cc) were rather associated with HLA-A and HLA-C. In total, 59 regions across the whole MV proteome were identified as targeted by HLA class I. Sequence coverage by epitopes was highest for internal proteins transcribed from the MV-P/V/C and -M genes and for hemagglutinin. At the genome level, the majority of the HLA class I-selected MV epitopes represented codons having a higher non-synonymous mutation rate than silent mutation rate, as established by comparison of a set of 58 unique full length MV genomes. Interestingly, more molecular variation was seen for the epitopes expressed at rates ≥1,000 cc. These data for the first time indicate that HLA class I broadly samples the MV proteome and that CTL pressure may contribute to the genomic evolution of MV. PMID:26579122

  5. Multiple intracranial hemorrhages in pregnancy: A common autoimmune etiology.

    PubMed

    Pahadiya, Hans Raj; Lakhotia, Manoj; Gandhi, Ronak; Choudhary, Akanksha; Madan, Shiva

    2016-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder, primarily affect female in fertile age. Pregnancy in SLE female is a high-risk situation which can adversely affect maternal-fetal dyad. SLE can flare during pregnancy or in postpartum period. We describe a case of a young pregnant female who presented because of right hemiparesis due multiple hemorrhages in the brain. The first presentation of the SLE with multiple intracranial hemorrhages in pregnancy, preceding the other characteristic clinical symptoms is rare. Here, we high lighten the major neurological issues and maternal-fetal dyad issues in SLE pregnancy and treatment strategies for management of SLE in pregnancy. PMID:27114665

  6. Multiple intracranial hemorrhages in pregnancy: A common autoimmune etiology

    PubMed Central

    Pahadiya, Hans Raj; Lakhotia, Manoj; Gandhi, Ronak; Choudhary, Akanksha; Madan, Shiva

    2016-01-01

    Systemic lupus erythematosus (SLE) is an autoimmune disorder, primarily affect female in fertile age. Pregnancy in SLE female is a high-risk situation which can adversely affect maternal-fetal dyad. SLE can flare during pregnancy or in postpartum period. We describe a case of a young pregnant female who presented because of right hemiparesis due multiple hemorrhages in the brain. The first presentation of the SLE with multiple intracranial hemorrhages in pregnancy, preceding the other characteristic clinical symptoms is rare. Here, we high lighten the major neurological issues and maternal-fetal dyad issues in SLE pregnancy and treatment strategies for management of SLE in pregnancy. PMID:27114665

  7. Theorizing University Identity Development: Multiple Perspectives and Common Goals

    ERIC Educational Resources Information Center

    MacDonald, Ginger Phillips

    2013-01-01

    Universities articulate their identities during moments of organizational change. The process of development of university identity is herein explored from multiple theoretical strands: (a) industrial/organizational psychology, (b) human development/social psychology, (c) marketing, and (d) postmodern sociological. This article provides an…

  8. Preclinical studies on targeted delivery of multiple IFNα2b to HLA-DR in diverse hematologic cancers

    PubMed Central

    Rossi, Diane L.; Cardillo, Thomas M.; Stein, Rhona; Chang, Chien-Hsing

    2011-01-01

    The short circulating half-life and side effects of IFNα affect its dosing schedule and efficacy. Fusion of IFNα to a tumor-targeting mAb (mAb-IFNα) can enhance potency because of increased tumor localization and improved pharmacokinetics. We used the Dock-and-Lock method to generate C2-2b-2b, a mAb-IFNα comprising tetrameric IFNα2b site-specifically linked to hL243 (humanized anti–HLA-DR). In vitro, C2-2b-2b inhibited various B-cell lymphoma leukemia and myeloma cell lines. In most cases, this immunocytokine was more effective than CD20-targeted mAb-IFNα or a mixture comprising the parental mAb and IFNα. Our findings indicate that responsiveness depends on HLA-DR expression/density and sensitivity to IFNα and hL243. C2-2b-2b induced more potent and longer-lasting IFNα signaling compared with nontargeted IFNα. Phosphorylation of STAT1 was more robust and persistent than that of STAT3, which may promote apoptosis. C2-2b-2b efficiently depleted lymphoma and myeloma cells from whole human blood but also exhibited some toxicity to B cells, monocytes, and dendritic cells. C2-2b-2b showed superior efficacy compared with nontargeting mAb-IFNα, peginterferonalfa-2a, or a combination of hL243 and IFNα, using human lymphoma and myeloma xenografts. These results suggest that C2-2b-2b should be useful in the treatment of various hematopoietic malignancies. PMID:21680794

  9. HLA-A, HLA-B, and HLA-DRB1 allele distribution in a large Armenian population sample.

    PubMed

    Matevosyan, L; Chattopadhyay, S; Madelian, V; Avagyan, S; Nazaretyan, M; Hyussian, A; Vardapetyan, E; Arutunyan, R; Jordan, F

    2011-07-01

    Human leukocyte antigen (HLA)-A, HLA-B, and HLA-DRB1 gene frequencies were investigated in 4279 unrelated Armenian bone marrow donors. HLA alleles were defined by using PCR amplification with sequence specific primers (PCR-SSP) high- and low-resolution kits. The aim of this study was to examine the HLA diversity at the high-resolution level in a large Armenian population sample, and to compare HLA allele group distribution in Armenian subpopulations. The most frequently observed alleles in the HLA class I were HLA-A*0201, A*0101, A*2402, A*0301, HLA-B*5101, HLA-B*3501, and B*4901. Among DRB1 alleles, high frequencies of DRB1*1104 and DRB1*1501 were observed, followed by DRB1*1101 and DRB1*1401. The most common three-locus haplotype found in the Armenian population was A*33-B*14-DRB1*01, followed by A*03-B*35-DRB1*01. Our results show a similar distribution of alleles in Armenian subpopulations from different countries, and from different regions of the Republics of Armenia and Karabagh. The low level of genetic distances between subpopulations indicates a high level of population homogeneity, and the genetic distances between Armenians and other populations show Armenians as a distinct ethnic group relative to others, reflecting the fact that Armenians have been an 'isolated population' throughout centuries. This study is the first comprehensive investigation of HLA-allele group distribution in a subset of Armenian populations, and the first to provide HLA-allele and haplotype frequencies at a high-resolution level. It is a valuable reference for organ transplantation and for future studies of HLA-associated diseases in Armenian populations.

  10. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity.

    PubMed

    Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K

    2016-01-01

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. PMID:26880555

  11. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity

    PubMed Central

    Raj, Prithvi; Rai, Ekta; Song, Ran; Khan, Shaheen; Wakeland, Benjamin E; Viswanathan, Kasthuribai; Arana, Carlos; Liang, Chaoying; Zhang, Bo; Dozmorov, Igor; Carr-Johnson, Ferdicia; Mitrovic, Mitja; Wiley, Graham B; Kelly, Jennifer A; Lauwerys, Bernard R; Olsen, Nancy J; Cotsapas, Chris; Garcia, Christine K; Wise, Carol A; Harley, John B; Nath, Swapan K; James, Judith A; Jacob, Chaim O; Tsao, Betty P; Pasare, Chandrashekhar; Karp, David R; Li, Quan Zhen; Gaffney, Patrick M; Wakeland, Edward K

    2016-01-01

    Targeted sequencing of sixteen SLE risk loci among 1349 Caucasian cases and controls produced a comprehensive dataset of the variations causing susceptibility to systemic lupus erythematosus (SLE). Two independent disease association signals in the HLA-D region identified two regulatory regions containing 3562 polymorphisms that modified thirty-seven transcription factor binding sites. These extensive functional variations are a new and potent facet of HLA polymorphism. Variations modifying the consensus binding motifs of IRF4 and CTCF in the XL9 regulatory complex modified the transcription of HLA-DRB1, HLA-DQA1 and HLA-DQB1 in a chromosome-specific manner, resulting in a 2.5-fold increase in the surface expression of HLA-DR and DQ molecules on dendritic cells with SLE risk genotypes, which increases to over 4-fold after stimulation. Similar analyses of fifteen other SLE risk loci identified 1206 functional variants tightly linked with disease-associated SNPs and demonstrated that common disease alleles contain multiple causal variants modulating multiple immune system genes. DOI: http://dx.doi.org/10.7554/eLife.12089.001 PMID:26880555

  12. Predicting White Matter Integrity from Multiple Common Genetic Variants

    PubMed Central

    Kohannim, Omid; Jahanshad, Neda; Braskie, Meredith N; Stein, Jason L; Chiang, Ming-Chang; Reese, April H; Hibar, Derrek P; Toga, Arthur W; McMahon, Katie L; de Zubicaray, Greig I; Medland, Sarah E; Montgomery, Grant W; Martin, Nicholas G; Wright, Margaret J; Thompson, Paul M

    2012-01-01

    Several common genetic variants have recently been discovered that appear to influence white matter microstructure, as measured by diffusion tensor imaging (DTI). Each genetic variant explains only a small proportion of the variance in brain microstructure, so we set out to explore their combined effect on the white matter integrity of the corpus callosum. We measured six common candidate single-nucleotide polymorphisms (SNPs) in the COMT, NTRK1, BDNF, ErbB4, CLU, and HFE genes, and investigated their individual and aggregate effects on white matter structure in 395 healthy adult twins and siblings (age: 20–30 years). All subjects were scanned with 4-tesla 94-direction high angular resolution diffusion imaging. When combined using mixed-effects linear regression, a joint model based on five of the candidate SNPs (COMT, NTRK1, ErbB4, CLU, and HFE) explained ∼6% of the variance in the average fractional anisotropy (FA) of the corpus callosum. This predictive model had detectable effects on FA at 82% of the corpus callosum voxels, including the genu, body, and splenium. Predicting the brain's fiber microstructure from genotypes may ultimately help in early risk assessment, and eventually, in personalized treatment for neuropsychiatric disorders in which brain integrity and connectivity are affected. PMID:22510721

  13. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

    PubMed Central

    Nejentsev, Sergey; Howson, Joanna M. M.; Walker, Neil M.; Szeszko, Jeffrey; Field, Sarah F.; Stevens, Helen E.; Reynolds, Pamela; Hardy, Matthew; King, Erna; Masters, Jennifer; Hulme, John; Maier, Lisa M.; Smyth, Deborah; Bailey, Rebecca; Cooper, Jason D.; Ribas, Gloria; Campbell, R. Duncan; Clayton, David G.; Todd, John A.

    2009-01-01

    The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region4-11. Owing to the region’s extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods—recursive partitioning and regression—to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios>1.5; Pcombined=2.01×10-19 and 2.35×10-13, respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies4-8,10-16, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes. PMID:18004301

  14. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy.

    PubMed

    Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling; Zheng, Xiuwen; Plazzi, Giuseppe; Dauvilliers, Yves; Pizza, Fabio; Hong, Seung-Chul; Jennum, Poul; Knudsen, Stine; Kornum, Birgitte R; Dong, Xiao Song; Yan, Han; Hong, Heeseung; Coquillard, Cristin; Mahlios, Joshua; Jolanki, Otto; Einen, Mali; Arnulf, Isabelle; Lavault, Sophie; Högl, Birgit; Frauscher, Birgit; Crowe, Catherine; Partinen, Markku; Huang, Yu Shu; Bourgin, Patrice; Vaarala, Outi; Désautels, Alex; Montplaisir, Jacques; Mack, Steven J; Mindrinos, Michael; Fernandez-Vina, Marcelo; Mignot, Emmanuel

    2015-01-01

    Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza. PMID:25574827

  15. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy.

    PubMed

    Ollila, Hanna M; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling; Zheng, Xiuwen; Plazzi, Giuseppe; Dauvilliers, Yves; Pizza, Fabio; Hong, Seung-Chul; Jennum, Poul; Knudsen, Stine; Kornum, Birgitte R; Dong, Xiao Song; Yan, Han; Hong, Heeseung; Coquillard, Cristin; Mahlios, Joshua; Jolanki, Otto; Einen, Mali; Arnulf, Isabelle; Lavault, Sophie; Högl, Birgit; Frauscher, Birgit; Crowe, Catherine; Partinen, Markku; Huang, Yu Shu; Bourgin, Patrice; Vaarala, Outi; Désautels, Alex; Montplaisir, Jacques; Mack, Steven J; Mindrinos, Michael; Fernandez-Vina, Marcelo; Mignot, Emmanuel

    2015-01-01

    Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1(∗)01:02-DQB1(∗)06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1(∗)01:03-DPB1(∗)04:02 (DP0402; odds ratio [OR] = 0.51 [0.38-0.67], p = 1.01 × 10(-6)) and HLA-DPA1(∗)01:03-DPB1(∗)04:01 (DP0401; OR = 0.61 [0.47-0.80], p = 2.07 × 10(-4)) and predisposing effects of HLA-DPB1(∗)05:01 in Asians (OR = 1.76 [1.34-2.31], p = 4.71 × 10(-05)). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38-0.55] p = 8.99 × 10(-17)) and DP0501 (OR = 1.38 [1.18-1.61], p = 7.11 × 10(-5)). HLA-class-II-independent associations with HLA-A(∗)11:01 (OR = 1.32 [1.13-1.54], p = 4.92 × 10(-4)), HLA-B(∗)35:03 (OR = 1.96 [1.41-2.70], p = 5.14 × 10(-5)), and HLA-B(∗)51:01 (OR = 1.49 [1.25-1.78], p = 1.09 × 10(-5)) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza.

  16. HLA-DPB1 and HLA Class I Confer Risk of and Protection from Narcolepsy

    PubMed Central

    Ollila, Hanna M.; Ravel, Jean-Marie; Han, Fang; Faraco, Juliette; Lin, Ling; Zheng, Xiuwen; Plazzi, Giuseppe; Dauvilliers, Yves; Pizza, Fabio; Hong, Seung-Chul; Jennum, Poul; Knudsen, Stine; Kornum, Birgitte R.; Dong, Xiao Song; Yan, Han; Hong, Heeseung; Coquillard, Cristin; Mahlios, Joshua; Jolanki, Otto; Einen, Mali; Lavault, Sophie; Högl, Birgit; Frauscher, Birgit; Crowe, Catherine; Partinen, Markku; Huang, Yu Shu; Bourgin, Patrice; Vaarala, Outi; Désautels, Alex; Montplaisir, Jacques; Mack, Steven J.; Mindrinos, Michael; Fernandez-Vina, Marcelo; Mignot, Emmanuel

    2015-01-01

    Type 1 narcolepsy, a disorder caused by a lack of hypocretin (orexin), is so strongly associated with human leukocyte antigen (HLA) class II HLA-DQA1∗01:02-DQB1∗06:02 (DQ0602) that very few non-DQ0602 cases have been reported. A known triggering factor for narcolepsy is pandemic 2009 influenza H1N1, suggesting autoimmunity triggered by upper-airway infections. Additional effects of other HLA-DQ alleles have been reported consistently across multiple ethnic groups. Using over 3,000 case and 10,000 control individuals of European and Chinese background, we examined the effects of other HLA loci. After careful matching of HLA-DR and HLA-DQ in case and control individuals, we found strong protective effects of HLA-DPA1∗01:03-DPB1∗04:02 (DP0402; odds ratio [OR] = 0.51 [0.38–0.67], p = 1.01 × 10−6) and HLA-DPA1∗01:03-DPB1∗04:01 (DP0401; OR = 0.61 [0.47–0.80], p = 2.07 × 10−4) and predisposing effects of HLA-DPB1∗05:01 in Asians (OR = 1.76 [1.34–2.31], p = 4.71 × 10−05). Similar effects were found by conditional analysis controlling for HLA-DR and HLA-DQ with DP0402 (OR = 0.45 [0.38–0.55] p = 8.99 × 10−17) and DP0501 (OR = 1.38 [1.18–1.61], p = 7.11 × 10−5). HLA-class-II-independent associations with HLA-A∗11:01 (OR = 1.32 [1.13–1.54], p = 4.92 × 10−4), HLA-B∗35:03 (OR = 1.96 [1.41–2.70], p = 5.14 × 10−5), and HLA-B∗51:01 (OR = 1.49 [1.25–1.78], p = 1.09 × 10−5) were also seen across ethnic groups in the HLA class I region. These effects might reflect modulation of autoimmunity or indirect effects of HLA class I and HLA-DP alleles on response to viral infections such as that of influenza. PMID:25574827

  17. Vitamin D Responsive Elements within the HLA-DRB1 Promoter Region in Sardinian Multiple Sclerosis Associated Alleles

    PubMed Central

    Murru, Maria Rita; Corongiu, Daniela; Tranquilli, Stefania; Fadda, Elisabetta; Murru, Raffaele; Schirru, Lucia; Secci, Maria Antonietta; Costa, Gianna; Asunis, Isadora; Cuccu, Stefania; Fenu, Giuseppe; Lorefice, Lorena; Carboni, Nicola; Mura, Gioia; Rosatelli, Maria Cristina; Marrosu, Maria Giovanna

    2012-01-01

    Vitamin D response elements (VDREs) have been found in the promoter region of the MS-associated allele HLA-DRB1*15∶01, suggesting that with low vitamin D availability VDREs are incapable of inducing *15∶01 expression allowing in early life autoreactive T-cells to escape central thymic deletion. The Italian island of Sardinia exhibits a very high frequency of MS and high solar radiation exposure. We test the contribution of VDREs analysing the promoter region of the MS-associated DRB1 *04∶05, *03∶01, *13∶01 and *15∶01 and non-MS-associated *16∶01, *01, *11, *07∶01 alleles in a cohort of Sardinians (44 MS patients and 112 healthy subjects). Sequencing of the DRB1 promoter region revealed a homozygous canonical VDRE in all *15∶01, *16∶01, *11 and in 45/73 *03∶01 and in heterozygous state in 28/73 *03∶01 and all *01 alleles. A new mutated homozygous VDRE was found in all *13∶03, *04∶05 and *07∶01 alleles. Functionality of mutated and canonical VDREs was assessed for its potential to modulate levels of DRB1 gene expression using an in vitro transactivation assay after stimulation with active vitamin D metabolite. Vitamin D failed to increase promoter activity of the *04∶05 and *03∶01 alleles carrying the new mutated VDRE, while the *16∶01 and *03∶01 alleles carrying the canonical VDRE sequence showed significantly increased transcriptional activity. The ability of VDR to bind the mutant VDRE in the DRB1 promoter was evaluated by EMSA. Efficient binding of VDR to the VDRE sequence found in the *16∶01 and in the *15∶01 allele reduced electrophoretic mobility when either an anti-VDR or an anti-RXR monoclonal antibody was added. Conversely, the Sardinian mutated VDRE sample showed very low affinity for the RXR/VDR heterodimer. These data seem to exclude a role of VDREs in the promoter region of the DRB1 gene in susceptibility to MS carried by DRB1* alleles in Sardinian patients. PMID:22848563

  18. HLA Type Inference via Haplotypes Identical by Descent

    NASA Astrophysics Data System (ADS)

    Setty, Manu N.; Gusev, Alexander; Pe'Er, Itsik

    The Human Leukocyte Antigen (HLA) genes play a major role in adaptive immune response and are used to differentiate self antigens from non self ones. HLA genes are hyper variable with nearly every locus harboring over a dozen alleles. This variation plays an important role in susceptibility to multiple autoimmune diseases and needs to be matched on for organ transplantation. Unfortunately, HLA typing by serological methods is time consuming and expensive compared to high throughput Single Nucleotide Polymorphism (SNP) data. We present a new computational method to infer per-locus HLA types using shared segments Identical By Descent (IBD), inferred from SNP genotype data. IBD information is modeled as graph where shared haplotypes are explored among clusters of individuals with known and unknown HLA types to identify the latter. We analyze performance of the method in a previously typed subset of the HapMap population, achieving accuracy of 96% in HLA-A, 94% in HLA-B, 95% in HLA-C, 77% in HLA-DR1, 93% in HLA-DQA1 and 90% in HLA-DQB1 genes. We compare our method to a tag SNP based approach and demonstrate higher sensitivity and specificity. Our method demonstrates the power of using shared haplotype segments for large-scale imputation at the HLA locus.

  19. Beyond Multiple Regression: Using Commonality Analysis to Better Understand R[superscript 2] Results

    ERIC Educational Resources Information Center

    Warne, Russell T.

    2011-01-01

    Multiple regression is one of the most common statistical methods used in quantitative educational research. Despite the versatility and easy interpretability of multiple regression, it has some shortcomings in the detection of suppressor variables and for somewhat arbitrarily assigning values to the structure coefficients of correlated…

  20. Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20-mer NY-ESO-1f (NY-ESO-1 91-110) peptide.

    PubMed

    Eikawa, Shingo; Kakimi, Kazuhiro; Isobe, Midori; Kuzushima, Kiyotaka; Luescher, Immanuel; Ohue, Yoshihiro; Ikeuchi, Kazuhiro; Uenaka, Akiko; Nishikawa, Hiroyoshi; Udono, Heiichiro; Oka, Mikio; Nakayama, Eiichi

    2013-01-15

    Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response.

  1. 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.

  2. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Boșcaiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania.

  3. The frequency of HLA alleles in the Romanian population.

    PubMed

    Constantinescu, Ileana; Boșcaiu, Voicu; Cianga, Petru; Dinu, Andrei-Antoniu; Gai, Elena; Melinte, Mihaela; Moise, Ana

    2016-03-01

    Knowledge of human leukocyte antigen (HLA) allele frequencies is essential for bone marrow and kidney donor searches. The Romanian Caucasian population is heterogeneous and information on HLA polymorphism has not been well studied. We characterized the HLA genetic profile and allele frequencies of regional populations in Romania. HLA-A, B and DRB1 alleles were examined in 8252 individuals, belonging to the four main regions of Romania. The most common alleles found in the Romanian population are the following: HLA-A*01, A*02, A*03, A*11, A*24; HLA-B*18, B*35, B*44, B*51 and HLA-DRB1*01, DRB1*03, DRB1*07, DRB1*11, DRB1*13, DRB1*15, DRB1*16. More than half of the alleles are non-homogeneously spread in Romania. These results provide a starting point for future analyses of genetic heterogeneity in Romania. PMID:26711124

  4. HLA polymorphism in three indigenous populations of Sabah and Sarawak.

    PubMed

    Dhaliwal, J S; Shahnaz, M; Azrena, A; Irda, Y A; Salawati, M; Too, C L; Lee, Y Y

    2010-02-01

    One hundred and fifty-eight Kadazan, Iban and Bidayuh individuals registered with the Malaysian Marrow Donor Registry were typed for human leukocyte antigen (HLA)-A, HLA-B and HLA-DR. Six, seven and eight HLA-A alleles as well as 13, 15 and 16 HLA-B alleles were detected in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-A allele in all three groups was HLA-A*24 with a frequency of 0.456, 0.490 and 0.422 in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-B allele detected in the Kadazan was HLA-B*40 with a frequency of 0.333; for the Bidayuh and the Iban it was HLA-B*15 with a frequency of 0.460 and 0.275, respectively. The HLA-DR allele with the highest frequency in the Kadazan was HLA-DR*1502 with a frequency of 0.500. In the Iban and the Bidayuh, HLA-DRB1*1202 was the most common DR allele with frequencies of 0.235 and 0.310, respectively. The two most common haplotypes for the Kadazan are A*34-B*38-DR*1502 and A*24-B*40-DR*0405, whereas for the Bidayuh they are A*24-B*15-DR*1602 and A*24-B*35-DR*1202 and for the Iban they are A*34-*B15-DR*1502 and A*24-B*15-DR*1202. PMID:20196825

  5. HLA polymorphism in three indigenous populations of Sabah and Sarawak.

    PubMed

    Dhaliwal, J S; Shahnaz, M; Azrena, A; Irda, Y A; Salawati, M; Too, C L; Lee, Y Y

    2010-02-01

    One hundred and fifty-eight Kadazan, Iban and Bidayuh individuals registered with the Malaysian Marrow Donor Registry were typed for human leukocyte antigen (HLA)-A, HLA-B and HLA-DR. Six, seven and eight HLA-A alleles as well as 13, 15 and 16 HLA-B alleles were detected in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-A allele in all three groups was HLA-A*24 with a frequency of 0.456, 0.490 and 0.422 in the Kadazan, Bidayuh and Iban, respectively. The most common HLA-B allele detected in the Kadazan was HLA-B*40 with a frequency of 0.333; for the Bidayuh and the Iban it was HLA-B*15 with a frequency of 0.460 and 0.275, respectively. The HLA-DR allele with the highest frequency in the Kadazan was HLA-DR*1502 with a frequency of 0.500. In the Iban and the Bidayuh, HLA-DRB1*1202 was the most common DR allele with frequencies of 0.235 and 0.310, respectively. The two most common haplotypes for the Kadazan are A*34-B*38-DR*1502 and A*24-B*40-DR*0405, whereas for the Bidayuh they are A*24-B*15-DR*1602 and A*24-B*35-DR*1202 and for the Iban they are A*34-*B15-DR*1502 and A*24-B*15-DR*1202.

  6. HLA polymorphism in the Havasupai: Evidence for balancing selection

    SciTech Connect

    Markow, T.; Hedrick, P.W.; Armstrong, C.; Martin, J. ); Zuerlein, K. ); Vyvial, T.; Danilov, J.

    1993-10-01

    The characterization and analysis of genetic variation at the HLA loci provides important insight for population geneticists trying to understand the evolutionary forces that have shaped human populations. This study describes the HLA-A and HLA-B loci serotyping and statistical analysis on an isolated Native American population, the Havasupai of Arizona. Four alleles at the HLA-A locus were identified, while eight alleles were found at the HLA-B locus. These variants were present as 20 of 32 potential two-locus haplotypes, with five of the six most common haplotypes exhibiting high positive linkage disequilibrium. Significant homozygote deficiency (heterozygosity excess) was detected both at HLA-A and at HLA-B. This deviation from Hardy-Weinberg proportions was not attributable to nonselective causes such as different alleles at both HLA-A and HLA-B was more even than expected from neutrality theory; that is, the observed Hardy-Weinberg homozygosity was only 62.4% of that expected under neutrality. These observations suggest that balancing selection is of major importance in maintaining genetic variation at HLA-A and HLA-B. 52 refs., 5 tabs.

  7. Common source-multiple load vs. separate source-individual load photovoltaic system

    NASA Technical Reports Server (NTRS)

    Appelbaum, Joseph

    1989-01-01

    A comparison of system performance is made for two possible system setups: (1) individual loads powered by separate solar cell sources; and (2) multiple loads powered by a common solar cell source. A proof for resistive loads is given that shows the advantage of a common source over a separate source photovoltaic system for a large range of loads. For identical loads, both systems perform the same.

  8. Very long haplotype tracts characterized at high resolution from HLA homozygous cell lines

    PubMed Central

    Norman, Paul J.; Norberg, Steve; Nemat-Gorgani, Neda; Royce, Thomas; Hollenbach, Jill A.; Won, Melissa Shults; Guethlein, Lisbeth A.; Gunderson, Kevin L.; Ronaghi, Mostafa; Parham, Peter

    2015-01-01

    The HLA region of chromosome 6 contains the most polymorphic genes in humans. Spanning ~5Mbp the densely packed region encompasses approximately 175 expressed genes including the highly polymorphic HLA class I and II loci. Most of the other genes and functional elements are also polymorphic, and many of them are directly implicated in immune function or immune-related disease. For these reasons this complex genomic region is subject to intense scrutiny by researchers with the common goal of aiding further understanding and diagnoses of multiple immune-related diseases and syndromes. To aid assay development and characterization of the classical loci, a panel of cell lines partially or fully homozygous for HLA class I and II was assembled over time by the International Histocompatibility Working Group (IHWG). Containing a minimum of 88 unique HLA haplotypes, we show this panel represents a significant proportion of European HLA allelic and haplotype diversity (60–95%). Using a high-density whole genome array that includes 13,331 HLA region SNPs, we analyzed 99 IHWG cells to map the coordinates of the homozygous tracts at a fine scale. The mean homozygous tract length within chromosome 6 from these individuals is 21Mbp. Within HLA the mean haplotype length is 4.3Mbp, and 65% of the cell lines were shown to be homozygous throughout the entire region. In addition, four cell lines are homozygous throughout the complex KIR region of chromosome 19 (~250kbp). The data we describe will provide a valuable resource for characterizing haplotypes, designing and refining imputation algorithms and developing assay controls. PMID:26198775

  9. Genome-wide Association Study Identifies Five Susceptibility Loci for Follicular Lymphoma outside the HLA Region

    PubMed Central

    Skibola, Christine F.; Berndt, Sonja I.; Vijai, Joseph; Conde, Lucia; Wang, Zhaoming; Yeager, Meredith; de Bakker, Paul I.W.; Birmann, Brenda M.; Vajdic, Claire M.; Foo, Jia-Nee; Bracci, Paige M.; Vermeulen, Roel C.H.; Slager, Susan L.; de Sanjose, Silvia; Wang, Sophia S.; Linet, Martha S.; Salles, Gilles; Lan, Qing; Severi, Gianluca; Hjalgrim, Henrik; Lightfoot, Tracy; Melbye, Mads; Gu, Jian; Ghesquières, Hervé; Link, Brian K.; Morton, Lindsay M.; Holly, Elizabeth A.; Smith, Alex; Tinker, Lesley F.; Teras, Lauren R.; Kricker, Anne; Becker, Nikolaus; Purdue, Mark P.; Spinelli, John J.; Zhang, Yawei; Giles, Graham G.; Vineis, Paolo; Monnereau, Alain; Bertrand, Kimberly A.; Albanes, Demetrius; Zeleniuch-Jacquotte, Anne; Gabbas, Attilio; Chung, Charles C.; Burdett, Laurie; Hutchinson, Amy; Lawrence, Charles; Montalvan, Rebecca; Liang, Liming; Huang, Jinyan; Ma, Baoshan; Liu, Jianjun; Adami, Hans-Olov; Glimelius, Bengt; Ye, Yuanqing; Nowakowski, Grzegorz S.; Dogan, Ahmet; Thompson, Carrie A.; Habermann, Thomas M.; Novak, Anne J.; Liebow, Mark; Witzig, Thomas E.; Weiner, George J.; Schenk, Maryjean; Hartge, Patricia; De Roos, Anneclaire J.; Cozen, Wendy; Zhi, Degui; Akers, Nicholas K.; Riby, Jacques; Smith, Martyn T.; Lacher, Mortimer; Villano, Danylo J.; Maria, Ann; Roman, Eve; Kane, Eleanor; Jackson, Rebecca D.; North, Kari E.; Diver, W. Ryan; Turner, Jenny; Armstrong, Bruce K.; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; McKay, James; Brooks-Wilson, Angela R.; Zheng, Tongzhang; Holford, Theodore R.; Chamosa, Saioa; Kaaks, Rudolph; Kelly, Rachel S.; Ohlsson, Bodil; Travis, Ruth C.; Weiderpass, Elisabete; Clavel, Jacqueline; Giovannucci, Edward; Kraft, Peter; Virtamo, Jarmo; Mazza, Patrizio; Cocco, Pierluigi; Ennas, Maria Grazia; Chiu, Brian C.H.; Fraumeni, Joseph F.; Nieters, Alexandra; Offit, Kenneth; Wu, Xifeng; Cerhan, James R.; Smedby, Karin E.; Chanock, Stephen J.; Rothman, Nathaniel

    2014-01-01

    Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10−20) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10−11) near ETS1; 3q28 (rs6444305, p = 1.10 × 10−10) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10−10) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10−8) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10−67 to 2.67 × 10−70). Additional independent signals included rs17203612 in HLA class II (odds ratio [ORper-allele] = 1.44; p = 4.59 × 10−16) and rs3130437 in HLA class I (ORper-allele = 1.23; p = 8.23 × 10−9). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk. PMID:25279986

  10. HLA Engineering of Human Pluripotent Stem Cells

    PubMed Central

    Riolobos, Laura; Hirata, Roli K; Turtle, Cameron J; Wang, Pei-Rong; Gornalusse, German G; Zavajlevski, Maja; Riddell, Stanley R; Russell, David W

    2013-01-01

    The clinical use of human pluripotent stem cells and their derivatives is limited by the rejection of transplanted cells due to differences in their human leukocyte antigen (HLA) genes. This has led to the proposed use of histocompatible, patient-specific stem cells; however, the preparation of many different stem cell lines for clinical use is a daunting task. Here, we develop two distinct genetic engineering approaches that address this problem. First, we use a combination of gene targeting and mitotic recombination to derive HLA-homozygous embryonic stem cell (ESC) subclones from an HLA-heterozygous parental line. A small bank of HLA-homozygous stem cells with common haplotypes would match a significant proportion of the population. Second, we derive HLA class I–negative cells by targeted disruption of both alleles of the Beta-2 Microglobulin (B2M) gene in ESCs. Mixed leukocyte reactions and peptide-specific HLA-restricted CD8+ T cell responses were reduced in class I–negative cells that had undergone differentiation in embryoid bodies. These B2M−/− ESCs could act as universal donor cells in applications where the transplanted cells do not express HLA class II genes. Both approaches used adeno-associated virus (AAV) vectors for efficient gene targeting in the absence of potentially genotoxic nucleases, and produced pluripotent, transgene-free cell lines. PMID:23629003

  11. Seven novel HLA alleles reflect different mechanisms involved in the evolution of HLA diversity: description of the new alleles and review of the literature.

    PubMed

    Adamek, Martina; Klages, Cornelia; Bauer, Manuela; Kudlek, Evelina; Drechsler, Alina; Leuser, Birte; Scherer, Sabine; Opelz, Gerhard; Tran, Thuong Hien

    2015-01-01

    The human leukocyte antigen (HLA) loci are among the most polymorphic genes in the human genome. The diversity of these genes is thought to be generated by different mechanisms including point mutation, gene conversion and crossing-over. During routine HLA typing, we discovered seven novel HLA alleles which were probably generated by different evolutionary mechanisms. HLA-B*41:21, HLA-DQB1*02:10 and HLA-DQA1*01:12 likely emerged from the common alleles of their groups by point mutations, all of which caused non-synonymous amino acid substitutions. In contrast, a deletion of one nucleotide leading to a frame shift with subsequent generation of a stop codon is responsible for the appearance of a null allele, HLA-A*01:123N. Whereas HLA-B*35:231 and HLA-B*53:31 were probably products of intralocus gene conversion between HLA-B alleles, HLA-C*07:294 presumably evolved by interlocus gene conversion between an HLA-C and an HLA-B allele. Our analysis of these novel alleles illustrates the different mechanisms which may have contributed to the evolution of HLA polymorphism.

  12. Supporting Student's Ability in Understanding Least Common Multiple (LCM) Concept Using Storytelling

    ERIC Educational Resources Information Center

    Triyani, Septi; Putri, Ratu Ilma Indra; Darmawijoyo

    2012-01-01

    Several researches showed that students had difficulty in understanding the concept of Least Common Multiple (LCM) in Elementary School. This underlies the researcher to design a learning of LCM using storytelling, Legend "Putri Dayang Merindu" (LPDM), which contains situational problem related to LCM. The purposes of this study are to…

  13. HLA genotyping in pediatric celiac disease patients

    PubMed Central

    Stanković, Biljana; Radlović, Nedeljko; Leković, Zoran; Ristić, Dragana; Radlović, Vladimir; Nikčević, Gordana; Kotur, Nikola; Vučićević, Ksenija; Kostić, Tatjana; Pavlović, Sonja; Zukić, Branka

    2014-01-01

    Celiac disease (CD) is a chronic inflammatory disease in the small intestine triggered by gluten uptake that occurs in genetically susceptible individuals. HLA-DQ2 protein encoded by HLA-DQA1*05 and DQB1*02 alleles is found in 90-95% of CD patients. All of the remaining patients carry HLA-DQ8 protein encoded by HLA-DQA1*03 and DQB1*03:02 alleles. Specific HLA-DQ genotypes define different risk for CD incidence. Presence of susceptible HLA-DQ genotypes does not predict certain disease development, but their absence makes CD very unlikely, close to 100%. Here we presented for the first time the distribution of HLA-DQ genotypes in the group of pediatric celiac patients from the University Children’s Hospital, Belgrade, Serbia and estimated risk for CD development that these genotypes confer. Seventy three celiac disease patients and 62 healthy individuals underwent genotyping for DQA1, DQB1 alleles and DRB1 allele. 94.5% of patients carried alleles that encode DQ2 protein variant and 2.7% carried alleles that encode DQ8 protein variant. Two patients carried single DQB1*02 allele. No patients were negative for all the alleles predisposing to CD. The highest HLA-DQ genotype risk for CD development was found in group of patients homozygous for DQ2.5 haplotype, followed by the group of heterozygous carriers of DQ2.5 haplotype in combination with DQB1*02 allele within the other haplotype. The lowest risk was observed in carriers of a single copy of DQB1*02 or DQA1*05 allele or other non-predisposing alleles. HLA genotyping, more informative than serological testing commonly used, proved to be a useful diagnostic tool for excluding CD development. PMID:25172978

  14. Differential immunogenicity of HLA mismatches: HLA-A2 versus HLA-A28.

    PubMed

    Dankers, Marlies K A; Roelen, Dave L; Van Der Meer-Prins, Ellen M W; De Lange, Peter; Korfage, Nelleke; Smits, Jacqueline M A; Persijn, Guido G; Welsh, Ken I; Doxiadis, Ilias I N; Claas, Frans H J

    2003-02-15

    The immunogenicity of human leukocyte antigen (HLA)-A2 versus HLA-A28 was analyzed by antibody production, cytotoxic T-lymphocyte (CTL) induction, and graft survival. We observed that an HLA-A2 mismatched child in HLA-A28 women leads to HLA-A2 specific antibodies in 32% of the women (n=31), whereas in the case of an HLA-A28 child and HLA-A2 women (n=30), no HLA-A28 specific antibodies were found ( P<0.002). Also, the CTL precursor frequencies were significantly lower against HLA-A28 compared with CTLp frequencies against HLA-A2 ( P=0.012). Finally, the kidney graft survival was slightly better in HLA-A2 positive recipients transplanted with HLA-A28 mismatches. We can conclude that single HLA-A28 mismatches are less immunogenic in HLA-A2 individuals compared with single HLA-A2 mismatches in HLA-A28 individuals, which is probably because the mismatched epitopes on the HLA-A2 molecule are unique epitopes, whereas the mismatched epitopes on HLA-A28 are shared by other HLA-A and HLA-B molecules. PMID:12589169

  15. A catalog of HLA type, HLA expression, and neo-epitope candidates in human cancer cell lines

    PubMed Central

    Boegel, Sebastian; Löwer, Martin; Bukur, Thomas; Sahin, Ugur; Castle, John C

    2014-01-01

    Cancer cell lines are a tremendous resource for cancer biology and therapy development. These multipurpose tools are commonly used to examine the genetic origin of cancers, to identify potential novel tumor targets, such as tumor antigens for vaccine devel­opment, and utilized to screen potential therapies in preclinical studies. Mutations, gene expression, and drug sensitivity have been determined for many cell lines using next-generation sequencing (NGS). However, the human leukocyte antigen (HLA) type and HLA expression of tumor cell lines, characterizations necessary for the development of cancer vaccines, have remained largely incomplete and, such information, when available, has been distributed in many publications. Here, we determine the 4-digit HLA type and HLA expression of 167 cancer and 10 non-cancer cell lines from publically available RNA-Seq data. We use standard NGS RNA-Seq short reads from “whole transcriptome” sequencing, map reads to known HLA types, and statistically determine HLA type, heterozygosity, and expression. First, we present previously unreported HLA Class I and II genotypes. Second, we determine HLA expression levels in each cancer cell line, providing insights into HLA downregulation and loss in cancer. Third, using these results, we provide a fundamental cell line “barcode” to track samples and prevent sample annotation swaps and contamination. Fourth, we integrate the cancer cell-line specific HLA types and HLA expression with available cell-line specific mutation information and existing HLA binding prediction algorithms to make a catalog of predicted antigenic mutations in each cell line. The compilation of our results are a fundamental resource for all researchers selecting specific cancer cell lines based on the HLA type and HLA expression, as well as for the development of immunotherapeutic tools for novel cancer treatment modalities. PMID:25960936

  16. HLA Genes in Mayos Population from Northeast Mexico.

    PubMed

    Arnaiz-Villena, A; Moscoso, J; Granados, J; Serrano-Vela, J I; de la Peña, A; Reguera, R; Ferri, A; Seclen, E; Izaguirre, R; Perez-Hernandez, N; Vargas-Alarcon, G

    2007-11-01

    HLA class I and class II alleles have been studied in 60 unrelated people belonging to Mayos ethnic group, which lives in the Mexican Pacific Sinaloa State. Mayos HLA profile was compared to other Amerindians and worldwide populations' profile. A total of 14,896 chromosomes were used for comparisons. Genetic distances between populations, Neigbour-Joining dendrograms and correspondence analyses were performed to determine the genetic relationship among population. The new specific Mayo HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301; HLA-A*02-B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302 and HLA-A*02-B*08-DRB1*0407-DQB1*0302. However, the typical Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles. While common HLA characteristics are found in Amerindian distant ethnic groups, still new group specific HLA haplotypes are being found, suggesting that a common founder effect (i.e. high DRB1*0407) is noticed. Moreover, new HLA haplotypes are almost certainly appearing along time probably due to specific pathogen (?) selection for diversity. Mayo language is close to the Tarahumara one (another geographically close group); notwithstanding both groups are not genetically close according to our results, showing again the different evolution of genes and languages, which do not correlate. Finally, Sinaloa is one of the Mexican States in which more European genes are found. However, the results presented in this paper, where no European HLA genes are seen in Mayos, should have a bearing in establishing transplant programs and in HLA and disease studies.

  17. HLA Genes in Mayos Population from Northeast Mexico

    PubMed Central

    Arnaiz-Villena, A; Moscoso, J; Granados, J; Serrano-Vela, J.I; de la Peña, A.; Reguera, R; Ferri, A; Seclen, E; Izaguirre, R; Perez-Hernandez, N; Vargas-Alarcon, G

    2007-01-01

    HLA class I and class II alleles have been studied in 60 unrelated people belonging to Mayos ethnic group, which lives in the Mexican Pacific Sinaloa State. Mayos HLA profile was compared to other Amerindians and worldwide populations’ profile. A total of 14,896 chromosomes were used for comparisons. Genetic distances between populations, Neigbour-Joining dendrograms and correspondence analyses were performed to determine the genetic relationship among population. The new specific Mayo HLA haplotypes found are: HLA-A*02-B*35-DRB1*1406-DQB1*0301; HLA-A*02-B*48-DRB1*0404-DQB1*0302; HLA-A*24-B*51-DRB1*0407-DQB1*0302 and HLA-A*02-B*08-DRB1*0407-DQB1*0302. However, the typical Meso American HLADRB1*0407 represents a 40% of all DRB1 alleles. While common HLA characteristics are found in Amerindian distant ethnic groups, still new group specific HLA haplotypes are being found, suggesting that a common founder effect (i.e. high DRB1*0407) is noticed. Moreover, new HLA haplotypes are almost certainly appearing along time probably due to specific pathogen (?) selection for diversity. Mayo language is close to the Tarahumara one (another geographically close group); notwithstanding both groups are not genetically close according to our results, showing again the different evolution of genes and languages, which do not correlate. Finally, Sinaloa is one of the Mexican States in which more European genes are found. However, the results presented in this paper, where no European HLA genes are seen in Mayos, should have a bearing in establishing transplant programs and in HLA and disease studies. PMID:19412332

  18. A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population.

    PubMed

    Chen, Dan; Hammer, Joanna; Lindquist, David; Idahl, Annika; Gyllensten, Ulf

    2014-02-01

    In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case-control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65-0.82; P = 1.6 × 10(-7)), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19-1.49; P = 5.8 × 10(-7)), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68-0.94; P = 6.7 × 10(-3)) and MICA-A5 (OR = 0.60, 95% CI = 0.50-0.72; P = 3.0 × 10(-8)) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer.

  19. Definition of the region on NS3 which contains multiple epitopes recognized by dengue virus serotype-cross-reactive and flavivirus-cross-reactive, HLA-DPw2-restricted CD4+ T cell clones.

    PubMed

    Okamoto, Y; Kurane, I; Leporati, A M; Ennis, F A

    1998-04-01

    The epitopes recognized by six CD4+ CD8- cytotoxic T lymphocyte (CTL) clones established from a dengue-3 virus-immune donor were defined. (i) Three CTL clones, JK10, JK34 and JK39, were cross-reactive for dengue virus types 1-4. (ii) One clone, JK28, was cross-reactive for dengue virus types 1-4 and West Nile virus. (iii) Two clones, JK26 and JK49, were cross-reactive for dengue virus types 1-4, West Nile virus and yellow fever virus. The clones, except for JK49, recognized the same epitope on NS3 in an HLA-DPw2-restricted fashion. The smallest synthetic peptide recognized by the five CTL clones was a 10 aa peptide which comprises aa 255-264 on dengue virus NS3. JK49 recognized the overlapping epitope which comprises aa 257-266 in an HLA-DPw2-restricted fashion. Analysis of T cell receptor (TCR) usage by these T cell clones revealed that (i) JK10 and JK34 use V alpha11, and JK34 and JK28 use V beta23, and (ii) the amino acid sequences of the V(D)J junctional region of the TCR were different among these five CTL clones. There were, however, single amino acid conservations among TCRs of some of these T cell clones. These results indicate that the region on NS3 which comprises aa 255-266 contains multiple epitopes recognized by dengue serotype-cross-reactive and flavivirus-cross-reactive CD4+ CTL in an HLA-DPw2-restricted fashion and that a single epitope can be recognized by T cells which have heterogeneous virus specificities.

  20. Association and frequency of HLA-A, B and HLA-DR genes in south Tunisian patients with spondyloarthritis (SpA).

    PubMed

    Mahfoudh, Nadia; Siala, Mariam; Rihl, Markus; Kammoun, Arwa; Frikha, Faten; Fourati, Hela; Younes, Mohamed; Gdoura, Radhouane; Gaddour, Lilia; Hakim, Faiza; Bahloul, Zouheir; Baklouti, Sofien; Bargaoui, Naceur; Sellami, Sleheddine; Hammami, Adnene; Makni, Hafedh

    2011-08-01

    The aim of this study is to investigate the association of HLA-A, B and HLA-DR gene expression and to assess an association of additional HLA antigens besides HLA-B27 in south Tunisian patients with spondyloarthritis (SpA). Eighty-five patients diagnosed with ankylosing spondylitis (AS, n=68) and reactive arthrithis (ReA, n=17) were selected and compared with 100 healthy controls (HC). HLA class I antigens were typed serologically using microlymphocytotoxicity technique. HLA-DRB1* alleles were studied by polymerase chain reaction amplification with sequence-specific primers. The significance of differences between patients and controls was tested by chi-square analysis. We found significantly increased frequencies of HLA-A3 (30.6%; pC=0.04; OR=2.95), HLA-B27 (62.35%; pC=4.10(-17), OR=53.55), and HLA-DRB1*15 (17.2%; pC=0.026; RR=2.58) alleles in SpA patients compared to HC. The most frequent and strongest association was observed for HLA-B27 in AS (pC=6.6 ×10(-16), OR=52.23). When AS and ReA patients were analysed separately, HLA-DRB1*15 and HLA-A3 were increased only in AS (pC=0.01, OR=2.99 and pC=0.03, OR=3.14, respectively). In ReA patients, HLA-DRB1*04 (p=0.033, pC=NS, OR=2.89) was found to be the most common allele. By analysing the HLA-B27-negative subgroup, HLA-A3 and HLA-DRB1*15 expression was found to be dependent on the presence of HLA-B27. HLA-B27 expression was higher in male (45/53; 85%) as compared to female (8/53; 15%) patients (p=0.03). Apart from HLA-B27, HLA-A3 and HLA-DRB1*15 are the MHC class I and II alleles found most frequent in Tunisian patients with AS, whereas HLA-DRB1*04 was found most frequent in ReA patients. HLA-B27 is more frequent in male than in female patients. PMID:21360006

  1. Oligoclonal band phenotypes in MS differ in their HLA class II association, while specific KIR ligands at HLA class I show association to MS in general.

    PubMed

    Gustavsen, Marte W; Viken, Marte K; Celius, Elisabeth G; Berge, Tone; Mero, Inger-Lise; Berg-Hansen, Pål; Aarseth, Jan H; Myhr, Kjell-Morten; Søndergaard, Helle B; Sellebjerg, Finn; Oturai, Annette B; Hillert, Jan; Alfredsson, Lars; Olsson, Tomas; Kockum, Ingrid; Lie, Benedicte A; Harbo, Hanne F

    2014-09-15

    Multiple sclerosis (MS) patients have been reported to have different HLA class II allele profiles depending on oligoclonal bands (OCBs) in the cerebrospinal fluid, but HLA class I alleles and killer cell immunoglobulin-like receptor (KIR) ligands have not been studied. We investigated the association of HLA alleles and KIR ligands according to OCB status in MS patients (n=3876). Specific KIR ligands were associated with patients when compared to controls (n=3148), supporting a role for NK cells in MS pathogenesis. HLA class I alleles and KIR ligands did not differ between OCB phenotypes, but HLA class II associations were convincingly replicated.

  2. The alpha1 domain of HLA-G1 and HLA-G2 inhibits cytotoxicity induced by natural killer cells: is HLA-G the public ligand for natural killer cell inhibitory receptors?

    PubMed

    Rouas-Freiss, N; Marchal, R E; Kirszenbaum, M; Dausset, J; Carosella, E D

    1997-05-13

    We have investigated the protective role of the membrane-bound HLA-G1 and HLA-G2 isoforms against natural killer (NK) cell cytotoxicity. For this purpose, HLA-G1 and HLA-G2 cDNAs were transfected into the HLA class I-negative human K562 cell line, a known reference target for NK lysis. The HLA-G1 protein, encoded by a full-length mRNA, presents a structure similar to that of classical HLA class I antigens. The HLA-G2 protein, deduced from an alternatively spliced transcript, consists of the alpha1 domain linked to the alpha3 domain. In this study we demonstrate that (i) HLA-G2 is present at the cell surface as a truncated class I molecule associated with beta2-microglobulin; (ii) NK cytolysis, observed in peripheral blood mononuclear cells and in polyclonal CD3(-) CD16(+) CD56(+) NK cells obtained from 20 donors, is inhibited by both HLA-G1 and HLA-G2; this HLA-G-mediated inhibition is reversed by blocking HLA-G with a specific mAb; this led us to the conjecture that HLA-G is the public ligand for NK inhibitory receptors (NKIR) present in all individuals; (iii) the alpha1 domain common to HLA-G1 and HLA-G2 could mediate this protection from NK lysis; and (iv) when transfected into the K562 cell line, both HLA-G1 and HLA-G2 abolish lysis by the T cell leukemia NK-like YT2C2 clone due to interaction between the HLA-G isoform on the target cell surface and a membrane receptor on YT2C2. Because NKIR1 and NKIR2, known to interact with HLA-G, were undetectable on YT2C2, we conclude that a yet-unknown specific receptor for HLA-G1 and HLA-G2 is present on these cells.

  3. HLA typing in congenital toxoplasmosis.

    PubMed Central

    Meenken, C; Rothova, A; de Waal, L P; van der Horst, A R; Mesman, B J; Kijlstra, A

    1995-01-01

    HLA-A, HLA-B, HLA-C, and HLA-D typing was performed in 47 mothers of patients suffering from ocular toxoplasmosis to investigate whether an immunogenetic predisposition exists for developing congenital toxoplasmosis in their offspring. No significant association between any HLA antigen was observed in the mothers of patients with ocular toxoplasmosis, although a total absence of the HLA-B51 antigen was found in this group. HLA-A, HLA-B, and HLA-C typing was also performed in their children (52 patients with ocular toxoplasmosis), to investigate a possible relation between the severity of ocular toxoplasmosis and an eventual immunogenetic factor. In the patients with ocular toxoplasmosis an increased frequency of the HLA-Bw62 antigen was observed in correlation with severe ocular involvement. PMID:7612565

  4. The nucleotide sequence of HLA-B{sup *}2704 reveals a new amino acid substitution in exon 4 which is also present in HLA-B{sup *}2706

    SciTech Connect

    Rudwaleit, M.; Bowness, P.; Wordsworth, P.

    1996-12-31

    The HLA-B27 subtype HLA-B{sup *}2704 is virtually absent in Caucasians but common in Orientals, where it is associated with ankylosing spondylitis. The amino acid sequence of HLA-B{sup *}2704 has been established by peptide mapping and was shown to differ by two amino acids from HLA-B{sup *}2705, HLA-B{sup *}2704 is characterized by a serine for aspartic acid substitution at position 77 and glutamic acid for valine at position 152. To date, however, no nucleotide sequence confirming these changes at the DNA level has been published. 13 refs., 2 figs.

  5. Parasites and health affect multiple sexual signals in male common wall lizards, Podarcis muralis

    NASA Astrophysics Data System (ADS)

    Martín, José; Amo, Luisa; López, Pilar

    2008-04-01

    Multiple advertising sexual traits may either advertise different characteristics of male condition or be redundant to reinforce reliability of signals. Research has focused on multiple visual traits. However, in animals that use different multiple additional sensory systems, such as chemoreception, different types of traits might have evolved to signal similar characteristics of a male quality using different sensory channels. We examined whether ventral coloration and chemicals in femoral gland secretions of male common wall lizards, Podarcis muralis, are affected by their health state (blood-parasite load and cell-mediated immune response). Our results indicated that less parasitized lizards had brighter and more yellowish ventral colorations and also femoral secretions with higher proportions of two esters of octadecenoic acid. In addition, lizards with a greater immune response had more saturated coloration and secretions with higher proportions of octadecenoic acid methyl ester. We suggest that these signals would be reliable because only healthier males seemed able to allocate more carotenoids to coloration and presumably costly chemicals to secretions. The use of multiple sensory channels may provide more opportunities to signal a male quality under different circumstances, but also may reinforce the reliability of the signal when both types of traits may be perceived simultaneously.

  6. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO 2...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. (a) (b... by the Administrator, such that these emissions are not underestimated. (e) Heat input rate....

  7. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO 2...

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO 2 emissions and heat input determinations. (a) (b... by the Administrator, such that these emissions are not underestimated. (e) Heat input rate....

  8. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO2...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. (a) (b... by the Administrator, such that these emissions are not underestimated. (e) Heat input rate....

  9. 40 CFR 75.16 - Special provisions for monitoring emissions from common, bypass, and multiple stacks for SO2...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. 75.16... emissions from common, bypass, and multiple stacks for SO2 emissions and heat input determinations. (a) (b... the control device inlet may be reported instead), and the hourly volumetric flow rate value...

  10. Estimating the proportion of variation in susceptibility to multiple sclerosis captured by common SNPs

    NASA Astrophysics Data System (ADS)

    Watson, Corey T.; Disanto, Giulio; Breden, Felix; Giovannoni, Gavin; Ramagopalan, Sreeram V.

    2012-10-01

    Multiple sclerosis (MS) is a complex disease with underlying genetic and environmental factors. Although the contribution of alleles within the major histocompatibility complex (MHC) are known to exert strong effects on MS risk, much remains to be learned about the contributions of loci with more modest effects identified by genome-wide association studies (GWASs), as well as loci that remain undiscovered. We use a recently developed method to estimate the proportion of variance in disease liability explained by 475,806 single nucleotide polymorphisms (SNPs) genotyped in 1,854 MS cases and 5,164 controls. We reveal that ~30% of MS genetic liability is explained by SNPs in this dataset, the majority of which is accounted for by common variants. These results suggest that the unaccounted for proportion could be explained by variants that are in imperfect linkage disequilibrium with common GWAS SNPs, highlighting the potential importance of rare variants in the susceptibility to MS.

  11. Hubble Legacy Archive (HLA) Pipeline Progression

    NASA Astrophysics Data System (ADS)

    Anderson, Rachel E.; Casertano, S.; Lindsay, K.

    2013-01-01

    The HLA maintains a strong commitment to continuing improvement of our Hubble Space Telescope data processing pipelines with the goal of generating better science-ready data products. The HLA image processing pipeline is transitioning from the use of MultiDrizzle to AstroDrizzle for image registration and combination. It is expected that this change will allow for the creation of higher quality science products with improved astrometric solutions. Headerlets, a newly developed tool for AstroDrizzle, will be utilized and made available to simplify access to multiple astrometric solutions for a given data set. The capabilities of AstroDrizzle will allow for functionally simplified data processing, standardizing and streamlining the data reduction process and making it easier for users to reproduce our results. We are beginning with the HLA WFC3 data processing pipeline, and then plan to extend its application to other HST instrument data.

  12. Detection of 549 new HLA alleles in potential stem cell donors from the United States, Poland and Germany.

    PubMed

    Hernández-Frederick, C J; Cereb, N; Giani, A S; Ruppel, J; Maraszek, A; Pingel, J; Sauter, J; Schmidt, A H; Yang, S Y

    2016-01-01

    We characterized 549 new human leukocyte antigen (HLA) class I and class II alleles found in newly registered stem cell donors as a result of high-throughput HLA typing. New alleles include 101 HLA-A, 132 HLA-B, 105 HLA-C, 2 HLA-DRB1, 89 HLA-DQB1 and 120 HLA-DPB1 alleles. Mainly, new alleles comprised single nucleotide variations when compared with homologous sequences. We identified nonsynonymous nucleotide mutations in 70.7% of all new alleles, synonymous variations in 26.4% and nonsense substitutions in 2.9% (null alleles). Some new alleles (55, 10.0%) were found multiple times, HLA-DPB1 alleles being the most frequent among these. Furthermore, as several new alleles were identified in individuals from ethnic minority groups, the relevance of recruiting donors belonging to such groups and the importance of ethnicity data collection in donor centers and registries is highlighted.

  13. Multiple pathologies are common and related to dementia in the oldest-old

    PubMed Central

    Kim, Ronald C.; Sonnen, Joshua A.; Bullain, Szofia S.; Trieu, Thomas; Corrada, María M.

    2015-01-01

    Objective: The purpose of this study was to examine the role of multiple pathologies in the expression of dementia in the oldest-old. Methods: A total of 183 participants of The 90+ Study with longitudinal follow-up and autopsy were included in this clinical-pathologic investigation. Eight pathologic diagnoses (Alzheimer disease [AD], microinfarcts, hippocampal sclerosis, macroinfarcts, Lewy body disease, cerebral amyloid angiopathy, white matter disease, and others) were dichotomized. We estimated the odds of dementia in relation to each individual pathologic diagnosis and to the total number of diagnoses. We also examined dementia severity in relation to number of pathologic diagnoses. Results: The presence of multiple pathologic diagnoses was common and occurred more frequently in those with dementia compared with those without dementia (45% vs 14%). Higher numbers of pathologic diagnoses were also associated with greater dementia severity. Participants with intermediate/high AD pathology alone were 3 times more likely to have dementia (odds ratio = 3.5), but those with single non-AD pathologies were 12 times more likely to have dementia (odds ratio = 12.4). When a second pathology was present, the likelihood of dementia increased 4-fold in those with intermediate/high AD pathology but did not change in those with non-AD pathologies, suggesting that pathologies may interrelate in different ways. Conclusions: In the oldest-old, the presence of multiple pathologies is associated with increased likelihood and severity of dementia. The effect of the individual pathologies may be additive or perhaps synergistic and requires further research. Multiple pathologies will need to be targeted to reduce the burden of dementia in the population. PMID:26180144

  14. Mutational and structural analysis of KIR3DL1 reveals a lineage-defining allotypic dimorphism that impacts both HLA and peptide sensitivity.

    PubMed

    O'Connor, Geraldine M; Vivian, Julian P; Widjaja, Jacqueline M; Bridgeman, John S; Gostick, Emma; Lafont, Bernard A P; Anderson, Stephen K; Price, David A; Brooks, Andrew G; Rossjohn, Jamie; McVicar, Daniel W

    2014-03-15

    Killer Ig-like receptors (KIRs) control the activation of human NK cells via interactions with peptide-laden HLAs. KIR3DL1 is a highly polymorphic inhibitory receptor that recognizes a diverse array of HLA molecules expressing the Bw4 epitope, a group with multiple polymorphisms incorporating variants within the Bw4 motif. Genetic studies suggest that KIR3DL1 variation has functional significance in several disease states, including HIV infection. However, owing to differences across KIR3DL1 allotypes, HLA-Bw4, and associated peptides, the mechanistic link with biological outcome remains unclear. In this study, we elucidated the impact of KIR3DL1 polymorphism on peptide-laden HLA recognition. Mutational analysis revealed that KIR residues involved in water-mediated contacts with the HLA-presented peptide influence peptide binding specificity. In particular, residue 282 (glutamate) in the D2 domain underpins the lack of tolerance of negatively charged C-terminal peptide residues. Allotypic KIR3DL1 variants, defined by neighboring residue 283, displayed differential sensitivities to HLA-bound peptide, including the variable HLA-B*57:01-restricted HIV-1 Gag-derived epitope TW10. Residue 283, which has undergone positive selection during the evolution of human KIRs, also played a central role in Bw4 subtype recognition by KIR3DL1. Collectively, our findings uncover a common molecular regulator that controls HLA and peptide discrimination without participating directly in peptide-laden HLA interactions. Furthermore, they provide insight into the mechanics of interaction and generate simple, easily assessed criteria for the definition of KIR3DL1 functional groupings that will be relevant in many clinical applications, including bone marrow transplantation.

  15. Human leukocyte antigen (HLA) pharmacogenomic tests: potential and pitfalls.

    PubMed

    Daly, Ann K

    2014-02-01

    Adverse drug reactions involving a range of prescribed drugs and affecting the skin, liver and other organs show strong associations with particular HLA alleles. For some reactions, HLA typing prior to prescription, so that those positive for the risk allele are not given the drug associated with the reaction, shows high positive and negative predictive values. The best example of clinical implementation relates to the hypersensitivity reaction induced by the anti-HIV drug abacavir. When this reaction is phenotyped accurately, 100% of those who develop it are positive for HLA-B*57:01. Drug regulators worldwide now recommend genotyping for HLA-B*57:01 before abacavir is prescribed. Serious skin rashes including Stevens-Johnson syndrome and toxic epidermal necrosis can be induced by carbamazepine and other anticonvulsant drugs. In certain East Asians, these reactions are significantly associated with HLA-B*15:02, and typing for this allele is now recommended prior to carbamazepine prescription in these populations. Other HLA associations have been described for skin rash induced by carbamazepine, allopurinol and nevirapine and for liver injury induced by flucloxacillin, amoxicillin-clavulanate, lapatanib, lumiracoxib and ticlopidine. However, the predictive values for typing HLA alleles associated with these adverse reactions are lower. Clinical implementation therefore seems unlikely. Performing HLA typing is relatively complex compared with genotyping assays for single nucleotide polymorphisms. With emphasis on HLA-B*57:01, the approaches used commonly, including use of sequence-specific oligonucleotide PCR primers and DNA sequencing are considered, together with their successful implementation. Genotyping single nucleotide polymorphisms tagging HLA alleles is a simpler alternative to HLA typing but appears insufficiently accurate for clinical use.

  16. HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies of 10 918 Koreans from bone marrow donor registry in Korea.

    PubMed

    Park, H; Lee, Y-J; Song, E Y; Park, M H

    2016-10-01

    The human leucocyte antigen (HLA) system is the most polymorphic genetic system in humans, and HLA matching is crucial in organ transplantation, especially in hematopoietic stem cell transplantation. We investigated HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies at allelic level in 10 918 Koreans from bone marrow donor registry in Korea. Intermediate resolution HLA typing was performed using Luminex technology (Wakunaga, Japan), and additional allelic level typing was performed using PCR-single-strand conformation polymorphism method and/or sequence-based typing (Abbott Molecular, USA). Allele and haplotype frequencies were calculated by direct counting and maximum likelihood methods, respectively. A total of 39 HLA-A, 66 HLA-B and 47 HLA-DRB1 alleles were identified. High-frequency alleles found at a frequency of ≥5% were 6 HLA-A (A*02:01, *02:06, *11:01, *24:02, *31:01 and *33:03), 6 HLA-B (B*15:01, *35:01, *44:03, *51:01, 54:01 and *58:01) and 8 HLA-DRB1 (DRB1*01:01, *04:05, *04:06, *07:01, *08:03, *09:01, *13:02 and *15:01) alleles. At each locus, A*02, B*15 and DRB1*14 generic groups were most diverse at allelic level, consisting of 9, 12 and 11 different alleles, respectively. A total of 366, 197 and 21 different HLA-A-B-DRB1 haplotypes were estimated with frequencies of ≥0.05%, ≥0.1% and ≥0.5%, respectively. The five most common haplotypes with frequencies of ≥2.0% were A*33:03-B*44:03-DRB1*13:02 (4.97%), A*33:03-B*58:01-DRB1*13:02, A*33:03-B*44:03-DRB1*07:01, A*24:02-B*07:02-DRB1*01:01 and A*24:02-B*52:01-DRB1*15:02. Among 34 serologic HLA-A-B-DR haplotypes with frequencies of ≥0.5%, 17 haplotypes revealed allele-level diversity and majority of the allelic variation was arising from A2, A26, B61, B62, DR4 and DR14 specificities. Haplotype diversity obtained in this study is the most comprehensive data thus far reported in Koreans, and the information will be useful for unrelated stem cell transplantation as well as for disease

  17. The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

    SciTech Connect

    Dai, Shaodong; Crawford, Frances; Marrack, Philippa; Kappler, John W.

    2008-09-05

    Class II major histocompatibility complex (MHCII) molecules present antigens to CD4{sup +} T cells. In addition to the most commonly studied human MHCII isotype, HLA-DR, whose {beta} chain is encoded by the HLA-DRB1 locus, several other isotypes that use the same {alpha} chain but have {beta} chains encoded by other genes. These other DR molecules also are expressed in antigen-presenting cells and are known to participate in peptide presentation to T cells and to be recognized as alloantigens by other T cells. Like some of the HLA-DRB1 alleles, several of these alternate DR molecules have been associated with specific autoimmune diseases and T cell hypersensitivity. Here we present the structure of an HLA-DR molecule (DR52c) containing one of these alternate {beta} chains (HLA-DRB3*0301) bound to a self-peptide derived from the Tu elongation factor. The molecule shares structurally conserved elements with other MHC class II molecules but has some unique features in the peptide-binding groove. Comparison of the three major HLA-DBR3 alleles (DR52a, b, and c) suggests that they were derived from one another by recombination events that scrambled the four major peptide-binding pockets at peptide positions 1, 4, 6, and 9 but left virtually no polymorphisms elsewhere in the molecules.

  18. Histocompatibility alloantigens in psoriasis and psoriatic arthritis. Evidence for the influence of multiple genes in the major histocompatibility complex.

    PubMed Central

    Murray, C; Mann, D L; Gerber, L N; Barth, W; Perlmann, S; Decker, J L; Nigra, T P

    1980-01-01

    The frequency of HLA-A, B, and Cw antigens as well as the antigens expressed preferentially on B cells and monocytes (DRw and Ia-like) was examined in a normal population and two related disease populations, psoriasis and psoriatic arthritis. HLA antigens distinguishing the two disease populations were found. Psoriatic patients demonstrated an increase in frequency of HLA-A1, B17, and B13. Patients with psoriatic arthritis demonstrated an increased frequency of HLA-A26, B38, and DRw4. Antigens showing a common increase in frequency in the two disease populations were HLA-Cw6, DRw7, and Ia744. These results demonstrate genetic differences as well as similarities in the two populations of patients with the common clinical feature of psoriasis. In addition to the above analysis, we examined the association of individual alloantigens elevated in frequency in the diseased population. These same alloantigens were examined for association in the normal population. This analysis revealed HLA antigen associations in the two disease groups that differed from the association of several antigens in the normal population. The results suggest that at least two genetic factors, one mapping in the HLA-A, C-B region and one mapping in the HLA-B-DRw region are associated with the disease states. Thus, multiple factors controlled by genes in the major histocompatibility complex appear to contribute to the disease entities under investigation. PMID:6932404

  19. Multiple independent autonomous hydraulic oscillators driven by a common gravity head.

    PubMed

    Kim, Sung-Jin; Yokokawa, Ryuji; Lesher-Perez, Sasha Cai; Takayama, Shuichi

    2015-06-15

    Self-switching microfluidic circuits that are able to perform biochemical experiments in a parallel and autonomous manner, similar to instruction-embedded electronics, are rarely implemented. Here, we present design principles and demonstrations for gravity-driven, integrated, microfluidic pulsatile flow circuits. With a common gravity head as the only driving force, these fluidic oscillator arrays realize a wide range of periods (0.4 s-2 h) and flow rates (0.10-63 μl min(-1)) with completely independent timing between the multiple oscillator sub-circuits connected in parallel. As a model application, we perform systematic, parallel analysis of endothelial cell elongation response to different fluidic shearing patterns generated by the autonomous microfluidic pulsed flow generation system.

  20. Review: Effect study of sex hormone in the multiple sclerosis of common neurological disorders.

    PubMed

    Xin, Yanyan; Xu, Dayong; Yang, Xiaoqing; Liu, Aizhen; Zhou, Xinhua; Guo, Baozhi

    2015-07-01

    Multiple sclerosis (MS) is one of most common neurological disorders, mainly affecting women. The central nervous system (CNS) of this autoimmune disease is characterized by intermittent or chronic damage to the myelin sheaths (demyelination), local inflammation and axonal degeneration. During the early relapsing/remitting stages of MS, myelin can regenerate. However, as the disease progresses, both amount and activity of regenerated axons becomes insufficient, leading to impaired axon conduction, neurodegeneration and the worsening symptoms. Epidemiological study found that distinct symptom alleviation of diseases at a certain periods would be shown in women during pregnancy. The following basic researches indicated that sex hormones especially progesterone can significantly reduce the disease severity, moreover, the protective effect of sex hormone on the nervous system has become the research focus. PMID:26431667

  1. Multiple independent autonomous hydraulic oscillators driven by a common gravity head

    PubMed Central

    Kim, Sung-Jin; Yokokawa, Ryuji; Lesher-Perez, Sasha Cai; Takayama, Shuichi

    2015-01-01

    Self-switching microfluidic circuits that are able to perform biochemical experiments in a parallel and autonomous manner similar to instruction-embedded electronics, are rarely implemented. Here, we present design principles and demonstrations for gravity-driven, integrated, microfluidic pulsatile flow circuits. With a common gravity-head as the only driving force, these fluidic oscillator arrays realize a wide range of periods (0.4 s – 2 h) and flow rates (0.10 – 63 μL min−1) with completely independent timing between the multiple oscillator sub-circuits connected in parallel. As a model application, we perform systematic, parallel analysis of endothelial cell elongation response to different fluidic shearing patterns generated by the autonomous microfluidic pulsed flow generation system. PMID:26073884

  2. Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients.

    PubMed

    Morandi, Fabio; Pozzi, Sarah; Carlini, Barbara; Amoroso, Loredana; Pistoia, Vito; Corrias, Maria Valeria

    2016-01-01

    The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up. PMID:27610393

  3. Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients

    PubMed Central

    Pozzi, Sarah; Carlini, Barbara; Amoroso, Loredana; Corrias, Maria Valeria

    2016-01-01

    The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up.

  4. Soluble HLA-G and HLA-E Levels in Bone Marrow Plasma Samples Are Related to Disease Stage in Neuroblastoma Patients

    PubMed Central

    Pozzi, Sarah; Carlini, Barbara; Amoroso, Loredana; Corrias, Maria Valeria

    2016-01-01

    The role of nonclassical HLA-class Ib molecules HLA-G and HLA-E in the progression of Neuroblastoma (NB), the most common pediatric extracranial solid tumor, has been characterized in the last years. Since BM infiltration by NB cells is an adverse prognostic factor, we have here analyzed for the first time the concentration of soluble (s)HLA-G and HLA-E in bone marrow (BM) plasma samples from NB patients at diagnosis and healthy donors. sHLA-G and sHLA-E are present in BM plasma samples, and their levels were similar between NB patients and controls, thus suggesting that these molecules are physiologically released by resident or stromal BM cell populations. This hypothesis was supported by the finding that sHLA-G and sHLA-E levels did not correlate with BM infiltration and other adverse prognostic factors (MYCN amplification and age at diagnosis). In contrast, BM plasma levels of both molecules were higher in patients with metastatic disease than in patients with localized NB, thus suggesting that concentration of these molecules might be correlated with disease progression. The prognostic role of sHLA-G and sHLA-E concentration in the BM plasma for NB patients will be evaluated in future studies, by analyzing the clinical outcome of the same NB patients at follow-up. PMID:27610393

  5. HLA-G coding region and 3'untranslated region (3'UTR) in two Chinese Han populations.

    PubMed

    Wang, Wen Yi; Tian, Wei; Liu, Xue Xiang; Li, Li Xin

    2016-08-01

    In this study, exons 2-4 and 3'untranslated region (3'UTR) of human leukocyte antigen (HLA)-G gene were investigated for 201 and 104 healthy unrelated Han samples recruited from Hunan Province, southern China and central Inner Mongolia Autonomous Region, northern China, respectively, using sequence-based typing and cloning methods. Totally 12 HLA-G alleles in the coding region, 9 variable sites in 3'UTR, 8 3'UTR haplotypes and 15 HLA-G extended haplotypes (EHs) incorporating the coding region and 3'UTR were observed. Very strong linkage disequilibrium (LD) was observed between HLA-A and HLA-G, and between HLA-G coding region and 3'UTR in each population (all global P=0.0000). Seven HLA-A-G haplotypes showed significant LD in both populations. Three HLA-G alleles in the coding region, 4 polymorphic sites in the 3'UTR, 3 3'UTR haplotypes and 4 HLA-G EHs differed significantly in their distributions between the 2 Chinese Han populations (all P≤0.0001). There was evidence for balancing selection acting on HLA-G 3'UTR positions +3010, +3142 and +3187 in the two populations. The NJ dendrograms demonstrated the existence of two basic HLA-G lineages and indicated that, HLA-G*01:01:01, the most common HLA-G allele, formed a separate lineage from other alleles. Our results shed new lights into HLA-G genetics among Chinese Han populations. The findings reported here are of importance for future studies related to post-transcriptional regulation of HLA-G allelic expression and the potential role of HLA-G in disease association in populations of Chinese ancestry. PMID:27262928

  6. HLA-G coding region and 3'untranslated region (3'UTR) in two Chinese Han populations.

    PubMed

    Wang, Wen Yi; Tian, Wei; Liu, Xue Xiang; Li, Li Xin

    2016-08-01

    In this study, exons 2-4 and 3'untranslated region (3'UTR) of human leukocyte antigen (HLA)-G gene were investigated for 201 and 104 healthy unrelated Han samples recruited from Hunan Province, southern China and central Inner Mongolia Autonomous Region, northern China, respectively, using sequence-based typing and cloning methods. Totally 12 HLA-G alleles in the coding region, 9 variable sites in 3'UTR, 8 3'UTR haplotypes and 15 HLA-G extended haplotypes (EHs) incorporating the coding region and 3'UTR were observed. Very strong linkage disequilibrium (LD) was observed between HLA-A and HLA-G, and between HLA-G coding region and 3'UTR in each population (all global P=0.0000). Seven HLA-A-G haplotypes showed significant LD in both populations. Three HLA-G alleles in the coding region, 4 polymorphic sites in the 3'UTR, 3 3'UTR haplotypes and 4 HLA-G EHs differed significantly in their distributions between the 2 Chinese Han populations (all P≤0.0001). There was evidence for balancing selection acting on HLA-G 3'UTR positions +3010, +3142 and +3187 in the two populations. The NJ dendrograms demonstrated the existence of two basic HLA-G lineages and indicated that, HLA-G*01:01:01, the most common HLA-G allele, formed a separate lineage from other alleles. Our results shed new lights into HLA-G genetics among Chinese Han populations. The findings reported here are of importance for future studies related to post-transcriptional regulation of HLA-G allelic expression and the potential role of HLA-G in disease association in populations of Chinese ancestry.

  7. Heme Oxygenase-1 and 2 Common Genetic Variants and Risk for Multiple Sclerosis

    PubMed Central

    Agúndez, José A. G.; García-Martín, Elena; Martínez, Carmen; Benito-León, Julián; Millán-Pascual, Jorge; Díaz-Sánchez, María; Calleja, Patricia; Pisa, Diana; Turpín-Fenoll , Laura; Alonso-Navarro, Hortensia; Pastor, Pau; Ortega-Cubero, Sara; Ayuso-Peralta, Lucía; Torrecillas, Dolores; García-Albea, Esteban; Plaza-Nieto, José Francisco; Jiménez-Jiménez, Félix Javier

    2016-01-01

    Several neurochemical, neuropathological, and experimental data suggest a possible role of oxidative stress in the ethiopathogenesis of multiple sclerosis(MS). Heme-oxygenases(HMOX) are an important defensive mechanism against oxidative stress, and HMOX1 is overexpressed in the brain and spinal cord of MS patients and in experimental autoimmune encephalomyelitis(EAE). We analyzed whether common polymorphisms affecting the HMOX1 and HMOX2 genes are related with the risk to develop MS. We analyzed the distribution of genotypes and allelic frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 SNPs, as well as the presence of Copy number variations(CNVs) of these genes in 292 subjects MS and 533 healthy controls, using TaqMan assays. The frequencies of HMOX2 rs1051308AA genotype and HMOX2 rs1051308A and HMOX1 rs2071746A alleles were higher in MS patients than in controls, although only that of the SNP HMOX2 rs1051308 in men remained as significant after correction for multiple comparisons. None of the studied polymorphisms was related to the age at disease onset or with the MS phenotype. The present study suggests a weak association between HMOX2 rs1051308 polymorphism and the risk to develop MS in Spanish Caucasian men and a trend towards association between the HMOX1 rs2071746A and MS risk. PMID:26868429

  8. No evidence for shared genetic basis of common variants in multiple sclerosis and amyotrophic lateral sclerosis

    PubMed Central

    Goris, An; van Setten, Jessica; Diekstra, Frank; Ripke, Stephan; Patsopoulos, Nikolaos A.; Sawcer, Stephen J.; van Es, Michael; Andersen, Peter M.; Melki, Judith; Meininger, Vincent; Hardiman, Orla; Landers, John E.; Brown, Robert H.; Shatunov, Aleksey; Leigh, Nigel; Al-Chalabi, Ammar; Shaw, Christopher E.; Traynor, Bryan J.; Chiò, Adriano; Restagno, Gabriella; Mora, Gabriele; Ophoff, Roel A.; Oksenberg, Jorge R.; Van Damme, Philip; Compston, Alastair; Robberecht, Wim; Dubois, Bénédicte; van den Berg, Leonard H.; De Jager, Philip L.; Veldink, Jan H.; de Bakker, Paul I.W.

    2014-01-01

    Genome-wide association studies have been successful in identifying common variants that influence the susceptibility to complex diseases. From these studies, it has emerged that there is substantial overlap in susceptibility loci between diseases. In line with those findings, we hypothesized that shared genetic pathways may exist between multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). While both diseases may have inflammatory and neurodegenerative features, epidemiological studies have indicated an increased co-occurrence within individuals and families. To this purpose, we combined genome-wide data from 4088 MS patients, 3762 ALS patients and 12 030 healthy control individuals in whom 5 440 446 single-nucleotide polymorphisms (SNPs) were successfully genotyped or imputed. We tested these SNPs for the excess association shared between MS and ALS and also explored whether polygenic models of SNPs below genome-wide significance could explain some of the observed trait variance between diseases. Genome-wide association meta-analysis of SNPs as well as polygenic analyses fails to provide evidence in favor of an overlap in genetic susceptibility between MS and ALS. Hence, our findings do not support a shared genetic background of common risk variants in MS and ALS. PMID:24234648

  9. Gene and Network Analysis of Common Variants Reveals Novel Associations in Multiple Complex Diseases

    PubMed Central

    Nakka, Priyanka; Raphael, Benjamin J.; Ramachandran, Sohini

    2016-01-01

    Genome-wide association (GWA) studies typically lack power to detect genotypes significantly associated with complex diseases, where different causal mutations of small effect may be present across cases. A common, tractable approach for identifying genomic elements associated with complex traits is to evaluate combinations of variants in known pathways or gene sets with shared biological function. Such gene-set analyses require the computation of gene-level P-values or gene scores; these gene scores are also useful when generating hypotheses for experimental validation. However, commonly used methods for generating GWA gene scores are computationally inefficient, biased by gene length, imprecise, or have low true positive rate (TPR) at low false positive rates (FPR), leading to erroneous hypotheses for functional validation. Here we introduce a new method, PEGASUS, for analytically calculating gene scores. PEGASUS produces gene scores with as much as 10 orders of magnitude higher numerical precision than competing methods. In simulation, PEGASUS outperforms existing methods, achieving up to 30% higher TPR when the FPR is fixed at 1%. We use gene scores from PEGASUS as input to HotNet2 to identify networks of interacting genes associated with multiple complex diseases and traits; this is the first application of HotNet2 to common variation. In ulcerative colitis and waist–hip ratio, we discover networks that include genes previously associated with these phenotypes, as well as novel candidate genes. In contrast, existing methods fail to identify these networks. We also identify networks for attention-deficit/hyperactivity disorder, in which GWA studies have yet to identify any significant SNPs. PMID:27489002

  10. Coding Variants at Hexa-allelic Amino Acid 13 of HLA-DRB1 Explain Independent SNP Associations with Follicular Lymphoma Risk

    PubMed Central

    Foo, Jia Nee; Smedby, Karin E.; Akers, Nicholas K.; Berglund, Mattias; Irwan, Ishak D.; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M.; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F.; de Bakker, Paul I.W.; Liu, Jianjun

    2013-01-01

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10−15). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9–6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10−14). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis. PMID:23791106

  11. Coding variants at hexa-allelic amino acid 13 of HLA-DRB1 explain independent SNP associations with follicular lymphoma risk.

    PubMed

    Foo, Jia Nee; Smedby, Karin E; Akers, Nicholas K; Berglund, Mattias; Irwan, Ishak D; Jia, Xiaoming; Li, Yi; Conde, Lucia; Darabi, Hatef; Bracci, Paige M; Melbye, Mads; Adami, Hans-Olov; Glimelius, Bengt; Khor, Chiea Chuen; Hjalgrim, Henrik; Padyukov, Leonid; Humphreys, Keith; Enblad, Gunilla; Skibola, Christine F; de Bakker, Paul I W; Liu, Jianjun

    2013-07-11

    Non-Hodgkin lymphoma represents a diverse group of blood malignancies, of which follicular lymphoma (FL) is a common subtype. Previous genome-wide association studies (GWASs) have identified in the human leukocyte antigen (HLA) class II region multiple independent SNPs that are significantly associated with FL risk. To dissect these signals and determine whether coding variants in HLA genes are responsible for the associations, we conducted imputation, HLA typing, and sequencing in three independent populations for a total of 689 cases and 2,446 controls. We identified a hexa-allelic amino acid polymorphism at position 13 of the HLA-DR beta chain that showed the strongest association with FL within the major histocompatibility complex (MHC) region (multiallelic p = 2.3 × 10⁻¹⁵). Out of six possible amino acids that occurred at that position within the population, we classified two as high risk (Tyr and Phe), two as low risk (Ser and Arg), and two as moderate risk (His and Gly). There was a 4.2-fold difference in risk (95% confidence interval = 2.9-6.1) between subjects carrying two alleles encoding high-risk amino acids and those carrying two alleles encoding low-risk amino acids (p = 1.01 × 10⁻¹⁴). This coding variant might explain the complex SNP associations identified by GWASs and suggests a common HLA-DR antigen-driven mechanism for the pathogenesis of FL and rheumatoid arthritis.

  12. HLA and fertility

    SciTech Connect

    Ober, C.

    1995-11-01

    The recent paper by Jin et al., reporting that class 11 region major histocompatibility complex genes may influence embryonic loss in outbred couples supports previous results of our studies of HLA and fertility in the Hutterites. However, the authors have incorrectly cited our work and have omitted the reference that is most relevant to their results. The paper by Kostyu et al. is incorrectly referred to in the introduction as providing evidence for HLA sharing being associated with recurrent spontaneous abortion. The Kostyu et al. paper does not include any data on fertility or reproduction but reports frequencies of individuals who are homozygous at the HLA-A, -C, -B, -DR, and -DQ loci in the Hutterite population. In fact, recurrent spontaneous abortion has not been observed in any of the couples in our sample of >500 Hutterite couples. References more appropriate to the association between HLA sharing and recurrent miscarriage are those by Komlos et al., Schacter et al., Gerencer and Kastelan, and Beer et al. It might also be worth pointing out that many studies of recurrent miscarriage in outbred couples have not found an association with HLA sharing; examples include the studies of Ergolu et al., Oksenberg et al., and Christiansen et al., among others. 11 refs.

  13. 40 CFR 75.17 - Specific provisions for monitoring emissions from common, bypass, and multiple stacks for NOX...

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... emissions from common, bypass, and multiple stacks for NOX emission rate. 75.17 Section 75.17 Protection of..., and multiple stacks for NOX emission rate. Notwithstanding the provisions of paragraphs (a), (b), (c... this part to meet the monitoring and reporting requirements of a State or federal NOX mass...

  14. 40 CFR 75.17 - Specific provisions for monitoring emissions from common, bypass, and multiple stacks for NOX...

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... emissions from common, bypass, and multiple stacks for NOX emission rate. 75.17 Section 75.17 Protection of... MONITORING Monitoring Provisions § 75.17 Specific provisions for monitoring emissions from common, bypass... § 75.17(d) for units with bypass stacks. Further, this option shall not be used unless the...

  15. Feasibility and utility of applications of the common data model to multiple, disparate observational health databases

    PubMed Central

    Makadia, Rupa; Matcho, Amy; Ma, Qianli; Knoll, Chris; Schuemie, Martijn; DeFalco, Frank J; Londhe, Ajit; Zhu, Vivienne; Ryan, Patrick B

    2015-01-01

    Objectives To evaluate the utility of applying the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) across multiple observational databases within an organization and to apply standardized analytics tools for conducting observational research. Materials and methods Six deidentified patient-level datasets were transformed to the OMOP CDM. We evaluated the extent of information loss that occurred through the standardization process. We developed a standardized analytic tool to replicate the cohort construction process from a published epidemiology protocol and applied the analysis to all 6 databases to assess time-to-execution and comparability of results. Results Transformation to the CDM resulted in minimal information loss across all 6 databases. Patients and observations excluded were due to identified data quality issues in the source system, 96% to 99% of condition records and 90% to 99% of drug records were successfully mapped into the CDM using the standard vocabulary. The full cohort replication and descriptive baseline summary was executed for 2 cohorts in 6 databases in less than 1 hour. Discussion The standardization process improved data quality, increased efficiency, and facilitated cross-database comparisons to support a more systematic approach to observational research. Comparisons across data sources showed consistency in the impact of inclusion criteria, using the protocol and identified differences in patient characteristics and coding practices across databases. Conclusion Standardizing data structure (through a CDM), content (through a standard vocabulary with source code mappings), and analytics can enable an institution to apply a network-based approach to observational research across multiple, disparate observational health databases. PMID:25670757

  16. Immunogenetics of HLA.

    PubMed

    Bach, F H

    1991-01-01

    The enormous contributions of Professor Karl Landsteiner are summarized focusing on his discovery of the ABO, MN, and P blood group systems as well as his conceptualization of the hapten concept. The HLA system, the major histocompatibility complex in humans, is discussed from the point of view of its genetic organization, the polymorphism that is recognized by T lymphocytes and the presently defined molecular polymorphism. The structure-function relationship of T cell recognition of class II molecules, based on the known crystallographic structure of an HLA class I molecule, is presented.

  17. Association of HLA-A and Non-Classical HLA Class I Alleles

    PubMed Central

    Carlini, Federico; Ferreira, Virginia; Buhler, Stéphane; Tous, Audrey; Eliaou, Jean-François; René, Céline; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

    2016-01-01

    The HLA-A locus is surrounded by HLA class Ib genes: HLA-E, HLA-H, HLA-G and HLA-F. HLA class Ib molecules are involved in immuno-modulation with a central role for HLA-G and HLA-E, an emerging role for HLA-F and a yet unknown function for HLA-H. Thus, the principal objective of this study was to describe the main allelic associations between HLA-A and HLA-H, -G, -F and -E. Therefore, HLA-A, -E, -G, -H and -F coding polymorphisms, as well as HLA-G UnTranslated Region haplotypes (referred to as HLA-G UTRs), were explored in 191 voluntary blood donors. Allelic frequencies, Global Linkage Disequilibrium (GLD), Linkage Disequilibrium (LD) for specific pairs of alleles and two-loci haplotype frequencies were estimated. We showed that HLA-A, HLA-H, HLA-F, HLA-G and HLA-G UTRs were all in highly significant pairwise GLD, in contrast to HLA-E. Moreover, HLA-A displayed restricted associations with HLA-G UTR and HLA-H. We also confirmed several associations that were previously found to have a negative impact on transplantation outcome. In summary, our results suggest complex functional and clinical implications of the HLA-A genetic region. PMID:27701438

  18. A common rejection module (CRM) for acute rejection across multiple organs identifies novel therapeutics for organ transplantation.

    PubMed

    Khatri, Purvesh; Roedder, Silke; Kimura, Naoyuki; De Vusser, Katrien; Morgan, Alexander A; Gong, Yongquan; Fischbein, Michael P; Robbins, Robert C; Naesens, Maarten; Butte, Atul J; Sarwal, Minnie M

    2013-10-21

    Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.

  19. Sexual selection, multiple male ornaments, and age- and condition-dependent signaling in the common yellowthroat.

    PubMed

    Freeman-Gallant, Corey R; Taff, Conor C; Morin, Douglas F; Dunn, Peter O; Whittingham, Linda A; Tsang, Susan M

    2010-04-01

    In many animals, sexual selection has resulted in complex signaling systems in which males advertise aspects of their phenotypic or genetic quality through elaborate ornamentation and display behaviors. Different ornaments might convey different information or be directed at different receivers, but they might also be redundant signals of quality that function reliably at different times (ages) or in different contexts. We explored sexual selection and age- and condition-dependent signaling in the common yellowthroat (Geothlypis trichas), a sexually dichromatic warbler with two prominent plumage ornaments--a melanin-based, black facial "mask" and carotenoid-based, UV-yellow "bib." In a three-year study, variance among males in the number of social (M(w)) and extra-pair (M(e)) mates generated strong sexual selection on mask and bib attributes. Some traits (mask size, bib yellow brightness) were correlated with male age and did not experience selection beyond age-related increases in M(w) and M(e). Other traits showed age-specific (bib size) or age-reversed (ultraviolet brightness) patterns of selection that paralleled changes in the information-content of each ornament. The components of male fitness generating selection in young versus old males were distinct, reflecting different sources of variation in male fertilization success. Age- and context-dependent changes in the strength, direction, and target of selection may help explain the maintenance of multiple ornaments in this and other species.

  20. Multiple payers, commonality and free-riding in health care: Medicare and private payers.

    PubMed

    Glazer, Jacob; McGuire, Thomas G

    2002-11-01

    Managed health care plans and providers in the US and elsewhere sell their services to multiple payers. For example, the three largest groups of purchasers from health plans in the US are employers, Medicaid plans, and Medicare, with the first two accounting for over 90% of the total enrollees. In the case of hospitals, Medicare is the largest buyer, but it alone only accounts for 40% of the total payments. While payers have different objectives and use different contracting practices, the plans and providers set some elements of the quality in common for all payers. In this paper, we study the interactions between a public payer, modeled on Medicare, which sets a price and takes any willing provider, a private payer, which limits providers and pays a price on the basis of quality, and a provider/plan, in the presence of shared elements of quality. The provider compromises in response to divergent incentives from payers. The private sector dilutes Medicare payment initiatives, and may, under some circumstances, repair Medicare payment policy mistakes. If Medicare behaves strategically in the presence of private payers, it can free-ride on the private payer and set its prices too low. Our paper has many testable implications, including a new hypothesis for why Medicare has failed to gain acceptance of health plans in the US. PMID:12475125

  1. A Space-Bounded Anytime Algorithm for the Multiple Longest Common Subsequence Problem

    PubMed Central

    Yang, Jiaoyun; Xu, Yun; Shang, Yi; Chen, Guoliang

    2014-01-01

    The multiple longest common subsequence (MLCS) problem, related to the identification of sequence similarity, is an important problem in many fields. As an NP-hard problem, its exact algorithms have difficulty in handling large-scale data and time- and space-efficient algorithms are required in real-world applications. To deal with time constraints, anytime algorithms have been proposed to generate good solutions with a reasonable time. However, there exists little work on space-efficient MLCS algorithms. In this paper, we formulate the MLCS problem into a graph search problem and present two space-efficient anytime MLCS algorithms, SA-MLCS and SLA-MLCS. SA-MLCS uses an iterative beam widening search strategy to reduce space usage during the iterative process of finding better solutions. Based on SA-MLCS, SLA-MLCS, a space-bounded algorithm, is developed to avoid space usage from exceeding available memory. SLA-MLCS uses a replacing strategy when SA-MLCS reaches a given space bound. Experimental results show SA-MLCS and SLA-MLCS use an order of magnitude less space and time than the state-of-the-art approximate algorithm MLCS-APP while finding better solutions. Compared to the state-of-the-art anytime algorithm Pro-MLCS, SA-MLCS and SLA-MLCS can solve an order of magnitude larger size instances. Furthermore, SLA-MLCS can find much better solutions than SA-MLCS on large size instances. PMID:25400485

  2. A Space-Bounded Anytime Algorithm for the Multiple Longest Common Subsequence Problem.

    PubMed

    Yang, Jiaoyun; Xu, Yun; Shang, Yi; Chen, Guoliang

    2014-11-01

    The multiple longest common subsequence (MLCS) problem, related to the identification of sequence similarity, is an important problem in many fields. As an NP-hard problem, its exact algorithms have difficulty in handling large-scale data and time- and space-efficient algorithms are required in real-world applications. To deal with time constraints, anytime algorithms have been proposed to generate good solutions with a reasonable time. However, there exists little work on space-efficient MLCS algorithms. In this paper, we formulate the MLCS problem into a graph search problem and present two space-efficient anytime MLCS algorithms, SA-MLCS and SLA-MLCS. SA-MLCS uses an iterative beam widening search strategy to reduce space usage during the iterative process of finding better solutions. Based on SA-MLCS, SLA-MLCS, a space-bounded algorithm, is developed to avoid space usage from exceeding available memory. SLA-MLCS uses a replacing strategy when SA-MLCS reaches a given space bound. Experimental results show SA-MLCS and SLA-MLCS use an order of magnitude less space and time than the state-of-the-art approximate algorithm MLCS-APP while finding better solutions. Compared to the state-of-the-art anytime algorithm Pro-MLCS, SA-MLCS and SLA-MLCS can solve an order of magnitude larger size instances. Furthermore, SLA-MLCS can find much better solutions than SA-MLCS on large size instances.

  3. Reduced Response to Multiple Vaccines Sharing Common Protein Epitopes That Are Administered Simultaneously to Infants

    PubMed Central

    Dagan, Ron; Eskola, Juhani; Leclerc, Claude; Leroy, Odile

    1998-01-01

    The plethora of newly discovered vaccines implies that, in the future, many vaccines will have to be administered simultaneously to infants. We examined the potential interference with the immune response of several coadministered vaccines containing the same protein component, namely, tetanus toxoid (TT). Infants simultaneously receiving a tetravalent pneumococcal vaccine conjugated to TT (PncT) and a diphtheria-tetanus-pertussis–poliovirus–Haemophilus influenzae type b-tetanus conjugate vaccine showed significantly lower anti-H. influenzae type b polysaccharide (polyribosylribitol phosphate [PRP]) antibody concentrations than those receiving either a tetravalent pneumococcal vaccine conjugated to diphtheria toxoid or placebo. A dose range study showed that anti-PRP antibody concentrations were inversely related to the TT content of the PncT vaccines administered in infancy. Postimmunization antitetanus antibody concentrations were also affected adversely as the TT content of the coadministered vaccines was increased. This phenomenon, which we believe derives from interference by a common protein carrier, should be taken into account when the introduction of an immunization program including multiple conjugate vaccines is considered. PMID:9573094

  4. Rare HLA drive additional HIV evolution compared to more frequent alleles.

    PubMed

    Rousseau, Christine M; Lockhart, David W; Listgarten, Jennifer; Maley, Stephen N; Kadie, Carl; Learn, Gerald H; Nickle, David C; Heckerman, David E; Deng, Wenjie; Brander, Christian; Ndung'u, Thumbi; Coovadia, Hoosen; Goulder, Philip J R; Korber, Bette T; Walker, Bruce D; Mullins, James I

    2009-03-01

    HIV-1 can evolve HLA-specific escape variants in response to HLA-mediated cellular immunity. HLA alleles that are common in the host population may increase the frequency of such escape variants at the population level. When loss of viral fitness is caused by immune escape variation, these variants may revert upon infection of a new host who does not have the corresponding HLA allele. Furthermore, additional escape variants may appear in response to the nonconcordant HLA alleles. Because individuals with rare HLA alleles are less likely to be infected by a partner with concordant HLA alleles, viral populations infecting hosts with rare HLA alleles may undergo a greater amount of evolution than those infecting hosts with common alleles due to the loss of preexisting escape variants followed by new immune escape. This hypothesis was evaluated using maximum likelihood phylogenetic trees of each gene from 272 full-length HIV-1 sequences. Recent viral evolution, as measured by the external branch length, was found to be inversely associated with HLA frequency in nef (p < 0.02), env (p < 0.03), and pol (p < or = 0.05), suggesting that rare HLA alleles provide a disproportionate force driving viral evolution compared to common alleles, likely due to the loss of preexisting escape variants during early stages postinfection.

  5. Anthrax lethal factor as an immune target in humans and transgenic mice and the impact of HLA polymorphism on CD4+ T cell immunity.

    PubMed

    Ascough, Stephanie; Ingram, Rebecca J; Chu, Karen K; Reynolds, Catherine J; Musson, Julie A; Doganay, Mehmet; Metan, Gökhan; Ozkul, Yusuf; Baillie, Les; Sriskandan, Shiranee; Moore, Stephen J; Gallagher, Theresa B; Dyson, Hugh; Williamson, E Diane; Robinson, John H; Maillere, Bernard; Boyton, Rosemary J; Altmann, Daniel M

    2014-05-01

    Bacillus anthracis produces a binary toxin composed of protective antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). Most studies have concentrated on induction of toxin-specific antibodies as the correlate of protective immunity, in contrast to which understanding of cellular immunity to these toxins and its impact on infection is limited. We characterized CD4+ T cell immunity to LF in a panel of humanized HLA-DR and DQ transgenic mice and in naturally exposed patients. As the variation in antigen presentation governed by HLA polymorphism has a major impact on protective immunity to specific epitopes, we examined relative binding affinities of LF peptides to purified HLA class II molecules, identifying those regions likely to be of broad applicability to human immune studies through their ability to bind multiple alleles. Transgenics differing only in their expression of human HLA class II alleles showed a marked hierarchy of immunity to LF. Immunogenicity in HLA transgenics was primarily restricted to epitopes from domains II and IV of LF and promiscuous, dominant epitopes, common to all HLA types, were identified in domain II. The relevance of this model was further demonstrated by the fact that a number of the immunodominant epitopes identified in mice were recognized by T cells from humans previously infected with cutaneous anthrax and from vaccinated individuals. The ability of the identified epitopes to confer protective immunity was demonstrated by lethal anthrax challenge of HLA transgenic mice immunized with a peptide subunit vaccine comprising the immunodominant epitopes that we identified.

  6. Polymorphisms of HLA-A, -B, -Cw and DRB1 antigens in Moroccan patients with ankylosing spondylitis and a comparison of clinical features with frequencies of HLA-B*27.

    PubMed

    El Mouraghi, I; Ouarour, A; Ghozlani, I; Collantes, E; Solana, R; El Maghraoui, A

    2015-02-01

    Ankylosing spondylitis (AS) is very often associated with human leukocyte antigen (HLA), particularly HLA-B*27. However, the strength of this association and clinical features may vary in different ethnic groups. Our study aims to assess the distribution of HLA-A, -B, -Cw and DRB1 alleles in Moroccan patients with AS and to compare the clinical features of AS and the frequencies of HLA-B27 in patients from Morocco with other series. Seventy-five patients diagnosed with AS and assessed for clinical manifestations were selected and compared to 100 healthy controls. HLA class I and II antigens were typed by polymerase chain reaction sequence-specific oligonucleotide. HLA-B27 subtypes were studied by polymerase chain reaction amplification with sequence-specific primers. HLA-B27 was found in 64% of patients. It was positively associated with younger age at disease onset, family history, and uveitis while it had a negative association with late onset. Six B*27 subtypes were identified in the AS group. HLA-B*2705 and B*2702 were the most common observed subtypes. Among other HLA genes, a significant increase in the prevalence of HLA-Cw*02 and HLA-DRB*15 was found in AS patients. HLA-B27 is involved in the predisposition of AS in the Moroccan population. HLA-B*2705 and B*2702 were the predominant subtypes supporting previous reports in Caucasian spondyloarthropathies. Other HLA genes, HLA-Cw*02 and HLA-DRB1*15, seem to confer predisposing effect to the disease. However, the lower frequency of HLA-B27 compared to the literature in our study suggests the existence of different genetic and/or environmental factors in Morocco.

  7. Optic neuritis, the most common initial presenting manifestation of multiple sclerosis in northern Iran

    PubMed Central

    Hojjati, Seyed Mohammad Masoud; Zarghami, Amin; Hojjati, Seyed Ali; Baes, Mobina

    2015-01-01

    Background: Multiple sclerosis (MS) is an inflammatory and demyelinating disease of central nervous system (CNS). The aim of the present study was to determine the type and the frequency of initial presenting symptoms in patients with MS and their relation with demographic characteristics in Babol, northern Iran. Methods: All patients of this study were recruited over a ten year period from 2002 to 2012 from single neurologic clinic. Diagnosis of MS was confirmed according to the McDonald criteria, demographic and clinical features Then, all the clinical findings and demographic variables including: age, sex, marital status, age at onset, education, place of residence, disease duration, initiation pattern of disease have been collected. Expanded Disability Status Scale (EDSS) was used for the evaluation of disability at the onset of disease. Data analysis was performed by chi-square test. Results: A total of 263 consecutive MS patients with the age range of 17 to 61 yr were examined. Optic neuritis was the most prevalent initial presenting symptom in 123 (46.8%) patients followed by sensory disturbances as the second common presenting symptom of MS. Significant difference was found between patients with or without optic neuritis and the onset age of the disease and EDSS (p<0.001). The mean EDSS score at the time of initial presentation was 1.67±0.77. Conclusion: The findings of this study indicated that optic neuritis is the most prevalent initial presentation of MS in the geographic region of northern Iran. In patients less than 30 years, development of visual disturbances justifies neurologic examination. PMID:26644882

  8. Disabled-1 is a large common fragile site gene, inactivated in multiple cancers.

    PubMed

    McAvoy, Sarah; Zhu, Yu; Perez, Damon S; James, C David; Smith, David I

    2008-02-01

    Common fragile sites (CFS) are large, genomically unstable regions, which are hot-spots for deletions and other alterations, especially in cancer cells. Several have been shown to contain genes that span large genomic regions, such as FHIT (1.5 Mb), WWOX (1.0 Mb), GRID2 (1.36 Mb), PARK2 (1.3 Mb), and RORA (730 kb). These genes are frequently inactivated in multiple different cancers, and FHIT and WWOX are shown to function as tumor suppressors. The disabled-1 gene (DAB1) is one of the human homologs of the Drosophila disabled locus, which in mammals is involved in neuronal migration and lamination in the developing cerebral cortex. Mice DAB1 inactivation results in the neurological mutant Scrambler, having similarities to mice with the inactivation of PARK2 (Quaker), GRID2 (Lurcher), and RORA (Staggerer). We were interested in whether DAB1 was another large CFS gene that could have cancer development importance. We demonstrated here that the human DAB1 gene (spanning 1.25 Mb) mapped within FRA1B CFS region on chromosomal band 1p32.2. Real-time RT-PCR analysis revealed that the expression level of DAB1 was decreased in many human cancer samples, including primary tumor tissues and cancer-derived cell lines, from several different cancers, especially in brain and endometrial cancer. Additionally, the introduction of an over-expression DAB1 plasmid into two different cell lines, having insignificant endogenous DAB1 expression, resulted in decreased cell growth. In summary, DAB1 is another gene that resides within an unstable CFS region and might play a role in human tumorigenesis. These data may provide further linkage between neurological development and cancer.

  9. The Protective Role of HLA-DRB1(∗)13 in Autoimmune Diseases.

    PubMed

    Bettencourt, Andreia; Carvalho, Cláudia; Leal, Bárbara; Brás, Sandra; Lopes, Dina; Martins da Silva, Ana; Santos, Ernestina; Torres, Tiago; Almeida, Isabel; Farinha, Fátima; Barbosa, Paulo; Marinho, António; Selores, Manuela; Correia, João; Vasconcelos, Carlos; Costa, Paulo P; da Silva, Berta Martins

    2015-01-01

    Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1(∗)15 (OR = 2.17) and HLA-DRB1(∗)03 (OR = 1.81) alleles with MS, HLA-DRB1(∗)03 with SLE (OR = 2.49), HLA-DRB1(∗)01 (OR = 1.79) and HLA-DRB1(∗)04 (OR = 2.81) with RA, HLA-DRB1(∗)07 with Ps + PsA (OR = 1.79), HLA-DRB1(∗)01 (OR = 2.28) and HLA-DRB1(∗)08 (OR = 3.01) with SSc, and HLA-DRB1(∗)03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1(∗)13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1(∗)13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1(∗)13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1(∗)13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection. PMID:26605347

  10. The Protective Role of HLA-DRB1∗13 in Autoimmune Diseases

    PubMed Central

    Bettencourt, Andreia; Carvalho, Cláudia; Leal, Bárbara; Brás, Sandra; Lopes, Dina; Martins da Silva, Ana; Santos, Ernestina; Torres, Tiago; Almeida, Isabel; Farinha, Fátima; Barbosa, Paulo; Marinho, António; Selores, Manuela; Correia, João; Vasconcelos, Carlos; Costa, Paulo P.; da Silva, Berta Martins

    2015-01-01

    Autoimmune diseases (AIDs) are characterized by a multifactorial aetiology and a complex genetic background, with the MHC region playing a major role. We genotyped for HLA-DRB1 locus 1228 patients with AIDs-213 with Systemic Lupus Erythematosus (SLE), 166 with Psoriasis or Psoriatic Arthritis (Ps + PsA), 153 with Rheumatoid Arthritis (RA), 67 with Systemic Sclerosis (SSc), 536 with Multiple Sclerosis (MS), and 93 with Myasthenia Gravis (MG) and 282 unrelated controls. We confirmed previously established associations of HLA-DRB1∗15 (OR = 2.17) and HLA-DRB1∗03 (OR = 1.81) alleles with MS, HLA-DRB1∗03 with SLE (OR = 2.49), HLA-DRB1∗01 (OR = 1.79) and HLA-DRB1∗04 (OR = 2.81) with RA, HLA-DRB1∗07 with Ps + PsA (OR = 1.79), HLA-DRB1∗01 (OR = 2.28) and HLA-DRB1∗08 (OR = 3.01) with SSc, and HLA-DRB1∗03 with MG (OR = 2.98). We further observed a consistent negative association of HLA-DRB1∗13 allele with SLE, Ps + PsA, RA, and SSc (18.3%, 19.3%, 16.3%, and 11.9%, resp., versus 29.8% in controls). HLA-DRB1∗13 frequency in the AIDs group was 20.0% (OR = 0.58). Although different alleles were associated with particular AIDs, the same allele, HLA-DRB1∗13, was underrepresented in all of the six diseases analysed. This observation suggests that this allele may confer protection for AIDs, particularly for systemic and rheumatic disease. The protective effect of HLA-DRB1∗13 could be explained by a more proficient antigen presentation by these molecules, favouring efficient clonal deletion during thymic selection. PMID:26605347

  11. Specific HLA-DQB and HLA-DRB1 alleles confer susceptibility to pemphigus vulgaris.

    PubMed Central

    Scharf, S J; Freidmann, A; Steinman, L; Brautbar, C; Erlich, H A

    1989-01-01

    The autoimmune dermatologic disease pemphigus vulgaris (PV) is associated with the serotypes HLA-DR4 and HLA-DRw6. Based on nucleotide sequence and oligonucleotide probe analysis of enzymatically amplified DNA encoding HLA-DR beta chain (HLA-DRB) and HLA-DQ beta chain (HLA-DQB; henceforth HLA is omitted from designations), we showed previously that the DR4 susceptibility was associated with the Dw10 DRB1 allele [encoding the mixed lymphocyte culture (MLC)-defined Dw10 specificity]. The DRw6 susceptibility similarly was shown to be associated with a rare DQB allele (DQB1.3), which differed from another nonsusceptible allele by only a valine-to-aspartic acid substitution at position 57. Given the linkage disequilibrium that characterizes HLA haplotypes, it is difficult to assign disease susceptibility to a specific locus rather than to a closely linked gene(s) on the same haplotype. To address this problem, we have analyzed all of the polymorphic loci of the class II HLA region (DRB1, DRB3, DQA, DQB, and DPB) on the DRw6 haplotypes in patients and controls. In 22 PV patients, 4 different DRw6 haplotypes were found that encode the same DQ beta chain (DQB1.3) but contained silent nucleotide differences at the DQB locus as well as coding sequence differences in the DQA and DRB loci. These results, obtained by using a method for allele-specific polymerase chain reaction amplification, strongly support the hypothesis that the allele DQB1.3 confers susceptibility. This DQB allele is correlated with the MLC-defined Dw9 specificity and is associated with two different DRB1 alleles (the common "6A" associated with DRw13 and the rare "6B" associated with DRw14). Since 86% (19 of 22) of DRw6+ patients contain the DQB1.3 allele (vs. 3% of controls), whereas 64% (14 of 22) contain the DRB1 allele 6B (vs. 6% of the controls), we conclude that most of the DRw6 susceptibility to PV can be accounted for by the DQ beta chain. Images PMID:2503828

  12. Human leukocyte antigen (HLA)-E and HLA-F expression in gastric cancer.

    PubMed

    Ishigami, Sumiya; Arigami, Takaaki; Okumura, Hiroshi; Uchikado, Yasuto; Kita, Yoshiaki; Kurahara, Hiroshi; Maemura, Kosei; Kijima, Yuko; Ishihara, Yuka; Sasaki, Ken; Uenosono, Yoshikazu; Natsugoe, Shoji

    2015-04-01

    Human leukocyte antigen (HLA)-E and HLA-F are classified as non-classical HLA class Ib antigens. Ectopic HLA-E and HLA-F expression was recently detected in cancer cells; however, the clinical implication of their expression remains unknown. A total of 209 patients with gastric cancer were enrolled in this study. Immunohistochemistry was used to evaluate the expression of HLA-E and HLA-F in gastric cancer specimens. HLA-E and HLA-F expression were seen in the cell membrane. HLA-E and HLA-F expression significantly correlated with depth of invasion, nodal involvement, lymphatic invasion, and venous invasion. No significant correlation between HLA-E and HLA-F expression was found (p<0.05, r=0.24). The five-year survival rate of the HLA-E-positive group and HLA-F-positive group were significantly poorer than that of their respective negative groups. Combination of HLA-E and HLA-F made the p-value smaller than single analysis (p<0.009). This is the first report detailing a clinical implication of HLA-E and HLA-F expression simultaneously in gastric cancer. We identified that the HLA-E and HLA-F in gastric cancer independently affected clinical factors, including postoperative outcome. For HLA-E- or HLA-F-positive gastric cancer, we should settle on a treatment strategy that reinforces the host immune response.

  13. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors

    PubMed Central

    Torikai, Hiroki; Reik, Andreas; Soldner, Frank; Warren, Edus H.; Yuen, Carrie; Zhou, Yuanyue; Crossland, Denise L.; Huls, Helen; Littman, Nicholas; Zhang, Ziying; Tykodi, Scott S.; Kebriaei, Partow; Lee, Dean A.; Miller, Jeffrey C.; Rebar, Edward J.; Holmes, Michael C.; Jaenisch, Rudolf; Champlin, Richard E.; Gregory, Philip D.

    2013-01-01

    Long-term engraftment of allogeneic cells necessitates eluding immune-mediated rejection, which is currently achieved by matching for human leukocyte antigen (HLA) expression, immunosuppression, and/or delivery of donor-derived cells to sanctuary sites. Genetic engineering provides an alternative approach to avoid clearance of cells that are recognized as “non-self” by the recipient. To this end, we developed designer zinc finger nucleases and employed a “hit-and-run” approach to genetic editing for selective elimination of HLA expression. Electro-transfer of mRNA species coding for these engineered nucleases completely disrupted expression of HLA-A on human T cells, including CD19-specific T cells. The HLA-Aneg T-cell pools can be enriched and evade lysis by HLA-restricted cytotoxic T-cell clones. Recognition by natural killer cells of cells that had lost HLA expression was circumvented by enforced expression of nonclassical HLA molecules. Furthermore, we demonstrate that zinc finger nucleases can eliminate HLA-A expression from embryonic stem cells, which broadens the applicability of this strategy beyond infusing HLA-disparate immune cells. These findings establish that clinically appealing cell types derived from donors with disparate HLA expression can be genetically edited to evade an immune response and provide a foundation whereby cells from a single donor can be administered to multiple recipients. PMID:23741009

  14. HLA class II and autoimmunity: epitope selection vs differential expression.

    PubMed

    Müller-Hilke, Brigitte

    2009-01-01

    Autoimmune diseases like rheumatoid arthritis (RA), multiple sclerosis, psoriasis and insulin-dependent diabetes mellitus are subject to a complex pathogenesis controlled by multiple genes and numerous environmental factors. The strongest genetic association is with certain HLA class II haplotypes and we here summarize the evidence supporting differential expression as a mechanism supporting the autoimmune process. PMID:19118870

  15. [Frequency of HLA-A, HLA-B and HLA-Cw antigens in the Slovak population].

    PubMed

    Kralovicova, J; Kusikova, M; Buc, M; Holomanova, D; Sakalova, A

    2000-01-01

    Results on HLA-A, -B and -Cw antigen frequencies in the Slovak population are presented. HLA-A, -B, -Cw antigens were determined in 654 healthy unrelated individuals. The highest frequency was observed for the antigens HLA-A2, -A1; HLA-B12, -B35, and HLA-Cw8. The least frequent antigens were HLA-A34, -A36, HLA-B58, -B67, -B70, -B77, and HLA-Cw8. The results were compared with those of the previous study and with those of Czech, Austrian and Hungarian populations. No statistically significant differences were observed. (Tab. 5, Fig. 2, Ref. 9.)

  16. 40 CFR 75.72 - Determination of NOX mass emissions for common stack and multiple stack configurations.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 17 2014-07-01 2014-07-01 false Determination of NOX mass emissions... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTINUOUS EMISSION MONITORING NOX Mass Emissions Provisions § 75.72 Determination of NOX mass emissions for common stack and multiple...

  17. Combining Multiple Performance Measures: Do Common Approaches Undermine Districts' Personnel Evaluation Systems? CALDER Working Paper No. 118

    ERIC Educational Resources Information Center

    Hansen, Michael; Lemke, Mariann; Sorensen, Nicholas

    2014-01-01

    Teacher and principal evaluation systems now emerging in response to federal, state and/or local policy initiatives typically require that a component of teacher evaluation be based on multiple performance metrics, which must be combined to produce summative ratings of teacher effectiveness. Districts have utilized three common approaches to…

  18. 40 CFR 75.72 - Determination of NOX mass emissions for common stack and multiple stack configurations.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 17 2013-07-01 2013-07-01 false Determination of NOX mass emissions... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTINUOUS EMISSION MONITORING NOX Mass Emissions Provisions § 75.72 Determination of NOX mass emissions for common stack and multiple...

  19. 40 CFR 75.72 - Determination of NOX mass emissions for common stack and multiple stack configurations.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 16 2011-07-01 2011-07-01 false Determination of NOX mass emissions... ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) CONTINUOUS EMISSION MONITORING NOX Mass Emissions Provisions § 75.72 Determination of NOX mass emissions for common stack and multiple...

  20. New meta-analysis tools reveal common transciptional regulatory basis for multiple determinants of behavior

    Technology Transfer Automated Retrieval System (TEKTRAN)

    : A fundamental problem in meta-analysis is how to systematically combine information from multiple statistical tests to rigorously evaluate a single overarching hypothesis. This occurs in systems biology when attempting to map genomic attributes to complex phenotypes such as ...

  1. Modeling Habitat Associations for the Common Loon (Gavia immer) at Multiple Scales in Northeastern North America

    EPA Science Inventory

    The Common Loon (Gavia immer) is considered an emblematic and ecologically important example of aquatic-dependent wildlife in North America. The northern breeding range of Common Loons has contracted over the last century, presumably as a result of habitat degradation from human ...

  2. We Don't Live in a Multiple-Choice World: Inquiry and the Common Core

    ERIC Educational Resources Information Center

    Jaeger, Paige

    2012-01-01

    The Common Core raises the bar for states struggling to decide what should be taught or tested. As low-performing schools strive to improve instruction, the blueprint has been defined. The Common Core defines the curriculum in enough detail and specifies ways to teach that content creatively and innovatively, to produce graduates who are problem…

  3. An Evaluation of the High Level Architecture (HLA) as a Framework for NASA Modeling and Simulation

    NASA Technical Reports Server (NTRS)

    Reid, Michael R.; Powers, Edward I. (Technical Monitor)

    2000-01-01

    The High Level Architecture (HLA) is a current US Department of Defense and an industry (IEEE-1516) standard architecture for modeling and simulations. It provides a framework and set of functional rules and common interfaces for integrating separate and disparate simulators into a larger simulation. The goal of the HLA is to reduce software costs by facilitating the reuse of simulation components and by providing a runtime infrastructure to manage the simulations. In order to evaluate the applicability of the HLA as a technology for NASA space mission simulations, a Simulations Group at Goddard Space Flight Center (GSFC) conducted a study of the HLA and developed a simple prototype HLA-compliant space mission simulator. This paper summarizes the prototyping effort and discusses the potential usefulness of the HLA in the design and planning of future NASA space missions with a focus on risk mitigation and cost reduction.

  4. Common Factors Predicting Long-term Changes in Multiple Health Behaviors

    PubMed Central

    BLISSMER, BRYAN; PROCHASKA, JAMES O.; VELICER, WAYNE F.; REDDING, COLLEEN A.; ROSSI, JOSEPH S.; GREENE, GEOFFREY W.; PAIVA, ANDREA; ROBBINS, MARK

    2010-01-01

    This study was designed to assess if there are consistent treatment, stage, severity, effort and demographic effects which predict long-term changes across the multiple behaviors of smoking, diet and sun exposure. A secondary data analysis integrated data from four studies on smoking cessation (N = 3927), three studies on diet (N = 4824) and four studies on sun exposure (N = 6465). Across all three behaviors, behavior change at 24 months was related to treatment, stage of change, problem severity and effort effects measured at baseline. There were no consistent demographic effects. Across multiple behaviors, long-term behavior changes are consistently related to four effects that are dynamic and open to change. Behavior changes were not consistently related to static demographic variables. Future intervention research can target the four effects to determine if breakthroughs can be produced in changing single and multiple behaviors. PMID:20207664

  5. Diversity of Extended HLA-DRB1 Haplotypes in the Finnish Population

    PubMed Central

    Wennerström, Annika; Vlachopoulou, Efthymia; Lahtela, L. Elisa; Paakkanen, Riitta; Eronen, Katja T.; Seppänen, Mikko; Lokki, Marja-Liisa

    2013-01-01

    The Major Histocompatibility Complex (MHC, 6p21) codes for traditional HLA and other host response related genes. The polymorphic HLA-DRB1 gene in MHC Class II has been associated with several complex diseases. In this study we focus on MHC haplotype structures in the Finnish population. We explore the variability of extended HLA-DRB1 haplotypes in relation to the other traditional HLA genes and a selected group of MHC class III genes. A total of 150 healthy Finnish individuals were included in the study. Subjects were genotyped for HLA alleles (HLA-A, -B, -DRB1, -DQB1, and -DPB1). The polymorphism of TNF, LTA, C4, BTNL2 and HLA-DRA genes was studied with 74 SNPs (single nucleotide polymorphism). The C4A and C4B gene copy numbers and a 2-bp silencing insertion at exon 29 in C4A gene were analysed with quantitative genomic realtime-PCR. The allele frequencies for each locus were calculated and haplotypes were constructed using both the traditional HLA alleles and SNP blocks. The most frequent Finnish A∼B∼DR -haplotype, uncommon in elsewhere in Europe, was A*03∼B*35∼DRB1*01∶01. The second most common haplotype was a common European ancestral haplotype AH 8.1 (A*01∼B*08∼DRB1*03∶01). Extended haplotypes containing HLA-B, TNF block, C4 and HLA-DPB1 strongly increased the number of HLA-DRB1 haplotypes showing variability in the extended HLA-DRB1 haplotype structures. On the contrary, BTNL2 block and HLA-DQB1 were more conserved showing linkage with the HLA-DRB1 alleles. We show that the use of HLA-DRB1 haplotypes rather than single HLA-DRB1 alleles is advantageous when studying the polymorphisms and LD patters of the MHC region. For disease association studies the HLA-DRB1 haplotypes with various MHC markers allows us to cluster haplotypes with functionally important gene variants such as C4 deficiency and cytokines TNF and LTA, and provides hypotheses for further assessment. Our study corroborates the importance of studying population-specific MHC

  6. In silico analysis of HLA associations with drug-induced liver injury: use of a HLA-genotyped DNA archive from healthy volunteers

    PubMed Central

    2012-01-01

    Background Drug-induced liver injury (DILI) is one of the most common adverse reactions leading to product withdrawal post-marketing. Recently, genome-wide association studies have identified a number of human leukocyte antigen (HLA) alleles associated with DILI; however, the cellular and chemical mechanisms are not fully understood. Methods To study these mechanisms, we established an HLA-typed cell archive from 400 healthy volunteers. In addition, we utilized HLA genotype data from more than four million individuals from publicly accessible repositories such as the Allele Frequency Net Database, Major Histocompatibility Complex Database and Immune Epitope Database to study the HLA alleles associated with DILI. We utilized novel in silico strategies to examine HLA haplotype relationships among the alleles associated with DILI by using bioinformatics tools such as NetMHCpan, PyPop, GraphViz, PHYLIP and TreeView. Results We demonstrated that many of the alleles that have been associated with liver injury induced by structurally diverse drugs (flucloxacillin, co-amoxiclav, ximelagatran, lapatinib, lumiracoxib) reside on common HLA haplotypes, which were present in populations of diverse ethnicity. Conclusions Our bioinformatic analysis indicates that there may be a connection between the different HLA alleles associated with DILI caused by therapeutically and structurally different drugs, possibly through peptide binding of one of the HLA alleles that defines the causal haplotype. Further functional work, together with next-generation sequencing techniques, will be needed to define the causal alleles associated with DILI. PMID:22732016

  7. Common colorectal cancer risk alleles contribute to the multiple colorectal adenoma phenotype, but do not influence colonic polyposis in FAP

    PubMed Central

    Cheng, Timothy H T; Gorman, Maggie; Martin, Lynn; Barclay, Ella; Casey, Graham; Newcomb, Polly A; Casey, Graham; Conti, David V; Schumacher, Fred; Gallinger, Steve; Lindor, Noralane M; Hopper, John; Jenkins, Mark; Hunter, David J; Kraft, Peter; Jacobs, Kevin B; Cox, David G; Yeager, Meredith; Hankinson, Susan E; Wacholder, Sholom; Wang, Zhaoming; Welch, Robert; Hutchinson, Amy; Wang, Junwen; Yu, Kai; Chatterjee, Nilanjan; Orr, Nick; Willett, Walter C; Colditz, Graham A; Ziegler, Regina G; Berg, Christine D; Buys, Saundra S; McCarty, Catherine A; Feigelson, Heather Spencer; Calle, Eugenia E; Thun, Michael J; Hayes, Richard B; Tucker, Margaret; Gerhard, Daniela S; Fraumeni, Joseph F; Hoover, Robert N; Thomas, Gilles; Chanock, Stephen J; Yeager, Meredith; Chatterjee, Nilanjan; Ciampa, Julia; Jacobs, Kevin B; Gonzalez-Bosquet, Jesus; Hayes, Richard B; Kraft, Peter; Wacholder, Sholom; Orr, Nick; Berndt, Sonja; Yu, Kai; Hutchinson, Amy; Wang, Zhaoming; Amundadottir, Laufey; Feigelson, Heather Spencer; Thun, Michael J; Diver, W Ryan; Albanes, Demetrius; Virtamo, Jarmo; Weinstein, Stephanie; Schumacher, Fredrick R; Cancel-Tassin, Geraldine; Cussenot, Olivier; Valeri, Antoine; Andriole, Gerald L; Crawford, E David; Haiman, Christopher A; Henderson, Brian; Kolonel, Laurence; Marchand, Loic Le; Siddiq, Afshan; Riboli, Elio; Key, Timothy J; Kaaks, Rudolf; Isaacs, William; Isaacs, Sarah; Wiley, Kathleen E; Gronberg, Henrik; Wiklund, Fredrik; Stattin, Pär; Xu, Jianfeng; Zheng, S Lilly; Sun, Jielin; Vatten, Lars J; Hveem, Kristian; Kumle, Merethe; Tucker, Margaret; Gerhard, Daniela S; Hoover, Robert N; Fraumeni, Joseph F; Hunter, David J; Thomas, Gilles; Chanock, Stephen J; Purdue, Mark P; Johansson, Mattias; Zelenika, Diana; Toro, Jorge R; Scelo, Ghislaine; Moore, Lee E; Prokhortchouk, Egor; Wu, Xifeng; Kiemeney, Lambertus A; Gaborieau, Valerie; Jacobs, Kevin B; Chow, Wong-Ho; Zaridze, David; Matveev, Vsevolod; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Péter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S; Davis, Faith G; Schwartz, Kendra L; Banks, Rosamonde E; Selby, Peter J; Harnden, Patricia; Berg, Christine D; Hsing, Ann W; Grubb III, Robert L; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Françoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J; Quirós, José Ramón; Sanchez, Maria-José; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E; Bueno-de-Mesquita, H Bas; Peeters, Petra H M; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Börje; Overvad, Kim; Tjønneland, Anne; Romieu, Isabelle; Riboli, Elio; Mukeria, Anush; Shangina, Oxana; Stevens, Victoria L; Thun, Michael J; Diver, W Ryan; Gapstur, Susan M; Pharoah, Paul D; Easton, Douglas F; Albanes, Demetrius; Weinstein, Stephanie J; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Njølstad, Inger; Tell, Grethe S; Stoltenberg, Camilla; Kumar, Rajiv; Koppova, Kvetoslava; Cussenot, Olivier; Benhamou, Simone; Oosterwijk, Egbert; Vermeulen, Sita H; Aben, Katja K H; van der Marel, Saskia L; Ye, Yuanqing; Wood, Christopher G; Pu, Xia; Mazur, Alexander M; Boulygina, Eugenia S; Chekanov, Nikolai N; Foglio, Mario; Lechner, Doris; Gut, Ivo; Heath, Simon; Blanche, Hélène; Hutchinson, Amy; Thomas, Gilles; Wang, Zhaoming; Yeager, Meredith; Fraumeni, Joseph F; Skryabin, Konstantin G; McKay, James D; Rothman, Nathaniel; Chanock, Stephen J; Lathrop, Mark; Brennan, Paul; Saunders, Brian; Thomas, Huw; Clark, Sue; Tomlinson, Ian

    2015-01-01

    The presence of multiple (5–100) colorectal adenomas suggests an inherited predisposition, but the genetic aetiology of this phenotype is undetermined if patients test negative for Mendelian polyposis syndromes such as familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). We investigated whether 18 common colorectal cancer (CRC) predisposition single-nucleotide polymorphisms (SNPs) could help to explain some cases with multiple adenomas who phenocopied FAP or MAP, but had no pathogenic APC or MUTYH variant. No multiple adenoma case had an outlying number of CRC SNP risk alleles, but multiple adenoma patients did have a significantly higher number of risk alleles than population controls (P=5.7 × 10−7). The association was stronger in those with ≥10 adenomas. The CRC SNPs accounted for 4.3% of the variation in multiple adenoma risk, with three SNPs (rs6983267, rs10795668, rs3802842) explaining 3.0% of the variation. In FAP patients, the CRC risk score did not differ significantly from the controls, as we expected given the overwhelming effect of pathogenic germline APC variants on the phenotype of these cases. More unexpectedly, we found no evidence that the CRC SNPs act as modifier genes for the number of colorectal adenomas in FAP patients. In conclusion, common colorectal tumour risk alleles contribute to the development of multiple adenomas in patients without pathogenic germline APC or MUTYH variants. This phenotype may have ‘polygenic' or monogenic origins. The risk of CRC in relatives of multiple adenoma cases is probably much lower for cases with polygenic disease, and this should be taken into account when counselling such patients. PMID:24801760

  8. A monoclonal antibody that recognizes an antigenic determinant shared by HLA A2 and B17.

    PubMed

    McMichael, A J; Parham, P; Rust, N; Brodsky, F

    1980-09-01

    A hybridoma monoclonal anti-HLA antibody has been produced by the technique of Kohler and Milstein [1]. This antibody recognizes a new specificity common to HLA A2 and B17. It was shown to be a single antibody by isoelectric focusing and absorption experiments.

  9. Multiple mutations in a specific gene in a small geographic area: A common phenomenon

    SciTech Connect

    Zlotogora, J.; Bach, G.; Gieselmann, V.

    1996-01-01

    We read with interest the article from Allamand et al., which demonstrates in a genetic isolate the presence of at least six different haplotypes in the limb-girdle muscular dystrophy type 2A chromosome. Several hypotheses were proposed by the authors to explain this finding, but, after the identification of calpain, the gene involved in the disorder, multiple mutations were proved to be at the origin of this observation. The authors proposed that both the presence of multiple distinct calpain mutations within the Reunion Island pedigrees and the relatively low frequency of the disease in the isolate may be explained by a digenic inheritance of the disorder. Their hypothesis postulates that, although calpain mutations may be frequent in all populations, the disease manifestations are controlled by another frequently mutated nuclear or mitochondrial gene in the Reunion isolate. 8 refs.

  10. Hierarchical Multiple Regression in Counseling Research: Common Problems and Possible Remedies.

    ERIC Educational Resources Information Center

    Petrocelli, John V.

    2003-01-01

    A brief content analysis was conducted on the use of hierarchical regression in counseling research published in the "Journal of Counseling Psychology" and the "Journal of Counseling & Development" during the years 1997-2001. Common problems are cited and possible remedies are described. (Contains 43 references and 3 tables.) (Author)

  11. Statistical inference from multiple iTRAQ experiments without using common reference standards.

    PubMed

    Herbrich, Shelley M; Cole, Robert N; West, Keith P; Schulze, Kerry; Yager, James D; Groopman, John D; Christian, Parul; Wu, Lee; O'Meally, Robert N; May, Damon H; McIntosh, Martin W; Ruczinski, Ingo

    2013-02-01

    Isobaric tags for relative and absolute quantitation (iTRAQ) is a prominent mass spectrometry technology for protein identification and quantification that is capable of analyzing multiple samples in a single experiment. Frequently, iTRAQ experiments are carried out using an aliquot from a pool of all samples, or "masterpool", in one of the channels as a reference sample standard to estimate protein relative abundances in the biological samples and to combine abundance estimates from multiple experiments. In this manuscript, we show that using a masterpool is counterproductive. We obtain more precise estimates of protein relative abundance by using the available biological data instead of the masterpool and do not need to occupy a channel that could otherwise be used for another biological sample. In addition, we introduce a simple statistical method to associate proteomic data from multiple iTRAQ experiments with a numeric response and show that this approach is more powerful than the conventionally employed masterpool-based approach. We illustrate our methods using data from four replicate iTRAQ experiments on aliquots of the same pool of plasma samples and from a 406-sample project designed to identify plasma proteins that covary with nutrient concentrations in chronically undernourished children from South Asia.

  12. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies

    PubMed Central

    Maziarz, M; Hagopian, W; Palmer, JP; Sanjeevi, CB; Kockum, I; Breslow, N; Lernmark, Å

    2015-01-01

    The possible interrelations between HLA-DQ, non-HLA single nucleotide polymorphisms (SNPs) and islet autoantibodies were investigated at clinical onset in 1-34 year old type 1 diabetes (T1D) patients (n=305) and controls (n=203). Among the non-HLA SNPs reported by the Type 1 Diabetes Genetics Consortium, 24% were supported in this Swedish replication set including that the increased risk of minor PTPN22 allele and high risk HLA was modified by GAD65 autoantibodies. The association between T1D and the minor AA+AC genotype in ERBB3 gene was stronger among IA-2 autoantibody-positive patients (comparison p=0.047). The association between T1D and the common insulin (AA) genotype was stronger among insulin autoantibody (IAA)-positive patients (comparison p=0.008). In contrast, the association between T1D and unidentified 26471 gene was stronger among IAA-negative (comparison p=0.049) and IA-2 autoantibody-negative (comparison p=0.052) patients. Finally, the association between IL2RA and T1D was stronger among IAA-positive than among IAA-negative patients (comparison p=0.028). These results suggest that the increased risk of T1D by non-HLA genes is often modified by both islet autoantibodies and HLA-DQ. The interactions between non-HLA genes, islet autoantibodies and HLA-DQ should be taken into account in T1D prediction studies as well as in prevention trials aimed at inducing immunological tolerance to islet autoantigens. PMID:26513234

  13. Analysis of HLA class I expression in different metastases from two melanoma patients undergoing peptide immunotherapy.

    PubMed

    Mendez, R; Serrano, A; Jäger, E; Maleno, I; Ruiz-Cabello, F; Knuth, A; Garrido, F

    2001-06-01

    We characterized the HLA class I alterations in five metastases obtained from two patients with melanoma immunized with Melan A/MART-1, tyrosinase and gp100 tumor peptides. All three metastases analyzed in the first patient (NW145) showed a similar HLA class I alteration with a dual population of melanoma cells. One population was HLA class I antigen positive and the other had loss of heterozygosity (LOH) in the short arm of chromosome 6 leading to an HLA haplotype loss (A02011, B4007, Cw1). The absence of HLA-A2 antigen may explain why this patient did not develop HLA-A2 restricted, Melan A/MART-1 specificity immunization, since this HLA molecule is the restriction element for the tumor peptides used. However, this HLA-deficient population was not selected after peptide immunotherapy. The primary tumor in this patient presented LOH in region 6q, but only in the vertical growth phase of the lesion, whereas LOH at 6p was observed only in DNA from metastatic material. The second patient (NW16) also presented two metastatic lesions with an identical HLA molecular defect, i.e. HLA B locus downregulation (HLA B51011: serological B51; B1503: serological B70). One lesion expressed the tumor antigen (Melan A/ MART-1), but the other did not. Interestingly, the antigen-positive metastasis regressed after peptide immunotherapy, whereas the other progressed rapidly. These findings provide the first indication that multiple metastases generated in the same host can have identically altered HLA class I phenotypes.

  14. Common single nucleotide polymorphisms in immunoregulatory genes and multiple myeloma risk among women in Connecticut

    PubMed Central

    Lee, Kyoung-Mu; Baris, Dalsu; Zhang, Yawei; Hosgood, H. Dean; Menashe, Idan; Yeager, Meredith; Zahm, Shelia Hoar; Wang, Sophia S.; Purdue, Mark P.; Chanock, Stephen; Zheng, Tongzhang; Rothman, Nathaniel; Lan, Qing

    2010-01-01

    In light of the relationship between immune system dysregulation and multiple myeloma (MM) risk, we investigated whether genetic variation in 92 immune function genes among 77 gene regions are associated with MM susceptibility in a population-based case-control study (108 cases and 482 controls) conducted among Caucasian women in Connecticut. Tagging single-nucleotide polymorphisms (SNPs; N=870) were selected using a pairwise linkage-disequilibrium based algorithm. Odds ratios (ORs) and 95% confidence intervals (CIs) for SNP genotypes were estimated using unconditional logistic regression. Tests of association for gene regions were conducted using the minP test. We applied the false discovery rate (FDR) method to the minP test results as a means of controlling for multiple comparisons. The CD4 gene region located on 12p13-q13 (minP=0.0009), had an FDR value < 0.1. In this region, a total of six tag SNPs in two genes (CD4 and LAG3) were significantly associated with MM risk (Ptrend<0.05), with the strongest association observed for the CD4 variant rs11064392 (ORAG/GG=2.53, 95% CI=1.59–4.02). Our findings suggest that genetic variation in CD4 may influence susceptibility to MM. Additional studies are needed to replicate these findings and, more generally, to explore the manner in which genes receptors may influence the pathogenesis of this poorly understood malignancy. PMID:20568250

  15. Assessment of differences in HLA-A, -B, and -DRB1 allele mismatches among African-American and non-African-American recipients of deceased kidney transplants.

    PubMed

    Kamoun, M; Israni, A K; Joffe, M M; Hoy, T; Kearns, J; Mange, K C; Feldman, D; Goodman, N; Rosas, S E; Abrams, J D; Brayman, K L; Feldman, H I

    2007-01-01

    Among recipients of deceased donor kidney transplants, African-Americans experience a more rapid rate of kidney allograft loss than non-African-Americans. The purpose of this study was to characterize and quantify the HLA-A, -B, and -DRB1 allele mismatches and amino acid substitutions at antigen recognition sites among African-American and non-African-American recipients of deceased donor kidney transplants matched at the antigen level. In recipients with zero HLA antigen mismatches, the degree of one or two HLA allele mismatches for both racial groups combined was 47%, 29%, and 11% at HLA-DRB1, HLA-B, and HLA-A, respectively. There was a greater number of allele mismatches in African-Americans than non-African-Americans at HLA-A (P < .0001), -B (P = .096), and -DRB1 loci (P < .0001). For both racial groups, the HLA allele mismatches were predominantly at A2 for HLA-A; B35 and B44 for HLA-B; but multiple specificities for HLA-DRB1. The observed amino acid mismatches were concentrated at a few functional positions in the antigen binding site of HLA-A and -B and -DRB1 molecules. Future studies are ongoing to assess the impact of these HLA mismatches on kidney allograft loss.

  16. Genetic analysis of HLA in the U.S. Schmiedenleut Hutterites.

    PubMed Central

    Kostyu, D D; Ober, C L; Dawson, D V; Ghanayem, M; Elias, S; Martin, A O

    1989-01-01

    The Hutterites are an Anabaptist population, highly inbred, with large family sizes and extensively documented pedigrees. As part of genetic-epidemiologic studies of the impact of HLA on fertility, HLA-A, -B, -C, -DR, and -DQ typing was performed on a total of 650 Schmiedenleut Hutterities in South Dakota. An extraordinary degree of homogeneity was found. HLA-A1, -A2, -A3, -A24, and -A26 accounted for 83%, HLA-B8, -B27, -B35, -B51, -Bw60, and -Bw62 for 75%, and HLA-DR1, -DR2, -DR3, and -DR4 for 66% of the antigens at the respective HLA-A, -B, and -DR loci. All Hutterites characterized for HLA were descendants of no more than 78 ancestors. However, family analysis identified only 45 unique HLA haplotypes thought to reflect the original gene pool. Eight haplotypes were particularly frequent, accounting for nearly 50% of all observed haplotypes; four of these were consistent with a European ancestry. Coefficients measuring linkage disequilibrium were computed from haplotypes identified by family analysis. Overall, HLA analysis portrayed the Schmiedenleut Hutterities as a homogeneous and unique population, with disequilibrium among particular alleles and a spectrum of common and uncommon European haplotypes. PMID:2757031

  17. Common but unappreciated sources of error in one, two, and multiple-color pyrometry

    NASA Technical Reports Server (NTRS)

    Spjut, R. Erik

    1988-01-01

    The most common sources of error in optical pyrometry are examined. They can be classified as either noise and uncertainty errors, stray radiation errors, or speed-of-response errors. Through judicious choice of detectors and optical wavelengths the effect of noise errors can be minimized, but one should strive to determine as many of the system properties as possible. Careful consideration of the optical-collection system can minimize stray radiation errors. Careful consideration must also be given to the slowest elements in a pyrometer when measuring rapid phenomena.

  18. Therapeutic approaches against common structural features of toxic oligomers shared by multiple amyloidogenic proteins.

    PubMed

    Guerrero-Muñoz, Marcos J; Castillo-Carranza, Diana L; Kayed, Rakez

    2014-04-15

    Impaired proteostasis is one of the main features of all amyloid diseases, which are associated with the formation of insoluble aggregates from amyloidogenic proteins. The aggregation process can be caused by overproduction or poor clearance of these proteins. However, numerous reports suggest that amyloid oligomers are the most toxic species, rather than insoluble fibrillar material, in Alzheimer's, Parkinson's, and Prion diseases, among others. Although the exact protein that aggregates varies between amyloid disorders, they all share common structural features that can be used as therapeutic targets. In this review, we focus on therapeutic approaches against shared features of toxic oligomeric structures and future directions.

  19. Strategies for generating multiple instances of common and ad hoc categories.

    PubMed

    Vallée-Tourangeau, F; Anthony, S H; Austin, N G

    1998-09-01

    In a free-emission procedure participants were asked to generate instances of a given category and to report, retrospectively, the strategies that they were aware of using in retrieving instances. In two studies reported here, participants generated instances for common categories (e.g. fruit) and for ad hoc categories (e.g., things people keep in their pockets) for 90 seconds and for each category described how they had proceeded in doing so. Analysis of the protocols identified three broad classes of strategy: (1) experiential, where memories of specific or generic personal experiences involving interactions with the category instances acted as cues; (2) semantic, where a consideration of abstract conceptual characteristics of a category were employed to retrieve category exemplars; (3) unmediated, where instances were effortlessly retrieved without mediating cognitions of which subjects were aware. Experiential strategies outnumbered semantic strategies (on average 4 to 1) not only for ad hoc categories but also for common categories. This pattern was noticeably reversed for ad hoc categories that subjects were unlikely to have experienced personally (e.g. things sold on the black market in Russia). Whereas more traditional accounts of semantic memory have favoured decontextualised abstract representations of category knowledge, to the extent that mode of access informs us of knowledge structures, our data suggest that category knowledge is significantly grounded in terms of everyday contexts where category instances are encountered. PMID:10197163

  20. A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts

    PubMed Central

    Irum, Bushra; Khan, Arif O.; Wang, Qiwei; Li, David; Khan, Asma A.; Husnain, Tayyab; Akram, Javed; Riazuddin, Sheikh

    2016-01-01

    Purpose This study was performed to investigate the genetic determinants of autosomal recessive congenital cataracts in large consanguineous families. Methods Affected individuals underwent a detailed ophthalmological examination and slit-lamp photographs of the cataractous lenses were obtained. An aliquot of blood was collected from all participating family members and genomic DNA was extracted from white blood cells. Initially, a genome-wide scan was performed with genomic DNAs of family PKCC025 followed by exclusion analysis of our familial cohort of congenital cataracts. Protein-coding exons of CRYBB1, CRYBB2, CRYBB3, and CRYBA4 were sequenced bidirectionally. A haplotype was constructed with SNPs flanking the causal mutation for affected individuals in all four families, while the probability that the four familial cases have a common founder was estimated using EM and CHM-based algorithms. The expression of Crybb3 in the developing murine lens was investigated using TaqMan assays. Results The clinical and ophthalmological examinations suggested that all affected individuals had nuclear cataracts. Genome-wide linkage analysis localized the causal phenotype in family PKCC025 to chromosome 22q with statistically significant two-point logarithm of odds (LOD) scores. Subsequently, we localized three additional families, PKCC063, PKCC131, and PKCC168 to chromosome 22q. Bidirectional Sanger sequencing identified a missense variation: c.493G>C (p.Gly165Arg) in CRYBB3 that segregated with the disease phenotype in all four familial cases. This variation was not found in ethnically matched control chromosomes, the NHLBI exome variant server, or the 1000 Genomes or dbSNP databases. Interestingly, all four families harbor a unique disease haplotype that strongly suggests a common founder of the causal mutation (p<1.64E-10). We observed expression of Crybb3 in the mouse lens as early as embryonic day 15 (E15), and expression remained relatively steady throughout

  1. Daphnia parasite dynamics across multiple Caullerya epidemics indicate selection against common parasite genotypes.

    PubMed

    González-Tortuero, Enrique; Rusek, Jakub; Turko, Patrick; Petrusek, Adam; Maayan, Inbar; Piálek, Lubomír; Tellenbach, Christoph; Gießler, Sabine; Spaak, Piet; Wolinska, Justyna

    2016-08-01

    Studies of parasite population dynamics in natural systems are crucial for our understanding of host-parasite coevolutionary processes. Some field studies have reported that host genotype frequencies in natural populations change over time according to parasite-driven negative frequency-dependent selection. However, the temporal patterns of parasite genotypes have rarely been investigated. Moreover, parasite-driven negative frequency-dependent selection is contingent on the existence of genetic specificity between hosts and parasites. In the present study, the population dynamics and host-genotype specificity of the ichthyosporean Caullerya mesnili, a common endoparasite of Daphnia water fleas, were analysed based on the observed sequence variation in the first internal transcribed spacer (ITS1) of the ribosomal DNA. The Daphnia population of lake Greifensee (Switzerland) was sampled and subjected to parasite screening and host genotyping during C. mesnili epidemics of four consecutive years. The ITS1 of wild-caught C. mesnili-infected Daphnia was sequenced using the 454 pyrosequencing platform. The relative frequencies of C. mesnili ITS1 sequences differed significantly among years: the most abundant C. mesnili ITS1 sequence decreased and rare sequences increased over the course of the study, a pattern consistent with negative frequency-dependent selection. However, only a weak signal of host-genotype specificity between C. mesnili and Daphnia genotypes was detected. Use of cutting edge genomic techniques will allow further investigation of the underlying micro-evolutionary relationships within the Daphnia-C. mesnili system.

  2. Multiple spring migration strategies in a population of Pacific Common Eiders

    USGS Publications Warehouse

    Petersen, M.R.

    2009-01-01

    Spring migration strategies vary within and among species. Examination of this variability extends our understanding of life histories and has implications for conservation. I used satellite transmitters to determine migration strategies and evaluate factors influencing the timing of spring migration of Pacific Common Eiders (Somateria mollissima v-nigrum) that nest along the western Beaufort Sea coast. Adult females were marked at nesting colonies in the summers of 2000, 2001, and 2003, and were followed throughout spring migration the following year. Each year approximately equal proportions of eiders used three distinct migration strategies varying in duration, staging locations (waters near the Chukotka Peninsula, Russia, and the Chukchi and Beaufort seas, Alaska), and arrival dates at the nesting areas. It is unlikely that differences in the timing of movements to stopover sites in the Chukchi and Beaufort seas were a result of responses to changes in weather, particularly wind direction. Ice distribution and melt/movement patterns vary substantially among staging areas and thus may affect risk of starvation and reproductive potential. Long-term (decadal) changes in climate may favor birds using one strategy during "warmer" and another during "colder" years. ?? 2009 by The Cooper Ornithological Society. All rights reserved.

  3. Recursive forward dynamics for multiple robot arms moving a common task object

    NASA Technical Reports Server (NTRS)

    Rodriguez, G.

    1988-01-01

    Recursive forward dynamics algorithms are developed for an arbitrary number of robot arms moving a commonly held object. The multiarm forward dynamics problem is to find the angular accelerations at the joints and the contact forces that the arms impart to the task object. The problem also involves finding the acceleration of this object. The multiarm forward dynamics solutions provide a thorough physical and mathematical understanding of the way several arms behave in response to a set of applied joint moments. Such an understanding simplifies and guides the subsequent control design and experimentation process. The forward dynamics algorithms also provide the necessary analytical foundation for conducting analysis and simulation studies. The multiarm algorithms are based on the filtering and smoothing approach recently advanced for single-arm dynamics, and they can be built up modularly from the single-arm algorithms. The algorithms compute recursively the joint-angle accelerations, the contact forces, and the task-object accelerations. Algorithms are also developed to evaluate in closed form the linear transformations from the active joint moments to the joint-angle accelerations, to the task-object accelerations., and to the task-object contact forces. A possible computing architecture is presented as a precursor to a more complete investigation of the computational performance of the dynamics algorithms.

  4. Common distal elements orchestrate CIITA isoform-specific expression in multiple cell types

    PubMed Central

    Lohsen, Sarah; Majumder, Parimal; Scharer, Christopher D.; Barwick, Benjamin G.; Austin, James W.; Zinzow-Kramer, Wendy M.

    2014-01-01

    Major histocompatibility class II (MHC-II) expression is critical for immune responses and is controlled by the MHC-II transactivator CIITA. CIITA is primarily regulated at the transcriptional level and is expressed from three main promoters with myeloid, lymphoid, and IFN-γ treated non-hematopoietic cells using promoters pI, pIII, and pIV, respectively. Recent studies in non-hematopoietic cells suggest a series of distal regulatory elements may be involved in regulating CIITA transcription. To identify distal elements in B cells, a DNase I-hypersensitivity screen was performed, revealing a series of potential novel regulatory elements. These elements were analyzed computationally and biochemically. Several regions displayed active histone modifications and/or enhanced expression of a reporter gene. Four of the elements interacted with pIII in B cells. These same four regions were also found to interact with pI in splenic dendritic cells (spDC). Intriguingly, examination of the above interactions in pI-knockout-derived spDC showed a switch to the next available promoter, pIII. Extensive DNA methylation was found at the pI region in B cells, suggesting that this promoter is not accessible in B cells. Thus, CIITA expression is likely mediated in hematopoietic cells by common elements with promoter accessibility playing a part in promoter choice. PMID:25101797

  5. Common-pull, multiple-push, vacuum-activated telescope mirror cell.

    PubMed

    Ruiz, Elfego; Sohn, Erika; Salas, Luis; Luna, Esteban; Araiza-Durán, José A

    2014-11-20

    A new concept for push-pull active optics is presented, where the push-force is provided by means of individual airbag type actuators and a common force in the form of a vacuum is applied to the entire back of the mirror. The vacuum provides the pull-component of the system, in addition to gravity. Vacuum is controlled as a function of the zenithal angle, providing correction for the axial component of the mirror's weight. In this way, the push actuators are only responsible for correcting mirror deformations, as well as for supporting the axial mirror weight at the zenith, allowing for a uniform, full dynamic-range behavior of the system along the telescope's pointing range. This can result in the ability to perform corrections of up to a few microns for low-order aberrations. This mirror support concept was simulated using a finite element model and was tested experimentally at the 2.12 m San Pedro Mártir telescope. Advantages such as stress-free attachments, lighter weight, large actuator area, lower system complexity, and lower required mirror-cell stiffness could make this a method to consider for future large telescopes.

  6. The Royan Public Umbilical Cord Blood Bank: Does It Cover All Ethnic Groups in Iran Based on HLA Diversity?

    PubMed Central

    Ebrahimkhani, Saeideh; Farjadian, Shirin; Ebrahimi, Marzieh

    2014-01-01

    Summary Background Umbilical cord blood (UCB) stem cells allow the transplantation of partially human leukocyte antigen (HLA)-matched grafts and are a valuable resource for the treatment of hematologic malignancies and heritable hematologic, immunologic and metabolic diseases, especially when a compatible bone marrow donor is unavailable. The aim of this study was to determine how many ethnic groups in Iran are covered by the available UCB units based on HLA diversity. Methods From 2009 until mid-2013, 4,981 (30.3%) of the 16,437 UCB samples collected met the storage criteria and were cryopreserved at a public cord blood bank (CBB) in Tehran, Iran. HLA-A, -B and -DRB1 were typed in 1,793 samples. Results The mean volume of the cryopreserved samples was 81.25 ± 20.3 ml. The range of total nucleated cells per unit was 51 × 107-107 × 107. The most common HLA alleles were HLA-A*2 (17%) and HLA-A*24 (15.6%), HLA-B*35 (16.8%) and HLA-B*51 (13.9%), and HLA-DRB1*11 (20%) and HLA-DRB1*15 (14%). The predominant haplotypes were HLA-A*24-B*35-DRB1*11 (2%), HLA-A*02-B*50-DR*07 (1.8%), and HLA-A*02-B*51-DRB1*11 (1.5%). Conclusions Based on the HLA-DRB1 profiles, the UCB units available at the Royan public UCB bank are a potentially adequate resource for hematopoietic stem cell transplantation for Iranian recipients belonging to particular ethnic groups. Regular educational programs to improve the public knowledge of UCB for transplantation can enhance the public CBB stocks for all Iranian ethnic groups in the future. PMID:24847189

  7. Multiple diverse circoviruses infect farm animals and are commonly found in human and chimpanzee feces.

    PubMed

    Li, Linlin; Kapoor, Amit; Slikas, Beth; Bamidele, Oderinde Soji; Wang, Chunlin; Shaukat, Shahzad; Masroor, Muhammad Alam; Wilson, Michael L; Ndjango, Jean-Bosco N; Peeters, Martine; Gross-Camp, Nicole D; Muller, Martin N; Hahn, Beatrice H; Wolfe, Nathan D; Triki, Hinda; Bartkus, Joanne; Zaidi, Sohail Zahoor; Delwart, Eric

    2010-02-01

    Circoviruses are known to infect birds and pigs and can cause a wide range of severe symptoms with significant economic impact. Using viral metagenomics, we identified circovirus-like DNA sequences and characterized 15 circular viral DNA genomes in stool samples from humans in Pakistan, Nigeria, Tunisia, and the United States and from wild chimpanzees. Distinct genomic features and phylogenetic analysis indicate that some viral genomes were part of a previously unrecognized genus in the Circoviridae family we tentatively named "Cyclovirus" whose genetic diversity is comparable to that of all the known species in the Circovirus genus. Circoviridae detection in the stools of U.S. adults was limited to porcine circoviruses which were also found in most U.S. pork products. To determine whether the divergent cycloviruses found in non-U.S. human stools were of dietary origin, we genetically compared them to the cycloviruses in muscle tissue samples of commonly eaten farm animals in Pakistan and Nigeria. Limited genetic overlap between cycloviruses in human stool samples and local cow, goat, sheep, camel, and chicken meat samples indicated that the majority of the 25 Cyclovirus species identified might be human viruses. We show that the genetic diversity of small circular DNA viral genomes in various mammals, including humans, is significantly larger than previously recognized, and frequent exposure through meat consumption and contact with animal or human feces provides ample opportunities for cyclovirus transmission. Determining the role of cycloviruses, found in 7 to 17% of non-U.S. human stools and 3 to 55% of non-U.S. meat samples tested, in both human and animal diseases is now facilitated by knowledge of their genomes.

  8. A common polymorphism in the LDL receptor gene has multiple effects on LDL receptor function.

    PubMed

    Gao, Feng; Ihn, Hansel E; Medina, Marisa W; Krauss, Ronald M

    2013-04-01

    A common synonymous single nucleotide polymorphism in exon 12 of the low-density lipoprotein receptor (LDLR) gene, rs688, has been associated with increased plasma total and LDL cholesterol in several populations. Using immortalized lymphoblastoid cell lines from a healthy study population, we confirmed an earlier report that the minor allele of rs688 is associated with increased exon 12 alternative splicing (P < 0.05) and showed that this triggered nonsense-mediated decay (NMD) of the alternatively spliced LDLR mRNA. However, since synonymous single nucleotide polymorphisms may influence structure and function of the encoded proteins by co-translational effects, we sought to test whether rs688 was also functional in the full-length mRNA. In HepG2 cells expressing LDLR cDNA constructs engineered to contain the major or minor allele of rs688, the latter was associated with a smaller amount of LDLR protein at the cell surface (-21.8 ± 0.6%, P = 0.012), a higher amount in the lysosome fraction (+25.7 ± 0.3%, P = 0.037) and reduced uptake of fluorescently labeled LDL (-24.3 ± 0.7%, P < 0.01). Moreover, in the presence of exogenous proprotein convertase subtilisin/kexin type 9 (PCSK9), a protein that reduces cellular LDL uptake by promoting lysosomal degradation of LDLR, the minor allele resulted in reduced capacity of a PCSK9 monoclonal antibody to increase LDL uptake. These findings are consistent with the hypothesis that rs688, which is located in the β-propeller region of LDLR, has effects on LDLR activity beyond its role in alternative splicing due to impairment of LDLR endosomal recycling and/or PCSK9 binding, processes in which the β-propeller is critically involved.

  9. HLA-B allele and haplotype diversity among Thai patients identified by PCR-SSOP: evidence for high risk of drug-induced hypersensitivity

    PubMed Central

    Puangpetch, Apichaya; Koomdee, Napatrupron; Chamnanphol, Montri; Jantararoungtong, Thawinee; Santon, Siwalee; Prommas, Santirhat; Hongkaew, Yaowaluck; Sukasem, Chonlaphat

    2015-01-01

    Background: There are 3 classes of HLA molecules; HLA class I, II and III, of which different classes have different functions. HLA-B gene which belongs to HLA class I play an important role predicting drug hypersensitivity. Materials and Methods: Nine hundred and eighty-six Thai subjects who registered at a pharmacogenomics laboratory were determined for HLA-B genotype using a two-stage sequence-specific oligonucleotide probe system (PCR-SSOP). Results: In this study, HLA-B alleles did not deviate from Hardy-Weinberg equilibrium (P > 0.05). The most common HLA-B alleles observed in this population were HLA-B*46:01 (11.51%), HLA-B*58:01 (8.62%), HLA-B*40:01 (8.22%), HLA-B*15:02 (8.16%) and HLA-B*13:01 (6.95%). This finding revealed that HLA-B allele frequency in the Thai population was consistent with the Chinese population (p > 0.05), however, differed from the Malaysian population (p < 0.05). The top five HLA-B genotypes were HLA-B*40:01/46:01 (2.13%), HLA-B*46:01/46:01 (2.03%), HLA-B*40:01/58:01 (2.03%), HLA-B*46:01/58:01 (1.93%) and HLA-B*15:02/46:01 (1.83%). This study found that 15.92% of Thai subjects carry HLA-B*15:02, which has been associated with carbamazepine-induced severe cutaneous adverse drug reactions (SCARs). Moreover, 16.33% of Thai subjects carry the HLA-B*58:01 allele, which has been associated with allopurinol-induced SCARs. Conclusion: This study demonstrates a high diversity of HLA-B polymorphisms in this Thai population. The high frequency of HLA-B pharmacogenomic markers in the population emphasizes the importance of such screening to predict/avoid drug hypersensitivity. PMID:25657656

  10. [Identification and analysis of the rare HLA-A/B/DRB1 allele genes of 10165 bone marrow registry donors in Shaanxi region].

    PubMed

    Liu, Meng-Li; Qi, Jun; Wang, Xiao-Fang; Liu, Sheng; Wang, Tian-Ju; Chen, Li-Ping

    2013-12-01

    This study was purposed to analyze the detected status of rare alleles from HLA-A/B/DRB1 typing of 10165 unrelated hematopoietic stem cell donors in Shaanxi region during 2009-2012. The rare allele distributions of HLA-A/B/DRB1 gene typing of 10165 unrelated-donors from Shaanxi sub-registry of Chinese National Marrow Donor Project (CMDP) were detected and analyzed by PCR-SBT. The results showed that there were 40 rare alleles from 48 donors identified by PCR-SBT in 10165 unrelated-donors of Shaanxi sub-registry. Among them, 10 rare alleles of A*02:04, B*07:10, B*27:09, B*35:11, B*44:29, DRB1*03:04, DRB1*08:18, DRB1*13:05, DRB1*13:14 and DRB1*14:11 from 15 donors were not included in the common alleles and well documented alleles (CWD) of China, but were included in the CWD of American Society for Histocompatibility and Immunogenetics (ASHI). The alleles of A*68:24, B*35:11, B*44:29, DRB1*03:04, DRB1*08:18 and DRB1*13:05 were confirmed in more than two samples. There were totally 21 novel HLA alleles identified by our laboratory and officially assigned by the WHO Nomenclature Committee from 2005 to 2012, and some of them were also detected from multiple donors in other HLA typing laboratories of China. Now the novel alleles of HLA-A*02:90, HLA-B*48:14 and HLA-DRB1*01:14 were added into the Chinese CWD list. It is concluded that to ensure the polymorphism integrity and accurate population distribution of HLA genes and its constant accumulations on CMDP, it is necessary to recognize and submit timely the potential novel alleles in our practical work, as well as to record and statistics the identified rare alleles, which can provide the basis for the modification of Chinese CWD. When CWD list is referred, it should be careful for ambiguous results containing the identified rare alleles in order to avoid the occurrence of false or undiscovered detection, and ensure that the patients carrying rare alleles could find a matching donor with the maximum opportunity.

  11. The prognostic impact of soluble and vesicular HLA-G and its relationship to circulating tumor cells in neoadjuvant treated breast cancer patients.

    PubMed

    König, Lisa; Kasimir-Bauer, Sabine; Hoffmann, Oliver; Bittner, Ann-Kathrin; Wagner, Bettina; Manvailer, Luis Felipe Santos; Schramm, Sabine; Bankfalvi, Agnes; Giebel, Bernd; Kimmig, Rainer; Horn, Peter A; Rebmann, Vera

    2016-09-01

    The non-classical human leukocyte antigen G (HLA-G) molecule and its soluble forms exert multiple immune suppressive regulatory functions in malignancy and in stem cells contributing to immune escape mechanisms. HLA-G can be secreted as free soluble HLA-G molecules or via extracellular vesicles (EVs). Here we evaluated these soluble HLA-G forms as prognostic marker for prediction of the clinical outcome of neoadjuvant chemotherapy (NACT) treated breast cancer (BC) patients. Plasma samples of BC patients procured before (n=142) and after (n=154) NACT were quantified for total soluble HLA-G (sHLA-Gtot) and HLA-G levels in ExoQuick™ derived EV fractions (sHLA-GEV) by ELISA. The corresponding increments were specified as free sHLA-G (sHLA-Gfree). Total and free sHLA-G were significantly increased in NACT treated BC patients compared to healthy controls (n=16). High sHLA-Gfree levels were exclusively associated to estrogen receptor expression before NACT. Importantly, high sHLA-GEV levels before NACT were related to disease progression and the detection of stem cell-like circulating tumor cells, but high sHLA-Gfree levels indicated an improved clinical outcome. Thus, this study demonstrates for the first time that the different sHLA-G subcomponents represent dissimilar qualitative prognostic impacts on the clinical outcome of NACT treated BC patients, whereas the total sHLA-G levels without separating into subcomponents are not related to clinical outcome.

  12. Characterization of two Epstein-Barr virus epitopes restricted by HLA-B7.

    PubMed

    Hill, A; Worth, A; Elliott, T; Rowland-Jones, S; Brooks, J; Rickinson, A; McMichael, A

    1995-01-01

    We have identified two epitopes for Epstein-Barr virus specific cytotoxic T lymphocytes (CTL) restricted by the common allele HLA-B7. They are EBNA 3C 881-9 (QPRAPIRPI) and EBNA 3A 379-387 (RPPIFIRRL). The epitopes conform well to the recently described motif for HLA-B7-binding peptides (Huckzo et al., J. Immunol. 1993. 151:2572). Titration of the peptides in CTL assays and detergent lysate binding assays revealed that extending the peptides at either the N or C terminus did not reduce their affinity for HLA-B7. This behavior contrasted with HLA-B51, which binds peptides with a similar motif to B7, and has identical amino acid residues at sites expected to form the "F" pocket of the peptide-binding groove. HLA-B51 also bound the peptide EBNA 3C 881-9, but was unable to bind peptides extended at the C terminus.

  13. Distribution of HLA haplotypes across Japanese Archipelago: similarity, difference and admixture.

    PubMed

    Nakaoka, Hirofumi; Inoue, Ituro

    2015-11-01

    The human leukocyte antigen (HLA) region is the most polymorphic region in the human genome. The polymorphic nature of the HLA region is thought to have been shaped from balancing selection. The complex migration events during the Out-of-Africa expansion have influenced geographic patterns of HLA allele frequencies and diversities across present-day human populations. Differences in the HLA allele frequency may contribute geographic differences in the susceptibility to many diseases, such as infectious, autoimmune and metabolic diseases. Here we briefly reviewed characteristics of frequency distribution of HLA alleles and haplotypes in Japanese population. A large part of HLA alleles and haplotypes that are common in Japanese are shared with neighboring Asian populations. The differentiations in HLA alleles and haplotypes across Japanese regional populations may provide clues to model for peopling of Japanese Archipelago and for design of genetic association studies. Finally, we introduce recent topics that new HLA alleles derived from ancient admixtures with Neanderthals and Denisovans are thought to have played an important role in the adaptation of modern humans to local pathogens during Out-of-Africa expansion. PMID:26202576

  14. HLA-A gene polymorphisms contribute to osteoporosis susceptibility in postmenopausal Han Chinese women.

    PubMed

    Li, S M; Guo, H; Yang, H J; Lv, M Q; Zhou, D X

    2015-08-28

    Osteoporosis is a common disease characterized by low bone mineral density, deterioration in bone microarchitecture, and increased fracture risk and is more prevalent in postmenopausal women. HLA is a complex gene family; previous studies have shown that it plays an important role in the pathogenesis of osteoporosis among Japanese and Greek populations. Prompted by these findings, this study was designed to explore the associations between HLA-A gene polymorphisms and postmenopausal osteoporosis in the Han Chinese population. The polymerase chain reaction-sequence-based typing method was used for DNA genotyping at the HLA-A locus in 70 patients with postmenopausal osteoporosis and 73 healthy controls. We identified 17 HLA-A alleles in patients with postmenopausal osteoporosis and 20 HLA-A alleles in control subjects. Furthermore, we found that the frequency of the HLA-A* 02:07 allele was significantly higher in patients with postmenopausal osteoporosis than in control subjects (P = 0.023), and the relative risk was 4.065 (95% confidence interval = 1.109-14.893). Our study provides supportive evidence for the contribution of HLA-A gene polymorphisms to the susceptibility to postmenopausal osteoporosis and suggests that HLA-A* 02:07 is likely an important genetic risk factor for postmenopausal osteoporosis in the Han Chinese population.

  15. HLA genotyping in the international Type 1 Diabetes Genetics Consortium

    PubMed Central

    Mychaleckyj, Josyf C; Noble, Janelle A; Moonsamy, Priscilla V; Carlson, Joyce A; Varney, Michael D; Post, Jeff; Helmberg, Wolfgang; Pierce, June J; Bonella, Persia; Fear, Anna Lisa; Lavant, Eva; Louey, Anthony; Boyle, Sean; Lane, Julie A; Sali, Paul; Kim, Samuel; Rappner, Rebecca; Williams, Dustin T; Perdue, Letitia H; Reboussin, David M; Tait, Brian D; Akolkar, Beena; Hilner, Joan E; Steffes, Michael W; Erlich, Henry A

    2010-01-01

    Background Although human leukocyte antigen (HLA) DQ and DR loci appear to confer the strongest genetic risk for type 1 diabetes, more detailed information is required for other loci within the HLA region to understand causality and stratify additional risk factors. The Type 1 Diabetes Genetics Consortium (T1DGC) study design included high-resolution genotyping of HLA-A, B, C, DRB1, DQ, and DP loci in all affected sibling pair and trio families, and cases and controls, recruited from four networks worldwide, for analysis with clinical phenotypes and immunological markers. Purpose In this article, we present the operational strategy of training, classification, reporting, and quality control of HLA genotyping in four laboratories on three continents over nearly 5 years. Methods Methods to standardize HLA genotyping at eight loci included: central training and initial certification testing; the use of uniform reagents, protocols, instrumentation, and software versions; an automated data transfer; and the use of standardized nomenclature and allele databases. We implemented a rigorous and consistent quality control process, reinforced by repeated workshops, yearly meetings, and telephone conferences. Results A total of 15,246 samples have been HLA genotyped at eight loci to four-digit resolution; an additional 6797 samples have been HLA genotyped at two loci. The genotyping repeat rate decreased significantly over time, with an estimated unresolved Mendelian inconsistency rate of 0.21%. Annual quality control exercises tested 2192 genotypes (4384 alleles) and achieved 99.82% intra-laboratory and 99.68% inter-laboratory concordances. Limitations The chosen genotyping platform was unable to distinguish many allele combinations, which would require further multiple stepwise testing to resolve. For these combinations, a standard allele assignment was agreed upon, allowing further analysis if required. Conclusions High-resolution HLA genotyping can be performed in multiple

  16. Increased epithelial expression of HLA-DQ and HLA-DP molecules in salivary glands from patients with Sjögren's syndrome compared with obstructive sialadenitis.

    PubMed Central

    Thrane, P S; Halstensen, T S; Haanaes, H R; Brandtzaeg, P

    1993-01-01

    Salivary gland specimens from 10 patients with primary Sjögren's syndrome (pSS) were examined by two-colour immunofluorescence with various combinations of monoclonal and polyclonal antibody reagents of the following specificities: human leucocyte antigen (HLA) class I and II (DR, DP and DQ), CD3, CD45 (leucocyte common antigen), various cytokeratins, and factor VIII-related antigen. Tissue specimens from 10 normal glands and 10 glands with obstructive sialadenitis (no known autoimmunity) served as controls. Only some intercalated ducts and scattered acini of the normal major glands expressed HLA class II determinants (< 5% of total epithelial area); the relative proportion of positive elements indicated differential expression (DR > DP > DQ). SS glands contained substantial T cell infiltrates and increased numbers of activated (DR+) T cells; adjacent epithelium showed extensive differential expression of HLA class II determinants (DR > DP > DQ). Glands with obstructive sialadenitis showed similarly increased epithelial expression of HLA-DR but with surprisingly small amounts of concomitant HLA-DP and -DQ expression. Epithelial HLA class II expression probably depends on cytokines as an inductive event, which is not unique for SS but particularly prominent in this disorder. Our results suggest that epithelial expression of HLA-DP or -DQ, rather than -DR, might be a prerequisite for the autoimmune process of SS to develop in genetically susceptible individuals. Images Fig. 2 PMID:8485911

  17. HLA class I expression in bladder carcinomas.

    PubMed

    Cabrera, T; Pedrajas, G; Cozar, J M; Garrido, A; Vicente, J; Tallada, M; Garrido, F

    2003-10-01

    HLA class I molecules are frequently lost in a large variety of human carcinomas, possibly because of T-cell immune selection of major histocompatibility complex class I deficient tumor variants. We report that this phenomenon is also a frequent event in bladder carcinomas. Of a total of 72 bladder carcinomas, 72% of the tumors had at least one alteration in HLA class I expression. These altered HLA class I phenotypes were classified as total HLA class I loss (25%; phenotype I); HLA-A or/and HLA-B locus-specific loss (12%; phenotype III); and HLA class I allelic loss (35%; phenotype II or IV). Comparison of histopathological parameters with HLA class I expression showed a statistically significant relationship with the degree of differentiation and tumor recurrence.

  18. HLA-linked rheumatoid arthritis

    SciTech Connect

    Hasstedt, S.J.; Clegg, D.O.; Ingles, L.; Ward, R.H.

    1994-10-01

    Twenty-eight pedigrees were ascertained through pairs of first-degree relatives diagnosed with rheumatoid arthritis (RA). RA was confirmed in 77 pedigree members including probands; the absence of disease was verified in an additional 261 pedigree members. Pedigree members were serologically typed for HLA. We used likelihood analysis to statistically characterize the HLA-linked RA susceptibility locus. The genetic model assumed tight linkage to HLA. The analysis supported the existence of an HLA-linked RA susceptibility locus, estimated the lifetime penetrance as 41% in male homozygotes and as 48% in female homozygotes. Inheritance was recessive in males and was nearly recessive in females. In addition, the analysis attributed 78% of the variance within genotypes to genetic or environmental effects shared by siblings. The genetic model inferred in this analysis is consistent with previous association, linkage, and familial aggregation studies of RA. The inferred HLA-linked RA susceptibility locus accounts for approximately one-fifth of the RA in the population. Although other genes may account for the remaining familial RA, a large portion of RA cases may occur sporadically. 79 refs., 9 tabs.

  19. HLA antigens in individuals with down syndrome and alopecia areata

    PubMed Central

    Estefan, Juliany L; Oliveira, Juliana C; Abad, Eliane D; Saintive, Simone B; Porto, Luis Cristóvão MS; Ribeiro, Marcia

    2014-01-01

    AIM: To describe human leukocyte antigen (HLA) alleles in individuals with Down syndrome and alopecia areata. METHODS: A cross-sectional study was conducted, which evaluated 109 individuals. Ten with down syndrome (DS) and alopecia areata (AA), ten with DS without AA and ten with AA without DS, and their families. The individuals were matched by gender and age. The following data were computed: gender, age, ethnic group, karyotype, clinical presentation and family history of alopecia areata. Descriptive analysis: measures of central tendency and frequency distribution. Inferential analysis: Fisher’s exact test to compare categorical data between the three groups and Kruskal-Wallis ANOVA test for numerical data. RESULTS: Seventy per cent of evaluated individuals in the DS and AA group were male; presented mean age of 18.6 (SD ± 7.2) years and 70% were Caucasian. We observed involvement of the scalp, with a single lesion in 10% and multiple in 90% of subjects. It was observed that there is no significant difference in the frequency distributions of the alleles HLA loci A, B, C, DRB1 and DQB1 of subjects studied. However, according to Fisher’s exact test, there is a trend (P = 0.089) of DS group to present higher proportions of HLA-A 36 and HLA-B 15 than the AA group and AA and DS group. CONCLUSION: There was a tendency for the DS group, to present proportion of HLA-A 36 and HLA-B 15 higher than the AA group and group of individuals with AA and DS. However, there was no significant difference in the frequency distribution of the alleles. PMID:25325065

  20. Associations of HLA-A, HLA-B and HLA-C Alleles Frequency with Prevalence of Herpes Simplex Virus Infections and Diseases Across Global Populations: Implication for the Development of an Universal CD8+ T-Cell Epitope-Based Vaccine

    PubMed Central

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S.; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A.; Lemonnier, François A.; BenMohamed, Lbachir

    2014-01-01

    A significant portion of the world’s population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) Over half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A*24, HLA-B*27, HLA-B*53 and HLA-B*58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B*44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy. PMID:24798939

  1. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine.

    PubMed

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A; Lemonnier, François A; BenMohamed, Lbachir

    2014-08-01

    A significant portion of the world's population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) over a half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A(∗)24, HLA-B(∗)27, HLA-B(∗)53 and HLA-B(∗)58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B(∗)44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy. PMID:24798939

  2. Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: implication for the development of an universal CD8+ T-cell epitope-based vaccine.

    PubMed

    Samandary, Sarah; Kridane-Miledi, Hédia; Sandoval, Jacqueline S; Choudhury, Zareen; Langa-Vives, Francina; Spencer, Doran; Chentoufi, Aziz A; Lemonnier, François A; BenMohamed, Lbachir

    2014-08-01

    A significant portion of the world's population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) over a half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A(∗)24, HLA-B(∗)27, HLA-B(∗)53 and HLA-B(∗)58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B(∗)44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy.

  3. Findings of Optical Coherence Tomography of Retinal Nerve Fiber Layer in Two Common Types of Multiple Sclerosis.

    PubMed

    Yousefipour, Gholamali; Hashemzahi, Zabihollah; Yasemi, Masood; Jahani, Pegah

    2016-06-01

    Multiple sclerosis (MS) is the most prevalent disease caused by the inflammatory demyelinating process that causes progressive nervous system degeneration over the time. Optical Coherence Tomography (OCT) is a non-invasive optical imaging technology, which can measure the thickness of retinal nerve fiber layer as well as the diameter of the macula. The purpose of the study is evaluation OCT findings in two common types of multiple sclerosis. For doing the cross-sectional study, 63 patients with two prevalent types of multiple sclerosis (35 patients with Relapse Remitting Multiple Sclerosis (RRMS) and 28 patients with Secondary Progressive Multiple Sclerosis (SPMS) were evaluated for 6 months. Exclusion criteria of the study were a history of optic neuritis, suffering from diabetes mellitus, hypertension, ocular disease, and the presence of other neurologic degenerative diseases. Then, the thickness of retinal nerve fiber layer (RNFL), as well as thickness and volume of the macula, were measured in the patients using OCT technology. The disability rate of patients was evaluated according to Expanded Disability Status Scale (EDSS). Finally, data was analyzed by means of SPSS software. Overall, 35 patients with RRMS (with mean age of 32.37+10.01, average disease period of 3.81+3.42 and mean EDSS of 1.84+0.45) and 28 patients with SPMS (with mean age of 39.21+9.33, average disease period of 11.32+5.87 and mean EDSS of 5.12+1.46) were assessed and compared in terms of retinal nerve fiber layer and size and thickness of macula. In all of these sections, the thicknesses were smaller in SPMS patients than patients with RRMS. But, there was a significant difference in total thickness (81.82µm versus 96.03µm with P=0.04) and thickness of temporal sector (54.5 µm versus 69.34 µm with P=0.04) of retinal nerve fiber layer and macular size at the superior sector of external ring (1.48 mm³ versus 1.58 mm³ with P=0.03), and nasal sector of external ring surrounding macula (1

  4. KIR3DL1 and HLA-B Density and Binding Calibrate NK Education and Response to HIV.

    PubMed

    Boudreau, Jeanette E; Mulrooney, Tiernan J; Le Luduec, Jean-Benoît; Barker, Edward; Hsu, Katharine C

    2016-04-15

    NK cells recognize self-HLA via killer Ig-like receptors (KIR). Homeostatic HLA expression signals for inhibition via KIR, and downregulation of HLA, a common consequence of viral infection, allows NK activation. Like HLA, KIR are highly polymorphic, and allele combinations of the most diverse receptor-ligand pair, KIR3DL1 and HLA-B, correspond to hierarchical HIV control. We used primary cells from healthy human donors to demonstrate how subtype combinations of KIR3DL1 and HLA-B calibrate NK education and their consequent capacity to eliminate HIV-infected cells. High-density KIR3DL1 and Bw4-80I partnerships endow NK cells with the greatest reactivity against HLA-negative targets; NK cells exhibiting the remaining KIR3DL1/HLA-Bw4 combinations demonstrate intermediate responsiveness; and Bw4-negative KIR3DL1(+) NK cells are poorly responsive. Cytotoxicity against HIV-infected autologous CD4(+) T cells strikingly correlated with reactivity to HLA-negative targets. These findings suggest that the programming of NK effector function results from defined features of receptor and ligand subtypes. KIR3DL1 and HLA-B subtypes exhibit an array of binding strengths. Like KIR3DL1, subtypes of HLA-Bw4 are expressed at distinct, predictable membrane densities. Combinatorial permutations of common receptor and ligand subtypes reveal binding strength, receptor density, and ligand density to be functionally important. These findings have immediate implications for prognosis in patients with HIV infection. Furthermore, they demonstrate how features of KIR and HLA modified by allelic variation calibrate NK cell reactive potential. PMID:26962229

  5. Evaluation of TNF-α serum level in patients with recalcitrant multiple common warts, treated by lipid garlic extract.

    PubMed

    Kenawy, Soha; Mohammed, Ghada Farouk; Younes, Soha; Elakhras, Atef Ibrahim

    2014-01-01

    No universal consensus about optimal modality for treating the recalcitrant multiple common warts (RMCW). The objective of the study was to evaluate the immunological mechanisms and clinical therapeutic effect of using lipid garlic extract (LGE) in the treatment of RMCW. The study included 50 patients with RMCW. They were randomly assigned into two groups: the first group (25 patients) received LGE, and the second group (25 patients) received saline as a control group. In both groups, treatments were made to single lesions, or largest wart in case of multiple lesions, until complete clearance of lesions or for a maximum of 4 weeks. Blood serum was taken at pre-study and at the fourth week to measure tumor necrosis factor alpha (TNF-α) level. A significant difference was found between the therapeutic responses of RMCW to LGE antigen and saline control group (p < 0.001). In the LGE group, complete response was achieved in 96% of patients presenting with RMCW. There was a statistically nonsignificant increase in TNF-α of LGE group versus saline group. No recurrence was observed in the LGE group. LGE as an immunotherapy is an inexpensive, effective, and safe modality with good cure rates for treatment of RMCWs, when other topical or physical therapies have failed. PMID:24910383

  6. Identification of a common Wnt-associated genetic signature across multiple cell types in pulmonary arterial hypertension

    PubMed Central

    West, James D.; Austin, Eric D.; Gaskill, Christa; Marriott, Shennea; Baskir, Rubin; Bilousova, Ganna; Jean, Jyh-Chang; Hemnes, Anna R.; Menon, Swapna; Bloodworth, Nathaniel C.; Fessel, Joshua P.; Kropski, Johnathan A.; Irwin, David; Ware, Lorraine B.; Wheeler, Lisa; Hong, Charles C.; Meyrick, Barbara; Loyd, James E.; Bowman, Aaron B.; Ess, Kevin C.; Klemm, Dwight J.; Young, Pampee P.; Merryman, W. David; Kotton, Darrell

    2014-01-01

    Understanding differences in gene expression that increase risk for pulmonary arterial hypertension (PAH) is essential to understanding the molecular basis for disease. Previous studies on patient samples were limited by end-stage disease effects or by use of nonadherent cells, which are not ideal to model vascular cells in vivo. These studies addressed the hypothesis that pathological processes associated with PAH may be identified via a genetic signature common across multiple cell types. Expression array experiments were initially conducted to analyze cell types at different stages of vascular differentiation (mesenchymal stromal and endothelial) derived from PAH patient-specific induced pluripotent stem (iPS) cells. Molecular pathways that were altered in the PAH cell lines were then compared with those in fibroblasts from 21 patients, including those with idiopathic and heritable PAH. Wnt was identified as a target pathway and was validated in vitro using primary patient mesenchymal and endothelial cells. Taken together, our data suggest that the molecular lesions that cause PAH are present in all cell types evaluated, regardless of origin, and that stimulation of the Wnt signaling pathway was a common molecular defect in both heritable and idiopathic PAH. PMID:24871858

  7. A NOVel ELISPOT assay to quantify HLA-specific B cells in HLA-immunized individuals.

    PubMed

    Heidt, S; Roelen, D L; de Vaal, Y J H; Kester, M G D; Eijsink, C; Thomas, S; van Besouw, N M; Volk, H D; Weimar, W; Claas, F H J; Mulder, A

    2012-06-01

    Quantification of the humoral alloimmune response is generally achieved by measuring serum HLA antibodies, which provides no information about the cells involved in the humoral immune response. Therefore, we have developed an HLA-specific B-cell ELISPOT assay allowing for quantification of B cells producing HLA antibodies. We used recombinant HLA monomers as target in the ELISPOT assay. Validation was performed with human B-cell hybridomas producing HLA antibodies. Subsequently, we quantified B cells producing HLA antibodies in HLA-immunized individuals, non-HLA-immunized individuals and transplant patients with serum HLA antibodies. B-cell hybridomas exclusively formed spots against HLA molecules of corresponding specificity with the sensitivity similar to that found in total IgG ELISPOT assays. HLA-immunized healthy individuals showed up to 182 HLA-specific B cells per million total B cells while nonimmunized individuals had none. Patients who were immunized by an HLA-A2-mismatched graft had up to 143 HLA-A2-specific B cells per million total B cells. In conclusion, we have developed and validated a highly specific and sensitive HLA-specific B-cell ELISPOT assay, which needs further validation in a larger series of transplant patients. This technique constitutes a new tool for quantifying humoral immune responses. PMID:22390272

  8. HLA genetic diversity in Hungarians and Hungarian Gypsies: complementary differentiation patterns and demographic signals revealed by HLA-A, -B and -DRB1 in Central Europe.

    PubMed

    Inotai, D; Szilvasi, A; Benko, S; Boros-Major, A; Illes, Z; Bors, A; Kiss, K P; Rajczy, K; Gelle-Hossó, A; Buhler, S; Nunes, J M; Sanchez-Mazas, A; Tordai, A

    2015-08-01

    Systematic analyses of human leukocyte antigen (HLA) profiles in different populations may increase the efficiency of bone marrow donor selection and help reconstructing human peopling history. We typed HLA-A, -B, and -DRB1 allele groups in two bone marrow donor cohorts of 2402 Hungarians and 186 Hungarian Gypsies and compared them with several Central-European, Spanish Gypsy, and Indian populations. Our results indicate that different European Gypsy populations share a common origin but diverged genetically as a consequence of founder effect and rapid genetic drift, whereas other European populations are related genetically in relation to geography. This study also suggests that while HLA-A accurately depicts the effects of genetic drift, HLA-B, and -DRB1 conserve more signatures of ancient population relationships, as a result of balancing selection. PMID:26149581

  9. HLA genetic diversity in Hungarians and Hungarian Gypsies: complementary differentiation patterns and demographic signals revealed by HLA-A, -B and -DRB1 in Central Europe.

    PubMed

    Inotai, D; Szilvasi, A; Benko, S; Boros-Major, A; Illes, Z; Bors, A; Kiss, K P; Rajczy, K; Gelle-Hossó, A; Buhler, S; Nunes, J M; Sanchez-Mazas, A; Tordai, A

    2015-08-01

    Systematic analyses of human leukocyte antigen (HLA) profiles in different populations may increase the efficiency of bone marrow donor selection and help reconstructing human peopling history. We typed HLA-A, -B, and -DRB1 allele groups in two bone marrow donor cohorts of 2402 Hungarians and 186 Hungarian Gypsies and compared them with several Central-European, Spanish Gypsy, and Indian populations. Our results indicate that different European Gypsy populations share a common origin but diverged genetically as a consequence of founder effect and rapid genetic drift, whereas other European populations are related genetically in relation to geography. This study also suggests that while HLA-A accurately depicts the effects of genetic drift, HLA-B, and -DRB1 conserve more signatures of ancient population relationships, as a result of balancing selection.

  10. HLA-B15: a widespread and diverse family of HLA-B alleles.

    PubMed

    Hildebrand, W H; Domena, J D; Shen, S Y; Lau, M; Terasaki, P I; Bunce, M; Marsh, S G; Guttridge, M G; Bias, W B; Parham, P

    1994-04-01

    HLA-B15 embraces a multiplicity of antigenic specificities which vary in their distribution amongst human populations. To correlate B15 molecular structure with the serological picture we have sequenced alleles encoding the various subspecificities of the B15 antigen: B62, B63, B75, B76 and B77, and a number of "variants" of these antigens including the 8w66 split of B63. HLA-B63 (B*1517) and 8w66 (B*1516) heavy chains have sequence identity to B17 in the alpha 1 helix correlating with the antigenic crossreactivity of these molecules. HLA-B77(B*1513) and B75 (B*1502) heavy chains differ solely in segments determining the Bw4 and Bw6 public epitopes, consistent with the serological description of the B77 and B75 antigens. One allele encoding the B76 antigen (B*1512) appears to be the product of gene conversion between the HLA-A and -B loci and differs from B*1501 in codons 166 and 167. In contrast, a second allele encoding the B76 antigen (B*1514) differs from B*1501 by an unrelated substitution in codon 167 which confers similarily with B45, an antigen crossreactive with B76. A third allele encoding B76, B*1519, differs from B*1512 by a unique point substitution in exon 4. Three alleles encoding variant B15 and B62 antigens (B*1508, B*1511 and B*1515) differ from B*1501 by localized clusters of substitutions that probably result from interallelic conversion. The B15 sequences described in this paper, in combination with those previously determined, define a family of 22 alleles, including those encoding the B46 and B70 antigens. Within this family the patterns of allelic substitution are analogous to those of other HLA-A and -B families, in that pairwise differences almost always involve functional positions of the antigen recognition site and recombination is the major agent of diversification.

  11. A schizophrenia-associated HLA locus affects thalamus volume and asymmetry.

    PubMed

    Brucato, Nicolas; Guadalupe, Tulio; Franke, Barbara; Fisher, Simon E; Francks, Clyde

    2015-05-01

    Genes of the Major Histocompatibility Complex (MHC) have recently been shown to have neuronal functions in the thalamus and hippocampus. Common genetic variants in the Human Leukocyte Antigens (HLA) region, human homologue of the MHC locus, are associated with small effects on susceptibility to schizophrenia, while volumetric changes of the thalamus and hippocampus have also been linked to schizophrenia. We therefore investigated whether common variants of the HLA would affect volumetric variation of the thalamus and hippocampus. We analysed thalamus and hippocampus volumes, as measured using structural magnetic resonance imaging, in 1.265 healthy participants. These participants had also been genotyped using genome-wide single nucleotide polymorphism (SNP) arrays. We imputed genotypes for single nucleotide polymorphisms at high density across the HLA locus, as well as HLA allotypes and HLA amino acids, by use of a reference population dataset that was specifically targeted to the HLA region. We detected a significant association of the SNP rs17194174 with thalamus volume (nominal P=0.0000017, corrected P=0.0039), as well as additional SNPs within the same region of linkage disequilibrium. This effect was largely lateralized to the left thalamus and is localized within a genomic region previously associated with schizophrenia. The associated SNPs are also clustered within a potential regulatory element, and a region of linkage disequilibrium that spans genes expressed in the thalamus, including HLA-A. Our data indicate that genetic variation within the HLA region influences the volume and asymmetry of the human thalamus. The molecular mechanisms underlying this association may relate to HLA influences on susceptibility to schizophrenia.

  12. Idiopathic focal segmental glomerulosclerosis and HLA antigens.

    PubMed

    Gerbase-DeLima, M; Pereira-Santos, A; Sesso, R; Temin, J; Aragão, E S; Ajzen, H

    1998-03-01

    The objective of the present study was to investigate a possible association between HLA class II antigens and idiopathic focal segmental glomerulosclerosis (FSGS). HLA-A, -B, -DR and -DQ antigens were determined in 19 Brazilian patients (16 white subjects and three subjects of Japanese origin) with biopsy-proven FSGS. Comparison of the HLA antigen frequencies between white patients and white local controls showed a significant increase in HLA-DR4 frequency among FSGS patients (37.7 vs 17.2%, P < 0.05). In addition, the three patients of Japanese extraction, not included in the statistical analysis, also presented HLA-DR4. In conclusion, our data confirm the association of FSGS with HLA-DR4 previously reported by others, thus providing further evidence for a role of genes of the HLA complex in the susceptibility to this disease. PMID:9698788

  13. HLA and other gene associations with dengue disease severity.

    PubMed

    Stephens, H A F

    2010-01-01

    Large case control gene association studies have been performed on cohorts of dengue virus (DENV) infected patients identified in mainland Southeast Asia, South Asia and the Caribbean. Candidate genes that have shown statistically significant associations with DENV disease severity encode HLA molecules, cell receptors for IgG (FcGII), vitamin D and ICAM3 (DCSIGN or CD209), pathogen recognition molecules such as mannose binding lectin (MBL), blood related antigens including ABO and human platelet antigens (HPA1 and HPA2). In ethnic Thais with secondary infections a variety of HLA class I alleles (HLA-A 0203, 0207, A11, B 15, B 44, B 46, B 48, B 51, B 52), DCSIGN promoter polymorphisms and the AB blood group, independently associate with either susceptibility or resistance to dengue fever (DF) and the more severe dengue hemorrhagic fever (DHF). There is also evidence that some HLA associations with disease severity correlate with the DENV serotype inducing secondary infections. Taken together, there is now evidence that allelic variants of multiple gene loci involved in both acquired and innate immune responses contribute significantly to DENV disease outcome and severity. Further analysis of the genetic basis of severe DENV disease in different at risk populations may contribute to the development of new preventative and therapeutic interventions.

  14. HLA dosage effect in narcolepsy with cataplexy.

    PubMed

    van der Heide, Astrid; Verduijn, Willem; Haasnoot, Geert W; Drabbels, Jos J M; Lammers, Gert J; Claas, Frans H J

    2015-01-01

    Narcolepsy with cataplexy is a sleep disorder caused by the loss of hypocretin-producing neurons in the hypothalamus. It is tightly associated with a specific human leukocyte antigen (HLA)-allele: HLA-DQB1*06:02. Based on this, an autoimmune process has been hypothesized. A functional HLA-DQ molecule consists of a DQα and a DQβ chain. HLA-DQB1*06:02 (DQβ) has a strong preference for binding to HLA-DQA1*01:02 (DQα), and together they form the functional DQ0602 dimer. A dosage effect would be expected if the HLA-DQ0602 dimer itself is directly involved in the aetiology. An increased expression of the HLA-DQ0602 dimer is expected in individuals homozygous for HLA-DQB1*06:02-DQA1*01:02, but is also hypothesized in individuals heterozygous for HLA-DQB1*06:02 and homozygous for HLA-DQA1*01:02. To study the impact of the expression of the HLA-DQ0602 dimer on narcolepsy susceptibility, 248 Dutch narcolepsy patients and 1272 Dutch control subjects, all of them positive for DQB1*06:02 (heterozygous and homozygous), were HLA-genotyped with attention not only to DQB1 but also to DQA1*01:02. DQB1*06:02-DQA1*01:02 homozygosity was significantly more often seen in patients compared to controls (O.R. 2.29) confirming previous observations. More importantly, a significantly higher prevalence of homozygosity for DQA1*01:02 was found in HLA-DQB1*06:02 heterozygous patients compared to controls (O.R. 2.37, p < 0.001). The latter finding clearly supports a direct role of the HLA-DQ molecule in the development of disease.

  15. Frequent HLA class I and DP sequence mismatches in serologically (HLA-A, HLA-B, HLA-DR) and molecularly (HLA-DRB1, HLA-DQA1, HLA-DQB1) HLA-identical unrelated bone marrow transplant pairs.

    PubMed

    Santamaria, P; Reinsmoen, N L; Lindstrom, A L; Boyce-Jacino, M T; Barbosa, J J; Faras, A J; McGlave, P B; Rich, S S

    1994-01-01

    The rates of graft-versus-host disease (GVHD) and rejection are significantly higher among recipients of unrelated donor marrow (BM) than in recipients of marrow from HLA-identical siblings, even when donors and recipients are mixed lymphocyte culture (MLC) compatible and serologically and Dw identical. It has been hypothesized that phenotypically silent HLA class I and DP sequence mismatches might be associated with these differences, but little is known about their incidence. We have sequenced the HLA-A, HLA-B, HLA-C, HLA-DPA1, and HLA-DPB1 genes expressed by 12 unrelated marrow transplant pairs, 11 of whom were molecularly matched at DRB, DQA1, and DQB1 loci. Nine of these pairs were also HLA-A and HLA-B matched by serology. Six of these nine "HLA-identical" pairs were HLA-A (2 of 6), HLA-B (1 of 6), and HLA-C (6 of 6) mismatched at the sequence level. The mismatched class I alleles of all these pairs had strikingly different sequence motifs in the six specificity pockets of their antigen recognition site, and in five pairs they also had sequence differences at positions implicated in T-cell receptor (TCR) binding. Two of the three pairs who were serologically mismatched for one HLA-A or HLA-B antigen were also sequence mismatched at HLA-C. Finally, 10 of 11 pairs tested expressed different DP sequences. These data indicate that HLA class I, especially HLA-C, and DP sequence mismatches are frequent among unrelated subjects defined as HLA identical by current typing methods. We speculate that these sequence differences may explain, at least in part, the higher incidence of acute GVHD and rejection in unrelated BM transplantation as opposed to transplantation between HLA-identical siblings. Because of their high frequency, the role of HLA-A, HLA-B, HLA-C, and HLA-DP mismatches in transplantation outcome is now amenable to direct study.

  16. HLA class I and II polymorphisms in the Gujjar population from Pakistan.

    PubMed

    Raza, Ali; Firasat, Sadaf; Khaliq, Shagufta; Abid, Aiysha; Shah, Syed Shoaib; Mehdi, Syed Qasim; Mohyuddin, Aisha

    2013-01-01

    HLA polymorphisms at the HLA -A, -B, -C, -DRB and -DQB1 loci were investigated in the Gujjar population from the Punjab province of Pakistan. The Gujjars (n = 97) were genotyped using sequence specific primers for polymerase chain reaction. The allele and haplotype frequencies were calculated and a neighbor-joining (NJ) tree comparing the Gujjar with other populations was constructed. The class I allelic groups with a frequency greater than 10% include A*01, A*02, A*11, A*26 and A*31 at the HLA-A locus, B*08 and B*51 at the HLA-B locus and C*07 and C*14 at the HLA-C locus. Among the 12 allelic groups detected at the DRB1* locus, *03, *13, and *15 were present at frequencies higher than 10% whereas at the DQB1 locus, the allelic groups*06 and *02 accounted for over half of the Gujjar population. HLA-A*31-B*51-DRB1*13 was the most common (8.8%) haplotype in this population. A NJ tree revealed that the Pakistani Gujjar are closely related to the Golla tribe from Andhra Pradesh in India. The two populations are dedicated to the same profession, cattle breeding. HLA analyses of additional Punjab castes would provide valuable information for anthropological, organ transplantation and genetic disease studies.

  17. HLA-DP, HLA-DQ, and HLA-DR-restricted epitopes in GRA5 of toxoplasma gondii strains

    NASA Astrophysics Data System (ADS)

    Haryati, S.; Sari, Y.; APrasetyo, A.; Sariyatun, R.

    2016-02-01

    The dense granular (GRA) proteins of Toxoplasma gondii(T. gondii) have been demonstrated as potential sources of T. gondii vaccine antigens. However, data of the GRA5 protein are limited. This study analyzed twenty-one complete GRA5 sequences of T. gondii GT1, RH, ME49, VEG, MAS, RUB, FOU, p89, VAND, and GAB2-2007-GAL-DOM2 strains to identify potential epitopes restricted by Major Histocompatibility Complex class II (MHC- II) molecules (human leukocyte antigen (HLA)-DP, HLA-DQ, and HLA-DR) in the protein. In all T. gondii strains, peptides positioned at amino acid (aa) 15-29, 16-30, 17-31, 18-32, 19-33, 83-97, 84-98, 86-100, 87-101, 89-103, and 90-104 were predicted to pose high affinity and binding with HLA-DRB1*0101, HLA-DRB1*0301 (DR17), HLA-DRB1*0401 (DR4Dw4), HLA-DRB1*0701, HLA-DRB1*1101, HLA-DRB1*1501 (DR2b), and/or HLA-DRB5*0101. Considering the epitope's affinity, ligation strength, and hydrophilicity, LRLLRRRRRRAIQEE sequence (aa 90-104) restricted by HLA-DRB1*0101, HlA- DRB1*0301 (DR17), and HLA-DRB1*0401 (DR4Dw4) was considered as the most potential MHC-II epitope in GRA5 of T. gondii. These results would be useful for studies concerning in developing T. gondii vaccine and diagnostic method.

  18. Production and delivery batch scheduling with a common due date and multiple vehicles to minimize total cost

    NASA Astrophysics Data System (ADS)

    Prasetyaningsih, E.; Suprayogi; Samadhi, TMAA; Halim, AH

    2016-02-01

    This paper studies production and delivery batch scheduling problems for a single- supplier-to-a-single-manufacturer case, with multiple capacitated vehicles wherein different holding costs between in-process and completed parts are allowed. In the problem, the parts of a single item are first batched,then the resulting batches are processed on a single machine. All completed batches are transported in a number of deliveries in order to be received at a common due date. The objective is to find the integrated schedule of production and delivery batches so as to satisfy its due date and to minimize the total cost of associated in-process parts inventory, completed parts inventory and delivery. It should be noted that both holding costs constitute a derivation of the so-called actual flow time, and the delivery cost is proportional to the required number of deliveries. The problem can be formulated as an integer non-linier programming and it is solved optimally by Lingo 11.0 software. Numerical experiences show that there are two patterns of batch sizes affected by the ratio of holding costs of in-process and completed parts. It can be used by practitioners to solve the realistic integrated production and delivery batch scheduling problem.

  19. A multiple-common-lines method to determine the orientation of snapshot diffraction patterns from single particles.

    PubMed

    Zhou, Liang; Zhang, Tian-Yi; Liu, Zhong-Chuan; Liu, Peng; Dong, Yu-Hui

    2014-07-01

    With the development of X-ray free-electron lasers (XFELs), it is possible to determine the three-dimensional structures of noncrystalline objects with coherent X-ray diffraction imaging. In this diffract-and-destroy mode, many snapshot diffraction patterns are obtained from the identical objects which are presented one by one in random orientations to the XFEL beam. Determination of the orientation of an individual object is essential for reconstruction of a three-dimensional structure. Here a new method, called the multiple-common-lines method, has been proposed to determine the orientations of high- and low-signal snapshot diffraction patterns. The mean errors of recovered orientations (α, β, γ) of high- and low-signal patterns are about 0.14, 0.06, 0.12 and 0.77, 0.31, 0.60°, respectively; both sets of errors can meet the requirements of the reconstruction of a three-dimensional structure. PMID:25970194

  20. Role of HLA antigens in Rh (D) alloimmunized pregnant women from Mumbai, Maharashtra, India.

    PubMed

    Kumar, U Shankar; Ghosh, K; Gupte, S S; Gupte, S C; Mohanty, D

    2002-03-01

    Immunogenetic studies in various diseases provide potential genetic markers. We have studied the incidence of HLA A, B, C, DR and DQ loci antigen in Rh (D) antigen isoimmunized mothers compared to those nonimmunized isoimmunized Rh negative mothers. Seventy six mothers who were immunized to Rh (D) antigen due to pregnancy (responders) and fifty four mothers who did not develop Rh (D) isoimmunization despite positive pregnancies (nonresponders) were selected for the study. Standard methods of serological HLA typing, ABO and Rh (D) groups, and screening for Rh D antibodies were used. 392 unrelated individuals from the population were compared as controls. In addition 45 unrelated individuals from the same population were typed for HLA DRB and DQB gene using PCR-SSP kits. The genotype frequencies of HLA A2, A3, A28, B13, B17, B35, B52, B60, Cw2, Cw6, DR4, and DQ3 were significantly increased, while the frequencies of the HLA A11, A29, A31, B7, B37, B51, Cw1 and DR9 were decreased in the responder women when compared to the non-responder women. HLA A30 (19) split antigen was not identified in immunized women while HLA A23 (9) split antigen was not identified in non immunized women. HLA A3, B17, Cw2 and DR4 showed a significant relative risk among the immunized responder women. When compared with Rh immunized women (responders) reported from USA, England and Hungary the phenotype frequencies of HLA A11, A24, A28, B5, B17, B40, DR2 and DR5 were increased while HLA A23, B8, B18, and DR6 were decreased in the Indian Rh immunized women. Two locus haplotype frequency analysis observed among the responders women revealed that among the significant haplotypes expressed A2-B5, B7-Cw1, DR2-DQ1 were highly significant haplotypes in positive linkage, while A1-B5, and A1-B7 were in significant negative linkage disequilibrium. The haplotype frequencies were common hapoltypes were compared with control population. Thus in the present study it is evident that the

  1. Human cytotoxic T cell responses to trinitrophenyl hapten and influenza virus. Diversity of restriction antigens and specificity of HLA-linked genetic regulation.

    PubMed

    Biddison, W E; Payne, S M; Shearer, G M; Shaw, S

    1980-08-01

    This report compares both the HLA restriction patterns and Ir gene regulation of human in vitro T cell-mediated cytotoxic responses to the trinitrophenyl (TNP) hapten and the type A and B influenza viruses. Comparison of the restriction patterns of these cytotoxic responses indicates that A/HK and B/HK are recognized in conjunction with polymorphic HLA-A and -B self determinants, whereas TNP is recognized in association with a more complex spectrum of self determinants. These self determinants include polymorphic HLA-A and -B determinants, polymorphic non-HLA-A and -B determinants that probably include DR antigens, and non-polymorphic determinants that appear to be species specific. Analysis of the self determinants recognized by human T cells in conjunction with influenza virus demonstrates that (a) the antigens recognized by virus-immune T cells can be distinguished from the serologically defined HLA-A and -B antigenic determinants, and (b) there may be multiple self determinants on individual HLA-A molecules that T cells can recognize in conjunction with virus. The results of family studies indicate that donors' T cells often preferentially respond to virus (and to a lesser extent TNP) in conjunction with products of one parental HLA haplotype (haplotype preference). In the family study, three HLA-identical siblings preferentially recognize paternal HLA antigens in conjunction with A/HK, and maternal HLA antigens in conjunction with B/HK and TNP, which indicates antigen-specific HLA-lined genetic control. Population studies demonstrate virus-specific differences in the ability of donors to respond to selected self HLA-A and -B antigens in conjunction with virus. These differences may be controlled by Ir genes that are distinct from HLA-A and -B, because differences are observed in the response patterns of HLA-A- and -B-matched individuals.

  2. HLA-A, HLA-B, HLA-DRB1 allele and haplotype frequencies in 6384 umbilical cord blood units and transplantation matching and engraftment statistics in the Zhejiang cord blood bank of China.

    PubMed

    Wang, F; He, J; Chen, S; Qin, F; Dai, B; Zhang, W; Zhu, F M; Lv, H J

    2014-02-01

    Umbilical cord blood (UCB) is a widely accepted source of progenitor cells, and now, many cord blood banks were established. Here, we analysed the HLA-A, HLA-B and HLA-DRB1 allele and haplotype frequencies, HLA matching possibilities for searching potential donors and outcome of UCB transplantations in Zhejiang cord blood bank of China. A total of 6384 UCB units were characterized for 17 HLA-A, 30 HLA-B and 13 HLA-DRB1 alleles at the first field resolution level. Additionally, B*14, B*15 and B*40 were typed to the second field level. A total of 1372 distinct A-B-DRB1 haplotypes were identified. The frequencies of 7 haplotypes were more than 1%, and 439 haplotypes were <0.01%. A*02-B*46-DRB1*09, A*33-B*58-DRB1*03 and A*30-B*13-DRB1*07 were the most common haplotypes, with frequencies of 4.4%, 3.3%, and 2.9%, respectively. Linkage disequilibrium(LD) analysis showed that there were 83 A-B, 106 B-DRB1, 54 A-DRB1 haplotypes with positive LD, in which 51 A-B, 60 B-DRB1, 32 A-DRB1 haplotypes exhibited a significant LD (P < 0.05). In 682 search requests, 12.9%, 40.0% and 42.7% of patients were found to have 6 of 6, 5 of 6 and 4 of 6 HLA-A, HLA-B and HLA-DRB1 matching donors, respectively. A total of 30 UCB units were transplanted to 24 patients (3 patients not evaluated due to early death); 14 of 21 patients (66.7%) engrafted. This study reveals the HLA distribution and its transplantation application in the cord blood bank of Zhejiang province. These data can help to select potential UCB donors for transplantation and used to assess the scale of new cord blood banking endeavours.

  3. HLA-E and HLA-G expression in classical HLA class I-negative tumors is of prognostic value for clinical outcome of early breast cancer patients.

    PubMed

    de Kruijf, Esther M; Sajet, Anita; van Nes, Johanna G H; Natanov, Russ; Putter, Hein; Smit, Vincent T H B M; Liefers, Gerrit Jan; van den Elsen, Peter J; van de Velde, Cornelis J H; Kuppen, Peter J K

    2010-12-15

    Nonclassical HLAs, HLA-E and HLA-G, are known to affect clinical outcome in various tumor types. We examined the clinical impact of HLA-E and HLA-G expression in early breast cancer patients, and related the results to tumor expression of classical HLA class I. Our study population (n = 677) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1995. Tissue microarray sections of arrayed tumor and normal control material were immunohistochemically stained for HLA-E and HLA-G. For evaluation of HLA-E and HLA-G and the combined variable, HLA-EG, a binary score was used. Expression of classical HLA class I molecules was determined previously. HLA-E, HLA-G, and HLA-EG on breast tumors were classified as expression in 50, 60, and 23% of patients, respectively. Remarkably, only in patients with loss of classical HLA class I tumor expression, expression of HLA-E (p = 0.027), HLA-G (p = 0.035), or HLA-EG (p = 0.001) resulted in a worse relapse-free period. An interaction was found between classical and nonclassical HLA class I expression (p = 0.002), suggestive for a biological connection. We have demonstrated that, next to expression of classical HLA class I, expression of HLA-E and HLA-G is an important factor in the prediction of outcome of breast cancer patients. These results provide further evidence that breast cancer is immunogenic, but also capable of evading tumor eradication by the host's immune system, by up- or downregulation of HLA class Ia and class Ib loci.

  4. Upregulation of Soluble HLA-G in Chronic Left Ventricular Systolic Dysfunction

    PubMed Central

    Olesen, Line Lisbeth

    2016-01-01

    Left ventricular systolic dysfunction (LVSD) defined by ejection fraction (EF) <40% is common, serious but treatable, and correct diagnosis is the cornerstone of effective treatment. Biomarkers may help to diagnose LVSD and give insight into the pathophysiology. The immune system is activated in LVSD, and the immunomodulatory molecule human leukocyte antigen-G (HLA-G) may be involved. The primary aim was to measure soluble HLA-G (sHLA-G) in the blood in different stages of LVSD (<30% and 30–40%), in the midrange EF 40–50%, and in preserved EF ≥ 50% and to validate sHLA-G as a LVSD biomarker. The secondary aim was to examine associations between HLA-G gene polymorphisms influencing expression levels and LVSD. The 260 study participants were ≥75 years old, many with risk factors for heart disease or with known heart disease. Soluble HLA-G was significantly and uniformly higher in the groups with EF < 50% (<30, 30–40, and 40–50%) compared to EF > 50% (p < 0.0001). N-terminal fragment-pro-B-type natriuretic peptide (NT-proBNP) and uric acid values were inversely related to EF. According to Receiver Operating Characteristic (ROC) curves NT-proBNP outperformed both sHLA-G and uric acid as biomarkers of LVSD. Soluble HLA-G in blood plasma was elevated in LVSD regardless of EF. A novel finding was that a combined 14 bp ins-del/+3142 SNP HLA-G haplotype was associated with EF < 40%. PMID:27800497

  5. New susceptibility variants to narcolepsy identified in HLA class II region.

    PubMed

    Miyagawa, Taku; Toyoda, Hiromi; Hirataka, Akane; Kanbayashi, Takashi; Imanishi, Aya; Sagawa, Yohei; Kotorii, Nozomu; Kotorii, Tatayu; Hashizume, Yuji; Ogi, Kimihiro; Hiejima, Hiroshi; Kamei, Yuichi; Hida, Akiko; Miyamoto, Masayuki; Imai, Makoto; Fujimura, Yota; Tamura, Yoshiyuki; Ikegami, Azusa; Wada, Yamato; Moriya, Shunpei; Furuya, Hirokazu; Kato, Mitsuhiro; Omata, Naoto; Kojima, Hiroto; Kashiwase, Koichi; Saji, Hiroh; Khor, Seik-Soon; Yamasaki, Maria; Wada, Yuji; Ishigooka, Jun; Kuroda, Kenji; Kume, Kazuhiko; Chiba, Shigeru; Yamada, Naoto; Okawa, Masako; Hirata, Koichi; Uchimura, Naohisa; Shimizu, Tetsuo; Inoue, Yuichi; Honda, Yutaka; Mishima, Kazuo; Honda, Makoto; Tokunaga, Katsushi

    2015-02-01

    Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1*06:01 (P = 1.4 × 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 × 10(-9), OR = 1.97). A comparison between DQB1*06:02 heterozygous cases and controls revealed dominant protective effects of DQB1*06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class II region (rs3117242, P = 4.1 × 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 × 10(-3), OR = 1.39). These results indicate that complex HLA class II associations contribute to the genetic predisposition to narcolepsy.

  6. HLA DR alloantigens in different subsets of patients with Sjögren's syndrome and in family members.

    PubMed Central

    Mann, D L; Moutsopoulos, H M

    1983-01-01

    Patients with Sjögren's syndrome alone (Ss), Sjögren's syndrome with rheumatoid arthritis (Ss-RA), and Sjögren's syndrome with Raynaud's phenomenon (Ss-RP) were typed for the HLA DR and MT antigens. Ss-RA patients had higher frequencies of HLA DR4 than did Ss patients. HLA-DR4 was also increased in frequency in patients with Ss-RP. This group of patients also showed increases in frequencies of HLA DR3. MT2 frequencies were elevated in all 3 patient groups, while MT1 was only increased in Ss. Three families with multiple individuals with Sjogren's syndrome were typed for HLA antigens. The affected individuals inherited unique combinations of haplotypes, suggesting the possibility of haplotype interaction in predisposition to disease. PMID:6605120

  7. HLA Allele E*01:01 Is Associated with a Reduced Risk of EBV-Related Classical Hodgkin Lymphoma Independently of HLA-A*01/*02

    PubMed Central

    Martín, Paloma; Krsnik, Isabel; Navarro, Belen; Provencio, Mariano; García, Juan F.; Bellas, Carmen; Vilches, Carlos; Gomez-Lozano, Natalia

    2015-01-01

    Background An inefficient immune response against Epstein-Barr virus (EBV) infection is related to the pathogenesis of a subgroup of classical Hodgkin lymphomas (cHL). Some EBV immune-evasion mechanisms target HLA presentation, including the non-classical HLA-E molecule. HLA-E can be recognized by T cells via the TCR, and it also regulates natural killer (NK) cell signaling through the inhibitory CD94/NKG2A receptor. Some evidences indicate that EBV-infected B-cells promote the proliferation of NK subsets bearing CD94/NKG2A, suggesting a relevant function of these cells in EBV control. Variations in CD94/NKG2A-HLA-E interactions could affect NK cell-mediated immunity and, consequently, play a role in EBV-driven transformation and lymphomagenesis. The two most common HLA-E alleles, E*01:01 and E*01:03, differ by a single amino acid change that modifies the molecule function. We hypothesized that the functional differences in these variants might participate in the pathogenicity of EBV. Aim We studied two series of cHL patients, both with EBV-positive and-negative cases, and a cohort of unrelated controls, to assess the impact of HLA-E variants on EBV-related cHL susceptibility. Results We found that the genotypes with at least one copy of E*01:01 (i.e., E*01:01 homozygous and heterozygous) were underrepresented among cHL patients from both series compared to controls (72.6% and 71.6% vs 83%, p = 0.001). After stratification by EBV status, we found low rates of E*01:01-carriers mainly among EBV-positive cases (67.6%). These reduced frequencies are seen independently of other factors such as age, gender, HLA-A*01 and HLA-A*02, HLA alleles positively and negatively associated with the disease (adjusted OR = 0.4, p = 0.001). Furthermore, alleles from both HLA loci exert a cumulative effect on EBV-associated cHL susceptibility. Conclusions These results indicate that E*01:01 is a novel protective genetic factor in EBV-associated cHL and support a role for HLA

  8. Do antibodies to myelin basic protein isolated from multiple sclerosis cross-react with measles and other common virus antigens?

    PubMed Central

    Bernard, C C; Townsend, E; Randell, V B; Williamson, H G

    1983-01-01

    Immunological activity to various antigens, including brain components, measles and other viruses, has been associated with IgG in multiple sclerosis (MS). One possible explanation for the presence of anti-viral antibodies and antibody to myelin basic protein (MBP) in MS patients is that there are antigenic determinants common to certain viruses and MBP. To assess this possibility, IgG from individual brains and sera from patients with MS, subacute sclerosing panencephalitis (SSPE) and controls was isolated by protein A and MBP-Sepharose affinity chromatography. Antibody to MBP was measured with a solid phase radioimmunoassay and antibody to measles and other viruses by immunofluorescence and/or complement fixation. Anti-MBP activity was detected in brain extracts and sera of all MS patients tested. In contrast to the low levels of antibody to MBP in control brains, high levels of anti-MBP antibodies were found in most of the normal sera. There was no correlation between the presence and levels of serum anti-measles antibodies and the anti-MBP activity. None of the anti-MBP antibodies affinity purified from brain and serum of MS patients reacted with any of the viruses tested, including measles. IgG purified from SSPE patients or from a rabbit hyperimmunized with measles antigen had no reactivity to MBP, despite high levels of anti-measles antibody. It is concluded that there is not direct link between the presence of antibody to MBP and antibody to measles and other viruses in MS patients. PMID:6190599

  9. Discordant Impact of HLA on Viral Replicative Capacity and Disease Progression in Pediatric and Adult HIV Infection.

    PubMed

    Adland, Emily; Paioni, Paolo; Thobakgale, Christina; Laker, Leana; Mori, Luisa; Muenchhoff, Maximilian; Csala, Anna; Clapson, Margaret; Flynn, Jacquie; Novelli, Vas; Hurst, Jacob; Naidoo, Vanessa; Shapiro, Roger; Huang, Kuan-Hsiang Gary; Frater, John; Prendergast, Andrew; Prado, Julia G; Ndung'u, Thumbi; Walker, Bruce D; Carrington, Mary; Jooste, Pieter; Goulder, Philip J R

    2015-06-01

    HLA class I polymorphism has a major influence on adult HIV disease progression. An important mechanism mediating this effect is the impact on viral replicative capacity (VRC) of the escape mutations selected in response to HLA-restricted CD8+ T-cell responses. Factors that contribute to slow progression in pediatric HIV infection are less well understood. We here investigate the relationship between VRC and disease progression in pediatric infection, and the effect of HLA on VRC and on disease outcome in adult and pediatric infection. Studying a South African cohort of >350 ART-naïve, HIV-infected children and their mothers, we first observed that pediatric disease progression is significantly correlated with VRC. As expected, VRCs in mother-child pairs were strongly correlated (p = 0.004). The impact of the protective HLA alleles, HLA-B*57, HLA-B*58:01 and HLA-B*81:01, resulted in significantly lower VRCs in adults (p<0.0001), but not in children. Similarly, in adults, but not in children, VRCs were significantly higher in subjects expressing the disease-susceptible alleles HLA-B*18:01/45:01/58:02 (p = 0.007). Irrespective of the subject, VRCs were strongly correlated with the number of Gag CD8+ T-cell escape mutants driven by HLA-B*57/58:01/81:01 present in each virus (p = 0.0002). In contrast to the impact of VRC common to progression in adults and children, the HLA effects on disease outcome, that are substantial in adults, are small and statistically insignificant in infected children. These data further highlight the important role that VRC plays both in adult and pediatric progression, and demonstrate that HLA-independent factors, yet to be fully defined, are predominantly responsible for pediatric non-progression.

  10. Epidemiology of multiple sclerosis in Arabs in Jordan: a comparative study between Jordanians and Palestinians.

    PubMed

    Najim Al-Din, A S; Kurdi, A; Mubaidin, A; El-Khateeb, M; Khalil, R W; Wriekat, A L

    1996-02-01

    In a 2-year hospital-based study in Jordan 131 Arab multiple sclerosis patients were identified including 84 Palestinians and 36 Jordanians. Based on MS/ALS case ratio, multiple sclerosis was found to be twice as common among Palestinians than Jordanians. Other than the less marked female preponderance among Jordanian patients, the disease had the same clinical and paraclinical characteristics in both groups. It was more likely for Palestinian and Jordanian patients to originate from the northern parts of their countries, to be Rh negative and to be HLA-DR2 positive than their controls. Palestinians (patients and controls) did not show significant differences from Jordanians (patients and controls) in relation to their eye color, ABO and Rh blood groups distribution nor the HLA-DR or HLA-DQ (apart from HLA-DQ3) epitopes frequency, thus not offering any significant difference in the genetic-racial markers studies to explain the difference in the observed disease susceptibility. Previous studies demonstrated that 2 racially different populations sharing the same environment can have different risk of developing multiple sclerosis, but this study has shown that this can also be true for 2 racially similar populations sharing the same environment.

  11. Co-expression of ILT4/HLA-G in human non-small cell lung cancer correlates with poor prognosis and ILT4-HLA-G interaction activates ERK signaling.

    PubMed

    Zhang, Yanwen; Zhao, Jianqiang; Qiu, Lijun; Zhang, Pei; Li, Juan; Yang, Dong; Wei, Xiaojuan; Han, Yali; Nie, Siyue; Sun, Yuping

    2016-08-01

    Non-small cell lung cancer (NSCLC) is the most common malignant tumor in the world, of which prognosis is generally poor due to insufficient mechanistic understanding. To explore the molecular pathogenesis of NSCLC, the co-expression of immunoglobulin-like transcript 4 (ILT4) and its ligand human leukocyte antigen G (HLA-G) in NSCLC tissues and cells were investigated. Here, we detected the expression of ILT4 and HLA-G in 81 tumor specimens from primary NSCLC patients, and we found that co-expression of ILT4/HLA-G was significantly associated with regional lymph node involvement, advanced stages, and the overall survival of patients. In NSCLC cell lines, HLA-G expression increased/decreased accordingly when ILT4 was up-/down-regulated, and ILT4 expression increased in a concentration-dependent manner via the stimulation of HLA-G fusion protein. Interestingly, HLA-G fusion protein could also up-regulate the phospho-ERK1/2 expression, which means the activation of extracellular signal-regulated kinase (ERK) signaling. All in all, our results indicate that the ILT4-HLA-G interaction might play an important role in NSCLC progression. Identification of ILT4 and HLA-G expression may provide an indicator to predict prognosis and guide prevention and treatment of NSCLC.

  12. Influence of stellar multiplicity on planet formation. II. Planets are less common in multiple-star systems with separations smaller than 1500 AU

    SciTech Connect

    Wang, Ji; Fischer, Debra A.; Xie, Ji-Wei; Ciardi, David R.

    2014-08-20

    Almost half of the stellar systems in the solar neighborhood are made up of multiple stars. In multiple-star systems, planet formation is under the dynamical influence of stellar companions, and the planet occurrence rate is expected to be different from that of single stars. There have been numerous studies on the planet occurrence rate of single star systems. However, to fully understand planet formation, the planet occurrence rate in multiple-star systems needs to be addressed. In this work, we infer the planet occurrence rate in multiple-star systems by measuring the stellar multiplicity rate for planet host stars. For a subsample of 56 Kepler planet host stars, we use adaptive optics (AO) imaging and the radial velocity (RV) technique to search for stellar companions. The combination of these two techniques results in high search completeness for stellar companions. We detect 59 visual stellar companions to 25 planet host stars with AO data. Three stellar companions are within 2'' and 27 within 6''. We also detect two possible stellar companions (KOI 5 and KOI 69) showing long-term RV acceleration. After correcting for a bias against planet detection in multiple-star systems due to flux contamination, we find that planet formation is suppressed in multiple-star systems with separations smaller than 1500 AU. Specifically, we find that compared to single star systems, planets in multiple-star systems occur 4.5 ± 3.2, 2.6 ± 1.0, and 1.7 ± 0.5 times less frequently when a stellar companion is present at a distance of 10, 100, and 1000 AU, respectively. This conclusion applies only to circumstellar planets; the planet occurrence rate for circumbinary planets requires further investigation.

  13. First report on the antibody verification of HLA-DR, HLA-DQ and HLA-DP epitopes recorded in the HLA Epitope Registry.

    PubMed

    Duquesnoy, Rene J; Marrari, Marilyn; Tambur, Anat R; Mulder, Arend; Sousa, Luiz Cláudio Demes da Mata; da Silva, Adalberto Socorro; do Monte, Semiramis J H

    2014-11-01

    The International Registry of Antibody-Defined HLA Epitopes (http://www.epregistry.com.br) has been recently established as a tool to understand humoral responses to HLA mismatches. These epitopes can be structurally defined as eplets by three-dimensional molecular modeling and amino acid sequence differences between HLA antigens. A major goal is to identify HLA eplets that have been verified experimentally with informative antibodies. This report addresses class II epitopes encoded by genes in the HLA-D region. Our analysis included reviews of many publications about epitope specificity of class II reactive human and murine monoclonal antibodies and informative alloantibodies from HLA sensitized patients as well as our own antibody testing results. As of July 1, 2014, 24 HLA-DRB1/3/4/5, 15 DQB, 3 DQA and 8 DPB antibody-verified epitopes have been identified and recorded. The Registry is still a work-in-progress and will become a useful resource for HLA professionals interested in histocompatibility testing at the epitope level and investigating antibody responses to HLA mismatches in transplant patients. PMID:25305456

  14. HLA Typing for the Next Generation

    PubMed Central

    Mayor, Neema P.; Robinson, James; McWhinnie, Alasdair J. M.; Ranade, Swati; Eng, Kevin; Midwinter, William; Bultitude, Will P.; Chin, Chen-Shan; Bowman, Brett; Marks, Patrick; Braund, Henny; Madrigal, J. Alejandro; Latham, Katy; Marsh, Steven G. E.

    2015-01-01

    Allele-level resolution data at primary HLA typing is the ideal for most histocompatibility testing laboratories. Many high-throughput molecular HLA typing approaches are unable to determine the phase of observed DNA sequence polymorphisms, leading to ambiguous results. The use of higher resolution methods is often restricted due to cost and time limitations. Here we report on the feasibility of using Pacific Biosciences’ Single Molecule Real-Time (SMRT) DNA sequencing technology for high-resolution and high-throughput HLA typing. Seven DNA samples were typed for HLA-A, -B and -C. The results showed that SMRT DNA sequencing technology was able to generate sequences that spanned entire HLA Class I genes that allowed for accurate allele calling. Eight novel genomic HLA class I sequences were identified, four were novel alleles, three were confirmed as genomic sequence extensions and one corrected an existing genomic reference sequence. This method has the potential to revolutionize the field of HLA typing. The clinical impact of achieving this level of resolution HLA typing data is likely to considerable, particularly in applications such as organ and blood stem cell transplantation where matching donors and recipients for their HLA is of utmost importance. PMID:26018555

  15. HLA-G UTR haplotype conservation in the Malian population: association with soluble HLA-G.

    PubMed

    Carlini, Federico; Traore, Karim; Cherouat, Nissem; Roubertoux, Pierre; Buhler, Stéphane; Cortey, Martì; Simon, Sophie; Doumbo, Ogobara; Chiaroni, Jacques; Picard, Christophe; Di Cristofaro, Julie

    2013-01-01

    The HLA-G molecule plays an important role in immunomodulation. In a previous study carried out on a southern French population our team showed that HLA-G haplotypes, defined by SNPs in the coding region and specific SNPs located in 5'URR and 3'UTR regulatory regions, are associated with differential soluble HLA-G expression (sHLA-G). Furthermore, the structure of these HLA-G haplotypes appears to be conserved in geographically distant populations. The aim of our study is to confirm these expectations in a sub-Saharan African population and to explore additional factors, such as HLA-A alleles, that might influence sHLA-G expression. DNA and plasma samples were collected from 229 Malians; HLA-G and HLA-A genotyping were respectively performed by the Snap Shot® method and by Luminex™ technology. sHLA-G dosage was performed using an ELISA kit. HLA-G and HLA-A allelic and haplotypic frequencies were estimated using an EM algorithm from the Gene[Rate] program. Associations between genetic and non genetic parameters with sHLA-G were performed using a non-parametric test with GRAPH PAD Prism 5. Our results reveal a good conservation of the HLA-G UTR haplotype structure in populations with different origins and demographic histories. These UTR haplotypes appear to be involved in different sHLA-G expression patterns. Specifically, the UTR-2 haplotype was associated with low sHLA-G levels, displaying a dominant negative effect. Furthermore, an allelic effect of both HLA-G and HLA-A, as well as non genetic parameters, such as age and gender possibly linked to osteogenesis and sexual hormones, also seem to be involved in the modulation of sHLA-G. These data suggest that further investigation in larger cohorts and in populations from various ethnical backgrounds is necessary not only to detect new functional polymorphism in HLA-G regulatory regions, but also to reveal the extent of biological phenomena that influence sHLA-G secretion and this might therefore have an impact

  16. Burden of Common Multiple-Morbidity Constellations on Out-of-Pocket Medical Expenditures among Older Adults

    ERIC Educational Resources Information Center

    Schoenberg, Nancy E.; Kim, Hyungsoo; Edwards, William; Fleming, Steven T.

    2007-01-01

    Purpose: On average, adults aged 60 years or older have 2.2 chronic diseases, contributing to the over 60 million Americans with multiple morbidities. We aimed to understand the financial implications of the most frequent multiple morbidities among older adults. Design and Methods: We analyzed Health and Retirement Study data, determining…

  17. Ancestral association between HLA and HFE H63D and C282Y gene mutations from northwest Colombia

    PubMed Central

    Rodriguez, Libia M; Giraldo, Mabel C; Velasquez, Laura I; Alvarez, Cristiam M; Garcia, Luis F; Jimenez-Del-Rio, Marlene; Velez-Pardo, Carlos

    2015-01-01

    A significant association between HFE gene mutations and the HLA-A*03-B*07 and HLA-A*29-B*44 haplotypes has been reported in the Spanish population. It has been proposed that these mutations are probably connected with Celtic and North African ancestry, respectively. We aimed to find the possible ancestral association between HLA alleles and haplotypes associated with the HFE gene (C282Y and H63D) mutations in 214 subjects from Antioquia, Colombia. These were 18 individuals with presumed hereditary hemochromatosis (“HH”) and 196 controls. The HLA-B*07 allele was in linkage disequilibrium (LD) with C282Y, while HLA-A*23, A*29, HLA-B*44, and B*49 were in LD with H63D. Altogether, our results show that, although the H63D mutation is more common in the Antioquia population, it is not associated with any particular HLA haplotype, whereas the C282Y mutation is associated with HLA-A*03-B*07, this supporting a northern Spaniard ancestry. PMID:25983618

  18. Amino acid residues 56 to 69 of HLA-A2 specify an antigenic determinant shared by HLA-A2 and HLA-B17.

    PubMed

    Ways, J P; Rothbard, J B; Parham, P

    1986-07-01

    The mouse monoclonal antibody MA2.1 was previously used to define an epitope shared by native HLA-A2 and HLA-B17 molecules and amino acid sequence comparison of nine HLA-A,B,C molecules identified residues 62 to 65 as the region most likely to form this epitope. An unabsorbed rabbit antiserum raised against a peptide corresponding to residues 56 to 69 of HLA-A2 gives highly specific reactions with HLA-A2 and HLA-B17 heavy chains in Western blots. No interactions with native HLA-A2 and B17 molecules were detected in a variety of assays. Although the topographic relationship between the epitopes recognized by the rabbit antiserum and the monoclonal antibody could not be determined, the results show that residues 56 to 69 of HLA-A2 can form epitopes with specificity for HLA-A2 and HLA-B17.

  19. Natalizumab-related anaphylactoid reactions in MS patients are associated with HLA class II alleles

    PubMed Central

    de la Hera, Belén; Urcelay, Elena; Brassat, David; Chan, Andrew; Vidal-Jordana, Angela; Salmen, Anke; Villar, Luisa Maria; Álvarez-Cermeño, José Carlos; Izquierdo, Guillermo; Fernández, Oscar; Oliver, Begoña; Saiz, Albert; Ara, Jose Ramón; Vigo, Ana G.; Arroyo, Rafael; Meca, Virginia; Malhotra, Sunny; Fissolo, Nicolás; Horga, Alejandro; Montalban, Xavier

    2014-01-01

    Objectives: We aimed to investigate potential associations between human leukocyte antigen (HLA) class I and class II alleles and the development of anaphylactic/anaphylactoid reactions in patients with multiple sclerosis (MS) treated with natalizumab. Methods: HLA class I and II genotyping was performed in patients with MS who experienced anaphylactic/anaphylactoid reactions and in patients who did not develop infusion-related allergic reactions following natalizumab administration. Results: A total of 119 patients with MS from 3 different cohorts were included in the study: 54 with natalizumab-related anaphylactic/anaphylactoid reactions and 65 without allergic reactions. HLA-DRB1*13 and HLA-DRB1*14 alleles were significantly increased in patients who developed anaphylactic/anaphylactoid reactions (pM-H = 3 × 10−7; odds ratio [OR]M-H = 8.96, 95% confidence interval [CI] = 3.40–23.64), with a positive predictive value (PPV) of 82%. In contrast, the HLA-DRB1*15 allele was significantly more represented in patients who did not develop anaphylactic/anaphylactoid reactions to natalizumab (pM-H = 6 × 10−4; ORM-H = 0.2, 95% CI = 0.08–0.50), with a PPV of 81%. Conclusions: HLA-DRB1 genotyping before natalizumab treatment may help neurologists to identify patients with MS at risk for developing serious systemic hypersensitivity reactions associated with natalizumab administration. PMID:25520955

  20. Classification of mutations at the HLA-A locus by use of the polymerase chain reaction

    SciTech Connect

    Joseph, G.; Grist, S.; Firgaira, F.; Turner, D.; Morley, A. )

    1993-01-01

    The authors investigated whether the polymerase chain reaction (PCR) could be used to determine the mechanism of mutation in lymphocyte clones mutated at the HLA-A locus. Three polymorphisms, at Factor XIIIA, D6S109, and intron 3 of the HLA-A gene, were used to study a series of clones previously characterized by Southern blotting (SB) at multiple loci on chromosome 6. For detection of loss of heterozygosity, the results of PCR and SB were concordant in 140 of 141 clones when polymorphism in the Factor XIIIA region was studied and in 144 of 145 clones when polymorphism in the HLA-A gene was studied. For classification of the mechanism of mutation, PCR and SB gave the same result in 88 of 92 clones (96%) when a combination of the HLA-A and Factor XIIIA polymorphisms was used and in 46 of 47 clones (98%) when a combination of the HLA-A and D6S109 polymorphisms was used. The results indicate that PCR provides a simple and reliable method for categorizing mutations at the HLA-A locus as arising from mitotic recombination, deletion, or from presumptive minor changes within the gene. Rare events such as gene conversion, nondisjunction, or large deletions extending to the telomere will be misclassified. However, such events are rare for mutations at this locus. 9 refs., 2 figs., 5 tabs.

  1. Obstructive sleep apnoea syndrome and HLA in the North of Portugal.

    PubMed

    Silva, Luís; Lopes, João; Ramalheira, João; Cunha, Daniela; Carvalho, Cláudia; Bettencourt, Andreia; Bras, Sandra; Costa, Sandra; Silva, M Berta; Martins-da-Silva, António

    2015-10-01

    Introduccion. El sindrome de apnea obstructiva del sueño (SAOS) es una enfermedad frecuente, compleja y poligenica, con diversas etiologias que interaccionan originando un fenotipo unico. El SAOS puede ocurrir a cualquier edad del individuo y se presume la existencia de agregacion familiar. Han sido descritos diversos factores de predisposicion, como la edad, el sexo y la obesidad. La relacion entre los polimorfismos del antigeno leucocitario humano (HLA) y trastornos del sueño esta confirmada, tanto en poblaciones europeas como no europeas. No obstante, las relaciones descritas entre los alelos HLA y SAOS no han sido coherentes y carecen de valor informativo para la clasificacion del trastorno del sueño. Objetivo. Explorar la asociacion genetica del HLA con el SAOS en una poblacion del norte de Portugal y evaluar el papel de la obesidad en el contexto del HLA en el SAOS. Pacientes y metodos. Se estudio una cohorte de 131 pacientes con SAOS. Los pacientes fueron atendidos en una clinica del sueño ambulatoria donde se valoraron los antecedentes clinicos, se les practico una polisomnografia nocturna, una prueba de latencia multiple del sueño (si lo exigio el diagnostico diferencial), analiticas y estudios demograficos. A efectos comparativos, se utilizo una poblacion de control de 223 personas sanas. Se efectuo el genotipado del HLA-DRB1 con la reaccion en cadena de la polimerasa mediante cebadores de secuencia especifica. Resultados. En esta cohorte, el alelo HLA-DRB1*03 fue identificado como un factor de predisposicion para el SAOS (24% del SAOS frente a 15% de la poblacion de control; p = 0,025; odds ratio = 1,861; intervalo de confianza al 95% = 1,081-3,205). No hubo diferencias significativas en lo referente a otros alelos HLA-DBR1*. Conclusion. El HLA-DRB1*03 es un factor de predisposicion para el SAOS en la poblacion portuguesa.

  2. Impact of peptides on the recognition of HLA class I molecules by human HLA antibodies.

    PubMed

    Mulder, Arend; Eijsink, Chantal; Kester, Michel G D; Franke, Marry E I; Kardol, Marrie J; Heemskerk, Mirjam H M; van Kooten, Cees; Verreck, Frank A; Drijfhout, Jan Wouter; Koning, Frits; Doxiadis, Ilias I N; Claas, Frans H J

    2005-11-01

    MHC class I molecules expressed on cell surfaces are composed of H chain, beta2-microglobulin and any of a vast array of peptides. The role of peptide in the recognition of HLA class I by serum HLA Abs is unknown. In this study, the solid-phase assay of a series (n = 11) of HLA-A2-reactive, pregnancy-induced, human mAbs on a panel (n = 12) of recombinant monomeric HLA-A2 molecules, each containing a single peptide, revealed peptide selectivity of the mAbs. The flow cytometry membrane staining intensities on the HLA-A2-transduced cell line K562, caused by these mAbs, correlated with the number of monomer species detected by the mAbs. Flow cytometry staining on HLA-A2-bearing cell lines of a variety of lineages was indicative of tissue selectivity of these HLA-A2 mAbs. This tissue selectivity suggests that the deleterious effect on allografts is confined to alloantibodies recognizing only HLA class I loaded with peptides that are derived from tissue-specific and household proteins. Since Abs that are only reactive with HLA loaded with irrelevant peptides are expected to be harmless toward allografts, the practice of HLA Ab determination on lymphocyte-derived HLA deserves reconsideration.

  3. The MAPK Pathway Is a Predominant Regulator of HLA-A Expression in Esophageal and Gastric Cancer

    PubMed Central

    Mimura, Kousaku; Shiraishi, Kensuke; Mueller, Anja; Izawa, Shinichiro; Kua, Ley-Fang; So, Jimmy; Yong, Wei-Peng; Fujii, Hideki; Seliger, Barbara; Kiessling, Rolf

    2013-01-01

    Downregulation of HLA class I expression may contribute to a poor prognosis in cancer patients. There is limited information about epigenetic and oncogenic regulation of HLA class I, and multiple mechanisms may be involved. In the current study, we examined the relationship between the HER2-signaling pathway (MAPK and PI3K-Akt) and the expression of HLA class I and Ag-processing machinery (APM) components. A panel of gastric and esophageal cancer cell lines was treated with wortmannin as an Akt-signal inhibitor; the MAPK signal inhibitor PD98059; lapatinib, which inhibits both the epidermal growth factor receptor and HER2 tyrosine kinase; or siRNA for MAPK. The levels of HER2-signaling molecules, APM components, and HLA class I were evaluated by Western blot, quantitative PCR, and flow cytometry. Resected gastric tumor tissues (n = 102) were analyzed for p-Erk and HLA class I expression by immunohistochemistry. As a result, inhibition of the MAPK pathway induced upregulation of HLA-A02 and HLA-A24 expression in parallel with an increase in APM components and enhanced target sensitivity to tumor Ag–specific CTL lysis. HLA-A expression was predominantly regulated by the MAPK pathway, but it was also influenced, in part, by the Akt pathway. There was a strong inverse correlation between p-Erk expression and HLA class I expression in clinical tumor samples. In conclusion, HLA-A expression is predominantly regulated by the MAPK pathway in gastric and esophageal cancer. PMID:24244023

  4. High-Throughput High-Resolution Class I HLA Genotyping in East Africa

    PubMed Central

    Koehler, Rebecca N.; Walsh, Anne M.; Sanders-Buell, Eric E.; Eller, Leigh Anne; Eller, Michael; Currier, Jeffrey R.; Bautista, Christian T.; Wabwire-Mangen, Fred; Hoelscher, Michael; Maboko, Leonard; Kim, Jerome; Michael, Nelson L.; Robb, Merlin L.; McCutchan, Francine E.; Kijak, Gustavo H.

    2010-01-01

    HLA, the most genetically diverse loci in the human genome, play a crucial role in host-pathogen interaction by mediating innate and adaptive cellular immune responses. A vast number of infectious diseases affect East Africa, including HIV/AIDS, malaria, and tuberculosis, but the HLA genetic diversity in this region remains incompletely described. This is a major obstacle for the design and evaluation of preventive vaccines. Available HLA typing techniques, that provide the 4-digit level resolution needed to interpret immune responses, lack sufficient throughput for large immunoepidemiological studies. Here we present a novel HLA typing assay bridging the gap between high resolution and high throughput. The assay is based on real-time PCR using sequence-specific primers (SSP) and can genotype carriers of the 49 most common East African class I HLA-A, -B, and -C alleles, at the 4-digit level. Using a validation panel of 175 samples from Kampala, Uganda, previously defined by sequence-based typing, the new assay performed with 100% sensitivity and specificity. The assay was also implemented to define the HLA genetic complexity of a previously uncharacterized Tanzanian population, demonstrating its inclusion in the major East African genetic cluster. The availability of genotyping tools with this capacity will be extremely useful in the identification of correlates of immune protection and the evaluation of candidate vaccine efficacy. PMID:20505773

  5. HLA Immunogenotype Determines Persistent Human Papillomavirus Virus Infection in HIV-Infected Patients Receiving Antiretroviral Treatment.

    PubMed

    Meys, Rhonda; Purdie, Karin J; de Koning, Maurits N C; Quint, Koen D; Little, Ann-Margaret; Baker, Finnuala; Francis, Nick; Asboe, David; Hawkins, David; Marsh, Steven G E; Harwood, Catherine A; Gotch, Frances M; Bunker, Christopher B

    2016-06-01

    A proportion of human immunodeficiency virus (HIV)-infected patients develop persistent, stigmatizing human papillomavirus (HPV)-related cutaneous and genital warts and anogenital (pre)cancer. This is the first study to investigate immunogenetic variations that might account for HPV susceptibility and the largest to date to categorize the HPV types associated with cutaneous warts in HIV-positive patients. The HLA class I and II allele distribution was analyzed in 49 antiretroviral (ART)-treated HIV-positive patients with persistent warts, 42 noninfected controls, and 46 HIV-positive controls. The allele HLA-B*44 was more frequently identified in HIV-positive patients with warts (P = .004); a susceptible haplotype (HLA-B*44, HLA-C*05; P = .001) and protective genes (HLA-DQB1*06; P = .03) may also contribute. Cutaneous wart biopsy specimens from HIV-positive patients harbored common wart types HPV27/57, the unusual wart type HPV7, and an excess of Betapapillomavirus types (P = .002), compared with wart specimens from noninfected controls. These findings suggest that HLA testing might assist in stratifying those patients in whom vaccination should be recommended. PMID:26908737

  6. Genetic analysis of dilated cardiomyopathy--HLA and immunoglobulin genes may confer susceptibility.

    PubMed

    Nishi, H; Kimura, A; Fukuta, S; Kusukawa, R; Kawamura, K; Nimura, Y; Nagano, M; Yasuda, H; Kawai, C; Sugimoto, T

    1992-10-01

    To identify genetic factors in the immune system which control the susceptibility to dilated cardiomyopathy (DCM), HLA class II DNA typing was performed in 61 Japanese patients, using PCR/SSO probe analyses. The frequencies of HLA-DQB1*0503 (15% vs 5%; RR = 3.06, chi 2 = 7.19) and DQB1*0604 (21% vs 10%; RR = 2.41, chi 2 = 6.20) were significantly increased and that of HLA-DQB1*0502 (RR = 1.74) was slightly increased in the DCM patients. The frequency of DQB1*0303 (16% vs 31%; RR = 0.44, chi 2 = 5.16) was significantly decreased in the patients. The increased HLA-DQB1 alleles have a histidine residue in common at the 30th codon for the HLA-DQ beta chain. Among the genetic markers studied by Southern blot analyses, IGLV (immunoglobulin lambda light chain, pV3.3) showed a strong association with DCM, i.e. A2/A2 genotype was found in 37.7% of patients whereas it was observed in only 18.9% of the control subjects (RR = 2.6, chi 2 = 7.77). The frequency of this genotype was higher in patients under age 45 years at the time of diagnosis (45.5%, RR = 3.6, chi 2 = 10.02). These results suggest that HLA and immunoglobulin genes are closely linked to susceptibility to DCM.

  7. Shared HLA Class II in Six Autoimmune Diseases in Latin America: A Meta-Analysis

    PubMed Central

    Cruz-Tapias, Paola; Pérez-Fernández, Oscar M.; Rojas-Villarraga, Adriana; Rodríguez-Rodríguez, Alberto; Arango, María-Teresa; Anaya, Juan-Manuel

    2012-01-01

    The prevalence and genetic susceptibility of autoimmune diseases (ADs) may vary depending on latitudinal gradient and ethnicity. The aims of this study were to identify common human leukocyte antigen (HLA) class II alleles that contribute to susceptibility to six ADs in Latin Americans through a meta-analysis and to review additional clinical, immunological, and genetic characteristics of those ADs sharing HLA alleles. DRB1∗03:01 (OR: 4.04; 95%CI: 1.41–11.53) was found to be a risk factor for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), and type 1 diabetes mellitus (T1D). DRB1∗04:05 (OR: 4.64; 95%CI: 2.14–10.05) influences autoimmune hepatitis (AIH), rheumatoid arthritis (RA), and T1D; DRB1∗04:01 (OR: 3.86; 95%CI: 2.32–6.42) is a susceptibility factor for RA and T1D. Opposite associations were found between multiple sclerosis (MS) and T1D. DQB1∗06:02 and DRB1∗15 alleles were risk factors for MS but protective factors for T1D. Likewise, DQB1∗06:03 allele was a risk factor for AIH but a protective one for T1D. Several common autoantibodies and clinical associations as well as additional shared genes have been reported in these ADs, which are reviewed herein. These results indicate that in Latin Americans ADs share major loci and immune characteristics. PMID:22577522

  8. HLA and Disease Associations in Koreans

    PubMed Central

    Ahn, Stephen; Choi, Hee-Back

    2011-01-01

    The human leukocyte antigen (HLA), the major histocompatibility complex (MHC) in humans has been known to reside on chromosome 6 and encodes cell-surface antigen-presenting proteins and many other proteins related to immune system function. The HLA is highly polymorphic and the most genetically variable coding loci in humans. In addition to a critical role in transplantation medicine, HLA and disease associations have been widely studied across the populations world-wide and are found to be important in prediction of disease susceptibility, resistance and of evolutionary maintenance of genetic diversity. Because recently developed molecular based HLA typing has several advantages like improved specimen stability and increased resolution of HLA types, the association between HLA alleles and a given disease could be more accurately quantified. Here, in this review, we have collected HLA association data on some autoimmune diseases, infectious diseases, cancers, drug responsiveness and other diseases with unknown etiology in Koreans and attempt to summarize some remarkable HLA alleles related with specific diseases. PMID:22346771

  9. Diversity in exon 5 of HLA-C(∗)04:01:01G is significant in anthropological studies.

    PubMed

    Dunn, Paul P J; Lamb, Gareth; Selwyn, Caroline; Compton, Jillian; Yang, Edward; Maiers, Martin; Fernandez-Vina, Marcelo

    2016-05-01

    Polymorphisms in Human Leukocyte Antigen (HLA) class I genes are generally considered to be relevant only if they reside in exons 2 and 3 or if they affect the expression of the allele. HLA-C(∗)04:82 differs from the common HLA-C(∗)04:01:01 by having a 9 nucleotide, or 3 amino acid duplication, in exon 5. Having observed HLA-C(∗)04:82 in a New Zealand Maori stem cell patient, we have attempted to examine the prevalence of this allele in different ethnicities. Although our studies are in a limited number of patients and donors, they have revealed that, in the Pacific region, HLA-C(∗)04:82 appears to be the most common allele of the HLA-C(∗)04:01:01G group of alleles, notably in Filippinos and in Maori/Polynesians. In these populations this allele has characteristic HLA-ABCDRB1 haplotypes. Thus, our studies have shown that polymorphisms outside of the clinically important exons can be considered to be relevant in anthropological studies. PMID:27018403

  10. PML nuclear bodies and SATB1 are associated with HLA class I expression in EBV+ Hodgkin lymphoma.

    PubMed

    Liu, Yuxuan; van den Berg, Anke; Veenstra, Rianne; Rutgers, Bea; Nolte, Ilja; van Imhoff, Gustaaf; Visser, Lydia; Diepstra, Arjan

    2013-01-01

    Tumor cells of classical Hodgkin lymphoma (cHL) are characterized by a general loss of B cell phenotype, whereas antigen presenting properties are commonly retained. HLA class I is expressed in most EBV+ cHL cases, with an even enhanced expression in a proportion of the cases. Promyelocytic leukemia protein (PML) and special AT-rich region binding protein 1 (SATB1) are two global chromatin organizing proteins that have been shown to regulate HLA class I expression in Jurkat cells. We analyzed HLA class I, number of PML nuclear bodies (NBs) and SATB1 expression in tumor cells of 54 EBV+ cHL cases and used 27 EBV- cHL cases as controls. There was a significant difference in presence of HLA class I staining between EBV+ and EBV- cases (p<0.0001). We observed normal HLA class I expression in 35% of the EBV+ and in 19% of the EBV- cases. A stronger than normal HLA class I expression was observed in approximately 40% of EBV+ cHL and not in EBV- cHL cases. 36 EBV+ cHL cases contained less than 10 PML-NBs per tumor cell, whereas 16 cases contained more than 10 PML-NBs. The number of PML-NBs was positively correlated to the level of HLA class I expression (p<0.01). The percentage of SATB1 positive cells varied between 0% to 100% in tumor cells and was inversely correlated with the level of HLA class I expression, but only between normal and strong expression (p<0.05). Multivariable analysis indicated that the number of PML-NBs and the percentage of SATB1+ tumor cells are independent factors affecting HLA class I expression in EBV+ cHL. In conclusion, both PML and SATB1 are correlated to HLA class I expression levels in EBV+ cHL.

  11. Generation of HLA-Universal iPSC-Derived Megakaryocytes and Platelets for Survival Under Refractoriness Conditions

    PubMed Central

    Börger, Ann-Kathrin; Eicke, Dorothee; Wolf, Christina; Gras, Christiane; Aufderbeck, Susanne; Schulze, Kai; Engels, Lena; Eiz-Vesper, Britta; Schambach, Axel; Guzman, Carlos A; Lachmann, Nico; Moritz, Thomas; Martin, Ulrich; Blasczyk, Rainer; Figueiredo, Constança

    2016-01-01

    Platelet (PLT) transfusion is indispensable to maintain homeostasis in thrombocytopenic patients. However, PLT transfusion refractoriness is a common life-threatening condition observed in multitransfused patients. The most frequent immune cause for PLT transfusion refractoriness is the presence of alloantibodies specific for human leukocyte antigen (HLA) class I epitopes. Here, we have silenced the expression of HLA class I to generate a stable HLA-universal induced pluripotent stem cell (iPSC) line that can be used as a renewable cell source for the generation of low immunogenic cell products. The expression of HLA class I was silenced by up to 82% and remained stable during iPSC cultivation. In this study, we have focused on the generation of megakaryocytes (MK) and PLTs from a HLA-universal iPSC source under feeder- and xeno-free conditions. On d 19, differentiation rates of MKs and PLTs with means of 58% and 76% were observed, respectively. HLA-universal iPSC-derived MKs showed polyploidy with DNA contents higher than 4n and formed proPLTs. Importantly, differentiated MKs remained silenced for HLA class I expression. HLA-universal MKs produced functional PLTs. Notably, iPSC-derived HLA-universal MKs were capable to escape antibody-mediated complement- and cellular-dependent cytotoxicity. Furthermore, HLA-universal MKs were able to produce PLTs after in vivo transfusion in a mouse model indicating that they might be used as an alternative to PLT transfusion. Thus, in vitro produced low immunogenic MKs and PLTs may become an alternative to PLT donation in PLT-based therapies and an important component in the management of severe alloimmunized patients. PMID:27262025

  12. Lack of association between alopecia areata and HLA class I and II in a southeastern Brazilian population*

    PubMed Central

    Barbosa, Ângela Marques; Prestes-Carneiro, Luiz Euribel; Sobral, Aldri Roberta Sodoschi; Sakiyama, Marcelo Jun; Lemos, Bruna Cerávolo; de Abreu, Marilda Aparecida Milanez Morgado; Martos, Luciana Leite Crivelin; Moliterno, Ricardo Alberto

    2016-01-01

    Background Alopecia areata (AA) is a common disorder of unknown etiology that affects approximately 0.7% to 3.8% of patients among the general population. Currently, genetic and autoimmune factors are emphasized as etiopathogenic. Studies linking Human Leukocyte Antigens (HLA) to AA have suggested that immunogenetic factors may play a role in the disease's onset/development. Objectives To investigate an association between AA and HLA class I/II in white Brazilians. Methods: Patients and control groups comprised 33 and 112 individuals, respectively. DNA extraction was performed by column method with BioPur kit. Allele's classification was undertaken using the PCR-SSO technique. HLA frequencies were obtained through direct counting and subjected to comparison by means of the chi-square test. Results Most patients were aged over 16, with no familial history, and developed partial AA, with no recurrent episodes. Patients showed a higher frequency of HLA-B*40, HLA-B*45, HLA-B*53 and HLA-C*04 compared with controls, although P was not significant after Bonferroni correction. Regarding HLA class II, only HLA-DRB1*07 revealed statistical significance; nevertheless, it featured more prominently in controls than patients (P=0.04; Pc=0.52; OR=0.29; 95%; CI=0.07 to 1.25). P was not significant after Bonferroni correction. Conclusions The development of AA does not seem to be associated with HLA in white Brazilians, nor with susceptibility or resistance. The studies were carried out in populations with little or no miscegenation, unlike the Brazilian population in general, which could explain the inconsistency found. PMID:27438193

  13. HLA Class I and Class II Alleles and Haplotypes Confirm the Berber Origin of the Present Day Tunisian Population

    PubMed Central

    Hajjej, Abdelhafidh; Almawi, Wassim Y.; Hattab, Lasmar; El-Gaaied, Amel; Hmida, Slama

    2015-01-01

    In view of its distinct geographical location and relatively small area, Tunisia witnessed the presence of many civilizations and ethnic groups throughout history, thereby questioning the origin of present-day Tunisian population. We investigated HLA class I and class II gene profiles in Tunisians, and compared this profile with those of Mediterranean and Sub-Sahara African populations. A total of 376 unrelated Tunisian individuals of both genders were genotyped for HLA class I (A, B) and class II (DRB1, DQB1), using reverse dot-blot hybridization (PCR-SSO) method. Statistical analysis was performed using Arlequin software. Phylogenetic trees were constructed by DISPAN software, and correspondence analysis was carried out by VISTA software. One hundred fifty-three HLA alleles were identified in the studied sample, which comprised 41, 50, 40 and 22 alleles at HLA-A,-B,-DRB1 and -DQB1 loci, respectively. The most frequent alleles were HLA-A*02:01 (16.76%), HLA-B*44:02/03 (17.82%), HLA-DRB1*07:01 (19.02%), and HLA-DQB1*03:01 (17.95%). Four-locus haplotype analysis identified HLA-A*02:01-B*50:01-DRB1*07:01-DQB1*02:02 (2.2%) as the common haplotype in Tunisians. Compared to other nearby populations, Tunisians appear to be genetically related to Western Mediterranean population, in particular North Africans and Berbers. In conclusion, HLA genotype results indicate that Tunisians are related to present-day North Africans, Berbers and to Iberians, but not to Eastern Arabs (Palestinians, Jordanians and Lebanese). This suggests that the genetic contribution of Arab invasion of 7th-11th century A.D. had little impact of the North African gene pool. PMID:26317228

  14. Increased frequency and function of KIR2DL1-3+ NK cells in primary HIV-1 infection are determined by HLA-C group haplotypes

    PubMed Central

    Körner, Christian; Granoff, Mitchell E.; Amero, Molly A.; Sirignano, Michael N.; Vaidya, Sagar A.; Jost, Stephanie; Allen, Todd M.; Rosenberg, Eric S.; Altfeld, Marcus

    2014-01-01

    Acquisition and maintenance of NK cell function is mediated by inhibitory killer-cell immunoglobulin-like receptors (KIR) through the interaction with HLA class I molecules. Recently, HLA-C expression levels were shown to be correlated with protection against multiple outcomes of HIV-1 infection; however the underlying mechanisms are poorly understood. As HLA-C is the natural ligand for the inhibitory receptors KIR2DL1 and KIR2DL2/3, we sought to determine whether HLA-C group haplotypes affect NK cell responses during primary HIV-1 infection. The phenotypes and functional capacity of NK cells derived from HIV-1(+) and HIV-1(-) individuals were assessed (N=42 and N=40, respectively). HIV-1 infection was associated with an increased frequency of KIR2DL1-3+ NK cells. Further analysis showed that KIR2DL1+ NK cells were selectively increased in individuals homozygous for HLA-C2, while HLA-C1-homozygous individuals displayed increased proportions of KIR2DL2/3+ NK cells. KIR2DL1-3+ NK cells were furthermore more polyfunctional during primary HIV-1 infection in individuals also encoding for their cognate HLA-C group haplotypes as measured by degranulation and cytokine production. These results identify a novel relationship between HLA-C and KIR2DL+ NK cell subsets and demonstrate that HLA-C-mediated licensing modulates NK cell responses to primary HIV-1 infection. PMID:25043727

  15. Tag SNPs for HLA-B alleles that are associated with drug response and disease risk in the Chinese Han population.

    PubMed

    Liu, X; Sun, J; Yu, H; Chen, H; Wang, J; Zou, H; Lu, D; Xu, J; Zheng, S L

    2015-10-01

    Multiple HLA-B alleles (haplotypes) are associated with drug-induced adverse responses and disease risks but are difficult to be directly genotyped. The goal of this study is to identify single nucleotide polymorphisms (SNPs) that are able to tag HLA-B alleles in the Chinese Han population. Twelve HLA-B alleles that are associated with drug adverse responses and disease risks were identified. They were sequenced initially in 880 Chinese Han subjects where high-density SNPs within the HLA-B gene were available. Performances of these SNPs to tag the HLA-B alleles were assessed primarily by sensitivity and specificity. Two HLA-B alleles can be reliably tagged by SNPs at 100% sensitivity and >95% specificity. For example, HLA-B*15:02 can be tagged by the 'C' allele of rs10484555, and HLA-B*58:01 can be tagged by the 'T' allele of rs9262570. These results were confirmed in 500 additional Chinese Han subjects. If confirmed in independent studies, these tag SNPs could be used as a reliable, simple and cost-effective alternative for genotyping a subset of HLA-B alleles.

  16. Comparative structural analysis of HLA-A2 antigens distinguishable by cytotoxic T lymphocytes. II. Variant DK1: evidence for a discrete CTL recognition region.

    PubMed

    Krangel, M S; Biddison, W E; Strominger, J L

    1983-04-01

    Multiple amino acid sequence differences distinguish individual HLA antigens. Those residues important in immune recognition events have not been defined. Recent studies have identified HLA-A2 structural variants that, although serologically indistinguishable from other HLA-A2 antigens, are recognized poorly, if at all, by HLA-A2-restricted, influenza virus-immune, or HLA-A2-specific alloimmune CTL. In this study we utilize double-label tryptic peptide comparisons performed by both reverse-phase HPLC and cation exchange chromatography, in conjunction with conventional and microsequence analysis, to characterize the HLA-A2 heavy chains derived from variant DK1. We detect a single tryptic peptide that distinguishes DK1 HLA-A2 from the predominant HLA-A2 heavy chain species. This peptide spans residues 147 to 157 in the second heavy chain domain, and carries substitutions at positions 149, 152, and 156. Residues in this segment of the polypeptide are also altered in another HLA-A2 variant, as well as one H-2Kb mutant. Thus, this segment appears to be critical in forming determinants important in CTL recognition of class I antigens in general. On the basis of these and other results, we suggest that in contrast to recognition by alloantibodies, a discrete region of class I antigens may be crucial for CTL recognition. PMID:6601143

  17. The T cell response of HLA-DR transgenic mice to human myelin basic protein and other antigens in the presence and absence of human CD4

    PubMed Central

    1995-01-01

    Analysis of HLA class II transgenic mice has progressed in recent years from analysis of single chain HLA class II transgenes with expression of mixed mouse/human heterodimers to double transgenic mice expressing normal human heterodimers. Previous studies have used either HLA transgenic mice in which there is a species-matched interaction with CD4 or mice which lack this interaction. Since both systems are reported to generate HLA-restricted responses, the matter of the requirement for species-matched CD4 remains unclear. We have generated triple transgenic mice expressing three human transgenes, DRA, DRB, and CD4, and compared HLA-restricted responses to peptide between human- CD4+ (Hu-CD4+) and Hu-CD4- littermates. We saw no difference between Hu- CD4+ and Hu-CD4- groups, supporting the notion that for some responses at least the requirement for species-matched CD4 may not be absolute. Evidence for positive selection of mouse T cell receptors in HLA-DR transgenic mice came both from the acquisition of new, HLA-restricted responses to various peptides and from an increased frequency of T cells using the TCR V beta 4 gene segment. An important goal with respect to the analysis of function in HLA transgenic mice is the clarification of mechanisms which underpin the recognition of self- antigens in human autoimmune disease. As a first step towards 'humanized' disease models in HLA transgenic mice, we analyzed the responses of HLA-DR transgenic mice to the human MPB 139-154 peptide which has been implicated as an epitope recognized by T cells of multiple sclerosis patients. We obtained T cell responses to this epitope in transgenic mice but not in nontransgenic controls. This study suggests that HLA transgenic mice will be valuable in the analysis of HLA-restricted T cell epitopes implicated in human disease and possibly in the design of new disease models. PMID:7532684

  18. Ankylosing spondylitis and HLA-B27: restriction fragment length polymorphism and sequencing of an HLA-B27 allele from a patient with ankylosing spondylitis.

    PubMed Central

    Higgins, C M; Lund, T; Shipley, M E; Ebringer, A; Sadowska-Wroblewska, M; Craig, R K

    1992-01-01

    Two groups of patients with ankylosing spondylitis (AS) from England and Poland were examined for restriction fragment length polymorphisms (RFLPs) associated with the disease. No preferential association was found between the 9.2 kb PvuII fragment in HLA-B27 positive patients with AS compared with HLA-B27 healthy subjects as had been previously reported. In the English group, however, a 14 kb PvuII fragment was more common in HLA-B27 positive subjects with AS than in normal controls. Also 4.6 and 3.7 kb PvuII fragments were more prevalent in subjects without AS than in the group with AS, but these results were confined to the English group. Furthermore, the sequence of an HLA-B*2705 gene isolated from a patient with AS was examined, and no significant differences were found compared with the sequence isolated from a healthy subject. There do not seem to be significant genetic differences in the coding or in the regulatory region in HLA-B27 alleles, in subjects with or without AS. Images PMID:1352961

  19. The IPD-IMGT/HLA Database - New developments in reporting HLA variation.

    PubMed

    Robinson, James; Soormally, Anup R; Hayhurst, James D; Marsh, Steven G E

    2016-03-01

    IPD-IMGT/HLA is a constituent of the Immuno Polymorphism Database (IPD), which was developed to provide a centralised system for the study of polymorphism in genes of the immune system. The IPD project works with specialist groups of nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The primary database within the IPD project is the IPD-IMGT/HLA Database, which provides a locus-specific database for the hyper-polymorphic allele sequences of the genes in the HLA system, also known as the human Major Histocompatibility Complex. The IPD-IMGT/HLA Database was first released over 17 years ago, building on the work of the WHO Nomenclature Committee for Factors of the HLA system that was initiated in 1968. The IPD-IMGT/HLA Database enhanced this work by providing the HLA community with an online, searchable repository of highly curated HLA sequences. Many of the genes encode proteins of the immune system and are hyper polymorphic, with some genes currently having over 4000 known allelic variants. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website, http://www.ebi.ac.uk/ipd/imgt/hla.

  20. The IPD-IMGT/HLA Database - New developments in reporting HLA variation.

    PubMed

    Robinson, James; Soormally, Anup R; Hayhurst, James D; Marsh, Steven G E

    2016-03-01

    IPD-IMGT/HLA is a constituent of the Immuno Polymorphism Database (IPD), which was developed to provide a centralised system for the study of polymorphism in genes of the immune system. The IPD project works with specialist groups of nomenclature committees who provide and curate individual sections before they are submitted to IPD for online publication. The primary database within the IPD project is the IPD-IMGT/HLA Database, which provides a locus-specific database for the hyper-polymorphic allele sequences of the genes in the HLA system, also known as the human Major Histocompatibility Complex. The IPD-IMGT/HLA Database was first released over 17 years ago, building on the work of the WHO Nomenclature Committee for Factors of the HLA system that was initiated in 1968. The IPD-IMGT/HLA Database enhanced this work by providing the HLA community with an online, searchable repository of highly curated HLA sequences. Many of the genes encode proteins of the immune system and are hyper polymorphic, with some genes currently having over 4000 known allelic variants. Through the work of the HLA Informatics Group and in collaboration with the European Bioinformatics Institute we are able to provide public access to this data through the website, http://www.ebi.ac.uk/ipd/imgt/hla. PMID:26826444

  1. Identification of the Variations in the CPT1B and CHKB Genes Along with the HLA-DQB1*06:02 Allele in Turkish Narcolepsy Patients and Healthy Persons

    PubMed Central

    Agilkaya, Sinem; Oztura, Ibrahim; Eroglu, Secil; Karadeniz, Derya; Evlice, Ahmet; Altungoz, Oguz; Yilmaz, Hikmet; Baklan, Baris

    2014-01-01

    Background: The HLA-DQB1*06:02 allele across all ethnic groups and the rs5770917 variation between CPT1B and CHKB genes in Japanese and Koreans are common genetic susceptibility factors for narcolepsy. This comprehensive genetic study sought to assess variations in CHKB and CPT1B susceptibility genes and HLA-DQB1*06:02 allele status in Turkish patients with narcolepsy and healthy persons. Methods: CHKB/CPT1B genes were sequenced in patients with narcolepsy (n=37) and healthy persons (n=100) to detect variations. The HLA-DQB1*06:02 allele status was determined by sequence specific polymerase chain reaction. Results: The HLA-DQB1*06:02 allele was significantly more frequent in narcoleptic patients than in healthy persons (p=2×10−7) and in patients with narcolepsy and cataplexy than in those without (p=0.018). The mean of the multiple sleep latency test, sleep-onset rapid eye movement periods, and frequency of sleep paralysis significantly differed in the HLA-DQB1*06:02–positive patients. rs5770917, rs5770911, rs2269381, and rs2269382 were detected together as a haplotype in three patients and 11 healthy persons. In addition to this haplotype, the indel variation (rs144647670) was detected in the 5′ upstream region of the human CHKB gene in the patients and healthy persons carrying four variants together. Conclusion: This study identified a novel haplotype consisting of the indel variation, which had not been detected in previous studies in Japanese and Korean populations, and observed four single-nucleotide polymorphisms in CHKB/CPT1B. The study confirmed the association of the HLA-DQB1*06:02 allele with narcolepsy and cataplexy susceptibility. The findings suggest that the presence of HLA-DQB1*06:02 may be a predictor of cataplexy in narcoleptic patients and could therefore be used as an additional diagnostic marker alongside hypocretin. PMID:24571861

  2. Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo

    PubMed Central

    Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A.; Hagman, James; Ferrara, Tracey M.; Jones, Kenneth L.; Cavalli, Giulio; Dinarello, Charles A.; Spritz, Richard A.

    2016-01-01

    HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A*02:01, which presents multiple vitiligo melanocyte autoantigens. Refined genetic mapping localizes vitiligo risk in the HLA-A region to an SNP haplotype ∼20-kb downstream, spanning an ENCODE element with many characteristics of a transcriptional enhancer. Convergent CTCF insulator sites flanking the HLA-A gene promoter and the predicted transcriptional regulator, with apparent interaction between these sites, suggests this element regulates the HLA-A promoter. Peripheral blood mononuclear cells from healthy subjects homozygous for the high-risk haplotype expressed 39% more HLA-A RNA than cells from subjects carrying nonhigh-risk haplotypes (P = 0.0048). Similarly, RNAseq analysis of 1,000 Genomes Project data showed more HLA-A mRNA expressed in subjects homozygous for the high-risk allele of lead SNP rs60131261 than subjects homozygous for the low-risk allele (P = 0.006). Reporter plasmid transfection and genomic run-on sequence analyses confirm that the HLA-A transcriptional regulator contains multiple bidirectional promoters, with greatest activity on the high-risk haplotype, although it does not behave as a classic enhancer. Vitiligo risk associated with the MHC class I region thus derives from combined quantitative and qualitative phenomena: a SNP haplotype in a transcriptional regulator that induces gain-of-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers *02:01 specificity. PMID:26787886

  3. Autoimmune vitiligo is associated with gain-of-function by a transcriptional regulator that elevates expression of HLA-A*02:01 in vivo.

    PubMed

    Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A; Hagman, James; Ferrara, Tracey M; Jones, Kenneth L; Cavalli, Giulio; Dinarello, Charles A; Spritz, Richard A

    2016-02-01

    HLA-A is a class I major histocompatibility complex receptor that presents peptide antigens on the surface of most cells. Vitiligo, an autoimmune disease in which skin melanocytes are destroyed by cognate T cells, is associated with variation in the HLA-A gene; specifically HLA-A*02:01, which presents multiple vitiligo melanocyte autoantigens. Refined genetic mapping localizes vitiligo risk in the HLA-A region to an SNP haplotype ∼20-kb downstream, spanning an ENCODE element with many characteristics of a transcriptional enhancer. Convergent CTCF insulator sites flanking the HLA-A gene promoter and the predicted transcriptional regulator, with apparent interaction between these sites, suggests this element regulates the HLA-A promoter. Peripheral blood mononuclear cells from healthy subjects homozygous for the high-risk haplotype expressed 39% more HLA-A RNA than cells from subjects carrying nonhigh-risk haplotypes (P = 0.0048). Similarly, RNAseq analysis of 1,000 Genomes Project data showed more HLA-A mRNA expressed in subjects homozygous for the high-risk allele of lead SNP rs60131261 than subjects homozygous for the low-risk allele (P = 0.006). Reporter plasmid transfection and genomic run-on sequence analyses confirm that the HLA-A transcriptional regulator contains multiple bidirectional promoters, with greatest activity on the high-risk haplotype, although it does not behave as a classic enhancer. Vitiligo risk associated with the MHC class I region thus derives from combined quantitative and qualitative phenomena: a SNP haplotype in a transcriptional regulator that induces gain-of-function, elevating expression of HLA-A RNA in vivo, in strong linkage disequilibrium with an HLA-A allele that confers *02:01 specificity.

  4. 40 CFR 75.72 - Determination of NOX mass emissions for common stack and multiple stack configurations.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... lbs) by multiplying the hourly NOX emission rate (in lbs/mmBtu) by the hourly heat input rate (in mm... determining the hourly unit heat input rates, either: (i) Apportion the common stack heat input rate to the... this part, (A) Use the procedures in appendix D to this part to determine heat input rate for that...

  5. 40 CFR 75.17 - Specific provisions for monitoring emissions from common, bypass, and multiple stacks for NOX...

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 16 2011-07-01 2011-07-01 false Specific provisions for monitoring... MONITORING Monitoring Provisions § 75.17 Specific provisions for monitoring emissions from common, bypass... the heat input estimation procedures in appendix F to this part. Alternatively, for units that...

  6. Unsupervised HLA Peptidome Deconvolution Improves Ligand Prediction Accuracy and Predicts Cooperative Effects in Peptide-HLA Interactions.

    PubMed

    Bassani-Sternberg, Michal; Gfeller, David

    2016-09-15

    Ag presentation on HLA molecules plays a central role in infectious diseases and tumor immunology. To date, large-scale identification of (neo-)Ags from DNA sequencing data has mainly relied on predictions. In parallel, mass spectrometry analysis of HLA peptidome is increasingly performed to directly detect peptides presented on HLA molecules. In this study, we use a novel unsupervised approach to assign mass spectrometry-based HLA peptidomics data to their cognate HLA molecules. We show that incorporation of deconvoluted HLA peptidomics data in ligand prediction algorithms can improve their accuracy for HLA alleles with few ligands in existing databases. The results of our computational analysis of large datasets of naturally processed HLA peptides, together with experimental validation and protein structure analysis, further reveal how HLA-binding motifs change with peptide length and predict new cooperative effects between distant residues in HLA-B07:02 ligands. PMID:27511729

  7. Unsupervised HLA Peptidome Deconvolution Improves Ligand Prediction Accuracy and Predicts Cooperative Effects in Peptide-HLA Interactions.

    PubMed

    Bassani-Sternberg, Michal; Gfeller, David

    2016-09-15

    Ag presentation on HLA molecules plays a central role in infectious diseases and tumor immunology. To date, large-scale identification of (neo-)Ags from DNA sequencing data has mainly relied on predictions. In parallel, mass spectrometry analysis of HLA peptidome is increasingly performed to directly detect peptides presented on HLA molecules. In this study, we use a novel unsupervised approach to assign mass spectrometry-based HLA peptidomics data to their cognate HLA molecules. We show that incorporation of deconvoluted HLA peptidomics data in ligand prediction algorithms can improve their accuracy for HLA alleles with few ligands in existing databases. The results of our computational analysis of large datasets of naturally processed HLA peptides, together with experimental validation and protein structure analysis, further reveal how HLA-binding motifs change with peptide length and predict new cooperative effects between distant residues in HLA-B07:02 ligands.

  8. Import pathways of precursor proteins into mitochondria: multiple receptor sites are followed by a common membrane insertion site

    PubMed Central

    1988-01-01

    The precursor of porin, a mitochondrial outer membrane protein, competes for the import of precursors destined for the three other mitochondrial compartments, including the Fe/S protein of the bc1- complex (intermembrane space), the ADP/ATP carrier (inner membrane), subunit 9 of the F0-ATPase (inner membrane), and subunit beta of the F1- ATPase (matrix). Competition occurs at the level of a common site at which precursors are inserted into the outer membrane. Protease- sensitive binding sites, which act before the common insertion site, appear to be responsible for the specificity and selectivity of mitochondrial protein uptake. We suggest that distinct receptor proteins on the mitochondrial surface specifically recognize precursor proteins and transfer them to a general insertion protein component (GIP) in the outer membrane. Beyond GIP, the import pathways diverge, either to the outer membrane or to translocation contact-sites, and then subsequently to the other mitochondrial compartments. PMID:2974457

  9. Allele and haplotype frequencies of HLA-A, B, C, DRB1 and DQB1 genes in polytransfused patients in ethnically diverse populations from Brazil.

    PubMed

    Rodrigues, C; Macedo, L C; Bruder, A V; Quintero, F d C; de Alencar, J B; Sell, A M; Visentainer, J E L

    2015-10-01

    The red blood transfusion is a practice often used in patients with haematological and oncological diseases. However, the investigation of human leucocyte antigen (HLA) system frequency in these individuals is of great importance because multiple transfusions may lead to HLA alloimmunization. Brazil is a country that was colonized by many other ethnicities, leading to a mixed ethnicity and regionalized population. In view of the importance of HLA typing in these patients, the aim of this study was to investigate the allele and haplotype frequencies from polytransfused patients from three different regions from Brazil. HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genotyping of 366 patients was performed by PCR-SSO, based on the Luminex technology (One Lambda(®) ), and the anti-HLA class I and class II antibodies were analysed using LabScreen Single Antigen Antibody Detection (One Lambda, Inc.). Allele and haplotype frequencies of polytransfused patients of three regions from Brazil were obtained using the Arlequin program. The most frequent allele frequencies observed were HLA-A*02, A*03, B*15, B*35, B*51, C*07, C*04, C*03, DRB1*13, DRB1*11, DRB1*07, DRB1*03, DRB1*01, DQB1*03, DQB1*02, DQB1*06 and DQB1*05. There were differences between the groups for allele variants HLA-B*57 (between Group 1 and Group 2) and HLA-C*12 (between Group 1 and Group 3). The most frequent haplotypes found in the sample were HLA-A*01B*08DRB1*03, DRBI*07DQB1*02, DRB1*01DQB1*05, DRB1*13DQB1*06 and A*02B*35. HLA class I and II antibodies were detected in 77.9% and 63.9% patients, respectively, while the both alloantibodies were detected in 62 (50.9%) patients. In conclusion, the HLA typing for polytransfused patients in each region has a great importance, as seen in this study; individuals from different regions from Brazil have HLA distribution not completely homogeneous.

  10. [HLA-B27 polymorphism and spondyloarthropathies].

    PubMed

    Peixoto, M J; Gonzales, T; Spinola, H; Couto, A R; Mora, M Gantes; Brehm, A; Santos, M R; Garrett, F; Armas, J Bruges

    2005-01-01

    The association of HLA-B27 with ankylosing spondylitis (AS), and other spondyloarthropathies (SpA), remains as one of the strongest between HLA molecules and human disease. Since it was reported, in 1973, it has been extensively studied in order to understand the underlying pathogenic mechanism. The objective of this article is to review the current knowledge on the structure and polymorphism of HLA-B27 molecule, as well as describe the main pathogenic hypotheses trying to explain its association with AS.

  11. The HLA system and diabetes mellitus.

    PubMed

    Cudworth, A G; Woodrow, J C

    1977-06-01

    There is a significant positive association between insulin dependent diabetes, irrespective of age of onset, and the HLA system, whereas there is no association of HLA antigens with non-insulin dependent diabetes. There is a significant concordance value for HLA antigen frequencies in insulin dependent diabetics from three different centres, indicating that the genes (s) conferring susceptibility to this type of diabetes is possibly present in all "juvenile-onset" diabetics and is in linkage disequilibrium with all the B locus alleles. PMID:892129

  12. Comprehensive Analysis of the Naturally Processed Peptide Repertoire: Differences between HLA-A and B in the Immunopeptidome

    PubMed Central

    Spijkers, Sanne N. M.; Poelen, Martien C. M.; van Gaans-van den Brink, Jacqueline A. M.; van der Poel, Kees; Costa, Ana I.; van Els, Cecile A. C. M.; van Baarle, Debbie; Kesmir, Can

    2015-01-01

    The cytotoxic T cell (CTL) response is determined by the peptide repertoire presented by the HLA class I molecules of an individual. We performed an in-depth analysis of the peptide repertoire presented by a broad panel of common HLA class I molecules on four B lymphoblastoid cell-lines (BLCL). Peptide elution and mass spectrometry analysis were utilised to investigate the number and abundance of self-peptides. Altogether, 7897 unique self-peptides, derived of 4344 proteins, were eluted. After viral infection, the number of unique self-peptides eluted significantly decreased compared to uninfected cells, paralleled by a decrease in the number of source proteins. In the overall dataset, the total number of unique self-peptides eluted from HLA-B molecules was larger than from HLA-A molecules, and they were derived from a larger number of source proteins. These results in B cells suggest that HLA-B molecules possibly present a more diverse repertoire compared to their HLA-A counterparts, which may contribute to their immunodominance. This study provides a unique data set giving new insights into the complex system of antigen presentation for a broad panel of HLA molecules, many of which were never studied this extensively before. PMID:26375851

  13. Common multiple dsRNAs are present in populations of the fungus Discula destructiva originating from widely separated geographic locations.

    PubMed

    Rong, R; Rao, S; Scott, S W; Tainter, F H

    2001-02-01

    DsRNAs were detected in 85/108 isolates of Discula destructiva, the cause of dogwood anthracnose, collected in South Carolina, Idaho, and Alabama. The eastern isolates contained a greater diversity of dsRNA than did Idaho isolates, but most isolates, irrespective of state of origin, contained two small bands (ca. 1.5-2.5 kb) with sequence homology indicated by Northern hybridization. Differences in the banding patterns suggest that genetic diversity of dsRNA in D. destructiva is generated rapidly and that D. destructiva can be simultaneously infected by multiple dsRNA viruses.

  14. KIR and HLA Genotypes Implicated in Reduced Killer Lymphocytes Immunity Are Associated with Vogt-Koyanagi-Harada Disease

    PubMed Central

    Levinson, Ralph D.; Yung, Madeline; Meguro, Akira; Ashouri, Elham; Yu, Fei; Mizuki, Nobuhisa; Ohno, Shigeaki

    2016-01-01

    Cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are killer lymphocytes that provide defense against viral infections and tumor transformation. Analogous to that of CTL, interactions of killer-cell immunoglobulin-like receptors (KIR) with specific human leukocyte antigen (HLA) class I ligands calibrate NK cell education and response. Gene families encoding KIRs and HLA ligands are located on different chromosomes, and feature variation in the number and type of genes. The independent segregation of KIR and HLA genes results in variable KIR-HLA interactions in individuals, which may impact disease susceptibility. We tested whether KIR-HLA combinations are associated with Vogt-Koyanagi-Harada (VKH) disease, a bilateral granulomatous panuveitis that has strong association with HLA-DR4. We present a case control study of 196 VKH patients and 209 controls from a highly homogeneous native population of Japan. KIR and HLA class I genes were typed using oligonucleotide hybridization method and analyzed using two-tailed Fisher’s exact probabilities. The incidence of Bx-KIR genotypes was decreased in VKH patients (odds ratio [OR] 0.58, P = 0.007), due primarily to a decrease in centromeric B-KIR motif and its associated KIRs 2DS2, 2DL2, 2DS3, and 2DL5B. HLA-B22, implicated in poor immune response, was increased in VKH (OR = 4.25, P = 0.0001). HLA-Bw4, the ligand for KIR3DL1, was decreased in VKH (OR = 0.59, P = 0.01). The KIR-HLA combinations 2DL2+C1/C2 and 3DL1+Bw4, which function in NK education, were also decreased in VKH (OR = 0.49, P = 0.012; OR = 0.59, P = 0.013). Genotypes missing these two inhibitory KIR-HLA combinations in addition to missing activating KIRs 2DS2 and 2DS3 were more common in VKH (OR = 1.90, P = 0.002). These results suggest that synergistic hyporesponsiveness of NK cells (due to poor NK education along with missing of activating KIRs) and CTL (due to HLA-B22 restriction) fail to mount an effective immune response against viral

  15. Optimal selection of natural killer cells to kill myeloma: the role of HLA-E and NKG2A.

    PubMed

    Sarkar, Subhashis; van Gelder, Michel; Noort, Willy; Xu, Yunping; Rouschop, Kasper M A; Groen, Richard; Schouten, Harry C; Tilanus, Marcel G J; Germeraad, Wilfred T V; Martens, Anton C M; Bos, Gerard M J; Wieten, Lotte

    2015-08-01

    Immunotherapy with allogeneic natural killer (NK) cells offers therapeutic perspectives for multiple myeloma patients. Here, we aimed to refine NK cell therapy by evaluation of the relevance of HLA-class I and HLA-E for NK anti-myeloma reactivity. We show that HLA-class I was strongly expressed on the surface of patient-derived myeloma cells and on myeloma cell lines. HLA-E was highly expressed by primary myeloma cells but only marginally by cell lines. HLA-E(low) expression on U266 cells observed in vitro was strongly upregulated after in vivo (bone marrow) growth in RAG-2(-/-) γc(-/-) mice, suggesting that in vitro HLA-E levels poorly predict the in vivo situation. Concurrent analysis of inhibitory receptors (KIR2DL1, KIR2DL2/3, KIR3DL1 and NKG2A) and NK cell degranulation upon co-culture with myeloma cells revealed that KIR-ligand-mismatched NK cells degranulate more than matched subsets and that HLA-E abrogates degranulation of NKG2A+ subsets. Inhibition by HLA-class I and HLA-E was also observed with IL-2-activated NK cells and at low oxygen levels (0.6 %) mimicking hypoxic bone marrow niches where myeloma cells preferentially reside. Our study demonstrates that NKG2A-negative, KIR-ligand-mismatched NK cells are the most potent subset for clinical application. We envision that infusion of high numbers of this subclass will enhance clinical efficacy.

  16. A common gene signature across multiple studies relate biomarkers and functional regulation in tolerance to renal allograft

    PubMed Central

    Baron, Daniel; Ramstein, Gérard; Chesneau, Mélanie; Echasseriau, Yann; Pallier, Annaick; Paul, Chloé; Degauque, Nicolas; Hernandez-Fuentes, Maria P; Sanchez-Fueyo, Alberto; Newell, Kenneth A; Giral, Magali; Soulillou, Jean-Paul; Houlgatte, Rémi; Brouard, Sophie

    2015-01-01

    Patients tolerant to a kidney graft display a specific blood cell transcriptional pattern but results from five different studies were inconsistent, raising the question of relevance for future clinical application. To resolve this, we sought to identify a common gene signature, specific functional and cellular components, and discriminating biomarkers for tolerance following kidney transplantation. A meta-analysis of studies identified a robust gene signature involving proliferation of B and CD4 T cells, and inhibition of CD14 monocyte related functions among 96 tolerant samples. This signature was further supported through a cross-validation approach, yielding 92.5% accuracy independent of the study of origin. Experimental validation, performed on new tolerant samples and using a selection of the top-20 biomarkers, returned 91.7% of good classification. Beyond the confirmation of B-cell involvement, our data also indicated participation of other cell subsets in tolerance. Thus, the use of the top 20 biomarkers, mostly centered on B cells, may provide a common and standardized tool towards personalized medicine for the monitoring of tolerant or low-risk patients among kidney allotransplant recipients. These data point to a global preservation of genes favoring the maintenance of a homeostatic and ‘healthy' environment in tolerant patients and may contribute to a better understanding of tolerance maintenance mechanisms. PMID:25629549

  17. Frequency of HLA-A alleles in the Syrian population genotyped by sequence-based typing.

    PubMed

    Madania, A; Ghoury, I; Al-Ashkar, W; Nweder, S; Zarzour, H

    2014-10-01

    HLA-A molecules are highly polymorphic. Their accurate typing at a high-resolution level is crucial for successful organ, bone marrow and cord blood transplantation. Furthermore, several HLA alleles have been involved in susceptibility to autoimmune diseases, allergies, cancers and inflammations. In order to determine common HLA-A alleles in Syria and their frequencies, sequence-based typing (SBT) was used to genotype HLA-A alleles at high resolution (four digit level) among one hundred and thirty randomly selected Syrian individuals. Exons 2, 3 and 4 of the HLA-A gene were amplified by PCR and sequenced. The sbt-engine software was used for allele assignment. Ambiguities were solved using group-specific sequencing primers (GSSPs). We could identify 32 different HLA-A alleles which were divided into 3 groups: high frequency (approximately 10%, A*01:01; A*24:02; A*03:01; A*02:01), moderate frequency (approximately 3%, such as A*02:05, A*31:01 and A*33:01), and low frequency (approximately 1%, such as A*02:11, A*29:01, A*02:02 and A*36:01). Homozygosity rate was higher than expected (11.5% vs. 7.15%). For high frequency alleles, our results show similarity to neighbouring countries. However, 15 alleles (such as A*02:04, A*02:06, A*02:11 and A*02:17) found in our cohort in low frequencies were never reported in some or all neighbouring countries. This is the first report on HLA-A allele frequencies in Syria. In spite of the relatively low number of tested subjects, our results revealed a high degree of diversity, with 32 different alleles, reflecting the high ethnic heterogeneity of the Syrian population. The identification of alleles rarely or never reported in neighbouring countries indicates a higher genetic diversity in Syria.

  18. The HLA system: structure and function.

    PubMed Central

    Bodmer, W F

    1987-01-01

    The HLA system is the major histocompatibility system of man and was found through a search for blood group-like determinants on white blood cells that would be effective in matching for transplantation. The HLA system has its counterparts in other species of mammals, birds, and reptiles including the much studied H2 system of the mouse. The HLA system started from a series of antigens defined by a combination of relatively crude serology and genetics, supported by extensive statistical analysis. It has turned out to be a complex genetic region determining two major sets of cell surface products which mediate essential functional interactions between cells of the immune system, and so have a major role in the control of the immune response. Polymorphism in the HLA region is thus associated with a wide variety of diseases with an immune aetiology. PMID:3312304

  19. The HLA DQB1 gene locus: Further evidence for an association with schizophrenia

    SciTech Connect

    Zhang, X.R.; Rudert, W.A.; Nimgaonkar, L.

    1994-09-01

    A genetic predisposition to schizophrenia is well-established. Immunological abnormalities suggestive of an auto-immune disorder have also been noted. However, no consistent associations with HLA have been detected. A negative association between schizophrenia and HLA DQB1*0602 among African-Americans, but not among Caucasian individuals, was reported recently. The association is plausible, because (i) an association of insulin dependent diabetes mellitus (IDDM) with the HLA DQB1 gene locus is known, and (ii) an inverse relationship between the prevalence of schizophrenia and IDDM has been suggested. In view of the ethnic differences in the above association, a cohort of Chinese ethnicity from Singapore was examined in the present study. Consenting male inpatients with schizophrenia (n=102, ICD-9 criteria) participated. The controls were male adults undergoing pre-employment checkup (n=111). HLA DQB1 gene polymorphisms were analyzed using a PCR-based reverse dot-blot assay. In case of ambiguity, samples were checked using PCR amplification with sequence-specific primers. In support of the earlier report, a negative association with HLA DQB1*0602 was noted (odds ratio 0.22, C.I. 0.18, 0.83; {chi}{sup 2}=8.0, p<0.005; both analyses uncorrected for multiple comparisons).

  20. Analysis of the contribution of HLA genes to genetic predisposition in inflammatory bowel disease

    SciTech Connect

    Naom, I.; Haris, I.; Hodgson, S.V.; Mathew, C.G.

    1996-07-01

    Crohn disease (CD) and ulcerative colitis (UC) are chronic inflammatory bowel diseases (IBDs) of unknown etiology. First-degree relatives of IBD patients have a 10-fold increase in risk of developing the same disease, and distinct associations between specific HLA types and both CD and UC have been reported. We have evaluated the contribution of genes at the HLA locus to susceptibility in IBD by linkage analysis of highly informative microsatellite polymorphisms in 43 families with multiple affected cases. No evidence for linkage of HLA to IBD was obtained under any of the four models tested. Analysis of HLA haplotype sharing in affected relatives indicated that the relative risk to a sibling conferred by the HLA locus was 1.11 in UC and 0.75 in CD, with upper (95%) confidence limits of 2.41 and 1.37, respectively. This suggests that other genetic or environmental factors are responsible for most of the familial aggregation in IBD. 31 refs., 1 fig., 2 tabs.

  1. Molecular typing of HLA-A, -B, and DRB using a high throughput micro array format.

    PubMed

    Balazs, I; Beekman, J; Neuweiler, J; Liu, H; Watson, E; Ray, B

    2001-08-01

    The goal of this study was to develop a DNA micro array procedure for molecular human leukocyte antigen (HLA) typing of a large number of samples. DNA was isolated from peripheral blood samples and polymerase chain reaction (PCR) amplified for HLA-A, -B, and -DRB. Amplified DNA samples were spotted on silane-treated glass slides using a micro array spotter. The spotter was capable of spotting multiple slides with up to 9216 samples per slide or 2304 samples in quadruplicate. The allele specific oligo nucleotide probes for HLA-A, -B, and -DRB were labeled with the fluorescent dye Cy3, while a control probe, to quantitate the total amount of PCR product in a sample, was labeled with Cy5. Each slide was hybridized with a mixture of an allele specific Cy3 probe plus the control Cy5 probe. Following hybridization and wash, the amount of probe hybridizing to each DNA sample on the slide was measured with a micro array scanner. A computer program was used for image analysis, to calculate the average Cy3/Cy5 ratios and to identify the positive and negative samples. In turn, this information was used to determine the HLA phenotype of each sample. There was very good concordance between the results obtained for all three loci using Cy-labeled probes as compared with those previously obtained by chemiluminescent detection of alkaline phosphatase labeled probes. This methodology has the potential of greatly simplifying HLA molecular typing of large number of samples.

  2. Identification of QTLs of resistance to white mold in common bean from multiple markers by using Bayesian analysis.

    PubMed

    Lara, L A C; Santos, J B; Balestre, M; Lima, I A; Pamplona, A K A; Veloso, J S; Silva, P H

    2015-02-06

    In this study, we identified simple sequence repeat, ampli-fied fragment length polymorphism, and sequence-related amplified poly-morphism markers linked to quantitative trait loci (QTLs) for resistance to white mold disease in common bean progenies derived from a cross between lines CNFC 9506 and RP-2, evaluated using the oxalic acid test and using Bayesian analysis. DNA was extracted from 186 F₂ plants and their parental lines for molecular analysis. Fifteen experiments were car-ried out for phenotypic analysis, which included 186 F₂:₄ progenies, the F₁ generation, the F₂ generation, and the lines CNFC 9506, RP-2, and G122 as common treatments. A completely randomized experimental design with 3 replications was used in controlled environments. The adjusted means for the F₂:₄ generation were to identify QTLs by Bayesian shrink-age analysis. Significant differences were observed among the progenies for the reaction to white mold. The moving away method under the Bayes-ian approach was effective for identifying QTLs when it was not possible to obtain a genetic map because of low marker density. Using the Wald test, 25 markers identified QTLs for resistance to white mold, as well as 16 simple sequence repeats, 7 amplified fragment length polymorphisms, and 2 sequence-related amplified polymorphisms. The markers BM184, BM211, and PV-gaat001 showed low distances from QTLs related white mold resistance. In addition, these markers showed, signal effects with increasing resistance to white mold and high heritability in the analysis with oxalic acid, and thus, are promising for marker-assisted selection.

  3. The HLA antigens of two Negrito populations in the Philippines.

    PubMed

    Horai, S; Omoto, K; Juji, T; Sonozaki, H; Mitsui, H; Misawa, S; Sumpaico, J S; Mercado, A S

    1981-03-01

    HLA antigens were determined for the A, B and C loci among 86 Aetas of west-central Luzon and 87 Mamanwas of north-eastern Mindanao, Philippines. The overall antigenic profiles of these two groups were essentially similar to those of other Asian-Pacific populations with some peculiarities in common with Papua New Guineans. However, the results of heterogeneity tests and the comparison of statistically significant phenotypic associations showed a highly significant difference between the Aeta and the Mamanwa groups. It was postulated that the two "Negrito" groups represent different migrations to the Philippines.

  4. HLA antigens and asthma in Greeks.

    PubMed

    Apostolakis, J; Toumbis, M; Konstantopoulos, K; Kamaroulias, D; Anagnostakis, J; Georgoulias, V; Fessas, P; Zervas, J

    1996-04-01

    HLA-A and -B antigens were determined in a group of 76 Greek asthmatic patients: 35 children (1.5-15 years) and 41 adults (18-73 years). The results were compared to those of 400 healthy unrelated controls from the same population. The standard NIH lymphocytotoxicity test was applied. When all 76 patients were compared to the controls, a statistically significant lower frequency of HLA-B5 and -B35 antigens was noted. When adults were analysed alone, an increased frequency of HLA-B8 was found. On the other hand, in the asthmatic children sub-group, the HLA-A10 antigen was significantly higher and the HLA-B5 was significantly lower than in the controls. These data imply that different HLA antigens may be involved in the pathogenesis of several clinical forms of asthma and that, in order to study the role of immunogenetic factor(s) in the pathogenesis of this disease, more adequate grouping criteria are needed.

  5. HLA antigen expression and malignant mesothelioma.

    PubMed

    Christmas, T I; Manning, L S; Davis, M R; Robinson, B W; Garlepp, M J

    1991-09-01

    The expression of HLA antigens by a tumor may determine its progression and metastatic potential by influencing the immune response to that tumor. The upregulation of HLA antigen expression on some cell types by interferons (IFNs) may contribute to their antitumor activity. Malignant mesothelioma (MM) is a tumor that has a poor prognosis and is unaffected by conventional therapy, although immunotherapy has not been adequately assessed. In this study, we have examined the constitutive and IFN-inducible expression of class I and class II HLA antigens on MM cell lines using indirect immunofluorescence and Northern blotting. All MM cell lines constitutively expressed class I, but not class II, surface antigen, and all three class I loci (HLA-A, HLA-B, and HLA-C) were expressed. The MM cell lines were heterogeneous in their response to the IFNs. Treatment with IFN-alpha marginally increased class I surface expression, but not class II. Class I mRNA was, however, clearly increased in all cell lines after IFN-alpha treatment, suggesting that class I surface antigen was already maximally expressed. IFN-gamma increased class I mRNA expression in all but one cell line and induced DR expression on three of the cell lines. DQ-beta, but not DQ-alpha, mRNA was inducible in the same three cell lines, but DQ surface antigen was never demonstrable.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Reduction in HLA-DR, HLA-DQ and HLA-DP expression by Leu-M3+ cells from the peripheral blood of patients with thermal injury.

    PubMed Central

    Gibbons, R A; Martinez, O M; Lim, R C; Horn, J K; Garovoy, M R

    1989-01-01

    Monocytes that bear HLA Class II antigens, such as HLA-DR, HLA-DQ, or HLA-DP, are obligatory for many cell-mediated immunological processes. Patients with thermal injury suffer from hypoimmunity and are at risk for developing life-threatening septic episodes. To determine whether an alteration in expression of HLA Class II antigens is involved in the defect, monocytes from the peripheral blood of burn patients and controls were double-stained with anti-Leu-M3 and either anti-HLA-DR, HLA-DQ, or HLA-DP monoclonal antibodies. As analysed by flow cytometry the percentage of Leu-M3+ monocytes from the peripheral blood from patients and controls was the same. The percentage of Leu-M3+ monocytes bearing the HLA Class II antigens and the density of antigen on the monocytes, however, was significantly reduced post-burn compared with controls. In nearly all cases these changes were detected as early as 24 h post-burn before any drug therapy was implemented. In-vivo re-expression of normal levels of HLA Class II coincided with patient recovery. In-vitro exposure of post-burn Leu-M3+ cells to IFN-gamma for 72 h restored HLA Class II expression to control levels. It is possible that the reductions in HLA Class II expression may be involved in the general immunosuppression that follows thermal injury. PMID:2495202

  7. Nonfrequent but well-documented, rare and very rare HLA alleles observed in the Croatian population.

    PubMed

    Grubic, Z; Burek Kamenaric, M; Maskalan, M; Stingl Jankovic, K; Zunec, R

    2014-12-01

    The aim of the study was to evaluate the presence of nonfrequent, rare and very rare alleles among Croats and to estimate whether they are associated with specific alleles at other human leukocyte antigen (HLA) loci. This retrospective study included the typing results from the last 10 years; total number of individuals included was approximately 45,000. Among 17 alleles so far observed only once in our population, 6 (A*24:41, B*07:02:28, B*35:03:03, B*39:40N, DRB1*13:23 and DRB1*14:111) belong to very rare alleles, 2 (B*44:16 and DRB1*01:31) belong to rare alleles according to the 'Rare Alleles Detector' tool ( www.allelefrequencies.net), while for the B*35:101:01 allele published data exist only in the IMGT/HLA database. The remaining eight HLA alleles observed only once among Croats are considered as frequent according to the 'Rare Alleles Detector'. Those 17 HLA alleles are not declared as common well defined (CWD) alleles in the CWD allele catalogue 2.0.0. Haplotype analysis of nonfrequent alleles detected in our sample supports the idea that different populations, although similar in some aspects regarding HLA allele and haplotype distribution, still have some unique characteristics. This is the case for A*01:02, B*39:10 and DRB1*13:32 which form haplotypes unreported to date among our subjects.

  8. Mutant HLA-A2 antigens as restricting elements for virus-specific cytotoxic T cells.

    PubMed

    Gaston, J S; Wallace, L E; Rickinson, A B; Epstein, M A; Pious, D

    1984-01-01

    Mutants of the EB virus-transformed cell line T5-1 (HLA-A1, 2; B8, 27), bearing well-characterized alterations in HLA-A2 antigen expression and unable to bind the HLA-A2-specific monoclonal antibody BB7.2, have been tested for their susceptibility to EB virus-specific cytolysis using effector T-cell preparations functionally restricted through relevant HLA antigens. Initial experiments first confirmed that the parent line T5-1 was susceptible to cytolysis by both "common" A2-restricted and B27-restricted effector cells. While those T5-1 mutants with little or no surface A2 expression were not lysed by A2-restricted effectors, those targets with quantitatively normal expression of mutant A2 molecules were as susceptible to A2-restricted lysis as the parent line itself. In contrast, all the T5-1 mutant lines were susceptible to B27-restricted cytolysis. The results demonstrate that experimentally induced mutations of HLA-A2 antigen structure, affecting a serologically defined site on the molecule, can occur without altering that same molecule's expression of the T cell-restricting determinant(s). Such experimentally induced mutations are quite different from the naturally occurring "variant" A2 antigens which are present within the serologically defined A2 antigen group and which show changes at the T cell-restricting site. PMID:6329950

  9. Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies.

    PubMed

    Melzer, N; Meuth, S G

    2014-03-01

    Multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent chronic, autoimmune demyelinating disorders of the central and peripheral nervous system. Although both disorders share some fundamental pathogenic elements, treatments do not provide uniform effects across both disorders. We aim at providing an overview of current and future disease-modifying strategies in these disorders to demonstrate communalities and distinctions. Intravenous immunoglobulins (IVIG) have demonstrated short- and long-term beneficial effects in CIDP but are not effective in MS. Dimethyl fumarate (BG-12), teriflunomide and laquinimod are orally administered immunomodulatory drugs that are already approved or likely to be approved in the near future for the basic therapy of patients with relapsing-remitting MS (RRMS) due to positive results in Phase III clinical trials. However, clinical trials with these drugs in CIDP have not (yet) been initiated. Natalizumab and fingolimod are approved for the treatment of RRMS, and trials to evaluate their safety and efficacy in CIDP are now planned. Alemtuzumab, ocrelizumab and daclizumab respresent monoclonal antibodies in advanced stages of clinical development for their use in RRMS patients. Attempts to study the safety and efficacy of alemtuzumab and B cell-depleting anti-CD20 antibodies, i.e. rituximab, ocrelizumab or ofatumumab, in CIDP patients are currently under way. We provide an overview of the mechanism of action and clinical data available on disease-modifying immunotherapy options for MS and CIDP. Enhanced understanding of the relative effects of therapies in these two disorders may aid rational treatment selection and the development of innovative treatment approaches in the future.

  10. Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: common and divergent current and future strategies.

    PubMed

    Melzer, N; Meuth, S G

    2014-03-01

    Multiple sclerosis (MS) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) represent chronic, autoimmune demyelinating disorders of the central and peripheral nervous system. Although both disorders share some fundamental pathogenic elements, treatments do not provide uniform effects across both disorders. We aim at providing an overview of current and future disease-modifying strategies in these disorders to demonstrate communalities and distinctions. Intravenous immunoglobulins (IVIG) have demonstrated short- and long-term beneficial effects in CIDP but are not effective in MS. Dimethyl fumarate (BG-12), teriflunomide and laquinimod are orally administered immunomodulatory drugs that are already approved or likely to be approved in the near future for the basic therapy of patients with relapsing-remitting MS (RRMS) due to positive results in Phase III clinical trials. However, clinical trials with these drugs in CIDP have not (yet) been initiated. Natalizumab and fingolimod are approved for the treatment of RRMS, and trials to evaluate their safety and efficacy in CIDP are now planned. Alemtuzumab, ocrelizumab and daclizumab respresent monoclonal antibodies in advanced stages of clinical development for their use in RRMS patients. Attempts to study the safety and efficacy of alemtuzumab and B cell-depleting anti-CD20 antibodies, i.e. rituximab, ocrelizumab or ofatumumab, in CIDP patients are currently under way. We provide an overview of the mechanism of action and clinical data available on disease-modifying immunotherapy options for MS and CIDP. Enhanced understanding of the relative effects of therapies in these two disorders may aid rational treatment selection and the development of innovative treatment approaches in the future. PMID:24032475

  11. The physiology of overwintering in a turtle that occupies multiple habitats, the common snapping turtle (Chelydra serpentina).

    PubMed

    Reese, Scott A; Jackson, Donald C; Ultsch, Gordon R

    2002-01-01

    Common snapping turtles, Chelydra serpentina (Linnaeus), were submerged in anoxic and normoxic water at 3 degrees C. Periodic blood samples were taken, and PO(2), PCO(2), pH, [Na(+)], [K(+)], [Cl(-)], total Ca, total Mg, [lactate], [glucose], hematocrit, and osmolality were measured; weight gain was determined; and plasma [HCO(3)(-)] was calculated. Submergence in normoxic water caused a decrease in PCO(2) from 10.8 to 6.9 mmHg after 125 d, partially compensating a slight increase in lactate and allowing the turtles to maintain a constant pH. Submergence in anoxic water caused a rapid increase in lactate from 1.8 to 168.1 mmol/L after 100 d. Associated with the increased lactate were decreases in pH from 8.057 to 7.132 and in [HCO(3)(-)] from 51.5 to 4.9 mmol/L and increases in total Ca from 2.0 to 36.6 mmol/L, in total Mg from 1.8 to 12.1 mmol/L, and in [K(+)] from 3.08 to 8.45 mmol/L. We suggest that C. serpentina is tolerant of anoxic submergence and therefore is able to exploit habitats unavailable to some other species in northern latitudes. PMID:12529844

  12. Predictive value of HLA-G and HLA-E in the prognosis of colorectal cancer patients.

    PubMed

    Guo, Zhang-Yan; Lv, Yong-Gang; Wang, Lei; Shi, Sheng-Jia; Yang, Fan; Zheng, Guo-Xu; Wen, Wei-Hong; Yang, An-Gang

    2015-01-01

    HLA-G and HLA-E are non-classical HLA Ib molecules. Recently, increasingly more reports have shown that HLA-G is highly expressed in different malignancies. In this article, we detected the expression levels of HLA-G and HLA-E in primary colorectal cancer patients. Our results showed that 70.6% and 65.7% of the colorectal cancer tissues had positive HLA-G or HLA-E expression, respectively, and that 46.1% positively expressed both molecules. We also analyzed the correlations between the expression levels of HLA-G, HLA-E or both combined and the clinical outcomes of the patients. Kaplan-Meier analysis results showed that the expression levels of HLA-G or HLA-E alone and the combined expression of both molecules were all statistically correlated with the overall survival of colorectal cancer patients. Cox multivariate analysis showed that only HLA-G expression can serve as independent factor for OS. Our results also showed that the expression of HLA-E was significantly correlated with tumor metastasis.

  13. Epstein-Barr virus BILF1 evolved to downregulate cell surface display of a wide range of HLA class I molecules through their cytoplasmic tail

    PubMed Central

    Griffin, Bryan D.; Gram, Anna M.; Mulder, Arend; Van Leeuwen, Daphne; Claas, Frans H. J.; Wang, Fred; Ressing, Maaike E.; Wiertz, Emmanuel

    2013-01-01

    Co-evolution of herpesviruses and their hosts has driven the development of both host antiviral mechanisms to detect and eliminate infected cells, and viral ploys to escape immune surveillance. Among the immune evasion strategies employed by the lymphocryptovirus (γ1-herpesvirus) EBV is the downregulation of surface HLA class I expression by the virally-encoded G-protein coupled receptor BILF1, thereby impeding presentation of viral antigens and cytotoxic T cell recognition of the infected cell. Here, we show EBV BILF1 to be expressed early in the viral lytic cycle. BILF1 targets a broad range of HLA class I molecules, including multiple HLA-A and -B types, and HLA-E. In contrast, HLA-C was only marginally affected. We advance the mechanistic understanding of the process by showing the cytoplasmic C-terminal tail of EBV BILF1 to be required for reducing surface HLA class I expression. Susceptibility to BILF1-mediated downregulation is in turn conferred by specific residues in the intracellular tail of the HLA class I heavy chain. Finally, we explore the evolution of BILF1 within the lymphocryptovirus genus. While the homolog of BILF1 encoded by the lymphocryptovirus infecting Old World rhesus primates shares the ability of EBV to downregulate cell surface HLA class I expression, this function is not possessed by New World marmoset lymphocryptovirus BILF1. This study therefore furthers our knowledge on the evolution of immunoevasive functions by the lymphocryptovirus genus of herpesviruses. PMID:23315076

  14. Efficacy of commonly used anthelmintics: first report of multiple drug resistance in gastrointestinal nematodes of sheep in Trinidad.

    PubMed

    George, N; Persad, K; Sagam, R; Offiah, V N; Adesiyun, A A; Harewood, W; Lambie, N; Basu, A K

    2011-12-29

    In Trinidad, small ruminant farms are semi-intensively managed under tropical conditions which support the development and survival of the infective stages of the helminths. Local farmers use anthelmintics to control gastrointestinal nematodes frequently. Frequent use of anthelmintics has the potential to select for populations of nematodes resistance to those chemicals. Hence, an attempt was made to study the efficacy of commonly used drugs on gastrointestinal nematodes of sheep. Three farms situated in different counties in Trinidad were selected. Sheep aged 6-15 months and not treated with anthelmintics for a minimum of six months previous and with faecal egg count (FEC)>150 eggs per gram were selected for study. They were allocated into 5 groups, each consisting 10 animals. The Group TA animals were treated once with albendazole (5mg/kg. b.wt.), group TF with fenbendazole (5mg/kg.b.wt.), group TI animals with ivermectin (200 μg/kg b.wt.), group TL with levamisol (7.5mg/kg b.wt.). The group NTC animals were not given any drug and served as control. The number of nematode eggs per gram of faeces from each animal was determined before treatment and at 14 days after treatment. The anthelmintic susceptibility to different drugs was detected by FECRT (in vivo) with EPG recorded at 14 day post-treatment. The data analysis using FECRT revealed that efficacy of albendazole (46-62%), fenbendazole (44-61%) and levamisol (53-81%) were reduced compared to ivermectin (95-97%). An attempt has also been made to find a suitable method for calculation of FECR (%).

  15. Identification of the HLA-DM/HLA-DR interface.

    PubMed

    Davies, Matthew N; Lamikanra, Abigail; Sansom, Clare E; Flower, Darren R; Moss, David S; Travers, Paul J

    2008-02-01

    Human leukocyte antigen (HLA)-DM is a critical participant in antigen presentation that catalyzes the dissociation of the Class II-associated Invariant chain-derived Peptide (CLIP) from the major histocompatibility complex (MHC) Class II molecules. There is competition amongst peptides for access to an MHC Class II groove and it has been hypothesised that DM functions as a 'peptide editor' that catalyzes the replacement of one peptide for another within the groove. It is established that the DM catalyst interacts directly with the MHC Class II but the precise location of the interface is unknown. Here, we combine previously described mutational data with molecular docking and energy minimisation simulations to identify a putative interaction site of >4000A2 which agrees with known point mutational data for both the DR and DM molecule. The docked structure is validated by comparison with experimental data and previously determined properties of protein-protein interfaces. A possible dissociation mechanism is suggested by the presence of an acidic cluster near the N terminus of the bound peptide. PMID:17870168

  16. A future with less HLA: potential clinical applications of HLA-universal cells.

    PubMed

    Figueiredo, C; Blasczyk, R

    2015-06-01

    The high variability of the human leukocyte antigen (HLA) remains a major obstacle to the application of allogeneic products in cell-based therapies. We have developed a strategy to decrease the immunogenicity of cell and tissues to improve their survival after allogeneic transplantation in the absence of immunosuppression. Using RNA interference technology, the expression of HLA class I and II was stably downregulated. HLA-silenced cells demonstrated to prevent a de novo and escape a pre-formed alloimmune response in vitro and in vivo. Also, they demonstrated to be capable of engraft and survive after allogeneic transplantation independently of the donor's and recipient's genetic background. The generation of HLA-universal cells has may open new horizons in the field of regenerative medicine. Some of the potential clinical applications of HLA universal cells will be discussed in this review.

  17. A future with less HLA: potential clinical applications of HLA-universal cells.

    PubMed

    Figueiredo, C; Blasczyk, R

    2015-06-01

    The high variability of the human leukocyte antigen (HLA) remains a major obstacle to the application of allogeneic products in cell-based therapies. We have developed a strategy to decrease the immunogenicity of cell and tissues to improve their survival after allogeneic transplantation in the absence of immunosuppression. Using RNA interference technology, the expression of HLA class I and II was stably downregulated. HLA-silenced cells demonstrated to prevent a de novo and escape a pre-formed alloimmune response in vitro and in vivo. Also, they demonstrated to be capable of engraft and survive after allogeneic transplantation independently of the donor's and recipient's genetic background. The generation of HLA-universal cells has may open new horizons in the field of regenerative medicine. Some of the potential clinical applications of HLA universal cells will be discussed in this review. PMID:25864470

  18. [Polymorphism of human HLA-DRB1 leukocyte antigen alleles and its association to juvenile rheumatoid arthritis in a sample of Colombian mestizo children].

    PubMed

    Garavito, Gloria; Malagón, Clara; Ramírez, Luis A; De La Cruz, Oscar F; Uribe, Oscar; Navarro, Edgar; Iglesias, Antonio; Martínez, Paz; Jaraquemada, Dolores; Egea, Eduardo

    2003-09-01

    Oligotypes of the human leukocyte antigen HLA Class II, DRB1 alleles were characterized at the molecular level in a group of Colombian children suffering juvenile rheumatoid arthritis (JRA). The distribution of these alleles was examined in a group of Colombian mestizo children (genetic admixture of Amerindians, Europeans and Africans) suffering from clinically distinct JRA subsets in order to detect HLA allele frequency differences in patients with different JRA subsets. A group of 65 patients with JRA and 65 controls were characterized for the subtypes of the HLA-DRB1 alleles using polymerase chain reaction with sequence-specific oligonucleotide probes (PCR-SSOP). The oligotyping protocol recommended by the 12th International Histocompatibility Workshop held in St. Malo, Paris, in 1996, was used. Subtype HLA-DRB1*1104 was the allele most strongly associated with susceptibility to JRA (Fisher's p = 0.013, odds ratio (OR) = 16.79, etiologic fraction (EF) = 0.93). HLA-DRB1*1602 was also associated with susceptibility to a lesser degree (Fisher's p = 0.016, OR = 8.98, EF = 0.88). HLA-DRB1 alleles participating in JRA protection were HLA-DRB1*1501 (preventive fraction (PF) = 0.466, p = 0.005) and HLA DRB1*1402 (PF = 0.49, p = 0.009). The relationship between some HLA-DRB1 alleles and clinical features was also compared. The presence of rheumatic factor was associated with the alleles HLA-DRB1*0407 (p = 0.05, OR = 11.2, EF = 0.45) and HLA-DRB1*1302 (p = 0.02, OR = 22.8, EF = 0.63). There was also an association between HLA-DRB1*0701 (p = 0.001, OR = 58, EF = 0.73) with expressing ANA +. We found that in the oligoarticular subset, the allele HLA-DRB1*1104 (p = 0.0034, OR = 41.53, EF = 0.97) was the one expressed most commonly. In the poliarticular group, the alleles most frequently expressed were HLA-DRB1*0404 (Fisher's p = 0.012, OR = 8.75, EF = 0.88). In patients with systemic JRA, the HLA-DRB1*1602 allele (p = 0.005, OR = 21.33, EF = 0.95) was most frequent. These

  19. Targeting agr- and agr-Like Quorum Sensing Systems for Development of Common Therapeutics to Treat Multiple Gram-Positive Bacterial Infections

    PubMed Central

    Gray, Brian; Hall, Pamela; Gresham, Hattie

    2013-01-01

    Invasive infection by the Gram-positive pathogen Staphylococcus aureus is controlled by a four gene operon, agr that encodes a quorum sensing system for the regulation of virulence. While agr has been well studied in S. aureus, the contribution of agr homologues and analogues in other Gram-positive pathogens is just beginning to be understood. Intriguingly, other significant human pathogens, including Clostridium perfringens, Listeria monocytogenes, and Enterococcus faecalis contain agr or analogues linked to virulence. Moreover, other significant human Gram-positive pathogens use peptide based quorum sensing systems to establish or maintain infection. The potential for commonality in aspects of these signaling systems across different species raises the prospect of identifying therapeutics that could target multiple pathogens. Here, we review the status of research into these agr homologues, analogues, and other peptide based quorum sensing systems in Gram-positive pathogens as well as the potential for identifying common pathways and signaling mechanisms for therapeutic discovery. PMID:23598501

  20. Examination of HLA-DR4 as a severity marker for rheumatoid arthritis in Greek patients.

    PubMed Central

    Boki, K A; Drosos, A A; Tzioufas, A G; Lanchbury, J S; Panayi, G S; Moutsopoulos, H M

    1993-01-01

    OBJECTIVES--Previous reports have shown that HLA-DR4 may be a severity marker for rheumatoid arthritis (RA) in patients of northern European origin. The aim of the present study was to investigate this relation in Greek patients with RA, as RA in Greece differs from the RA described previously on clinical, serological, and immunological grounds. METHODS--Eighty four patients were studied in whom HLA-DR typing was performed by restriction fragment length polymorphism and the subtypes of HLA-DR4 were determined by the polymerase chain reaction. The absence or presence of HLA-DR4 and its subtypes was correlated with the clinical and serological characteristics of the patients and with the side effects due to disease modifying drugs. RESULTS--Twenty one of the 84 (25%) patients with RA were DR4+. There was no difference between the DR4+ and DR4-patients with respect to duration of disease, severity of arthritis, functional grade, and joint erosion score. The DR4+ group were more likely to have side effects due to disease modifying drugs (43%) than DR4- patients (36%), but this difference was not statistically significant. DR4-patients had more extra-articular manifestations, including Sjögren's syndrome (47 v 19%). Analysis of the DR4 subtypes showed that Dw15 was the most common variant (9/21 patients; 43%). There was no statistical difference in the clinical manifestations among patients with different DR4 subtypes. The same was also true when the clinical picture was correlated with the 'shared RA epitope' (QKRAA/QRRAA/RRRAA), which is common to all HLA-DRB1 alleles positively associated with RA. CONCLUSIONS--These results suggest that HLA-DR4 is not a severity marker in Greek patients with RA and further indicate differences in the clinical expression of RA in Greece. PMID:8102226

  1. Distribution of HLA-B alleles in Mexican Amerindian populations.

    PubMed

    Vargas-Alarcón, Gilberto; Hernández-Pacheco, Guadalupe; Zuñiga, Joaquín; Rodríguez-Pérez, José Manuel; Pérez-Hernández, Nonanzit; Rangel, Carlos; Villarreal-Garza, Cynthia; Martínez-Laso, Jorge; Granados, Julio; Arnaiz-Villena, Antonio

    2003-02-01

    In the present study we analyzed by PCR-SSO technique the HLA-B gene frequencies in 281 healthy individuals from four Mexican Amerindian populations (66 Mayos, 90 Mazatecans, 72 Nahuas and 53 Teenek). The most frequent alleles in all studied populations were HLA-B35, HLA-B39, and HLA-B40; however, some differences were observed between populations. The HLA-B35 allele was the most frequent in three of the four populations studied (Mayos, Nahuas and Teenek), whereas in Mazatecans the most frequent allele was HLA-B39. HLA-B40 presented frequencies higher than 10% in all groups. On the other hand, only Mayos presented an HLA-B51 gene frequency higher than 10%. When comparisons were made, important differences between groups were observed. The Teenek group presented an increased frequency of HLA-B35 when compared to Mazatecans and the HLA-B52 allele was increased in Nahuas and Teenek when compared to Mayos. An increased frequency of HLA-B39 was observed in Mazatecans when compared to Nahuas, Mayos and Teenek. Also, an increased frequency of HLA-B51 was observed in Mayos when compared to Mazatecans and Nahuas. These data corroborate the restricted polymorphism of HLA-B alleles and the high frequency of HLA-B35, HLA-B39 and HLA-B40 alleles in autochthonous American populations. In spite of the restriction in this polymorphism, differences in frequencies of HLA-B alleles could be helpful in distinguishing each of these populations.

  2. Identification of a crucial energetic footprint on the alpha1 helix of human histocompatibility leukocyte antigen (HLA)-A2 that provides functional interactions for recognition by tax peptide/HLA-A2-specific T cell receptors.

    PubMed

    Baker, B M; Turner, R V; Gagnon, S J; Wiley, D C; Biddison, W E

    2001-03-01

    Structural studies have shown that class I major histocompatibility complex (MHC)-restricted peptide-specific T cell receptor (TCR)-alpha/betas make multiple contacts with the alpha1 and alpha2 helices of the MHC, but it is unclear which or how many of these interactions contribute to functional binding. We have addressed this question by performing single amino acid mutagenesis of the 15 TCR contact sites on the human histocompatibility leukocyte antigen (HLA)-A2 molecule recognized by the A6 TCR specific for the Tax peptide presented by HLA-A2. The results demonstrate that mutagenesis of only three amino acids (R65, K66, and A69) that are clustered on the alpha1 helix affected T cell recognition of the Tax/HLA-A2 complex. At least one of these three mutants affected T cell recognition by every member of a large panel of Tax/HLA-A2-specific T cell lines. Biacore measurements showed that these three HLA-A2 mutations also altered A6 TCR binding kinetics, reducing binding affinity. These results show that for Tax/HLA-A2-specific TCRs, there is a location on the central portion of the alpha1 helix that provides interactions crucial to their function with the MHC molecule. PMID:11238586

  3. Contribution of a Non-classical HLA Gene, HLA-DOA, to the Risk of Rheumatoid Arthritis.

    PubMed

    Okada, Yukinori; Suzuki, Akari; Ikari, Katsunori; Terao, Chikashi; Kochi, Yuta; Ohmura, Koichiro; Higasa, Koichiro; Akiyama, Masato; Ashikawa, Kyota; Kanai, Masahiro; Hirata, Jun; Suita, Naomasa; Teo, Yik-Ying; Xu, Huji; Bae, Sang-Cheol; Takahashi, Atsushi; Momozawa, Yukihide; Matsuda, Koichi; Momohara, Shigeki; Taniguchi, Atsuo; Yamada, Ryo; Mimori, Tsuneyo; Kubo, Michiaki; Brown, Matthew A; Raychaudhuri, Soumya; Matsuda, Fumihiko; Yamanaka, Hisashi; Kamatani, Yoichiro; Yamamoto, Kazuhiko

    2016-08-01

    Despite the progress in human leukocyte antigen (HLA) causal variant mapping, independent localization of major histocompatibility complex (MHC) risk from classical HLA genes is challenging. Here, we conducted a large-scale MHC fine-mapping analysis of rheumatoid arthritis (RA) in a Japanese population (6,244 RA cases and 23,731 controls) population by using HLA imputation, followed by a multi-ethnic validation study including east Asian and European populations (n = 7,097 and 23,149, respectively). Our study identified an independent risk of a synonymous mutation at HLA-DOA, a non-classical HLA gene, on anti-citrullinated protein autoantibody (ACPA)-positive RA risk (p = 1.4 × 10(-9)), which demonstrated a cis-expression quantitative trait loci (cis-eQTL) effect on HLA-DOA expression. Trans-ethnic comparison revealed different linkage disequilibrium (LD) patterns in HLA-DOA and HLA-DRB1, explaining the observed HLA-DOA variant risk heterogeneity among ethnicities, which was most evident in the Japanese population. Although previous HLA fine-mapping studies have identified amino acid polymorphisms of the classical HLA genes as driving genetic susceptibility to disease, our study additionally identifies the dosage contribution of a non-classical HLA gene to disease etiology. Our study contributes to the understanding of HLA immunology in human diseases and suggests the value of incorporating additional ancestry in MHC fine-mapping. PMID:27486778

  4. HLA-B*51 and Behçet Disease.

    PubMed

    Gul, Ahmet; Ohno, Shigeaki

    2012-02-01

    Behçet disease (BD) is a multisystem inflammatory disorder of unknown etiology. BD has a multifactorial pathogenesis, and genetics plays a critical role in the development of the disease. Association of HLA-B5/B*51 has been recognized as the strongest genetic susceptibility factor for BD discovered so far. Pathogenic role of HLA-B*51 in BD has yet to be clarified, and available data suggest that there is possibly no single mechanism associated with HLA-B*51. HLA-B*51 may accomplish its effects as a combination of different HLA class I-associated functions and/or structural properties of HLA-B*51 heavy chain. There is no evidence supporting the use of HLA-B*51 as a diagnostic or prognostic marker for BD, and more clinical data must be collected in addition to basic immunological studies to exploit the potential of HLA-B*51 as a biomarker for BD management.

  5. A gene feature enumeration approach for describing HLA allele polymorphism.

    PubMed

    Mack, Steven J

    2015-12-01

    HLA genotyping via next generation sequencing (NGS) poses challenges for the use of HLA allele names to analyze and discuss sequence polymorphism. NGS will identify many new synonymous and non-coding HLA sequence variants. Allele names identify the types of nucleotide polymorphism that define an allele (non-synonymous, synonymous and non-coding changes), but do not describe how polymorphism is distributed among the individual features (the flanking untranslated regions, exons and introns) of a gene. Further, HLA alleles cannot be named in the absence of antigen-recognition domain (ARD) encoding exons. Here, a system for describing HLA polymorphism in terms of HLA gene features (GFs) is proposed. This system enumerates the unique nucleotide sequences for each GF in an HLA gene, and records these in a GF enumeration notation that allows both more granular dissection of allele-level HLA polymorphism and the discussion and analysis of GFs in the absence of ARD-encoding exon sequences.

  6. Close genetic linkage between HLA and renal glycosuria.

    PubMed

    De Marchi, S; Cecchin, E; Basile, A; Proto, G; Donadon, W; Jengo, A; Schinella, D; Jus, A; Villalta, D; De Paoli, P

    1984-01-01

    Renal glycosuria is an inherited disorder of renal tubule function in which significant amounts of glucose are excreted in the urine in the simultaneous presence of normal blood glucose levels. Renal glucose titration analyses and HLA genotypes were performed in 5 unrelated affected families with a total of 25 patients and 40 healthy relatives. In each family the gene responsible for renal glycosuria segregates with the HLA complex suggesting a close genetic linkage. 2 cases carry intra-HLA recombinant haplotypes; in these subjects our findings indicate that the abnormal gene is closer to the HLA-A locus than the HLA-B locus. No HLA-A, HLA-B or HLA-C specific antigen is selectively increased among the 5 unrelated families affected with renal glycosuria.

  7. Hereditary angioneurotic edema and HLA types in two Danish families.

    PubMed

    Eggert, J; Zachariae, H; Svejgaard, E; Svejgaard, A; Kissmeyer-Nielsen, F

    1982-01-01

    HLA types were determined in 19 patients and 9 healthy members of 2 Danish families with hereditary angioneurotic edema. The study revealed no connections between hereditary angioneurotic edema and the HLA system. PMID:7165360

  8. HLA typing from RNA-Seq sequence reads.

    PubMed

    Boegel, Sebastian; Löwer, Martin; Schäfer, Michael; Bukur, Thomas; de Graaf, Jos; Boisguérin, Valesca; Türeci, Ozlem; Diken, Mustafa; Castle, John C; Sahin, Ugur

    2012-01-01

    We present a method, seq2HLA, for obtaining an individual's human leukocyte antigen (HLA) class I and II type and expression using standard next generation sequencing RNA-Seq data. RNA-Seq reads are mapped against a reference database of HLA alleles, and HLA type, confidence score and locus-specific expression level are determined. We successfully applied seq2HLA to 50 individuals included in the HapMap project, yielding 100% specificity and 94% sensitivity at a P-value of 0.1 for two-digit HLA types. We determined HLA type and expression for previously un-typed Illumina Body Map tissues and a cohort of Korean patients with lung cancer. Because the algorithm uses standard RNA-Seq reads and requires no change to laboratory protocols, it can be used for both existing datasets and future studies, thus adding a new dimension for HLA typing and biomarker studies. PMID:23259685

  9. Advantage of rare HLA supertype in HIV disease progression.

    PubMed

    Trachtenberg, Elizabeth; Korber, Bette; Sollars, Cristina; Kepler, Thomas B; Hraber, Peter T; Hayes, Elizabeth; Funkhouser, Robert; Fugate, Michael; Theiler, James; Hsu, Yen S; Kunstman, Kevin; Wu, Samuel; Phair, John; Erlich, Henry; Wolinsky, Steven

    2003-07-01

    The highly polymorphic human leukocyte antigen (HLA) class I molecules help to determine the specificity and repertoire of the immune response. The great diversity of these antigen-binding molecules confers differential advantages in responding to pathogens, but presents a major obstacle to distinguishing HLA allele-specific effects. HLA class I supertypes provide a functional classification for the many different HLA alleles that overlap in their peptide-binding specificities. We analyzed the association of these discrete HLA supertypes with HIV disease progression rates in a population of HIV-infected men. We found that HLA supertypes alone and in combination conferred a strong differential advantage in responding to HIV infection, independent of the contribution of single HLA alleles that associate with progression of the disease. The correlation of the frequency of the HLA supertypes with viral load suggests that HIV adapts to the most frequent alleles in the population, providing a selective advantage for those individuals who express rare alleles.

  10. Effect of HLA-B and HLA-DR genes on susceptibility to and severity of spondyloarthropathies in Mexican patients

    PubMed Central

    Vargas-Alarcon, G; Londono, J; Hernandez-Pacheco, G; Pacheco-Tena, C; Castillo, E; Cardiel, M; Granados, J; Burgos-Vargas, R

    2002-01-01

    Objective: To investigate the role of HLA-B and HLA-DR genes as contributors to genetic susceptibility and clinical expression of the spondyloarthropathies (SpA) in the Mexican population. Methods: The study included 172 patients with SpA (undifferentiated SpA 83, ankylosing spondylitis (AS) 64, and reactive arthritis 25) and 99 healthy controls. The HLA-B and HLA-DR alleles were detected by the polymerase chain reaction with sequence-specific primers technique. Patient assessment included demographic data, diagnostic categories, and disease patterns. Statistical methods included the Mantel-Haenzel χ2 test, Fisher's exact test, and Woolf method for odds ratio (OR). Differences of continuous variables between HLA allele groups were calculated by Student's t test. Results: Increased frequencies of HLA-B27 (pCh10-3, OR=28.7), HLA-DR1 (pC=0.045, OR=2.77), and HLA-B15 (p=0.034, pC=NS, OR=2.04) alleles in the whole group were found. HLA-B27 strength of association (OR) was 41.4 in AS; 20.9 in undifferentiated SpA; 27.2 in reactive arthritis. HLA-DR1 and HLA-B15 were increased in undifferentiated SpA (pC=0.045, OR=2.98 and p=0.004, pC=NS, OR=2.75). By analysing 58 HLA-B27 negative patients it was found that HLA-B15 and HLA-DR1 associations with SpA were independent of HLA-B27; increased frequencies of HLA-B15 were found in the whole SpA group and in patients with undifferentiated SpA (pC=0.03, OR=3.09 and pCh0.01, OR=3.77) and of HLA-DR1 in the latter (p=0.04, pC=NS, OR=3.15). HLA-B27 positive patients were younger than HLA-B27 negative patients at onset (p=0.03), but HLA-DR1 positive patients were older than HLA-DR1 negative patients (p=0.03). Bath indices for disease activity and functioning were higher in HLA-B27 positive patients (p=0.006 and p=0.004 v HLA-B27 negative patients). In contrast, neither HLA-DR1 nor HLA-B15 influenced these indices. Conclusion: Apart from HLA-B27, there is a significant association of HLA-DR1 and HLA-B15 with SpA in Mexicans which is

  11. Extended HLA-D region haplotype associated with celiac disease

    SciTech Connect

    Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

    1988-01-01

    Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II ..beta..-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this ..beta..-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP ..beta..-chain. This celiac disease-associated HLA-DP ..beta..-chain gene was flanked by HLA-DP ..cap alpha..-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP..cap alpha..-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP ..cap alpha..- and ..beta..-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.

  12. Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders.

    PubMed

    Morgan, Ling Z; Rollins, Brandi; Sequeira, Adolfo; Byerley, William; DeLisi, Lynn E; Schatzberg, Alan F; Barchas, Jack D; Myers, Richard M; Watson, Stanley J; Akil, Huda; Bunney, William E; Vawter, Marquis P

    2016-03-07

    Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a

  13. Quantitative Trait Locus and Brain Expression of HLA-DPA1 Offers Evidence of Shared Immune Alterations in Psychiatric Disorders.

    PubMed

    Morgan, Ling Z; Rollins, Brandi; Sequeira, Adolfo; Byerley, William; DeLisi, Lynn E; Schatzberg, Alan F; Barchas, Jack D; Myers, Richard M; Watson, Stanley J; Akil, Huda; Bunney, William E; Vawter, Marquis P

    2016-01-01

    Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a

  14. A limit to the divergent allele advantage model supported by variable pathogen recognition across HLA-DRB1 allele lineages.

    PubMed

    Lau, Q; Yasukochi, Y; Satta, Y

    2015-11-01

    Genetic diversity in human leukocyte antigen (HLA) molecules is thought to have arisen from the co-evolution between host and pathogen and maintained by balancing selection. Heterozygote advantage is a common proposed scenario for maintaining high levels of diversity in HLA genes, and extending from this, the divergent allele advantage (DAA) model suggests that individuals with more divergent HLA alleles bind and recognize a wider array of antigens. While the DAA model seems biologically suitable for driving HLA diversity, there is likely an upper threshold to the amount of sequence divergence. We used peptide-binding and pathogen-recognition capacity of DRB1 alleles as a model to further explore the DAA model; within the DRB1 locus, we examined binding predictions based on two distinct phylogenetic groups (denoted group A and B) previously identified based on non-peptide-binding region (PBR) nucleotide sequences. Predictions in this study support that group A allele and group B allele lineages have contrasting binding/recognition capacity, with only the latter supporting the DAA model. Furthermore, computer simulations revealed an inconsistency in the DAA model alone with observed extent of polymorphisms, supporting that the DAA model could only work effectively in combination with other mechanisms. Overall, we support that the mechanisms driving HLA diversity are non-exclusive. By investigating the relationships among HLA alleles, and pathogens recognized, we can provide further insights into the mechanisms on how humans have adapted to infectious diseases over time.

  15. Protective immunity provided by HLA-A2 epitopes for fusion and hemagglutinin proteins of measles virus

    SciTech Connect

    Oh, Sang Kon . E-mail: sangkono@baylorhealth.edu; Stegman, Brian; Pendleton, C. David; Ota, Martin O.; Pan, C.-H.; Griffin, Diane E.; Burke, Donald S.; Berzofsky, Jay A. . E-mail: berzofsk@helix.nih.gov

    2006-09-01

    Natural infection and vaccination with a live-attenuated measles virus (MV) induce CD8{sup +} T-cell-mediated immune responses that may play a central role in controlling MV infection. In this study, we show that newly identified human HLA-A2 epitopes from MV hemagglutinin (H) and fusion (F) proteins induced protective immunity in HLA-A2 transgenic mice challenged with recombinant vaccinia viruses expressing F or H protein. HLA-A2 epitopes were predicted and synthesized. Five and four peptides from H and F, respectively, bound to HLA-A2 molecules in a T2-binding assay, and four from H and two from F could induce peptide-specific CD8{sup +} T cell responses in HLA-A2 transgenic mice. Further experiments proved that three peptides from H (H9-567, H10-250, and H10-516) and one from F protein (F9-57) were endogenously processed and presented on HLA-A2 molecules. All peptides tested in this study are common to 5 different strains of MV including Edmonston. In both A2K{sup b} and HHD-2 mice, the identified peptide epitopes induced protective immunity against recombinant vaccinia viruses expressing H or F. Because F and H proteins induce neutralizing antibodies, they are major components of new vaccine strategies, and therefore data from this study will contribute to the development of new vaccines against MV infection.

  16. Peptides presented by HLA-DR molecules in synovia of patients with rheumatoid arthritis or antibiotic-refractory Lyme arthritis.

    PubMed

    Seward, Robert J; Drouin, Elise E; Steere, Allen C; Costello, Catherine E

    2011-03-01

    Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220-464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions.

  17. Peptides Presented by HLA-DR Molecules in Synovia of Patients with Rheumatoid Arthritis or Antibiotic-Refractory Lyme Arthritis*

    PubMed Central

    Seward, Robert J.; Drouin, Elise E.; Steere, Allen C.; Costello, Catherine E.

    2011-01-01

    Disease-associated HLA-DR molecules, which may present autoantigens, constitute the greatest genetic risk factor for rheumatoid arthritis (RA) and antibiotic-refractory Lyme arthritis (LA). The peptides presented by HLA-DR molecules in synovia have not previously been defined. Using tandem mass spectrometry, rigorous database searches, and manual spectral interpretation, we identified 1,427 HLA-DR-presented peptides (220–464 per patient) from the synovia of four patients, two diagnosed with RA and two diagnosed with LA. The peptides were derived from 166 source proteins, including a wide range of intracellular and plasma proteins. A few epitopes were found only in RA or LA patients. However, two patients with different diseases who had the same HLA allele had the largest number of epitopes in common. In one RA patient, peptides were identified as originating from source proteins that have been reported to undergo citrullination under other circumstances, yet neither this post-translational modification nor anti-cyclic citrullinated peptide antibodies were detected. Instead, peptides with the post-translational modification of S-cysteinylation were identified. We conclude that a wide range of proteins enter the HLA-DR pathway of antigen-presenting cells in the patients' synovial tissue, and their HLA-DR genotype, not the disease type, appears to be the primary determinant of their HLA-DR-peptide repertoire. New insights into the naturally presented HLA-DR epitope repertoire in target tissues may allow the identification of pathogenic T cell epitopes, and this could lead to innovative therapeutic interventions. PMID:21081667

  18. Production of human anti-HLA monoclonal antibodies

    SciTech Connect

    Walker, M.C.; Mercier, F.; Roger, J.; Varin, M.

    1986-03-01

    Only 40% of the several hundred anti-HLA murine monoclonal antibodies (MAbs) that have been made detect HLA-A,B,C or DR specificities previously defined by human alloantisera, the range of recognized specificities is very narrow, and few of the MAbs have proven useful as tissue typing reagents. In hopes of obtaining HLA typing reagents, the authors are developing a protocol for the production of human anti-HLA MAbs from HLA-antigen (Ag) immunized peripheral blood B cells of volunteering renal patients, immunized to one or more HLA Ags through therapeutic blood transfusions. A simple enrichment of the donor B cells has not been sufficient for anti-HLA MAb production, the authors are currently delineating the conditions necessary for increasing the number of HLA-specific donor B cells by in vitro stimulation with cells expressing the HLA Ag to which the B cell donor is immunized. For the production of MAbs, the stimulated B cells are transformed with Epstein-Barr virus and subsequently fused with KR-4 lymphoblastoid cells. Hybridomas are selected by HAT and Ouabain. Supernatants are screened for anti-HLA activity against lymphocyte targets expressing the original immunizing HLA Ag by complement mediated /sup 51/Cr release assay. Antibody specificity is determined by the complement-dependent microcytotoxicity test used for HLA typing.

  19. Maternal anti-HLA class I antibodies are associated with reduced birth weight in thrombocytopenic neonates.

    PubMed

    Dahl, J; Husebekk, A; Acharya, G; Flo, K; Stuge, T B; Skogen, B; Straume, B; Tiller, H

    2016-02-01

    In this comparative cross-sectional study, possible associations between maternal anti-HLA class I antibodies and birth weight in neonatal thrombocytopenia are explored. Although commonly detected in pregnancies and generally regarded as harmless, it has been suggested that such antibodies might be associated with fetal and neonatal alloimmune thrombocytopenia (FNAIT). As a link between FNAIT due to human platelet antigen 1a-specific antibodies and reduced birth weight in boys has previously been demonstrated, we wanted to explore whether maternal anti-HLA class I antibodies might also affect birth weight. To examine this, suspected cases of FNAIT referred to the Norwegian National Unit for Platelet Immunology during the period 1998-2009 were identified. Pregnancies where the only finding was maternal anti-HLA class I antibodies were included. An unselected group of pregnant women participating in a prospective study investigating maternal-fetal hemodynamics at the University Hospital North Norway during the years 2006-2010 served as controls. Twenty-nine percent of controls had anti-HLA class I antibodies. The thrombocytopenic neonates had a significantly lower adjusted birth weight (linear regression, P=0.036) and significantly higher odds of being small for gestational age (OR=6.72, P<0.001) compared with controls. Increasing anti-HLA class I antibody levels in the mother were significantly associated with lower birth weight and placental weight among thrombocytopenic neonates, but not among controls. These results indicate that maternal anti-HLA class I antibodies in thrombocytopenic neonates are associated with reduced fetal growth. Further studies are needed to test if placental function is affected.

  20. Cloning and Sequencing the First HLA Gene

    PubMed Central

    Jordan, Bertrand R.

    2010-01-01

    This Perspectives article recounts the isolation and sequencing of the first human histocompatibility gene (HLA) in 1980–1981. At the time, general knowledge of the molecules of the immune system was already fairly extensive, and gene rearrangements in the immunoglobulin complex (discovered in 1976) had generated much excitement: HLA was quite obviously the next frontier. The author was able to use a homologous murine H-2 cDNA to identify putative human HLA genomic clones in a λ-phage library and thus to isolate and sequence the first human histocompatibility gene. This personal account relates the steps that led to this result, describes the highly competitive international environment, and highlights the role of location, connections, and sheer luck in such an achievement. It also puts this work in perspective with a short description of the current knowledge of histocompatibility genes and, finally, presents some reflections on the meaning of “discovery.” PMID:20457890

  1. HLA and autoimmune endocrine disease 1985.

    PubMed

    Farid, N R; Thompson, C

    1986-02-01

    We typed patient groups with type I diabetes (n = 78), Graves' disease (n = 81), goitrous autoimmune (n = 52), "silent" (n = 18) and postpartum thyroiditis (n = 15) for human leucocyte antigens (HLA) A, B, C, DR and DQ. The results were compared to those obtained from 256 healthy controls typed for HLA-A, -B, -C and 140 typed for -DR. All these 140 controls were genotyped. Previously described associations of DR3 (OR (odds ratio) = 2.68, p less than 0.005) and DR4 (OR = 3.26, p less than 0.0001) in type I diabetes is confirmed. In this series, however, HLA-DR3/DR4 heterozygotes were apparently at no greater risk for type I diabetes than DR3 or DR4 homozygotes. The relative risk conferred by DR3/DR4 heterozygotes (6.48) was less than that for DR3 homozygosity (2.8), suggesting a recessive major histocompatibility complex-related susceptibility to type I diabetes. Graves' disease was associated with DR3 (OR = 3.02, p less than 0.0005); the increased frequency of DR3 homozygotes in this series is consistent with recessive HLA-linked susceptibility to Graves' disease proposed on the basis of family data. Hashimoto's thyroiditis, on the other hand, was associated with HLA-DR4 (OR = 3.08, p less than 0.0001), the latter finding confirming our earlier report on 21 patients. The increase of HLA-DR4 in both post-partum and silent thyroiditis suggests that these conditions are immunogenetically related, and may well represent variants of chronic autoimmune thyroiditis.

  2. HLA-A*02:07 Is a Protective Allele for EBV Negative and a Susceptibility Allele for EBV Positive Classical Hodgkin Lymphoma in China

    PubMed Central

    Huang, Xin; Hepkema, Bouke; Nolte, Ilja; Kushekhar, Kushi; Jongsma, Theo; Veenstra, Rianne; Poppema, Sibrand; Gao, Zifen; Visser, Lydia; Diepstra, Arjan; van den Berg, Anke

    2012-01-01

    HLA-A2 protects from EBV+ classical Hodgkin lymphoma (cHL) in Western Europe, but it is unknown whether this protective effect also exists in the Chinese population. We investigated the association of HLA-A2 and specific common and well documented HLA-A2 subtypes with EBV stratified cHL patients (n = 161) from the northern part of China. Quantitative-PCR and sequence-based subtyping was performed to identify HLA-A2 positive samples and their subtypes. 67 (42%) of the cHL patients were EBV+. There were no significant differences in percentages of HLA-A2 positivity between cHL and controls (65% vs 66%) and between EBV+ and EBV− cHL patients (70% vs 61%). The frequency distribution of HLA-A2 subtypes was significantly different between EBV stratified cHL subgroups and controls. This difference was most striking for the HLA-A*02:07 type with a frequency of 38% in EBV+ cHL, 8% in EBV− cHL and 20% in controls. Significant differences were also observed for the HLA-A*02:07, HLA-A2 (non-02:07) and the A2-negative typings between EBV+ cHL vs controls (p = 0.028), EBV− cHL vs controls (p = 0.045) and EBV+ vs EBV− cHL cases (p = 2×10−5). In conclusion, HLA-A*02:07 is a predisposing allele for EBV+ cHL and a protective allele for EBV− cHL in the northern Chinese population. PMID:22355400

  3. [HLA antigens in juvenile rheumatoid arthritis].

    PubMed

    Rumba, I V; Sochnev, A M; Kukaĭne, E M; Burshteĭn, A M; Benevolenskaia, L I

    1990-01-01

    Antigens of I class HLA system (locus A and B) were investigated in 67 patients of Latvian nationality suffering from juvenile rheumatoid arthritis (JRA). Associations of HLA antigens with juvenile rheumatoid arthritis partially coincided with the ones revealed earlier. Typing established an increased incidence of antigen B27 (p less than 0.01) and gaplotype A2, B40 (p less than 0.01). Antigen B15 possessed a protective action with respect to JRA. Interlocus combinations demonstrated a closer association with the disease than a single antigen. The authors also revealed markers of various clinico-anatomical variants of JRA.

  4. Recognition of the immunodominant myelin basic protein peptide by autoantibodies and HLA-DR2-restricted T cell clones from multiple sclerosis patients. Identity of key contact residues in the B-cell and T-cell epitopes.

    PubMed Central

    Wucherpfennig, K W; Catz, I; Hausmann, S; Strominger, J L; Steinman, L; Warren, K G

    1997-01-01

    Myelin basic protein (MBP) may be an important autoantigen in multiple sclerosis (MS), with the MBP(82-100) region being immunodominant for T cells and autoantibodies. The structural requirements for autoantibody recognition were compared to those previously defined for MBP-specific T cell clones. MBP autoantibodies were affinity-purified from central nervous system lesions of 11/12 postmortem cases studied. The MBP(83-97) peptide was immunodominant in all 11 cases since it inhibited autoantibody binding to MBP > 95%. Residues contributing to autoantibody binding were located in a 10-amino acid segment (V86-T95) that also contained the MHC/T cell receptor contact residues of the T cell epitope. In the epitope center, the same residues were important for antibody binding and T cell recognition. Based on the antibody-binding motif, microbial peptides were identified that were bound by purified autoantibodies. Autoantibody binding of microbial peptides required sequence identity at four or five contiguous residues in the epitope center. Microbial peptides previously found to activate T cell clones did not have such obvious homology to MBP since sequence identity was not required at MHC contacts. The similar fine specificity of B cells and T cells may be useful for tolerance induction to MBP in MS. PMID:9276728

  5. Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

    PubMed

    Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C; Otto, Markus; Tumani, Hayrettin

    2015-01-01

    Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs. PMID:26263977

  6. Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

    PubMed

    Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C; Otto, Markus; Tumani, Hayrettin

    2015-07-31

    Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

  7. Familial spontaneous pneumothorax in three generations and its HLA.

    PubMed

    Yamada, Akitoshi; Takeda, Yoshitaka; Hayashi, Satoru; Shimizu, Kazuta

    2003-09-01

    We experienced a case of familial spontaneous pneumothorax in three generations. Six of 13 family members had episodes of spontaneous pneumothorax. It is well established that there are some diseases associated with human leukocyte antigen (HLA). We performed HLA phenotyping for HLA of A, B and C. In our study, we detected the HLA haplotype A2, B61 in three of 4 who had episodes of spontaneous pneumothorax. The HLA haplotype A2, B70 were also detected in three of 4 who had episodes. This suggests that familial spontaneous pneumothorax might have hereditary factors.

  8. Specific HLA genotypes confer susceptibility to acute necrotizing encephalopathy.

    PubMed

    Hoshino, A; Saitoh, M; Miyagawa, T; Kubota, M; Takanashi, J-I; Miyamoto, A; Tokunaga, K; Oka, A; Mizuguchi, M

    2016-09-01

    Acute necrotizing encephalopathy (ANE) is a rare and severe syndrome of acute encephalopathy triggered by viral infections. Cytokine storm is considered as the main pathogenetic mechanism of ANE. ANE is prevalent in East Asia, suggesting the association of host genetic factors. To elucidate the genetic background of Japanese ANE, we examined genotypes of human leukocyte antigen (HLA)-A, C, B, DRB1, DQB1 and DPB1 in 31 patients. Significant positive association was observed in both the allele frequency and positivity of DRB1*09:01 (P=0.043 and 0.025, respectively), as well as those of DQB1*03:03 (P=0.034 and 0.026, respectively). The carrier frequency of DRB1*09:01 and DQB1*03:03 alleles was higher in the patients (45.16%) than in controls (28.57%). These alleles are more common in East Asian than in European populations, and are reportedly associated with various autoimmune diseases in Japanese patients. Our data provide further evidence that altered immune response based on individual HLA genotypes may contribute to ANE pathogenesis. PMID:27467284

  9. Abnormal urothelial HLA-DR expression in interstitial cystitis.

    PubMed

    Christmas, T J; Bottazzo, G F

    1992-03-01

    Interstitial cystitis is a chronic inflammatory disorder of the urinary bladder that predominantly afflicts middle-age women. The end stage of the disease is ulceration of the urothelium, the so-called Hunner's ulcer. The aetiology of interstitial cystitis remains obscure. We have studied bladder biopsies from 22 cases of interstitial cystitis and control groups consisting of six cases of bacterial cystitis and eight healthy women. Indirect immunofluorescence was performed on the biopsies using murine MoAbs to human HLA class I molecules, and class II molecules, HLA-DP, HLA-DQ and HLA-DR. In interstitial cystitis, bacterial cystitis and normal controls most cells expressed HLA class I products. In six cases of interstitial cystitis and one case of bacterial cystitis there was evidence of HLA class I hyperexpression. In normal bladder and bacterial cystitis HLA class II expression was restricted to submucosal dendritic cells, Langerhans cells macrophages, vascular endothelial cells and activated lymphocytes. All but two cases of interstitial cystitis showed surface expression of HLA-DR (but not HLA-DP or DQ). In all cases of interstitial cystitis there was an increase in the numbers of macrophages, activated lymphocytes and vascular endothelial cells expressing HLA class II molecules within the submucosa. These findings provide further evidence for the importance of inappropriate HLA molecule expression in a disease suspected of having an autoimmune pathogenesis and where cellular autoimmune mechanisms play a decisive role in the destruction of the target cells--the bladder urothelium.

  10. From HLA typing to anti-HLA antibody detection and beyond: The road ahead.

    PubMed

    Picascia, Antonietta; Grimaldi, Vincenzo; Napoli, Claudio

    2016-10-01

    The complex polymorphism of the HLA genes and the need of a proper identification of anti-HLA antibodies have led to continuously develop novel practical and feasible technologies in the field of organ and tissue transplantation. Technologies to identify HLA molecules have evolved from the serological to the molecular methods and a true innovation in the DNA sequencing has taken place with the development of next generation sequencing. An interesting field to explore is how the information resulting from the HLA-DNA sequencing can be applied in the clinical setting by including the alloimmunization assessment. Indeed, a good characterization of anti-HLA antibody at epitope level can reduce the risk of immunization. Many anti-HLA antibodies are specific for epitopes rather than for HLA antigens and the knowledge of unacceptable epitopes allows to reduce the number of mismatched antigens. Furthermore, high resolution HLA allele typing could help to understand the epitopes against which antibodies are developed. However, the improvements should not only concern the diagnostic tools in the pre-transplantation phase, but also the monitoring of post transplantation outcome. There is a growing interest in developing new non-invasive biomarkers to monitor the rejection. Currently, increasing evidence has focused on miRNAs, epigenetic markers emerged as regulators of molecular events that are differently expressed in biopsies and blood as well as in urinary samples of transplanted recipients. The implementation of next generation sequencing and genome-wide expression analysis together with functional assays may provide useful tools to evaluate the epigenetic modulation in transplantation biology but many efforts are requested for translating in the clinical arena the results obtained in experimental models. PMID:27531697

  11. Linking neuroscientific research on decision making to the educational context of novice students assigned to a multiple-choice scientific task involving common misconceptions about electrical circuits.

    PubMed

    Potvin, Patrice; Turmel, Elaine; Masson, Steve

    2014-01-01

    Functional magnetic resonance imaging was used to identify the brain-based mechanisms of uncertainty and certainty associated with answers to multiple-choice questions involving common misconceptions about electric circuits. Twenty-two scientifically novice participants (humanities and arts college students) were asked, in an fMRI study, whether or not they thought the light bulbs in images presenting electric circuits were lighted up correctly, and if they were certain or uncertain of their answers. When participants reported that they were unsure of their responses, analyses revealed significant activations in brain areas typically involved in uncertainty (anterior cingulate cortex, anterior insula cortex, and superior/dorsomedial frontal cortex) and in the left middle/superior temporal lobe. Certainty was associated with large bilateral activations in the occipital and parietal regions usually involved in visuospatial processing. Correct-and-certain answers were associated with activations that suggest a stronger mobilization of visual attention resources when compared to incorrect-and-certain answers. These findings provide insights into brain-based mechanisms of uncertainty that are activated when common misconceptions, identified as such by science education research literature, interfere in decision making in a school-like task. We also discuss the implications of these results from an educational perspective. PMID:24478680

  12. Immunophenotyping of rheumatoid arthritis reveals a linkage between HLA-DRB1 genotype, CXCR4 expression on memory CD4+ T cells, and disease activity

    PubMed Central

    Nagafuchi, Yasuo; Shoda, Hirofumi; Sumitomo, Shuji; Nakachi, Shinichiro; Kato, Rika; Tsuchida, Yumi; Tsuchiya, Haruka; Sakurai, Keiichi; Hanata, Norio; Tateishi, Shoko; Kanda, Hiroko; Ishigaki, Kazuyoshi; Okada, Yukinori; Suzuki, Akari; Kochi, Yuta; Fujio, Keishi; Yamamoto, Kazuhiko

    2016-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4+CD4+ T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells. Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig. Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA. PMID:27385284

  13. [Preliminary study on HLA-B genotyping by oligonucleotide chips].

    PubMed

    Lan, Ke; Hu, Shou-Wang; Zhang, Fan; Wang, Hui; Guan, Wei; Ding, Yu; Sun, Ou-Jun; Wang, Sheng-Qi

    2003-04-01

    HLA genes constitute a highly polymorphic multigene system. In the present study, HLA-B oligonucleotide chips were manufactured by using a set of sequence-specific oligonucleotide probes derived from polymorphic regions in exon 2 and exon 3 of HLA-B gene spotted by microarrayer onto the aldehyde modified glass slides. In addition, the sequenced HLA-B gene clones used as standard samples were amplified from exon 2 and exon 3 by PCR. Together with the correct hybridization and wash conditions, the PCR products were bound with the array probes on the chip, and the hybridization patterns were transformed to HLA-B genotypes. The results showed that the genotypes of standard samples by the HLA-B oligonucleotide chips were completely identical with the sequenced clones. In conclusion, the oligonucleotide chip method presented here for HLA-B genotyping is a rapid, accurate, sensitive and attractive high throughput biochemical way.

  14. Imputing Variants in HLA-DR Beta Genes Reveals That HLA-DRB1 Is Solely Associated with Rheumatoid Arthritis and Systemic Lupus Erythematosus

    PubMed Central

    Kim, Kwangwoo; Bang, So-Young; Yoo, Dae Hyun; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Kang, Young Mo; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Kim, Seong-Kyu; Choe, Jung-Yoon; Nath, Swapan K.; Lee, Hye-Soon; Bae, Sang-Cheol

    2016-01-01

    The genetic association of HLA-DRB1 with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) is well documented, but association with other HLA-DR beta genes (HLA-DRB3, HLA-DRB4 and HLA-DRB5) has not been thoroughly studied, despite their similar functions and chromosomal positions. We examined variants in all functional HLA-DR beta genes in RA and SLE patients and controls, down to the amino-acid level, to better understand disease association with the HLA-DR locus. To this end, we improved an existing HLA reference panel to impute variants in all protein-coding HLA-DR beta genes. Using the reference panel, HLA variants were inferred from high-density SNP data of 9,271 RA-control subjects and 5,342 SLE-control subjects. Disease association tests were performed by logistic regression and log-likelihood ratio tests. After imputation using the newly constructed HLA reference panel and statistical analysis, we observed that HLA-DRB1 variants better accounted for the association between MHC and susceptibility to RA and SLE than did the other three HLA-DRB variants. Moreover, there were no secondary effects in HLA-DRB3, HLA-DRB4, or HLA-DRB5 in RA or SLE. Of all the HLA-DR beta chain paralogs, those encoded by HLA-DRB1 solely or dominantly influence susceptibility to RA and SLE. PMID:26919467

  15. HLA-related lymphocyte responsiveness in psoriasis.

    PubMed

    Gross, W L; Vorwerk, I; Westphal, E; Christophers, E; Hahn, G; Schlaak, M

    1983-01-01

    In order to find associations among the genetic, immunological and environmental factors that might be important in the pathogenesis of psoriasis, the relationship between streptococcal antigen- or mitogen-induced lymphocyte responses in vitro and HLA phenotypes was studied in 23 patients with psoriasis. Patients showed an elevated lymphocyte response to somatic A-streptococcal antigens when compared with healthy controls. In contrast, the response to mitogens (PHA, Con A, PWM) was impaired in patients with psoriasis. The impaired mitogen-induced lymphocyte transformation was found mostly in psoriatics with HLA-B13/B17. The elevated cellular immune response to somatic A-streptococcal antigens, on the other hand, was observed mainly in psoriatics without HLA-B13/B17. The results indicate that gene products of the HLA region known to be associated with psoriasis are involved in the cellular immune response, as expected from clinical trials. These findings also provide further evidence of at least two different subtypes of psoriasis, characterized by genetically and immunologically defined markers.

  16. Serum antibodies to human leucocyte antigen (HLA)-E, HLA-F and HLA-G in patients with systemic lupus erythematosus (SLE) during disease flares: Clinical relevance of HLA-F autoantibodies.

    PubMed

    Jucaud, V; Ravindranath, M H; Terasaki, P I; Morales-Buenrostro, L E; Hiepe, F; Rose, T; Biesen, R

    2016-03-01

    T lymphocyte hyperactivity and progressive inflammation in systemic lupus erythematosus (SLE) patients results in over-expression of human leucocyte antigen (HLA)-Ib on the surface of lymphocytes. These are shed into the circulation upon inflammation, and may augment production of antibodies promoting pathogenicity of the disease. The objective was to evaluate the association of HLA-Ib (HLA-E, HLA-F and HLA-G) antibodies to the disease activity of SLE. The immunoglobulin (Ig)G/IgM reactivity to HLA-Ib and β2m in the sera of 69 German, 29 Mexican female SLE patients and 17 German female controls was measured by multiplex Luminex(®)-based flow cytometry. The values were expressed as mean flourescence intensity (MFI). Only the German SLE cohort was analysed in relation to the clinical disease activity. In the controls, anti-HLA-G IgG predominated over other HLA-Ib antibodies, whereas SLE patients had a preponderance of anti-HLA-F IgG over the other HLA-Ib antibodies. The disease activity index, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)-2000, was reflected only in the levels of anti-HLA-F IgG. Anti-HLA-F IgG with MFI level of 500-1999 was associated with active SLE, whereas inactive SLE revealed higher MFI (>2000). When anti-HLA-F IgG were cross-reactive with other HLA-Ib alleles, their reactivity was reflected in the levels of anti-HLA-E and -G IgG. The prevalence of HLA-F-monospecific antibodies in SLE patients was also associated with the clinical disease activity. Anti-HLA-F IgG is possibly involved in the clearance of HLA-F shed from lymphocytes and inflamed tissues to lessen the disease's severity, and thus emerges as a beneficial immune biomarker. Therefore, anti-HLA-Ib IgG should be considered as a biomarker in standard SLE diagnostics.

  17. HLA-G and classical HLA class I expression in primary colorectal cancer and associated liver metastases.

    PubMed

    Swets, Marloes; König, Marion H; Zaalberg, Anniek; Dekker-Ensink, Neeltje G; Gelderblom, Hans; van de Velde, Cornelis J H; van den Elsen, Peter J; Kuppen, Peter J K

    2016-09-01

    De novo expression of HLA-G has been demonstrated in colorectal cancer. HLA-G, amongst others, inhibits natural killer cell function, contributing to host immune defense evasion. Another mechanism to escape anti-tumor immunity is loss of HLA class I. Therefore, we determined HLA-G and HLA class I expression on primary colorectal tumors and associated liver metastases, in order to get insight in the metastasizing process regarding escaping anti-tumor immunity. HLA-G expression was evaluated using three mAbs; 4H84, MEM-G/1 and MEM-G/2. In total 81 colorectal cancer patients were evaluated. Formalin-fixed paraffin-embedded tissue sections of primary tumors and associated liver metastases, were immunohistochemically stained. A concordance between expression or loss/downregulation in the primary tumor and associated liver metastasis regarding HLA class I expression was observed in 80% of the cases. In contrast with the hypothesis of escaping NK cell-killing, we demonstrated for each HLA-G detecting mAbs used in this study, that the majority of the primary tumors that positively stained for HLA-G did not express HLA-G in the associated liver metastasis. Furthermore, we revealed the existence of non-specific binding and in addition we found that the different epitopes of HLA-G detected by 4H84, MEM-G/1 and MEM-G/2 mAbs were expressed differentially in colorectal tumor tissues.

  18. HLA-DQ rather than HLA-DR region might be involved in dominant nonsusceptibility to diabetes.

    PubMed Central

    Sterkers, G; Zeliszewski, D; Chaussée, A M; Deschamps, I; Font, M P; Freidel, C; Hors, J; Betuel, H; Dausset, J; Levy, J P

    1988-01-01

    Since HLA-DRw15 (a subdivision of the HLA-DR2 specificity previously called DR2 long) is associated with dominant nonsusceptibility to insulin-dependent diabetes mellitus (IDDM), while HLA-DRw16 (another subdivision of HLA-DR2, previously called DR2 short) is positively associated with the disease, we looked for particular characteristics of HLA products encoded by the DR2 haplotypes of IDDM patients. The results show the following: (i) HLA-DQ molecules of HLA-DRw15-positive IDDM patients are different from those of HLA-DRw15-positive controls, suggesting that the HLA-DQ gene of DRw15 haplotypes is involved in a protective effect. (ii) HLA-DR and -DQ products of DRw16-positive IDDM are functionally indistinguishable from those of HLA-DRw16-positive controls. Furthermore, our data provide evidence that the residue at position 57 on the DQ beta chain could play a crucial biological role in antigen presentation to T cells as far as the DRw16 haplotype is concerned. This observation fits with the recent observation of correlation between DQ beta allelic polymorphism at position 57 and both susceptibility and resistance to IDDM. PMID:2901099

  19. Association of HLA-DQ alleles with the presence of an anti-β2-glycoprotein I antibody in patients with recurrent miscarriage.

    PubMed

    Chen, X; Liang, P-Y; Li, G-G; Diao, L-H; Liu, C-C; Huang, C-Y; Wu, T-H; Xu, J; Zeng, Y

    2016-01-01

    Immunogenetic studies have suggested that autoantibody production is commonly associated with particular human leukocyte antigens (HLA) class II genotypes in certain autoimmune diseases. The objective of this study was to investigate whether the production of anti-β2-glycoprotein I antibody (aβ2GPI) was associated with particular HLA-DQ alleles in patients with recurrent miscarriage (RM). The HLA-DQ genotypes in 126 patients with RM were determined using the polymerase chain reaction-sequence-specific primer method. Both the IgG and IgM isotypes of aβ2GPI were measured via enzyme-linked immunosorbent assay. Positive results for either IgG or IgM on two occasions within an interval of 12 weeks were defined as antiphospholipid antibody-positive. The frequencies of the HLA-DQA1*01:02 [odds ratio (OR) 3.4, 95% confidence interval (CI) 1.6-7.0, Pc = 0.018] and HLA-DQB1*02:01 alleles (OR 4.6, 95% CI 2.1-10.2, Pc = 9.18 × 10(-4)) were significantly increased in aβ2GPI-positive RM patients compared with aβ2GPI-negative RM patients. These results suggest that the HLA-DQA1*0102 and HLA-DQB1*0201 alleles may be involved in the production of aβ2GPI in RM patients.

  20. A Panel of Artificial APCs Expressing Prevalent HLA Alleles Permits Generation of Cytotoxic T Cells Specific for Both Dominant and Subdominant Viral Epitopes for Adoptive Therapy1

    PubMed Central

    Hasan, Aisha N.; Kollen, Wouter J.; Trivedi, Deepa; Selvakumar, Annamalai; Dupont, Bo; Sadelain, Michel; O'Reilly, Richard J.

    2009-01-01

    Adoptive transfer of virus-specific T cells can treat infections complicating allogeneic hematopoietic cell transplants. However, autologous antigen-presenting cells (APCs) are often limited in supply. Here, we describe a panel of artificial APCs (AAPCs) consisting of murine 3T3 cells transduced to express human B7.1, ICAM-1 and LFA-3 that each stably express one of a series of 6 common HLA class I alleles. In comparative analyses, T cells sensitized with AAPCs expressing a shared HLA allele or autologous APCs loaded with a pool of 15-mers spanning the sequence of CMVpp65 produced similar yields of HLA-restricted CMVpp65 specific T cells; significantly higher yields could be achieved by sensitization with AAPCs transduced to express the CMVpp65 protein. T cells generated were CD8+, IFNγ+ and exhibited HLA-restricted CMVpp65 specific cytotoxicity. T cells sensitized with either peptide-loaded or transduced AAPCs recognized epitopes presented by each HLA allele known to be immunogenic in man. Sensitization with AAPCs also permitted expansion of IFNγ+ cytotoxic effector cells against subdominant epitopes that were either absent or in low frequencies in T cells sensitized with autologous APCs. This replenishable panel of AAPCs can be used for immediate sensitization and expansion of virus-specific T cells of desired HLA restriction for adoptive immunotherapy. It may be of particular value for recipients of transplants from HLA disparate donors. PMID:19635907

  1. Co-localization of gluten consumption and HLA-DQ2 and -DQ8 genotypes, a clue to the history of celiac disease.

    PubMed

    Lionetti, Elena; Catassi, Carlo

    2014-12-01

    Celiac disease is an immune-mediated disorder triggered by gluten in genetically susceptible persons. Despite its detrimental effects on human health, it has not disappeared over time. The current evolutionary theory is that celiac disease is more common in areas reached later by agricultural revolution than in countries that started consumption of wheat earlier, due to negative selection caused by celiac disease. We reviewed data on worldwide prevalence of celiac disease, wheat consumption, and frequencies of HLA-celiac-disease-predisposing-genotypes to investigate their mutual relationship. Studies assessing prevalence of celiac disease were identified through a MEDLINE search. Wheat consumption and frequencies of HLA-DQ2-DQ8 were obtained from Food and Agriculture Organization of the United Nations and allelefrequencies.net database. Correlations between celiac disease, wheat consumption, and HLA were analyzed by linear regression. We observed a significant correlation between wheat consumption and HLA DQ2 (p=0.01) and the sum of DQ2 and DQ8 (p=0.01) frequencies. Wheat consumption and HLA-DQ2 tend to co-localize in different continents. The correlation between the prevalence of celiac disease and either DQ2 and/or DQ8, or the product of DQ2+DQ8*wheat consumption was not statistically significant. Co-localization of gluten consumption and HLA-celiac-disease-predisposing-genotypes can be explained by positive selection of HLA-DQ2 genes in wheat-consuming areas, and "demic diffusion" of Middle East farmers into Europe.

  2. Clinical characteristics and HLA alleles of a family with simultaneously occurring alopecia areata.

    PubMed

    Emre, Selma; Metin, Ahmet; Caykoylu, Ali; Akoglu, Gulsen; Ceylan, Gülay G; Oztekin, Aynure; Col, Esra S

    2016-06-01

    Alopecia areata (AA) is a T-cell-mediated autoimmune disease resulting in partial or total noncicatricial hair loss. HLA class II antigens are the most important markers that constitute genetic predisposition to AA. Various life events and intense psychological stress may play an important role in triggering AA attacks. We report an unusual case series of 4 family members who had simultaneously occurring active AA lesions. Our aim was to evaluate the clinical and psychiatric features of 4 cases of active AA lesions occurring simultaneously in a family and determine HLA alleles. The clinical and psychological features of all patients were examined. HLA antigen DNA typing was performed by polymerase chain reaction with sequence-specific primers. All patients had typical AA lesions over the scalp and/or beard area. Psychological examinations revealed obsessive-compulsive personality disorder in the proband's parents as well as anxiety and lack of self-confidence in both the proband and his sister. HLA antigen types were not commonly shared with family members. These findings suggest that AA presenting concurrently in members of the same family was not associated with genetic predisposition. Shared psychological disorders and stressful life events might be the major key points in the concurrent presentation of these familial AA cases and development of resistance against treatments.

  3. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases.

    PubMed

    Lenz, Tobias L; Deutsch, Aaron J; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W J; Abecasis, Gonçalo; Becker, Jessica; Boeckxstaens, Guy E; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P; Nöthen, Markus M; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E; Tsoi, Lam C; van Heel, David A; Worthington, Jane; Wouters, Mira M; Klareskog, Lars; Elder, James T; Gregersen, Peter K; Schumacher, Johannes; Rich, Stephen S; Wijmenga, Cisca; Sunyaev, Shamil R; de Bakker, Paul I W; Raychaudhuri, Soumya

    2015-09-01

    Human leukocyte antigen (HLA) genes confer substantial risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen-binding repertoires between a heterozygote's two expressed HLA variants might result in additional non-additive risk effects. We tested the non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (ncases = 5,337), type 1 diabetes (T1D; ncases = 5,567), psoriasis vulgaris (ncases = 3,089), idiopathic achalasia (ncases = 727) and celiac disease (ncases = 11,115). In four of the five diseases, we observed highly significant, non-additive dominance effects (rheumatoid arthritis, P = 2.5 × 10(-12); T1D, P = 2.4 × 10(-10); psoriasis, P = 5.9 × 10(-6); celiac disease, P = 1.2 × 10(-87)). In three of these diseases, the non-additive dominance effects were explained by interactions between specific classical HLA alleles (rheumatoid arthritis, P = 1.8 × 10(-3); T1D, P = 8.6 × 10(-27); celiac disease, P = 6.0 × 10(-100)). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (rheumatoid arthritis, 1.4%; T1D, 4.0%; celiac disease, 4.1%) beyond a simple additive model. PMID:26258845

  4. Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    PubMed Central

    Lenz, Tobias L.; Deutsch, Aaron J.; Han, Buhm; Hu, Xinli; Okada, Yukinori; Eyre, Stephen; Knapp, Michael; Zhernakova, Alexandra; Huizinga, Tom W.J.; Abecasis, Goncalo; Becker, Jessica; Boeckxstaens, Guy E.; Chen, Wei-Min; Franke, Andre; Gladman, Dafna D.; Gockel, Ines; Gutierrez-Achury, Javier; Martin, Javier; Nair, Rajan P.; Nöthen, Markus M.; Onengut-Gumuscu, Suna; Rahman, Proton; Rantapää-Dahlqvist, Solbritt; Stuart, Philip E.; Tsoi, Lam C.; Van Heel, David A.; Worthington, Jane; Wouters, Mira M.; Klareskog, Lars; Elder, James T.; Gregersen, Peter K.; Schumacher, Johannes; Rich, Stephen S.; Wijmenga, Cisca; Sunyaev, Shamil R.; de Bakker, Paul I.W.; Raychaudhuri, Soumya

    2015-01-01

    Human leukocyte antigen (HLA) genes confer strong risk for autoimmune diseases on a log-additive scale. Here we speculated that differences in autoantigen binding repertoires between a heterozygote’s two expressed HLA variants may result in additional non-additive risk effects. We tested non-additive disease contributions of classical HLA alleles in patients and matched controls for five common autoimmune diseases: rheumatoid arthritis (RA, Ncases=5,337), type 1 diabetes (T1D, Ncases=5,567), psoriasis vulgaris (Ncases=3,089), idiopathic achalasia (Ncases=727), and celiac disease (Ncases=11,115). In four out of five diseases, we observed highly significant non-additive dominance effects (RA: P=2.5×1012; T1D: P=2.4×10−10; psoriasis: P=5.9×10−6; celiac disease: P=1.2×10−87). In three of these diseases, the dominance effects were explained by interactions between specific classical HLA alleles (RA: P=1.8×10−3; T1D: P=8.6×1027; celiac disease: P=6.0×10−100). These interactions generally increased disease risk and explained moderate but significant fractions of phenotypic variance (RA: 1.4%, T1D: 4.0%, and celiac disease: 4.1%, beyond a simple additive model). PMID:26258845

  5. Clinical characteristics and HLA alleles of a family with simultaneously occurring alopecia areata.

    PubMed

    Emre, Selma; Metin, Ahmet; Caykoylu, Ali; Akoglu, Gulsen; Ceylan, Gülay G; Oztekin, Aynure; Col, Esra S

    2016-06-01

    Alopecia areata (AA) is a T-cell-mediated autoimmune disease resulting in partial or total noncicatricial hair loss. HLA class II antigens are the most important markers that constitute genetic predisposition to AA. Various life events and intense psychological stress may play an important role in triggering AA attacks. We report an unusual case series of 4 family members who had simultaneously occurring active AA lesions. Our aim was to evaluate the clinical and psychiatric features of 4 cases of active AA lesions occurring simultaneously in a family and determine HLA alleles. The clinical and psychological features of all patients were examined. HLA antigen DNA typing was performed by polymerase chain reaction with sequence-specific primers. All patients had typical AA lesions over the scalp and/or beard area. Psychological examinations revealed obsessive-compulsive personality disorder in the proband's parents as well as anxiety and lack of self-confidence in both the proband and his sister. HLA antigen types were not commonly shared with family members. These findings suggest that AA presenting concurrently in members of the same family was not associated with genetic predisposition. Shared psychological disorders and stressful life events might be the major key points in the concurrent presentation of these familial AA cases and development of resistance against treatments. PMID:27416096

  6. 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.

  7. The Potential of HLA-G-Bearing Extracellular Vesicles as a Future Element in HLA-G Immune Biology

    PubMed Central

    Rebmann, Vera; König, Lisa; Nardi, Fabiola da Silva; Wagner, Bettina; Manvailer, Luis Felipe Santos; Horn, Peter A.

    2016-01-01

    The HLA-G molecule is a member of the non-classical HLA class I family. Its surface expression is physiologically restricted to the maternal–fetal interface and to immune privileged adult tissues. Despite the restricted tissue expression, HLA-G is detectable in body fluids as secreted soluble molecules. A unique feature of HLA-G is the structural diversity as surface expressed and as secreted molecules. Secreted HLA-G can be found in various body fluids either as free soluble HLA-G or as part of extracellular vesicles (EVs), which are composed of various antigens/ligands/receptors, bioactive lipids, cytokines, growth factors, and genetic information, such as mRNA and microRNA. Functionally, HLA-G and its secreted forms are considered to play a crucial role in the network of immune-regulatory tolerance mechanisms, preferentially interacting with the cognate inhibitory receptors LILRB1 and LILRB2. The HLA-G mediated tolerance is described in processes of pregnancy, inflammation, and cancer. However, almost all functional and clinical implications of HLA-G in vivo and in vitro have been established based on simple single ligand/receptor interactions at the cell surface, whereas HLA-G-bearing EVs were in minor research focus. Indeed, cytotrophoblast cells, mesenchymal stem cells, and cancer cells were recently described to secrete HLA-G-bearing EVs, displaying immunosuppressive effects and modulating the tumor microenvironment. However, numerous functional and clinical open questions persist. Here, we (i) introduce basic aspects of EVs biology, (ii) summarize the functional knowledge, clinical implications and open questions of HLA-G-bearing EVs, and (iii) discuss HLA-G-bearing EVs as a future element in HLA-G biology. PMID:27199995

  8. Presentation of human minor histocompatibility antigens by HLA-B35 and HLA-B38 molecules.

    PubMed Central

    Yamamoto, J; Kariyone, A; Akiyama, N; Kano, K; Takiguchi, M

    1990-01-01

    Cytotoxic T lymphocyte (CTL) clones specific for human minor histocompatibility antigens (hmHAs) were produced from a patient who had been grafted with the kidneys from his mother and two HLA-identical sisters. Of eight CTL clones generated, four recognized an hmHA (hmHA-1) expressed on cells from the mother and sister 3 (second donor); two recognized another antigen (hmHA-2) on cells from the father, sister 2 (third donor), and sister 3; and the remaining two clones recognized still another antigen (hmHA-3) on cells from the father and sister 3. Panel studies revealed that CTL recognition of hmHA-1 was restricted by HLA-B35 and that of hmHA-2 and hmHA-3 was restricted by HLA-B38. The HLA-B35 restriction of the hmHA-1-specific CTL clones was substantiated by the fact that they killed HLA-A null/HLA-B null Hmy2CIR targets transfected with HLA-B35 but not HLA-B51, -Bw52, or -Bw53 transfected Hmy2CIR targets. These data demonstrated that the five amino acids substitutions on the alpha 1 domain between HLA-B35 and -Bw53, which are associated with Bw4/Bw6 epitopes, play a critical role in the relationship of hmHA-1 to HLA-B35 molecules. The fact that the hmHA-1-specific CTLs failed to kill Hmy2CIR cells expressing HLA-B35/51 chimeric molecules composed of the alpha 1 domain of HLA-B35 and other domains of HLA-B51 indicated that eight residues on the alpha 2 domain also affect the interaction of hmHA-1 and the HLA-B35 molecules. PMID:2157206

  9. Epstein-Barr virus-specific cytotoxic T lymphocytes as probes of HLA polymorphism. Heterogeneity of T cell-restricting determinants associated with the serologically defined HLA-A2 antigen.

    PubMed

    Gaston, J S; Rickinson, A B; Epstein, M A

    1983-08-01

    Epstein-Barr (EB) virus-specific effector T cell lines were established from nine virus-immune donors positive for the serologically defined HLA-A2 antigen; of these, four lines contained a demonstrable A2-restricted cytotoxic component. When these four effector populations were each tested on the same panel of EB virus-transformed lines from 20 HLA-A2-positive individuals, 16 of the target cell lines were consistently killed at levels above 25% of the relevant autologous cell lysis. Cytotoxicity appeared to be mediated through a restricting determinant associated with the 'common A2' antigen that these lines shared; indeed the lysis could be specifically blocked by high concentrations of an HLA-A2-specific monoclonal antibody. In contrast, 4 out of 20 target cell lines were not killed by HLA-A2-restricted effector cells, even though they did express the serologically defined A2 antigen and were found in other tests to be susceptible to EB virus-specific cytolysis restricted through other HLA-A or -B antigens on their surface. These results suggest that EB virus-specific cytotoxic T cells can distinguish between serologically identical HLA-A2 molecules via the heterogeneity of their T cell-restricting determinants. Data from one of the effector cell populations further suggested that a serologically defined cross-reaction between the otherwise distinct HLA-A2 and -Bw57 antigens might also be reflected in a cross-reactivity of T cell-restricting determinants. PMID:6193217

  10. The HLA-DRB1 allele polymorphisms and nasopharyngeal carcinoma.

    PubMed

    Yang, Huimin; Yu, Kaihui; Zhang, Ruoheng; Li, Jiatong; Wei, Xiaomou; Zhang, Yuening; Zhang, Chengdong; Xiao, Feifan; Zhao, Dong; Lin, Xuandong; Wu, Huayu; Yang, Xiaoli

    2016-06-01

    Human leukocyte antigen (HLA)-DRB1 has been reported to influence individual's susceptibility to nasopharyngeal carcinoma (NPC) by many studies in recent years; however, these studies provided controversial results. The meta-analysis was thus conducted here to estimate the relationship between HLA-DRB1 polymorphisms and NPC. After an extensive review of journals from various databases (PubMed, the Web of Science, Embase, China National Knowledge Internet (CNKI), and Wanfang Database), 8 out of 69 case-control studies, including 778 cases and 1148 controls, were extracted. The results showed that 4 of 13 polymorphisms allele are statistically significantly associated with NPC, among them, HLA-DRB1*3, HLA-DRB1*9, and HLA-DRB1*10 may increase the risk of NPC while HLA-DRB1*01 has the opposite effect. The pooled odds ratio and 95 % confidence interval (CI) were 1.702 [95 % CI (1.047, 2.765)], 1.363 [95 % CI (1.029, 1.806)], 1.989 [95 % CI (1.042, 3.799)], and 0.461 [95 % CI (0.315, 0.676)], respectively. In a further ethnicity-based subgroup analysis, HLA-DRB1*08, HLA-DRB1*11, and HLA-DRB1*16 were found to be linked with NPC in Asian, Tunisian, and Caucasian, respectively. In Asian, HLA-DRB1*03, 08, and 10 may elevate the risk whereas HLA-DRB1*09 could lower it. In Tunisian, HLA-DRB1*01 and 11 are the protective factors while HLA-DRB1*03 is the only risk factor. In Caucasian, HLA-DRB1*01 and 03 increase the risk and HLA-DRB1*16 lowers it. The most frequent statistically associated gene is found to be HLA-DRB1*03 which has protective influence on Asian and Tunisian. In conclusion, HLA-DRB1*01, DRB1*03, DRB1*09, and DRB1*10 are related with NPC susceptibility, and the association of HLA-DRB1*08, DRB1*11, and DRB1*16 with NPC risk are significantly different in different ethnicities. PMID:27059731

  11. HLA class II genes: typing by DNA analysis.

    PubMed

    Bidwell, J L; Bidwell, E A; Bradley, B A

    1990-04-01

    A detailed understanding of the structure and function of the human major histocompatibility complex (MHC) has ensued from studies by molecular biologist during the last decade. Virtually all of the HLA genes have now been cloned, and the nucleotide sequences of their different allelic forms have been determined. Typing for these HLA alleles is a fundamental prerequisite for tissue matching in allogeneic organ transplantation. Until very recently, typing procedures have been dominated by serological and cellular methods. The availability of cloned DNA from HLA genes has now permitted the technique of restriction fragment length polymorphism (RFLP) analysis to be applied, with remarkable success and advantage, to phenotyping of both HLA Class I and Class II determinants. For the HLA Class II genes DR and DQ, a simple two-stage RFLP analysis permits the accurate identification of all specificities defined by serology, and of many which are defined by cellular typing. At the present time, however, RFLP typing of HLA Class I genes is not as practicable or as informative as that for HLA Class II genes. The present clinical applications of HLA-DR and DQ RFLP typing are predominantly in phenotyping of living donors, including selection of HLA-matched volunteer bone marrow donors, in allograft survival studies, and in studies of HLA Class II-associated diseases. However, the time taken to perform RFLP analysis precludes its use for the typing of cadaveric kidney donors. Nucleotide sequence data for the alleles of HLA Class II genes have now permitted the development of allele-specific oligonucleotide (ASO) typing, a second category of DNA analysis. This has been greatly facilitated by the ability to amplify specific HLA Class II DNA 'target' sequences using the polymerase chain reaction (PCR) technique. The accuracy of DNA typing techniques should ensure that this methodology will eventually replace conventional HLA phenotyping.

  12. High density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis

    PubMed Central

    Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot; Ellinghaus, Eva; Jostins, Luke; Huang, Hailiang; Ripke, Stephan; Gusareva, Elena S; Annese, Vito; Hauser, Stephen L; Oksenberg, Jorge R; Thomsen, Ingo; Leslie, Stephen; Daly, Mark J; Van Steen, Kristel; Duerr, Richard H; Barrett, Jeffrey C; McGovern, Dermot PB; Schumm, L Philip; Traherne, James A; Carrington, Mary N; Kosmoliaptsis, Vasilis; Karlsen, Tom H; Franke, Andre; Rioux, John D

    2014-01-01

    Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn’s disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical HLA molecules1. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but lacked the statistical power to define the architecture of association and causal alleles2,3. To address this, we performed high-density SNP typing of the MHC in >32,000 patients with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn’s disease and ulcerative colitis. Significant differences were observed between these diseases, including a predominant role of class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response to the colonic environment in the pathogenesis of IBD. PMID:25559196

  13. Polymorphisms of HLA-DRB1, -DQA1 and -DQB1 in Inhabitants of Astana, the Capital City of Kazakhstan

    PubMed Central

    Kuranov, Alexandr B.; Vavilov, Mikhail N.; Abildinova, Gulshara Zh.; Akilzhanova, Ainur R.; Iskakova, Aisha N.; Zholdybayeva, Elena V.; Boldyreva, Margarita N.; Müller, Claudia A.; Momynaliev, Kuvat T.

    2014-01-01

    Background Kazakhstan has been inhabited by different populations, such as the Kazakh, Kyrgyz, Uzbek and others. Here we investigate allelic and haplotypic polymorphisms of human leukocyte antigen (HLA) genes at DRB1, DQA1 and DQB1 loci in the Kazakh ethnic group, and their genetic relationship between world populations. Methodology/Principal Findings A total of 157 unrelated Kazakh ethnic individuals from Astana were genotyped using sequence based typing (SBT-Method) for HLA-DRB1, -DQA1 and -DQB1 loci. Allele frequencies, neighbor-joining method, and multidimensional scaling analysis have been obtained for comparison with other world populations. Statistical analyses were performed using Arlequin v3.11. Applying the software PAST v. 2.17 the resulting genetic distance matrix was used for a multidimensional scaling analysis (MDS). Respectively 37, 17 and 19 alleles were observed at HLA-DRB1, -DQA1 and -DQB1 loci. The most frequent alleles were HLA-DRB1*07:01 (13.1%), HLA-DQA1*03:01 (13.1%) and HLA-DQB1*03:01 (17.6%). In the observed group of Kazakhs DRB1*07:01-DQA1*02:01-DQB1*02:01 (8.0%) was the most common three loci haplotype. DRB1*10:01-DQB1*05:01 showed the strongest linkage disequilibrium. The Kazakh population shows genetic kinship with the Kazakhs from China, Uyghurs, Mongolians, Todzhinians, Tuvinians and as well as with other Siberians and Asians. Conclusions/Significance The HLA-DRB1, -DQA1and -DQB1 loci are highly polymorphic in the Kazakh population, and this population has the closest relationship with other Asian and Siberian populations. PMID:25531278

  14. Identification of 2127 new HLA class I alleles in potential stem cell donors from Germany, the United States and Poland.

    PubMed

    Hernández-Frederick, C J; Giani, A S; Cereb, N; Sauter, J; Silva-González, R; Pingel, J; Schmidt, A H; Ehninger, G; Yang, S Y

    2014-03-01

    We describe 2127 new human leukocyte antigen (HLA) class I alleles found in registered stem cell donors. These alleles represent 28.9% of the currently known class I alleles. Comparing new allele sequences to homologous sequences, we found 68.1% nonsynonymous nucleotide substitutions, 28.9% silent mutations and 3.0% nonsense mutations. Many substitutions occurred at positions that have not been known to be polymorphic before. A large number of HLA alleles and nucleotide variations underline the extreme diversity of the HLA system. Strikingly, 156 new alleles were found not only multiple times, but also in carriers of various parentage, suggesting that some new alleles are not necessarily rare. Moreover, new alleles were found especially often in minority donors. This emphasizes the benefits of specifically recruiting such groups of individuals.

  15. Mutational analysis of the HLA-DQ3.2 insulin-dependent diabetes mellitus susceptibility gene.

    PubMed Central

    Kwok, W W; Lotshaw, C; Milner, E C; Knitter-Jack, N; Nepom, G T

    1989-01-01

    The human major histocompatibility complex includes approximately 14 class II HLA genes within the HLA-D region, most of which exist in multiple allelic forms. One of these genes, the DQ3.2 beta gene, accounts for the well-documented association of HLA-DR4 with insulin-dependent diabetes mellitus and is the single allele most highly correlated with this disease. We analyzed the amino acid substitutions that lead to the structural differences distinguishing DQ3.2 beta from its nondiabetogenic, but closely related allele, DQ3.1 beta. Site-directed mutagenesis of the DQ3.2 beta gene was used to convert key nucleotides into DQ3.1 beta codons. Subsequent expression studies of these mutated DQ3.2 beta clones using retroviral vectors defined amino acid 45 as critical for generating serologic epitopes characterizing the DQw3.1 beta and DQw3.2 beta molecules. Images PMID:2783780

  16. Human leukocyte antigen (HLA) class I restricted epitope discovery in yellow fewer and dengue viruses: importance of HLA binding strength.

    PubMed

    Lund, Ole; Nascimento, Eduardo J M; Maciel, Milton; Nielsen, Morten; Larsen, Mette Voldby; Lundegaard, Claus; Harndahl, Mikkel; Lamberth, Kasper; Buus, Søren; Salmon, Jérôme; August, Thomas J; Marques, Ernesto T A

    2011-01-01

    Epitopes from all available full-length sequences of yellow fever virus (YFV) and dengue fever virus (DENV) restricted by Human Leukocyte Antigen class I (HLA-I) alleles covering 12 HLA-I supertypes were predicted using the NetCTL algorithm. A subset of 179 predicted YFV and 158 predicted DENV epitopes were selected using the EpiSelect algorithm to allow for optimal coverage of viral strains. The selected predicted epitopes were synthesized and approximately 75% were found to bind the predicted restricting HLA molecule with an affinity, K(D), stronger than 500 nM. The immunogenicity of 25 HLA-A*02:01, 28 HLA-A*24:02 and 28 HLA-B*07:02 binding peptides was tested in three HLA-transgenic mice models and led to the identification of 17 HLA-A*02:01, 4 HLA-A*2402 and 4 HLA-B*07:02 immunogenic peptides. The immunogenic peptides bound HLA significantly stronger than the non-immunogenic peptides. All except one of the immunogenic peptides had K(D) below 100 nM and the peptides with K(D) below 5 nM were more likely to be immunogenic. In addition, all the immunogenic peptides that were identified as having a high functional avidity had K(D) below 20 nM. A*02:01 transgenic mice were also inoculated twice with the 17DD YFV vaccine strain. Three of the YFV A*02:01 restricted peptides activated T-cells from the infected mice in vitro. All three peptides that elicited responses had an HLA binding affinity of 2 nM or less. The results indicate the importance of the strength of HLA binding in shaping the immune response.

  17. Analysis of HLA-DP association with beryllium disease susceptibility in pooled exposed populations

    SciTech Connect

    Cesare Saltini, Massimo Amicosante

    2009-12-19

    in each immunogenetic study. In this context, the populations of the study already performed in this field by the University of Modena and Rome (by Prof. C. Saltini) and the University of Pennsylvania (by Prof. M. Rossman) have been evaluated by using similar HLA molecular typing methodologies and that both populations have now been followed up for a period of 4 to 7 years. The general objective of this study has to generate a larger data base comprising the two population with which analyze gene disease association with greater statistical power and ascertain the effect of lesser common gener variants which may be missed when analyzing associations on small populations. In particular addressing the role suggested in previous study such as: (1) the role of HLA-DP rare alleles and polymorphisms, and (2) the role of the HLA markers in disease progression from sensitization. The two populations from the already published studies (Saltini et al Eur Respir J. 2001 18:677-84; Rossman et al Am J Respir Crit Care Med. 2002 165:788-94) present similar aspects about: ethnicity, type and length of exposure to Be dust, a broadly similar association between beryllium related abnormalities and HLA. The two population have been pooled and evaluated using common criteria of diagnosis (Sensitized subject: at least 2 positive BeLPT tests each with 2 positive wells; CBD-affected subject: identification of well formed non-caseating granulomas on biopsy), follow up and HLA typing technique (complete HLA-DRB, DQB, DPB high resolution typing using amplification with sequence specific primers or sequence based typing). The two populations included 137 subjects with Beryllium hypersensitized (BH) and 155 Be-exposed controls. Inclusion criteria were met by one hundred and six subjects with Be-hypersensitivity of whom 55 were affected by CBD (age 52 {+-} 11 years; 50 caucasians, 2 African-Americans 2 Hispanics and 1 Asian; 46 males and 9 females; mean duration of Be-exposure 15 {+-} 9 years

  18. Detection of Ancestry Informative HLA Alleles Confirms the Admixed Origins of Japanese Population

    PubMed Central

    Nakaoka, Hirofumi; Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Shyh-Yuh, Liou; Sawamoto, Taiji; Fujiwara, Tsutomu; Tsutsui, Naohisa; Suematsu, Koji; Shinagawa, Akira; Inoko, Hidetoshi; Inoue, Ituro

    2013-01-01

    The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago. PMID:23577161

  19. Detection of ancestry informative HLA alleles confirms the admixed origins of Japanese population.

    PubMed

    Nakaoka, Hirofumi; Mitsunaga, Shigeki; Hosomichi, Kazuyoshi; Shyh-Yuh, Liou; Sawamoto, Taiji; Fujiwara, Tsutomu; Tsutsui, Naohisa; Suematsu, Koji; Shinagawa, Akira; Inoko, Hidetoshi; Inoue, Ituro

    2013-01-01

    The polymorphisms in the human leukocyte antigen (HLA) region are powerful tool for studying human evolutionary processes. We investigated genetic structure of Japanese by using five-locus HLA genotypes (HLA-A, -B, -C, -DRB1, and -DPB1) of 2,005 individuals from 10 regions of Japan. We found a significant level of population substructure in Japanese; particularly the differentiation between Okinawa Island and mainland Japanese. By using a plot of the principal component scores, we identified ancestry informative alleles associated with the underlying population substructure. We examined extent of linkage disequilibrium (LD) between pairs of HLA alleles on the haplotypes that were differentiated among regions. The LDs were strong and weak for pairs of HLA alleles characterized by low and high frequencies in Okinawa Island, respectively. The five-locus haplotypes whose alleles exhibit strong LD were unique to Japanese and South Korean, suggesting that these haplotypes had been recently derived from the Korean Peninsula. The alleles characterized by high frequency in Japanese compared to South Korean formed segmented three-locus haplotype that was commonly found in Aleuts, Eskimos, and North- and Meso-Americans but not observed in Korean and Chinese. The serologically equivalent haplotype was found in Orchid Island in Taiwan, Mongol, Siberia, and Arctic regions. It suggests that early Japanese who existed prior to the migration wave from the Korean Peninsula shared ancestry with northern Asian who moved to the New World via the Bering Strait land bridge. These results may support the admixture model for peopling of Japanese Archipelago. PMID:23577161

  20. HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis

    PubMed Central

    Laivoranta-Nyman, S; Mottonen, T; Hermann, R; Tuokko, J; Luukkainen, R; Hakala, M; Hannonen, P; Korpela, M; Yli-Kerttula, U; Toivanen, A; Ilonen, J; t and

    2004-01-01

    Objectives: To elucidate the contribution of HLA-DR-DQ haplotypes and their genotypic combinations to susceptibility to rheumatoid arthritis, and to evaluate the various models for HLA associated risk for the disease in a series of Finnish patients. Methods: 322 Finnish patients with rheumatoid arthritis were typed for common north European HLA-DR-DQ haplotypes and compared with a series of 1244 artificial family based control haplotypes. Results: The association of the so called shared epitope (SE) haplotypes (DRB1*0401, *0404, *0408, and *01) with rheumatoid arthritis was confirmed. The DRB1*0401 haplotypes carried a far stronger risk for the disease than the (DRB1*01/10)-(DQA1*01)-DQB1*0501 haplotypes. Seven protective HLA haplotypes—(DRB1*15)-(DQA1*01)-DQB1*0602; (DRB1*08)-(DQA1*04)-DQB1*04; (DRB1*11/12)-DQA1*05-DQB1*0301; (DRB1*1301)-(DQA1*01)-DQB1*0603; (DRB1*1302)-(DQA1*01)-DQB1*0604; (DRB1*07)-DQA1*0201-DQB1*0303; and (DRB1*16)- (DQA1*01)-DQB1*0502—were identified. In accordance with the reshaped shared epitope hypothesis, all the protective DRB1 alleles in these haplotypes share either isoleucine at position 67 or aspartic acid at position 70 in their third hypervariable region motif. However, differences in the disease risk of haplotypes carrying the same DR but different DQ alleles were also found: (DRB1*07)-DQA1*0201-DQB1*0303 was protective, while (DRB1*07)-DQA1*0201-DQB1*02 was neutral. The same haplotypes carried different risks for rheumatoid arthritis depending on their combination in genotypes. Conclusions: When assessing the influence of HLA genes on the susceptibility to rheumatoid arthritis, not only should the HLA-DR or -DQ alleles or haplotypes be unravelled but also the genotype. The effect of HLA class II region genes is more complicated than any of the existing hypotheses can explain. PMID:15479890

  1. Multiple myeloma

    MedlinePlus

    Plasma cell dyscrasia; Plasma cell myeloma; Malignant plasmacytoma; Plasmacytoma of bone; Myeloma - multiple ... Multiple myeloma most commonly causes: Low red blood cell count ( anemia ), which can lead to fatigue and ...

  2. [The HLA system in the Moroccan population: General review].

    PubMed

    Brick, C; Atouf, O; Essakalli, M

    2015-01-01

    The Moroccan population is an interesting study model of Human Leukocyte Antigen (HLA) polymorphism given its ethnic and genetic diversity. Through an analysis of the literature, this work proposes to establish a balance of knowledge for this population in the field of histocompatibility: HLA diversity, anthropology, transplantation and HLA associations and diseases. This analysis shows that the HLA system has not been fully explored within the Moroccan population. However, the results obtained allowed us to initiate a database reflecting the specific healthy Moroccan population HLA polymorphism to identify immigration flows and relationships with different people of the world and to reveal the association of certain HLA alleles with frequent pathologies. We also propose to analyze the reasons hindering the development of this activity in Morocco and we will try to identify some perspectives. PMID:26597780

  3. Rga (Rodgers) and the HLA region: linkage and associations.

    PubMed

    Giles, C M; Gedde-Dahl, T; Robson, E B; Thorsby, E; Olaisen, B; Arnason, A; Kissmeyer-Nielsen, F; Schreuder, I

    1976-08-01

    In 19 families with 97 children the segregation of Rga (Rodgers) was found to be compatible with Mendelian inheritance and five backcross and 14 intercross families were found among HLA and Bf typed families. Close linkage (lods + 17.82) without recombination was found between Rg and the HLA region, with a direct count of 96 nonrecombinant meioses for Rg-HLA-B. Rg- was strongly associated with HLA-B8 (29 of 30 haplotypes) and probably associated with Bw40, but did occur on other HLA-B haplotypes. By inference Rg- is negatively associated with Ch- (Chido). The Rg-Ch- haplotype has not been observed. Rga and Cha may or may not be coded for by different sites of the same cistron closely linked to HLA-B:C and cannot as yet be excluded from being parts of B or C.

  4. Involvement of position-147 for HLA-E expression

    SciTech Connect

    Matsunami, Katsuyoshi; Kusama, Tamiko; Okura, Eiji; Shirakura, Ryota; Fukuzawa, Masahiro; Miyagawa, Shuji . E-mail: miyagawa@orgtrp.med.osaka-u.ac.jp

    2006-09-01

    HLA-E functions as an inhibitory signaling molecule of natural killer (NK) cell-mediated cytolysis. However, the cell surface expression of HLA-E molecules is quite restricted because of the limited repertoire of binding peptide sequences, such as signal peptides of other HLA molecules, especially on xenogeneic cells. In this study, we successfully determined that position-147 is an important amino acid position for cell surface expression by producing point substitutions. For further studies concerning transplantation therapy, the point substitution, Ser147Cys, that resulted in a single atom change, oxygen to sulfur, designated as HLA-Ev(147), led to a much higher expression on the human and pig cell surface and a greater inhibitory function against human NK cells than wild type HLA-E in an in vitro model system of pig to human xenotransplantation. Consequently, HLA-Ev(147) might be a promising alternative gene tool for future transplantation therapy such as xenotransplantation.

  5. Detection of HLA-DR on microglia in the human brain is a function of both clinical and technical factors.

    PubMed Central

    Mattiace, L. A.; Davies, P.; Dickson, D. W.

    1990-01-01

    Detection of HLA-DR, a class II major histocompatibility antigen, on glial cells is dependent not only on duration and type of tissue fixation and processing, but also on clinical factors. Glial cells labeled by anti-HLA-DR were consistent with microglia by light microscopic and ultrastructural criteria, and were colabeled with other microglial markers, including LN-1, Leu-M5, and leukocyte common antigen (LCA). In young and elderly subjects who died suddenly, anti-HLA-DR labeled microglia in the white matter, but far fewer cells in the gray matter. In subjects who died of chronic debilitating illness, such as Alzheimer's disease and carcinomatosis, anti-HLA-DR labeled numerous microglia throughout both the gray and white matter. In Alzheimer's disease, microglia were aggregated in compact senile plaques, but loosely associated with diffuse amyloid deposits. These results suggest that HLA-DR may be constitutively expressed in white matter, but induced in gray matter microglia in chronic disease states or in association with amyloid deposits. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 PMID:1693471

  6. A human homologue to the yeast omnipotent suppressor 45 maps 100 kb centromeric to HLA-A

    SciTech Connect

    Chauvel, B.; Dorval, I.; Fergelot, P.

    1995-04-01

    Idipathic hemochromatosis is a common autosomal recessive inherited disorder of iron metabolism. The molecular defect is unknown. However, the gene responsible for the disease (HFE) has been localized on the short arm of chromosome 6. It is closely linked to the HLA class I genes and possibly within a 350 kilobase (kb) region around the HLA-A locus. In order to identify candidate genes for hemochromatosis, we applied a cDNA selection technique to isolate transcribed sequences encoded on yeast artificial chromosomes (YAC). At first, we screened a cDNA library derived from normal human duodenal mucosa with the YAC B30 H3. This YAC contains a 320 kb DNA insert including the HLA-A gene and spanning 150 kb of the 350 kb zone where the hemochromatosis gene is in linkage disequilibrium with restriction fragment length polymorphism (RFLP) markers. Preparation of the cDNA library of duodenal mucosa in Lambda Zap II phage and library screening with YAC B30 were carried out as previously described. In this way, we isolated seven non-HLA-A cDNAs corresponding to seven new genomic sequences. These potential genes were named hemochromatosis candidate gene (HCG) and numbered I to VII. The survey of all these cDNAs and their corresponding genomic sequences is in progress. In this work, we are especially interested in one of the seven non-HLA class I cDNA clones, named clone 58. 12 refs., 2 figs.

  7. HLA-DQB1*02 and DQB1*06:03P are associated with peanut allergy.

    PubMed

    Madore, Anne-Marie; Vaillancourt, Vanessa T; Asai, Yuka; Alizadehfar, Reza; Ben-Shoshan, Moshe; Michel, Deborah L; Kozyrskyj, Anita L; Becker, Allan; Chan-Yeung, Moira; Clarke, Ann E; Hull, Peter; Daley, Denise; Sandford, Andrew J; Laprise, Catherine

    2013-10-01

    Peanut allergy (PA) is a common and serious food allergy and its prevalence has increased in the past decade. Although there is strong evidence of inheritance, the genetic causes of this disease are not well understood. Previously, a large-scale genome-wide association study described an association between human leukocyte antigen (HLA)-DQB1 and asthma; the aim of this study was to evaluate the association between HLA-DQB1 and PA. Genotypic and allelic profiles were established for 311 Caucasian members of a well-described Canadian group of children with PA and 226 Caucasian controls. Firth's logistic regression analyses showed associations between HLA-DQB1 alleles and PA for DQB1*02 (P=1.1 × 10(-8), odds ratio (OR)=0.09 (CI=0.03-0.23)) and DQB1*06:03P alleles (P=2.1 × 10(-2), OR=2.82 (CI=1.48-5.45)). This study of HLA in PA demonstrates specific association between two allelic groups of the HLA-DQB1 gene (DQB1*02 and DQB1*06:03P) and PA, highlighting its possible role in the development of this disease. PMID:23443026

  8. Analysis of the adequate size of a cord blood bank and comparison of HLA haplotype distributions between four populations.

    PubMed

    Haimila, Katri; Penttilä, Antti; Arvola, Anne; Auvinen, Marja-Kaisa; Korhonen, Matti

    2013-02-01

    The number of units and especially the number of different HLA haplotypes present in a cord blood (CB) bank is a crucial determinant of its usefulness. We generated data relevant to the development of our national CB in Finland. The HLA haplotype distribution was examined between specific populations. We developed graphical ways of data presentation that enable easy visualization of differences. First, we estimated the optimal size of a CB bank for Finland and found that approximately 1700 units are needed to provide a 5/6 HLA-matched donor for 80% of Finnish patients. Secondly, we evaluated HLA haplotype distributions between four locations, Finland, Japan, Sweden and Belgium. Our results showed that the Japanese Tokyo Cord Blood Bank differs in both the frequency and distribution of haplotypes from the European banks. The European banks (Finnish Cord Blood Registry, The Swedish National Cord Blood Bank, and Marrow Donor Program-Belgium) have similar frequencies of common haplotypes, but 26% of the haplotypes in the Finnish CB bank are unique, which justifies the existence of a national bank. The tendency to a homogenous HLA haplotype distribution in banks underlines the need for targeting recruitment at the poorly represented minority populations.

  9. HLA-C Downmodulation by HIV-1 Vpu.

    PubMed

    Barker, Edward; Evans, David T

    2016-05-11

    It is widely held that HIV-1 Nef downmodulates HLA-A and -B to protect infected cells from CD8(+) T cells but leaves HLA-C on the cell surface to inhibit NK cells. In this issue of Cell Host & Microbe, Apps et al. (2016) revise this model by showing that the Vpu protein of primary HIV-1 isolates downmodulate HLA-C.

  10. Logistic transmission modeling of HLA and ankylosing spondylitis

    SciTech Connect

    Scofield, R.H.; Neas, B.R.; Harley, J.B.

    1994-09-01

    A nonparametric and general method of linkage analysis has been developed and used to evaluate histocompatibility (HLA) linkage to ankylosing spondylitis (AS) from the data of Berg & Moller. The conditional logistic function has been used to establish linkage by stepwise modelling of transmission from parent to progeny. Logistic transmission models have been explored to better understand the relationship of HLA to AS. The alleles at HLA-A and -B were determined in 38 families (32 monoplex and 6 multiplex). We have found that linkage is supported in this data over the random transmission of alleles at only HLA-B. Models constructed at HLA-B are powerful with, for example, coefficients for B27 of 1.9 (S.E. = 0.4) and B40 of 1.6 (S.E. = 0.8) contributing to a model with {chi}{sup 2} = 30 with 2 df and p < 3x10{sup -7}. No models are found supporting linkage at HLA-A and, therefore, the data at HLA-A does not add support for linkage beyond that present at HLA-B (e.g., {chi}{sup 2} for improvement < 1). These results establish that HLA-B is linked to AS. They further provide evidence that the gene responsible for AS is located nearer to HLA-B than it is to HLA-A. Also, the analysis shows that a number of HLA-B alleles may contribute to the risk of AS, beyond the B27 allele which has repeatedly been associated with AS.

  11. Recent developments in HLA-haploidentical transplantations

    PubMed Central

    Showel, Margaret; Fuchs, Ephraim J.

    2016-01-01

    While allogeneic hematopoietic stem cell transplantations have a curative potential, several patients with hematologic malignancies cannot avail themselves of this therapeutic option due to lack of matched donor availability. Although HLA-haploidentical transplantations were previously associated with poor outcomes, recent evidence with use of post transplantation cyclophosphamide indicate improved safety and efficacy. The following paper discusses the most recent developments in this area. PMID:26590771

  12. HLA-E: A Novel Player for Histocompatibility

    PubMed Central

    Kraemer, Thomas; Blasczyk, Rainer; Bade-Doeding, Christina

    2014-01-01

    The classical class I human leukocyte antigens (HLA-A, -B, and -C) present allele-specific self- or pathogenic peptides originated by intracellular processing to CD8+ immune effector cells. Even a single mismatch in the heavy chain (hc) of an HLA class I molecule can impact on the peptide binding profile. Since HLA class I molecules are highly polymorphic and most of their polymorphisms affect the peptide binding region (PBR), it becomes obvious that systematic HLA matching is crucial in determining the outcome of transplantation. The opposite holds true for the nonclassical HLA class I molecule HLA-E. HLA-E polymorphism is restricted to two functional versions and is thought to present a limited set of highly conserved peptides derived from class I leader sequences. However, HLA-E appears to be a ligand for the innate and adaptive immune system, where the immunological response to peptide-HLA-E complexes is dictated through the sequence of the bound peptide. Structural investigations clearly demonstrate how subtle amino acid differences impact the strength and response of the cognate CD94/NKG2 or T cell receptor. PMID:25401109

  13. The Relevance of HLA Sequencing in Population Genetics Studies

    PubMed Central

    Sanchez-Mazas, Alicia

    2014-01-01

    Next generation sequencing (NGS) is currently being adapted by different biotechnological platforms to the standard typing method for HLA polymorphism, the huge diversity of which makes this initiative particularly challenging. Boosting the molecular characterization of the HLA genes through efficient, rapid, and low-cost technologies is expected to amplify the success of tissue transplantation by enabling us to find donor-recipient matching for rare phenotypes. But the application of NGS technologies to the molecular mapping of the MHC region also anticipates essential changes in population genetic studies. Huge amounts of HLA sequence data will be available in the next years for different populations, with the potential to change our understanding of HLA variation in humans. In this review, we first explain how HLA sequencing allows a better assessment of the HLA diversity in human populations, taking also into account the methodological difficulties it introduces at the statistical level; secondly, we show how analyzing HLA sequence variation may improve our comprehension of population genetic relationships by facilitating the identification of demographic events that marked human evolution; finally, we discuss the interest of both HLA and genome-wide sequencing and genotyping in detecting functionally significant SNPs in the MHC region, the latter having also contributed to the makeup of the HLA molecular diversity observed today. PMID:25126587

  14. A common prostate cancer risk variant 5’ of MSMB (microseminoprotein-beta) is a strong predictor of circulating MSP (microseminoprotein) in multiple populations

    PubMed Central

    Waters, Kevin M.; Stram, Daniel O.; Le Marchand, Loic; Klein, Robert J.; Valtonen-André, Camilla; Peltola, Mari; Kolonel, Laurence N.; Henderson, Brian E.; Lilja, Hans; Haiman, Christopher A.

    2010-01-01

    Background Beta-microseminoprotein (MSP) is one of the three most abundantly secreted proteins of the prostate, and has been suggested as a biomarker for prostate cancer risk. A common variant, rs10993994, in the 5’ region of the gene which encodes MSP (MSMB), has recently been identified as a risk factor for prostate cancer. Methods We examined the association between rs10993994 genotype and MSP levels in a sample of 500 prostate cancer-free men from four racial/ethnic populations in the Multiethnic Cohort (European Americans, African Americans, Latinos, and Japanese Americans). Generalized linear models were used to estimate the association between rs10993994 genotype and MSP levels. Results We observed robust associations between rs10994994 genotype and MSP levels in each racial/ethnic population (all P<10−8) with carriers of the C allele having lower geometric mean MSP levels (ng/mL) (CC/CT/TT genotypes: European Americans, 28.8/20.9/10.0; African Americans, 29.0/21.9/10.9; Latinos, 29.2/17.1/8.3; and Japanese Americans 25.8/16.4/6.7). We estimated the variant accounts for 30–50% of the variation in MSP levels in each population. We also observed significant differences in MSP levels between populations (P=3.5×10−6), with MSP levels observed to be highest in African Americans and lowest in Japanese Americans. Conclusions Rs10993994 genotype is strongly associated with plasma MSP levels in multiple racial/ethnic populations. Impact This supports the hypothesis that rs10993994 may be the biologically functional allele. PMID:20736317

  15. Novel associations between contaminant body burdens and biomarkers of reproductive condition in male Common Carp along multiple gradients of contaminant exposure in Lake Mead National Recreation Area, USA

    USGS Publications Warehouse

    Patino, Reynaldo; VanLandeghem, Matthew M.; Goodbred, Steven L.; Orsak, Erik; Jenkins, Jill A.; Echols, Kathy R.; Rosen, Michael R.; Torres, Leticia

    2015-01-01

    Adult male Common Carp were sampled in 2007/08 over a full reproductive cycle at Lake Mead National Recreation Area. Sites sampled included a stream dominated by treated wastewater effluent, a lake basin receiving the streamflow, an upstream lake basin (reference), and a site below Hoover Dam. Individual body burdens for 252 contaminants were measured, and biological variables assessed included physiological [plasma vitellogenin (VTG), estradiol-17β (E2), 11-ketotestosterone (11KT)] and organ [gonadosomatic index (GSI)] endpoints. Patterns in contaminant composition and biological condition were determined by Principal Component Analysis, and their associations modeled by Principal Component Regression. Three spatially distinct but temporally stable gradients of contaminant distribution were recognized: a contaminant mixture typical of wastewaters (PBDEs, methyl triclosan, galaxolide), PCBs, and DDTs. Two spatiotemporally variable patterns of biological condition were recognized: a primary pattern consisting of reproductive condition variables (11KT, E2, GSI), and a secondary pattern including general condition traits (condition factor, hematocrit, fork length). VTG was low in all fish, indicating low estrogenic activity of water at all sites. Wastewater contaminants associated negatively with GSI, 11KT and E2; PCBs associated negatively with GSI and 11KT; and DDTs associated positively with GSI and 11KT. Regression of GSI on sex steroids revealed a novel, nonlinear association between these variables. Inclusion of sex steroids in the GSI regression on contaminants rendered wastewater contaminants nonsignificant in the model and reduced the influence of PCBs and DDTs. Thus, the influence of contaminants on GSI may have been partially driven by organismal modes-of-action that include changes in sex steroid production. The positive association of DDTs with 11KT and GSI suggests that lifetime, sub-lethal exposures to DDTs have effects on male carp opposite of those

  16. Multiple virus lineages sharing recent common ancestry were associated with a Large Rift Valley fever outbreak among livestock in Kenya during 2006-2007.

    PubMed

    Bird, Brian H; Githinji, Jane W K; Macharia, Joseph M; Kasiiti, Jacqueline L; Muriithi, Rees M; Gacheru, Stephen G; Musaa, Joseph O; Towner, Jonathan S; Reeder, Serena A; Oliver, Jennifer B; Stevens, Thomas L; Erickson, Bobbie R; Morgan, Laura T; Khristova, Marina L; Hartman, Amy L; Comer, James A; Rollin, Pierre E; Ksiazek, Thomas G; Nichol, Stuart T

    2008-11-01

    Rift Valley fever (RVF) virus historically has caused widespread and extensive outbreaks of severe human and livestock disease throughout Africa, Madagascar, and the Arabian Peninsula. Following unusually heavy rainfall during the late autumn of 2006, reports of human and animal illness consistent with RVF virus infection emerged across semiarid regions of the Garissa District of northeastern Kenya and southern Somalia. Following initial RVF virus laboratory confirmation, a high-throughput RVF diagnostic facility was established at the Kenyan Central Veterinary Laboratories in Kabete, Kenya, to support the real-time identification of infected livestock and to facilitate outbreak response and control activities. A total of 3,250 specimens from a variety of animal species, including domesticated livestock (cattle, sheep, goats, and camels) and wildlife collected from a total of 55 of 71 Kenyan administrative districts, were tested by molecular and serologic assays. Evidence of RVF infection was found in 9.2% of animals tested and across 23 districts of Kenya, reflecting the large number of affected livestock and the geographic extent of the outbreak. The complete S, M, and/or L genome segment sequence was obtained from a total of 31 RVF virus specimens spanning the entire known outbreak period (December-May) and geographic areas affected by RVF virus activity. Extensive genomic analyses demonstrated the concurrent circulation of multiple virus lineages, gene segment reassortment, and the common ancestry of the 2006/2007 outbreak viruses with those from the 1997-1998 east African RVF outbreak. Evidence of recent increases in genomic diversity and effective population size 2 to 4 years prior to the 2006-2007 outbreak also was found, indicating ongoing RVF virus activity and evolution during the interepizootic/epidemic period. These findings have implications for further studies of basic RVF virus ecology and the design of future surveillance/diagnostic activities, and

  17. Novel associations between contaminant body burdens and biomarkers of reproductive condition in male Common Carp along multiple gradients of contaminant exposure in Lake Mead National Recreation Area, USA.

    PubMed

    Patiño, Reynaldo; VanLandeghem, Matthew M; Goodbred, Steven L; Orsak, Erik; Jenkins, Jill A; Echols, Kathy; Rosen, Michael R; Torres, Leticia

    2015-08-01

    Adult male Common Carp were sampled in 2007/08 over a full reproductive cycle at Lake Mead National Recreation Area. Sites sampled included a stream dominated by treated wastewater effluent, a lake basin receiving the streamflow, an upstream lake basin (reference), and a site below Hoover Dam. Individual body burdens for 252 contaminants were measured, and biological variables assessed included physiological [plasma vitellogenin (VTG), estradiol-17β (E2), 11-ketotestosterone (11KT)] and organ [gonadosomatic index (GSI)] endpoints. Patterns in contaminant composition and biological condition were determined by Principal Component Analysis, and their associations modeled by Principal Component Regression. Three spatially distinct but temporally stable gradients of contaminant distribution were recognized: a contaminant mixture typical of wastewaters (PBDEs, methyl triclosan, galaxolide), PCBs, and DDTs. Two spatiotemporally variable patterns of biological condition were recognized: a primary pattern consisting of reproductive condition variables (11KT, E2, GSI), and a secondary pattern including general condition traits (condition factor, hematocrit, fork length). VTG was low in all fish, indicating low estrogenic activity of water at all sites. Wastewater contaminants associated negatively with GSI, 11KT and E2; PCBs associated negatively with GSI and 11KT; and DDTs associated positively with GSI and 11KT. Regression of GSI on sex steroids revealed a novel, nonlinear association between these variables. Inclusion of sex steroids in the GSI regression on contaminants rendered wastewater contaminants nonsignificant in the model and reduced the influence of PCBs and DDTs. Thus, the influence of contaminants on GSI may have been partially driven by organismal modes-of-action that include changes in sex steroid production. The positive association of DDTs with 11KT and GSI suggests that lifetime, sub-lethal exposures to DDTs have effects on male carp opposite of those

  18. HLA-G1, but Not HLA-G3, Suppresses Human Monocyte/Macrophage-mediated Swine Endothelial Cell Lysis.

    PubMed

    Eguchi, H; Maeda, A; Lo, P C; Matsuura, R; Esquivel, E L; Asada, M; Sakai, R; Nakahata, K; Yamamichi, T; Umeda, S; Deguchi, K; Ueno, T; Okuyama, H; Miyagawa, S

    2016-05-01

    The inhibitory function of HLA-G1, a class Ib molecule, on monocyte/macrophage-mediated cytotoxicity was examined. The expression of inhibitory receptors that interact with HLA-G, immunoglobulin-like transcript 2 (ILT2), ILT4, and KIR2DL4 (CD158d) on in vitro-generated macrophages obtained from peripheral blood mononuclear cells and the phorbol 12-myristate 13-acetate (PMA)-activated THP-1 cells were examined by flow cytometry. cDNAs of HLA-G1, HLA-G3, HLA-E, and human β2-microglobulin were prepared, transfected into pig endothelial cells (PECs), and macrophage- and the THP-1 cell-mediated PEC cytolysis was then assessed. In vitro-generated macrophages expressed not only ILT2 and ILT4 but CD158d as well. The transgenic HLA-G1 on PEC indicated a significant suppression in macrophage-mediated cytotoxicity, which was equivalent to that of transgenic HLA-E. HLA-G1 was clearly expressed on the cell surface of PEC, whereas the levels of HLA-G3 were much lower and remained in the intracellular space. On the other hand, the PMA-activated THP-1 cell was less expressed these inhibitory molecules than in vitro-generated macrophages. Therefore, the HLA-G1 on PECs showed a significant but relatively smaller suppression to THP-1 cell-mediated cytotoxicity compared to in vitro-generated macrophages. These results indicate that by generating HLA-G1, but not HLA-G3, transgenic pigs can protect porcine grafts from monocyte/macrophage-mediated cytotoxicity. PMID:27320605

  19. Understanding of HLA-conferred susceptibility to chronic hepatitis B infection requires HLA genotyping-based association analysis

    PubMed Central

    Nishida, Nao; Ohashi, Jun; Khor, Seik-Soon; Sugiyama, Masaya; Tsuchiura, Takayo; Sawai, Hiromi; Hino, Keisuke; Honda, Masao; Kaneko, Shuichi; Yatsuhashi, Hiroshi; Yokosuka, Osamu; Koike, Kazuhiko; Kurosaki, Masayuki; Izumi, Namiki; Korenaga, Masaaki; Kang, Jong-Hon; Tanaka, Eiji; Taketomi, Akinobu; Eguchi, Yuichiro; Sakamoto, Naoya; Yamamoto, Kazuhide; Tamori, Akihiro; Sakaida, Isao; Hige, Shuhei; Itoh, Yoshito; Mochida, Satoshi; Mita, Eiji; Takikawa, Yasuhiro; Ide, Tatsuya; Hiasa, Yoichi; Kojima, Hiroto; Yamamoto, Ken; Nakamura, Minoru; Saji, Hiroh; Sasazuki, Takehiko; Kanto, Tatsuya; Tokunaga, Katsushi; Mizokami, Masashi

    2016-01-01

    Associations of variants located in the HLA class II region with chronic hepatitis B (CHB) infection have been identified in Asian populations. Here, HLA imputation method was applied to determine HLA alleles using genome-wide SNP typing data of 1,975 Japanese individuals (1,033 HBV patients and 942 healthy controls). Together with data of an additional 1,481 Japanese healthy controls, association tests of six HLA loci including HLA-A, C, B, DRB1, DQB1, and DPB1, were performed. Although the strongest association was detected at a SNP located in the HLA-DP locus in a SNP-based GWAS using data from the 1,975 Japanese individuals, HLA genotyping-based analysis identified DQB1*06:01 as having the strongest association, showing a greater association with CHB susceptibility (OR = 1.76, P = 6.57 × 10−18) than any one of five HLA-DPB1 alleles that were previously reported as CHB susceptibility alleles. Moreover, HLA haplotype analysis showed that, among the five previously reported HLA-DPB1 susceptibility and protective alleles, the association of two DPB1 alleles (DPB1*09:01, and *04:01) had come from linkage disequilibrium with HLA-DR-DQ haplotypes, DRB1*15:02-DQB1*06:01 and DRB1*13:02-DQB1*06:04, respectively. The present study showed an example that SNP-based GWAS does not necessarily detect the primary susceptibility locus in the HLA region. PMID:27091392

  20. HLA genes in Mexican Teeneks: HLA genetic relationship with other worldwide populations.

    PubMed

    Vargas-Alarcón, Gilberto; Hernández-Pacheco, Guadalupe; Moscoso, Juan; Pérez-Hernández, Nonanzit; Murguía, Luis Enrique; Moreno, Almudena; Serrano-Vela, Juan Ignacio; Granados, Julio; Arnaiz-Villena, Antonio

    2006-03-01

    The HLA allele frequency distribution of the Mexican Teenek Indians has been studied and compared with those of other First American Natives and worldwide populations (a total of 15694 chromosomes from 73 different populations were analyzed). This study corroborate the restricted HLA polymorphism in the Amerindian populations and demonstrate how the Amerindians show a relatively homogeneity as opposed to other First Native American groups. Finally, the present data support previous ones that state the lack of complete correlation between language and genetics in micro-environmental studies; Teenek Mayan language does not correspond with a close Mayan (Guatemala) relatedness.

  1. Comparison of HIV-1 nef and gag Variations and Host HLA Characteristics as Determinants of Disease Progression among HIV-1 Vertically Infected Kenyan Children

    PubMed Central

    Saina, Matilda Chelimo; Bi, Xiuqiong; Lihana, Raphael; Lwembe, Raphael; Ishizaki, Azumi; Panikulam, Annie; Palakudy, Tresa; Musoke, Rachel; Owens, Mary; Songok, Elijah Maritim; Ichimura, Hiroshi

    2015-01-01

    Objectives Disease progression varies among HIV-1-infected individuals. The present study aimed to explore possible viral and host factors affecting disease progression in HIV-1-infected children. Methods Since 2000, 102 HIV-1 vertically-infected children have been followed-up in Kenya. Here we studied 29 children (15 male/14 female) who started antiretroviral treatment at <5 years of age (rapid progressors; RP), and 32 (17 male/15 female) who started at >10 years of age (slow progressors; SP). Sequence variations in the HIV-1 gag and nef genes and the HLA class I-related epitopes were compared between the two groups. Results Based on nef sequences, HIV-1 subtypes A1/D were detected in 62.5%/12.5% of RP and 66.7%/20% of SP, with no significant difference in subtype distribution between groups (p = 0.8). In the ten Nef functional domains, only the PxxP3 region showed significantly greater variation in RP (33.3%) than SP (7.7%, p = 0.048). Gag sequences did not significantly differ between groups. The reportedly protective HLA-A alleles, A*74:01, A*32:01 and A*26, were more commonly observed in SP (50.0%) than RP (11.1%, p = 0.010), whereas the reportedly disease-susceptible HLA-B*45:01 was more common in RP (33.3%) than SP (7.4%, p = 0.045). Compared to RP, SP showed a significantly higher median number of predicted HLA-B-related 12-mer epitopes in Nef (3 vs. 2, p = 0.037), HLA-B-related 11-mer epitopes in Gag (2 vs. 1, p = 0.029), and HLA-A-related 9-mer epitopes in Gag (4 vs. 1, p = 0.051). SP also had fewer HLA-C-related epitopes in Nef (median 4 vs. 5, p = 0.046) and HLA-C-related 11-mer epitopes in Gag (median 1 vs. 1.5, p = 0.044) than RP. Conclusions Compared to rapid progressors, slow progressors had more protective HLA-A alleles and more HLA-B-related epitopes in both the Nef and Gag proteins. These results suggest that the host factor HLA plays a stronger role in disease progression than the Nef and Gag sequence variations in HIV-1-infected Kenyan children

  2. Molecular genetics (HLA) of Behçet's disease.

    PubMed

    Mizuki, N; Inoko, H; Ohno, S

    1997-12-01

    Behçet's disease (BD) has been known to be strongly associated with the human leukocyte antigen (HLA) B51. This B51 association has been confirmed in many different ethnic groups between the Middle East and Japan, and it has been proposed that BD is prevalent in those ethnic groups along the old Silk Route. The hypothesis could be made that B51 molecules are primarily involved in BD development through specific antigen presentation. However, polymorphic analyses of the TNFB gene and Tau-a microsatellite between the HLA-B and TNF genes indicate that the pathogenic gene of BD is not the HLA-B51 gene itself but another gene located around the HLA-B gene. HLA-C genotyping by the PCR-SSP method also suggests that the BD pathogenic gene is not the HLA-C gene itself but other gene located near the HLA-B gene. Recently we sequenced a single contig of 236,822 bp from the MICA gene (58.2 kb centromeric of HLA-B) to 90.8 kb telomeric of HLA-C and identified 8 novel genes designated NOB1-8 (NOB: new organization associated with HLA-B). During the course of the genomic sequence analysis we clarified the genetic structure of the MICA (MHC class I chain-related gene A) gene and found a triplet repeat microsatellite polymorphism of (GCT/AGC)n in the transmebrane (TM) region. Furthermore, the microsatellite allele consisting of 6 repetitions of GCT/AGC (MICA A6 allele) was present at a significantly higher frequency in the BD patient group than in the control group and a significant fraction of B51-negative patients were positive for this MICA A6 allele. These results suggest the possibility of a primary association of BD with MICA rather than HLA-B.

  3. Combined Effects of Ankylosing Spondylitis-associated ERAP1 Polymorphisms Outside the Catalytic and Peptide-binding Sites on the Processing of Natural HLA-B27 Ligands*

    PubMed Central

    Martín-Esteban, Adrian; Gómez-Molina, Patricia; Sanz-Bravo, Alejandro; López de Castro, José A.

    2014-01-01

    ERAP1 polymorphism involving residues 528 and 575/725 is associated with ankylosing spondylitis among HLA-B27-positive individuals. We used four recombinant variants to address the combined effects of the K528R and D575N polymorphism on the processing of HLA-B27 ligands. The hydrolysis of a fluorogenic substrate, Arg-528/Asp-575 < Lys-528/Asp-575 < Arg-528/Asn-575 < Lys-528/Asn-575, indicated that the relative activity of variants carrying Arg-528 or Lys-528 depends on residue 575. Asp-575 conferred lower activity than Asn-575, but the difference depended on residue 528. The same hierarchy was observed with synthetic precursors of HLA-B27 ligands, but the effects were peptide-dependent. Sometimes the epitope yields were variant-specific at all times. For other peptides, concomitant generation and destruction led to similar epitope amounts with all the variants at long, but not at short, digestion times. The generation/destruction balance of two related HLA-B27 ligands was analyzed in vitro and in live cells. Their relative yields at long digestion times were comparable with those from HLA-B27-positive cells, suggesting that ERAP1 was a major determinant of the abundance of these peptides in vivo. The hydrolysis of fluorogenic and peptide substrates by an HLA-B27 ligand or a shorter peptide, respectively, was increasingly inhibited as a function of ERAP1 activity, indicating that residues 528 and 575 affect substrate inhibition of ERAP1 trimming. The significant and complex effects of co-occurring ERAP1 polymorphisms on multiple HLA-B27 ligands, and their potential to alter the immunological and pathogenetic features of HLA-B27 as a function of the ERAP1 context, explain the epistatic association of both molecules in ankylosing spondylitis. PMID:24352655

  4. Structural analysis of the HLA-A/HLA-F subregion: Precise localization of two new multigene families closely associated with the HLA class I sequences

    SciTech Connect

    Pichon, L.; Carn, G.; Bouric, P.

    1996-03-01

    Positional cloning strategies for the hemochromatosis gene have previously concentrated on a target area restricted to a maximum genomic expanse of 400 kb around the HLA-A and HLA-F loci. Recently, the candidate region has been extended to 2-3 Mb on the distal side of the MHC. In this study, 10 coding sequences [hemochromatosis candidate genes (HCG) I to X] were isolated by cDNA selection using YACs covering the HLA-A/HLA-F subregion. Two of these (HCG II and HCG IV) belong to multigene families, as well as other sequences already described in this region, i.e., P5, pMC 6.7, and HLA class I. Fingerprinting of the four YACSs overlapping the region was performed and allowed partial localization of the different multigene family sequences on each YAC without defining their exact positions. Fingerprinting on cosmids isolated from the ICRF chromosome 6-specific cosmid library allowed more precise localization of the redundant sequences in all of the multigene families and revealed their apparent organization in clusters. Further examination of these intertwined sequences demonstrated that this structural organization resulted from a succession of complex phenomena, including duplications and contractions. This study presents a precise description of the structural organization of the HLA-A/HLA-F region and a determination of the sequences involved in the megabase size polymorphism observed among the A3, A24, and A31 haplotypes. 29 refs., 2 figs., 2 tabs.

  5. Promiscuous Recognition of a Trypanosoma cruzi CD8+ T Cell Epitope among HLA-A2, HLA-A24 and HLA-A1 Supertypes in Chagasic Patients

    PubMed Central

    Guzmán, Fanny; Rosas, Fernando; Thomas, M. Carmen; López, Manuel Carlos; González, John Mario; Cuéllar, Adriana; Puerta, Concepción J.

    2016-01-01

    Background TcTLE is a nonamer peptide from Trypanosoma cruzi KMP-11 protein that is conserved among different parasite strains and that is presented by different HLA-A molecules from the A2 supertype. Because peptides presented by several major histocompatibility complex (MHC) supertypes are potential targets for immunotherapy, the aim of this study was to determine whether MHC molecules other than the A2 supertype present the TcTLE peptide. Methodology/Principal Findings From 36 HLA-A2-negative chagasic patients, the HLA-A genotypes of twenty-eight patients with CD8+ T cells that recognized the TcTLE peptide using tetramer (twenty) or functional (eight) assays, were determined. SSP-PCR was used to identify the A locus and the allelic variants. Flow cytometry was used to analyze the frequency of TcTLE-specific CD8+ T cells, and their functional activity (IFN-γ, TNFα, IL-2, perforin, granzyme and CD107a/b production) was induced by exposure to the TcTLE peptide. All patients tested had TcTLE-specific CD8+ T cells with frequencies ranging from 0.07–0.37%. Interestingly, seven of the twenty-eight patients had HLA-A homozygous alleles: A*24 (5 patients), A*23 (1 patient) and A*01 (1 patient), which belong to the A24 and A1 supertypes. In the remaining 21 patients with HLA-A heterozygous alleles, the most prominent alleles were A24 and A68. The most common allele sub-type was A*2402 (sixteen patients), which belongs to the A24 supertype, followed by A*6802 (six patients) from the A2 supertype. Additionally, the A*3002/A*3201 alleles from the A1 supertype were detected in one patient. All patients presented CD8+ T cells producing at least one cytokine after TcTLE peptide stimulation. Conclusion/Significance These results show that TcTLE is a promiscuous peptide that is presented by the A24 and A1 supertypes, in addition to the A2 supertype, suggesting its potential as a target for immunotherapy. PMID:26974162

  6. Networks of intergenic long-range enhancers and snpRNAs drive castration-resistant phenotype of prostate cancer and contribute to pathogenesis of multiple common human disorders

    PubMed Central

    Glinskii, Anna B; Ma, Shuang; Ma, Jun; Grant, Denise; Lim, Chang-Uk; Guest, Ian; Sell, Stewart; Buttyan, Ralph

    2011-01-01

    The mechanistic relevance of intergenic disease-associated genetic loci (IDAGL) containing highly statistically significant disease-linked SNPs remains unknown. Here, we present experimental and clinical evidence supporting the importantance of the role of IDAGL in human diseases. A targeted RT-PCR screen coupled with sequencing of purified PCR products detects widespread transcription at multiple IDAGL and identifies 96 small noncoding trans-regulatory RNAs of ∼100–300 nt in length containing SNPs (snpRNAs) associated with 21 common disorders. Multiple independent lines of experimental evidence support functionality of snpRNAs by documenting their cell type-specific expression and evolutionary conservation of sequences, genomic coordinates and biological effects. Chromatin state signatures, expression profiling experiments and luciferase reporter assays demonstrate that many IDAGL are Polycomb-regulated long-range enhancers. Expression of snpRNAs in human and mouse cells markedly affects cellular behavior and induces allele-specific clinically relevant phenotypic changes: NLRP1-locus snpRNAs rs2670660 exert regulatory effects on monocyte/macrophage transdifferentiation, induce prostate cancer (PC) susceptibility snpRNAs and transform low-malignancy hormone-dependent human PC cells into highly malignant androgen-independent PC. Q-PCR analysis and luciferase reporter assays demonstrate that snpRNA sequences represent allele-specific “decoy” targets of microRNAs that function as SNP allele-specific modifiers of microRNA expression and activity. We demonstrate that trans-acting RNA molecules facilitating resistance to androgen depletion (RAD) in vitro and castration-resistant phenotype (CRP) in vivo of PC contain intergenic 8q24-locus SNP variants (rs1447295; rs16901979; rs6983267) that were recently linked with increased risk of PC. Q-PCR analysis of clinical samples reveals markedly increased and highly concordant (r = 0.896; p < 0.0001) snpRNA expression

  7. Establishing a Population-Based HLA-Antibody Panel for Flow Cytometric Monitoring of Chimerism in HLA-Haploidentical Stem Cell Transplantation.

    PubMed

    Choe, Wonho; Hwang, Min-A; Jang, Seongsoo; Park, Chan-Jeoung; Chi, Hyun-Sook; Im, Ho Joon

    2016-01-01

    Determining the chimerism in stem cell transplantation (SCT) is important in the monitoring of engraftment. Conventional monitoring methods such as short tandem repeat polymerase chain reaction (STR-PCR) are labor intensive and difficult in showing the dynamics of cell subpopulations. In HLA-haploidentical SCT, flow cytometric analysis using anti-HLA antibody for the mismatched HLA can be useful in observing changes of cell subpopulations and determining chimerism. We designed a specific panel of HLA antibody reagents for the Korean population, and verified its clinical application in flow cytometric monitoring of chimerism after haploidentical stem cell transplantation. A total of 12 anti-HLA-A, -B-antibodies were selected, which could cover 82.5% of HLA-A and 16.5% of HLA-B in Korean population. This HLA panel distinguished donor and recipient cells in 22 of 23 HLA-haploidentical SCT cases. In one case, the patient had HLA-A*02/A*24, B*48/B*61 while the donor had HLA-A*02/A*33, B*44/B*48. The donor type HLA-B*44(+) and CD3(+) T cells, and HLA-B*44(+) and CD56(+) NK cells were seen at day 14 and day 8, respectively. Increased HLA-B*44(+) cells throughout the study period indicated the engraftment of donor stem cells. We were able to design a population specific panel of HLA-antibodies, and verified that flow cytometric analysis using HLA antibody for the detection of chimerism in HLA-haploidentical SCT was a simple and sensitive monitoring technique. This method allowed us to observe the dynamic changes in cell subpopulations after HLA-haploidentical SCT. Flow cytometric analysis can be considered as a strong tool for the monitoring of engraftment in HLA-haploidentical SCT.

  8. Allele Name Translation Tool and Update NomenCLature: software tools for the automated translation of HLA allele names between successive nomenclatures.

    PubMed

    Mack, S J; Hollenbach, J A

    2010-05-01

    In this brief communication, we describe the Allele Name Translation Tool (antt) and Update NomenCLature (uncl), free programs developed to facilitate the translation of human leukocyte antigen (HLA) allele names recorded using the December 2002 version of the HLA allele nomenclature (e.g. A*01010101) to those recorded using the colon-delimited version of the HLA allele nomenclature (e.g. A*01:01:01:01) that was adopted in April 2010. In addition, the antt and uncl translate specific HLA allele-name changes (e.g. DPB1*0502 is translated to DPB1*104:01), as well as changes to the locus prefix for HLA-C (i.e. Cw* is translated to C*). The antt and uncl will also translate allele names that have been truncated to two, four, or six digits, as well as ambiguous allele strings. The antt is a locally installed and run application, while uncl is a web-based tool that requires only an Internet connection and a modern browser. The antt accepts a variety of HLA data-presentation and allele-name formats. In addition, the antt can translate using user-defined conversion settings (e.g. the names of alleles that encode identical peptide binding domains can be translated to a common 'P-code'), and can serve as a preliminary data-sanity tool. The antt is available for download, and uncl for use, at www.igdawg.org/software.

  9. HLA polymorphism in a Guarani-Indian population from Paraguay and its usefulness for the Hispano-Indian admixture study in Paraguay.

    PubMed

    Benitez, O; Busson, M; Charron, D; Loiseau, P

    2011-02-01

    In this study we investigated the human leucocyte antigen-A (HLA-A), -B and DRB1 polymorphism of Native American population of Paraguay, the Guarani Indians. We found that the HLA variability consisted of 5 HLA-A, 7 HLA-B and 6 HLA-DRB1 groups of alleles and of several specific alleles (B*1504, B*3505, B*3912, B*4004, B*5104, DRB1*0411, DRB1*1413) common in other Native American populations. The comparison of the HLA polymorphism of the Guaranis from Paraguay with the «Mestizos» of Paraguay and the Spaniards showed that the «Mestizos» of Paraguay are genetically very distant from the Guarani Indians of Paraguay but much more close to the Spaniards. This can be explained, at least in part, by the history of the country. Our results are of importance in transplantation, in particular in the search for an unrelated donor for a Paraguayan patient requiring hematopoietic stem cell transplantation.

  10. Allele Name Translation Tool and Update NomenCLature: software tools for the automated translation of HLA allele names between successive nomenclatures.

    PubMed

    Mack, S J; Hollenbach, J A

    2010-05-01

    In this brief communication, we describe the Allele Name Translation Tool (antt) and Update NomenCLature (uncl), free programs developed to facilitate the translation of human leukocyte antigen (HLA) allele names recorded using the December 2002 version of the HLA allele nomenclature (e.g. A*01010101) to those recorded using the colon-delimited version of the HLA allele nomenclature (e.g. A*01:01:01:01) that was adopted in April 2010. In addition, the antt and uncl translate specific HLA allele-name changes (e.g. DPB1*0502 is translated to DPB1*104:01), as well as changes to the locus prefix for HLA-C (i.e. Cw* is translated to C*). The antt and uncl will also translate allele names that have been truncated to two, four, or six digits, as well as ambiguous allele strings. The antt is a locally installed and run application, while uncl is a web-based tool that requires only an Internet connection and a modern browser. The antt accepts a variety of HLA data-presentation and allele-name formats. In addition, the antt can translate using user-defined conversion settings (e.g. the names of alleles that encode identical peptide binding domains can be translated to a common 'P-code'), and can serve as a preliminary data-sanity tool. The antt is available for download, and uncl for use, at www.igdawg.org/software. PMID:20412076

  11. Analysis of HLA-B15 and HLA-B27 in spondyloarthritis with peripheral and axial clinical patterns

    PubMed Central

    Londono, John; Santos, Ana Maria; Peña, Paola; Calvo, Enrique; Espinosa, Luis R; Reveille, John D; Vargas-Alarcon, Gilberto; Jaramillo, Carlos A; Valle-Oñate, Rafael; Avila, Mabel; Romero, Consuelo; Medina, Juan F

    2015-01-01

    Objective Human leucocyte antigen (HLA) B27 and HLA-B15 are associated with spondyloarthritis (SpA). Recent Assessment of SpondyloArthritis international Society (ASAS) criteria emphasise a distinction between SpA with axial and peripheral patterns. We analysed whether HLA-A, HLA-B and HLA-DRB1 alleles could associate with these patterns. Methods We studied 100 healthy individuals and 178 patients with SpA according to European Spondyloarthropathy Study Group (ESSG) criteria. Patients were then classified according to ASAS criteria, the axial spondyloarthritis pattern (axSpA) being defined by ascertained sacroiliitis and the peripheral pattern (pSpA) by enthesitis and/or arthritis in extremities. A combined ax/p pattern was also considered. Results Only HLA-B27 and HLA-B15 alleles were associated with SpA. ASAS criteria for axSpA were met in 152 patients (12 with isolated axSpA and 140 with a combined ax/p patterns). When the ASAS peripheral criteria were applied, 161 patients met these criteria (13 with isolated pSpA and 148 with a combined ax/p pattern). HLA-B27 was found in 83% of patients with axSpA and 43% of ax/pSpA patients according to axASAS. HLA-B27 occurred in 7% controls but not in any patient with isolated pSpA. HLA-B15 was encountered in 31% of patients with isolated pSpA and 20% of ax/pSpA patients according to pASAS criteria. Moreover, 2 healthy controls, but none of our patients with isolated axSpA were positive for HLA-B15. Conclusions Our data suggest that the presence of HLA-B15 favours the development of isolated/combined peripheral rather than isolated axSpA, while HLA-B27 promotes an isolated/combined axial disease and excludes a peripheral pattern. HLA-B15 should be considered in addition to HLA-B27 when diagnosing patients with SpA according to ASAS criteria. PMID:26560062

  12. Virus-specific HLA-restricted lysis of herpes simplex virus-infected human monocytes and macrophages mediated by cytotoxic T lymphocytes

    SciTech Connect

    Torpey, D.J. III

    1987-01-01

    Freshly-isolated peripheral blood human monocytes and 5 day in vitro cultured macrophages were infected with herpes simplex virus type 1 (HSV-1), labeled with /sup 51/Cr, and used as target cells in a 12-14 hour cell-mediated cytotoxicity assay. Mononuclear leukocytes (MNL) from HSV-1 non-immune individuals, whether unstimulated or stimulated with HSV-1 antigen, did not mediate significant lysis of either target cell. HSV-immune MNL, both freshly-isolated and cultured for 5 days without antigen, demonstrated only low levels of natural killer (NK) cell-mediate lysis. MNL from HSV-immune individuals incubated for 5 days in vitro with HSV-1 antigen mediated significant virus-specific lysis of both target cells. Mean virus-specific lysis of autologous monocytes was 8.5(/+-/2.0)% compared to a three-fold greater virus-specific lysis of autologous macrophages. Greater than 70% of this lytic activity was mediated by Leu-11-negative, T3-positive cytotoxic T lymphocytes (CTL). Allogeneic target cells lacking a common HLA determinant were not significantly lysed while T8-positive CTL mediated infrequent lysis of target cells sharing a common HLA-A and/or HLA-B determinant. T4-positive lymphocytes were demonstrated to be the predominant cell mediating lysis of autologous target cells and allogeneic target cells sharing both HLA-A and/or HLA-B plus HLA-DR determinants with the CTL; the T4-positive cell was the sole CTL mediator of lysis of allogeneic target cells having a common HLA-DR determinant.

  13. HLA-B27 and pathogenesis of spondyloarthropathies.

    PubMed

    Turner, Matthew J; Colbert, Robert A

    2002-07-01

    Although the influence of HLA-B27 on the development of spondyloarthropathies is undisputed, its role in pathogenesis remains unclear. New ideas have focused on abnormal characteristics of HLA-B27 resulting from aberrant folding, disulfide bond formation, or both, rather than a predilection for selecting arthritogenic peptides. This reflects, in part, unanswered questions about whether immunologic recognition of HLA-B27 is required for disease. Recent studies suggest that CD4+ T cells, immunomodulatory killer cell Ig receptors, and Ig-like transcript receptors may recognize aberrant forms of HLA-B27. Other reports suggest that HLA-B27 expression can alter cytokine production from monocytes and T cells-effects that appear unrelated to antigen presentation. Novel bioinformatics approaches have led to the identification of HLA-B27-restricted pathogen-derived peptides and may prove useful in determining whether HLA-B27 presents arthritogenic peptides. Elucidating the role of HLA-B27 in the pathogenesis of these conditions will require an integration of information from animal models, genome-wide screens for susceptibility alleles, and translational studies using human samples.

  14. New Developments in HLA-G in Cardiac Transplantation.

    PubMed

    Lazarte, Julieta; Tumiati, Laura C; Rao, Vivek; Delgado, Diego H

    2016-09-01

    Human Leukocyte Antigen-G (HLA-G) is a non-classical class 1b protein, whose gene is located on chromosome 6 (6p21.31). HLA-G inhibits the immune cells' cytotoxic activity by interacting with specific receptors on their membranes. Since it is a naturally occurring immune modulator, HLA-G has been investigated in transplantation. Indeed, a number of investigations reveal that HLA-G expression is influenced by genetic polymorphisms and in turn, those polymorphisms are associated with detrimental or beneficial outcomes in various pathological situations. The present review introduces the HLA-G molecule, the gene and its polymorphisms. It focuses on the expression of HLA-G and the role of polymorphisms primarily in heart transplant outcomes, secondarily in other transplant organs, as well as the role of the allograft and effect of medical therapy. We discuss the limitations in HLA-G transplant investigations and future directions. The immune inhibiting activity of HLA-G has a great deal of potential for its utilization in enhancing diagnostic, preventive and therapeutic strategies against rejection in the setting of transplantation.

  15. HLA-Modeler: Automated Homology Modeling of Human Leukocyte Antigens.

    PubMed

    Amari, Shinji; Kataoka, Ryoichi; Ikegami, Takashi; Hirayama, Noriaki

    2013-01-01

    The three-dimensional (3D) structures of human leukocyte antigen (HLA) molecules are indispensable for the studies on the functions at molecular level. We have developed a homology modeling system named HLA-modeler specialized in the HLA molecules. Segment matching algorithm is employed for modeling and the optimization of the model is carried out by use of the PFROSST force field considering the implicit solvent model. In order to efficiently construct the homology models, HLA-modeler uses a local database of the 3D structures of HLA molecules. The structure of the antigenic peptide-binding site is important for the function and the 3D structure is highly conserved between various alleles. HLA-modeler optimizes the use of this structural motif. The leave-one-out cross-validation using the crystal structures of class I and class II HLA molecules has demonstrated that the rmsds of nonhydrogen atoms of the sites between homology models and crystal structures are less than 1.0 Å in most cases. The results have indicated that the 3D structures of the antigenic peptide-binding sites can be reproduced by HLA-modeler at the level almost corresponding to the crystal structures.

  16. Expression of the Classical and Nonclassical HLA Molecules in Breast Cancer

    PubMed Central

    da Silva, Gisela Bevilacqua Rolfsen Ferreira; Silva, Tarsia Giabardo Alves; Duarte, Roberta Aparecida; Neto, Nicolino Lia; Carrara, Hélio Humberto Angotti; Donadi, Eduardo Antônio; Gonçalves, Maria Alice Guimarães; Soares, Edson Garcia; Soares, Christiane Pienna

    2013-01-01

    Considering that downregulation of HLA expression could represent a potential mechanism for breast carcinogenesis and metastasis, the aim of the present study was to use immunohistochemical methods to analyze the expression of HLA-Ia, HLA-DR, HLA-DQ, HLA-E, and HLA-G in invasive ductal carcinoma (IDC) of the breast and to relate this HLA profile to anatomopathological parameters. Fifty-two IDC from breast biopsies were stratified according to histological differentiation (well, moderately, and poorly differentiated) and to the presence of metastases in axillary lymph nodes. The expression of HLA molecules was assessed by immunohistochemistry, using a computer-assisted system. Overall, 31 (59.6%) out of the 52 IDC breast biopsies exhibited high expression of HLA-G, but only 14 (26.9%) showed high expression of HLA-E. A large number (41, 78.8%) of the biopsies showed low expression of HLA-Ia, while 45 (86.5%) showed high expression of HLA-DQ and 36 (69.2%) underexpressed HLA-DR. Moreover, 24 (41.2%) of 52 biopsies had both low HLA-Ia expression and high HLA-G expression, while 11 (21.2%) had low HLA-Ia expression and high HLA-E expression. These results suggest that, by different mechanisms, the downregulation of HLA-Ia, HLA-E, and HLA-DR and the upregulation of HLA-G and HLA-DQ are associated with immune response evasion and breast cancer aggressiveness. PMID:24363939

  17. Age-dependent HLA profiles of the Israeli population: impact on hematopoietic cell donor recruitment and availability.

    PubMed

    Israeli, Moshe; Oudshoorn, Machteld; Haasnoot, Geert W; Klein, Tirza; Zisser, Bracha; Bach, Gideon; Claas, Frans H J

    2014-10-01

    Approximately three million people have immigrated to the state of Israel since it was founded. Consequently, the immunogenetic profile of the younger generation may consist of a genetic mixture of formerly distinct population groups. We aimed to investigate whether HLA profiles in the Israeli population are age dependent and how this influences representation of various age groups in local donor registries. We determined HLA-A*, HLA-B*, and HLA-DRB1* low-resolution phenotypes of three age groups (n = 4,169 in each): (1) cord blood units collected between 2009 and 2013 (BABIES) and adult registry donors (2) aged 18-28 years (YOUNG) and (3) aged 49-60 years (OLD). We compared the results with virtual groups that simulate the offspring of the actual study groups. None of the three actual age groups were in Hardy-Weinberg equilibrium. The YOUNG presented four HLA-B alleles that were absent in the OLD and BABIES. A significantly higher percentage among the OLD and BABIES had a "matched" individual within their group in comparison to the YOUNG. In the YOUNG, the 10 most common haplotypes account for 16.7 % of the population, in comparison to 18.2 % in the OLD or 19.8 % in the BABIES group. The BABIES group was genetically remote from all other groups. Further disparities were found between the actual and the corresponding virtual groups. We conclude that discrete age groups in Israel present distinct immunogenetic profiles, where the younger generation is more heterogeneous. The population dynamics of the age-dependent HLA profile is multifactorial: gradual intersubgroup admixture, nonrandom mating, and entry of new alleles.

  18. Hereditary hemochromatosis: Generation of a transcription map within a refined and extended map of the HLA class I region

    SciTech Connect

    Totaro, A.; Grifa, A.; Gasparini, P.

    1996-02-01

    Hereditary hemochromatosis, a common severe inherited disease, maps to the short arm of chromosome 6 close to the HLA-A locus. Recently, linkage data on Italian and French populations confirmed this location, while a similar analysis on Australian and British populations located the gene closer to D6S105, a marker residing telomeric of HLA-A. To increase our knowledge on the region of highest linkage disequilibrium in our population and possibly to identify the disease gene, a 1.2-Mb detailed physical and transcription map was generated, spanning the HLA class I region. Thirty-eight unique cDNA fragments, retrieved following the hybridization of immobilized YACs to primary pools of cDNAs prepared from RNA of fetal brain, adult brain, liver, placenta, and the CaCo{sub 2} cell line, were characterized. All cDNA fragments were positioned in a refined and extended map of the human major histocompatibility complex spanning from HLA-E to approximately 500 kb telomeric of HLA-F. The localization of known genes was refined, and a new gene from the RNA helicase superfamily was identified. Overall, 14 transcription units in addition to the HLA genes have been detected and integrated in the map. Thirteen cDNA fragments show no similarity with known sequences and could be candidates for the disease. Their characterization and assessment for involvement in hemochromatosis are still under investigation. Seven new polymorphisms, some tightly linked to the disease, were also identified and localized. 29 refs., 2 figs., 3 tabs.

  19. Influence of HLA on human partnership and sexual satisfaction

    PubMed Central

    Kromer, J.; Hummel, T.; Pietrowski, D.; Giani, A. S.; Sauter, J.; Ehninger, G.; Schmidt, A. H.; Croy, I.

    2016-01-01

    The major histocompatibility complex (MHC, called HLA in humans) is an important genetic component of the immune system. Fish, birds and mammals prefer mates with different genetic MHC code compared to their own, which they determine using olfactory cues. This preference increases the chances of high MHC variety in the offspring, leading to enhanced resilience against a variety of pathogens. Humans are also able to discriminate HLA related olfactory stimuli, however, it is debated whether this mechanism is of behavioural relevance. We show on a large sample (N = 508), with high-resolution typing of HLA class I/II, that HLA dissimilarity correlates with partnership, sexuality and enhances the desire to procreate. We conclude that HLA mediates mate behaviour in humans. PMID:27578547

  20. Influence of HLA on human partnership and sexual satisfaction.

    PubMed

    Kromer, J; Hummel, T; Pietrowski, D; Giani, A S; Sauter, J; Ehninger, G; Schmidt, A H; Croy, I

    2016-01-01

    The major histocompatibility complex (MHC, called HLA in humans) is an important genetic component of the immune system. Fish, birds and mammals prefer mates with different genetic MHC code compared to their own, which they determine using olfactory cues. This preference increases the chances of high MHC variety in the offspring, leading to enhanced resilience against a variety of pathogens. Humans are also able to discriminate HLA related olfactory stimuli, however, it is debated whether this mechanism is of behavioural relevance. We show on a large sample (N = 508), with high-resolution typing of HLA class I/II, that HLA dissimilarity correlates with partnership, sexuality and enhances the desire to procreate. We conclude that HLA mediates mate behaviour in humans. PMID:27578547

  1. HLA-A*0201-restricted CEA-derived peptide CAP1 is not a suitable target for T-cell-based immunotherapy.

    PubMed

    Fauquembergue, Emilie; Toutirais, Olivier; Tougeron, David; Drouet, Aurélie; Le Gallo, Matthieu; Desille, Mireille; Cabillic, Florian; de La Pintière, Cécile Thomas; Iero, Manuela; Rivoltini, Licia; Baert-Desurmont, Stéphanie; Leprince, Jérôme; Vaudry, Hubert; Sesboué, Richard; Frébourg, Thierry; Latouche, Jean-Baptiste; Catros, Véronique

    2010-05-01

    Carcinoembryonic antigen (CEA) is a potential target for antigen-specific immunotherapy, as it is frequently overexpressed in human carcinomas. Moreover, an epitope derived from CEA, designated CAP1 (YLSGANLNL), has been proposed as naturally processed and presented by tumors in the human leukocyte antigen (HLA)-A*0201 context. Our aim was to fully characterize and assess the clinical relevance of the HLA-A*0201-restricted cytotoxic T lymphocyte (CTL) response against CEA. Stable and potent artificial antigen presenting cells (AAPCs) were used to evaluate T-cell response against CEA. These cells efficiently activate CTLs against tumor-derived epitopes after transduction with the antigenic peptides or full-length proteins. We found that AAPCs genetically modified to express CAP1, the agonist peptide CAP1-6D, or the whole CEA protein were not able to activate CAP1-specific CTLs from HLA-A*0201+ healthy donors or patients with colorectal carcinoma, even after multiple stimulations. In addition, we showed that a CAP1-specific T-cell clone, obtained after multiple stimulations of T cells of a HLA-A*0201+ healthy donor in vitro with autologous antigen presenting cells, recognized CEA(-) HLA-A*0201+ tumors transduced with a minigene encoding CAP1 but failed to react against HLA-A*0201+ tumor cells expressing CEA. Finally, AAPCs expressing the whole CEA protein did not induce any specific CTL response against CEA+ HLA-A*0201+ tumor cells highlighting the potential difficulty of mounting an efficacious T-cell response against this autoantigen. Altogether, our data indicate that CAP1 is not efficiently processed and presented by CEA+ tumor cells, and therefore, is not an appropriate target for T-cell-based immunotherapy. PMID:20386466

  2. An In-Depth Characterization of the Major Psoriasis Susceptibility Locus Identifies Candidate Susceptibility Alleles within an HLA-C Enhancer Element

    PubMed Central

    Clop, Alex; Bertoni, Anna; Spain, Sarah L.; Simpson, Michael A.; Pullabhatla, Venu; Tonda, Raul; Hundhausen, Christian; Di Meglio, Paola; De Jong, Pieter; Hayday, Adrian C.; Nestle, Frank O.; Barker, Jonathan N.; Bell, Robert J. A.; Capon, Francesca; Trembath, Richard C.

    2013-01-01

    Psoriasis is an immune-mediated skin disorder that is inherited as a complex genetic trait. Although genome-wide association scans (GWAS) have identified 36 disease susceptibility regions, more than 50% of the genetic variance can be attributed to a single Major Histocompatibility Complex (MHC) locus, known as PSORS1. Genetic studies indicate that HLA-C is the strongest PSORS1 candidate gene, since markers tagging HLA-Cw*0602 consistently generate the most significant association signals in GWAS. However, it is unclear whether HLA-Cw*0602 is itself the causal PSORS1 allele, especially as the role of SNPs that may affect its expression has not been investigated. Here, we have undertaken an in-depth molecular characterization of the PSORS1 interval, with a view to identifying regulatory variants that may contribute to disease susceptibility. By analysing high-density SNP data, we refined PSORS1 to a 179 kb region encompassing HLA-C and the neighbouring HCG27 pseudogene. We compared multiple MHC sequences spanning this refined locus and identified 144 candidate susceptibility variants, which are unique to chromosomes bearing HLA-Cw*0602. In parallel, we investigated the epigenetic profile of the critical PSORS1 interval and uncovered three enhancer elements likely to be active in T lymphocytes. Finally we showed that nine candidate susceptibility SNPs map within a HLA-C enhancer and that three of these variants co-localise with binding sites for immune-related transcription factors. These data indicate that SNPs affecting HLA-Cw*0602 expression are likely to contribute to psoriasis susceptibility and highlight the importance of integrating multiple experimental approaches in the investigation of complex genomic regions such as the MHC. PMID:23990973

  3. Promoter methylation and mRNA expression of HLA-G in relation to HLA-G protein expression in colorectal cancer.

    PubMed

    Swets, Marloes; Seneby, Lina; Boot, Arnoud; van Wezel, Tom; Gelderblom, Hans; van de Velde, Cornelis J H; van den Elsen, Peter J; Kuppen, Peter J K

    2016-09-01

    Expression of human leukocyte antigen-G (HLA-G) is a suggested mechanism used by tumor cells to escape from host immune recognition and destruction. Advances in the field have made it evident that HLA-G is expressed in different types of malignancies including colorectal cancer (CRC). We analyzed HLA-G expression in 21 low passage CRC cell lines. The level of DNA methylation of the HLA-G gene and the presence of mRNA encoding HLA-G was measured. Moreover, HLA-G protein expression was determined by flow cytometry and immunohistochemistry (IHC). IHC was performed with three different monoclonal antibodies (mAbs) (4H84, MEM-G/1 and MEM-G/2). In addition, HLA-G protein expression was measured in matching primary tumor tissues. RNA analysis using RT-PCR followed by sequencing in 6 samples indicated strong homology of the PCR product with HLA-G3 in 5 samples. In accordance, in none of the cell lines, HLA-G1 expression was detected by flow-cytometry. Furthermore, no association between HLA-G DNA methylation patterns and HLA-G mRNA expression was observed. In addition, different immunohistochemical staining profiles among various anti-HLA-G mAbs were observed. In conclusion, the results of this study show that the HLA-G3 isoform was expressed in some of the CRC cell lines irrespective of the level of DNA methylation of HLA-G.

  4. Novel strategies for adoptive therapy following HLA disparate transplants.

    PubMed

    O'Reilly, Richard J; Hasan, Aisha; Doubrovina, Ekaterina; Koehne, Guenther; Prockop, Susan

    2011-09-01

    Transplants of SBA-E- allogeneic marrow or G-CSF mobilized CD34+ (ISOLEX) E- peripheral blood progenitor cells which are adequately depleted of T-cells, when administered without post-transplant immunosuppression now induce consistent engraftment with low incidences of acute and chronic GVHD both in HLA matched and HLA disparate recipients. Furthermore, the incidence of relapse post transplant is not increased in patients transplanted for AML, MDS or ALL. In our series, the incidence of severe infections in HLA-matched recipients of such T-cell depleted grafts also does not differ from that detected following similarly matched unmodified grafts. However, in recipients of HLA-haplotype disparate T-cell depleted grafts, the risk of lethal viral infections is increased and prolonged. In many cases, this risk is closely correlated with failures of immunodominant virus-specific donor T-cells transferred in the graft to recognize infected host cells because they are restricted by HLA alleles not shared by the host. To address this limitation, we have developed a panel of artificial antigen presenting cells, each expressing a single prevalent HLA-allele. Using this panel, we are able to selectively generate virus-specific cytotoxic T-cells of desired HLA restriction, to insure their effectiveness in HLA haplotype-disparate transplant recipients. We have also shown that partially HLA-matched, third party-derived EBV-specific T-cells, selected from our bank of previously generated and characterized GMP-grade cell lines on the basis of their HLA restriction, can induce durable remissions of rituximab-refractory EBV lymphomas. These approaches may thus provide new, immediately accessible resources for the generation and broad application of immune cell therapies to treat and prevent severe viral diseases post transplant. PMID:21925091

  5. Classical HLA-DRB1 and DPB1 Alleles Account for HLA Associations with Primary Biliary Cirrhosis

    PubMed Central

    Invernizzi, Pietro; Ransom, Michael; Raychaudhuri, Soumya; Kosoy, Roman; Lleo, Ana; Shigeta, Russell; Franke, Andre; Bossa, Fabrizio; Amos, Christopher I.; Gregersen, Peter K.; Siminovitch, Katherine A.; Cusi, Daniele; de Bakker, Paul I.W.; Podda, Mauro; Gershwin, M. Eric; Seldin, Michael F.

    2012-01-01

    Susceptibility to primary biliary cirrhosis (PBC) is strongly associated with HLA region polymorphisms. To determine if associations can be explained by classical HLA determinants we studied Italian 676 cases and 1440 controls with genotyped with dense single nucleotide polymorphisms (SNPs) for which classical HLA alleles and amino acids were imputed. Although previous genome-wide association studies and our results show stronger SNP associations near DQB1, we demonstrate that the HLA signals can be attributed to classical DRB1 and DPB1 genes. Strong support for the predominant role of DRB1 is provided by our conditional analyses. We also demonstrate an independent association of DPB1. Specific HLA-DRB1 genes (*08, *11 and *14) account for most of the DRB1 association signal. Consistent with previous studies, DRB1*08 (p = 1.59 × 10−11) was the strongest predisposing allele where as DRB1*11 (p = 1.42 × 10−10) was protective. Additionally DRB1*14 and the DPB1 association (DPB1*03:01) (p = 9.18 × 10−7) were predisposing risk alleles. No signal was observed in the HLA class 1 or class 3 regions. These findings better define the association of PBC with HLA and specifically support the role of classical HLA-DRB1 and DPB1 genes and alleles in susceptibility to PBC. PMID:22573116

  6. Association between HLA Class I and Class II Alleles and the Outcome of West Nile Virus Infection: An Exploratory Study

    PubMed Central

    Lanteri, Marion C.; Kaidarova, Zhanna; Peterson, Trevor; Cate, Steven; Custer, Brian; Wu, Shiquan; Agapova, Maria; Law, Jacqueline P.; Bielawny, Thomas; Plummer, Frank; Tobler, Leslie H.; Loeb, Mark; Busch, Michael P.; Bramson, Jonathan; Luo, Ma; Norris, Philip J.

    2011-01-01

    Background West Nile virus (WNV) infection is asymptomatic in most individuals, with a minority developing symptoms ranging from WNV fever to serious neuroinvasive disease. This study investigated the impact of host HLA on the outcome of WNV disease. Methods A cohort of 210 non-Hispanic mostly white WNV+ subjects from Canada and the U.S. were typed for HLA-A, B, C, DP, DQ, and DR. The study subjects were divided into three WNV infection outcome groups: asymptomatic (AS), symptomatic (S), and neuroinvasive disease (ND). Allele frequency distribution was compared pair-wise between the AS, S, and ND groups using χ2 and Fisher's exact tests and P values were corrected for multiple comparisons (Pc). Allele frequencies were compared between the groups and the North American population (NA) used as a control group. Logistic regression analysis was used to evaluate the potential synergistic effect of age and HLA allele phenotype on disease outcome. Results The alleles HLA-A*68, C*08 and DQB*05 were more frequently associated with severe outcomes (ND vs. AS, PA*68 = 0.013/Pc = 0.26, PC*08 = 0.0075/Pc = 0.064, and PDQB1*05 = 0.029/Pc = 0.68), However the apparent DQB1*05 association was driven by age. The alleles HLA-B*40 and C*03 were more frequently associated with asymptomatic outcome (AS vs. S, PB*40 = 0.021/Pc = 0.58 and AS vs. ND PC*03 = 0.039/Pc = 0.64) and their frequencies were lower within WNV+ subjects with neuroinvasive disease than within the North American population (NA vs. S, PB*40 = 0.029 and NA vs. ND, PC*03 = 0.032). Conclusions Host HLA may be associated with the outcome of WNV disease; HLA-A*68 and C*08 might function as “susceptible” alleles, whereas HLA-B*40 and C*03 might function as “protective” alleles. PMID:21829673

  7. Multiple sclerosis

    PubMed Central

    Rühl, Geraldine; Niedl, Anna G.; Patronov, Atanas; Siewert, Katherina; Pinkert, Stefan; Kalemanov, Maria; Friese, Manuel A.; Attfield, Kathrine E.; Antes, Iris; Hohlfeld, Reinhard

    2016-01-01

    Objective: To identify target antigens presented by human leukocyte antigen (HLA)–A*02:01 to the myelin-reactive human T-cell receptor (TCR) 2D1, which was originally isolated from a CD8+ T-cell clone recognizing proteolipid protein (PLP) in the context of HLA-A*03:01, we employed a new antigen search technology. Methods: We used our recently developed antigen search technology that employs plasmid-encoded combinatorial peptide libraries and a highly sensitive single cell detection system to identify endogenous candidate peptides of mice and human origin. We validated candidate antigens by independent T-cell assays using synthetic peptides and refolded HLA:peptide complexes. A molecular model of HLA-A*02:01:peptide complexes was obtained by molecular dynamics simulations. Results: We identified one peptide from glycerolphosphatidylcholine phosphodiesterase 1, which is identical in mice and humans and originates from a protein that is expressed in many cell types. When bound to HLA-A*02:01, this peptide cross-stimulates the PLP-reactive HLA-A3-restricted TCR 2D1. Investigation of molecular details revealed that the peptide length plays a crucial role in its capacity to bind HLA-A*02:01 and to activate TCR 2D1. Molecular modeling illustrated the 3D structures of activating HLA:peptide complexes. Conclusions: Our results show that our antigen search technology allows us to identify new candidate antigens of a presumably pathogenic, autoreactive, human CD8+ T-cell-derived TCR. They further illustrate how this TCR, which recognizes a myelin peptide bound to HLA-A*03:01, may cross-react with an unrelated peptide presented by the protective HLA class I allele HLA-A*02:01. PMID:27231714

  8. HLA and genetic susceptibility to sleepwalking.

    PubMed

    Lecendreux, M; Bassetti, C; Dauvilliers, Y; Mayer, G; Neidhart, E; Tafti, M

    2003-01-01

    HLA-DQB1 typing was performed in 60 Caucasian subjects with sleepwalking (SW) disorder and their families and 60 ethnically matched subjects without any diagnosed sleep disorder. A total of 21 sleepwalkers (35.0%) were DQB1*0501 positive vs eight (13.3%) controls (P = 0.0056; odds ratio = 3.5, 95% CI = 1.4-8.7). The family data for all HLA subtypes were further assessed for allelic association with SW using the transmission-disequilibrium test. A significant excess transmission was observed for DQB1*05 and *04 alleles in familial cases, strongly suggesting that a DQB1 polymorphic amino acid might be more tightly associated than any single allele. Sequence screening revealed that Ser74 in the second exon shared by all DQB1*05 and *04 was 20 times transmitted against 4 times non-transmitted (P = 0.001) in familial cases of SW. Thus, together with narcolepsy and REM sleep behavior disorder, these findings suggest that specific DQB1 genes are implicated in disorders of motor control during sleep. PMID:12556916

  9. Role of HLA Adaptation in HIV Evolution

    PubMed Central

    Kløverpris, Henrik N.; Leslie, Alasdair; Goulder, Philip

    2016-01-01

    Killing of HIV-infected cells by CD8+ T-cells imposes strong selection pressure on the virus toward escape. The HLA class I molecules that are successful in mediating some degree of control over the virus are those that tend to present epitopes in conserved regions of the proteome, such as in p24 Gag, in which escape also comes at a significant cost to viral replicative capacity (VRC). In some instances, compensatory mutations can fully correct for the fitness cost of such an escape variant; in others, correction is only partial. The consequences of these events within the HIV-infected host, and at the population level following transmission of escape variants, are discussed. The accumulation of escape mutants in populations over the course of the epidemic already shows instances of protective HLA molecules losing their impact, and in certain cases, a modest decline in HIV virulence in association with population-level increase in mutants that reduce VRC. PMID:26834742

  10. Insulin-dependent diabetes and HLA.

    PubMed

    Dausset, J; Hors, J; Contu, L; Busson, M; Schmid, M; Cathelineau, G; Lestradet, H; Baron, D

    1979-12-01

    The study of a hundred and fifteen unrelated insulin-dependent diabetes and eight families with at least two insulin-dependent diabetes members made it possible to confirm the higher frequency of HLA-B8 and B18 (p less than 0.001) among patients, producing a RR of 2.24 and 2.47 respectively. The increased B15 frequency did not achieve statistical significance. B18 whose gametic association (delta = 0.0438) was significant only in diabetic patients was often related to Aw19-2 (Aw30 + Aw31). The B8/B18 genotype gave a relative risk (RR = 4.98) which was significantly higher than that of B8, B18 and B15 heterozygotes (1.50, 1.24 and 1.39 respectively). Pairs of diabetic siblings were more frequently HLA identical than would be expected by chance, and distribution of the pairs of affected sibs into the three categories, identical, semi-identical and different, was closer to the recessive model than to the dominant one. The fact that the B8/B18 individuals had a RR slightly higher than the B8 and B18 homozygotes and distinctly higher than the heterozygotes for only one of these genes, favours the hypothesis of two dominant genes, giving the appearance of recessivity. The gene associated with B18 in Southern Europe seems to play the same part as that of the gene associated with B15 in Northern Europe. PMID:398300

  11. A polymorphism in HLA-G modifies statin benefit in asthma

    PubMed Central

    Naidoo, Devesh; Wu, Ann C; Brilliant, Murray H; Denny, Joshua; Ingram, Christie; Kitchner, Terrie E; Linneman, James G; McGeachie, Michael J; Roden, Dan M; Shaffer, Christian M; Shah, Anushi; Weeke, Peter; Weiss, Scott T; Xu, Hua; Medina, Marisa W

    2014-01-01

    Several reports have shown that statin treatment benefits patients with asthma, however inconsistent effects have been observed. The mir-152 family (148a, 148b and 152) has been implicated in asthma. These microRNAs suppress HLA-G expression, and rs1063320, a common SNP in the HLA-G 3’UTR which is associated with asthma risk, modulates miRNA binding. We report that statins up-regulate mir-148b and 152, and affect HLA-G expression in an rs1063320 dependent fashion. In addition, we found that individuals who carried the G minor allele of rs1063320 had reduced asthma related exacerbations (emergency department visits, hospitalizations or oral steroid use) compared to non-carriers (p=0.03) in statin users ascertained in the Personalized Medicine Research Project at the Marshfield Clinic (n=421). These findings support the hypothesis that rs1063320 modifies the effect of statin benefit in asthma, and thus may contribute to variation in statin efficacy for the management of this disease. PMID:25266681

  12. HAPCAD: An open-source tool to detect PCR crossovers in next-generation sequencing generated HLA data.

    PubMed

    McDevitt, Shana L; Bredeson, Jessen V; Roy, Scott W; Lane, Julie A; Noble, Janelle A

    2016-03-01

    Next-generation sequencing (NGS) based HLA genotyping can generate PCR artifacts corresponding to IMGT/HLA Database alleles, for which multiple examples have been observed, including sequence corresponding to the HLA-DRB1(∗)03:42 allele. Repeat genotyping of 131 samples, previously genotyped as DRB1(∗)03:01 homozygotes using probe-based methods, resulted in the heterozygous call DRB1(∗)03:01+DRB1(∗)03:42. The apparent rare DRB1(∗)03:42 allele is hypothesized to be a "hybrid amplicon" generated by PCR crossover, a process in which a partial PCR product denatures from its template, anneals to a different allele template, and extends to completion. Unlike most PCR crossover products, "hybrid amplicons" always corresponds to an IMGT/HLA Database allele, necessitating a case-by-case analysis of whether its occurrence reflects the actual allele or is simply the result of PCR crossover. The Hybrid Amplicon/PCR Crossover Artifact Detector (HAPCAD) program mimics jumping PCR in silico and flags allele sequences that may also be generated as hybrid amplicon.

  13. Detection of Intergenerational Genetic Effects with Application to HLA-B Matching as a Risk Factor for Schizophrenia

    PubMed Central

    Childs, Erica J.; Sobel, Eric M.; Palmer, Christina G.S.; Sinsheimer, Janet S.

    2011-01-01

    Background and Methods Association studies using unrelated individuals cannot detect intergenerational genetic effects contributing to disease. To detect these effects, we improve the extended maternal-fetal genotype (EMFG) incompatibility test to estimate any combination of maternal effects, offspring effects, and their interactions at polymorphic loci or multiple SNPs, using any size pedigrees. We explore the advantages of using extended pedigrees rather than nuclear families. We apply our methods to schizophrenia pedigrees to investigate whether the previously associated mother-daughter HLA-B matching is a genuine risk or the result of bias. Results Simulations demonstrate that using the EMFG test with extended pedigrees increases power and precision, while partitioning extended pedigrees into nuclear families can underestimate intergenerational effects. Application to actual data demonstrates that mother-daughter HLA-B matching remains a schizophrenia risk factor. Furthermore, ascertainment and mate selection biases cannot by themselves explain the observed HLA-B matching and schizophrenia association. Conclusions Our results demonstrate the power of the EMFG test to examine intergenerational genetic effects, highlight the importance of pedigree rather than case/control or case-mother/control-mother designs, illustrate that pedigrees provide a means to examine alternative, non-causal mechanisms, and they strongly support the hypothesis that HLA-B matching is causally involved in the etiology of schizophrenia in females. PMID:22004985

  14. Clinically relevant interpretation of solid phase assays for HLA antibody

    PubMed Central

    Bettinotti, Maria P.; Zachary, Andrea A.; Leffell, Mary S.

    2016-01-01

    Purpose of review Accurate and timely detection and characterization of human leukocyte antigen (HLA) antibodies are critical for pre-transplant and post-transplant immunological risk assessment. Solid phase immunoassays have provided increased sensitivity and specificity, but test interpretation is not always straightforward. This review will discuss the result interpretation considering technical limitations; assessment of relative antibody strength; and the integration of data for risk stratification from complementary testing and the patient's immunological history. Recent findings Laboratory and clinical studies have provided insight into causes of test failures – false positive reactions because of antibodies to denatured HLA antigens and false negative reactions resulting from test interference and/or loss of native epitopes. Test modifications permit detection of complement-binding antibodies and determination of the IgG subclasses. The high degree of specificity of single antigen solid phase immunoassays has revealed the complexity and clinical relevance of antibodies to HLA-C, HLA-DQ, and HLA-DP antigens. Determination of antibody specificity for HLA epitopes enables identification of incompatible antigens not included in test kits. Summary Detection and characterization of HLA antibodies with solid phase immunoassays has led to increased understanding of the role of those antibodies in graft rejection, improved treatment of antibody-mediated rejection, and increased opportunities for transplantation. However, realization of these benefits requires careful and accurate interpretation of test results. PMID:27200498

  15. Immunoregulatory Role of HLA-G in Allergic Diseases

    PubMed Central

    Contini, Paola; Negrini, Simone; Ciprandi, Giorgio; Puppo, Francesco

    2016-01-01

    Allergic diseases are sustained by a T-helper 2 polarization leading to interleukin-4 secretion, IgE-dependent inflammation, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, play a central role in modulation of immune responses. Elevated levels of soluble HLA-G (sHLA-G) molecules are detected in serum of patients with allergic rhinitis to seasonal and perennial allergens and correlate with allergen-specific IgE levels, clinical severity, drug consumption, and response to allergen-specific immunotherapy. sHLA-G molecules are also found in airway epithelium of patients with allergic asthma and high levels of sHLA-G molecules are detectable in plasma and bronchoalveolar lavage of asthmatic patients correlating with allergen-specific IgE levels. Finally, HLA-G molecules are expressed by T cells, monocytes-macrophages, and Langerhans cells infiltrating the dermis of atopic dermatitis patients. Collectively, although at present it is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation. PMID:27413762

  16. Gorgan (Turkmen in Iran) HLA genetics: transplantation, pharmacogenomics and anthropology.

    PubMed

    Rey, Diego; Amirzargar, Ali; Areces, Cristina; Enríquez-de-Salamanca, Mercedes; Marco, Javier; Abd-El-Fatah-Khalil, Sedeka; Fernández-Honrado, Mercedes; Muñiz, Ester; Martín-Villa, José Manuel; Arnaiz-Villena, Antonio

    2015-01-01

    HLA class I and II alleles have been studied in a population from Gorgan (North East Iranian city bordering Turkmenistan). This population is composed of mainly Turkmen who speak Oghuz Turkish language. Comparison of Gorgan people HLA profile has been carried out with about 7984 HLA chromosomes from other worldwide populations; extended haplotypes and three dimension genetic distances have been calculated by using neighbor-joining and correspondence relatedness analyses. Most frequent extended HLA haplotypes show a Siberian/Mediterranean admixture and closest populations are Chuvashians (North Caspian Sea, Russia) and other geographically close populations like Siberian Mansi, Buryats and other Iranians. New extended HLA haplotypes have been found, such as: A*31:01-B*35:01-DRB1*15:01-DQB1*03:01, A*01:01-B*35:01-DRB1*03:01-DQB1*02:01. Relationships of Turkmen with Kurgan (Gorgan) archaeological mounds, Scythians and Sarmatians are discussed. This study is also useful for a future transplantation Gorgan waiting list, Gorgan HLA and disease epidemiology and HLA pharmacogenomics.

  17. Addressing questions about including environmental effects in the DMSO HLA

    SciTech Connect

    Hummel, J.R.

    1996-10-01

    The Defense Modeling and Simulation Office (DMSO) is developing a High Level Architecture (HLA) to support the DOD Modeling and Simulation (M and S) community. Many, if not all, of the simulations involve the environment in some fashion. In some applications, the simulation takes place in an acknowledged environment without any environmental functionality being taken into account. The Joint Training Federation Prototype (JTFp) is one of several prototype efforts that have been created to provide a test of the DMSO HLA. In addition to addressing the applicability of the HLA to a training community, the JTFp is also one of two prototype efforts that is explicitly including environmental effects in their simulation effort. These two prototyping efforts are examining the issues associated with the inclusion of the environment in an HLA federation. In deciding whether or not to include an environmental federation in the JTFp effort, a number of questions have been raised about the environment and the HLA. These questions have raised the issue of incompatibility between the environment and the HLA and also shown that there is something unique about including the environment in simulations. The purpose of this White Paper, which was developed with inputs from the National Air and Space [Warfare] Model Program among others, is to address the various questions that have been posed about including environmental effects in an HLA simulation.

  18. Immunoregulatory Role of HLA-G in Allergic Diseases.

    PubMed

    Murdaca, Giuseppe; Contini, Paola; Negrini, Simone; Ciprandi, Giorgio; Puppo, Francesco

    2016-01-01

    Allergic diseases are sustained by a T-helper 2 polarization leading to interleukin-4 secretion, IgE-dependent inflammation, and mast cell and eosinophil activation. HLA-G molecules, both in membrane-bound and in soluble forms, play a central role in modulation of immune responses. Elevated levels of soluble HLA-G (sHLA-G) molecules are detected in serum of patients with allergic rhinitis to seasonal and perennial allergens and correlate with allergen-specific IgE levels, clinical severity, drug consumption, and response to allergen-specific immunotherapy. sHLA-G molecules are also found in airway epithelium of patients with allergic asthma and high levels of sHLA-G molecules are detectable in plasma and bronchoalveolar lavage of asthmatic patients correlating with allergen-specific IgE levels. Finally, HLA-G molecules are expressed by T cells, monocytes-macrophages, and Langerhans cells infiltrating the dermis of atopic dermatitis patients. Collectively, although at present it is difficult to completely define the role of HLA-G molecules in allergic diseases, it may be suggested that they are expressed and secreted by immune cells during the allergic reaction in an attempt to suppress allergic inflammation. PMID:27413762

  19. The Monospecificity of Novel Anti-HLA-E Monoclonal Antibodies Enables Reliable Immunodiagnosis, Immunomodulation of HLA-E, and Upregulation of CD8+ T Lymphocytes.

    PubMed

    Ravindranath, Mepur H; Terasaki, Paul I; Pham, Tho; Jucaud, Vadim

    2015-06-01

    In human cancers, over-expression of HLA-E is marked by gene expression. However, immunolocalization of HLA-E on tumor cells is impeded by the HLA-Ia reactivity of commercial anti-HLA-E monoclonal antibodies (MAbs). So there was a clear need to develop monospecific anti-HLA-E MAbs for reliable immunodiagnosis of HLA-E, particularly considering the prognostic relevance of HLA-E in human cancer. HLA-E overexpression is correlated with disease progression and poor survival of patients, both of which are attributed to the suppression of anti-tumor activity of cytotoxic T cells mediated by HLA-E. The suppression mechanism involves the binding of HLA-E-specific amino acids located on the α1 and α2 helices of HLA-E to the inhibitory receptors (CD94/NKG2a) on CD8+ T lymphocytes. An anti-HLA-E MAb that recognizes these HLA-E-specific sequences can not only be a monospecific MAb with potential for specific immunolocalization of HLA-E but can also block the sequences from interacting with the CD94/NKG2a receptors. We therefore developed several clones that secrete such HLA-E-specific MAbs; then we assessed the ability of the MAbs to bind to the amino acid sequences interacting with the CD94/NKG2a receptors by inhibiting them from binding to HLA-E with peptides that inhibit receptor binding. Elucidation of the immunomodulatory capabilities of these monospecific MAbs showed that they can induce proliferation of CD8+ T cells with or without co-stimulation. These novel MAbs can serve a dual role in combating cancer by blocking interaction of HLA-E with CD94/NKG2a and by promoting proliferation of both non-activated and activated CD8+ cytotoxic αβ T cells.

  20. Discrimination of HLA null and low expression alleles by cytokine-induced secretion of recombinant soluble HLA.

    PubMed

    Hinrichs, Jan; Figueiredo, Constança; Hirv, Kaimo; Mytilineos, Joannis; Blasczyk, Rainer; Horn, Peter A; Eiz-Vesper, Britta

    2009-04-01

    The disruption of disulfide bridges can decrease or abolish the cell surface expression of HLA class I molecules. Such disulfide bridges are formed by cysteine residues between amino acid (aa) positions 101/164 (alpha(2) domain) and 203/259 (alpha(3) domain). Sequence alterations in codons 101, 164, 203 and 259 have been observed in eleven HLA-A molecules. All of these variants except of A*3014L and A*3211Q have been reported to result in null expression alleles. In the case of HLA-A*3014L, a transversion at nucleotide position 563 replaces cysteine by serine at position 164 of the mature polypeptide. HLA-A*3014L is not detectable by standard microlymphocytotoxicity assay. To verify low or non-expression of this allele, we cloned soluble HLA-A*3014L and the reference allele HLA-A*3001 into a eukaryotic expression vector and transfected K562, C1R and HEK293 cells. Expression of soluble HLA-A*3014L and HLA-A*3001 was measured in the supernatants of transfected and untransfected cells incubated with or without IFN-gamma and/or TNF-alpha using a W6/32 and anti-beta(2)-microglobulin-based sandwich ELISA. Expression of mRNA transcripts of both alleles was determined by real-time RT-PCR. HLA-A*3014L was not detected in the supernatant of unstimulated transfectants. Stimulation with IFN-gamma and/or TNF-alpha led to an increase of HLA-A*3014L secretion to a detectable level and increased HLA-A*3001 expression up to 8-fold, but did not show any difference in the increase of mRNA levels between HLA-A*3014L and A*3001. Because of this lack of any difference in the mRNA transcription, the protein expression defect is most likely caused by the missing disulfide bond formation in the alpha2 domain. Thus, exposing the cells to cytokine stress allows to distinguish between low- and non-expressed alleles and to classify alleles with a questionable expression pattern (Q alleles). Classifying HLA alleles in expressed and non-expressed variants is essential for matching assessments

  1. Relative Resistance of HLA-B to Downregulation by Naturally Occurring HIV-1 Nef Sequences

    PubMed Central

    Mahiti, Macdonald; Toyoda, Mako; Jia, Xiaofei; Kuang, Xiaomei T.; Mwimanzi, Francis; Mwimanzi, Philip; Walker, Bruce D.; Xiong, Yong; Brumme, Zabrina L.; Brockman, Mark A.

    2016-01-01

    ABSTRACT HIV-1 Nef binds to the cytoplasmic region of HLA-A and HLA-B and downregulates these molecules from the surface of virus-infected cells, thus evading immune detection by CD8+ T cells. Polymorphic residues within the HLA cytoplasmic region may affect Nef’s downregulation activity. However, the effects of HLA polymorphisms on recognition by primary Nef isolates remain elusive, as do the specific Nef regions responsible for downregulation of HLA-A versus HLA-B. Here, we examined 46 Nef clones isolated from chronically HIV-1 subtype B-infected subjects for their ability to downregulate various HLA-A, HLA-B, and HLA-C molecules on the surface of virus-infected cells. Overall, HLA-B exhibited greater resistance to Nef-mediated downregulation than HLA-A, regardless of the cell type examined. As expected, no Nef clone downregulated HLA-C. Importantly, the differential abilities of patient-derived Nef clones to downregulate HLA-A and HLA-B correlated inversely with the sensitivities of HIV-infected target cells to recognition by effector cells expressing an HIV-1 Gag-specific T cell receptor. Nef codon function analysis implicated amino acid variation at position 202 (Nef-202) in differentially affecting the ability to downregulate HLA-A and HLA-B, an observation that was subsequently confirmed by experiments using Nef mutants constructed by site-directed mutagenesis. The in silico and mutagenesis analyses further suggested that Nef-202 may interact with the C-terminal Cys-Lys-Val residues of HLA-A, which are absent in HLA-B. Taken together, the results show that natural polymorphisms within Nef modulate its interaction with natural polymorphisms in the HLA cytoplasmic tails, thereby affecting the efficiency of HLA downregulation and consequent recognition by HIV-specific T cells. These results thus extend our understanding of this complex pathway of retroviral immune evasion. PMID:26787826

  2. Indirectly Recognized HLA-C Mismatches and Their Potential Role in Transplant Outcome

    PubMed Central

    Thus, Kirsten A.; Te Boome, Liane; Kuball, Jürgen; Spierings, Eric

    2014-01-01

    HLA-C mismatches are clearly associated to alloreactivity after hematopoietic stem-cell transplantation; in a number of large cohorts, HLA-C mismatches are correlated to an increased risk of acute graft-versus-host disease (GVHD) or even impaired survival. While for HLA-A and -B, both antigenic as well as allelic mismatches are associated with an increased risk of acute GVHD, such an increased risk is only observed for antigenic HLA-C mismatches and not for allelic mismatches. These observations raise the question what sets HLA-C apart from HLA-A and -B. The difference may well be related to the reduced levels of cell-surface expression of HLA-C as compared to HLA-A and -B, possibly due to, among other factors, a limited peptide-binding capacity. This limited peptide-binding capacity may retain HLA-C in the ER and enhance degradation of the HLA-C protein. Once degraded, HLA-C-derived peptides can be presented to the immune system via other HLA alleles and are thus available for indirect recognition. Indeed, such HLA-C-derived peptides have previously been eluted from other HLA alleles. We have recently developed an approach to predict indirect recognition of HLA molecules, by establishing the numbers of predicted indirectly recognizable HLA epitopes (PIRCHES). The number of PIRCHES presented on HLA class I and II (PIRCHE-I and -II, respectively), are highly correlated to clinical measures of alloreactivity, such as acute GVHD. In the present “Hypothesis & Theory,” we reviewed the current knowledge on HLA-C mismatches and alloreactivity. Moreover, we speculate about the role of direct and indirect recognition of HLA-C and the consequences for donor selection in HLA-C mismatched stem-cell transplantation. PMID:24860572

  3. Transcriptional and Posttranscriptional Regulations of the HLA-G Gene

    PubMed Central

    Castelli, Erick C.; Veiga-Castelli, Luciana C.; Yaghi, Layale; Donadi, Eduardo A.

    2014-01-01

    HLA-G has a relevant role in immune response regulation. The overall structure of the HLA-G coding region has been maintained during the evolution process, in which most of its variable sites are synonymous mutations or coincide with introns, preserving major functional HLA-G properties. The HLA-G promoter region is different from the classical class I promoters, mainly because (i) it lacks regulatory responsive elements for IFN-γ and NF-κB, (ii) the proximal promoter region (within 200 bases from the first translated ATG) does not mediate transactivation by the principal HLA class I transactivation mechanisms, and (iii) the presence of identified alternative regulatory elements (heat shock, progesterone and hypoxia-responsive elements) and unidentified responsive elements for IL-10, glucocorticoids, and other transcription factors is evident. At least three variable sites in the 3′ untranslated region have been studied that may influence HLA-G expression by modifying mRNA stability or microRNA binding sites, including the 14-base pair insertion/deletion, +3142C/G and +3187A/G polymorphisms. Other polymorphic sites have been described, but there are no functional studies on them. The HLA-G coding region polymorphisms might influence isoform production and at least two null alleles with premature stop codons have been described. We reviewed the structure of the HLA-G promoter region and its implication in transcriptional gene control, the structure of the HLA-G 3′UTR and the major actors of the posttranscriptional gene control, and, finally, the presence of regulatory elements in the coding region. PMID:24741620

  4. Nucleotide sequence analysis of HLA-B*1523 and B*8101. Dominant alpha-helical motifs produce complex serologic recognition patterns for the HLA-B"DT" and HLA-B"NM5" antigens.

    PubMed

    Ellexson, M E; Zhang, G; Stewart, D; Lau, M; Teresi, G; Terasaki, P; Roe, B; Hildebrand, W

    1995-10-01

    Assigning a precise serologic specificity to the class I HLA-B"NM5" and HLA-B"DT" molecules has proven difficult, with patterns of serologic cross-reactivity suggesting that NM5 is most like antigens in the B5 CREG and that DT is either B7 or B40 like. To better understand the relationship these antigens share with other HLA-B molecules we determined the nucleotide sequence of the alleles encoding HLA-B"NM5" and HLA-B"DT". Sequencing results show that NM5 shares the most overall sequence homology with the B70 antigens and that differences at the alpha-helical Bw4/Bw6 epitope preclude serologic cross-reactivity between NM5 and the B70 antigens. Accordingly, NM5 has been assigned the name B*1523. The strong serologic impact of helical sequence conservations and variations is reiterated for the class I HLA-B"DT" molecule. Comparative analysis demonstrates that sequence conservations in the first domain's alpha-helix stimulate cross-reactivity between HLA-B"DT" and HLA-B7, whereas epitopes conserved in the second domain's alpha-helix impel cross-reactivity between HLA-B"DT" and HLA-B48. To convey the unique lineage of this hybrid B7/B48 molecule the name HLA-B*8101 has been assigned to HLA-B"DT".

  5. Specific human B lymphocyte alloantigens linked to HL-A.

    PubMed Central

    Mann, D L; Abelson, L; Henkart, P; Harris, S D; Amos, D B

    1975-01-01

    Sera, previously found to react specifically with B lymphoid cultured cells, were tested on isolated T and B peripheral blood lymphocytes in a microcytotoxicity assay. Studies were performed on lymphocytes obtained from several large Amish families. The sera used in these studies were cytotoxic to peripheral blood, B lymphocytes, but not cytotoxic to T lymphocytes. The antigens detected followed the inheritance pattern of HL-A haplotypes. The strong linkage disequilibrium with HL-A antigens suggests that genes controlling the expression of B lymphocyte antigens are linked to genes controlling HL-A alloantigens. PMID:1082138

  6. Development of a high-resolution NGS-based HLA-typing and analysis pipeline

    PubMed Central

    Wittig, Michael; Anmarkrud, Jarl A.; Kässens, Jan C.; Koch, Simon; Forster, Michael; Ellinghaus, Eva; Hov, Johannes R.; Sauer, Sascha; Schimmler, Manfred; Ziemann, Malte; Görg, Siegfried; Jacob, Frank; Karlsen, Tom H.; Franke, Andre

    2015-01-01

    The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions. PMID:25753671

  7. Development of a high-resolution NGS-based HLA-typing and analysis pipeline.

    PubMed

    Wittig, Michael; Anmarkrud, Jarl A; Kässens, Jan C; Koch, Simon; Forster, Michael; Ellinghaus, Eva; Hov, Johannes R; Sauer, Sascha; Schimmler, Manfred; Ziemann, Malte; Görg, Siegfried; Jacob, Frank; Karlsen, Tom H; Franke, Andre

    2015-06-23

    The human leukocyte antigen (HLA) complex contains the most polymorphic genes in the human genome. The classical HLA class I and II genes define the specificity of adaptive immune responses. Genetic variation at the HLA genes is associated with susceptibility to autoimmune and infectious diseases and plays a major role in transplantation medicine and immunology. Currently, the HLA genes are characterized using Sanger- or next-generation sequencing (NGS) of a limited amplicon repertoire or labeled oligonucleotides for allele-specific sequences. High-quality NGS-based methods are in proprietary use and not publicly available. Here, we introduce the first highly automated open-kit/open-source HLA-typing method for NGS. The method employs in-solution targeted capturing of the classical class I (HLA-A, HLA-B, HLA-C) and class II HLA genes (HLA-DRB1, HLA-DQA1, HLA-DQB1, HLA-DPA1, HLA-DPB1). The calling algorithm allows for highly confident allele-calling to three-field resolution (cDNA nucleotide variants). The method was validated on 357 commercially available DNA samples with known HLA alleles obtained by classical typing. Our results showed on average an accurate allele call rate of 0.99 in a fully automated manner, identifying also errors in the reference data. Finally, our method provides the flexibility to add further enrichment target regions.

  8. Prospective HLA-DR matching in cadaveric renal transplants: a single center study.

    PubMed

    Mendez, R; Iwaki, Y; Mendez, R; Bogaard, T; Self, B

    1983-03-01

    We reviewed 77 potential cadaveric allograft recipients who had undergone prospective HLA-A and B locus and HLA-DR antigen identification. Matching was accomplished, giving first priority to HLA-DR compatibility and relying on HLA-A and B antigen matching only in situations of total HLA-DR incompatibility. Complete HLA-DR identification occurred in 56 per cent of all patients. There were 15 patients (19.5 per cent) who received a 2/2 HLA-DR perfect match, with 86.7 plus or minus 8.8 per cent 1-year actuarial graft survival, and 41 (53 per cent) who received a 1/2 HLA-DR match, with 58.2 plus or minus 7.8 per cent 1-year actual allograft survival. Finally, 21 patients (27 per cent) received a 0/2 HLA-DR match, with 64.9 plus or minus 10.7 per cent actual survival. These results and their mirrored mismatching results showed statistically significant allograft success in only the HLA-DR 2/2 matches. Matching for HLA 2 DR donors proved a statistically significant success over the other HLA-DR allograft matches and the older controversial matching system based on HLA-A and B locus antigens. The restricted gene polymorphism of the HLA-DR systems allows for a relatively high percentage of perfect HLA-DR matches.

  9. How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire.

    PubMed

    Blevins, Sydney J; Pierce, Brian G; Singh, Nishant K; Riley, Timothy P; Wang, Yuan; Spear, Timothy T; Nishimura, Michael I; Weng, Zhiping; Baker, Brian M

    2016-03-01

    How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs. PMID:26884163

  10. How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

    PubMed Central

    Blevins, Sydney J.; Pierce, Brian G.; Singh, Nishant K.; Riley, Timothy P.; Wang, Yuan; Spear, Timothy T.; Nishimura, Michael I.; Weng, Zhiping; Baker, Brian M.

    2016-01-01

    How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged “hot-spot” region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs. PMID:26884163

  11. Identification of five different Patr class I molecules that bind HLA supertype peptides and definition of their peptide binding motifs.

    PubMed

    McKinney, D M; Erickson, A L; Walker, C M; Thimme, R; Chisari, F V; Sidney, J; Sette, A

    2000-10-15

    We have sequenced the Pan troglodytes class I (Patr) molecules from three common chimpanzees and expressed them as single molecules in a class I-deficient cell line. These lines were utilized to obtain purified class I molecules to define the peptide binding motifs associated with five different Patr molecules. Based on these experiments, as well as analysis of the predicted structure of the B and F polymorphic MHC pockets, we classified five Patr molecules (Patr-A*0101, Patr-B*0901, Patr-B*0701, Patr-A*0602, and Patr-B*1301) within previously defined supertype specificities associated with HLA class I molecules (HLA-A3, -B7, -A1, and -A24 supertypes). The overlap in the binding repertoire between specific HLA and Patr class I molecules was in the range of 33 to 92%, depending on the particular Patr molecule as assessed by the binding of HIV-, hepatitis B virus-, and hepatitis C virus-derived epitopes. Finally, live cell binding assays of nine chimpanzee-derived B cell lines demonstrated that HLA supertype peptides bound to Patr class I molecules with frequencies in the 20-50% range. PMID:11035079

  12. Antiretroviral Therapy Normalizes Autoantibody Profile of HIV Patients by Decreasing CD33+CD11b+HLA-DR+ Cells

    PubMed Central

    Meng, Zhefeng; Du, Ling; Hu, Ningjie; Byrd, Daniel; Amet, Tohti; Desai, Mona; Shepherd, Nicole; Lan, Jie; Han, Renzhi; Yu, Qigui

    2016-01-01

    Abstract Autoimmune manifestations are common in human immunodeficiency virus (HIV) patients. However, the autoantibody spectrum associated with HIV infection and the impact of antiretroviral therapy (ART) remains to be determined. The plasma autoantibody spectrum for HIV patients was characterized by protein microarrays containing 83 autoantigens and confirmed by enzyme-linked immunosorbent assay (ELISA). Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) were analyzed by flow cytometry and their effects on autoantibodies production were determined by B cell ELISpot. Higher levels of autoantibody and higher prevalence of elevated autoantibodies were observed in ART-naive HIV patients compared to healthy subjects and HIV patients on ART. The highest frequency of CD33+CD11b+HLA-DR+ cells was observed in ART-naive HIV patients and was associated with the quantity of elevated autoantibodies. In addition, CD33+CD11b+HLA-DR+ cells other than Tregs or MDSCs boost the B cell response in a dose-dependent manner by in vitro assay. In summary, HIV infection leads to elevation of autoantibodies while ART suppresses the autoimmune manifestation by decreasing CD33+CD11b+HLA-DR+ cells in vivo. The roles of CD33+CD11b+HLA-DR+ cells on disease progression in HIV patients needs further assessment. PMID:27082567

  13. Molecular dynamics at the receptor level of immunodominant myelin oligodendrocyte glycoprotein 35-55 epitope implicated in multiple sclerosis.

    PubMed

    Yannakakis, Mary Patricia; Tzoupis, Haralambos; Michailidou, Elena; Mantzourani, Efthimia; Simal, Carmen; Tselios, Theodore

    2016-07-01

    Multiple Sclerosis (MS) is a common autoimmune disease whereby myelin is destroyed by the immune system. The disease is triggered by the stimulation of encephalitogenic T-cells via the formation of a trimolecular complex between the Human Leukocyte Antigen (HLA), an immunodominant epitope of myelin proteins and T-cell Receptor (TCR). Myelin Oligodendrocyte Glycoprotein (MOG) is located on the external surface of myelin and has been implicated in MS induction. The immunodominant 35-55 epitope of MOG is widely used for in vivo biological evaluation and immunological studies that are related with chronic Experimental Autoimmune Encephalomyelitis (EAE, animal model of MS), inflammatory diseases and MS. In this report, Molecular Dynamics (MD) simulations were used to explore the interactions of MOG35-55 at the receptor level. A detailed mapping of the developed interactions during the creation of the trimolecular complex is reported. This is the first attempt to gain an understanding of the molecular recognition of the MOG35-55 epitope by the HLA and TCR receptors. During the formation of the trimolecular complex, the residues Arg(41) and Arg(46) of MOG35-55 have been confirmed to serve as TCR anchors while Tyr(40) interacts with HLA. The present structural findings indicate that the Arg at positions 41 and 46 is a key residue for the stimulation of the encephalitogenic T-cells. PMID:27388119

  14. Association between a Functional HLA-G 14-bp Insertion/deletion Polymorphism and Susceptibility to Autoimmune Diseases: A Meta-analysis.

    PubMed

    Lee, Y H; Bae, S-C

    2015-12-09

    The aim of this study was to determine whether a functional human leukocyte antigen-G (HLA-G) 14-bp insertion (I)/deletion (D) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted to assess the association between an HLA-G 14-bp I/D polymorphism and autoimmune diseases using 1) allele contrast, as well as 2) recessive, 3) dominant, and 4) codominant models. Sixteen articles that included 20 comparative studies with 3,555 patients and 5,225 controls were included in the meta-analysis. These studies were performed on nine Caucasian, six South American, three Asian, one Arab, and one African population samples. Our meta-analysis revealed no association between autoimmune diseases and the HLA-G 14-bp I/D polymorphism [odds ratio (OR) for allele I = 1.055; 95% confidence interval (CI) = 0.963-1.156; p = 0.251)]. However, meta-analysis according to autoimmune disease type revealed an association between systemic lupus erythematosus (SLE) and the II+ID genotype of the HLA-G 14-bp I/D polymorphism (OR = 1.205; 95% CI = 1.036-1.403; p = 0.016). Furthermore, analysis using a codominant model revealed an association between this polymorphism and SLE (OR for ID vs. DD = 1.203; 95% CI = 1.024-1.413; p = 0.024). In contrast, our meta-analysis revealed no association between rheumatoid arthritis (RA), multiple sclerosis (MS), or Crohn's disease (CD) and the HLA-G 14-bp I/D polymorphism. This meta-analysis showed that the HLA-G 14-bp I/D polymorphism is associated with susceptibility to a subgroup of autoimmune diseases such as SLE, but not RA, MS, or CD. These results support the existence of an association between the HLA-G gene and a subgroup of autoimmune diseases.

  15. Interplay between immune responses to HLA and non-HLA self-antigens in allograft rejection.

    PubMed

    Angaswamy, Nataraju; Tiriveedhi, Venkataswarup; Sarma, Nayan J; Subramanian, Vijay; Klein, Christina; Wellen, Jason; Shenoy, Surendra; Chapman, William C; Mohanakumar, T

    2013-11-01

    Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.

  16. MHC Class I Chain-Related Gene A Polymorphisms and Linkage Disequilibrium with HLA-B and HLA-C Alleles in Ocular Toxoplasmosis

    PubMed Central

    Ayo, Christiane Maria; Camargo, Ana Vitória da Silveira; Frederico, Fábio Batista; Siqueira, Rubens Camargo; Previato, Mariana; Murata, Fernando Henrique Antunes; Silveira-Carvalho, Aparecida Perpétuo; Barbosa, Amanda Pires; Brandão de Mattos, Cinara de Cássia; de Mattos, Luiz Carlos

    2015-01-01

    This study investigated whether polymorphisms of the MICA (major histocompatibility complex class I chain-related gene A) gene are associated with eye lesions due to Toxoplasma gondii infection in a group of immunocompetent patients from southeastern Brazil. The study enrolled 297 patients with serological diagnosis of toxoplasmosis. Participants were classified into two distinct groups after conducting fundoscopic exams according to the presence (n = 148) or absence (n = 149) of ocular scars/lesions due to toxoplasmosis. The group of patients with scars/lesions was further subdivided into two groups according to the type of the ocular manifestation observed: primary (n = 120) or recurrent (n = 28). Genotyping of the MICA and HLA alleles was performed by the polymerase chain reaction-sequence specific oligonucleotide technique (PCR-SSO; One Lambda®) and the MICA-129 polymorphism (rs1051792) was identified by nested polymerase chain reaction (PCR-RFLP). Significant associations involving MICA polymorphisms were not found. Although the MICA*002~HLA-B*35 haplotype was associated with increased risk of developing ocular toxoplasmosis (P-value = 0.04; OR = 2.20; 95% CI = 1.05–4.60), and the MICA*008~HLA-C*07 haplotype was associated with protection against the development of manifestations of ocular toxoplasmosis (P-value = 0.009; OR: 0.44; 95% CI: 0.22–0.76), these associations were not statistically significant after adjusting for multiple comparisons. MICA polymorphisms do not appear to influence the development of ocular lesions in patients diagnosed with toxoplasmosis in this study population. PMID:26672749

  17. [Study of the HLA-DQ system by the complement fixation test on lymphocytes stimulated by phytohemagglutinin. Existence of HLA-DQX allele(s)].

    PubMed

    Chidiac, A; Colombani, M; Lepage, V; Raffoux, C; Sansonetti, N; Colombani, J

    1986-04-01

    The complement fixation microtechnique against PHA blasts has been used to study HLA-DQw1, 2, 3 specificities with sera from multiple transfused patients and/or from multiparous women. Several sera (6 or 7) have been used to define each DQ specificity. The sera have been chosen because of their reactivity with cells from HLA-DR 1, 2 or w6 donors (for DQw1), DR3 or 7 donors (for DQw2,) DR4 or 5 donors (for DQw3). Correlation coefficients between DQ and DR specificities were from 0.56 to 0.91. Correlation coefficients between sera were from 0.51 to 0.92 in each cluster of sera. The segregation of DQw1, 2, 3 specificities has been studied in 46 families with 234 children. This study showed haplotypes lacking DQw1, 2, 3 specificities. The segregation of such 11 DQX haplotypes has been observed in 38 children from 8 families; 5 children were DQX/DQX homozygotes. Up to now, no serological reagent defining the specificity (or specificities) corresponding to DQX has been found. No preferential association was observed between DQX and DR specificities. The gene frequencies observed in 170 haplotypes in these 46 families were as follows: DQw1: 0.400; DQw2: 0.252; DQw3: 0.282; DQX: 0.065. Detecting DQ specificities seems easier by CF on PHA blasts than by lymphocytotoxicity microtechnique against B lymphocytes and monocytes from pheripheral blood. This suggests that PHA blasts express larger quantities of DQ molecules than B lymphocytes and monocytes. The results confirm that complement fixation microtechnique against PHA blasts is efficient for HLA-DQw typing. PMID:3092321

  18. Common Cold

    MedlinePlus

    ... nose, coughing - everyone knows the symptoms of the common cold. It is probably the most common illness. In ... avoid colds. There is no cure for the common cold. For relief, try Getting plenty of rest Drinking ...

  19. Analysis of the functional epitopes on different HLA-A2 molecules.

    PubMed

    Goulmy, E; van der Poel, J; Giphart, M; van Rood, J J

    1984-01-01

    Recent studies show that the serologically defined HLA-A2 molecule can be subdivided according to functional and biochemical characteristics. By the use of various HLA-A2-specific cytotoxic T lymphocytes (CTLs) and isoelectric focusing, the serologically homogeneous HLA-A2 molecule can be divided into four subtypes. The polymorphism of the serologically defined HLA-A2 molecule has also been demonstrated by the use of HLA-A2-restricted CTLs. This study was designed to analyze the functional epitopes on different HLA-A2 molecules with special regard to the recognition patterns of different types of HLA-A2-restricted CTLs directed against minor histocompatibility (minor H) antigens. Fifteen so-called HLA-A2 variants belonging to distinct HLA-A2 subtypes were tested as target cells in the cell-mediated lympholysis (CML) assay against (1) HLA-A2-restricted antiminor H-Y CTLs, (2) HLA-A2 and -B7-restricted antiminor H-Y CTLs, and (3) HLA-A2, -Bw62 and -B27-restricted antiminor "HA" CTLs. We found that those three CTLs recognized only one of those HLA-A2 variants. Furthermore, positive reactions by the antiminor H CTLs were only observed on those variant cells which carried, in addition to the HLA-A2 variant, either another "normal" HLA-A2 molecule or another required restricting class I molecule necessary for associative recognition. These results indicate that the absence of HLA-A2 normal allotypic target determinant(s) leads to the loss of epitope(s) necessary for recognition of minor H-Y and minor "HA" transplantation antigens by HLA-restricted CTLs. We can conclude from the present study that HLA-A2-restricted antiminor H CTLs use, in general, the same epitope (or cluster of epitopes) for cellular recognition as alloimmune HLA-A2-specific CTLs. PMID:6204938

  20. Soluble monomers, dimers and HLA-G-expressing extracellular vesicles: the three dimensions of structural complexity to use HLA-G as a clinical biomarker.

    PubMed

    Nardi, F da Silva; König, L; Wagner, B; Giebel, B; Santos Manvailer, L F; Rebmann, V

    2016-09-01

    The HLA-G molecule belongs to the family of nonclassical human leukocyte antigen (HLA) class I. At variance to classical HLA class I, HLA-G displays (i) a low number of nucleotide variations within the coding region, (ii) a high structural diversity, (iii) a restricted peptide repertoire, (iv) a limited tissue distribution and (v) strong immune-suppressive properties. The physiological HLA-G surface expression is restricted to the maternal-fetal interface and to immune-privileged adult tissues. Soluble forms of HLA-G (sHLA-G) are detectable in various body fluids. Cellular activation and pathological processes are associated with an aberrant or a neo-expression of HLA-G/sHLA-G. Functionally, HLA-G and its secreted forms are considered to be key players in the induction of short- and long-term tolerance. Thus, its unique expression profile and tolerance-inducing functions render HLA-G/sHLA-G an attractive biomarker to monitor the systemic health/disease status and disease activity/progression for clinical approaches in disease management and treatments. Here, we place emphasis on (i) the current status of the tolerance-inducing functions by HLA-G/sHLA-G, (ii) the current complexity to implement this molecule as a meaningful clinical biomarker regarding the three dimensions of structural diversity (monomers, dimers and HLA-G-expressing extracellular vesicles) with its functional implications, and (iii) novel and future approaches to detect and quantify sHLA-G structures and functions.

  1. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.

    PubMed

    Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot; Ellinghaus, Eva; Jostins, Luke; Huang, Hailiang; Ripke, Stephan; Gusareva, Elena S; Annese, Vito; Hauser, Stephen L; Oksenberg, Jorge R; Thomsen, Ingo; Leslie, Stephen; Daly, Mark J; Van Steen, Kristel; Duerr, Richard H; Barrett, Jeffrey C; McGovern, Dermot P B; Schumm, L Philip; Traherne, James A; Carrington, Mary N; Kosmoliaptsis, Vasilis; Karlsen, Tom H; Franke, Andre; Rioux, John D

    2015-02-01

    Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD.

  2. High-density mapping of the MHC identifies a shared role for HLA-DRB1*01:03 in inflammatory bowel diseases and heterozygous advantage in ulcerative colitis.

    PubMed

    Goyette, Philippe; Boucher, Gabrielle; Mallon, Dermot; Ellinghaus, Eva; Jostins, Luke; Huang, Hailiang; Ripke, Stephan; Gusareva, Elena S; Annese, Vito; Hauser, Stephen L; Oksenberg, Jorge R; Thomsen, Ingo; Leslie, Stephen; Daly, Mark J; Van Steen, Kristel; Duerr, Richard H; Barrett, Jeffrey C; McGovern, Dermot P B; Schumm, L Philip; Traherne, James A; Carrington, Mary N; Kosmoliaptsis, Vasilis; Karlsen, Tom H; Franke, Andre; Rioux, John D

    2015-02-01

    Genome-wide association studies of the related chronic inflammatory bowel diseases (IBD) known as Crohn's disease and ulcerative colitis have shown strong evidence of association to the major histocompatibility complex (MHC). This region encodes a large number of immunological candidates, including the antigen-presenting classical human leukocyte antigen (HLA) molecules. Studies in IBD have indicated that multiple independent associations exist at HLA and non-HLA genes, but they have lacked the statistical power to define the architecture of association and causal alleles. To address this, we performed high-density SNP typing of the MHC in >32,000 individuals with IBD, implicating multiple HLA alleles, with a primary role for HLA-DRB1*01:03 in both Crohn's disease and ulcerative colitis. Noteworthy differences were observed between these diseases, including a predominant role for class II HLA variants and heterozygous advantage observed in ulcerative colitis, suggesting an important role of the adaptive immune response in the colonic environment in the pathogenesis of IBD. PMID:25559196

  3. An HLA-DR/DP recombinant family involving DPw6. Evidence for cross-reactivity between DPw6 and GNN2B.

    PubMed

    Odum, N; Hartzman, R; Jakobsen, B K; Morling, N; Platz, P; Robbins, F M; Ryder, L P; Shaw, S; Svejgaard, A

    1986-01-01

    HLA typing of an HLA-B/GLO recombinant family using bulk-expanded DP(SB) alloreactive T-cells (GNN1 to 6) as well as conventional HLA-ABC, D, DR, and DQ typing showed that a paternal recombination had taken place between HLA-DR and DQ on the one hand and HLA-DP(SB) on the other. The recombinant child was DPw4,6-heterozygous and differed in terms of class II determinants only for DPw6 from two otherwise HLA identical siblings, who were probably DPw4/4-homozygous. These siblings did not stimulate the recombinant in MLC whereas they responded to his cells indicating that DPw6 can stimulate in primary MLC. Moreover, it was possible to generate and bulk-expand DPw6-reactive lymphocytes (PLs) between MT and MA as responders and BN as stimulator. The correlation coefficient (r) between the reaction of these PLs and the GNN6 (anti-DPw6) reagents was 1.0 when tested against a panel of 71 individuals. This is the first report demonstrating that the DPw6 gene, like the DPw1-w5 genes, is located between DR/DQ and GLO. The frequency of the DPw6 antigen in 41 unrelated, randomly selected Danes was 7%. HLA-DP typing of the BN family revealed that the DPw6 positive but not DPw6 negative family members gave intermediate responses with one (GNN2B) but not with another (GNN2A) anti-DPw2-reagent. Studies of 63 healthy individuals (unrelated to the BN family) revealed seven similar discrepancies between GNN2A and GNN2B. Strikingly, all four DPw6 positive stimulators gave rise to such discrepancies indicating that the GNN2B reagent is cross-reactive and recognize a common part of the DPw2 and DPw6 molecules. No cases of GNN2A+/GNN2B- stimulators were found.

  4. HLA ASSOCIATIONS IN OBESE WHITE AND BLACK ADULTS

    PubMed Central

    Butler, Merlin G.; Walton, Dominique; Zhu, Weitong; Niblack, Gary

    2016-01-01

    We summarized HLA-A and -B data from 1095 black and white adult men and women with or without obesity to determine if specific HLA tissue types are overrepresented in obese individuals compared with nonobese. None of the three HLA types (Aw30, B18, Bw35) previously reported to relate to obesity was overrepresented in obese subjects in our study. However, B14 and B41 haplotypes were overrepresented in obese white men compared with nonobese men, and B7 was overrepresented in obese black men compared with nonobese men. Additional research will be required to confirm the HLA associations we found and to determine if methodologic differences could account for the differences among the previous studies.

  5. Reappraisal of HLA antibody analysis and crossmatching in kidney transplantation.

    PubMed

    Lee, Po-Chang; Ozawa, Miyuki

    2007-01-01

    It has been established that preformed IgG antibodies specific for donor HLA antigens may accelerate graft failure. An increasing number of studies have demonstrated adverse graft survival in patients who have anti-HLA antibodies, whether preformed or developed post-transplant. More recently, ELISA and flow cytometric techniques were introduced to overcome the limited sensitivity and specificity of the CDC assay. These emerging approaches can be reliably used to predict crossmatches in highly sensitized patients and also to monitor the development of clinically relevant anti-HLA antibody after transplantation. This retrospective study used LAT-M screening and Luminex HLA class I and II specificity assay to re-examine: (a), the impact of pre-transplant HLA antibody on long term graft survival; (b), the accuracy with which detection of HLA antibody and specificity by ELISA predicts pretransplant CDC crossmatch; (c), a comparison of Luminex and ELISA methods in detecting HLA antibodies. In this study, pre-transplant sera from 288 renal patients followed up at NCKUH were tested by the ELISA method, LAT-M. The tests showed that 19% had HLA antibodies before transplantation. Among the 234 of the patients who did not have pre-transplant antibodies, 85% enjoyed 5-year functional graft survival, 76% 10-year, and 56% 15-year functional graft survival. The corresponding functional graft survival for the 54 patients who tested HLA antibody-positive was 65%, 53% and 28% (P=0.0021). Sera from 481 patients awaiting kidney transplantation at NCKUH were tested by the ELISA method LAT-M and by CDC to determine how well HLA antibodies detected by ELISA predict the crossmatches shown by CDC. HLA antibodies found by ELISA ranged from 24% weak reactivity (OD "2") to 17% strongly reactive (OD "8"). The positive predictive value (PPV) of ELISA-detected antibodies for positive CDC crossmatch at the time of transplant was found to be 43-54%. The negative predictive value (NPV)-ELISA found

  6. Neonatal alloimmune thrombocytopenia due to HLA-A2 antibody.

    PubMed

    Chow, M P; Sun, K J; Yung, C H; Hu, H Y; Tzeng, J L; Lee, T D

    1992-01-01

    A male, full-term baby with thrombocytopenia was born by a G3P2A1 mother who was not associated with autoimmune disease. Platelet antibody screening was positive by using lymphocytotoxicity test, platelet suspension immunofluorescence test and solid-phase red cell adherence test. The identified HLA antibody was of A2 specificity. It was confirmed by testing the mother's and the baby's sera against the lymphocytes and platelets of 10 HLA-A2-positive donors. The possibility of platelet-specific antibody as the cause of neonatal alloimmune thrombocytopenia was ruled out by testing against platelets of 10 HLA-A2-negative donors and the known platelet-specific antigens utilizing immobil