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Sample records for histocompatibility class ii

  1. Regulation of major histocompatibility complex class II genes

    PubMed Central

    Choi, Nancy M.; Majumder, Parimal; Boss, Jeremy M.

    2010-01-01

    Summary The major histocompatibility complex class II (MHC-II) genes are regulated at the level of transcription. Recent studies have shown that chromatin modification is critical for efficient transcription of these genes, and a number of chromatin modifying complexes recruited to MHC-II genes have been described. The MHC-II genes are segregated from each other by a series of chromatin elements, termed MHC-II insulators. Interactions between MHC-insulators and the promoters of MHC-II genes are mediated by the insulator factor CCCTC-binding protein and are critical for efficient expression. This regulatory mechanism provides a novel view of how the entire MHC-II locus is assembled architecturally and can be coordinately controlled. PMID:20970972

  2. Interactions between the Class II Transactivator and CREB Binding Protein Increase Transcription of Major Histocompatibility Complex Class II Genes

    PubMed Central

    Fontes, Joseph D.; Kanazawa, Satoshi; Jean, Dickson; Peterlin, B. Matija

    1999-01-01

    Class II major histocompatibility (class II) genes are regulated in a B-cell-specific and gamma interferon-inducible fashion. The master switch for the expression of these genes is the class II transactivator (CIITA). In this report, we demonstrate that one of the functions of CIITA is to recruit the CREB binding protein (CBP) to class II promoters. Not only functional but also specific binding interactions between CIITA and CBP were demonstrated. Moreover, a dominant negative form of CBP decreased the activity of class II promoters and levels of class II determinants on the surface of cells. Finally, the inhibition of class II gene expression by the glucocorticoid hormone could be attributed to the squelching of CBP by the glucocorticoid receptor. We conclude that CBP, a histone acetyltransferase, plays an important role in the transcription of class II genes. PMID:9858618

  3. Evolution of major histocompatibility complex class I and class II genes in the brown bear

    PubMed Central

    2012-01-01

    Background Major histocompatibility complex (MHC) proteins constitute an essential component of the vertebrate immune response, and are coded by the most polymorphic of the vertebrate genes. Here, we investigated sequence variation and evolution of MHC class I and class II DRB, DQA and DQB genes in the brown bear Ursus arctos to characterise the level of polymorphism, estimate the strength of positive selection acting on them, and assess the extent of gene orthology and trans-species polymorphism in Ursidae. Results We found 37 MHC class I, 16 MHC class II DRB, four DQB and two DQA alleles. We confirmed the expression of several loci: three MHC class I, two DRB, two DQB and one DQA. MHC class I also contained two clusters of non-expressed sequences. MHC class I and DRB allele frequencies differed between northern and southern populations of the Scandinavian brown bear. The rate of nonsynonymous substitutions (dN) exceeded the rate of synonymous substitutions (dS) at putative antigen binding sites of DRB and DQB loci and, marginally significantly, at MHC class I loci. Models of codon evolution supported positive selection at DRB and MHC class I loci. Both MHC class I and MHC class II sequences showed orthology to gene clusters found in the giant panda Ailuropoda melanoleuca. Conclusions Historical positive selection has acted on MHC class I, class II DRB and DQB, but not on the DQA locus. The signal of historical positive selection on the DRB locus was particularly strong, which may be a general feature of caniforms. The presence of MHC class I pseudogenes may indicate faster gene turnover in this class through the birth-and-death process. South–north population structure at MHC loci probably reflects origin of the populations from separate glacial refugia. PMID:23031405

  4. Induction of class II major histocompatibility complex expression in human multiple myeloma cells by retinoid.

    PubMed

    Sanda, Takaomi; Iida, Shinsuke; Kayukawa, Satoshi; Ueda, Ryuzo

    2007-01-01

    Class II major histocompatibility complex (MHC II) is normally silenced in plasma/multiple myeloma (MM) cells at the transcriptional level through downregulation of class II transactivator (CIITA), allowing MM cells to escape from immunological responses. Here we demonstrate that a retinoic acid receptor-alpha/beta-selective retinoid Am80 (tamibarotene) could induce the expression of functional MHC II molecules in human MM cell lines. Am80 upregulated expression of the interferon regulatory factor-1 gene, followed by enhancement of CIITA expression. This is the first report demonstrating that retinoid can induce the expression of MHC II in terminally-differentiated plasma/MM cells. PMID:17229644

  5. Cohesin regulates major histocompatibility complex class II genes through interactions with MHC-II insulators1

    PubMed Central

    Majumder, Parimal; Boss, Jeremy M.

    2011-01-01

    Cohesin is a multiprotein ringed complex that is most well known for its role in stabilizing the association of sister chromatids between S phase and M. More recently cohesin was found to be associated with transcriptional insulators, elements that are associated with the organization of chromatin into regulatory domains. The human major histocompatibility complex class II (MHC-II) locuscontains ten intergenic elements, termed MHC-II insulators, which bind the transcriptional insulator protein CCCTC transcription factor (CTCF). MHC-II insulators interact with each other forming a base architecture of discrete loops and potential regulatory domains. When MHC-II genes are expressed, their proximal promoter regulatory regions reorganize to the foci established by the interacting MHC-II insulators. MHC-II insulators also bind cohesin, but the functional role of cohesin in regulating this system is not known. Here we show that the binding of cohesin to MHC-II insulators occurred irrespective of MHC-II expression but was required for optimal expression of the HLA-DR and HLA-DQ genes. In a DNA dependent manner, cohesin subunits interacted with CTCF and the MHC-II specific transcription factors RFX and CIITA. Intriguingly, cohesin subunits were important for DNA looping interactions between the HLA-DRA promoter region and a 5’ MHC-II insulator but were not required for interactions between the MHC-II insulators themselves. This latter observation introduces cohesin as a regulator of MHC-II expression by initiating or stabilizing MHC-II promoter regulatory element interactions with the MHC-II insulator elements; events which are required for maximal MHC-II transcription. PMID:21911605

  6. Activated rat T cells synthesize and express functional major histocompatibility class II antigens.

    PubMed Central

    Broeren, C P; Wauben, M H; Lucassen, M A; Van Meurs, M; Van Kooten, P J; Boog, C J; Claassen, E; Van Eden, W

    1995-01-01

    In the present report, we studied the presence and functional significance of major histocompatibility complex (MHC) class II antigen on rat T cells. Most rat T-cell lines cultured in vitro were found to be MHC class II+. Also, these T-cell lines were shown to synthesize MHC class II molecules. Immunohistochemical and flow cytometric double stainings for T-cell receptor (TCR) and MHC class II showed that in vivo as well a large proportion of T cells was MHC class II+. The immunohistochemical staining of spleen sections enabled us to characterize the MHC class II+ and MHC class II- T cells. It was shown that resting T cells in vivo were MHC class II-. In contrast, activated T cells, as determined by their localization in the marginal zone of the spleen, proved to be MHC class II+. Finally, T-cell clones were found to be able to present peptidic antigens, but could only poorly present more complex exogenous antigens, probably due to inefficient uptake of such antigens. These features would endow activated rat T cells with the capacity to present cell-specific self-proteins, such as TCR, to regulatory CD4+ MHC class II-restricted T cells, as was described by our group elsewhere. Images Figure 2 Figure 5 PMID:7750994

  7. Class I and class II major histocompatibility molecules play a role in bone marrow-derived macrophage development

    NASA Technical Reports Server (NTRS)

    Armstrong, J. W.; Simske, S. J.; Beharka, A. A.; Balch, S.; Luttges, M. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Class I and class II major histocompatibility complex (MHC) molecules play significant roles in T cell development and immune function. We show that MHCI- and MHCII-deficient mice have low numbers of macrophage precursors and circulating monocytes, as well as abnormal bone marrow cell colony-stimulating factor type 1 secretion and bone composition. We suggest that MHCI and MHCII molecules play a significant role in macrophage development.

  8. Interferon-γ Induces Major Histocompatibility Class II Transactivator (CIITA) That Mediates Collagen Repression and Major Histocompatibility Class II Activation by Human Aortic Smooth Muscle Cells

    PubMed Central

    Butticè, Giovanna; Miller, Janice; Wang, Lin; Smith, Barbara D.

    2006-01-01

    Chronic inflammation in atherosclerosis is responsible for plaque instability through alterations in extracellular matrix. Previously, we demonstrated that major histocompatibility class II (MHC II) transactivator (CIITA) in a complex with regulatory factor for X box 5 (RFX5) is a crucial protein mediating interferon (IFN)-γ–induced repression of collagen type I gene transcription in fibroblasts. This article demonstrates that, in smooth muscle cells (SMCs), IFN-γ dramatically increases the expression of CIITA isoforms III and IV, with no increase in expression of CIITA isoform I. Expression of CIITA III and IV correlates with decreased collagen type I and increased MHC II gene expression. Exogenous expression of CIITA I, III, and IV, in transiently transfected SMCs, represses collagen type I promoters (COL1A1 and COL1A2) and activates MHC II promoter. Levels of CIITA and RFX5 increase in the nucleus of cells treated with IFN-γ. Moreover, simvastatin lowers the IFN-γ–induced expression of RFX5 and MHC II in addition to repressing collagen expression. However, simvastatin does not block the IFN-γ–induced expression of CIITA III and IV, suggesting a CIITA-independent mechanism. This first demonstration that RFX5 and CIITA isoforms are expressed in SMCs after IFN-γ stimulation suggest that CIITA could be a key factor in plaque stability in atherosclerosis. PMID:16439692

  9. Neurotrophins inhibit major histocompatibility class II inducibility of microglia: Involvement of the p75 neurotrophin receptor

    PubMed Central

    Neumann, Harald; Misgeld, Thomas; Matsumuro, Kenji; Wekerle, Hartmut

    1998-01-01

    Major histocompatibility complex (MHC) molecules are rare in the healthy brain tissue, but are heavily expressed on microglial cells after inflammatory or neurodegenerative processes. We studied the conditions leading to the induction of MHC class II molecules in microglia by using explant cultures of neonatal rat hippocampus, a model of interacting neuronal networks. Interferon-γ (IFN-γ)-dependent MHC class II inducibility in microglia cells was very low, but strongly increased in the hippocampal slices after the blockade of neuronal activity by neurotoxins [tetrodotoxin (TTX), ω-conotoxin] or glutamate antagonists. None of these agents acted directly on isolated microglia cells. We found that neurotrophins modulate microglial MHC class II expression. MHC class II inducibility was enhanced by neutralization of neurotrophins produced locally within the cultured tissues and was inhibited by the addition of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), or neurotrophin-3 (NT3). NGF and, to a lower extent, NT3 acted directly on isolated microglia via the p75 neurotrophin receptor and inhibited MHC class II inducibility as shown by blockade of the p75 neurotrophin receptor with antibodies. Our data suggest that neurotrophins secreted by electrically active neurons control the antigen-presenting potential of microglia cells, and indicate that this effect is mediated partly via the p75 neurotrophin receptor. PMID:9576961

  10. Isolation and characterization of major histocompatibility complex class II B genes in cranes.

    PubMed

    Kohyama, Tetsuo I; Akiyama, Takuya; Nishida, Chizuko; Takami, Kazutoshi; Onuma, Manabu; Momose, Kunikazu; Masuda, Ryuichi

    2015-11-01

    In this study, we isolated and characterized the major histocompatibility complex (MHC) class II B genes in cranes. Genomic sequences spanning exons 1 to 4 were amplified and determined in 13 crane species and three other species closely related to cranes. In all, 55 unique sequences were identified, and at least two polymorphic MHC class II B loci were found in most species. An analysis of sequence polymorphisms showed the signature of positive selection and recombination. A phylogenetic reconstruction based on exon 2 sequences indicated that trans-species polymorphism has persisted for at least 10 million years, whereas phylogenetic analyses of the sequences flanking exon 2 revealed a pattern of concerted evolution. These results suggest that both balancing selection and recombination play important roles in the crane MHC evolution. PMID:26452363

  11. Expression Regulation of Major Histocompatibility Complex Class I and Class II Encoding Genes

    PubMed Central

    van den Elsen, Peter J.

    2011-01-01

    Major histocompatibility complex (MHC)-I and MHC-II molecules play an essential role in the immune response to pathogens by virtue of their ability to present peptides to CD8+ and CD4+ T cells, respectively. Given this critical role, MHC-I and MHC-II genes are regulated in a tight fashion at the transcriptional level by a variety of transcription factors that interact with conserved cis-acting regulatory promoter elements. In addition to the activities of these regulatory factors, modification of chromatin also plays an essential role in the efficient transcription of these genes to meet with local requirement for an effective immune response. The focus of this review is on the transcription factors that interact with conserved cis-acting promoter elements and the epigenetic mechanisms that modulate induced and constitutive expression of these MHC genes. PMID:22566838

  12. Binding and activation of major histocompatibility complex class II-deficient macrophages by staphylococcal exotoxins

    NASA Technical Reports Server (NTRS)

    Beharka, A. A.; Armstrong, J. W.; Iandolo, J. J.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1994-01-01

    Macrophages from C2D transgenic mice deficient in the expression of major histocompatibility complex (MHC) class II proteins were used to identify binding sites for superantigens distinct from the MHC class II molecule. Iodinated staphylococcal enterotoxins A and B (SEA and SEB) and exfoliative toxins A and B (ETA and ETB) bound to C2D macrophages in a concentration-dependent and competitive manner. All four toxins increased F-actin concentration within 30 s of their addition to C2D macrophages, indicating that signal transduction occurred in response to toxin in the absence of class II MHC. Furthermore, ETA, ETB, SEA, and, to a lesser extent, SEB induced C2D macrophages to produce interleukin 6. Several molecular species on C2D macrophages with molecular masses of 140, 97, 61, 52, 43, and 37 kDa bound SEA in immunoprecipitation experiments. These data indicate the presence of novel, functionally active toxin binding sites on murine macrophages distinct from MHC class II molecules.

  13. Stress-induced alterations in interferon production and class II histocompatibility antigen expression

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, G.; Cunnick, J. E.; Armfield, A. V.; Wood, P. G.; Rabin, B. S.

    1992-01-01

    Mild electric foot-shock has been shown to be a stressor that can alter immune responses. Male Lewis rats were exposed to one session of 16 5.0-s 1.6-mA foot-shocks. Production of interferon-gamma by splenocytes in response to concanavalin-A was decreased in spleens from the shocked rats compared to control spleens. Spleen cells from rats treated with nadolol, a peripherally acting beta-adrenergic receptor antagonist, and then shocked, showed dose-dependent attenuation of the suppression of interferon-gamma production. This suggests that catecholamines mediate shock-induced suppression of interferon-gamma production. The percentage of splenic mononuclear cells expressing class II histocompatibility (Ia) antigens on their surfaces from spleens of shocked rats was determined by flow cytometry. Significantly decreased class II positive mononuclear cells were present in the spleens of shocked rats in comparison to the spleens of control rats. This may reflect an alteration of cell trafficking or decreased production of class II antigens.

  14. Engineering an intracellular pathway for major histocompatibility complex class II presentation of antigens.

    PubMed Central

    Wu, T C; Guarnieri, F G; Staveley-O'Carroll, K F; Viscidi, R P; Levitsky, H I; Hedrick, L; Cho, K R; August, J T; Pardoll, D M

    1995-01-01

    The presentation of antigenic peptides by major histocompatibility complex (MHC) class II molecules to CD4+ T cells is critical to the function of the immune system. In this study, we have utilized the sorting signal of the lysosomal-associated membrane protein LAMP-1 to target a model antigen, human papillomavirus 16 E7 (HPV-16 E7), into the endosomal and lysosomal compartments. The LAMP-1 sorting signal reroutes the antigen into the MHC class II processing pathway, resulting in enhanced presentation to CD4+ cells in vitro. In vivo immunization experiments in mice demonstrated that vaccinia containing the chimeric E7/LAMP-1 gene generated greater E7-specific lymphoproliferative activity, antibody titers, and cytotoxic T-lymphocyte activities than vaccinia containing the wild-type HPV-16 E7 gene. These results suggest that specific targeting of an antigen to the endosomal and lysosomal compartments enhances MHC class II presentation and vaccine potency. Images Fig. 2 Fig. 3 PMID:8524826

  15. Mutations and selection in the generation of class II histocompatibility antigen polymorphism.

    PubMed Central

    Gustafsson, K; Wiman, K; Emmoth, E; Larhammar, D; Böhme, J; Hyldig-Nielsen, J J; Ronne, H; Peterson, P A; Rask, L

    1984-01-01

    A comparison of seven human DR and DC class II histocompatibility antigen beta-chain amino acid sequences indicates that the allelic variation is of comparable magnitude within the DR and DC beta-chain genes. Silent and replacement nucleotide substitutions in six DR and DC beta-chain sequences, as well as in seven murine class II sequences (three I-A beta and four I-A alpha alleles) were analyzed. The results suggest that the mutation rates are of a comparable magnitude in the nucleotide sequences encoding the first and second external domains of the class II molecules. Nevertheless, the allelic amino acid replacements are predominantly located in the first domains. We conclude that a conservative selective pressure acts on the second domains, whereas in many positions in the first domains replacement substitutions are selectively neutral or maybe even favoured. Thus, the difference between the first and second domains as regards the number of amino acid replacements is mainly due to selection. PMID:6589154

  16. Remarkably low affinity of CD4/peptide-major histocompatibility complex class II protein interactions.

    PubMed

    Jönsson, Peter; Southcombe, Jennifer H; Santos, Ana Mafalda; Huo, Jiandong; Fernandes, Ricardo A; McColl, James; Lever, Melissa; Evans, Edward J; Hudson, Alexander; Chang, Veronica T; Hanke, Tomáš; Godkin, Andrew; Dunne, Paul D; Horrocks, Mathew H; Palayret, Matthieu; Screaton, Gavin R; Petersen, Jan; Rossjohn, Jamie; Fugger, Lars; Dushek, Omer; Xu, Xiao-Ning; Davis, Simon J; Klenerman, David

    2016-05-17

    The αβ T-cell coreceptor CD4 enhances immune responses more than 1 million-fold in some assays, and yet the affinity of CD4 for its ligand, peptide-major histocompatibility class II (pMHC II) on antigen-presenting cells, is so weak that it was previously unquantifiable. Here, we report that a soluble form of CD4 failed to bind detectably to pMHC II in surface plasmon resonance-based assays, establishing a new upper limit for the solution affinity at 2.5 mM. However, when presented multivalently on magnetic beads, soluble CD4 bound pMHC II-expressing B cells, confirming that it is active and allowing mapping of the native coreceptor binding site on pMHC II. Whereas binding was undetectable in solution, the affinity of the CD4/pMHC II interaction could be measured in 2D using CD4- and adhesion molecule-functionalized, supported lipid bilayers, yielding a 2D Kd of ∼5,000 molecules/μm(2) This value is two to three orders of magnitude higher than previously measured 2D Kd values for interacting leukocyte surface proteins. Calculations indicated, however, that CD4/pMHC II binding would increase rates of T-cell receptor (TCR) complex phosphorylation by threefold via the recruitment of Lck, with only a small, 2-20% increase in the effective affinity of the TCR for pMHC II. The affinity of CD4/pMHC II therefore seems to be set at a value that increases T-cell sensitivity by enhancing phosphorylation, without compromising ligand discrimination. PMID:27114505

  17. Effects of major histocompatibility complex class II knockout on mouse bone mechanical properties during development.

    PubMed

    Simske, Steven J; Bateman, Ted A; Smith, Erin E; Ferguson, Virginia L; Chapes, Stephen K

    2002-01-01

    We investigated the effect of major histocompatibility complex class II (MHC II) knockout on the development of the mouse peripheral skeleton. These C2D mice had less skeletal development at 8, 12 and 16 weeks of age compared to wild-type C57BL/6J (B6) male mice. The C2D mice had decreased femur mechanical, geometric and compositional measurements compared to wild type mice at each of these ages. C2D femur stiffness (S), peak force in 3-pt bending (Pm), and mineral mass (Min-M) were 74%, 64% and 66%, respectively, of corresponding B6 values at 8 weeks of age. Similar differences were measured at 12 weeks (for which C2D femoral S, Pm and Min-M were 71%, 72% and 73%, respectively, of corresponding B6 values) and at 16 weeks (for which C2D femoral S, Pm and Min-M were 80%, 66% and 61%, respectively, of corresponding B6 values). MHC II knockout delays the development of adult bone properties and is accompanied by lower body mass compared to wild-type controls. PMID:12085652

  18. Effects of major histocompatibility complex class II knockout on mouse bone mechanical properties during development

    NASA Technical Reports Server (NTRS)

    Simske, Steven J.; Bateman, Ted A.; Smith, Erin E.; Ferguson, Virginia L.; Chapes, Stephen K.

    2002-01-01

    We investigated the effect of major histocompatibility complex class II (MHC II) knockout on the development of the mouse peripheral skeleton. These C2D mice had less skeletal development at 8, 12 and 16 weeks of age compared to wild-type C57BL/6J (B6) male mice. The C2D mice had decreased femur mechanical, geometric and compositional measurements compared to wild type mice at each of these ages. C2D femur stiffness (S), peak force in 3-pt bending (Pm), and mineral mass (Min-M) were 74%, 64% and 66%, respectively, of corresponding B6 values at 8 weeks of age. Similar differences were measured at 12 weeks (for which C2D femoral S, Pm and Min-M were 71%, 72% and 73%, respectively, of corresponding B6 values) and at 16 weeks (for which C2D femoral S, Pm and Min-M were 80%, 66% and 61%, respectively, of corresponding B6 values). MHC II knockout delays the development of adult bone properties and is accompanied by lower body mass compared to wild-type controls.

  19. Persistent Ehrlichia chaffeensis infection occurs in the absence of functional major histocompatibility complex class II genes

    NASA Technical Reports Server (NTRS)

    Ganta, Roman Reddy; Wilkerson, Melinda J.; Cheng, Chuanmin; Rokey, Aaron M.; Chapes, Stephen K.

    2002-01-01

    Human monocytic ehrlichiosis is an emerging tick-borne disease caused by the rickettsia Ehrlichia chaffeensis. We investigated the impact of two genes that control macrophage and T-cell function on murine resistance to E. chaffeensis. Congenic pairs of wild-type and toll-like receptor 4 (tlr4)- or major histocompatibility complex class II (MHC-II)-deficient mice were used for these studies. Wild-type mice cleared the infection within 2 weeks, and the response included macrophage activation and the synthesis of E. chaffeensis-specific Th1-type immunoglobulin G response. The absence of a functional tlr4 gene depressed nitric oxide and interleukin 6 secretion by macrophages and resulted in short-term persistent infections for > or =30 days. In the absence of MHC-II alleles, E. chaffeensis infections persisted throughout the entire 3-month evaluation period. Together, these data suggest that macrophage activation and cell-mediated immunity, orchestrated by CD4(+) T cells, are critical for conferring resistance to E. chaffeensis.

  20. Diversity at the major histocompatibility complex Class II in the platypus, Ornithorhynchus anatinus.

    PubMed

    Lillie, Mette; Woodward, Rachael E; Sanderson, Claire E; Eldridge, Mark D B; Belov, Katherine

    2012-07-01

    The platypus (Ornithorhynchus anatinus) is the sole survivor of a previously widely distributed and diverse lineage of ornithorhynchid monotremes. Its dependence on healthy water systems imposes an inherent sensitivity to habitat degradation and climate change. Here, we compare genetic diversity at the major histocompatibility complex (MHC) Class II-DZB gene and 3 MHC-associated microsatellite markers with diversity at 6 neutral microsatellite markers in 70 platypuses from across their range, including the mainland of Australia and the isolated populations of Tasmania, King Island, and Kangaroo Island. Overall, high DZB diversity was observed in the platypus, with 57 DZB β1 alleles characterized. Significant positive selection was detected within the DZB peptide-binding region, promoting variation in this domain. Low levels of genetic diversity were detected at all markers in the 2 island populations, King Island (endemic) and Kangaroo Island (introduced), with the King Island platypuses monomorphic at the DZB locus. Loss of MHC diversity on King Island is of concern, as the population may have compromised immunological fitness and reduced ability to resist changing environmental conditions. PMID:22563128

  1. Expression of major histocompatibility complex class II antigens in porcine leptospiral nephritis.

    PubMed

    Radaelli, E; Del Piero, F; Aresu, L; Sciarrone, F; Vicari, N; Mattiello, S; Tagliabue, S; Fabbi, M; Scanziani, E

    2009-09-01

    Class II major histocompatibility complex (MHCII) is required for the presentation of antigens to CD4 helper T cells. During nephritis, not only primary antigen presenting cells such as histiocytes and lymphocytes, but also cytokine-stimulated tubular epithelial cells express MHCII. Leptospirosis in fattening pigs is characterized by several degrees of nephritis, from absence of lesions to severe multifocal tubulo-interstitial inflammation. Renal tissue from 20 8-month-old pigs with spontaneous nephritis and 6 control pigs without renal lesions were investigated for leptospirosis by indirect immunohistochemistry (IHC) and polymerase chain reaction (PCR). IHC for MHCII also was performed on renal samples. Serum samples were tested for different serovars of Leptospira interrogans. Control pigs were free of interstitial nephritis and negative for leptospirosis by all tests. In pigs with nephritis, serology was positive for serovar Pomona in 19/20 pigs. In 16 of these 19 pigs, leptospiral renal infection was confirmed by PCR and/or indirect IHC. Nephritic lesions were classified histologically into perivascular lymphocytic (4 pigs), lymphofollicular (6 pigs), lymphohistiocytic (8 pigs), and neutrophilic (2 pigs) pattern. MHCII expression by histiocytes and lymphocytes was observed in all lesions. Prominent MHCII expression in regenerating tubular epithelium was observed in lymphofollicular and lymphohistiocytic nephritis. No tubular colocalization between leptospiral and MHCII antigen was observed. Results suggest that during leptospiral nephritis, MHCII contributes to the intensity of the inflammatory response. Furthermore de novo MHCII expression in regenerating tubules may play a role in the defence mechanism against leptospiral tubular colonization. PMID:19179617

  2. Staphylococcus-mediated T-cell activation and spontaneous natural killer cell activity in the absence of major histocompatibility complex class II molecules

    NASA Technical Reports Server (NTRS)

    Chapes, S. K.; Hoynowski, S. M.; Woods, K. M.; Armstrong, J. W.; Beharka, A. A.; Iandolo, J. J.; Spooner, B. S. (Principal Investigator)

    1993-01-01

    We used major histocompatibility complex class II antigen-deficient transgenic mice to show that in vitro natural killer cell cytotoxicity and T-cell activation by staphylococcal exotoxins (superantigens) are not dependent upon the presence of major histocompatibility complex class II molecules. T cells can be activated by exotoxins in the presence of exogenously added interleukin 1 or 2 or in the presence of specific antibody without exogenously added cytokines.

  3. Major histocompatibility complex class II genetic variation in forest musk deer (Moschus berezovskii) in China.

    PubMed

    Yao, Gang; Zhu, Ying; Wan, Qiu-Hong; Fang, Sheng-Guo

    2015-10-01

    The major histocompatibility complex (MHC) plays an important role in the immune system of vertebrates. We used the second exon of four MHC class II genes (DRA, DQA1, DQA2 and DRB3) to assess the overall MHC variation in forest musk deer (Moschus berezovskii). We also compared the MHC variation in captive and wild populations. We observed 22 alleles at four loci (four at DRA, four at DQA1, four at DQA2 and 10 at DRB3), 15 of which were newly identified alleles. Results suggest that forest musk deer maintain relatively high MHC variation, which may result from balancing selection. Moreover, considerable diversity was observed at the DRA locus. We found a high frequency of Mobe-DRA*02, Mobe-DQA1*01 and Mobe-DQA2*05 alleles, which may be important for pathogen resistance. A Ewens-Watterson test showed that the DRB3 locus in the wild population had experienced recent balancing selection. We detected a small divergence at the DRA locus, suggesting the effect of weak positive selection on the DRA gene. Alternatively, this locus may be young and not yet adapted a wide spectrum of alleles for pathogen resistance. The significant heterozygosity deficit observed at the DQA1 and DRB3 loci in the captive population and at all four loci in the wild population may be the result of a population bottleneck. Additionally, MHC genetic diversity was higher in the wild population than in the captive, suggesting that the wild population may have the ability to respond to a wider range of pathogens. PMID:26370614

  4. Active suppression of major histocompatibility complex class II gene expression during differentiation from B cells to plasma cells.

    PubMed Central

    Latron, F; Jotterand-Bellomo, M; Maffei, A; Scarpellino, L; Bernard, M; Strominger, J L; Accolla, R S

    1988-01-01

    Constitutive expression of major histocompatibility complex class II genes is acquired very early in B-cell ontogeny and is maintained up to the B-cell blast stage. Terminal differentiation in plasma cells is, however, accompanied by a loss of class II gene expression. In B cells this gene system is under the control of several loci encoding transacting factors with activator function, one of which, the aIr-1 gene product, operates across species barriers. In this report human class II gene expression is shown to be extinguished in somatic cell hybrids between the human class II-positive B-cell line Raji and the mouse class II-negative plasmacytoma cell line P3-U1. Since all murine chromosomes are retained in these hybrids and no preferential segregation of a specific human chromosome is observed, the results are compatible with the presence of suppressor factors of mouse origin, operating across species barriers and inhibiting class II gene expression. Suppression seems to act at the level of transcription or accumulation of class II-specific mRNA, since no human, and very few murine, class II transcripts are detectable in the hybrids. Images PMID:3127829

  5. Major histocompatibility complex haplotypes and class II genes in non-Jewish patients with pemphigus vulgaris.

    PubMed Central

    Ahmed, A R; Wagner, R; Khatri, K; Notani, G; Awdeh, Z; Alper, C A; Yunis, E J

    1991-01-01

    Previous studies demonstrated that HLA-DR4 was markedly increased among Ashkenazi Jewish patients with pemphigus vulgaris (PV), almost entirely as the common Jewish extended haplotype [HLA-B38, SC21, DR4, DQw8] or as the haplotype HLA-B35, SC31, DR4, DQw8, and that HLA-DR4, DQw8 was distributed among patients in a manner consistent with dominant expression of a class II (D-region or D-region-linked) susceptibility gene. In the present study of major histocompatibility complex (MHC) haplotypes in 25 non-Jewish PV patients, DR4, DQw8 was found in 12 of the patients and DRw6, DQw5 was found in 15. Only 3 patients had neither. Only 1 of the DR4, DQw8 haplotypes was [HLA-B38, SC21, DR4, DQw8] and 2 were HLA-B35, SC31, DR4, DQw8; most were the presumed fragments (SC31, DR4, DQw8) or (SC21, DR4, DQw8) or DR4, DQw8 with some other complotype. Of the patients with DRw6, DQw5, all were DRw14, DQw5, and 6 had a rare Caucasian haplotype, HLA-Bw55, SB45, DRw14, DQw5. Four of 6 of these were found in patients of Italian extraction, as was the 1 normal example. The non-Jewish patients were of more Southern European extraction than our controls. This suggests that there are two major MHC susceptibility alleles in American patients with PV. The more ancient apparently arose on a haplotype in the Jews, HLA-B38(35), SC21(SC31), DR4, DQw8, and spread to other populations largely as D-region segments. The other arose in or near Italy on the haplotype HLA-Bw55, SB45, DRw14, DQw5 and has also partially fragmented so that many patients carry only DRw14, DQw5. The available data do not permit the specific localization of either the DR4, DQw8- or the DRw14, DQw5-linked susceptibility genes. Images PMID:1675792

  6. Human chromosome 16 encodes a factor involved in induction of class II major histocompatibility antigens by interferon gamma.

    PubMed Central

    Bono, M R; Alcaïde-Loridan, C; Couillin, P; Letouzé, B; Grisard, M C; Jouin, H; Fellous, M

    1991-01-01

    Interferon gamma (IFN-gamma) induces expression of class II major histocompatibility complex (MHC)-encoded antigens in immunocompetent cells. To gain further insight into the mechanism of this induction, we prepared somatic cell hybrids between different human cell lines and a murine cell line, RAG, that does not express murine class II MHC antigens before or after treatment with murine IFN-gamma. Some of the resulting cell hybrids express murine class II MHC antigens when treated with murine IFN-gamma. This inducible phenotype is correlated with the presence of human chromosome 16. It has been shown previously that the induction of class I MHC antigens by human IFN-gamma in human-rodent hybrids requires the presence of species-specific factors encoded by chromosome 6, which bears the gene for the human IFN-gamma receptor, and chromosome 21, whose product(s) is necessary for the transduction of human IFN-gamma signals. In this report, we show that the induction of murine class II MHC antigens by human IFN-gamma in the human-RAG cell hybrids requires, likewise, the presence of human chromosomes 6 and 21, in addition to chromosome 16. In some of these hybrids, when all three of these human chromosomes were present, induction of cell-surface HLA-DR antigens was also observed. Our results demonstrate that human chromosome 16 encodes a non-species-specific factor involved in the induction of class II MHC antigens by IFN-gamma. Images PMID:1906174

  7. Organization and characteristics of the major histocompatibility complex class II region in the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis)

    PubMed Central

    Ruan, Rui; Ruan, Jue; Wan, Xiao-Ling; Zheng, Yang; Chen, Min-Min; Zheng, Jin-Song; Wang, Ding

    2016-01-01

    Little is known about the major histocompatibility complex (MHC) in the genome of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) (YFP) or other cetaceans. In this study, a high-quality YFP bacterial artificial chromosome (BAC) library was constructed. We then determined the organization and characterization of YFP MHC class II region by screening the BAC library, followed by sequencing and assembly of positive BAC clones. The YFP MHC class II region consists of two segregated contigs (218,725 bp and 328,435 bp respectively) that include only eight expressed MHC class II genes, three pseudo MHC genes and twelve non-MHC genes. The YFP has fewer MHC class II genes than ruminants, showing locus reduction in DRB, DQA, DQB, and loss of DY. In addition, phylogenic and evolutionary analyses indicated that the DRB, DQA and DQB genes might have undergone birth-and-death evolution, whereas the DQB gene might have evolved under positive selection in cetaceans. These findings provide an essential foundation for future work, such as estimating MHC genetic variation in the YFP or other cetaceans. This work is the first report on the MHC class II region in cetaceans and offers valuable information for understanding the evolution of MHC genome in cetaceans. PMID:26932528

  8. Organization and characteristics of the major histocompatibility complex class II region in the Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis).

    PubMed

    Ruan, Rui; Ruan, Jue; Wan, Xiao-Ling; Zheng, Yang; Chen, Min-Min; Zheng, Jin-Song; Wang, Ding

    2016-01-01

    Little is known about the major histocompatibility complex (MHC) in the genome of Yangtze finless porpoise (Neophocaena asiaeorientalis asiaeorientalis) (YFP) or other cetaceans. In this study, a high-quality YFP bacterial artificial chromosome (BAC) library was constructed. We then determined the organization and characterization of YFP MHC class II region by screening the BAC library, followed by sequencing and assembly of positive BAC clones. The YFP MHC class II region consists of two segregated contigs (218,725 bp and 328,435 bp respectively) that include only eight expressed MHC class II genes, three pseudo MHC genes and twelve non-MHC genes. The YFP has fewer MHC class II genes than ruminants, showing locus reduction in DRB, DQA, DQB, and loss of DY. In addition, phylogenic and evolutionary analyses indicated that the DRB, DQA and DQB genes might have undergone birth-and-death evolution, whereas the DQB gene might have evolved under positive selection in cetaceans. These findings provide an essential foundation for future work, such as estimating MHC genetic variation in the YFP or other cetaceans. This work is the first report on the MHC class II region in cetaceans and offers valuable information for understanding the evolution of MHC genome in cetaceans. PMID:26932528

  9. Complex architecture of major histocompatibility complex class II promoters: reiterated motifs and conserved protein-protein interactions.

    PubMed Central

    Jabrane-Ferrat, N; Fontes, J D; Boss, J M; Peterlin, B M

    1996-01-01

    The S box (also known as at the H, W, or Z box) is the 5'-most element of the conserved upstream sequences in promoters of major histocompatibility complex class II genes. It is important for their B-cell-specific and interferon gamma-inducible expression. In this study, we demonstrate that the S box represents a duplication of the downstream X box. First, RFX, which is composed of the RFX5-p36 heterodimer that binds to the X box, also binds to the S box and its 5'-flanking sequence. Second, NF-Y, which binds to the Y box and increases interactions between RFX and the X box, also increases the binding of RFX to the S box. Third, RFXs bound to S and X boxes interact with each other in a spatially constrained manner. Finally, we confirmed these protein-protein and protein-DNA interactions by expressing a hybrid RFX5-VP16 protein in cells. We conclude that RFX binds to S and X boxes and that complex interactions between RFX and NF-Y direct B-cell-specific and interferon gamma-inducible expression or major histocompatibility complex class II genes. PMID:8756625

  10. Selection and Trans-Species Polymorphism of Major Histocompatibility Complex Class II Genes in the Order Crocodylia

    PubMed Central

    Jaratlerdsiri, Weerachai; Isberg, Sally R.; Higgins, Damien P.; Miles, Lee G.; Gongora, Jaime

    2014-01-01

    Major Histocompatibility Complex (MHC) class II genes encode for molecules that aid in the presentation of antigens to helper T cells. MHC characterisation within and between major vertebrate taxa has shed light on the evolutionary mechanisms shaping the diversity within this genomic region, though little characterisation has been performed within the Order Crocodylia. Here we investigate the extent and effect of selective pressures and trans-species polymorphism on MHC class II α and β evolution among 20 extant species of Crocodylia. Selection detection analyses showed that diversifying selection influenced MHC class II β diversity, whilst diversity within MHC class II α is the result of strong purifying selection. Comparison of translated sequences between species revealed the presence of twelve trans-species polymorphisms, some of which appear to be specific to the genera Crocodylus and Caiman. Phylogenetic reconstruction clustered MHC class II α sequences into two major clades representing the families Crocodilidae and Alligatoridae. However, no further subdivision within these clades was evident and, based on the observation that most MHC class II α sequences shared the same trans-species polymorphisms, it is possible that they correspond to the same gene lineage across species. In contrast, phylogenetic analyses of MHC class II β sequences showed a mixture of subclades containing sequences from Crocodilidae and/or Alligatoridae, illustrating orthologous relationships among those genes. Interestingly, two of the subclades containing sequences from both Crocodilidae and Alligatoridae shared specific trans-species polymorphisms, suggesting that they may belong to ancient lineages pre-dating the divergence of these two families from the common ancestor 85–90 million years ago. The results presented herein provide an immunogenetic resource that may be used to further assess MHC diversity and functionality in Crocodylia. PMID:24503938

  11. Selection and trans-species polymorphism of major histocompatibility complex class II genes in the order Crocodylia.

    PubMed

    Jaratlerdsiri, Weerachai; Isberg, Sally R; Higgins, Damien P; Miles, Lee G; Gongora, Jaime

    2014-01-01

    Major Histocompatibility Complex (MHC) class II genes encode for molecules that aid in the presentation of antigens to helper T cells. MHC characterisation within and between major vertebrate taxa has shed light on the evolutionary mechanisms shaping the diversity within this genomic region, though little characterisation has been performed within the Order Crocodylia. Here we investigate the extent and effect of selective pressures and trans-species polymorphism on MHC class II α and β evolution among 20 extant species of Crocodylia. Selection detection analyses showed that diversifying selection influenced MHC class II β diversity, whilst diversity within MHC class II α is the result of strong purifying selection. Comparison of translated sequences between species revealed the presence of twelve trans-species polymorphisms, some of which appear to be specific to the genera Crocodylus and Caiman. Phylogenetic reconstruction clustered MHC class II α sequences into two major clades representing the families Crocodilidae and Alligatoridae. However, no further subdivision within these clades was evident and, based on the observation that most MHC class II α sequences shared the same trans-species polymorphisms, it is possible that they correspond to the same gene lineage across species. In contrast, phylogenetic analyses of MHC class II β sequences showed a mixture of subclades containing sequences from Crocodilidae and/or Alligatoridae, illustrating orthologous relationships among those genes. Interestingly, two of the subclades containing sequences from both Crocodilidae and Alligatoridae shared specific trans-species polymorphisms, suggesting that they may belong to ancient lineages pre-dating the divergence of these two families from the common ancestor 85-90 million years ago. The results presented herein provide an immunogenetic resource that may be used to further assess MHC diversity and functionality in Crocodylia. PMID:24503938

  12. Major histocompatibility complex class II A genes in cichlid fishes: identification, expression, linkage relationships, and haplotype variation.

    PubMed

    Murray, B W; Shintani, S; Sültmann, H; Klein, J

    2000-06-01

    Two cichlid species, the haplochromine Aulonocara hansbaenschi and the tilapiine Oreochromis niloticus, were used to study the major histocompatibility complex (Mhc) class II A variation within this group. Multiple class II A sequences were recovered from A. hansbaenschi and O. niloticus cDNA libraries and three sequence families, DAA, DBA, and DCA, were identified. Sets of O. niloticus haploid embryo families were used to determine the linkage relationships of these genes. Two independently assorting linkage groups were detected, DAA and DBA/DCA, neither of which is linked to the previously described Mhc class I gene cluster. Three DCA genes and up to four DBA genes were found to segregate in different haplotypes, whereas DAA occurred as a single locus. Four DBA haplotypes, DBA*H1-H4, were identified and shown to co-segregate with the previously described class II B haplotypes. Four DCA haplotypes, DCA*H1-H4, were found at a distance of 37 cM from the DBA/class II B cluster; in one DCA haplotype, DCA*H5, the genes were tightly linked to the DBA/class II B clusters. Transcripts of DAA and DBA genes were found in O. niloticus hepatopancreas and spleen; transcripts of DCA genes were detected in the A. hansbaenschi cDNA library, but not in O. niloticus. These findings provide a basis for using class II haplotypes as markers in the study of adaptive radiation in the cichlid species flocks of the East African Great Lakes. PMID:10912508

  13. Structure and Polymorphism of the Major Histocompatibility Complex Class II Region in the Japanese Crested Ibis, Nipponia nippon

    PubMed Central

    Taniguchi, Yukio; Matsumoto, Keisuke; Matsuda, Hirokazu; Yamada, Takahisa; Sugiyama, Toshie; Homma, Kosuke; Kaneko, Yoshinori; Yamagishi, Satoshi; Iwaisaki, Hiroaki

    2014-01-01

    The major histocompatibility complex (MHC) is a highly polymorphic genomic region that plays a central role in the immune system. Despite its functional consistency, the genomic structure of the MHC differs substantially among organisms. In birds, the MHC-B structures of Galliformes, including chickens, have been well characterized, but information about other avian MHCs remains sparse. The Japanese Crested Ibis (Nipponia nippon, Pelecaniformes) is an internationally conserved, critically threatened species. The current Japanese population of N. nippon originates from only five founders; thus, understanding the genetic diversity among these founders is critical for effective population management. Because of its high polymorphism and importance for disease resistance and other functions, the MHC has been an important focus in the conservation of endangered species. Here, we report the structure and polymorphism of the Japanese Crested Ibis MHC class II region. Screening of genomic libraries allowed the construction of three contigs representing different haplotypes of MHC class II regions. Characterization of genomic clones revealed that the MHC class II genomic structure of N. nippon was largely different from that of chicken. A pair of MHC-IIA and -IIB genes was arranged head-to-head between the COL11A2 and BRD2 genes. Gene order in N. nippon was more similar to that in humans than to that in chicken. The three haplotypes contained one to three copies of MHC-IIA/IIB gene pairs. Genotyping of the MHC class II region detected only three haplotypes among the five founders, suggesting that the genetic diversity of the current Japanese Crested Ibis population is extremely low. The structure of the MHC class II region presented here provides valuable insight for future studies on the evolution of the avian MHC and for conservation of the Japanese Crested Ibis. PMID:25247679

  14. Class II major histocompatibility complex antigen expression on peripheral blood monocytes in patients with inflammatory bowel disease.

    PubMed Central

    Gardiner, K R; Crockard, A D; Halliday, M I; Rowlands, B J

    1994-01-01

    Macrophage major histocompatibility complex (MHC) class II antigen expression is associated with defective antigen presentation to T lymphocytes in animals and is predictive of patient outcome after major trauma or sepsis. In this study, class II antigen (HLA-DR and DQ) expression on peripheral blood monocytes was investigated in patients with inflammatory bowel disease in relation to disease activity and outcome. The percentage positivity and fluorescent intensity of expression of HLA-DR and DQ antigens on monocytes were determined in whole blood samples using dual colour immunofluorescence labelling and flow cytometry. Disease activity was assessed using clinical and laboratory indices. There was no significant difference in percentage positivity or fluorescent intensity of class II antigen expression between patients with Crohn's disease, those with ulcerative colitis, and healthy volunteers. The percentage of monocytes displaying HLA-DR positivity was significantly decreased in patients with active ulcerative colitis (active %: 49.5 (5.6); inactive %: 78.9 (6.9); p = 0.01). Data expressed as mean (SEM). In patients requiring surgical resection of diseased bowel, the percentage of monocytes displaying HLA-DR positivity (51.9 (4.0) %) was significantly reduced compared with patients receiving medical treatment alone (81.1 (3.5) %; p < 0.001). Reduced monocyte HLA-DR expression is therefore associated with disease activity and seems to predict outcome in patients with inflammatory bowel disease. PMID:8174990

  15. Association of hypothyroid disease in Doberman Pinscher dogs with a rare major histocompatibility complex DLA class II haplotype.

    PubMed

    Kennedy, L J; Huson, H J; Leonard, J; Angles, J M; Fox, L E; Wojciechowski, J W; Yuncker, C; Happ, G M

    2006-01-01

    Canine hypothyroid disease is similar to Hashimoto's disease in humans, which has been shown to be associated with human major histocompatibility complex (MHC) genes. We have collected 27 Doberman Pinschers affected with primary hypothyroid disease and compared their MHC class II haplotypes with 129 unaffected Doberman Pinschers. Three dog-leucocyte antigen (DLA) genes, DLA-DRB1, DQA1 and DQB1, were characterized by sequence-based typing and assigned to haplotypes for each dog. One rare haplotype was found at an increased frequency in the affected dogs compared to the unaffected dogs (Odds ratio = 2.43, P < 0.02). This haplotype has only been found in Doberman Pinschers and Labradors to date. PMID:16451201

  16. Inflammatory bowel diseases influence major histocompatibility complex class I (MHC I) and II compartments in intestinal epithelial cells.

    PubMed

    Bär, F; Sina, C; Hundorfean, G; Pagel, R; Lehnert, H; Fellermann, K; Büning, J

    2013-05-01

    Antigen presentation by intestinal epithelial cells (IEC) is crucial for intestinal homeostasis. Disturbances of major histocompatibility complex class I (MHC I)- and II-related presentation pathways in IEC appear to be involved in an altered activation of CD4(+) and CD8(+) T cells in inflammatory bowel disease. However, a comprehensive analysis of MHC I- and II-enriched compartments in IEC of the small and large bowel in the healthy state as opposed to inflammatory bowel diseases is lacking. The aim of this study was to characterize the subcellular expression of MHC I and II in the endocytic pathway of IEC throughout all parts of the intestinal tract, and to identify differences between the healthy state and inflammatory bowel diseases. Biopsies were taken by endoscopy from the duodenum, jejunum, ileum and colon in healthy individuals (n = 20). In Crohn's disease (CD), biopsies were obtained from the ileum and colon and within the colon from ulcerative colitis (UC) patients (n = 15). Analysis of IEC was performed by immunoelectron microscopy. MHC I and II were identified in early endosomes and multi-vesicular, multi-lamellar, electrondense and vacuolar late endosomes. Both molecules were enriched in multi-vesicular bodies. No differences were found between the distinct parts of the gut axis. In CD and UC the expression of MHC I and II showed a shift from multi-vesicular bodies towards the basolateral membranes. Within the multi-vesicular bodies, MHC I and II moved from internal vesicles to the limiting membranes upon inflammation in CD and UC. MHC I- and II-enriched compartments in IEC were identical in all parts of the small and large bowel. CD and UC appear to modulate the MHC I- and II-related presentation pathways of exogenous antigens in IEC. PMID:23574324

  17. Major histocompatibility complex class II deficiency complicated by Mycobacterium avium complex in a boy of mixed ethnicity.

    PubMed

    Dimitrova, Dimana; Ong, Peck Y; O'Gorman, Maurice R G; Church, Joseph A

    2014-08-01

    Major histocompatibility complex class II (MHCII) deficiency represents a rare form of severe immunodeficiency associated with increased susceptibility to viral, bacterial, and fungal pathogens and commonly leads to failure to thrive and early death. This autosomal recessive disorder is caused by mutations in MHCII transcription regulator genes, resulting in impaired expression of MHCII, and it is usually seen in consanguineous populations. Our patient presented at age 15 months with a history of developmental delay, multiple respiratory infections and skin abscesses, and recently, at 5 years of age, he was found to have disseminated Mycobacterium avium complex. His mother is Mexican-American, and his father is Persian. Laboratory investigations showed hypogammaglobulinemia, modest T-lymphopenia, borderline mitogen responses, absent tetanus toxoid and candida antigen lymphoproliferative assays, and absent tetanus toxoid and Haemophilus influenzae type b antibody levels. Flow cytometry demonstrated absent HLA-DR antigen on monocytes and B-cells, and a diagnosis of MHCII deficiency was made. Genetic analysis yielded a homozygous pathogenic class II transactivator (CIITA) mutation. The same mutation was found in both parents. Coincidently, an Xq28 microduplication was identified and likely was the cause of the patient's developmental delay. This patient demonstrated some of the typical features of MHCII deficiency with the addition of several unique findings: disseminated M. avium complex, homozygosity in a CIITA mutation despite remarkably diverse parental ethnicity, and coincident Xq28 microdeletion with mild intellectual disability. PMID:24789686

  18. Zinc Induces Dimerization of the Class II Major Histocompatibility Complex Molecule That Leads to Cooperative Binding to a Superantigen

    SciTech Connect

    Li,H.; Zhao, Y.; Guo, Y.; Li, Z.; Eislele, L.; Mourad, W.

    2007-01-01

    Dimerization of class II major histocompatibility complex (MHC) plays an important role in the MHC biological function. Mycoplasma arthritidis-derived mitogen (MAM) is a superantigen that can activate large fractions of T cells bearing specific T cell receptor V{beta} elements. Here we have used structural, sedimentation, and surface plasmon resonance detection approaches to investigate the molecular interactions between MAM and the class II MHC molecule HLA-DR1 in the context of a hemagglutinin peptide-(306-318) (HA). Our results revealed that zinc ion can efficiently induce the dimerization of the HLA-DR1/HA complex. Because the crystal structure of the MAM/HLA-DR1/hemagglutinin complex in the presence of EDTA is nearly identical to the structure of the complex crystallized in the presence of zinc ion, Zn{sup 2+} is evidently not directly involved in the binding between MAM and HLA-DR1. Sedimentation and surface plasmon resonance studies further revealed that MAM binds the HLA-DR1/HA complex with high affinity in a 1:1 stoichiometry, in the absence of Zn{sup 2+}. However, in the presence of Zn{sup 2+}, a dimerized MAM/HLA-DR1/HA complex can arise through the Zn{sup 2+}-induced DR1 dimer. In the presence of Zn{sup 2+}, cooperative binding of MAM to the DR1 dimer was also observed.

  19. Major histocompatibility complex class II alleles and haplotypes associated with non-suppurative meningoencephalitis in greyhounds.

    PubMed

    Shiel, R E; Kennedy, L J; Nolan, C M; Mooney, C T; Callanan, J J

    2014-09-01

    Non-suppurative meningoencephalitis is a breed-restricted canine neuroinflammatory disorder affecting young greyhounds in Ireland. A genetic risk factor is suspected because of the development of disease in multiple siblings and an inability to identify a causative infectious agent. The aim of this study was to examine potential associations between dog leucocyte antigen (DLA) class II haplotype and the presence of the disease. DLA three locus haplotypes were determined in 31 dogs with non-suppurative meningoencephalitis and in 115 healthy control dogs using sequence-based typing (SBT) methods. All dogs were unrelated at the parental level. Two haplotypes (DRB1*01802/DQA1*00101/DQB1*00802 and DRB1*01501/DQA1*00601/DQB1*02201) were significantly (P = 0.0099 and 0.037) associated with the presence of meningoencephalitis, with odds ratios (95% confidence interval) of 5.531 (1.168-26.19) and 3.736 (1.446-9.652), respectively. These results confirm that there is an association between DLA class II haplotype and greyhound meningoencephalitis, suggesting an immunogenetic risk factor for the development of the disease. Greyhound meningoencephalitis may be a suitable model for human neuroinflammatory diseases with an immunogenetic component. PMID:24851745

  20. Relationship between target antigens and major histocompatibility complex (MHC) class II genes in producing two pathogenic antibodies simultaneously

    PubMed Central

    Zakka, L R; Keskin, D B; Reche, P; Ahmed, A R

    2010-01-01

    In this report, we present 15 patients with histological and immunopathologically proven pemphigus vulgaris (PV). After a mean of 80 months since the onset of disease, when evaluated serologically, they had antibodies typical of PV and pemphigoid (Pg). Similarly, 18 patients with bullous pemphigoid (BP) and mucous membrane pemphigoid (MMP) were diagnosed on the basis of histology and immunopathology. After a mean of 60 months since the onset of disease, when their sera were evaluated they were found to have Pg and PV autoantibodies. In both groups of patients the diseases were characterized by a chronic course, which included several relapses and recurrences and were non-responsive to conventional therapy. The major histocompatibility complex class II (MHC II) genes were studied in both groups of patients and phenotypes associated typically with them were observed. Hence, in 33 patients, two different pathogenic autoantibodies were detected simultaneously. The authors provide a computer model to show that each MHC II gene has relevant epitopes that recognize the antigens associated with both diseases. Using the databases in these computer models, the authors present the hypothesis that these two autoantibodies are produced simultaneously due to the phenomena of epitope spreading. PMID:21069937

  1. Schwann cell differentiation inhibits interferon-gamma induction of expression of major histocompatibility complex class II and intercellular adhesion molecule-1.

    PubMed

    Lisak, Robert P; Bealmear, Beverly; Benjamins, Joyce A

    2016-06-15

    Interferon-gamma (IFN-γ) upregulates major histocompatibility complex class II (MHC class II) antigens and intercellular adhesion molecule-1 (ICAM-1) on Schwann cells (SC) in vitro, but in nerves of animals and patients MHC class II is primarily expressed on inflammatory cells. We investigated whether SC maturation influences their expression. IFN-γ induced MHC class II and upregulated ICAM-1; the axolemma-like signal 8-bromo cyclic adenosine monophosphate (8 Br cAMP) with IFN-γ inhibited expression. Delaying addition of 8 Br cAMP to SC already exposed to IFN-γ inhibited ongoing expression; addition of IFN-γ to SC already exposed to 8 Br cAMP resulted in minimal expression. Variability of cytokine-induced MHC class II and ICAM-1 expression by SC in vivo may represent the variability of signals from axolemma. PMID:27235355

  2. Two-dimensional nuclear magnetic resonance analysis of a labeled peptide bound to a class II major histocompatibility complex molecule.

    PubMed

    Driscoll, P C; Altman, J D; Boniface, J J; Sakaguchi, K; Reay, P A; Omichinski, J G; Appella, E; Davis, M M

    1993-07-20

    The formation of peptide/major histocompatibility complex (MHC) complexes and their subsequent recognition by T cells is a pivotal event in the initiation of an immune response. While X-ray crystal structures are now available for class I MHC/peptide complexes, little detailed structural information is known about the class II MHC equivalent, and there are no solution structure data for either. A 16 amino acid residue moth cytochrome c peptide (residues 88 to 103) was 13C-labeled for two-dimensional isotope-edited NMR analysis. The peptide was labeled either selectively in the methyl groups of alanine residues or uniformly at every carbon position, and bound to unlabeled soluble mouse I-Ek class II MHC molecules. Although alpha-helical in the native cytochrome c protein and with no uniform structure in solution, the peptide is bound to the I-Ek molecule with the alpha-carbon atoms of the 11 C-terminal residues held in the binding groove. This indicates that the class II MHC peptide binding site is somewhat larger than that of class I MHC molecules (> or = 11 amino acid residues versus 8 to 10 amino acid residues), consistent with recent data on eluted peptides. Despite the large size of the complex (approximately 70 kDa), nuclear Overhauser effects are clearly detectable between peptide side-chains and the MHC molecule. Indications of the buried or exposed nature of particular side-chains within the bound peptide are derived from the NMR data and these are used together with information from previous biological studies to propose a crude model of the interaction of the peptide with the groove of the MHC molecule. We find no evidence for a conformational change in the peptide/MHC complex in the spectra at pH 5.0 versus pH 7.0, despite a 40-fold faster on-rate for the peptide at the lower pH value. PMID:8393933

  3. Tissue factor initiates glomerular fibrin deposition and promotes major histocompatibility complex class II expression in crescentic glomerulonephritis.

    PubMed Central

    Erlich, J. H.; Holdsworth, S. R.; Tipping, P. G.

    1997-01-01

    Increased glomerular tissue factor (TF) expression is associated with glomerular fibrin deposition and renal failure in human and experimental crescentic glomerulonephritis (GN). However, the in vivo functional contribution of TF to the development of glomerular fibrin deposition, crescent formation, and renal failure in GN has not been established. The contribution of TF to fibrin deposition and renal injury was studied in a rabbit model of crescentic GN in which glomerular macrophage infiltration, augmented TF expression, and fibrin deposition are prominent. Administration of anti-TF antibody inhibited glomerular TF activity in nephritic glomeruli by 96%, without affecting macrophage accumulation or systemic indices of coagulation. Anti-TF antibody significantly reduced glomerular fibrin deposition (fibrin scores, 0.43 +/- 0.10 (treated) and 1.40 +/- 0.19 (control); P < 0.0005), crescent formation (0.33 +/- 0.05 (treated) and 1.0 +/- 0.06 (control); P < 0.0005), and development of renal failure (serum creatinine, 168 +/- 22 mumol/l (treated) and 267 +/- 35 mumol/l (control); P < 0.04). This was associated with significant reduction in proteinuria (1189 +/- 277 mg/24 hours (treated) and 2060 +/- 336 mg/24 hours (control); P < 0.03) and expression of MHC class II antigen in glomeruli (1.25 +/- 0.41 (treated) and 2.83 +/- 0.53 (control); P < 0.03) and in tubules and interstitial areas. These data demonstrate that TF is the major in vivo initiator of fibrin deposition in crescentic GN. The reduction in proteinuria and glomerular major histocompatibility class II antigen expression by TF inhibition suggests that TF may also activate other mediators that contribute to glomerular injury. Images Figure 1 PMID:9060825

  4. In situ detection of autoreactive CD4 T cells in brain and heart using major histocompatibility complex class II dextramers.

    PubMed

    Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Jia, Ting; Elowsky, Christian; Li, Qingsheng; Zhou, You; Reddy, Jay

    2014-01-01

    This report demonstrates the use of major histocompatibility complex (MHC) class II dextramers for detection of autoreactive CD4 T cells in situ in myelin proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice and cardiac myosin heavy chain-α (Myhc) 334-352-induced experimental autoimmune myocarditis (EAM) in A/J mice. Two sets of cocktails of dextramer reagents were used, where dextramers(+) cells were analyzed by laser scanning confocal microscope (LSCM): EAE, IA(s)/PLP 139-151 dextramers (specific)/anti-CD4 and IA(s)/Theiler's murine encephalomyelitis virus (TMEV) 70-86 dextramers (control)/anti-CD4; and EAM, IA(k)/Myhc 334-352 dextramers/anti-CD4 and IA(k)/bovine ribonuclease (RNase) 43-56 dextramers (control)/anti-CD4. LSCM analysis of brain sections obtained from EAE mice showed the presence of cells positive for CD4 and PLP 139-151 dextramers, but not TMEV 70-86 dextramers suggesting that the staining obtained with PLP 139-151 dextramers was specific. Likewise, heart sections prepared from EAM mice also revealed the presence of Myhc 334-352, but not RNase 43-56-dextramer(+) cells as expected. Further, a comprehensive method has also been devised to quantitatively analyze the frequencies of antigen-specific CD4 T cells in the 'Z' serial images. PMID:25145797

  5. In Situ Detection of Autoreactive CD4 T Cells in Brain and Heart Using Major Histocompatibility Complex Class II Dextramers

    PubMed Central

    Massilamany, Chandirasegaran; Gangaplara, Arunakumar; Jia, Ting; Elowsky, Christian; Li, Qingsheng; Zhou, You; Reddy, Jay

    2014-01-01

    This report demonstrates the use of major histocompatibility complex (MHC) class II dextramers for detection of autoreactive CD4 T cells in situ in myelin proteolipid protein (PLP) 139-151-induced experimental autoimmune encephalomyelitis (EAE) in SJL mice and cardiac myosin heavy chain-α (Myhc) 334-352-induced experimental autoimmune myocarditis (EAM) in A/J mice. Two sets of cocktails of dextramer reagents were used, where dextramers+ cells were analyzed by laser scanning confocal microscope (LSCM): EAE, IAs/PLP 139-151 dextramers (specific)/anti-CD4 and IAs/Theiler’s murine encephalomyelitis virus (TMEV) 70-86 dextramers (control)/anti-CD4; and EAM, IAk/Myhc 334-352 dextramers/anti-CD4 and IAk/bovine ribonuclease (RNase) 43-56 dextramers (control)/anti-CD4. LSCM analysis of brain sections obtained from EAE mice showed the presence of cells positive for CD4 and PLP 139-151 dextramers, but not TMEV 70-86 dextramers suggesting that the staining obtained with PLP 139-151 dextramers was specific. Likewise, heart sections prepared from EAM mice also revealed the presence of Myhc 334-352, but not RNase 43-56-dextramer+ cells as expected. Further, a comprehensive method has also been devised to quantitatively analyze the frequencies of antigen-specific CD4 T cells in the ‘Z’ serial images. PMID:25145797

  6. Potent T Cell Activation with Dimeric Peptide–Major Histocompatibility Complex Class II Ligand: The Role of CD4 Coreceptor

    PubMed Central

    Hamad, Abdel Rahim A.; O'Herrin, Sean M.; Lebowitz, Michael S.; Srikrishnan, Ananth; Bieler, Joan; Schneck, Jonathan; Pardoll, Drew

    1998-01-01

    The interaction of the T cell receptor (TCR) with its cognate peptide–major histocompatibility complex (MHC) on the surface of antigen presenting cells (APCs) is a primary event during T cell activation. Here we used a dimeric IEk-MCC molecule to study its capacity to activate antigen-specific T cells and to directly analyze the role of CD4 in physically stabilizing the TCR–MHC interaction. Dimeric IEk-MCC stably binds to specific T cells. In addition, immobilized dimeric IEk-MCC can induce TCR downregulation and activate antigen-specific T cells more efficiently than anti-CD3. The potency of the dimeric IEk-MCC is significantly enhanced in the presence of CD4. However, CD4 does not play any significant role in stabilizing peptide-MHC–TCR interactions as it fails to enhance binding of IEk-MCC to specific T cells or influence peptide-MHC–TCR dissociation rate or TCR downregulation. Moreover, these results indicate that dimerization of peptide-MHC class II using an IgG molecular scaffold significantly increases its binding avidity leading to an enhancement of its stimulatory capacity while maintaining the physiological properties of cognate peptide–MHC complex. These peptide-MHC–IgG chimeras may, therefore, provide a novel approach to modulate antigen-specific T cell responses both in vitro and in vivo. PMID:9802975

  7. Genetic variation of the major histocompatibility complex (MHC class II B gene) in the threatened Hume's pheasant, Syrmaticus humiae.

    PubMed

    Chen, Weicai; Bei, Yongjian; Li, Hanhua

    2015-01-01

    Major histocompatibility complex (MHC) genes are the most polymorphic genes in vertebrates and encode molecules that play a crucial role in pathogen resistance. As a result of their diversity, they have received much attention in the fields of evolutionary and conservation biology. Here, we described the genetic variation of MHC class II B (MHCIIB) exon 2 in a wild population of Hume's pheasant (Syrmaticus humiae), which has suffered a dramatic decline in population over the last three decades across its ranges in the face of heavy exploitation and habitat loss. Twenty-four distinct alleles were found in 73 S. humiae specimens. We found seven shared alleles among four geographical groups as well as six rare MHCIIB alleles. Most individuals displayed between one to five alleles, suggesting that there are at least three MHCIIB loci of the Hume's pheasant. The dN ⁄ dS ratio at putative antigen-binding sites (ABS) was significantly greater than one, indicating balancing selection is acting on MHCIIB exon 2. Additionally, recombination and gene conversion contributed to generating MHCIIB diversity in the Hume's pheasant. One to three recombination events and seventy-five significant gene conversion events were observed within the Hume's pheasant MHCIIB loci. The phylogenetic tree and network analysis revealed that the Hume's pheasant alleles do not cluster together, but are scattered through the tree or network indicating a trans-species evolutionary mode. These findings revealed the evolution of the Hume's pheasant MHC after suffering extreme habitat fragmentation. PMID:25629763

  8. Characterization of class II β chain major histocompatibility complex genes in a family of Hawaiian honeycreepers: 'amakihi (Hemignathus virens).

    PubMed

    Jarvi, Susan I; Bianchi, Kiara R; Farias, Margaret Em; Txakeeyang, Ann; McFarland, Thomas; Belcaid, Mahdi; Asano, Ashley

    2016-07-01

    Hawaiian honeycreepers (Drepanidinae) have evolved in the absence of mosquitoes for over five million years. Through human activity, mosquitoes were introduced to the Hawaiian archipelago less than 200 years ago. Mosquito-vectored diseases such as avian malaria caused by Plasmodium relictum and Avipoxviruses have greatly impacted these vulnerable species. Susceptibility to these diseases is variable among and within species. Due to their function in adaptive immunity, the role of major histocompatibility complex genes (Mhc) in disease susceptibility is under investigation. In this study, we evaluate gene organization and levels of diversity of Mhc class II β chain genes (exon 2) in a captive-reared family of Hawaii 'amakihi (Hemignathus virens). A total of 233 sequences (173 bp) were obtained by PCR+1 amplification and cloning, and 5720 sequences were generated by Roche 454 pyrosequencing. We report a total of 17 alleles originating from a minimum of 14 distinct loci. We detected three linkage groups that appear to represent three distinct haplotypes. Phylogenetic analysis revealed one variable cluster resembling classical Mhc sequences (DAB) and one highly conserved, low variability cluster resembling non-classical Mhc sequences (DBB). High net evolutionary divergence values between DAB and DBB resemble that seen between chicken BLB system and YLB system genes. High amino acid identity among non-classical alleles from 12 species of passerines (DBB) and four species of Galliformes (YLB) was found, suggesting that these non-classical passerine sequences may be related to the Galliforme YLB sequences. PMID:26971289

  9. Small organic compounds enhance antigen loading of class II major histocompatibility complex proteins by targeting the polymorphic P1 pocket.

    PubMed

    Höpner, Sabine; Dickhaut, Katharina; Hofstätter, Maria; Krämer, Heiko; Rückerl, Dominik; Söderhäll, J Arvid; Gupta, Shashank; Marin-Esteban, Viviana; Kühne, Ronald; Freund, Christian; Jung, Günther; Falk, Kirsten; Rötzschke, Olaf

    2006-12-15

    Major histocompatibility complex (MHC) molecules are a key element of the cellular immune response. Encoded by the MHC they are a family of highly polymorphic peptide receptors presenting peptide antigens for the surveillance by T cells. We have shown that certain organic compounds can amplify immune responses by catalyzing the peptide loading of human class II MHC molecules HLA-DR. Here we show now that they achieve this by interacting with a defined binding site of the HLA-DR peptide receptor. Screening of a compound library revealed a set of adamantane derivatives that strongly accelerated the peptide loading rate. The effect was evident only for an allelic subset and strictly correlated with the presence of glycine at the dimorphic position beta86 of the HLA-DR molecule. The residue forms the floor of the conserved pocket P1, located in the peptide binding site of MHC molecule. Apparently, transient occupation of this pocket by the organic compound stabilizes the peptide-receptive conformation permitting rapid antigen loading. This interaction appeared restricted to the larger Gly(beta86) pocket and allowed striking enhancements of T cell responses for antigens presented by these "adamantyl-susceptible" MHC molecules. As catalysts of antigen loading, compounds targeting P1 may be useful molecular tools to amplify the immune response. The observation, however, that the ligand repertoire can be affected through polymorphic sites form the outside may also imply that environmental factors could induce allergic or autoimmune reactions in an allele-selective manner. PMID:17005558

  10. Localization of major histocompatibility complex class II molecules in phagolysosomes of murine macrophages infected with Leishmania amazonensis.

    PubMed Central

    Antoine, J C; Jouanne, C; Lang, T; Prina, E; de Chastellier, C; Frehel, C

    1991-01-01

    Leishmania-infected macrophages are potential antigen-presenting cells for CD4+ T lymphocytes, which recognize parasite antigens bound to major histocompatibility complex class II molecules (Ia). However, the intracellular sites where Ia and antigens may interact are far from clear, since parasites grow within the modified lysosomal compartment of the host cell, whereas Ia molecules seem to be targeted to endosomes. To address this question, the expression and fate of Ia molecules were studied by immunocytochemistry in Leishmania amazonensis-infected murine macrophages stimulated with gamma interferon. In uninfected macrophages, Ia molecules were localized on the plasma membrane and in perinuclear vesicles, but they underwent a dramatic redistribution after infection, since most of the intracellular staining was then associated with the periphery of the parasitophorous vacuoles (p.v.) and quite often polarized towards amastigote-binding sites. The Ii invariant chain, which is transiently associated with Ia during their intracellular transport, although well expressed in infected macrophages, apparently did not reach the p.v. Similar findings were observed with macrophages from mice either resistant or highly susceptible to Leishmania infection. In order to determine the origin of p.v.-associated Ia, the fate of plasma membrane, endosomal, and lysosomal markers, detected with specific antibodies, was determined after infection. At 48 h after infection, p.v. was found to exhibit a membrane composition typical of mature lysosomes. Overall, these data suggest that (i) Ia located in p.v. originate from secondary lysosomes involved in the biogenesis of this compartment or circulate in several endocytic organelles, including lysosomes and (ii) p.v. could play a role in antigen processing and presentation. Alternatively, the presence of high amounts of Ia in p.v. could be due to a Leishmania-induced mechanism by means of which this organism may evade the immune response

  11. The great diversity of major histocompatibility complex class II genes in Philippine native cattle.

    PubMed

    Takeshima, S N; Miyasaka, T; Polat, M; Kikuya, M; Matsumoto, Y; Mingala, C N; Villanueva, M A; Salces, A J; Onuma, M; Aida, Y

    2014-12-01

    Bovine leukocyte antigens (BoLA) are extensively used as markers for bovine disease and immunological traits. However, none of the BoLA genes in Southeast Asian breeds have been characterized by polymerase chain reaction (PCR)-sequence-based typing (SBT). Therefore, we sequenced exon 2 of the BoLA class II DRB3 gene from 1120 individual cows belonging to the Holstein, Sahiwal, Simbrah, Jersey, Brahman, and Philippine native breeds using PCR-SBT. Several cross-breeds were also examined. BoLA-DRB3 PCR-SBT identified 78 previously reported alleles and five novel alleles. The number of BoLA-DRB3 alleles identified in each breed from the Philippines was higher (71 in Philippine native cattle, 58 in Brahman, 46 in Holstein × Sahiwal, and 57 in Philippine native × Brahman) than that identified in breeds from other countries (e.g., 23 alleles in Japanese Black and 35 in Bolivian Yacumeño cattle). A phylogenetic tree based on the DA distance calculated from the BoLA-DRB3 allele frequency showed that Philippine native cattle from different Philippine islands are closely related, and all of them are closely similar to Philippine Brahman cattle but not to native Japanese and Latin American breeds. Furthermore, the BoLA-DRB3 allele frequency in Philippine native cattle from Luzon Island, located in the Northern Philippines was different from that in cattle from Iloilo, Bohol, and Leyte Islands, which are located in the Southern Philippines. Therefore, we conclude that Philippine native cattle can be divided into two populations, North and South areas. Moreover, a neutrality test revealed that Philippine native cattle from Leyte showed significantly greater genetic diversity, which may be maintained by balancing selection. This study shows that Asian breeds have high levels of BoLA-DRB3 polymorphism. This finding, especially the identification of five novel BoLA-DRB3 alleles, will be helpful for future SBT studies of BoLA-DRB3 alleles in East Asian cattle. PMID:25606401

  12. The great diversity of major histocompatibility complex class II genes in Philippine native cattle

    PubMed Central

    Takeshima, S.N.; Miyasaka, T.; Polat, M.; Kikuya, M.; Matsumoto, Y.; Mingala, C.N.; Villanueva, M.A.; Salces, A.J.; Onuma, M.; Aida, Y.

    2014-01-01

    Bovine leukocyte antigens (BoLA) are extensively used as markers for bovine disease and immunological traits. However, none of the BoLA genes in Southeast Asian breeds have been characterized by polymerase chain reaction (PCR)-sequence-based typing (SBT). Therefore, we sequenced exon 2 of the BoLA class II DRB3 gene from 1120 individual cows belonging to the Holstein, Sahiwal, Simbrah, Jersey, Brahman, and Philippine native breeds using PCR-SBT. Several cross-breeds were also examined. BoLA-DRB3 PCR-SBT identified 78 previously reported alleles and five novel alleles. The number of BoLA-DRB3 alleles identified in each breed from the Philippines was higher (71 in Philippine native cattle, 58 in Brahman, 46 in Holstein × Sahiwal, and 57 in Philippine native × Brahman) than that identified in breeds from other countries (e.g., 23 alleles in Japanese Black and 35 in Bolivian Yacumeño cattle). A phylogenetic tree based on the DA distance calculated from the BoLA-DRB3 allele frequency showed that Philippine native cattle from different Philippine islands are closely related, and all of them are closely similar to Philippine Brahman cattle but not to native Japanese and Latin American breeds. Furthermore, the BoLA-DRB3 allele frequency in Philippine native cattle from Luzon Island, located in the Northern Philippines was different from that in cattle from Iloilo, Bohol, and Leyte Islands, which are located in the Southern Philippines. Therefore, we conclude that Philippine native cattle can be divided into two populations, North and South areas. Moreover, a neutrality test revealed that Philippine native cattle from Leyte showed significantly greater genetic diversity, which may be maintained by balancing selection. This study shows that Asian breeds have high levels of BoLA-DRB3 polymorphism. This finding, especially the identification of five novel BoLA-DRB3 alleles, will be helpful for future SBT studies of BoLA-DRB3 alleles in East Asian cattle. PMID:25606401

  13. Inhibition of Class II Major Histocompatibility Complex Antigen Processing by Escherichia coli Heat-Labile Enterotoxin Requires an Enzymatically Active A Subunit

    PubMed Central

    Matousek, Milita P.; Nedrud, John G.; Cieplak, Witold; Harding, Clifford V.

    1998-01-01

    Escherichia coli heat-labile enterotoxin (LT) and cholera toxin (CT) were found to inhibit intracellular antigen processing. Processing was not inhibited by mutant LT with attenuated ADP-ribosyltransferase activity, CT B or LT B subunit, which enhanced presentation of preexisting cell surface peptide-class II major histocompatibility complex complexes. Inhibition of antigen processing correlated with A subunit ADP-ribosyltransferase activity. PMID:9632629

  14. Major histocompatibility complex class II (DR) antigen and costimulatory molecules on in vitro and in vivo activated human polymorphonuclear neutrophils

    PubMed Central

    Sandilands, Gavin P; McCrae, Jame; Hill, Kathryn; Perry, Martin; Baxter, Derek

    2006-01-01

    We have previously shown that normal human peripheral blood polymorphonuclear neutrophils (PMNs) contain cytoplasmic ‘stores’ of three key molecules normally associated with antigen presentation and T-cell costimulation, i.e. major histocompatibility complex class II (DR) antigen, CD80 (B7-1) and CD86 (B7-2). These cytoplasmic molecules were found to translocate to the cell surface within a few minutes following cross-linking (X-L) of Mac-1: an early neutrophil activation signal. In this study we have compared X-L of Mac −1 in parallel with four other well documented in vitro neutrophil activators: phorbol myristate acetate, N-formyl methionyl leucyl phenylalanine, lipopolysaccharide, and phagocytosis of immunoglobulin G–Latex particles. In addition, we have used paired samples of neutrophils obtained from peripheral blood (as a control) and synovial fluid from patients with rheumatoid arthritis as a source of in vivo activated cells. With the exception of phagocytosis, all activators resulted in the rapid (within 30 min) generation of two populations of activated neutrophils (designated P1 and P2) based on flow-cytometry measurements of size, granularity and phenotype. Significant up-regulation of DR and costimulatory molecules was observed, predominantly on P2 cells, with all activators except phagocytosis. CD80 and CD86 were noted to respond to the various activation signals in a different pattern suggesting that their intracellular granule location may be different. Dual-staining confocal laser microscopy studies showed that CD80 is largely confined to secretory vesicles (SVs) while CD86 appears to have a much wider distribution being found in SVs and within secondary (specific) and primary (azurophilic) granules. Increased surface expression of these antigens was also observed on P2 synovial fluid neutrophils appearing as large heterogeneous clusters on the cell surface when visualized by confocal laser microscopy. PMID:17034427

  15. Hepatitis B virus-like particles access major histocompatibility class I and II antigen presentation pathways in primary dendritic cells.

    PubMed

    Moffat, Jessica M; Cheong, Wan-Shoo; Villadangos, José A; Mintern, Justine D; Netter, Hans J

    2013-04-26

    Virus-like particles (VLPs) represent high density displays of viral proteins that efficiently trigger immunity. VLPs composed of the small hepatitis B virus envelope protein (HBsAgS) are useful vaccine platforms that induce humoral and cellular immune responses. Notably, however, some studies suggest HBsAgS VLPs impair dendritic cell (DC) function. Here we investigated HBsAgS VLP interaction with DC subsets and antigen access to major histocompatibility complex (MHC) class I and II antigen presentation pathways in primary DCs. HBsAgS VLPs impaired plasmacytoid DC (pDC) interferon alpha (IFNα) production in response to CpG in vitro, but did not alter conventional DC (cDC) or pDC phenotype when administered in vivo. To assess cellular immune responses, HBsAgS VLPs were generated containing the ovalbumin (OVA) model epitopes OVA(257-264) and OVA(323-339) to access MHCI and MHCII antigen presentation pathways, respectively; both in vitro and following immunisation in vivo. HBsAgS VLP-OVA(257-264) elicited CTL responses in vivo that were not enhanced by inclusion of an additional MHCII helper epitope. HBsAgS VLP-OVA(257-264) administered in vivo was cross-presented by CD8(+) DCs, but not CD8(-) DCs. Therefore, HBsAgS VLPs can deliver antigen to both MHCI and MHCII antigen presentation pathways in primary DCs and promote cytotoxic and helper T cell priming despite their suppressive effect on pDCs. PMID:23473776

  16. Role of major histocompatibility complex class II in resistance of mice to naturally acquired infection with Syphacia obvelata

    NASA Technical Reports Server (NTRS)

    Stewart, Patricia W.; Chapes, Stephen K.

    2003-01-01

    Genetics plays a substantial role in host resistance in many host-parasite interactions. We examined the prevalence of naturally acquired infection with Syphacia obvelata in a number of mouse strains housed in a non-barrier facility. These mice, which included cross-bred and congenic, inbred strains on various genetic backgrounds, differ in the loci for the immune function genes--major histocompatibility complex class II (MHCII), toll-like receptor 4 (Tlr4), and solute carrier family 11, member 1 (Slc11a1)--which allowed comparisons of the impact of these genes on resistance to pinworm infection. Male and female mice of various ages were sampled over an 18-month period; infection was determined by use of the cellophane tape test. Results indicated that mice that were MHCII+/+ had a significantly lower prevalence of infection than did mice that were MHCII-/-. Differences were not seen between male and female mice. Although MHCII+/+ mice had an age-associated decrease in infection prevalence, such decrease was not seen in MHCII-/- mice. In contrast, infection prevalence in mice with the normal Tlr4 gene (Tlr4(LPS-n/LPS-n)) gene did not differ significantly compared with that in mice that were homozygous for either the point mutation (Tlr4(LPS-d/LPS-d)) or deletion (Tlr4(LPS-del/LPS-del)) of that gene. Likewise, the presence (Sle11a1r/r) or absence (Slc11a1s/s) of functional alleles for Slc11a1 had no effect on the prevalence of infection with S. obvelata. In conclusion, presence of MHCII, but not Tlr4 or Slc11a1 significantly influences prevalence of naturally acquired infection with S. obvelata. These data justify further comprehensive analyses of the immune components that are involved in pinworm resistance.

  17. Accuracy of a structural homology model for a class II histocompatibility protein, HLA-DR1: comparison to the crystal structure.

    PubMed

    Nauss, J L; Reid, R H; Sadegh-Nasseri, S

    1995-06-01

    Structural homology modeling is used to test the accuracy by which a Class I major histocompatibility complex (MHC) could be used to model a Class II MHC. The crystal structure of HLA-aw68 served as a reference molecule to model HLA-DR1. The resulting model was compared to the recently released crystal structure by Brown et al. (Nature, Vol. 364, p. 33-39 (1993)). The overall tertiary structure motif (two alpha-helices and a beta-sheet forming a peptide binding cleft) was maintained. However, significant deviations in the secondary structure elements were found between the model and the DR1 crystal structure. These deviations were consistent with the differences between Class I and Class II crystal structures. In regions where the model and DR1 crystals structures are most similar, side chain orientations are also similar. Specific peptide-MHC interactions are discussed and compared with the crystal structure results. PMID:7669268

  18. Patterns of selection and allele diversity of class I and class II major histocompatibility loci across the species range of sockeye salmon (Oncorhynchus nerka).

    PubMed

    McClelland, Erin K; Ming, Tobi J; Tabata, Amy; Kaukinen, Karia H; Beacham, Terry D; Withler, Ruth E; Miller, Kristina M

    2013-09-01

    The major histocompatibility complex (MHC), an important component of the vertebrate immune system, provides an important suite of genes to examine the role of genetic diversity at non-neutral loci for population persistence. We contrasted patterns of diversity at the two classical MHC loci in sockeye salmon (Oncorhynchus nerka), MHC class I (UBA) and MHC class II (DAB), and neutral microsatellite loci across 70 populations spanning the species range from Washington State to Japan. There was no correlation in allelic richness or heterozygosity between MHC loci or between MHC loci and microsatellites. The two unlinked MHC loci may be responding to different selective pressures; the distribution of FST values for the two loci was uncorrelated, and evidence for both balancing and directional selection on alleles and lineages of DAB and UBA was observed in populations throughout the species range but rarely on both loci within a population. These results suggest that fluctuating selection has resulted in the divergence of MHC loci in contemporary populations. PMID:24033436

  19. Evidence for a trans-acting factor that regulates the transcription of class II major histocompatibility complex genes: genetic and functional analysis.

    PubMed Central

    Calman, A F; Peterlin, B M

    1988-01-01

    The study of specific trans-acting transcription factors in prokaryotes and lower eukaryotes has been greatly facilitated by genetic analysis of mutant strains deficient in such factors. We have developed such a system to study mammalian trans-acting factors that regulate the transcription of class II major histocompatibility complex genes, using the mutant cell lines RM2 and RM3. These cells, derived from the human B-cell line Raji, specifically fail to transcribe their class II major histocompatibility complex genes. Here we show that a transfected HLA-DR alpha class II major histocompatibility complex gene, like the endogenous HLA-DR alpha genes, is efficiently transcribed in Raji cells but not in RM2 or RM3 cells, demonstrating that the mutant cells are deficient in a specific trans-acting factor required for transcription of these genes. HLA-DR expression in RM2 and RM3 cells is rescued by fusion to another B-cell line but not by fusion to each other. Thus, the defects in the two cell lines are recessive and noncomplementing and define a locus whose wild-type product we designate TF-X1. We show that TF-X1 influences the activity of a 24-base-pair B-cell-specific cis-acting transcription element in the HLA-DR alpha promoter. However, in three different biochemical assays, we detect no difference between wild-type and mutant cells in the DNA-binding proteins that interact with these DNA sequences. Thus, the defective version of TF-X1 may be a DNA-binding protein that binds to the HLA-DR alpha promoter but fails to activate transcription. Alternatively, TF-X1 may not be a DNA-binding protein at all. Images PMID:3143110

  20. Disruption of Hydrogen Bonds between Major Histocompatibility Complex Class II and the Peptide N-Terminus Is Not Sufficient to Form a Human Leukocyte Antigen-DM Receptive State of Major Histocompatibility Complex Class II

    PubMed Central

    Schulze, Monika-Sarah E. D.; Anders, Anne-Kathrin; Sethi, Dhruv K.; Call, Melissa J.

    2013-01-01

    Peptide presentation by MHC class II is of critical importance to the function of CD4+ T cells. HLA-DM resides in the endosomal pathway and edits the peptide repertoire of newly synthesized MHC class II molecules before they are exported to the cell surface. HLA-DM ensures MHC class II molecules bind high affinity peptides by targeting unstable MHC class II:peptide complexes for peptide exchange. Research over the past decade has implicated the peptide N-terminus in modulating the ability of HLA-DM to target a given MHC class II:peptide combination. In particular, attention has been focused on both the hydrogen bonds between MHC class II and peptide, and the occupancy of the P1 anchor pocket. We sought to solve the crystal structure of a HLA-DR1 molecule containing a truncated hemagglutinin peptide missing three N-terminal residues compared to the full-length sequence (residues 306–318) to determine the nature of the MHC class II:peptide species that binds HLA-DM. Here we present structural evidence that HLA-DR1 that is loaded with a peptide truncated to the P1 anchor residue such that it cannot make select hydrogen bonds with the peptide N-terminus, adopts the same conformation as molecules loaded with full-length peptide. HLA-DR1:peptide combinations that were unable to engage up to four key hydrogen bonds were also unable to bind HLA-DM, while those truncated to the P2 residue bound well. These results indicate that the conformational changes in MHC class II molecules that are recognized by HLA-DM occur after disengagement of the P1 anchor residue. PMID:23976922

  1. Major histocompatibility complex class II dextramers: New tools for the detection of antigen-specific, CD4 T cells in basic and clinical research

    PubMed Central

    Massilamany, Chandirasegaran; Krishnan, Bharathi; Reddy, Jay

    2015-01-01

    The advent of major histocompatibility complex (MHC) tetramer technology has been a major contribution to T cell immunology, because tetramer reagents permit detection of antigen-specific T cells at the single-cell level in heterogeneous populations by flow cytometry. However, unlike MHC class I tetramers, the utility of MHC class II tetramers has been less frequently reported. MHC class II tetramers can be used successfully to enumerate the frequencies of antigen-specific CD4 T cells in cells activated in vitro, but their use for ex vivo analyses continues to be a problem, due in part to their activation dependency for binding with T cells. To circumvent this problem, we recently reported the creation of a new generation of reagents called MHC class II dextramers, which were found to be superior to their counterparts. In this review, we discuss the utility of class II dextramers vis-a-vis tetramers, with respect to their specificity and sensitivity, including potential applications and limitations. PMID:26207337

  2. Constitutive expression of major histocompatibility complex class II antigens in pulmonary epithelium and endothelium varies among different species.

    PubMed

    Houser, Stuart L; Benjamin, Louis C; Wain, John C; Madsen, Joren C; Allan, James S

    2004-02-27

    We have observed high constitutive levels of class II antigen expression on porcine and human coronary endothelium, but not on the endothelium of rats and mice. This study examines whether a similar interspecies difference exists in the expression of class II molecules on pulmonary epithelium and endothelium. Lung tissues from naïve human, porcine, and rodent sources were stained with the monoclonal antibody ISCR3 and examined by light microscopy. Immunoperoxidase staining of class II molecules was observed on human and porcine pulmonary epithelium and endothelium, but was absent in rats and mice. By using an antibody with cross-species reactivity, we demonstrated that naïve swine pulmonary epithelium and endothelium, unlike those of rodent species, express basal levels of class II antigens in a manner similar to that observed in human lung tissue. These interspecies differences may explain experimental differences observed between murine and large-animal constructs. PMID:15084944

  3. A step-by-step overview of the dynamic process of epitope selection by major histocompatibility complex class II for presentation to helper T cells

    PubMed Central

    Sadegh-Nasseri, Scheherazade

    2016-01-01

    T cell antigen receptors (TCRs) expressed on cytotoxic or helper T cells can only see their specific target antigen as short sequences of peptides bound to the groove of proteins of major histocompatibility complex (MHC) class I, and class II respectively. In addition to the many steps, several participating proteins, and multiple cellular compartments involved in the processing of antigens, the MHC structure, with its dynamic and flexible groove, has perfectly evolved as the underlying instrument for epitope selection. In this review, I have taken a step-by-step, and rather historical, view to describe antigen processing and determinant selection, as we understand it today, all based on decades of intense research by hundreds of laboratories. PMID:27347387

  4. A step-by-step overview of the dynamic process of epitope selection by major histocompatibility complex class II for presentation to helper T cells.

    PubMed

    Sadegh-Nasseri, Scheherazade

    2016-01-01

    T cell antigen receptors (TCRs) expressed on cytotoxic or helper T cells can only see their specific target antigen as short sequences of peptides bound to the groove of proteins of major histocompatibility complex (MHC) class I, and class II respectively. In addition to the many steps, several participating proteins, and multiple cellular compartments involved in the processing of antigens, the MHC structure, with its dynamic and flexible groove, has perfectly evolved as the underlying instrument for epitope selection. In this review, I have taken a step-by-step, and rather historical, view to describe antigen processing and determinant selection, as we understand it today, all based on decades of intense research by hundreds of laboratories. PMID:27347387

  5. Localization of major histocompatibility complex class I and II mRNA in human first-trimester chorionic villi by in situ hybridization.

    PubMed

    Lata, J A; Tuan, R S; Shepley, K J; Mulligan, M M; Jackson, L G; Smith, J B

    1992-04-01

    Maternal immune recognition of pregnancy occurs despite the nonexpression of classical major histocompatibility complex (MHC) antigenic determinants by chorionic villous trophoblast, which comprise the major surface area where maternal blood contacts fetal-derived cells. cDNA-mRNA in situ hybridization was used to probe expression of transcripts corresponding to nonpolymorphic MHC determinants in first-trimester chorionic villus samples. The HLA-B7 probe hybridization signals were localized to syncytiotrophoblast and to cells of the mesenchyme but not to villous cytotrophoblast. HLA-G mRNA was found only in syncytiotrophoblast. A DR beta clone hybridized to both villous cytotrophoblast and syncytiotrophoblast. The results suggest that expression of trophoblast class I and class II determinants early in gestation (10 wk) may be regulated by posttranscriptional events. This also suggests the potential for maternal antifetal alloimmune responses. PMID:1552281

  6. Sequence polymorphism of two major histocompatibility (MH) class II B genes and their association with Vibrio anguillarum infection in half-smooth tongue sole ( Cynoglossus semilaevis)

    NASA Astrophysics Data System (ADS)

    Li, Chunmei; Zhang, Quanqi; Yu, Yan; Li, Shuo; Zhong, Qiwang; Sun, Yeying; Wang, Zhigang; Qi, Jie; Zhai, Jieming; Wang, Xubo

    2011-11-01

    Major histocompatibility complex (MHC) class II B molecules play an important role in the adaptive immune response in fish. Previous study has reported that two highly polymorphic class II B genes, Cyse-DAB and Cyse-DBB exist in half-smooth tongue sole ( Cynoglossus semilaevis). In this study, the polymorphism within exon 2 of the class II B genes following bacterial challenge was evaluated. Two hundred C. semilaevis individuals were injected intraperitoneally with Vibrio anguillarum. Muscle tissue from the first 20 dead and 20 of the survivors was collected for genotyping. Sixty alleles from the 40 individuals were isolated, of which 32 belonged to Cyse-DAB and 28 belonged to Cyse-DBB. The rate of d N (non-synonymous substitution) was higher than that of d S (synonymous substitution) in the PBRs (peptide binding residues) of both class II B genes. Conversely, the rate of d S was higher than d N in the non-PBRs and the complete exon 2 sequence. Thus, the results suggest that positive selection has occurred in the PBRs and purifying selection in the non-PBRs and exon 2. Thirteen class II B alleles were used to study the association between alleles and resistance to infection. Though not significant, alleles Cyse-DAB*0601, Cyse-DAB*0706, and Cyse-DBB*0101, Cyse-DBB*1301 were only found in surviving individuals and may represent alleles that have resistance against V. anguillarum infection. Alleles Cyse-DAB*0701 and Cyse-DAB*1301 were significantly more prevalent in dead individuals than in surviving ones and may represent alleles that are associated with increased susceptibility to V. anguillarum infection.

  7. Versatility of using major histocompatibility complex class II dextramers for derivation and characterization of antigen-specific, autoreactive T cell hybridomas.

    PubMed

    Krishnan, Bharathi; Massilamany, Chandirasegaran; Basavalingappa, Rakesh H; Rajasekaran, Rajkumar A; Kuszynski, Charles; Switzer, Barbara; Peterson, Daniel A; Reddy, Jay

    2015-11-01

    Antigen-specific, T cell hybridomas are useful to study the cellular, molecular and functional events, but their generation is a lengthy process. Thus, there is a need to develop robust methods to generate the hybridoma clones rapidly in a short period of time. To this end, we have demonstrated a novel approach using major histocompatibility complex (MHC) class II dextramers to generate T cell hybridomas for an autoantigen, proteolipid protein (PLP) 139-151. Using MHC class II dextramers assembled with PLP 139-151 as screening and sorting tools, we successfully obtained mono antigen-specific clones within seven to eight weeks. In conjunction with other T cell markers, dextramers permitted phenotypic characterization of hybridoma clones for their antigen specificity in a single step by flow cytometry. Importantly, we achieved successful fusions using dextramer(+) cells sorted by flow cytometry as a starting population, resulting in direct identification of multiple antigen-specific clones. Characterization of selected clones led us to identify chemokine receptor, CCR4(+) to be expressed consistently, but their cytokine-producing ability was variable. Our work provides a proof-of principle that the antigen-specific, CD4 T cell hybridoma clones can be generated directly using MHC class II dextramers. The availability of hybridoma clones that bind dextramers may serve as useful tools for various in vitro and in vivo applications. PMID:26268454

  8. Histone deacetylase 1/mSin3A disrupts gamma interferon-induced CIITA function and major histocompatibility complex class II enhanceosome formation.

    PubMed

    Zika, Eleni; Greer, Susanna F; Zhu, Xin-Sheng; Ting, Jenny P-Y

    2003-05-01

    The class II transactivator (CIITA) is a master transcriptional regulator of major histocompatibility complex class II (MHC-II) promoters. CIITA does not bind DNA, but it interacts with the transcription factors RFX5, NF-Y, and CREB and associated chromatin-modifying enzymes to form an enhanceosome. This report examines the effects of histone deacetylases 1 and 2 (HDAC1/HDAC2) on MHC-II gene induction by gamma interferon (IFN-gamma) and CIITA. The results show that an inhibitor of HDACs, trichostatin A, enhances IFN-gamma-induced MHC-II expression, while HDAC1/HDAC2 inhibits IFN-gamma- and CIITA-induced MHC-II gene expression. mSin3A, a corepressor of HDAC1/HDAC2, is important for this inhibition, while NcoR, a corepressor of HDAC3, is not. The effect of this inhibition is directed at CIITA, since HDAC1/HDAC2 reduces transactivation by a GAL4-CIITA fusion protein. CIITA binds to overexpressed and endogenous HDAC1, suggesting that HDAC and CIITA may affect each other by direct or indirect association. Inhibition of HDAC activity dramatically increases the association of NF-YB and RFX5 with CIITA, the assembly of CIITA, NF-YB, and RFX5 enhanceosome, and the extent of H3 acetylation at the MHC-II promoter. These results suggest a model where HDAC1/HDAC2 affect the function of CIITA through a disruption of MHC-II enhanceosome and relevant coactivator-transcription factor association and provide evidence that CIITA may act as a molecular switch to modulate MHC-II transcription by coordinating the functions of both histone acetylases and HDACs. PMID:12697811

  9. Parasite Manipulation of the Invariant Chain and the Peptide Editor H2-DM Affects Major Histocompatibility Complex Class II Antigen Presentation during Toxoplasma gondii Infection

    PubMed Central

    Leroux, Louis-Philippe; Nishi, Manami; El-Hage, Sandy; Fox, Barbara A.; Bzik, David J.

    2015-01-01

    Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4+ T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, namely, the MHC-II-associated invariant chain (Ii or CD74) and the peptide editor H2-DM, in professional antigen-presenting cells (pAPCs). Genetic deletion of CD74 restored the ability of infected dendritic cells to present a parasite antigen in the context of MHC-II in vitro. CD74 mRNA and protein levels were, surprisingly, elevated in infected cells, whereas MHC-II and H2-DM expression was inhibited. CD74 accumulated mainly in the endoplasmic reticulum (ER), and this phenotype required live parasites, but not active replication. Finally, we compared the impacts of genetic deletion of CD74 and H2-DM genes on parasite dissemination toward lymphoid organs in mice, as well as activation of CD4+ T cells and interferon gamma (IFN-γ) levels during acute infection. Cyst burdens and survival during the chronic phase of infection were also evaluated in wild-type and knockout mice. These results highlight the fact that the infection is influenced by multiple levels of parasite manipulation of the MHC-II antigen presentation pathway. PMID:26195549

  10. Parasite Manipulation of the Invariant Chain and the Peptide Editor H2-DM Affects Major Histocompatibility Complex Class II Antigen Presentation during Toxoplasma gondii Infection.

    PubMed

    Leroux, Louis-Philippe; Nishi, Manami; El-Hage, Sandy; Fox, Barbara A; Bzik, David J; Dzierszinski, Florence S

    2015-10-01

    Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, namely, the MHC-II-associated invariant chain (Ii or CD74) and the peptide editor H2-DM, in professional antigen-presenting cells (pAPCs). Genetic deletion of CD74 restored the ability of infected dendritic cells to present a parasite antigen in the context of MHC-II in vitro. CD74 mRNA and protein levels were, surprisingly, elevated in infected cells, whereas MHC-II and H2-DM expression was inhibited. CD74 accumulated mainly in the endoplasmic reticulum (ER), and this phenotype required live parasites, but not active replication. Finally, we compared the impacts of genetic deletion of CD74 and H2-DM genes on parasite dissemination toward lymphoid organs in mice, as well as activation of CD4(+) T cells and interferon gamma (IFN-γ) levels during acute infection. Cyst burdens and survival during the chronic phase of infection were also evaluated in wild-type and knockout mice. These results highlight the fact that the infection is influenced by multiple levels of parasite manipulation of the MHC-II antigen presentation pathway. PMID:26195549

  11. Detection and Quantification of CD4+ T Cells with Specificity for a New Major Histocompatibility Complex Class II-Restricted Influenza A Virus Matrix Protein Epitope in Peripheral Blood of Influenza Patients

    PubMed Central

    Linnemann, Thomas; Jung, Günther; Walden, Peter

    2000-01-01

    FVFTLTVPS was identified as the core sequence of a new major histocompatibility complex class II-restricted T-cell epitope of influenza virus matrix protein. Epitope-specific CD4+ T cells were detected in the peripheral blood of patients with frequencies of up to 0.94%, depending on the number of additional terminal amino acids. PMID:10954576

  12. Kaposi's Sarcoma-Associated Herpesvirus Viral Interferon Regulatory Factor 3 Inhibits Gamma Interferon and Major Histocompatibility Complex Class II Expression▿†

    PubMed Central

    Schmidt, Katharina; Wies, Effi; Neipel, Frank

    2011-01-01

    Kaposi's sarcoma-associated herpesvirus (KSHV) carries four genes with homology to human interferon regulatory factors (IRFs). One of these IRFs, the viral interferon regulatory factor 3 (vIRF-3), is expressed in latently infected primary effusion lymphoma (PEL) cells and required for their continuous proliferation. Moreover, vIRF-3 is known to be involved in modulation of the type I interferon (IFN) response. We now show that vIRF-3 also interferes with the type II interferon system and antigen presentation to the adaptive immune system. Starting with an analysis of the transcriptome, we show that vIRF-3 inhibits expression of major histocompatibility complex class II (MHC II) molecules: small interfering RNA (siRNA)-mediated knockdown of vIRF-3 in KSHV-infected PEL cell lines resulted in increased MHC II levels; overexpression of vIRF-3 in KSHV-negative B cells leads to downmodulation of MHC II. This regulation could be traced back to inhibition of class II transactivator (CIITA) transcription by vIRF-3. Reporter assays revealed that the gamma interferon (IFN-γ)-sensitive CIITA promoters PIV and PIII were inhibited by vIRF-3. Consistently, IFN-γ levels increased upon vIRF-3 knockdown in PEL cells. IFN-γ regulation by vIRF-3 was confirmed in reporter assays as well as by upregulation of typical IFN-γ target genes upon knockdown of vIRF-3 in PEL cells. In summary, we conclude that vIRF-3 contributes to the viral immunoevasion by downregulation of IFN-γ and CIITA and thus MHC II expression. PMID:21345951

  13. Identification of two major histocompatibility (MH) class II A genes and their association to Vibrio anguillarum infection in half-smooth tongue sole ( Cynoglossus semilaevis)

    NASA Astrophysics Data System (ADS)

    Li, Chunmei; Wang, Xubo; Zhang, Quanqi; Wang, Zhigang; Qi, Jie; Yi, Qilin; Liu, Zhipeng; Wang, Yanan; Yu, Haiyang

    2012-03-01

    Major histocompatibility complex class II antigens are important in vertebrate immune system. In the present study, the full cDNA sequence of class II A gene was synthesized by RACE-PCR from half-smooth tongue sole ( Cynoglossus semilaevis), and its open reading frame (ORF) polymorphism was studied. The whole cDNA sequence was 992 bp in length, including the ORF with 717 bp. Twenty-five alleles were identified and clustered into two distinct groups according to the specific nucleotides/ amino acids in specific positions. Eleven alleles belonged to Cyse-DAA while fourteen alleles belonged to Cyse-DBA. Four Cyse-DAA alleles were observed in one individual, and three to five Cyse-DBA alleles were observed in each of the three detected individuals, which indicated that at least two loci existed in each gene. Moreover, in order to study the function of the alleles in resistance to infection, 200 individuals were intraperitoneally injected with Vibrio anguillarum and the first 20 dead individuals and 20 surviving ones were selected for genotype analysis. Fifty-six alleles were identified among the 40 individuals. Twenty-nine alleles belonged to Cyse-DAA and the other 27 alleles belonged to Cyse-DBA. Eighteen alleles were selected for studying their function in resistance to infection. Alleles Cyse-DAA*0201, Cyse-DAA*1101, Cyse-DBA*0401, Cyse-DBA*1102, Cyse-DBA*1801 and Cyse-DBA*2201 were identified only in surviving individuals, while alleles Cyse- DAA*0901, Cyse-DBA*1101 and Cyse-DBA*1401 occurred more frequently in dead individuals. This study confirmed the existence and polymorphism of two class II A genes as well as the relationship between alleles of class II A genes and disease susceptibility/ resistance in half-smooth tongue sole.

  14. Domain structures and molecular evolution of class I and class II major histocompatibility gene complex (MHC) products deduced from amino acid and nucleotide sequence homologies

    NASA Astrophysics Data System (ADS)

    Ohnishi, Koji

    1984-12-01

    Domain structures of class I and class II MHC products were analyzed from a viewpoint of amino acid and nucleotide sequence homologies. Alignment statistics revealed that class I (transplantation) antigen H chains consist of four mutually homologous domains, and that class II (HLA-DR) antigen β and α chains are both composed of three mutually homologous ones. The N-terminal three and two domains of class I and class II (both β and α) gene products, respectively, all of which being ˜90 residues long, were concluded to be homologous to β2-microglobulin (β2M). The membraneembedded C-terminal shorter domains of these MHC products were also found to be homologous to one another and to the third domain of class I H chains. Class I H chains were found to be more closely related to class II α chains than to class II β chains. Based on these findings, an exon duplication history from a common ancestral gene encoding a β2M-like primodial protein of one-domain-length up to the contemporary MHC products was proposed.

  15. Association between Single Nucleotide Polymorphisms of the Major Histocompatibility Complex Class II Gene and Newcastle Disease Virus Titre and Body Weight in Leung Hang Khao Chickens

    PubMed Central

    Molee, A.; Kongroi, K.; Kuadsantia, P.; Poompramun, C.; Likitdecharote, B.

    2016-01-01

    The aim of the present study was to investigate the effect of single nucleotide polymorphisms in the major histocompatibility complex (MHC) class II gene on resistance to Newcastle disease virus and body weight of the Thai indigenous chicken, Leung Hang Khao (Gallus gallus domesticus). Blood samples were collected for single nucleotide polymorphism analysis from 485 chickens. Polymerase chain reaction sequencing was used to classify single nucleotide polymorphisms of class II MHC. Body weights were measured at the ages of 3, 4, 5, and 7 months. Titres of Newcastle disease virus at 2 weeks to 7 months were determined and the correlation between body weight and titre was analysed. The association between single nucleotide polymorphisms and body weight and titre were analysed by a generalized linear model. Seven single nucleotide polymorphisms were identified: C125T, A126T, C209G, C242T, A243T, C244T, and A254T. Significant correlations between log titre and body weight were found at 2 and 4 weeks. Associations between single nucleotide polymorphisms and titre were found for C209G and A254T, and between all single nucleotide polymorphisms (except A243T) and body weight. The results showed that class II MHC is associated with both titre of Newcastle disease virus and body weight in Leung Hang Khao chickens. This is of concern because improved growth traits are the main goal of breeding selection. Moreover, the results suggested that MHC has a pleiotropic effect on the titre and growth performance. This mechanism should be investigated in a future study. PMID:26732325

  16. Key Role of Toll-Like Receptor 2 in the Inflammatory Response and Major Histocompatibility Complex Class II Downregulation in Brucella abortus-Infected Alveolar Macrophages

    PubMed Central

    Ferrero, Mariana C.; Hielpos, M. Soledad; Carvalho, Natalia B.; Barrionuevo, Paula; Corsetti, Patricia P.; Giambartolomei, Guillermo H.; Oliveira, Sergio C.

    2014-01-01

    Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-α), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1β (IL-1β), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-α and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-γ) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. PMID:24478078

  17. Characterization and evolution of major histocompatibility complex class II genes in the aye-aye, Daubentonia madagascariensis.

    PubMed

    Go, Yasuhiro; Rakotoarisoa, Gilbert; Kawamoto, Yoshi; Shima, Taizo; Koyama, Naoki; Randrianjafy, Albert; Mora, Roger; Hirai, Hirohisa

    2005-04-01

    Major histocompatibility complex genes (Mhc-DQB and Mhc-DRB) were sequenced in seven aye-ayes (Daubentonia madagascariecsis), which is an endemic and endangered species in Madagascar. An aye-aye from a north-eastern population showed genetic relatedness to individuals of a north-western population and had a somewhat different repertoire from another north-eastern individual. These observations suggest that the extent of genetic variation in Mhc genes is not excessively small in the aye-aye in spite of recent rapid destruction of their habitat by human activities. In light of Mhc gene evolution, trans-species and allelic polymorphisms can be estimated to have been retained for more than 50 Ma (million years) based on the time scale of lemur evolution. PMID:15322927

  18. Expression of major histocompatibility complex class I and class II antigens in human Schwann cell cultures and effects of infection with Mycobacterium leprae.

    PubMed

    Samuel, N M; Mirsky, R; Grange, J M; Jessen, K R

    1987-06-01

    Recent experiments on rats have raised the possibility that Schwann cells can present antigens to T lymphocytes. We have investigated whether this mechanism might be relevant in leprosy by determining under what conditions human Schwann cells express class I and class II antigens, and whether infection with Mycobacterium leprae affects this expression. The distribution of these antigens was examined on human Schwann cells in dissociated cell cultures derived from human fetal peripheral nerves. We find that both Schwann cells and fibroblastic cells in these cultures normally express class I antigens but not class II antigens. When Schwann cells are infected with live Mycobacterium leprae for 48 h, 73% of Schwann cells phagocytose the bacteria. Mycobacterium leprae prevents 3H-thymidine incorporation into cultured human Schwann cells, but does not affect class I expression in these cells. Treatment of normal and Mycobacterium leprae infected cultures with gamma-interferon for 72 h induces class II expression on most Schwann cells but not on the majority of fibroblastic cells. The fact that human Schwann cells infected with Mycobacterium leprae can be induced by gamma-interferon to express class II antigens suggests that they may be able to present Mycobacterium leprae antigens to T lymphocytes and thus initiate immune responses against the bacteria. We suggest that a failure of this response, such as that seen within nerve trunks in lepromatous leprosy, is caused by deficient class II expression on Schwann cells. This deficiency in class II expression, in turn, may be caused by the reduced gamma-interferon production characteristic of lepromatous leprosy. PMID:3115648

  19. Dominating expression of negative regulatory factors downmodulates major histocompatibility complex Class-II expression on dendritic cells in chronic hepatitis C infection

    PubMed Central

    Tomer, Shallu; Chawla, Yogesh K; Duseja, Ajay; Arora, Sunil K

    2016-01-01

    AIM: To elucidate the molecular mechanisms leading to development of functionally impaired dendritic cells (DCs) in chronic hepatitis C (CHC) patients infected with genotype 3 virus. METHODS: This prospective study was conducted on the cohorts of CHC individuals identified as responders or non-responders to antiviral therapy. Myeloid DCs were isolated from the peripheral blood of each subject using CD1c (BDCA1)+ DC isolation Kit. Monocytes from healthy donor were cultured with DC growth factors such as IL-4 and GM-CSF either in the presence or absence of hepatitis C virus (HCV) viral proteins followed by LPS stimulation. Phenotyping was done by flowcytometry and gene expression profiling was evaluated by real-time PCR. RESULTS: Non-responders [sustained virological response (SVR)-ve] to conventional antiviral therapy had significantly higher expression of genes associated with interferon responsive element such as IDO1 and PD-L1 (6-fold) and negative regulators of JAK-STAT pathway such as SOCS (6-fold) as compared to responders (SVR+ve) to antiviral therapy. The down-regulated genes in non-responders included factors involved in antigen processing and presentation mainly belonging to major histocompatibility complex (MHC) Class-II family as HLA-DP, HLA-DQ (2-fold) and superoxide dismutase (2-fold). Cells grown in the presence of HCV viral proteins had genes down-regulated for factors involved in innate response, interferon signaling, DC maturation and co-stimulatory signaling to T-cells, while the genes for cytokine signaling and Toll-like receptors (4-fold) were up-regulated as compared to cells grown in absence of viral proteins. CONCLUSION: Underexpressed MHC class-II genes and upregulated negative regulators in non-responders indicate diminished capacity to present antigen and may constitute mechanism of functionally defective state of DCs. PMID:27298560

  20. Major Histocompatibility Complex Class II Inhibits Fas Antigen-Mediated Gastric Mucosal Cell Apoptosis through Actin-Dependent Inhibition of Receptor Aggregation

    PubMed Central

    Stoicov, Calin; Cai, Xun; Li, Hanchen; Klucevsek, Kristine; Carlson, Jane; Saffari, Reza; Houghton, JeanMarie

    2005-01-01

    Escape from normal apoptotic controls is thought to be essential for the development of cancer. During Helicobacter pylori infection, the leading cause of gastric cancer, activation of the Fas antigen (Fas Ag) apoptotic pathway is responsible for early atrophy and tissue loss. As disease progresses, metaplastic and dysplastic glands arise which express Fas Ag but are resistant to apoptosis and are believed to be the precursor cells for adenocarcinoma. In this report, we show that one mechanism of acquired Fas resistance is inhibition of receptor aggregation via a major histocompatibility complex class II (MHCII)-mediated, actin-dependent mechanism. For these studies we used the well-described C57BL/6 mouse model of Helicobacter pylori and Helicobacter felis infection. Under normal conditions, Fas Ag is expressed at low levels, and MHCII expression on gastric mucosal cells is negligible. With infection and inflammation, both receptors are upregulated, and 6.1% of gastric mucosal cells express MHCII in combination with Fas Ag. Using the rat gastric mucosal cell line RGM-1 transfected with murine Fas Ag and MHCIIαβ chains, we demonstrate that MHCII prevents Fas receptor aggregation and inhibits Fas-mediated signaling through its effects on the actin cytoskeleton. Depolymerization of actin with cytochalasin D allows receptors to aggregate and restores Fas sensitivity. These findings offer one mechanism by which gastric mucosal cells acquire Fas resistance. PMID:16177302

  1. Low Major Histocompatibility Complex Class II Variation in the Endangered Indo-Pacific Humpback Dolphin (Sousa chinensis): Inferences About the Role of Balancing Selection.

    PubMed

    Zhang, Xiyang; Lin, Wenzhi; Zhou, Ruilian; Gui, Duan; Yu, Xinjian; Wu, Yuping

    2016-03-01

    It has been widely reported that the major histocompatibility complex (MHC) is under balancing selection due to its immune function across terrestrial and aquatic mammals. The comprehensive studies at MHC and other neutral loci could give us a synthetic evaluation about the major force determining genetic diversity of species. Previously, a low level of genetic diversity has been reported among the Indo-Pacific humpback dolphin (Sousa chinensis) in the Pearl River Estuary (PRE) using both mitochondrial marker and microsatellite loci. Here, the expression and sequence polymorphism of 2 MHC class II genes (DQB and DRB) in 32 S. chinensis from PRE collected between 2003 and 2011 were investigated. High ratios of non-synonymous to synonymous substitution rates, codon-based selection analysis, and trans-species polymorphism (TSP) support the hypothesis that balancing selection acted on S. chinensis MHC sequences. However, only 2 haplotypes were detected at either DQB or DRB loci. Moreover, the lack of deviation from the Hardy-Weinberg expectation at DRB locus combined with the relatively low heterozygosity at both DQB locus and microsatellite loci suggested that balancing selection might not be sufficient, which further suggested that genetic drift associated with historical bottlenecks was not mitigated by balancing selection in terms of the loss of MHC and neutral variation in S. chinensis. The combined results highlighted the importance of maintaining the genetic diversity of the endangered S. chinensis. PMID:26787544

  2. Allelic and haplotype variation of major histocompatibility complex class II DRB1 and DQB loci in the St Lawrence beluga (Delphinapterus leucas).

    PubMed

    1999-07-01

    In order to assess levels of major histocompatibility complex (Mhc) variation within the St Lawrence beluga (Delphinapterus leucas) the variation at the beluga Mhc DRB1 class II locus was assessed by single-strand conformation polymorphism (SSCP) analysis of the peptide-binding region for 313 whales collected from 13 sampling locations across North America. In addition, samples from west Greenland and the St Lawrence were also typed at the DQB locus, allowing comparison to a previous study and assessment of linkage disequilibrium of alleles at the two loci. Comparisons of DRB1 and DQB allele frequencies among all sampling locations indicated genetic structure (alpha < 0.005). Most of this structure resulted from differences between the different wintering groups. Significant genetic structure (alpha = 0.05) exists among each pair of the following groups at both the DRB1 and DQB loci; St Lawrence, Hudson Strait, Bering Sea, Cunningham Inlet, and Davis Strait (minus Cunningham Inlet), except the St Lawrence and Hudson Strait for the DQB locus. In the St Lawrence population, six of the eight DRB1 alleles are present representing all five known allelic lineages. Evidence of linkage disequilibrium between the DRB1 and DQB is present in two sampling locations, the St Lawrence and Nuussuaq (alpha = 0.05). Analysis of probable DRB1-DQB haplotypes among groups of beluga suggests a haplotype reduction in the St Lawrence. PMID:10447854

  3. Major histocompatibility complex class II DAB alleles associated with intestinal parasite load in the vulnerable Chinese egret (Egretta eulophotes).

    PubMed

    Lei, Wei; Zhou, Xiaoping; Fang, Wenzhen; Lin, Qingxian; Chen, Xiaolin

    2016-07-01

    The maintenance of major histocompatibility complex (MHC) polymorphism has been hypothesized to result from many mechanisms such as rare-allele advantage, heterozygote advantage, and allele counting. In the study reported herein, 224 vulnerable Chinese egrets (Egretta eulophotes) were used to examine these hypotheses as empirical results derived from bird studies are rare. Parasite survey showed that 147 (65.63%) individuals were infected with 1-3 helminths, and 82.31% of these infected individuals carried Ascaridia sp. Using asymmetric polymerase chain reaction technique, 10 DAB1, twelve DAB2, and three DAB3 exon 2 alleles were identified at each single locus. A significant association of the rare allele Egeu-DAB2*05 (allele frequency: 0.022) with helminth resistance was found for all helminths, as well as for the most abundant morphotype Ascaridia sp. in the separate analyses. Egeu-DAB2*05 occurred frequently in uninfected individuals, and individuals carrying Egeu-DAB2*05 had significantly lower helminth morphotypes per individual (HMI) (the number of HMI) and the fecal egg count values. Further, the parasite infection measurements were consistently lower in individuals with an intermediate number of different alleles in the duplicated DAB loci. Significantly, heterozygosity within each DAB locus was not correlated with any parasite infection measurements. These results indicate that the diversity in MHC Egeu-DAB gene is associated with intestinal parasite load and maintained by pathogen-driven selection that probably operate through both the rare-allele advantage and the allele counting strategy, and suggest that Egeu-DAB2*05 might be a valuable indicator of better resistance to helminth diseases in the vulnerable Chinese egret. PMID:27386085

  4. Genetic drift vs. natural selection in a long-term small isolated population: major histocompatibility complex class II variation in the Gulf of California endemic porpoise (Phocoena sinus).

    PubMed

    Munguia-Vega, Adrian; Esquer-Garrigos, Yareli; Rojas-Bracho, Lorenzo; Vazquez-Juarez, Ricardo; Castro-Prieto, Aines; Flores-Ramirez, Sergio

    2007-10-01

    Although many studies confirm long-term small isolated populations (e.g. island endemics) commonly sustain low neutral genetic variation as a result of genetic drift, it is less clear how selection on adaptive or detrimental genes interplay with random forces. We investigated sequence variation at two major histocompatibility complex (Mhc) class II loci on a porpoise endemic to the upper Gulf of California, México (Phocoena sinus, or vaquita). Its unique declining population is estimated around 500 individuals. Single-strand conformation polymorphism analysis revealed one putative functional allele fixed at the locus DQB (n = 25). At the DRB locus, we found two presumed functional alleles (n = 29), differing by a single nonsynonymous nucleotide substitution that could increase the stability at the dimer interface of alphabeta-heterodimers on heterozygous individuals. Identical trans-specific DQB1 and DRB1 alleles were identified between P. sinus and its closest relative, the Burmeister's porpoise (Phocoena spinipinnis). Comparison with studies on four island endemic mammals suggests fixation of one allele, due to genetic drift, commonly occurs at the DQA or DQB loci (effectively neutral). Similarly, deleterious alleles of small effect are also effectively neutral and can become fixed; a high frequency of anatomical malformations on vaquita gave empirical support to this prediction. In contrast, retention of low but functional polymorphism at the DRB locus was consistent with higher selection intensity. These observations indicated natural selection could maintain (and likely also purge) some crucial alleles even in the face of strong and prolonged genetic drift and inbreeding, suggesting long-term small populations should display low inbreeding depression. Low levels of Mhc variation warn about a high susceptibility to novel pathogens and diseases in vaquita. PMID:17727623

  5. Antigen-Specific Signaling by a Soluble, Dimeric Peptide/Major Histocompatibility Complex Class II/Fc Chimera Leading to T Helper Cell Type 2 Differentiation

    PubMed Central

    Casares, Sofia; Zong, Cong S.; Radu, Dorel L.; Miller, Alexander; Bona, Constantin A.; Brumeanu, Teodor-Doru

    1999-01-01

    Interaction between a T cell receptor (TCR) and various ligands, i.e., anti-TCR antibodies, superantigens, peptides, or altered peptide ligands in the context of major histocompatibility complex (MHC) molecules can trigger different T helper cell (Th) effector functions. Herein, we studied the T cell response induced by a soluble, dimeric peptide/MHC class II chimera, namely hemagglutinin (HA)110-120/I-Edαβ/Fcγ2a (DEF). We have previously demonstrated that the soluble DEF molecule binds stably and specifically to HA110-120–specific TCRs expressed by a T cell hybridoma. Administration of DEF in vivo induced differentiation of resting and activated peptide-specific T cells toward a Th2 response, as indicated by the increase of interleukin (IL)-4, IL-10, and specific immunoglobulin (Ig)G1 antibodies and decrease of IL-2, specific IgG2a antibodies, and cytotoxic T lymphocyte activity. In contrast to HA110-120 peptide presented by the DEF molecule to T cells, the nominal synthetic peptide induced a predominant Th1 response, and the PR8 virus–derived HA110-120 peptides induced a mixed Th1/Th2 response. Independent of antigen processing, soluble DEF was almost 2 logs more potent in stimulating cognate T cells than the nominal peptide. Polarization of cognate T cells toward the Th2 response occurred upon interaction of soluble DEF with TCR and CD4 molecules followed by early activation of p56lck and ZAP-70 tyrosine kinases, and negative signaling of the signal transducer and activator of transcription (STAT)4 pathway of Th1 differentiation. DEF-like molecules may provide a new tool to study the mechanisms of signaling toward Th2 differentiation and may also provide a potential immunotherapeutic approach to modulate autoreactive T cells toward protective Th2 immune responses. PMID:10449525

  6. Bordetella pertussis Proteins Dominating the Major Histocompatibility Complex Class II-Presented Epitope Repertoire in Human Monocyte-Derived Dendritic Cells

    PubMed Central

    Stenger, Rachel M.; Meiring, Hugo D.; Kuipers, Betsy; Poelen, Martien; van Gaans-van den Brink, Jacqueline A. M.; Boog, Claire J. P.; de Jong, Ad P. J. M.

    2014-01-01

    Knowledge of naturally processed Bordetella pertussis-specific T cell epitopes may help to increase our understanding of the basis of cell-mediated immune mechanisms to control this reemerging pathogen. Here, we elucidate for the first time the dominant major histocompatibility complex (MHC) class II-presented B. pertussis CD4+ T cell epitopes, expressed on human monocyte-derived dendritic cells (MDDC) after the processing of whole bacterial cells by use of a platform of immunoproteomics technology. Pertussis epitopes identified in the context of HLA-DR molecules were derived from two envelope proteins, i.e., putative periplasmic protein (PPP) and putative peptidoglycan-associated lipoprotein (PAL), and from two cytosolic proteins, i.e., 10-kDa chaperonin groES protein (groES) and adenylosuccinate synthetase (ASS). No epitopes were detectable from known virulence factors. CD4+ T cell responsiveness in healthy adults against peptide pools representing epitope regions or full proteins confirmed the immunogenicity of PAL, PPP, groES, and ASS. Elevated lymphoproliferative activity to PPP, groES, and ASS in subjects within a year after the diagnosis of symptomatic pertussis suggested immunogenic exposure to these proteins during clinical infection. The PAL-, PPP-, groES-, and ASS-specific responses were associated with secretion of functional Th1 (tumor necrosis factor alpha [TNF-α] and gamma interferon [IFN-γ]) and Th2 (interleukin 5 [IL-5] and IL-13) cytokines. Relative paucity in the natural B. pertussis epitope display of MDDC, not dominated by epitopes from known protective antigens, can interfere with the effectiveness of immune recognition of B. pertussis. A more complete understanding of hallmarks in B. pertussis-specific immunity may advance the design of novel immunological assays and prevention strategies. PMID:24599530

  7. Bordetella pertussis proteins dominating the major histocompatibility complex class II-presented epitope repertoire in human monocyte-derived dendritic cells.

    PubMed

    Stenger, Rachel M; Meiring, Hugo D; Kuipers, Betsy; Poelen, Martien; van Gaans-van den Brink, Jacqueline A M; Boog, Claire J P; de Jong, Ad P J M; van Els, Cécile A C M

    2014-05-01

    Knowledge of naturally processed Bordetella pertussis-specific T cell epitopes may help to increase our understanding of the basis of cell-mediated immune mechanisms to control this reemerging pathogen. Here, we elucidate for the first time the dominant major histocompatibility complex (MHC) class II-presented B. pertussis CD4(+) T cell epitopes, expressed on human monocyte-derived dendritic cells (MDDC) after the processing of whole bacterial cells by use of a platform of immunoproteomics technology. Pertussis epitopes identified in the context of HLA-DR molecules were derived from two envelope proteins, i.e., putative periplasmic protein (PPP) and putative peptidoglycan-associated lipoprotein (PAL), and from two cytosolic proteins, i.e., 10-kDa chaperonin groES protein (groES) and adenylosuccinate synthetase (ASS). No epitopes were detectable from known virulence factors. CD4(+) T cell responsiveness in healthy adults against peptide pools representing epitope regions or full proteins confirmed the immunogenicity of PAL, PPP, groES, and ASS. Elevated lymphoproliferative activity to PPP, groES, and ASS in subjects within a year after the diagnosis of symptomatic pertussis suggested immunogenic exposure to these proteins during clinical infection. The PAL-, PPP-, groES-, and ASS-specific responses were associated with secretion of functional Th1 (tumor necrosis factor alpha [TNF-α] and gamma interferon [IFN-γ]) and Th2 (interleukin 5 [IL-5] and IL-13) cytokines. Relative paucity in the natural B. pertussis epitope display of MDDC, not dominated by epitopes from known protective antigens, can interfere with the effectiveness of immune recognition of B. pertussis. A more complete understanding of hallmarks in B. pertussis-specific immunity may advance the design of novel immunological assays and prevention strategies. PMID:24599530

  8. Genetic Variation of the Major Histocompatibility Complex (MHC Class II B Gene) in the Threatened Hume’s Pheasant, Syrmaticus humiae

    PubMed Central

    Chen, Weicai; Bei, Yongjian; Li, Hanhua

    2015-01-01

    Major histocompatibility complex (MHC) genes are the most polymorphic genes in vertebrates and encode molecules that play a crucial role in pathogen resistance. As a result of their diversity, they have received much attention in the fields of evolutionary and conservation biology. Here, we described the genetic variation of MHC class II B (MHCIIB) exon 2 in a wild population of Hume’s pheasant (Syrmaticus humiae), which has suffered a dramatic decline in population over the last three decades across its ranges in the face of heavy exploitation and habitat loss. Twenty-four distinct alleles were found in 73 S. humiae specimens. We found seven shared alleles among four geographical groups as well as six rare MHCIIB alleles. Most individuals displayed between one to five alleles, suggesting that there are at least three MHCIIB loci of the Hume’s pheasant. The dN ⁄ dS ratio at putative antigen-binding sites (ABS) was significantly greater than one, indicating balancing selection is acting on MHCIIB exon 2. Additionally, recombination and gene conversion contributed to generating MHCIIB diversity in the Hume’s pheasant. One to three recombination events and seventy-five significant gene conversion events were observed within the Hume’s pheasant MHCIIB loci. The phylogenetic tree and network analysis revealed that the Hume’s pheasant alleles do not cluster together, but are scattered through the tree or network indicating a trans-species evolutionary mode. These findings revealed the evolution of the Hume’s pheasant MHC after suffering extreme habitat fragmentation. PMID:25629763

  9. Comprehensive Analysis of Contributions from Protein Conformational Stability and Major Histocompatibility Complex Class II-Peptide Binding Affinity to CD4+ Epitope Immunogenicity in HIV-1 Envelope Glycoprotein

    PubMed Central

    Li, Tingfeng; Steede, N. Kalaya; Nguyen, Hong-Nam P.; Freytag, Lucy C.; McLachlan, James B.; Mettu, Ramgopal R.; Robinson, James E.

    2014-01-01

    ABSTRACT Helper T-cell epitope dominance in human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp120 is not adequately explained by peptide binding to major histocompatibility complex (MHC) proteins. Antigen processing potentially influences epitope dominance, but few, if any, studies have attempted to reconcile the influences of antigen processing and MHC protein binding for all helper T-cell epitopes of an antigen. Epitopes of gp120 identified in both humans and mice occur on the C-terminal flanks of flexible segments that are likely to be proteolytic cleavage sites. In this study, the influence of gp120 conformation on the dominance pattern in gp120 from HIV strain 89.6 was examined in CBA mice, whose MHC class II protein has one of the most well defined peptide-binding preferences. Only one of six dominant epitopes contained the most conserved element of the I-Ak binding motif, an aspartic acid. Destabilization of the gp120 conformation by deletion of single disulfide bonds preferentially enhanced responses to the cryptic I-Ak motif-containing sequences, as reported by T-cell proliferation or cytokine secretion. Conversely, inclusion of CpG in the adjuvant with gp120 enhanced responses to the dominant CD4+ T-cell epitopes. The gp120 destabilization affected secretion of some cytokines more than others, suggesting that antigen conformation could modulate T-cell functions through mechanisms of antigen processing. IMPORTANCE CD4+ helper T cells play an essential role in protection against HIV and other pathogens. Thus, the sites of helper T-cell recognition, the dominant epitopes, are targets for vaccine design; and the corresponding T cells may provide markers for monitoring infection and immunity. However, T-cell epitopes are difficult to identify and predict. It is also unclear whether CD4+ T cells specific for one epitope are more protective than T cells specific for other epitopes. This work shows that the three-dimensional (3D) structure of an

  10. Affinity-purified CCAAT-box-binding protein (YEBP) functionally regulates expression of a human class II major histocompatibility complex gene and the herpes simplex virus thymidine kinase gene

    SciTech Connect

    Zeleznik-Le, N.J.; Azizkhan, J.C.; Ting, J.P.Y. )

    1991-03-01

    Efficient major histocompatibility complex class II gene expression requires conseved protein-binding promoter elements, including X and Y elements. The authors affinity purified an HLA-DRA Y-element (CCAAT)-binding protein (YEBP) and used it to reconstitute Y-depleted HLA-DRA in vitro transcription. This directly demonstrates a positive functional role for YEBP in HLA-DRA transcription. The ability of YEBP to regulate divergent CCAAT elements was also assessed; YEBP was found to partially activate the thymidine kinase promoter. This functional analysis of YEBP shows that this protein plays an important role in the regulation of multiple genes.

  11. Specialized functions of major histocompatibility complex class I molecules. II. Hmt binds N-formylated peptides of mitochondrial and prokaryotic origin

    PubMed Central

    1991-01-01

    The physiological functions of the mouse telomeric major histocompatibility complex (MHC) class I molecules, including Hmt, are unknown. Hmt presents a polymorphic, N-formylated peptide encoded by the mitochondrial gene ND1 forming the cell surface maternally transmitted antigen (Mta). Because the N-formyl moiety is required for Hmt binding, we proposed that Hmt may function generally in presentation of N-formylated antigens. This hypothesis was validated by a competitive binding assay, demonstrating that synthetic N-formyl peptides from other mitochondrial genes also bound Hmt. Bacteria similarly initiate protein synthesis with N-formylmethionine; indeed, we established that Hmt can also present prokaryotic peptides in an N- formyl-dependent manner. These results indicate biochemical specialization of this MHC-peptide interaction and suggest a unique role for Hmt in prokaryotic host defenses. PMID:1919442

  12. Human X-box-binding protein 1 is required for the transcription of a subset of human class II major histocompatibility genes and forms a heterodimer with c-fos

    SciTech Connect

    Ono, S.J.; Strominger, J.L. ); Hsiouchi Liou; Davidon, R.; Glimcher, L.H. )

    1991-05-15

    A complementary DNA encoding a member of the leucine-zipper class of proteins (human X-box-binding protein, hXBP-1) that binds to the 3{prime} end of the conserved X box (X2) of the HLA-DRA major histocompatibility complex gene was recently described. Further gel-retardation analysis has demonstrated that hXBP-1 also binds to HLA-DPB X2 but not to other X2 sequences. Transient transfection of a mammalian expression vector with the hXBP-1 cDNA inserted in the antisense orientation represses the surface expression of HLA-DR and HLA-DP in Raji cells. Cotransfection of the antisense hXBP-1 vector with a HLA-DRA/chloramphenicol acetyltransferase (but not a HLA-DQB/chloramphenicol acetyltransferase) reporter plasmid decreases chloramphenicol acetyltransferase activity in Raji cells and in {gamma}-interferon-treated HeLa cells relative to cells cotransfected with a control antisense vector. Moreover, hXBP-1 is shown to form a stable heterodimer with the product of the c-fos protooncogene. These data suggest that the hXBP-1 c-fos heterodimer is critical for the transcription of a subset of the human class II major histocompatibility complex genes and that the regulatory mechanisms for the different class II genes are distinct.

  13. Narcolepsy: autoimmunity, effector T cell activation due to infection, or T cell independent, major histocompatibility complex class II induced neuronal loss?

    PubMed

    Fontana, Adriano; Gast, Heidemarie; Reith, Walter; Recher, Mike; Birchler, Thomas; Bassetti, Claudio L

    2010-05-01

    Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of narcolepsy being an immune-mediated disease. Narcolepsy is associated with polymorphisms of the genes encoding T cell receptor alpha chain, tumour necrosis factor alpha and tumour necrosis factor receptor II. Moreover the rate of streptococcal infection is increased at onset of narcolepsy. The hallmarks of anti-self reactions in the tissue--namely upregulation of major histocompatibility antigens and lymphocyte infiltrates--are missing in the hypothalamus. These findings are questionable because they were obtained by analyses performed many years after onset of disease. In some patients with narcolepsy autoantibodies to Tribbles homolog 2, which is expressed by hypocretin neurons, have been detected recently. Immune-mediated destruction of hypocretin producing neurons may be mediated by microglia/macrophages that become activated either by autoantigen specific CD4(+) T cells or superantigen stimulated CD8(+) T cells, or independent of T cells by activation of DQB1*0602 signalling. Activation of microglia and macrophages may lead to the release of neurotoxic molecules such as quinolinic acid, which has been shown to cause selective destruction of hypocretin neurons in the hypothalamus. PMID:20403960

  14. Modified Vaccinia Virus Ankara-Infected Dendritic Cells Present CD4+ T-Cell Epitopes by Endogenous Major Histocompatibility Complex Class II Presentation Pathways

    PubMed Central

    Thiele, Frank; Tao, Sha; Zhang, Yi; Muschaweckh, Andreas; Zollmann, Tina; Protzer, Ulrike; Abele, Rubert

    2014-01-01

    ABSTRACT CD4+ T lymphocytes play a central role in the immune system and mediate their function after recognition of their respective antigens presented on major histocompatibility complex II (MHCII) molecules on antigen-presenting cells (APCs). Conventionally, phagocytosed antigens are loaded on MHCII for stimulation of CD4+ T cells. Certain epitopes, however, can be processed directly from intracellular antigens and are presented on MHCII (endogenous MHCII presentation). Here we characterized the MHCII antigen presentation pathways that are possibly involved in the immune response upon vaccination with modified vaccinia virus Ankara (MVA), a promising live viral vaccine vector. We established CD4+ T-cell lines specific for MVA-derived epitopes as tools for in vitro analysis of MHCII antigen processing and presentation in MVA-infected APCs. We provide evidence that infected APCs are able to directly transfer endogenous viral proteins into the MHCII pathway to efficiently activate CD4+ T cells. By using knockout mice and chemical inhibitory compounds, we further elucidated the molecular basis, showing that among the various subcellular pathways investigated, proteasomes and autophagy are key players in the endogenous MHCII presentation during MVA infection. Interestingly, although proteasomal processing plays an important role, neither TAP nor LAMP-2 was found to be involved in the peptide transport. Defining the molecular mechanism of MHCII presentation during MVA infection provides a basis for improving MVA-based vaccination strategies by aiming for enhanced CD4+ T-cell activation by directing antigens into the responsible pathways. IMPORTANCE This work contributes significantly to our understanding of the immunogenic properties of pathogens by deciphering antigen processing pathways contributing to efficient activation of antigen-specific CD4+ T cells. We identified autophagosome formation, proteasomal activity, and lysosomal integrity as being crucial for

  15. Molecular characterization by high-resolution isoelectric focusing of the products encoded by the class II region loci of the major histocompatibility complex in humans. I. DR and DQ gene variants.

    PubMed

    Rodriguez de Cordoba, S; Nunez-Roldan, A; Winchester, R; Marshall, P; Carrier, C; Mollen, N; Walker, M; Ginsberg-Fellner, F; Rubinstein, P

    1987-09-01

    We describe a new approach to the analysis of the structural polymorphism of the DR beta, DQ alpha, and DQ beta polypeptide chains of human histocompatibility class II antigens. In comparison to conventional two-dimensional gel studies, this method provides sharper definition of the protein bands and side-by-side comparisons within the same gel, thereby permitting the detection of minor differences in the isoelectric points of the protein chains. Using this methodology we have analyzed the IEF polymorphism and the variability in the number of the DR beta chains encoded by different DR haplotypes. Twenty DR beta chain variants, which include the products of no less than two separate DR beta loci, have been thus far identified. Alleles at one of these loci are assumed to code for DR beta chains carrying the DR alloespecificities DR1, DR2, DR3, DR4, DR5, DRw6, DR7, and DR8. Alleles at a second DR beta locus encode DR beta chains that may be shared by serologically DR-different haplotypes and carry supertypic serologic specificities (i.e., DRw52 and DRw53). We also demonstrate here that the structural polymorphisms of the DQ alpha and DQ beta chains are more extensive than previously thought, report the characterization of 14 DQ beta variants, and define their relationship to the previously described DQw serologic specificities. In addition, we describe the class II haplotype associations observed for the different DR and DQ variants characterized. PMID:3679903

  16. Relative abilities of distinct isotypes of human major histocompatibility complex class II molecules to bind streptococcal pyrogenic exotoxin types A and B.

    PubMed Central

    Imanishi, K; Igarashi, H; Uchiyama, T

    1992-01-01

    The relative ability of distinct isotypes of human leukocyte antigen class II molecules to bind streptococcal pyrogenic exotoxins A and B (SPE A and SPE B, respectively) was investigated by a direct-binding assay with 125I-labeled toxin for SPE A and by a functional assay system measuring the accessory cell activity of human leukocyte antigen class II transfectants in toxin-induced T-cell activation for SPE A and SPE B. SPE A binding was observed in L cells transfected with DQw1 genes. By contrast, it was not detected in L cells transfected with DR2, DR4, DPw4 or DP(Cp63) genes. All the transfectants supported SPE-induced interleukin-2 production by human T cells except the DP transfectants for SPE B. Levels of accessory cell activity were low in the DP transfectants induced by stimulation with SPE A and in the DR and DP transfectants induced by SPE B. The results indicate that SPE A and SPE B bind well to DQ molecules, less well to DR molecules, and very weakly to DP molecules. PMID:1452333

  17. Organizing MHC Class II Presentation

    PubMed Central

    Fooksman, David R.

    2014-01-01

    Major histocompatibility complex (MHC) class II molecules are ligands for CD4+ T cells and are critical for initiating the adaptive immune response. This review is focused on what is currently known about MHC class II organization at the plasma membrane of antigen presenting cells and how this affects antigen presentation to T cells. The organization and diffusion of class II molecules have been measured by a variety of biochemical and microscopic techniques. Membrane lipids and other proteins have been implicated in MHC class II organization and function. However, when compared with the organization of MHC class I or TCR complexes, much less is known about MHC class II. Since clustering of T cell receptors occurs during activation, the organization of MHC molecules prior to recognition and during synapse formation may be critical for antigen presentation. PMID:24782863

  18. Dendritic cells use macropinocytosis and the mannose receptor to concentrate macromolecules in the major histocompatibility complex class II compartment: downregulation by cytokines and bacterial products.

    PubMed

    Sallusto, F; Cella, M; Danieli, C; Lanzavecchia, A

    1995-08-01

    We have previously demonstrated that human peripheral blood low density mononuclear cells cultured in granulocyte/macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4 develop into dendritic cells (DCs) that are extremely efficient in presenting soluble antigens to T cells. To identify the mechanisms responsible for efficient antigen capture, we studied the endocytic capacity of DCs using fluorescein isothiocyanate-dextran, horseradish peroxidase, and lucifer yellow. We found that DCs use two distinct mechanisms for antigen capture. The first is a high level of fluid phase uptake via macropinocytosis. In contrast to what has been found with other cell types, macropinocytosis in DCs is constitutive and allows continuous internalization of large volumes of fluid. The second mechanism of capture is mediated via the mannose receptor (MR), which is expressed at high levels on DCs. At low ligand concentrations, the MR can deliver a large number of ligands to the cell in successive rounds. Thus, while macropinocytosis endows DCs with a high capacity, nonsaturable mechanism for capture of any soluble antigen, the MR gives an extra capacity for antigen capture with some degree of selectivity for non-self molecules. In addition to their high endocytic capacity, DCs from GM-CSF + IL-4-dependent cultures are characterized by the presence of a large intracellular compartment that contains high levels of class II molecules, cathepsin D, and lysosomal-associated membrane protein-1, and is rapidly accessible to endocytic markers. We investigated whether the capacity of DCs to capture and process antigen could be modulated by exogenous stimuli. We found that DCs respond to tumor necrosis factor alpha, CD40 ligand, IL-1, and lipopolysaccharide with a coordinate series of changes that include downregulation of macropinocytosis and Fc receptors, disappearance of the class II compartment, and upregulation of adhesion and costimulatory molecules. These changes occur

  19. Assessment of biodiversity in Chilean cattle using the distribution of major histocompatibility complex class II BoLA-DRB3 allele.

    PubMed

    Takeshima, S-N; Miyasaka, T; Matsumoto, Y; Xue, G; Diaz, V de la Barra; Rogberg-Muñoz, A; Giovambattista, G; Ortiz, M; Oltra, J; Kanemaki, M; Onuma, M; Aida, Y

    2015-01-01

    Bovine leukocyte antigens (BoLAs) are used extensively as markers for bovine disease and immunological traits. In this study, we estimated BoLA-DRB3 allele frequencies using 888 cattle from 10 groups, including seven cattle breeds and three crossbreeds: 99 Red Angus, 100 Black Angus, 81 Chilean Wagyu, 49 Hereford, 95 Hereford × Angus, 71 Hereford × Jersey, 20 Hereford × Overo Colorado, 113 Holstein, 136 Overo Colorado, and 124 Overo Negro cattle. Forty-six BoLA-DRB3 alleles were identified, and each group had between 12 and 29 different BoLA-DRB3 alleles. Overo Negro had the highest number of alleles (29); this breed is considered in Chile to be an 'Old type' European Holstein Friesian descendant. By contrast, we detected 21 alleles in Holstein cattle, which are considered to be a 'Present type' Holstein Friesian cattle. Chilean cattle groups and four Japanese breeds were compared by neighbor-joining trees and a principal component analysis (PCA). The phylogenetic tree showed that Red Angus and Black Angus cattle were in the same clade, crossbreeds were closely related to their parent breeds, and Holstein cattle from Chile were closely related to Holstein cattle in Japan. Overall, the tree provided a thorough description of breed history. It also showed that the Overo Negro breed was closely related to the Holstein breed, consistent with historical data indicating that Overo Negro is an 'Old type' Holstein Friesian cattle. This allelic information will be important for investigating the relationship between major histocompatibility complex (MHC) and disease. PMID:25430590

  20. Identification of the transcription factors NF-YA and NF-YB as factors A and B that bound to the promoter of the major histocompatibility complex class II gene I-A beta.

    PubMed Central

    Celada, A; McKercher, S R; Maki, R A

    1996-01-01

    The Y box is a conserved sequence in the promoter of major histocompatibility complex (MHC) class II genes, which contains a CCAAT sequence (CCAAT box). Previously, we partially purified the DNA-binding protein that recognizes the Y box of the I-A beta gene and showed that it consisted of two components (factors A and B) both of which were necessary for optimal DNA binding. The genes for the heteromeric protein NF-Y (NF-YA and NF-YB), which binds to the I-E alpha Y box have been cloned. We subsequently isolated the genes for NF-YA and NF-YB using oligonucleotides designed from the published sequences. NF-YA and NF-YB were tested for binding to the I-A beta and I-E alpha Y boxes. While neither NF-YA or NF-YB alone bound to the Y box, when the components were mixed the complex bound to the I-A beta Y box with high affinity. Moreover, NF-YA and NF-YB could be complemented for binding to DNA by factor B or factor A, respectively. These results suggest that the active binding protein is NF-YA in factor A extracts and NF-YB in factor B extracts. Finally, antibodies against NF-YA and NF-YB were shown to induce a supershift when nuclear extracts were added to the double-stranded oligodeoxynucleotide covering the Y box of the I-A beta gene. Antisense expression constructs of both NF-YA and NF-YB were made and their effect on expression from the I-A beta promoter was tested. Either antisense construction, when transfected into cells, lowered the expression of a reporter gene linked to the I-A beta promoter. This study provides direct evidence of the identification of NF-YA and NF-YB as the previously described factors A and B. Moreover, these results strongly implicate NF-Y in the expression of the MHC class II gene I-A beta. PMID:8760361

  1. Zygosity at the major histocompatibility class IIB locus predicts susceptibility to Renibacterium salmoninarum in Atlantic salmon (Salmo salar L.).

    PubMed

    Turner, S M; Faisal, M; DeWoody, J A

    2007-10-01

    Major histocompatibility (MH) class II genes play an important role in the vertebrate immune response. Here, we investigate the relationship between Atlantic salmon (Salmo salar) MH class IIB zygosity and susceptibility to Renibacterium salmoninarum, the causal agent of bacterial kidney disease. By combining DNA sequences from the salmon MH class IIB gene with quantitative ELISA data on R. salmoninarum antigen levels, we found that MH class IIB homozygotes were significantly more susceptible to R. salmoninarum than heterozygotes. These findings are discussed in the context of current evolutionary theory. PMID:17627802

  2. Cytokines Regulate Proteolysis in Major Histocompatibility Complex Class II–Dependent Antigen Presentation by Dendritic Cells

    PubMed Central

    Fiebiger, Edda; Meraner, Paul; Weber, Ekkehard; Fang, I-Fei; Stingl, Georg; Ploegh, Hidde; Maurer, Dieter

    2001-01-01

    Endo/lysosomal proteases control two key events in antigen (Ag) presentation: the degradation of protein Ag and the generation of peptide-receptive major histocompatibility complex (MHC) class II molecules. Here we show that the proinflammatory cytokines tumor necrosis factor α and interleukin (IL)-1β rapidly increase the activity of cathepsin (cat) S and catB in human dendritic cells (DCs). As a consequence, a wave of MHC class II sodium dodecyl sulfate stable dimer formation ensues in a catS-dependent fashion. In contrast, the antiinflammatory cytokine IL-10 renders DCs incapable of upregulating catS and catB activity and in fact, attenuates the level of both enzymes. Suppressed catS and catB activity delays MHC class II sodium dodecyl sulfate stable dimer formation and impairs Ag degradation. In DCs exposed to tetanus toxoid, IL-10 accordingly reduces the number of MHC class II–peptide complexes accessible to tetanus toxoid–specific T cell receptors, as analyzed by measuring T cell receptor downregulation in Ag-specific T cell clones. Thus, the control of protease activity by pro- and antiinflammatory cytokines is an essential feature of the Ag presentation properties of DCs. PMID:11304549

  3. Enriched HLA-DQ3 phenotype and decreased class I major histocompatibility complex antigen expression in recurrent respiratory papillomatosis.

    PubMed Central

    Bonagura, V R; Siegal, F P; Abramson, A L; Santiago-Schwarz, F; O'Reilly, M E; Shah, K; Drake, D; Steinberg, B M

    1994-01-01

    Respiratory papillomas, caused by human papillomaviruses, are benign tumors that recur following removal. We evaluated immune function and major histocompatibility complex (MHC) phenotype and expression in these patients. MHC-independent immune function appeared normal. The frequency of peripheral blood MHC class II phenotypes was highly enriched for DQ3 and DR11, one split of DR5. Class I MHC antigen expression on papilloma tissue was markedly reduced. Together, these phenomena may facilitate papillomavirus evasion of the cellular immune response. Images PMID:7496977

  4. Rhinovirus infection induces major histocompatibility complex class I and costimulatory molecule upregulation on respiratory epithelial cells.

    PubMed

    Papi, A; Stanciu, L A; Papadopoulos, N G; Teran, L M; Holgate, S T; Johnston, S L

    2000-05-01

    Human respiratory epithelial cells may act as antigen-presenting cells during respiratory viral infections. In addition to major histocompatibility complex (MHC) molecules, antigen presentation requires participation of costimulatory molecules. Here the authors investigated class I and class II antigens and B7-1 and B7-2 costimulatory molecule expression in human A549 pulmonary epithelial cells and primary bronchial epithelial cells (HBECs) at baseline and after rhinovirus infection. Constitutive expression of MHC class I and B7-1 molecules was observed on both cell types. MHC class I molecules were up-regulated by rhinovirus infection, while B7-1 was up-regulated only on A549 cells. B7-2 molecules were constitutively expressed at a low level and were up-regulated by rhinovirus only on HBECs. Rhinovirus induction of antigen-presenting molecule expression on A549 cells was accompanied by cellular activation in terms of induction of release of the chemokines RANTES and Groalpha. These data show that respiratory epithelium expresses full antigen-presentation machinery and that rhinovirus infection up-regulates this expression. PMID:10823784

  5. Macrophage cell lines derived from major histocompatibility complex II-negative mice

    NASA Technical Reports Server (NTRS)

    Beharka, A. A.; Armstrong, J. W.; Chapes, S. K.; Spooner, B. S. (Principal Investigator)

    1998-01-01

    Two bone-marrow-derived macrophage cell lines, C2D and C2Dt, were isolated from major histocompatibility class II negative knock-out mice. The C2D cell line was stabilized by continuous culture in colony-stimulating factor-1 and the C2Dt cell line was transformed with SV40 virus large T antigen. These cells exhibited phenotypic properties of macrophages including morphology and expression of Mac 1 and Mac 2 cell surface molecules. These cells also had comparable growth to the bone-marrow-derived macrophage cell line B6MP102. These new cell lines were not spontaneously cytotoxic and were only capable of modest killing of F5b tumor cells when stimulated with LPS and interferon-gamma, but not when stimulated with LPS alone or with staphylococcal exotoxin. C2D and C2Dt cells phagocytosed labeled Staphylococcus aureus similarly to B6MP102 cells but less well than C2D peritoneal macrophages. These cell lines secreted interleukin-6, but not tumor necrosis factor or nitric oxide in response to LPS or staphlococcal enterotoxins A or B C2D(t) cells were tumorigenic in C2D and C57BL/6J mice but C2D cells were not. These data suggest that macrophage cell lines can be established from bone marrow cells of major histocompatibility complex II-negative mice.

  6. Porcine major histocompatibility complex (MHC) class I molecules and analysis of their peptide-binding specificities

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In all vertebrate animals, CD8+ cytotoxic T lymphocytes (CTLs) are controlled by major histocompatibility complex class I (MHC-I) molecules, which are highly polymorphic peptide receptors selecting and presenting endogenously derived epitopes to circulating cytotoxic lymphocytes (CTLs). The polymorp...

  7. Biosynthesis of major histocompatibility complex molecules and generation of T cells in Ii TAP1 double-mutant mice.

    PubMed Central

    Tourne, S; van Santen, H M; van Roon, M; Berns, A; Benoist, C; Mathis, D; Ploegh, H

    1996-01-01

    Major histocompatibility complex (MHC) class I and II molecules are loaded with peptides in distinct subcellular compartments. The transporter associated with antigen processing (TAP) is responsible for delivering peptides derived from cytosolic proteins to the endoplasmic reticulum, where they bind to class I molecules, while the invariant chain (Ii) directs class II molecules to endosomal compartments, where they bind peptides originating mostly from exogenous sources. Mice carrying null mutations of the TAP1 or Ii genes (TAP10) or Ii0, respectively) have been useful tools for elucidating the two MHC/peptide loading pathways. To evaluate to what extent these pathways functionally intersect, we have studied the biosynthesis of MHC molecules and the generation of T cells in Ii0TAP10 double-mutant mice. We find that the assembly and expression of class II molecules in Ii0 and Ii0TAP10 animals are indistinguishable and that formation and display of class I molecules is the same in TAP10 and Ii0TAP10 animals. Thymic selection in the double mutants is as expected, with reduced numbers of both CD4+ CD8- and CD4- CD8+ thymocyte compartments. Surprisingly, lymph node T-cell populations look almost normal; we propose that population expansion of peripheral T cells normalizes the numbers of CD4+ and CD8+ cells in Ii0TAP10 mice. Images Fig. 1 Fig. 2 PMID:8643655

  8. Inhibition by chloroquine of the class II major histocompatibility complex-restricted presentation of endogenous antigens varies according to the cellular origin of the antigen-presenting cells, the nature of the T-cell epitope, and the responding T cell.

    PubMed Central

    Lombard-Platlet, S; Bertolino, P; Deng, H; Gerlier, D; Rabourdin-Combe, C

    1993-01-01

    Chloroquine treatment of antigen-presenting cells (APC) was explored as a tool to investigate the processing pathway for major histocompatibility complex (MHC) class II-restricted presentation of the endogenous secreted hen egg lysozyme (HEL) and transmembrane measles virus haemagglutinin (HA). A 72-hr pretreatment of the APC with 25 microM chloroquine blocked the presentation of the HEL(52-61) T-cell epitope generated from endogenous HEL to the I-Ak-restricted 3A9 T-cell hybridoma by MHC class II-transfected L cells expressing the invariant chain (Ii). The presentation of exogenously added HEL peptides was not affected. Under the same conditions, no inhibition of the presentation of HEL(106-116) to the I-Ed-restricted G28 high-avidity T-cell hybridoma, nor of HA when synthesized by L cells, was observed. When B-lymphoid APC were used, inhibition was observed in every case with a low number of B APC pretreated for 48 hr with chloroquine prior to the T-cell stimulation test. Moreover, addition of chloroquine to untreated B APC during the T-cell stimulation assay was sufficient to inhibit completely the presentation of HEL(106-116) to the B10.D24.42 low avidity T-cell hybridoma. Altogether these studies suggest that an apparent resistance of endogenous Ag presentation to chloroquine inhibition may not necessarily indicate the existence of a non-endosomal pathway but may be due to the nature of the T-cell epitope, to the use of 'non-professional' APC such as L cells, to the use of T cells of high avidity, and to high amounts of pre-existing MHC class II-peptide complexes expressed by the APC. We demonstrate here that, at least in conventional APC such as B cells, class II-restricted presentation of both endogenous secreted HEL and transmembrane HA involves an endosomal pathway. PMID:7508420

  9. Characterisation of Major Histocompatibility Complex Class I in the Australian Cane Toad, Rhinella marina

    PubMed Central

    Lillie, Mette; Shine, Richard; Belov, Katherine

    2014-01-01

    The Major Histocompatibility Complex (MHC) class I is a highly variable gene family that encodes cell-surface receptors vital for recognition of intracellular pathogens and initiation of immune responses. The MHC class I has yet to be characterised in bufonid toads (Order: Anura; Suborder: Neobatrachia; Family: Bufonidae), a large and diverse family of anurans. Here we describe the characterisation of a classical MHC class I gene in the Australian cane toad, Rhinella marina. From 25 individuals sampled from the Australian population, we found only 3 alleles at this classical class I locus. We also found large number of class I alpha 1 alleles, implying an expansion of class I loci in this species. The low classical class I genetic diversity is likely the result of repeated bottleneck events, which arose as a result of the cane toad's complex history of introductions as a biocontrol agent and its subsequent invasion across Australia. PMID:25093458

  10. Cell stress-regulated human major histocompatibility complex class I gene expressed in gastrointestinal epithelium.

    PubMed Central

    Groh, V; Bahram, S; Bauer, S; Herman, A; Beauchamp, M; Spies, T

    1996-01-01

    Conventional major histocompatibility complex (MHC) class I genes encode molecules that present intracellular peptide antigens to T cells. They are ubiquitously expressed and regulated by interferon gamma. Two highly divergent human MHC class I genes, MICA and MICB, are regulated by promoter heat shock elements similar to those of HSP70 genes. MICA encodes a cell surface glycoprotein, which is not associated with beta 2-microglobulin, is conformationally stable independent of conventional class I peptide ligands, and almost exclusively expressed in gastrointestinal epithelium. Thus, this MHC class I molecule may function as an indicator of cell stress and may be recognized by a subset of gut mucosal T cells in an unusual interaction. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:8901601

  11. Characterization of the human CD4(+) T-cell repertoire specific for major histocompatibility class I-restricted antigens.

    PubMed

    Legoux, François; Gautreau, Laetitia; Hesnard, Leslie; Leger, Alexandra; Moyon, Melinda; Devilder, Marie-Claire; Bonneville, Marc; Saulquin, Xavier

    2013-12-01

    While CD4(+) T lymphocytes usually recognize antigens in the context of major histocompatibility (MHC) class II alleles, occurrence of MHC class-I restricted CD4(+) T cells has been reported sporadically. Taking advantage of a highly sensitive MHC tetramer-based enrichment approach allowing detection and isolation of scarce Ag-specific T cells, we performed a systematic comparative analysis of HLA-A*0201-restricted CD4(+) and CD8(+) T-cell lines directed against several immunodominant viral or tumoral antigens. CD4(+) T cells directed against every peptide-MHC class I complexes tested were detected in all donors. These cells yielded strong cytotoxic and T helper 1 cytokine responses when incubated with HLA-A2(+) target cells carrying the relevant epitopes. HLA-A2-restricted CD4(+) T cells were seldom expanded in immune HLA-A2(+) donors, suggesting that they are not usually engaged in in vivo immune responses against the corresponding peptide-MHC class I complexes. However, these T cells expressed TCR of very high affinity and were expanded following ex vivo stimulation by relevant tumor cells. Therefore, we describe a versatile and efficient strategy for generation of MHC class-I restricted T helper cells and high affinity TCR that could be used for adoptive T-cell transfer- or TCR gene transfer-based immunotherapies. PMID:23963968

  12. Inhibition of selective signaling events in natural killer cells recognizing major histocompatibility complex class I.

    PubMed Central

    Kaufman, D S; Schoon, R A; Robertson, M J; Leibson, P J

    1995-01-01

    Many studies have characterized the transmembrane signaling events initiated after T-cell antigen receptor recognition of major histocompatibility complex (MHC)-bound peptides. Yet, little is known about signal transduction from a set of MHC class I recognizing receptors on natural killer (NK) cells whose ligation dramatically inhibits NK cell-mediated killing. In this study we evaluated the influence of MHC recognition on the proximal signaling events in NK cells binding tumor targets. We utilized two experimental models where NK cell-mediated cytotoxicity was fully inhibited by the recognition of specific MHC class I molecules. NK cell binding to either class I-deficient or class I-transfected target cells initiated rapid protein tyrosine kinase activation. In contrast, whereas NK cell binding to class I-deficient targets led to inositol phosphate release and increased intracellular free calcium ([Ca2+]i), NK recognition of class I-bearing targets did not induce the activation of these phospholipase C-dependent signaling events. The recognition of class I by NK cells clearly had a negative regulatory effect since blocking this interaction using anti-class I F(ab')2 fragments increased inositol 1,4,5-trisphosphate release and [Ca2+]i and increased the lysis of the targets. These results suggest that one of the mechanisms by which NK cell recognition of specific MHC class I molecules can block the development of cell-mediated cytotoxicity is by inhibiting specific critical signaling events. Images Fig. 2 Fig. 4 PMID:7604018

  13. A recombinant, soluble, single-chain class I major histocompatibility complex molecule with biological activity.

    PubMed Central

    Mage, M G; Lee, L; Ribaudo, R K; Corr, M; Kozlowski, S; McHugh, L; Margulies, D H

    1992-01-01

    Heterodimeric class I major histocompatibility complex molecules, which consist of a 45-kDa heavy-chain and a 12-kDa beta 2-microglobulin (beta 2m) light chain, bind endogenously synthesized peptides for presentation to antigen-specific T cells. We have synthesized a gene encoding a single-chain, soluble class I molecule derived from mouse H-2Dd, in which the carboxyl terminus of beta 2m is linked via a peptide spacer to the amino terminus of the heavy chain. The chimeric protein is secreted efficiently from transfected L cells, is thermostable, and when loaded with an appropriate antigenic peptide, stimulates an H-2Dd-restricted antigen-specific T-cell hybridoma. Thus, functional binding of peptide does not require the complete dissociation of beta 2m, implying that a heavy chain/peptide complex is not an obligate intermediate in the assembly of the heavy-chain/beta 2m/peptide heterotrimer. Single-chain major histocompatibility complex molecules uniformly loaded with peptide have potential uses for structural studies, toxin or fluor conjugates, and vaccines. Images PMID:1438262

  14. Cyclophilin C Participates in the US2-Mediated Degradation of Major Histocompatibility Complex Class I Molecules

    PubMed Central

    Chapman, Daniel C.; Stocki, Pawel; Williams, David B.

    2015-01-01

    Human cytomegalovirus uses a variety of mechanisms to evade immune recognition through major histocompatibility complex class I molecules. One mechanism mediated by the immunoevasin protein US2 causes rapid disposal of newly synthesized class I molecules by the endoplasmic reticulum-associated degradation pathway. Although several components of this degradation pathway have been identified, there are still questions concerning how US2 targets class I molecules for degradation. In this study we identify cyclophilin C, a peptidyl prolyl isomerase of the endoplasmic reticulum, as a component of US2-mediated immune evasion. Cyclophilin C could be co-isolated with US2 and with the class I molecule HLA-A2. Furthermore, it was required at a particular expression level since depletion or overexpression of cyclophilin C impaired the degradation of class I molecules. To better characterize the involvement of cyclophilin C in class I degradation, we used LC-MS/MS to detect US2-interacting proteins that were influenced by cyclophilin C expression levels. We identified malectin, PDIA6, and TMEM33 as proteins that increased in association with US2 upon cyclophilin C knockdown. In subsequent validation all were shown to play a functional role in US2 degradation of class I molecules. This was specific to US2 rather than general ER-associated degradation since depletion of these proteins did not impede the degradation of a misfolded substrate, the null Hong Kong variant of α1-antitrypsin. PMID:26691022

  15. Genetic diversity and differentiation of the rhesus macaque (Macaca mulatta) population in western Sichuan, China, based on the second exon of the major histocompatibility complex class II DQB (MhcMamu-DQB1) alleles

    PubMed Central

    2014-01-01

    Abstracts Background Rhesus macaques living in western Sichuan, China, have been separated into several isolated populations due to habitat fragmentation. Previous studies based on the neutral or nearly neutral markers (mitochondrial DNA or microsatellites) showed high levels of genetic diversity and moderate genetic differentiation in the Sichuan rhesus macaques. Variation at the major histocompatibility complex (MHC) loci is widely accepted as being maintained by balancing selection, even with a low level of neutral variability in some species. However, in small and isolated or bottlenecked populations, balancing selection may be overwhelmed by genetic drift. To estimate microevolutionary forces acting on the isolated rhesus macaque populations, we examined genetic variation at Mhc-DQB1 loci in 119 wild rhesus macaques from five geographically isolated populations in western Sichuan, China, and compared the levels of MHC variation and differentiation among populations with that previously observed at neutral microsatellite markers. Results 23 Mamu-DQB1 alleles were identified in 119 rhesus macaques in western Sichuan, China. These macaques exhibited relatively high levels of genetic diversity at Mamu-DQB1. The Hanyuan population presented the highest genetic variation, whereas the Heishui population was the lowest. Analysis of molecular variance (AMOVA) and pairwise FST values showed moderate genetic differentiation occurring among the five populations at the Mhc-DQB1 locus. Non-synonymous substitutions occurred at a higher frequency than synonymous substitutions in the peptide binding region. Levels of MHC variation within rhesus macaque populations are concordant with microsatellite variation. On the phylogenetic tree for the rhesus and crab-eating macaques, extensive allele or allelic lineage sharing is observed betweenthe two species. Conclusions Phylogenetic analyses confirm the apparent trans-species model of evolution of the Mhc-DQB1 genes in these

  16. Selection, trans-species polymorphism, and locus identification of major histocompatibility complex class IIβ alleles of New World ranid frogs

    USGS Publications Warehouse

    Kiemnec-Tyburczy, Karen M.; Richmond, Jonathan Q.; Savage, Anna E.; Zamudio, Kelly R.

    2010-01-01

    Genes encoded by the major histocompatibility complex (MHC) play key roles in the vertebrate immune system. However, our understanding of the evolutionary processes and underlying genetic mechanisms shaping these genes is limited in many taxa, including amphibians, a group currently impacted by emerging infectious diseases. To further elucidate the evolution of the MHC in frogs (anurans) and develop tools for population genetics, we surveyed allelic diversity of the MHC class II ??1 domain in both genomic and complementary DNA of seven New World species in the genus Rana (Lithobates). To assign locus affiliation to our alleles, we used a "gene walking" technique to obtain intron 2 sequences that flanked MHC class II?? exon 2. Two distinct intron sequences were recovered, suggesting the presence of at least two class II?? loci in Rana. We designed a primer pair that successfully amplified an orthologous locus from all seven Rana species. In total, we recovered 13 alleles and documented trans-species polymorphism for four of the alleles. We also found quantitative evidence of selection acting on amino acid residues that are putatively involved in peptide binding and structural stability of the ??1 domain of anurans. Our results indicated that primer mismatch can result in polymerase chain reaction (PCR) bias, which influences the number of alleles that are recovered. Using a single locus may minimize PCR bias caused by primer mismatch, and the gene walking technique was an effective approach for generating single-copy orthologous markers necessary for future studies of MHC allelic variation in natural amphibian populations. ?? 2010 Springer-Verlag.

  17. Enhanced Direct Major Histocompatibility Complex Class I Self-Antigen Presentation Induced by Chlamydia Infection

    PubMed Central

    Cram, Erik D.; Simmons, Ryan S.; Palmer, Amy L.; Hildebrand, William H.; Rockey, Daniel D.

    2015-01-01

    The direct major histocompatibility complex (MHC) class I antigen presentation pathway ensures intracellular peptides are displayed at the cellular surface for recognition of infected or transformed cells by CD8+ cytotoxic T lymphocytes. Chlamydia spp. are obligate intracellular bacteria and, as such, should be targeted by CD8+ T cells. It is likely that Chlamydia spp. have evolved mechanisms to avoid the CD8+ killer T cell responses by interfering with MHC class I antigen presentation. Using a model system of self-peptide presentation which allows for posttranslational control of the model protein's stability, we tested the ability of various Chlamydia species to alter direct MHC class I antigen presentation. Infection of the JY lymphoblastoid cell line limited the accumulation of a model host protein and increased presentation of the model-protein-derived peptides. Enhanced self-peptide presentation was detected only when presentation was restricted to defective ribosomal products, or DRiPs, and total MHC class I levels remained unaltered. Skewed antigen presentation was dependent on a bacterial synthesized component, as evidenced by reversal of the observed phenotype upon preventing bacterial transcription, translation, and the inhibition of bacterial lipooligosaccharide synthesis. These data suggest that Chlamydia spp. have evolved to alter the host antigen presentation machinery to favor presentation of defective and rapidly degraded forms of self-antigen, possibly as a mechanism to diminish the presentation of peptides derived from bacterial proteins. PMID:26597986

  18. Sibling rivalry: competition between MHC class II family members inhibits immunity.

    PubMed

    Denzin, Lisa K; Cresswell, Peter

    2013-01-01

    Peptide loading of major histocompatibility complex (MHC) class II molecules in the endosomes and lysosomes of antigen-presenting cells is catalyzed by human leukocyte antigen-DM (HLA-DM) and modulated by HLA-DO. In a structural study in this issue, Guce et al. show that HLA-DO is an MHC class II mimic and functions as a competitive and essentially irreversible inhibitor of HLA-DM activity, thereby inhibiting MHC class II antigen presentation. PMID:23288359

  19. The molecular chaperone calnexin facilitates folding and assembly of class I histocompatibility molecules.

    PubMed Central

    Vassilakos, A; Cohen-Doyle, M F; Peterson, P A; Jackson, M R; Williams, D B

    1996-01-01

    Calnexin, a membrane protein of the endoplasmic reticulum, is generally thought to function as a molecular chaperone, based on indirect or correlative evidence. To examine calnexin's functions more directly, we reconstituted the assembly of class I histocompatibility molecules in the absence or presence of calnexin in Drosophila melanogaster cells. Calnexin enhanced the assembly of class I heavy chains with beta 2-microglobulin as much as 5-fold. The improved assembly appeared largely due to more efficient folding of heavy chains, as evidenced by increased reactivity with a conformation-sensitive monoclonal antibody and by a reduction in the level of aggregates. Similar findings were obtained in mouse or human cells when the interaction of calnexin with class I heavy chains was prevented by treatment with the oligosaccharide processing inhibitor castanospermine. The ability of calnexin to facilitate castanospermine. The ability of calnexin to facilitate heavy chain folding and to prevent the formation of aggregates provides compelling evidence that calnexin functions as a bona fide molecular chaperone. Images PMID:8612572

  20. Efficient major histocompatibility complex class I presentation of exogenous antigen upon phagocytosis by macrophages.

    PubMed Central

    Kovacsovics-Bankowski, M; Clark, K; Benacerraf, B; Rock, K L

    1993-01-01

    Antigens in extracellular fluids can be processed and presented with major histocompatibility complex (MHC) class I molecules by a subset of antigen presenting cells (APCs). Chicken egg ovalbumin (Ova) linked to beads was presented with MHC class I molecules by these cells up to 10(4)-fold more efficiently than soluble Ova. This enhanced presentation was observed with covalently or noncovalently linked Ova and with beads of different compositions. A key parameter in the activity of these conjugates was the size of the beads. The APC that is responsible for this form of presentation is a macrophage. These cells internalize the antigen constructs through phagocytosis, since cytochalasin B inhibited presentation. Processing of the antigen and association with MHC class I molecules appears to occur intracellularly as presentation was observed under conditions where there was no detectable release of peptides into the extracellular fluids. When injected in vivo in C57BL/6 mice, Ova-beads, but not soluble Ova, primed CD4- CD8+ cytotoxic T lymphocytes (CTLs). Similar results were obtained in BALB/c mice immunized with beta-galactosidase-beads. The implications of these findings for development of nonliving vaccines that stimulate CTL immunity are discussed. PMID:8506338

  1. Isolation and characterization of major histocompatibility complex class IIB genes from the nurse shark.

    PubMed Central

    Bartl, S; Weissman, I L

    1994-01-01

    The major histocompatibility complex (MHC) contains a set of linked genes which encode cell surface proteins involved in the binding of small peptide antigens for their subsequent recognition by T lymphocytes. MHC proteins share structural features and the presence and location of polymorphic residues which play a role in the binding of antigens. In order to compare the structure of these molecules and gain insights into their evolution, we have isolated two MHC class IIB genes from the nurse shark, Ginglymostoma cirratum. Two clones, most probably alleles, encode proteins which differ by 13 amino acids located in the putative antigen-binding cleft. The protein structure and the location of polymorphic residues are similar to their mammalian counterparts. Although these genes appear to encode a typical MHC protein, no T-cell-mediated responses have been demonstrated in cartilaginous fish. The nurse shark represents the most phylogenetically primitive organism in which both class IIA [Kasahara, M., Vazquez, M., Sato, K., McKinney, E.C. & Flajnik, M.F. (1992) Proc. Natl. Acad. Sci USA 89, 6688-6692] and class IIB genes, presumably encoding the alpha/beta heterodimer, have been isolated. Images Fig. 2 PMID:8278377

  2. Major histocompatibility complex class II DR alleles DRB1*1501 and those encoding HLA-DR13 are preferentially associated with a diminution in maternally transmitted human immunodeficiency virus 1 infection in different ethnic groups: determination by an automated sequence-based typing method.

    PubMed Central

    Winchester, R; Chen, Y; Rose, S; Selby, J; Borkowsky, W

    1995-01-01

    Transmission of human immunodeficiency virus 1 (HIV-1) from an infected women to her offspring during gestation and delivery was found to be influenced by the infant's major histocompatibility complex class II DRB1 alleles. Forty-six HIV-infected infants and 63 seroreverting infants, born with passively acquired anti-HIV antibodies but not becoming detectably infected, were typed by an automated nucleotide-sequence-based technique that uses low-resolution PCR to select either the simpler Taq or the more demanding T7 sequencing chemistry. One or more DR13 alleles, including DRB1*1301, 1302, and 1303, were found in 31.7% of seroreverting infants and 15.2% of those becoming HIV-infected [OR (odds ratio) = 2.6 (95% confidence interval 1.0-6.8); P = 0.048]. This association was influenced by ethnicity, being seen more strongly among the 80 Black and Hispanic children [OR = 4.3 (1.2-16.4); P = 0.023], with the most pronounced effect among Black infants where 7 of 24 seroreverters inherited these alleles with none among 12 HIV-infected infants (Haldane OR = 12.3; P = 0.037). The previously recognized association of DR13 alleles with some situations of long-term nonprogression of HIV suggests that similar mechanisms may regulate both the occurrence of infection and disease progression after infection. Upon examining for residual associations, only only the DR2 allele DRB1*1501 was associated with seroreversion in Caucasoid infants (OR = 24; P = 0.004). Among Caucasoids the DRB1*03011 allele was positively associated with the occurrence of HIV infection (P = 0.03). PMID:8618904

  3. Cross-linking staphylococcal enterotoxin A bound to major histocompatibility complex class I is required for TNF-alpha secretion

    NASA Technical Reports Server (NTRS)

    Wright, A. D.; Chapes, S. K.

    1999-01-01

    The mechanism of how superantigens function to activate cells has been linked to their ability to bind and cross-link the major histocompatibility complex class II (MHCII) molecule. Cells that lack the MHCII molecule also respond to superantigens, however, with much less efficiency. Therefore, the purpose of this study was to confirm that staphylococcal enterotoxin A (SEA) could bind the MHCI molecule and to test the hypothesis that cross-linking SEA bound to MHCII-deficient macrophages would induce a more robust cytokine response than without cross-linking. We used a capture enzyme-linked immunosorbent assay and an immunprecipitation assay to directly demonstrate that MHCI molecules bind SEA. Directly cross-linking MHCI using monoclonal antibodies or cross-linking bound SEA with an anti-SEA antibody or biotinylated SEA with avidin increased TNF-alpha and IL-6 secretion by MHCII(-/-) macrophages. The induction of a vigorous macrophage cytokine response by SEA/anti-SEA cross-linking of MHCI offers a mechanism to explain how MHCI could play an important role in superantigen-mediated pathogenesis. Copyright 1999 Academic Press.

  4. Trophoblast Major Histocompatibility Complex Class I Expression Is Associated with Immune-Mediated Rejection of Bovine Fetuses Produced by Cloning.

    PubMed

    Rutigliano, Heloisa M; Thomas, Aaron J; Wilhelm, Amanda; Sessions, Benjamin R; Hicks, Brady A; Schlafer, Donald H; White, Kenneth L; Davies, Christopher J

    2016-08-01

    Trophoblast cells from bovine somatic cell nuclear transfer (SCNT) conceptuses express major histocompatibility complex class I (MHC-I) proteins early in gestation, and this may be one cause of the significant first-trimester embryonic mortality observed in these pregnancies. MHC-I homozygous-compatible (n = 9), homozygous-incompatible (n = 8), and heterozygous-incompatible (n = 5) SCNT pregnancies were established. The control group consisted of eight pregnancies produced by artificial insemination. Uterine and placental samples were collected on Day 35 ± 1 of pregnancy, and expression of MHC-I, leukocyte markers, and cytokines were examined by immunohistochemistry. Trophoblast cells from all SCNT pregnancies expressed MHC-I, while trophoblast cells from age-matched control pregnancies were negative for MHC-I expression. Expression of MHC-I antigens by trophoblast cells from SCNT pregnancies was associated with lymphocytic infiltration in the endometrium. Furthermore, MHC-I-incompatible conceptuses, particularly the heterozygous-incompatible ones, induced a more pronounced lymphocytic infiltration than MHC-I-compatible conceptuses. Cells expressing cluster of differentiation (CD) 3, gamma/deltaTCR, and MHC-II were increased in the endometrium of SCNT pregnancies compared to the control group. CD4(+) lymphocytes were increased in MHC-I-incompatible pregnancies compared to MHC-I-compatible and control pregnancies. CD8(+), FOXP3(+), and natural killer cells were increased in MHC-I heterozygous-incompatible SCNT pregnancies compared to homozygous SCNT and control pregnancies. PMID:27385783

  5. Diacylglycerol Kinase α Regulates Tubular Recycling Endosome Biogenesis and Major Histocompatibility Complex Class I Recycling*

    PubMed Central

    Xie, Shuwei; Naslavsky, Naava; Caplan, Steve

    2014-01-01

    Major histocompatibility complex class I (MHC I) presents intracellular-derived peptides to cytotoxic T lymphocytes and its subcellular itinerary is important in regulating the immune response. While a number of diacylglycerol kinase isoforms have been implicated in clathrin-dependent internalization, MHC I lacks the typical motifs known to mediate clathrin-dependent endocytosis. Here we show that depletion of diacylglycerol kinase α (DGKα), a kinase devoid of a clathrin-dependent adaptor protein complex 2 binding site, caused a delay in MHC I recycling to the plasma membrane without affecting the rate of MHC I internalization. We demonstrate that DGKα knock-down causes accumulation of intracellular and surface MHC I, resulting from decreased degradation. Furthermore, we provide evidence that DGKα is required for the generation of phosphatidic acid required for tubular recycling endosome (TRE) biogenesis. Moreover, we show that DGKα forms a complex with the TRE hub protein, MICAL-L1. Given that MICAL-L1 and the F-BAR-containing membrane-tubulating protein Syndapin2 associate selectively with phosphatidic acid, we propose a positive feedback loop in which DGKα generates phosphatidic acid to drive its own recruitment to TRE via its interaction with MICAL-L1. Our data support a novel role for the involvement of DGKα in TRE biogenesis and MHC I recycling. PMID:25248744

  6. Covalent assembly of a soluble T cell receptor-peptide-major histocompatibility class I complex.

    PubMed Central

    Grégoire, C; Lin, S Y; Mazza, G; Rebai, N; Luescher, I F; Malissen, B

    1996-01-01

    We used stepwise photochemical cross-linking for specifically assembling soluble and covalent complexes made of a T-cell antigen receptor (TCR) and a class I molecule of the major histocompatibility complex (MHC) bound to an antigenic peptide. For that purpose, we have produced in myeloma cells a single-chain Fv construct of a TCR specific for a photoreactive H-2Kd-peptide complex. Photochemical cross-linking of this TCR single-chain Fv with a soluble form of the photoreactive H-2Kd-peptide ligand resulted in the formation of a ternary covalent complex. We have characterized the soluble ternary complex and showed that it reacted with antibodies specific for epitopes located either on the native TCR or on the Kd molecules. By preventing the fast dissociation kinetics observed with most T cell receptors, this approach provides a means of preparing soluble TCR-peptide-MHC complexes on large-scale levels. Images Fig. 3 Fig. 4 PMID:8692966

  7. Plasticity of empty major histocompatibility complex class I molecules determines peptide-selector function.

    PubMed

    van Hateren, Andy; Bailey, Alistair; Werner, Jörn M; Elliott, Tim

    2015-12-01

    Major histocompatibility complex class I (MHC I) proteins provide protection from intracellular pathogens and cancer via each of a cell's MHC I molecules binding and presenting a peptide to cytotoxic T lymphocytes. MHC I genes are highly polymorphic and can have significant diversity, with polymorphisms predominantly localised in the peptide-binding groove where they can change peptide-binding specificity. However, polymorphic residues may also determine other functional properties, such as how dependent MHC I alleles are on the peptide-loading complex for optimal acquisition of peptide cargo. We describe how differences in the peptide-binding properties of two MHC I alleles correlates with altered conformational flexibility in the peptide-empty state. We hypothesise that plasticity is an intrinsic property encoded by the protein sequence, and that co-ordinated movements of the membrane-proximal and membrane-distal domains collectively determines how dependent MHC I are on the peptide-loading complex for efficient assembly with high affinity peptides. PMID:25818313

  8. Contrasting evolutionary histories of MHC class I and class II loci in grouse-effects of selection and gene conversion.

    PubMed

    Minias, P; Bateson, Z W; Whittingham, L A; Johnson, J A; Oyler-McCance, S; Dunn, P O

    2016-05-01

    Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens. PMID:26860199

  9. Contrasting evolutionary histories of MHC class I and class II loci in grouse—Effects of selection and gene conversion

    USGS Publications Warehouse

    Minias, Piotr; Bateson, Zachary W; Whittingham, Linda A; Johnson, Jeff A.; Oyler-McCance, Sara J.; Dunn, Peter O

    2016-01-01

    Genes of the major histocompatibility complex (MHC) encode receptor molecules that are responsible for recognition of intracellular and extracellular pathogens (class I and class II genes, respectively) in vertebrates. Given the different roles of class I and II MHC genes, one might expect the strength of selection to differ between these two classes. Different selective pressures may also promote different rates of gene conversion at each class. Despite these predictions, surprisingly few studies have looked at differences between class I and II genes in terms of both selection and gene conversion. Here, we investigated the molecular evolution of MHC class I and II genes in five closely related species of prairie grouse (Centrocercus and Tympanuchus) that possess one class I and two class II loci. We found striking differences in the strength of balancing selection acting on MHC class I versus class II genes. More than half of the putative antigen-binding sites (ABS) of class II were under positive or episodic diversifying selection, compared with only 10% at class I. We also found that gene conversion had a stronger role in shaping the evolution of MHC class II than class I. Overall, the combination of strong positive (balancing) selection and frequent gene conversion has maintained higher diversity of MHC class II than class I in prairie grouse. This is one of the first studies clearly demonstrating that macroevolutionary mechanisms can act differently on genes involved in the immune response against intracellular and extracellular pathogens.

  10. Localization of eight additional genes in the human major histocompatibility complex, including the gene encoding the casein kinase II {beta} subunit (CSNK2B)

    SciTech Connect

    Albertella, M.R.; Jones, H.; Thomson, W.

    1996-09-01

    A wide range of autoimmune and other diseases are known to be associated with the major histocompatibility complex. Many of these diseases are linked to the genes encoding the polymorphic histocompatibility complex. Many of these diseases are linked to the genes encoding the polymorphic histocompatibility antigens in the class I and class II regions, but some appear to be more strongly associated with genes in the central 1100-kb class III region, making it important to characterize this region fully for the presence of novel genes. An {approximately}220-kb segment of DNA in the class III region separating the Hsp70 (HSPA1L) and BAT1 (D6S8IE) genes, which was previously known to contain 14 genes. Genomic DNA fragments spanning the gaps between the known genes were used as probes to isolate cDNAs corresponding to five new genes within this region. Evidence from Northern blot analysis and exon trapping experiments that suggested the presence of at least two more new genes was also obtained. Partial cDNA and complete exonic genomic sequencing of one of the new genes has identified it as the casein kinase II{beta} subunit (CSNK2B). Two of the other novel genes lie within a region syntenic to that implicated in susceptibility to experimental allergic orchitis in the mouse, an autoimmune disease of the testis, and represent additional candidates for the Orch-1 locus associated with this disease. In addition, characterization of the 13-kb intergenic gap separating the RD (D6545) and G11 (D6S60E) genes has revealed the presence of a gene encoding a 1246-amino-acid polypeptide that shows significant sequence similarity to the yeast anti-viral Ski2p gene product. 49 refs., 8 figs.

  11. [Modified Class II tunnel preparation].

    PubMed

    Rimondini, L; Baroni, C

    1991-05-15

    Tunnel preparations for restoration of Class II carious lesions in primary molars preserve the marginal ridge and minimize sacrifice of healthy tooth substructure. Materials with improved bonding to tooth structure and increase potential for fluoride release allow Class II restorations without "extension for prevention". PMID:1864420

  12. Characterisation of major histocompatibility complex class I genes at the fetal-maternal interface of marsupials.

    PubMed

    Buentjen, Ina; Drews, Barbara; Frankenberg, Stephen R; Hildebrandt, Thomas B; Renfree, Marilyn B; Menzies, Brandon R

    2015-07-01

    Major histocompatibility complex class I molecules (MHC-I) are expressed at the cell surface and are responsible for the presentation of self and non-self antigen repertoires to the immune system. Eutherian mammals express both classical and non-classical MHC-I molecules in the placenta, the latter of which are thought to modulate the maternal immune response during pregnancy. Marsupials last shared a common ancestor with eutherian mammals such as humans and mice over 160 million years ago. Since, like eutherians, they have an intra-uterine development dependent on a placenta, albeit a short-lived and less invasive one, they provide an opportunity to investigate the evolution of MHC-I expression at the fetal-maternal interface. We have characterised MHC-I mRNA expression in reproductive tissues of the tammar wallaby (Macropus eugenii) from the time of placental attachment to day 25 of the 26.5 day pregnancy. Putative classical MHC-I genes were expressed in the choriovitelline placenta, fetus, and gravid endometrium throughout the whole of this period. The MHC-I classical sequences were phylogenetically most similar to the Maeu-UC (50/100 clones) and Maeu-UA genes (7/100 clones). Expression of three non-classical MHC-I genes (Maeu-UD, Maeu-UK and Maeu-UM) were also present in placental samples. The results suggest that expression of classical and non-classical MHC-I genes in extant marsupial and eutherian mammals may have been necessary for the evolution of the ancestral therian placenta and survival of the mammalian fetus at the maternal-fetal interface. PMID:25957041

  13. Regulation of a bovine nonclassical major histocompatibility complex class I gene promoter.

    PubMed

    O'Gorman, Grace M; Al Naib, Abdullah; Naib, Abdullah Al; Ellis, Shirley A; Mamo, Solomon; O'Doherty, Alan M; Lonergan, Pat; Fair, Trudee

    2010-08-01

    Studies have shown in humans and other species that the major histocompatibility complex class I (MHC-I) region is involved at a number of levels in the establishment and maintenance of pregnancy. The aim of this study was to characterize how a bovine nonclassical MHC-I gene (NC1) is regulated. Initial serial deletion experiments of a 2-kb fragment of the NC1 promoter identified regions with positive regulatory elements in the proximal promoter and evidence for a silencer module(s) further upstream that cooperatively contributed to constitutive NC1 expression. The cytokines interferon tau (IFNT), interferon gamma (IFNG), and interleukin 4 (IL4) significantly increased luciferase expression in NC1 promoter reporter constructs and endogenous NC1 mRNA levels in a bovine endometrial cell line. In addition, IFNG, IL3, IL4, and progesterone significantly increased Day 7 bovine blastocyst NC1 mRNA expression when supplemented during in vitro embryo culture. Site-directed mutagenesis analysis identified a STAT6 binding site that conferred IL4 responsiveness in the NC1 proximal promoter. Furthermore, methylation treatment of the proximal promoter, which contains a CpG island, completely abrogated constitutive NC1 expression. Overall, the findings presented here suggest that constitutive NC1 expression is regulated positively by elements in the proximal promoter, which are further controlled by upstream silencer modules. The promoter is responsive to IFNT, IFNG, and IL4, suggesting possible roles for these cytokines in bovine preimplantation embryo survival and/or maternal-fetal tolerance. Our studies also suggest that methylation of the proximal promoter, in particular, could play a significant role in regulating NC1 expression. PMID:20427761

  14. NetMHCcons: a consensus method for the major histocompatibility complex class I predictions.

    PubMed

    Karosiene, Edita; Lundegaard, Claus; Lund, Ole; Nielsen, Morten

    2012-03-01

    A key role in cell-mediated immunity is dedicated to the major histocompatibility complex (MHC) molecules that bind peptides for presentation on the cell surface. Several in silico methods capable of predicting peptide binding to MHC class I have been developed. The accuracy of these methods depends on the data available characterizing the binding specificity of the MHC molecules. It has, moreover, been demonstrated that consensus methods defined as combinations of two or more different methods led to improved prediction accuracy. This plethora of methods makes it very difficult for the non-expert user to choose the most suitable method for predicting binding to a given MHC molecule. In this study, we have therefore made an in-depth analysis of combinations of three state-of-the-art MHC-peptide binding prediction methods (NetMHC, NetMHCpan and PickPocket). We demonstrate that a simple combination of NetMHC and NetMHCpan gives the highest performance when the allele in question is included in the training and is characterized by at least 50 data points with at least ten binders. Otherwise, NetMHCpan is the best predictor. When an allele has not been characterized, the performance depends on the distance to the training data. NetMHCpan has the highest performance when close neighbours are present in the training set, while the combination of NetMHCpan and PickPocket outperforms either of the two methods for alleles with more remote neighbours. The final method, NetMHCcons, is publicly available at www.cbs.dtu.dk/services/NetMHCcons , and allows the user in an automatic manner to obtain the most accurate predictions for any given MHC molecule. PMID:22009319

  15. Identification of the class I genes of the mouse major histocompatibility complex by DNA-mediated gene transfer.

    PubMed

    Goodenow, R S; McMillan, M; Nicolson, M; Sher, B T; Eakle, K; Davidson, N; Hood, L

    1982-11-18

    DNA-mediated gene transfer was used to identify cloned class I genes from the major histocompatibility complex of the BALB/c mouse. Three genes encoding the transplantation antigens H-2 Kd, Dd and Ld were identified as well as genes encoding the Qa-2,3 and two TL differentiation antigens. As many as 10 putative novel class I genes were detected by the association of their gene products with beta 2-microglobulin. Alloantiserum prepared to one of the novel antigens was used to demonstrate the expression of the previously undetected antigen on spleen cells of various inbred, congeneic, and recombinant congeneic strains of mice. PMID:6815535

  16. Characterization of anti-channel catfish MHC class II monoclonal antibodies

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This study characterizes four monoclonal antibodies (mAb) developed against the major histocompatibility complex (MHC) class II beta chain of the channel catfish, Ictalurus punctatus. Immunoprecipitations using catfish clonal B cells revealed that each of these mAbs immunoselected proteins of appro...

  17. Features of target cell lysis by class I and class II MHC restricted cytolytic T lymphocytes

    SciTech Connect

    Maimone, M.M.; Morrison, L.A.; Braciale, V.L.; Braciale, T.J.

    1986-12-01

    The lytic activity of influenza virus-specific muvine cytolytic T lymphocyte (CTL) clones that are restricted by either H-2K/D (class I) or H-2I (class II) major histocompatibility (MHC) locus products was compared on an influenza virus-infected target cell expressing both K/D and I locus products. With the use of two in vitro measurements of cytotoxicity, conventional /sup 51/Cr release, and detergent-releasable radiolabeled DNA (as a measure of nuclear disintegration in the early post-lethal hit period), the authors found no difference between class I and class II MHC-restricted CTL in the kinetics of target cell destruction. In addition, class II MHC-restricted antiviral CTL failed to show any lysis of radiolabeled bystander cells. Killing of labeled specific targets by these class II MHC-restricted CTL was also efficiently inhibited by unlabeled specific competitor cells in a cold target inhibition assay. In sum, these data suggest that class I and class II MHC-restricted CTL mediate target cell destruction by an essentially similar direct mechanism.

  18. Endogenous Antigen Presentation of MHC Class II Epitopes through Non-Autophagic Pathways

    PubMed Central

    Leung, Carol S. K.

    2015-01-01

    Antigenic peptides presented by major histocompatibility complex (MHC) class II molecules are generally derived from exogenous proteins acquired by antigen presenting cells. However, in some circumstances, MHC class II molecules can present intracellular proteins expressed within the antigen-presenting cells. There are several described pathways by which endogenous antigens are degraded and gain access to MHC class II molecules. These include autophagy and other non-autophagic pathways; the latter category includes the MHC class I-like pathways, heat shock protein 90-mediated pathways, and internalization from the plasma membrane. This review will summarize and discuss the non-autophagic pathways. PMID:26441969

  19. Blocking MHC class II on human endothelium mitigates acute rejection

    PubMed Central

    Abrahimi, Parwiz; Qin, Lingfeng; Chang, William G.; Bothwell, Alfred L.M.; Tellides, George; Saltzman, W. Mark; Pober, Jordan S.

    2016-01-01

    Acute allograft rejection is mediated by host CD8+ cytotoxic T lymphocytes (CTL) targeting graft class I major histocompatibility complex (MHC) molecules. In experimental rodent models, rejection requires differentiation of naive CD8+ T cells into alloreactive CTL within secondary lymphoid organs, whereas in humans, CTL may alternatively develop within the graft from circulating CD8+ effector memory T cells (TEM) that recognize class I MHC molecules on graft endothelial cells (EC). This latter pathway is poorly understood. Here, we show that host CD4+ TEM, activated by EC class II MHC molecules, provide critical help for this process. First, blocking HLA-DR on EC lining human artery grafts in immunodeficient mice reduces CD8+ CTL development within and acute rejection of the artery by adoptively transferred allogeneic human lymphocytes. Second, siRNA knockdown or CRISPR/Cas9 ablation of class II MHC molecules on EC prevents CD4+ TEM from helping CD8+ TEM to develop into CTL in vitro. Finally, implanted synthetic microvessels, formed from CRISPR/Cas9-modified EC lacking class II MHC molecules, are significantly protected from CD8+ T cell–mediated destruction in vivo. We conclude that human CD8+ TEM–mediated rejection targeting graft EC class I MHC molecules requires help from CD4+ TEM cells activated by recognition of class II MHC molecules. PMID:26900601

  20. Expression of bovine non-classical major histocompatibility complex class 1 proteins in mouse P815 and human K562 cells

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-class...

  1. Mechanism for Amyloid Precursor-like Protein 2 Enhancement of Major Histocompatibility Complex Class I Molecule Degradation*

    PubMed Central

    Tuli, Amit; Sharma, Mahak; Capek, Haley L.; Naslavsky, Naava; Caplan, Steve; Solheim, Joyce C.

    2009-01-01

    Earlier studies have demonstrated interaction of the murine major histocompatibility complex (MHC) class I molecule Kd with amyloid precursor-like protein 2 (APLP2), a ubiquitously expressed member of the amyloid precursor protein family. Our current findings indicate that APLP2 is internalized in a clathrin-dependent manner, as shown by utilization of inhibitors of the clathrin pathway. Furthermore, we demonstrated that APLP2 and Kd bind at the cell surface and are internalized together. The APLP2 cytoplasmic tail contains two overlapping consensus motifs for binding to the adaptor protein-2 complex, and mutation of a tyrosine shared by both motifs severely impaired APLP2 internalization and ability to promote Kd endocytosis. Upon increased expression of wild type APLP2, Kd molecules were predominantly directed to the lysosomes rather than recycled to the plasma membrane. These findings suggest a model in which APLP2 binds Kd at the plasma membrane, facilitates uptake of Kd in a clathrin-dependent manner, and routes the endocytosed Kd to the lysosomal degradation pathway. Thus, APLP2 has a multistep trafficking function that influences the expression of major histocompatibility complex class I molecules at the plasma membrane. PMID:19808674

  2. Major histocompatibility complex class I expression on neurons in subacute sclerosing panencephalitis and experimental subacute measles encephalitis

    SciTech Connect

    Gogate, N.; Yamabe, Toshio; Verma, L.; Dhib-Jalbut, S.

    1996-04-01

    Lack of major histocompatibility class I antigens on neurons has been implicated as a possible mechanism for viral persistence in the brain since these antigens are required for cytotoxic T-lymphocyte recognition of infected cells. In subacute sclerosing panencephalitis (SSPE), measles virus (MV) persists in neurons, resulting in a fatal chronic infection. MHC class I mRNA expression was examined in formalin-fixed brain tissue from 6 SSPE patients by in situ hybridization. In addition MHC class I protein expression in MV-infected neurons was examined in experimental Subacute Measles Encephalitis (SME) by double immunohistochemistry. MHC class I mRNA expression was found to be upregulated in SSPE tissues studied, and in 5 out of 6 cases the expression was definitively seen on neurons. The percentage of neurons expressing MHC class I mRNA ranged between 20 to 84% in infected areas. There was no correlation between the degree of infection and expression of MHC class I molecules on neurons. Importantly, the number of neurons co-expressing MHC class I and MV antigens was markedly low, varying between 2 to 8%. Similar results were obtained in SME where 20 to 30% of the neurons expressed MHC class I but < 8% co-expressed MHC class I and MV antigens. Perivascular infiltrating cells in the infected regions in SME expressed IFN{gamma} immunoreactivity. The results suggest that MV may not be directly involved in the induction of MHC class I on neurons and that cytokines such as IFN{gamma} may play an important role. Furthermore, the paucity of neurons co-expressing MHC class I and MV antigens in SSPE and SME suggests that such cells are either rapidly cleared by cytotoxic T lymphocytes (CTL), or, alternatively, lack of co-expression of MHC class I on MV infected neurons favors MV persistence in these cells by escaping CTL recognition. 33 refs., 3 figs., 3 tabs.

  3. A Case of Probable MHC Class II Deficiency with Disseminated BCGitis.

    PubMed

    Alyasin, Soheyla; Abolnezhadian, Farhad; Khoshkhui, Maryam

    2015-09-01

    Major histocompatibility complex (MHC) class II deficiency is a primary immunodeficiency disease characterized by abnormality of MHC class II molecules surface expression on peripheral blood lymphocytes and monocytes. Clinical manifestations include extreme susceptibility to viral, bacterial, and fungal infections but the immunodeficiency is not as severe as SCID (severe combined immunodeficiency), as evidenced by failure to develop disseminated infection after BCG vaccination. Therefore, MHC II deficiency with BCGosis, that is disseminated BCGitis, is not reported commonly. We report an interesting case of BCGosis after vaccination that was diagnosed to have probable MHC II deficiency. PMID:26412640

  4. Restriction fragment length polymorphism within the class I gene loci of the equine major histocompatibility complex

    SciTech Connect

    Alexander, A.J.; Bailey, E.; Woodward, J.G.

    1986-03-05

    Fourteen standard bred horses were serotyped as homozygous for 1 of 6 Equine Leukocyte Antigen (ELA) specificities. DNA was purified from peripheral leukocytes and digested with Hind III or Pvu II. Southern blot hybridization analysis was carried out using a /sup 32/P-labeled mouse cDNA probe (PH2IIa) specific for class I MHC genes. Both enzymes generated blots that contained a large number of bands (23 to 30) per horse. Significant polymorphism existed among most fragment sizes, while a dozen highly conserved band sizes suggested the presence of Qa/tla - like genes. Only 2 animals (both W6's) showed identical band patterns. Polymorphism was greatest between horses of different serotypes and was significantly decreased within serotypes. Unique bands were present on both blots for both W1's and W6's and may account for the serologic specificity seen in ELA W1 and W6 horses. This study is consistent with the findings in other higher vertebrates and implies that the MHC of the horse includes a highly polymorphic class I multigene family.

  5. T cell receptor recognition of a 'super-bulged' major histocompatibility complex class I-bound peptide

    SciTech Connect

    Tynan, Fleur E; Burrows, Scott R; Buckle, Ashley M; Clements, Craig S; Borg, Natalie A; Miles, John J; Beddoe, Travis; Whisstock, James C; Wilce, Matthew C; Silins, Sharon L; Burrows, Jacqueline M; Kjer-Nielsen, Lars; Kostenko, Lyudmila; Purcell, Anthony W; McCluskey, James; Rossjohn, Jamie

    2010-07-20

    Unusually long major histocompatibility complex (MHC) class I-restricted epitopes are important in immunity, but their 'bulged' conformation represents a potential obstacle to {alpha}{beta} T cell receptor (TCR)-MHC class I docking. To elucidate how such recognition is achieved while still preserving MHC restriction, we have determined here the structure of a TCR in complex with HLA-B*3508 presenting a peptide 13 amino acids in length. This complex was atypical of TCR-peptide-MHC class I interactions, being dominated at the interface by peptide-mediated interactions. The TCR assumed two distinct orientations, swiveling on top of the centrally bulged, rigid peptide such that only limited contacts were made with MHC class I. Although the TCR-peptide recognition resembled an antibody-antigen interaction, the TCR-MHC class I contacts defined a minimal 'generic footprint' of MHC-restriction. Thus our findings simultaneously demonstrate the considerable adaptability of the TCR and the 'shape' of MHC restriction.

  6. Two putative subunits of a peptide pump encoded in the human major histocompatability complex class 2 region

    SciTech Connect

    Bahram, S.; Arnold, D.; Bresnahan, M.; Strominger, J.L.; Spies, T. )

    1991-11-15

    The class 2 region of the human major histocompatibility complex (MHC) may encode several genes controlling the processing of endogenous antigen and the presentation of peptide epitopes by MHC class 1 molecules to cytotoxic T lymphocytes. A previously described peptide supply factor (PSF1) is a member of the multidrug-resistance family of transporters and may pump cytosolic peptides into the membrane-bound compartment where class 1 molecules assemble. A second transporter gene, PSF2, was identified 10 kilobases (kb) from PSF1, near the class 2 DOB gene. The complete sequences of PSF1 and PSF2 were determined from cDNA clones. The translation products are closely related in sequence and predicted secondary structure. Both contain a highly conserved ATP-binding fold and share 25% homology in a hydrophobic domain with a tentative number of eight membrane-spanning segments. Based on the principle dimeric organization of these two domains in other transporters, PSF1 and PSF2 may function as complementary subunits, independently as homodimers, or both. Taken together with previous genetic evidence, the coregulation of PSF1 and PSF2 by {gamma} interferon and the to-some-degree coordinate transcription of these genes suggest a common role in peptide-loading of class 1 molecules, although a distinct function of PSF2 cannot be ruled out.

  7. New horizons in mouse immunoinformatics: reliable in silico prediction of mouse class I histocompatibility major complex peptide binding affinity.

    PubMed

    Hattotuwagama, Channa K; Guan, Pingping; Doytchinova, Irini A; Flower, Darren R

    2004-11-21

    Quantitative structure-activity relationship (QSAR) analysis is a main cornerstone of modern informatic disciplines. Predictive computational models, based on QSAR technology, of peptide-major histocompatibility complex (MHC) binding affinity have now become a vital component of modern day computational immunovaccinology. Historically, such approaches have been built around semi-qualitative, classification methods, but these are now giving way to quantitative regression methods. The additive method, an established immunoinformatics technique for the quantitative prediction of peptide-protein affinity, was used here to identify the sequence dependence of peptide binding specificity for three mouse class I MHC alleles: H2-D(b), H2-K(b) and H2-K(k). As we show, in terms of reliability the resulting models represent a significant advance on existing methods. They can be used for the accurate prediction of T-cell epitopes and are freely available online ( http://www.jenner.ac.uk/MHCPred). PMID:15534705

  8. Activation of cytomegalovirus-specific CD8+ T-cell response by antibody-mediated peptide-major histocompatibility class I complexes

    PubMed Central

    Schmittnaegel, Martina; Klein, Christian; Levitsky, Victor; Knoetgen, Hendrik

    2016-01-01

    Imposing antigenicity on tumor cells is a key step toward successful cancer-immunotherapy. A cytomegalovirus-derived peptide recombinantly fused to a major histocompatibility class I complex and a monoclonal antibody can be targeted to tumor cells by antibody-mediated delivery and activate a strong and specific CD8+ T cell response. PMID:26942061

  9. MHC evolution in three salmonid species: a comparison between class II alpha and beta genes.

    PubMed

    Gómez, Daniela; Conejeros, Pablo; Marshall, Sergio H; Consuegra, Sofia

    2010-08-01

    The genes of the major histocompatibility complex (MHC) are amongst the most variable in vertebrates and represent some of the best candidates to study processes of adaptive evolution. However, despite the number of studies available, most of the information on the structure and function of these genes come from studies in mammals and birds in which the MHC class I and II genes are tightly linked and class II alpha exhibits low variability in many cases. Teleost fishes are among the most primitive vertebrates with MHC and represent good organisms for the study of MHC evolution because their class I and class II loci are not physically linked, allowing for independent evolution of both classes of genes. We have compared the diversity and molecular mechanisms of evolution of classical MH class II alpha and class II beta loci in farm populations of three salmonid species: Oncorhynchus kisutch, Oncorhynchus mykiss and Salmo salar. We found single classical class II loci and high polymorphism at both class II alpha and beta genes in the three species. Mechanisms of evolution were common for both class II genes, with recombination and point mutation involved in generating diversity and positive selection acting on the peptide-binding residues. These results suggest that the maintenance of variability at the class IIalpha gene could be a mechanism to increase diversity in the MHC class II in salmonids in order to compensate for the expression of one single classical locus and to respond to a wider array of parasites. PMID:20521040

  10. Dissociation of β2-microglobulin determines the surface quality control of major histocompatibility complex class I molecules.

    PubMed

    Montealegre, Sebastián; Venugopalan, Vaishnavi; Fritzsche, Susanne; Kulicke, Corinna; Hein, Zeynep; Springer, Sebastian

    2015-07-01

    Major histocompatibility complex class I proteins, which present antigenic peptides to cytotoxic T lymphocytes at the surface of all nucleated cells, are endocytosed and destroyed rapidly once their peptide ligand has dissociated. The molecular mechanism of this cellular quality control process, which prevents rebinding of exogenous peptides and thus erroneous immune responses, is unknown. To identify the nature of the decisive step in endocytic sorting of class I molecules and its location, we have followed the removal of optimally and suboptimally peptide-loaded murine H-2K(b) class I proteins from the cell surface. We find that the binding of their light chain, β2-microglobulin (β2m), protects them from endocytic destruction. Thus, the extended survival of suboptimally loaded K(b) molecules at 25°C is attributed to decreased dissociation of β2m. Because all forms of K(b) are constantly internalized but little β2m-receptive heavy chain is present at the cell surface, it is likely that β2m dissociation and recognition of the heavy chain for lysosomal degradation take place in an endocytic compartment. PMID:25782992

  11. Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules.

    PubMed

    Parham, Peter; Norman, Paul J; Abi-Rached, Laurent; Guethlein, Lisbeth A

    2012-03-19

    In placental mammals, natural killer (NK) cells are a population of lymphocytes that make unique contributions to immune defence and reproduction, functions essential for survival of individuals, populations and species. Modulating these functions are conserved and variable NK-cell receptors that recognize epitopes of major histocompatibility complex (MHC) class I molecules. In humans, for example, recognition of human leucocyte antigen (HLA)-E by the CD94:NKG2A receptor is conserved, whereas recognition of HLA-A, B and C by the killer cell immunoglobulin-like receptors (KIRs) is diversified. Competing demands of the immune and reproductive systems, and of T-cell and NK-cell immunity-combined with the segregation on different chromosomes of variable NK-cell receptors and their MHC class I ligands-drive an unusually rapid evolution that has resulted in unprecedented levels of species specificity, as first appreciated from comparison of mice and humans. Counterparts to human KIR are present only in simian primates. Observed in these species is the coevolution of KIR and the four MHC class I epitopes to which human KIR recognition is restricted. Unique to hominids is the emergence of the MHC-C locus as a supplier of specialized and superior ligands for KIR. This evolutionary trend is most highly elaborated in the chimpanzee. Unique to the human KIR locus are two groups of KIR haplotypes that are present in all human populations and subject to balancing selection. Group A KIR haplotypes resemble chimpanzee KIR haplotypes and are enriched for genes encoding KIR that bind HLA class I, whereas group B KIR haplotypes are enriched for genes encoding receptors with diminished capacity to bind HLA class I. Correlating with their balance in human populations, B haplotypes favour reproductive success, whereas A haplotypes favour successful immune defence. Evolution of the B KIR haplotypes is thus unique to the human species. PMID:22312047

  12. Pathogenicity of Bovine Neonatal Pancytopenia-associated vaccine-induced alloantibodies correlates with Major Histocompatibility Complex class I expression

    PubMed Central

    Benedictus, Lindert; Luteijn, Rutger D.; Otten, Henny; Jan Lebbink, Robert; van Kooten, Peter J. S.; Wiertz, Emmanuel J. H. J.; Rutten, Victor P. M. G.; Koets, Ad P.

    2015-01-01

    Bovine Neonatal Pancytopenia (BNP), a fatal bleeding syndrome of neonatal calves, is caused by maternal alloantibodies absorbed from colostrum and is characterized by lymphocytopenia, thrombocytopenia and bone marrow hypoplasia. An inactivated viral vaccine is the likely source of alloantigens inducing BNP-associated alloantibodies in the dam. In this study the specificity of BNP alloantibodies was assessed and was linked to the pathology of BNP. We demonstrated that Major Histocompatibility Complex class I (MHC I) and Very Late Antigen-3, an integrin α3/β1 heterodimer, were the major targets of BNP alloantibodies. However, alloantibody binding to various bovine cell types correlated with MHC I expression, rather than integrin β1 or α3 expression. Likewise, alloantibody-dependent complement-mediated cell lysis correlated strongly with MHC I expression. Examination of several tissues of third trimester bovine foetuses revealed that cells, shown to be affected in calves with BNP, were characterized by high MHC class I expression and high levels of alloantibody binding. We conclude that in spite of the heterogeneous specificity of BNP associated maternal alloantibodies, MHC I-specific antibodies mediate the pathogenicity of BNP in the calf and that cells with high MHC I expression were preferentially affected in BNP. PMID:26235972

  13. Proteasome Subtypes and Regulators in the Processing of Antigenic Peptides Presented by Class I Molecules of the Major Histocompatibility Complex

    PubMed Central

    Vigneron, Nathalie; Van den Eynde, Benoît J.

    2014-01-01

    The proteasome is responsible for the breakdown of cellular proteins. Proteins targeted for degradation are allowed inside the proteasome particle, where they are cleaved into small peptides and released in the cytosol to be degraded into amino acids. In vertebrates, some of these peptides escape degradation in the cytosol, are loaded onto class I molecules of the major histocompatibility complex (MHC) and displayed at the cell surface for scrutiny by the immune system. The proteasome therefore plays a key role for the immune system: it provides a continued sampling of intracellular proteins, so that CD8-positive T-lymphocytes can kill cells expressing viral or tumoral proteins. Consequently, the repertoire of peptides displayed by MHC class I molecules at the cell surface depends on proteasome activity, which may vary according to the presence of proteasome subtypes and regulators. Besides standard proteasomes, cells may contain immunoproteasomes, intermediate proteasomes and thymoproteasomes. Cells may also contain regulators of proteasome activity, such as the 19S, PA28 and PA200 regulators. Here, we review the effects of these proteasome subtypes and regulators on the production of antigenic peptides. We also discuss an unexpected function of the proteasome discovered through the study of antigenic peptides: its ability to splice peptides. PMID:25412285

  14. Amino Acid Polymorphisms in Hepatitis C Virus Core Affect Infectious Virus Production and Major Histocompatibility Complex Class I Molecule Expression.

    PubMed

    Tasaka-Fujita, Megumi; Sugiyama, Nao; Kang, Wonseok; Masaki, Takahiro; Masaski, Takahiro; Murayama, Asako; Yamada, Norie; Sugiyama, Ryuichi; Tsukuda, Senko; Watashi, Koichi; Asahina, Yasuhiro; Sakamoto, Naoya; Wakita, Takaji; Shin, Eui-Cheol; Kato, Takanobu

    2015-01-01

    Amino acid (aa) polymorphisms in the hepatitis C virus (HCV) genotype 1b core protein have been reported to be a potent predictor for poor response to interferon (IFN)-based therapy and a risk factor for hepatocarcinogenesis. We investigated the effects of these polymorphisms with genotype 1b/2a chimeric viruses that contained polymorphisms of Arg/Gln at aa 70 and Leu/Met at aa 91. We found that infectious virus production was reduced in cells transfected with chimeric virus RNA that had Gln at aa 70 (aa70Q) compared with RNA with Arg at aa 70 (aa70R). Using flow cytometry analysis, we confirmed that HCV core protein accumulated in aa70Q clone transfected cells, and it caused a reduction in cell-surface expression of major histocompatibility complex (MHC) class I molecules induced by IFN treatment through enhanced protein kinase R phosphorylation. We could not detect any effects due to the polymorphism at aa 91. In conclusion, the polymorphism at aa 70 was associated with efficiency of infectious virus production, and this deteriorated virus production in strains with aa70Q resulted in the intracellular accumulation of HCV proteins and attenuation of MHC class I molecule expression. These observations may explain the strain-associated resistance to IFN-based therapy and hepatocarcinogenesis of HCV. PMID:26365522

  15. Characterization and expression of MHC class II alpha and II beta genes in mangrove red snapper (Lutjanus argentimaculatus).

    PubMed

    Wang, Tianyan; Tan, Shangjin; Cai, Zhonghua

    2015-12-01

    The major histocompatibility complex (MHC) class II plays a key role in adaptive immunity by presenting foreign peptides to CD4(+) T cells and by triggering the adaptive immune response. While the structure and function of MHC class II have been well characterized in mammalian, limited research has been done on fishes. In this study, we characterized the gene structure and expression of MHC class II α (Lunar-DAA) and II β (Lunar-DAB) of mangrove red snapper (Lutjanus argentimaculatus). Both genes shared, respectively, a high similarity and typical features with other vertebrate MHC class II α and II β. The phylogenetic analysis of the deduced peptides revealed that both Lunar-DAA and Lunar-DAB were located in the teleost subclass. Western blotting analyses indicated that both MHC class II α and II β were expressed ubiquitously in immune-related cells, tissues and organs, and that MHC class II α and II β chains existed mainly as heterodimers. While it was highly expressed in gills, thymus, head kidney (HK), spleen, head kidney macrophage and spleen leucocytes, MHC class II β chain was expressed with a low abundance in skin, intestine, stomach and heart. The highest expression of MHC class II β in thymus confirmed the conclusion that thymus is one of the primary lymphoid organs in fishes. The detection of MHC class II αβ dimers in HK macrophages and spleen leucocytes indicated that HK macrophages and spleen leucocytes play a critical role in the adaptive immunity in fishes. All these results provide valuable information for understanding the structure of MHC class II α and II β and their function in immune responses. PMID:26454477

  16. Regulation of calreticulin–major histocompatibility complex (MHC) class I interactions by ATP

    PubMed Central

    Wijeyesakere, Sanjeeva Joseph; Gagnon, Jessica K.; Arora, Karunesh; Brooks, Charles L.; Raghavan, Malini

    2015-01-01

    The MHC class I peptide loading complex (PLC) facilitates the assembly of MHC class I molecules with peptides, but factors that regulate the stability and dynamics of the assembly complex are largely uncharacterized. Based on initial findings that ATP, in addition to MHC class I-specific peptide, is able to induce MHC class I dissociation from the PLC, we investigated the interaction of ATP with the chaperone calreticulin, an endoplasmic reticulum (ER) luminal, calcium-binding component of the PLC that is known to bind ATP. We combined computational and experimental measurements to identify residues within the globular domain of calreticulin, in proximity to the high-affinity calcium-binding site, that are important for high-affinity ATP binding and for ATPase activity. High-affinity calcium binding by calreticulin is required for optimal nucleotide binding, but both ATP and ADP destabilize enthalpy-driven high-affinity calcium binding to calreticulin. ATP also selectively destabilizes the interaction of calreticulin with cellular substrates, including MHC class I molecules. Calreticulin mutants that affect ATP or high-affinity calcium binding display prolonged associations with monoglucosylated forms of cellular MHC class I, delaying MHC class I dissociation from the PLC and their transit through the secretory pathway. These studies reveal central roles for ATP and calcium binding as regulators of calreticulin–substrate interactions and as key determinants of PLC dynamics. PMID:26420867

  17. Immunological Functions of the Membrane Proximal Region of MHC Class II Molecules

    PubMed Central

    Harton, Jonathan; Jin, Lei; Hahn, Amy; Drake, Jim

    2016-01-01

    Major histocompatibility complex (MHC) class II molecules present exogenously derived antigen peptides to CD4 T cells, driving activation of naïve T cells and supporting CD4-driven immune functions. However, MHC class II molecules are not inert protein pedestals that simply bind and present peptides. These molecules also serve as multi-functional signaling molecules delivering activation, differentiation, or death signals (or a combination of these) to B cells, macrophages, as well as MHC class II-expressing T cells and tumor cells. Although multiple proteins are known to associate with MHC class II, interaction with STING (stimulator of interferon genes) and CD79 is essential for signaling. In addition, alternative transmembrane domain pairing between class II α and β chains influences association with membrane lipid sub-domains, impacting both signaling and antigen presentation. In contrast to the membrane-distal region of the class II molecule responsible for peptide binding and T-cell receptor engagement, the membrane-proximal region (composed of the connecting peptide, transmembrane domain, and cytoplasmic tail) mediates these “non-traditional” class II functions. Here, we review the literature on the function of the membrane-proximal region of the MHC class II molecule and discuss the impact of this aspect of class II immunobiology on immune regulation and human disease. PMID:27006762

  18. MHC Class II Auto-Antigen Presentation is Unconventional

    PubMed Central

    Sadegh-Nasseri, Scheherazade; Kim, AeRyon

    2015-01-01

    Antigen presentation is highly critical in adoptive immunity. Only by interacting with antigens presented by major histocompatibility complex class II molecules, helper T cells can be stimulated to fight infections or diseases. The degradation of a full protein into small peptide fragments bound to class II molecules is a dynamic, lengthy process consisting of many steps and chaperons. Deregulation in any step of antigen processing could lead to the development of self-reactive T cells or defective immune response to pathogens. Indeed, human leukocyte antigens class II genes are the predominant contributors to susceptibility to autoimmune diseases. Conventional antigen-processing calls for internalization of extracellular antigens followed by processing and epitope selection within antigen-processing subcellular compartments, enriched with all necessary accessory molecules, processing enzymes, and proper pH and denaturing conditions. However, recent data examining the temporal relationship between antigen uptakes, processing, and epitope selection revealed unexpected characteristics for auto-antigenic epitopes, which were not shared with antigenic epitopes from pathogens. This review provides a discussion of the relevance of these findings to the mechanisms of autoimmunity. PMID:26257739

  19. Soluble histocompatibility class I antigens and beta 2-microglobulin in pregnant females and cord blood samples.

    PubMed

    Inostroza, J; Ferrada, J; Navarrete, C; Sorensen, R U

    1997-04-15

    Pregnancy can be considered a successful transplantation of allogeneic paternal tissue to the mother. Soluble HLA class I serum levels have been found to increase during solid organ rejection episodes and during graft-versus-host disease after bone marrow transplantation. We wished to determine whether significant changes in sHLA class I and beta 2-microglobulin light chain levels occurred during pregnancy, because these may reflect adaptive changes permitting the acceptance of the fetal graft. Serum samples were obtained from women at different stages of pregnancy and in the postpartum period. Cord blood samples and serum samples from nonpregnant female and male controls living in the same geographic area in Southern Chile were also studied. The levels of sHLA class I heterodimers were determined by an ELISA sandwich technique; beta 2-microglobulin levels were measured by MEIA IMX-Abbott. There was a significant elevation of sHLA class I levels in the first 2 trimesters of pregnancy, followed by a significant drop below normal levels at the end of pregnancy, with normalization in the post-partum period. beta 2-microglobulin levels did not change significantly during pregnancy and did not correlate with sHLA class I levels. In cord blood samples, sHLA class I levels were lower and beta 2-microglobulin levels higher than those of adult controls and of mothers at the time of delivery. The variations in sHLA class I levels during pregnancy may reflect or contribute to immunoregulatory events related to the acceptance of the fetal graft. PMID:9154459

  20. FCRL6 is an MHC class II receptor1

    PubMed Central

    Schreeder, Daniel M.; Cannon, John P.; Wu, Jiongru; Li, Ran; Shakhmatov, Mikhail A.; Davis, Randall S.

    2016-01-01

    Receptors for the Fc portion (FCR) of Ig have been extensively characterized and are known to regulate humoral responses, but members of the closely related FCR-like (FCRL) family have not been found to bind Ig and to date no ligand has been identified for any FCRL. Using a cell-based GFP reporter system and a recombinant Fc chimeric protein, we show that human FCRL6, a receptor selectively expressed by cytotoxic T and NK cells, directly binds HLA-DR, a major histocompatibility complex (MHC) class II molecule. Given the similarity among constant regions of Ig and MHC molecules, these findings suggest that representatives of the FCR and FCRL multigene families may have independently evolved to engage two ancestral elements fundamental to adaptive immunity. This discovery may offer new insight into the interaction between cytotoxic lymphocytes and antigen presenting cells and may have important implications for better understanding HLA disease susceptibility and pathogenesis. PMID:20519654

  1. Unusual evolutionary conservation and frequent DNA segment exchange in class I genes of the major histocompatibility complex.

    PubMed Central

    Hayashida, H; Miyata, T

    1983-01-01

    From comparisons of homologous DNA sequences for many different genes, it was shown that the silent positions of protein-encoding regions and introns evolve at high and remarkably similar rates for different genes. In addition, both silent positions and introns behave like clocks; they accumulated base substitutions at approximately constant rates with respect to geological time. The rates of evolution were estimated to be 5.5 X 10(-9), 3.7 X 10(-9), and 5.3 X 10(-9) per site per year for silent positions, short introns (less than approximately equal to 300 base pairs), and long introns (more than approximately equal to 500 base pairs), respectively. Contrary to expectation from the evolutionary clocks, DNA sequence comparison between pHLA 12.4 (a cloned HLA sequence) of man and Ld together with other H-2 genes of mouse, the class I genes of the major histocompatibility complex, revealed a surprisingly small amount of base substitution for both the introns and the silent positions; the degree of divergence is only about 60% of that of standard genes in the same species comparison. Furthermore, several segmental homologies have been observed between the class I genes of mouse, suggesting the frequent occurrence of gene conversion or double unequal crossing-over in evolution. Interrelations between the extreme polymorphism of the class I genes, the low evolutionary drift of the introns and the silent positions, and the frequent gene conversion or unequal crossing-over within the mouse genes are discussed. PMID:6573677

  2. Constraints within major histocompatibility complex class I restricted peptides: Presentation and consequences for T-cell recognition

    SciTech Connect

    Theodossis, Alex; Guillonneau, Carole; Welland, Andrew; Ely, Lauren K.; Clements, Craig S.; Williamson, Nicholas A.; Webb, Andrew I.; Wilce, Jacqueline A.; Mulder, Roger J.; Dunstone, Michelle A.; Doherty, Peter C.; McCluskey, James; Purcell, Anthony W.; Turner, Stephen J.; Rossjohn, Jamie

    2010-03-24

    Residues within processed protein fragments bound to major histocompatibility complex class I (MHC-I) glycoproteins have been considered to function as a series of 'independent pegs' that either anchor the peptide (p) to the MHC-I and/or interact with the spectrum of {alpha}{beta}-T-cell receptors (TCRs) specific for the pMHC-I epitope in question. Mining of the extensive pMHC-I structural database established that many self- and viral peptides show extensive and direct interresidue interactions, an unexpected finding that has led us to the idea of 'constrained' peptides. Mutational analysis of two constrained peptides (the HLA B44 restricted self-peptide (B44DP{alpha}-EEFGRAFSF)) and an H2-D{sup b} restricted influenza peptide (D{sup b}PA, SSLENFRAYV) demonstrated that the conformation of the prominently exposed arginine in both peptides was governed by interactions with MHC-I-orientated flanking residues from the peptide itself. Using reverse genetics in a murine influenza model, we revealed that mutation of an MHC-I-orientated residue (SSLENFRAYV {yields} SSLENARAYV) within the constrained PA peptide resulted in a diminished cytotoxic T lymphocyte (CTL) response and the recruitment of a limited pMHC-I specific TCR repertoire. Interactions between individual peptide positions can thus impose fine control on the conformation of pMHC-I epitopes, whereas the perturbation of such constraints can lead to a previously unappreciated mechanism of viral escape.

  3. Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain.

    PubMed

    Lazarczyk, Maciej J; Kemmler, Julia E; Eyford, Brett A; Short, Jennifer A; Varghese, Merina; Sowa, Allison; Dickstein, Daniel R; Yuk, Frank J; Puri, Rishi; Biron, Kaan E; Leist, Marcel; Jefferies, Wilfred A; Dickstein, Dara L

    2016-01-01

    Major histocompatibility complex class I (MHCI) proteins have been implicated in neuronal function through the modulation of neuritogenesis, synaptogenesis, synaptic plasticity, and memory consolidation during development. However, the involvement of MHCI in the aged brain is unclear. Here we demonstrate that MHCI deficiency results in significant dendritic atrophy along with an increase in thin dendritic spines and a reduction in stubby spines in the hippocampus of aged (12 month old) mice. Ultrastructural analyses revealed a decrease in spine head diameter and post synaptic density (PSD) area, as well as an increase in overall synapse density, and non-perforated, small spines. Interestingly, we found that the changes in synapse density and morphology appear relatively late (after the age of 6 months). Finally, we found a significant age dependent increase in the levels of the glutamate receptor, GluN2B in aged MHCI knockout mice, with no change in GluA2/3, VGluT1, PSD95 or synaptophysin. These results indicate that MHCI may be also be involved in maintaining brain integrity at post-developmental stages notably in the modulation of neuronal and spine morphology and synaptic function during non-pathological aging which could have significant implications for cognitive function. PMID:27229916

  4. Major Histocompatibility Complex class I proteins are critical for maintaining neuronal structural complexity in the aging brain

    PubMed Central

    Lazarczyk, Maciej J.; Kemmler, Julia E.; Eyford, Brett A.; Short, Jennifer A.; Varghese, Merina; Sowa, Allison; Dickstein, Daniel R.; Yuk, Frank J.; Puri, Rishi; Biron, Kaan E.; Leist, Marcel; Jefferies, Wilfred A.; Dickstein, Dara L.

    2016-01-01

    Major histocompatibility complex class I (MHCI) proteins have been implicated in neuronal function through the modulation of neuritogenesis, synaptogenesis, synaptic plasticity, and memory consolidation during development. However, the involvement of MHCI in the aged brain is unclear. Here we demonstrate that MHCI deficiency results in significant dendritic atrophy along with an increase in thin dendritic spines and a reduction in stubby spines in the hippocampus of aged (12 month old) mice. Ultrastructural analyses revealed a decrease in spine head diameter and post synaptic density (PSD) area, as well as an increase in overall synapse density, and non-perforated, small spines. Interestingly, we found that the changes in synapse density and morphology appear relatively late (after the age of 6 months). Finally, we found a significant age dependent increase in the levels of the glutamate receptor, GluN2B in aged MHCI knockout mice, with no change in GluA2/3, VGluT1, PSD95 or synaptophysin. These results indicate that MHCI may be also be involved in maintaining brain integrity at post-developmental stages notably in the modulation of neuronal and spine morphology and synaptic function during non-pathological aging which could have significant implications for cognitive function. PMID:27229916

  5. Elevation of soluble major histocompatibility complex class I related chain A protein in malignant and infectious diseases in Chinese patients

    PubMed Central

    2012-01-01

    Background Elevation of soluble major histocompatibility complex class I chain-related gene A (sMICA) products in serum has been linked to tissue/organ transplantation, autoimmune diseases and some malignant disorders. Cells infected by microbiological pathogens may release sMICA, whereas less is known whether and to what extent serum sMICA levels may change in infectious diseases. Methods The present study determined serum sMICA levels by enzyme-linked immunosorbent assay (ELISA) in a southern China population, including patients (n = 1041) suffering from several types of malignant and infectious diseases and healthy controls (n = 141). Results Relative to controls, serum sMICA elevation was significant in patients of hepatic cancer, and was approaching statistical significance in patients with lung, gastric and nasopharyngeal cancers. sMICA elevation was also associated with some bacterial (Enterobacteriaceae, Mycobacterium tuberculosis, non-fermenting Gram-negative bacteria and Gram-positive cocci), viral (hepatitis B and C) and the Microspironema pallidum infections. Conclusion Serum sMICA levels may be informative for the diagnosis of some malignant and infectious diseases. The results also indicate that microbiological infections should be considered as a potential confounding clinical condition causing serum sMICA elevation while using this test to evaluate the status of other disorders, such as cancers, host-graft response and autoimmune diseases. PMID:23181907

  6. MOLECULAR GENETICS OF THE SWINE MAJOR HISTOCOMPATIBILITY COMPLEX, THE SLA COMPLEX

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The swine major histocompatibility complex (MHC) or swine leukocyte antigen (SLA) complex is one of the most gene-dense regions in the swine genome. It consists of three major gene clusters, the SLA class I, class III and class II regions, that span ~1.1, 0.7 and 0.5 Mb, respectively, making the swi...

  7. Time-resolved fluorescence anisotropy and fluctuation correlation analysis of major histocompatibility complex class I proteins in fibroblast cells.

    PubMed

    Heikal, Ahmed A

    2014-03-15

    Major histocompatibility complex class I proteins, MHC(I), are expressed in almost all nucleated cells and synthesized in the endoplasmic reticulum (ER). The orientation and mobility of these complexes are crucial in their biological function in the immune system, i.e., the cytosolic pathogen peptides loading and their presentation to T-cell receptors at the plasma membrane, where cell destruction is triggered. Here, we investigate the structural flexibility and associations of GFP-encoded MHC(I) alleles (H2L(d)), namely H2L(d)GFPin and H2L(d)GFPout, in cultured mouse fibroblast cells. Time-resolved fluorescence anisotropy of H2L(d)GFPin in the ER indicates a dominant overall tumbling motion of 56±7 ns (ER), with a fast conformational flexibility, as compared with a restricted rotation of H2L(d)GFPout. At the single-molecule level, the diffusion coefficient of H2L(d)GFPin and H2L(d)GFPout in the ER is (1.8±0.5)×10(-9) and (2.1±0.6)×10(-9) cm(2)/s, respectively, as revealed by fluorescence correlation spectroscopy. A complementary immunoblotting of H2L(d)GFP constructs, isolated from mouse fibroblast cells, reveals band at 75 kDa as compared with 29 kDa of the free EGFP. These real-time dynamics provide new insights into the structural flexibility and intracellular associations of GFP-labeled MHC(I) alleles (H2L(d)) in living cells. PMID:23811298

  8. Molecular Architecture of the Major Histocompatibility Complex Class I-Binding Site of Ly49 Natural Killer Cell Receptors

    SciTech Connect

    Deng,L.; Cho, S.; Malchiodi, E.; Kerzic, M.; Dam, J.; Mariuzza, R.

    2008-01-01

    Natural killer (NK) cells play a vital role in the detection and destruction of virally infected and tumor cells during innate immune responses. The highly polymorphic Ly49 family of NK receptors regulates NK cell function by sensing major histocompatibility complex class I (MHC-I) molecules on target cells. Despite the determination of two Ly49-MHC-I complex structures, the molecular features of Ly49 receptors that confer specificity for particular MHC-I alleles have not been identified. To understand the functional architecture of Ly49-binding sites, we determined the crystal structures of Ly49C and Ly49G and completed refinement of the Ly49C-H-2Kb complex. This information, combined with mutational analysis of Ly49A, permitted a structure-based classification of Ly49s that we used to dissect the binding site into three distinct regions, each having different roles in MHC recognition. One region, located at the center of the binding site, has a similar structure across the Ly49 family and mediates conserved interactions with MHC-I that contribute most to binding. However, the preference of individual Ly49s for particular MHC-I molecules is governed by two regions that flank the central region and are structurally more variable. One of the flanking regions divides Ly49s into those that recognize both H-2D and H-2K versus only H-2D ligands, whereas the other discriminates among H-2D or H-2K alleles. The modular design of Ly49-binding sites provides a framework for predicting the MHC-binding specificity of Ly49s that have not been characterized experimentally.

  9. Murine cytomegalovirus perturbs endosomal trafficking of major histocompatibility complex class I molecules in the early phase of infection.

    PubMed

    Tomas, Maja Ilić; Kucić, Natalia; Mahmutefendić, Hana; Blagojević, Gordana; Lucin, Pero

    2010-11-01

    Murine cytomegalovirus (MCMV) functions interfere with protein trafficking in the secretory pathway. In this report we used Δm138-MCMV, a recombinant virus with a deleted viral Fc receptor, to demonstrate that MCMV also perturbs endosomal trafficking in the early phase of infection. This perturbation had a striking impact on cell surface-resident major histocompatibility complex class I (MHC-I) molecules due to the complementary effect of MCMV immunoevasins, which block their egress from the secretory pathway. In infected cells, constitutively endocytosed cell surface-resident MHC-I molecules were arrested and retained in early endosomal antigen 1 (EEA1)-positive and lysobisphosphatidic acid (LBPA)-negative perinuclear endosomes together with clathrin-dependent cargo (transferrin receptor, Lamp1, and epidermal growth factor receptor). Their progression from these endosomes into recycling and degradative routes was inhibited. This arrest was associated with a reduction of the intracellular content of Rab7 and Rab11, small GTPases that are essential for the maturation of recycling and endolysosomal domains of early endosomes. The reduced recycling of MHC-I in Δm138-MCMV-infected cells was accompanied by their accelerated loss from the cell surface. The MCMV function that affects cell surface-resident MHC-I was activated in later stages of the early phase of viral replication, after the expression of known immunoevasins. MCMV without the three immunoevasins (the m04, m06, and m152 proteins) encoded a function that affects endosomal trafficking. This function, however, was not sufficient to reduce the cell surface expression of MHC-I in the absence of the transport block in the secretory pathway. PMID:20719942

  10. Archaebacterial class I and class II aldolases from extreme halophiles.

    PubMed

    Altekar, W; Dhar, N M

    1988-01-01

    Both, class I (Schiff-base forming) and class II (metal requiring) fructose biphosphate aldolases were found to be distributed among halophilic archaebacteria. The aldolase activity from Halobacteriium halobium, H. salinarium, H. cutirubrum, H. mediterranei and H. volcanii exhibited properties of a bacterial class II aldolase as it was metal-dependent for activity and therefore inhibited by EDTA. In contrast, aldolase from H. saccharovorum, Halobacterium R-113, H. vallismortis and Halobacterium CH-1 formed a Schiff-base intermediate with the substrate and therefore resembled to eukaryotic class I type. The type of aldolase did not vary by changes in the growth medium. PMID:11536602

  11. Archaebacterial class I and class II aldolases from extreme halophiles

    NASA Astrophysics Data System (ADS)

    Alterkar, Wijaya; Dhar, Nenoo M.

    1988-03-01

    Both, class I (Schiff-base forming) and class II (metal requiring) fructose biphosphate aldolases were found to be distributed among halophilic archaebacteria. The aldolase activity fromHalobacterium halobium, H. salinarium, H. cutirubrum, H. mediterranei andH. volcanii exhibited properties of a bacterial class II aldolase as it was metal-dependent for activity and therefore inhibited by EDTA. In contrast, aldolase fromH. saccharovorum, Halobacterium R-113, H. vallismortis andHalobacterium CH-1 formed a Schiff-base intermediate with the substrate and therefore resembled to eukaryotic class I type. The type of aldolase did not vary by changes in the growth medium.

  12. DNA sequence of the Peromyscus leucopus MHC class II gene Aa (MhcPeleAa)

    SciTech Connect

    Crew, M.D.; Bates, L.M.

    1996-09-01

    The genus Peromyscus has been extensively studied by populations biologists and ecologists for over eighty years, with P. leucopus (the white-footed mouse) being one of the most intensively investigated species. Polymorphic major histocompatibility complex (MHC) genes have proven useful in population genetic studies and might be helpful in understanding the population dynamics of Peromyscus species which are ubiquitously distributed over North and Central America. Polymorphism of P. leucopus MHC (MhcPele) class II genes was evident by restriction fragment length polymorphism (RFLP) analyses using human and mouse probes and Pele class II loci exhibited degrees of polymorphism similar to H2 class II genes (A-like>E-like). 8 refs., 2 figs.

  13. Role of Plasmacytoid Dendritic Cells for Aberrant Class II Expression in Exocrine Glands from Estrogen-Deficient Mice of Healthy Background

    PubMed Central

    Arakaki, Rieko; Nagaoka, Ai; Ishimaru, Naozumi; Yamada, Akiko; Yoshida, Satoko; Hayashi, Yoshio

    2009-01-01

    Although it has been well documented that aberrant major histocompatibility complex class II molecules may contribute to the development of autoimmune disorders, the precise mechanisms responsible for their tissue-specific expression remain unknown. Here we show that estrogen deficiency induces aberrant class II major histocompatibility complex expression in exocrine glands via interactions between epithelial cells and plasmacytoid dendritic cells. Relatively modest but functionally significant expression levels of major histocompatibility complex class II and class II transactivator molecules were observed in the exocrine glands of ovariectomized (Ovx) C57BL/6 (B6) mice, but were not seen in the exocrine glands of control B6 mice. We observed that the salivary dendritic cells adjacent to the apoptotic epithelial cells positive for terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling, were activated in Ovx mice, but were not activated in control mice. We obtained evidence that the salivary gland cells express both interferon regulatory factor-1 and class II transactivator type IV molecules in Ovx mice. Salivary gland cells from Ovx mice were also capable of inducing the activation of antigen-specific T cells from OT-II transgenic mice. These findings indicate that estrogen deficiency initiates class II transactivator type IV mRNA expression in exocrine glands via interactions between epithelial cells and plasmacytoid dendritic cells, suggesting that plasmacytoid dendritic cells play a pivotal role in gender-based autoimmune disorders in postmenopausal women. PMID:19359524

  14. Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells

    PubMed Central

    Weiler, Andrea M.; Das, Arpita; Akinyosoye, Oluwasayo; Cui, Sherry; O'Connor, Shelby L.; Scheef, Elizabeth A.; Reed, Jason S.; Panganiban, Antonito T.; Sacha, Jonah B.; Rakasz, Eva G.; Friedrich, Thomas C.

    2015-01-01

    Nef-specific CD8+ T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef165–173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T170I, unexpectedly and uniquely degraded Nef's major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication. PMID:26637459

  15. Acute Viral Escape Selectively Impairs Nef-Mediated Major Histocompatibility Complex Class I Downmodulation and Increases Susceptibility to Antiviral T Cells.

    PubMed

    Weiler, Andrea M; Das, Arpita; Akinyosoye, Oluwasayo; Cui, Sherry; O'Connor, Shelby L; Scheef, Elizabeth A; Reed, Jason S; Panganiban, Antonito T; Sacha, Jonah B; Rakasz, Eva G; Friedrich, Thomas C; Maness, Nicholas J

    2016-02-01

    Nef-specific CD8(+) T lymphocytes (CD8TL) are associated with control of simian immunodeficiency virus (SIV) despite extensive nef variation between and within animals. Deep viral sequencing of the immunodominant Mamu-B*017:01-restricted Nef165-173IW9 epitope revealed highly restricted evolution. A common acute escape variant, T170I, unexpectedly and uniquely degraded Nef's major histocompatibility complex class I (MHC-I) downregulatory capacity, rendering the virus more vulnerable to CD8TL targeting other epitopes. These data aid in a mechanistic understanding of Nef functions and suggest means of immunity-mediated control of lentivirus replication. PMID:26637459

  16. ALVAC-SIV-gag-pol-env-Based Vaccination and Macaque Major Histocompatibility Complex Class I (A*01) Delay Simian Immunodeficiency Virus SIVmac-Induced Immunodeficiency

    PubMed Central

    Pal, R.; Venzon, D.; Letvin, N. L.; Santra, S.; Montefiori, D. C.; Miller, N. R.; Tryniszewska, E.; Lewis, M. G.; VanCott, T. C.; Hirsch, V.; Woodward, R.; Gibson, A.; Grace, M.; Dobratz, E.; Markham, P. D.; Hel, Z.; Nacsa, J.; Klein, M.; Tartaglia, J.; Franchini, G.

    2002-01-01

    T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination- and infection-induced T-cell responses are dependent on the host major histocompatibility complex classes I and II (MHC-I and MHC-II) antigens. Here we report that both inherent, host-dependent immune responses to SIVmac251 infection and vaccination-induced immune responses to viral antigens were able to reduce virus replication and/or CD4+ T-cell loss. Both the presence of the MHC-I Mamu-A*01 genotype and vaccination of rhesus macaques with ALVAC-SIV-gag-pol-env (ALVAC-SIV-gpe) contributed to the restriction of SIVmac251 replication during primary infection, preservation of CD4+ T cells, and delayed disease progression following intrarectal challenge exposure of the animals to SIVmac251 (561). ALVAC-SIV-gpe immunization induced cytotoxic T-lymphocyte (CTL) responses cumulatively in 67% of the immunized animals. Following viral challenge, a significant secondary virus-specific CD8+ T-cell response was observed in the vaccinated macaques. In the same immunized macaques, a decrease in virus load during primary infection (P = 0.0078) and protection from CD4 loss during both acute and chronic phases of infection (P = 0.0099 and P = 0.03, respectively) were observed. A trend for enhanced survival of the vaccinated macaques was also observed. Neither boosting the ALVAC-SIV-gpe with gp120 immunizations nor administering the vaccine by the combination of mucosal and systemic immunization routes increased significantly the protective effect of the ALVAC-SIV-gpe vaccine. While assessing the role of MHC-I Mamu-A*01 alone in the restriction of viremia following challenge of nonvaccinated animals with other SIV isolates, we observed that the virus load was not significantly lower in Mamu-A*01-positive macaques following intravenous challenge with either SIVmac251 (561) or

  17. Endoplasmic reticulum aminopeptidase 1 function and its pathogenic role in regulating innate and adaptive immunity in cancer and major histocompatibility complex class I-associated autoimmune diseases.

    PubMed

    Fruci, D; Romania, P; D'Alicandro, V; Locatelli, F

    2014-08-01

    Major histocompatibility complex (MHC) class I molecules present antigenic peptides on the cell surface to alert natural killer (NK) cells and CD8(+) T cells for the presence of abnormal intracellular events, such as virus infection or malignant transformation. The generation of antigenic peptides is a multistep process that ends with the trimming of N-terminal extensions in the endoplasmic reticulum (ER) by aminopeptidases ERAP1 and ERAP2. Recent studies have highlighted the potential role of ERAP1 in reprogramming the immunogenicity of tumor cells in order to elicit innate and adaptive antitumor immune responses, and in conferring susceptibility to autoimmune diseases in predisposed individuals. In this review, we will provide an overview of the current knowledge about the role of ERAP1 in MHC class I antigen processing and how its manipulation may constitute a promising tool for cancer immunotherapy and treatment of MHC class I-associated autoimmune diseases. PMID:25066018

  18. Molecular and biological interaction between major histocompatibility complex class I antigens and luteinizing hormone receptors or beta-adrenergic receptors triggers cellular response in mice.

    PubMed Central

    Solano, A R; Cremaschi, G; Sánchez, M L; Borda, E; Sterin-Borda, L; Podestá, E J

    1988-01-01

    Purified IgG from BALB/c mouse anti-C3H serum exerts positive inotropic and chronotropic effects in C3H mouse atria and induces testosterone synthesis in C3H mouse Leydig cells. The effect depends on IgG concentration and can be abolished by beta-adrenergic-receptor and luteinizing hormone-receptor antagonists. IgG interferes with the binding of dihydroalprenolol and luteinizing hormone. Monoclonal antibodies against major histocompatibility complex class I antigens were active on the Leydig cells of C3H and BALB/c mice. There was a parallelism between the effect of each individual monoclonal antibody with specificity for a particular haplotype and the response of the target cell from the strains carrying such haplotypes. These antibodies could precipitate the soluble luteinizing hormone-receptor complex. The results suggested that bound hormone triggers the association of major histocompatibility class I antigen with the receptor, thereby activating the respective target cells. PMID:2839829

  19. 49 CFR 238.317 - Class II brake test.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Class II brake test. 238.317 Section 238.317... Requirements for Tier I Passenger Equipment § 238.317 Class II brake test. (a) A Class II brake test shall be.... In these circumstances, a Class II brake test shall be performed prior to the train's departure...

  20. 49 CFR 238.317 - Class II brake test.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Class II brake test. 238.317 Section 238.317... Requirements for Tier I Passenger Equipment § 238.317 Class II brake test. (a) A Class II brake test shall be.... In these circumstances, a Class II brake test shall be performed prior to the train's departure...

  1. 49 CFR 238.317 - Class II brake test.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Class II brake test. 238.317 Section 238.317... Requirements for Tier I Passenger Equipment § 238.317 Class II brake test. (a) A Class II brake test shall be.... In these circumstances, a Class II brake test shall be performed prior to the train's departure...

  2. 49 CFR 238.317 - Class II brake test.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Class II brake test. 238.317 Section 238.317... Requirements for Tier I Passenger Equipment § 238.317 Class II brake test. (a) A Class II brake test shall be.... In these circumstances, a Class II brake test shall be performed prior to the train's departure...

  3. Association of major histocompatibility complex class 1 chain-related gene a dimorphism with type 1 diabetes and latent autoimmune diabetes in adults in the Algerian population.

    PubMed

    Raache, Rachida; Belanteur, Khadidja; Amroun, Habiba; Benyahia, Amel; Heniche, Amel; Azzouz, Malha; Mimouni, Safia; Gervais, Thibaud; Latinne, Dominique; Boudiba, Aissa; Attal, Nabila; Abbadi, Mohamed Cherif

    2012-04-01

    Major histocompatibility complex class I chain-related gene A (MICA-129) dimorphism was investigated in 73 autoimmune diabetes patients (type 1 diabetes and latent autoimmune diabetes in adults) and 75 controls from Algeria. Only MICA-129 Val allele and MICA-129 Val/Val genotype frequencies were higher among patients than in the control group. Statistical analysis of the estimated extended HLA-DR-DQ-MICA haplotypes shown that individual effects of MICA alleles on HLA-DQ2-DR3-MICA-129 Val/Val and HLA-DQ8-DR4-MICA-129 Val/Val haplotypes were significantly higher in patients than in the control groups. These preliminary data might suggest a relevant role of MICA-129 Val/Val single nucleotide polymorphism (weak/weak binders of NKG2D receptor) in the pathogenesis of T1D and LADA. PMID:22323559

  4. Association of Major Histocompatibility Complex Class 1 Chain-Related Gene A Dimorphism with Type 1 Diabetes and Latent Autoimmune Diabetes in Adults in the Algerian Population

    PubMed Central

    Belanteur, Khadidja; Amroun, Habiba; Benyahia, Amel; Heniche, Amel; Azzouz, Malha; Mimouni, Safia; Gervais, Thibaud; Latinne, Dominique; Boudiba, Aissa; Attal, Nabila; Abbadi, Mohamed Cherif

    2012-01-01

    Major histocompatibility complex class I chain-related gene A (MICA-129) dimorphism was investigated in 73 autoimmune diabetes patients (type 1 diabetes and latent autoimmune diabetes in adults) and 75 controls from Algeria. Only MICA-129 Val allele and MICA-129 Val/Val genotype frequencies were higher among patients than in the control group. Statistical analysis of the estimated extended HLA-DR-DQ-MICA haplotypes shown that individual effects of MICA alleles on HLA-DQ2-DR3-MICA-129 Val/Val and HLA-DQ8-DR4-MICA-129 Val/Val haplotypes were significantly higher in patients than in the control groups. These preliminary data might suggest a relevant role of MICA-129 Val/Val single nucleotide polymorphism (weak/weak binders of NKG2D receptor) in the pathogenesis of T1D and LADA. PMID:22323559

  5. Gene Conversion in the Evolution of Both the H-2 and Qa Class I Genes of the Murine Major Histocompatibility Complex

    PubMed Central

    Kuhner, M.; Watts, S.; Klitz, W.; Thomson, G.; Goodenow, R. S.

    1990-01-01

    In order to better understand the role of gene conversion in the evolution of the class I gene family of the major histocompatibility complex (MHC), we have used a computer algorithm to detect clustered sequence similarities among 24 class I DNA sequences from the H-2, Qa, and Tla regions of the murine MHC. Thirty-four statistically significant clusters were detected; individual analysis of the clusters suggested at least 25 past gene conversion or recombination events. These clusters are comparable in size to the conversions observed in the spontaneously occurring H-2K(bm) and H-2K(km2) mutations, and are distributed throughout all exons of the class I gene. Thus, gene conversion does not appear to be restricted to the regions of the class I gene encoding their antigen-presentation function. Moreover, both the highly polymorphic H-2 loci and the relatively monomorphic Qa and Tla loci appear to have participated as donors and recipients in conversion events. If gene conversion is not limited to the highly polymorphic loci of the MHC, then another factor, presumably natural selection, must be responsible for maintaining the observed differences in level of variation. PMID:2076814

  6. Herpes B Virus, Macacine Herpesvirus 1, Breaks Simplex Virus Tradition via Major Histocompatibility Complex Class I Expression in Cells from Human and Macaque Hosts

    PubMed Central

    Vasireddi, Mugdha

    2012-01-01

    B virus of the family Herpesviridae is endemic to rhesus macaques but results in 80% fatality in untreated humans who are zoonotically infected. Downregulation of major histocompatibility complex (MHC) class I in order to evade CD8+ T-cell activation is characteristic of most herpesviruses. Here we examined the cell surface presence and total protein expression of MHC class I molecules in B virus-infected human foreskin fibroblast cells and macaque kidney epithelial cells in culture, which are representative of foreign and natural host initial target cells of B virus. Our results show <20% downregulation of surface MHC class I molecules in either type of host cells infected with B virus, which is statistically insignificantly different from that observed in uninfected cells. We also examined the surface expression of MHC class Ib molecules, HLA-E and HLA-G, involved in NK cell inhibition. Our results showed significant upregulation of HLA-E and HLA-G in host cells infected with B virus relative to the amounts observed in other herpesvirus-infected cells. These results suggest that B virus-infected cell surfaces maintain normal levels of MHC class Ia molecules, a finding unique among simplex viruses. This is a unique divergence in immune evasion for B virus, which, unlike human simplex viruses, does not inhibit the transport of peptides for loading onto MHC class Ia molecules because B virus ICP47 lacks a transporter-associated protein binding domain. The fact that MHC class Ib molecules were significantly upregulated has additional implications for host-pathogen interactions. PMID:22973043

  7. High-resolution analysis of the murine MHC class II immunopeptidome.

    PubMed

    Sofron, Adriana; Ritz, Danilo; Neri, Dario; Fugmann, Tim

    2016-02-01

    The reliable identification of peptides bound to major histocompatibility complex (MHC) class II is fundamental for the study of the host immune response against pathogens and the pathogenesis of autoimmune conditions. Here, we describe an improved methodology combining immuno-affinity enrichment of MHC class II complexes, optimized elution conditions and quadrupole Orbitrap mass spectrometry-based characterization of the immunopeptidome. The methodology allowed the identification of over 1000 peptides with 1% false discovery rate from 10(8) murine A20 lymphoma cells. The study revealed the I-A(d) -specific motif in high resolution after multisequence alignment. The methodology was generally applied to the purification of MHC class II from cell lines and murine spleens. We identified 2963 peptides from BALB/c and 2712 from C57BL/6 mouse spleens. The identification of peptides bound to MHC class II in vitro and in vivo will facilitate the characterization of T-cell specificities, as well as the development of biotherapeutics and vaccines. PMID:26495903

  8. Introduction of protein or DNA delivered via recombinant Salmonella typhimurium into the major histocompatibility complex class I presentation pathway of macrophages.

    PubMed

    Catic, A; Dietrich, G; Gentschev, I; Goebel, W; Kaufmann, S H; Hess, J

    1999-02-01

    Recombinant (r) Salmonella typhimurium aroA strains which display the hen egg ovalbumin OVA(257-264) peptide SIINFEKL in secreted form were constructed. In addition, attenuated rS. typhimurium pcDNA-OVA constructs harbouring a eukaryotic expression plasmid encoding complete OVA were used to introduce the immunodominant OVA(257-264) epitope into the major histocompatibility complex (MHC) class I presentation pathway. Both modes of antigen delivery (DNA and protein) by Salmonella vaccine carriers stimulated OVA(257-264)-specific CD8 T-cell hybridomas. An in vitro infection system was established that allowed both rSalmonella carrier devices to facilitate MHC class I delivery of OVA(257-264) by coexpression of listeriolysin (Hly) or by coinfection with rS. typhimurium Hlys (Hess J., Gentschev I., Miko D., Welzel M., Ladel C., Goebel W., Kaufmann S.H.E., Proc. Natl. Acad. Sci. USA 93 (1996) 1458-1463). Coexpression of Hly and coinfection with rS. typhimurium Hlys slightly improved MHC class I processing of OVA. Our data provide further evidence for the feasibility of attenuated, Hly-expressing rS. typhimurium carriers secreting heterologous antigens or harbouring heterologous DNA as effective vaccines for stimulating CD8 T cells in addition to CD4 T cells. PMID:10594975

  9. Respiratory Syncytial Virus Infection Upregulates NLRC5 and Major Histocompatibility Complex Class I Expression through RIG-I Induction in Airway Epithelial Cells

    PubMed Central

    Guo, Xuancheng; Liu, Taixiang; Shi, Hengfei; Wang, Jingjing; Ji, Ping; Wang, Hongwei; Hou, Yayi; Tan, Ren Xiang

    2015-01-01

    ABSTRACT Respiratory syncytial virus (RSV) is the leading cause of acute respiratory tract viral infection in infants, causing bronchiolitis and pneumonia. The host antiviral response to RSV acts via retinoic acid-inducible gene I (RIG-I). We show here that RSV infection upregulates major histocompatibility complex class I (MHC-I) expression through the induction of NLRC5, a NOD-like, CARD domain-containing intracellular protein that has recently been identified as a class I MHC transactivator (CITA). RSV infection of A549 cells promotes upregulation of NLRC5 via beta interferon (IFN-β) production, since the NLRC5-inducing activity in a conditioned medium from RSV-infected A549 cells was removed by antibody to IFN-β, but not by antibody to IFN-γ. RSV infection resulted in RIG-I upregulation and induction of NLRC5 and MHC-I. Suppression of RIG-I induction significantly blocked NLRC5, as well as MHC-I, upregulation and diminished IRF3 activation. Importantly, Vero cells deficient in interferon production still upregulated MHC-I following introduction of the RSV genome by infection or transfection, further supporting a key role for RIG-I. A model is therefore proposed in which the host upregulates MHC-I expression during RSV infection directly via the induction of RIG-I and NLRC5 expression. Since elevated expression of MHC-I molecules can sensitize host cells to T lymphocyte-mediated cytotoxicity or immunopathologic damage, the results have significant implications for the modification of immunity in RSV disease. IMPORTANCE Human respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and pneumonia in infants and young children worldwide. Infection early in life is linked to persistent wheezing and allergic asthma in later life, possibly related to upregulation of major histocompatibility class I (MHC-I) on the cell surface, which facilitates cytotoxic T cell activation and antiviral immunity. Here, we show that RSV infection of lung epithelial

  10. Class I and Class II Lanthipeptides Produced by Bacillus spp.

    PubMed

    Barbosa, Joana; Caetano, Tânia; Mendo, Sónia

    2015-11-25

    The increasing number of multidrug-resistant pathogens, along with the small number of new antimicrobials under development, leads to an increased need for novel alternatives. Class I and class II lanthipeptides (also known as lantibiotics) have been considered promising alternatives to classical antibiotics. In addition to their relevant medical applications, they are used as probiotics, prophylactics, preservatives, and additives in cosmetics and personal-care products. The genus Bacillus is a prolific source of bioactive compounds including ribosomally and nonribosomally synthesized antibacterial peptides. Accordingly, there is significant interest in the biotechnological potential of members of the genus Bacillus as producers of antimicrobial lanthipeptides. The present review focuses on aspects of the biosynthesis, gene cluster organization, structure, antibacterial spectrum, and bioengineering approaches of lanthipeptides produced by Bacillus strains. Their efficacy and potency against some clinically relevant strains, including MRSA and VRE, are also discussed. Although no lanthipeptides are currently in clinical use, the information herein highlights the potential of these compounds. PMID:26448102

  11. Effective suppression of class I major histocompatibility complex expression by the US11 or ICP47 genes can be limited by cell type or interferon-gamma exposure.

    PubMed

    Radosevich, Thomas J; Seregina, Tatiana; Link, Charles J

    2003-12-10

    An impediment encountered in many viral-based gene therapy clinical trials has been the rapid destruction of the transgene by the host's immune response. The processing and presentation of antigens through the class I major histocompatibility complex (MHC) pathway is the initial specific response to viral infection. Disruption of the class I MHC pathway by herpes simplex virus (HSV) or the human cytomegalovirus (HCMV) results in a decrease of the CD8(+) cytotoxic T lymphocyte (CTL) response and prolongs survival of infected cells in the host. Two viral immune suppression genes that interfere with the class I MHC presentation pathway, the HSV type I ICP47 gene and HCMV US11 gene, were cloned and each incorporated into a retroviral vector. HSV ICP47 and HCMV US11 transgenes were expressed in multiple cells lines and compared for their abilities to reduce antigen presentation on the cell surface by class I MHC. Retroviral supernatants were used to transduce human, canine, and rat cell lines. Fluorescence-activated cell sorter (FACS) analysis of US11- and ICP47-transduced cell lines demonstrated substantial reductions in class I MHC cell surface expression in most cell lines except in rodent cells where ICP47 is nonfunctional. The decrease in the level of class I MHC expression for ICP47 transduced cell lines ranged from 31-98% relative to negative controls. US11 decreased class I cell surface MHC by 67-96%. When both ICP47 and US11 are expressed in human cells, a further reduction of class I MHC was observed. Next, human A375 melanoma cells were tested to determine if the resulting reduction in cell surface class I MHC would reduce in vitro cytotoxicity by CTL. A375 cells expressing either ICP47 or US11 demonstrated a twofold to threefold reduction of specific lysis by primed CD8(+) CTL. These data clearly establish an ability to convey immune protection to human cells by viral genes. However, further analysis demonstrated that interferon (IFN)-gamma could reverse

  12. Hazardous pollutants in class II landfills

    SciTech Connect

    Wood, J.A.; Porter, M.L.

    1987-05-01

    Class II landfills accept nontoxic municipal trash. Their gaseous emissions were originally assumed to be relatively free of hazardous substances. However, one Class II site in Southern California was found to be emitting enough vinyl chloride to exceed the California Air Quality Standard of 10 ppb for a 24-hour average in surrounding neighborhood. This paper presents a summary of the results of the analysis of landfill gas from over 20 additional Class II landfills. Ambient air surveys were conducted around five of the landfills. About 90% of the landfills contained measurable amounts of vinyl chloride and/or benzene. The concentrations exceeded 1 ppm in about half of the sites studied. Vinyl chloride is produced in situ by the action of bacteria on chlorinated solvents, and can be found in landfills that have been closed for over 30 years. The relative amounts of methane and vinyl chloride vary so much within a single landfill that methane measurements cannot be used as a surrogate for vinyl chloride.

  13. Recognition of Major Histocompatibility Complex Antigens on Cultured Human Biliary Epithelial Cells by Alloreactive Lymphocytes

    PubMed Central

    Saidman, Susan L.; Duquesnoy, Rene J.; Zeevi, Adriana; Fung, John J.; Starzl, Thomas E.; Demetris, A. Jake

    2010-01-01

    We have developed an in vitro system to study the interactions between biliary epithelium and lymphocytes using cultured human biliary epithelial cells. No class II antigens were detected by immunoperoxidase staining of the normal biliary epithelial cells, but alloactivated lymphocyte culture supernatants were able to induce class II expression. The activity of the supernatants was blocked with an anti-γ-interferon monoclonal antibody. In addition, recombinant human γ-interferon alone induced the expression of class II antigens and increased the intensity of class I staining of cultured biliary epithelial cells. Biliary epithelial cell–induced proliferation of alloreactive T lymphocytes demonstrated that the major histocompatibility complex molecules carry functional lymphocyte-activating determinants. The recognition of major histocompatibility complex determinants was confirmed by monoclonal antibody–blocking studies and by stimulation of an alloreactive T-cell clone. However, the biliary epithelial cells were much less potent stimulators than arterial endothelial cells tested in the same assay system. PMID:1704868

  14. Generation of Antiviral Major Histocompatibility Complex Class I-Restricted T Cells in the Absence of CD8 Coreceptors ▿

    PubMed Central

    Andrews, Nicolas P.; Pack, Christopher D.; Lukacher, Aron E.

    2008-01-01

    The CD8 coreceptor is important for positive selection of major histocompatibility complex I (MHC-I)-restricted thymocytes and in the generation of pathogen-specific T cells. However, the requirement for CD8 in these processes may not be essential. We previously showed that mice lacking β2-microglobulin are highly susceptible to tumors induced by mouse polyoma virus (PyV), but CD8-deficient mice are resistant to these tumors. In this study, we show that CD8-deficient mice also control persistent PyV infection as efficiently as wild-type mice and generate a substantial virus-specific, MHC-I-restricted, T-cell response. Infection with vesicular stomatitis virus (VSV), which is acutely cleared, also recruited antigen-specific, MHC-I-restricted T cells in CD8-deficient mice. Yet, unlike in VSV infection, the antiviral MHC-I-restricted T-cell response to PyV has a prolonged expansion phase, indicating a requirement for persistent infection in driving T-cell inflation in CD8-deficient mice. Finally, we show that the PyV-specific, MHC-I-restricted T cells in CD8-deficient mice, while maintained long term at near-wild-type levels, are short lived in vivo and have extremely narrow T-cell receptor repertoires. These findings provide a possible explanation for the resistance of CD8-deficient mice to PyV-induced tumors and have implications for the maintenance of virus-specific MHC-I-restricted T cells during persistent infection. PMID:18337581

  15. Strategic mutations in the class I major histocompatibility complex HLA-A2 independently affect both peptide binding and T cell receptor recognition.

    PubMed

    Baxter, Tiffany K; Gagnon, Susan J; Davis-Harrison, Rebecca L; Beck, John C; Binz, Anne-Kathrin; Turner, Richard V; Biddison, William E; Baker, Brian M

    2004-07-01

    Mutational studies of T cell receptor (TCR) contact residues on the surface of the human class I major histocompatibility complex (MHC) molecule HLA-A2 have identified a "functional hot spot" that comprises Arg(65) and Lys(66) and is involved in recognition by most peptide-specific HLA-A2-restricted TCRs. Although there is a significant amount of functional data on the effects of mutations at these positions, there is comparatively little biochemical information that could illuminate their mode of action. Here, we have used a combination of fluorescence anisotropy, functional assays, and Biacore binding experiments to examine the effects of mutations at these positions on the peptide-MHC interaction and TCR recognition. The results indicate that mutations at both position 65 and position 66 influence peptide binding by HLA-A2 to various extents. In particular, mutations at position 66 result in significantly increased peptide dissociation rates. However, these effects are independent of their effects on TCR recognition, and the Arg(65)-Lys(66) region thus represents a true "hot spot" for TCR recognition. We also made the observation that in vitro T cell reactivity does not scale with the half-life of the peptide-MHC complex, as is often assumed. Finally, position 66 is implicated in the "dual recognition" of both peptide and TCR, emphasizing the multiple roles of the class I MHC peptide-binding domain. PMID:15131131

  16. Low MHC class II diversity in the Tasmanian devil (Sarcophilus harrisii).

    PubMed

    Cheng, Yuanyuan; Sanderson, Claire; Jones, Menna; Belov, Katherine

    2012-07-01

    The largest remaining carnivorous marsupial, the Tasmanian devil (Sarcophilus harrisii), is currently under threat of extinction due to a fatal contagious cancer-devil facial tumour disease. Low major histocompatibility complex (MHC) class I diversity is believed to have contributed to the transmission of the tumour allograft through devil populations. Here, we report low MHC class II variability in this species, with DA β chain genes (Saha-DAB1, 2 and 3) exhibiting very limited diversity and the sole α chain gene (Saha-DAA) monomorphic. Three, six and three alleles were found at Saha-DAB1, 2 and 3, respectively, with a predominant allele found at each locus. Heterozygosity at these three loci is low in the eastern population and modestly higher in northwestern individuals. The results are indicative of a selective sweep likely due to an infectious disease resulting in the fixation of selectively favoured alleles and depletion of genetic diversity at devil class II loci. Several attempts were made to isolate the other marsupial classical class II gene family, namely, DB, resulting in only one DBB pseudogene being found. These findings further support the view that this species has a compromised capacity to respond to pathogen evolution, emerging infectious diseases and environmental changes. PMID:22460528

  17. Autoantibody Profiles in Collagen Disease Patients with Interstitial Lung Disease (ILD): Antibodies to Major Histocompatibility Complex Class I-Related Chain A (MICA) as Markers of ILD.

    PubMed

    Furukawa, Hiroshi; Oka, Shomi; Shimada, Kota; Masuo, Kiyoe; Nakajima, Fumiaki; Funano, Shunichi; Tanaka, Yuki; Komiya, Akiko; Fukui, Naoshi; Sawasaki, Tatsuya; Tadokoro, Kenji; Nose, Masato; Tsuchiya, Naoyuki; Tohma, Shigeto

    2015-01-01

    Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients' prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they may be useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, Proto-Array Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10(-5)). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6). PMID:26327779

  18. Autoantibody Profiles in Collagen Disease Patients with Interstitial Lung Disease (ILD): Antibodies to Major Histocompatibility Complex Class I-Related Chain A (MICA) as Markers of ILD

    PubMed Central

    Furukawa, Hiroshi; Oka, Shomi; Shimada, Kota; Masuo, Kiyoe; Nakajima, Fumiaki; Funano, Shunichi; Tanaka, Yuki; Komiya, Akiko; Fukui, Naoshi; Sawasaki, Tatsuya; Tadokoro, Kenji; Nose, Masato; Tsuchiya, Naoyuki; Tohma, Shigeto

    2015-01-01

    Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients’ prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they may be useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, Proto-Array Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10−5). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6). PMID:26327779

  19. Peripherin: an islet antigen that is cross-reactive with nonobese diabetic mouse class II gene products.

    PubMed Central

    Boitard, C; Villa, M C; Becourt, C; Gia, H P; Huc, C; Sempe, P; Portier, M M; Bach, J F

    1992-01-01

    The nonobese diabetic (NOD) mouse, in which major histocompatibility complex genes may be involved in the susceptibility to diabetes, has been developed as a model of autoimmune diabetes. The NOD mouse expresses I-A-encoded class II major histocompatibility complex antigens, which differ from those of other mouse haplotypes by the presence of a serine at position 57 of the A beta chain. Identifying islet autoantigens may help elucidate the role of class II antigens in the activation of autoreactive T cells and, thus, in the development of diabetes. We have detected autoantibodies directed against a 58-kDa islet cell antigen in NOD mice but not in other strains, including lupus-prone mice. Apart from insulin-secreting cells, the 58-kDa antigen was only found to be expressed by neuroblastoma cells and was identified as peripherin, an intermediate filament protein previously characterized in well-defined neuronal populations. This autoantigen cross-reacted with I-Anod class II antigens, suggesting that it may contribute to defective self-tolerance of islet beta cells in the NOD mouse. Images PMID:1729686

  20. 46 CFR 50.30-15 - Class II pressure vessels.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 46 Shipping 2 2014-10-01 2014-10-01 false Class II pressure vessels. 50.30-15 Section 50.30-15... Fabrication Inspection § 50.30-15 Class II pressure vessels. (a) Class II pressure vessels shall be subject to... pressure vessels shall be performed during the welding of the longitudinal joint. At this time the...

  1. 46 CFR 50.30-15 - Class II pressure vessels.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 2 2012-10-01 2012-10-01 false Class II pressure vessels. 50.30-15 Section 50.30-15... Fabrication Inspection § 50.30-15 Class II pressure vessels. (a) Class II pressure vessels shall be subject to... pressure vessels shall be performed during the welding of the longitudinal joint. At this time the...

  2. 46 CFR 50.30-15 - Class II pressure vessels.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 2 2011-10-01 2011-10-01 false Class II pressure vessels. 50.30-15 Section 50.30-15... Fabrication Inspection § 50.30-15 Class II pressure vessels. (a) Class II pressure vessels shall be subject to... pressure vessels shall be performed during the welding of the longitudinal joint. At this time the...

  3. 46 CFR 50.30-15 - Class II pressure vessels.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 46 Shipping 2 2010-10-01 2010-10-01 false Class II pressure vessels. 50.30-15 Section 50.30-15... Fabrication Inspection § 50.30-15 Class II pressure vessels. (a) Class II pressure vessels shall be subject to... pressure vessels shall be performed during the welding of the longitudinal joint. At this time the...

  4. 46 CFR 50.30-15 - Class II pressure vessels.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 2 2013-10-01 2013-10-01 false Class II pressure vessels. 50.30-15 Section 50.30-15... Fabrication Inspection § 50.30-15 Class II pressure vessels. (a) Class II pressure vessels shall be subject to... pressure vessels shall be performed during the welding of the longitudinal joint. At this time the...

  5. The major histocompatibility class I locus in Atlantic salmon (Salmo salar L.): polymorphism, linkage analysis and protein modelling.

    PubMed

    Grimholt, Unni; Drabløs, Finn; Jørgensen, Sven Martin; Høyheim, Bjørn; Stet, René J M

    2002-11-01

    A cDNA library screening using the conserved exon 4 of Atlantic salmon Mhc class I as probe provided the basis for a study on Mhc class I polymorphism in a breeding population. Twelve different alleles were identified in the 82 dams and sires studied. No individual expressed more than two alleles, which corresponded to the diploid segregation patterns of the polymorphic marker residing within the 3'-untranslated tail. Close linkage between the Sasa-UBA and Sasa-TAP2B loci strengthens the claim that Sasa-UBA is the major Mhc class I locus in Atlantic salmon. We found no evidence for a second expressed classical or non-classical Mhc class I locus in Atlantic salmon. A phylogenetic analysis of salmonid Mhc class I sequences showed domains conserved between rainbow trout, brown trout and Atlantic salmon. Evidence for shuffling of the alpha(1) domain was identified and lineages of the remaining alpha(2) through the cytoplasmic tail gene segment can be defined. The coding sequence of one allele was found associated with two different markers, suggesting recombination within the 3'-tail dinucleotide repeat itself. Protein modelling of several Sasa-UBA alleles shows distinct differences in their peptide binding domains and enables a further understanding of the functionality of the high polymorphism. PMID:12439620

  6. Closely Related Mycobacterial Strains Demonstrate Contrasting Levels of Efficacy as Antitumor Vaccines and Are Processed for Major Histocompatibility Complex Class I Presentation by Multiple Routes in Dendritic Cells

    PubMed Central

    Cheadle, Eleanor J.; O'Donnell, Dearbhaile; Selby, Peter J.; Jackson, Andrew M.

    2005-01-01

    Mycobacteria expressing recombinant antigens are already being developed as vaccines against both infections and tumors. Little is known about how dendritic cells might process such antigens. Two different mycobacterial species, the fast-growing Mycobacterium smegmatis and the slow-growing M. bovis M. bovis BCG, were engineered to express a model tumor antigen, the Kb-restricted dominant cytotoxic T-lymphocyte epitope OVA257-264. Recombinant M. bovis BCG but not recombinant M. smegmatis conferred protection to mice challenged with the B16-OVA tumor cell line. We went on to investigate whether the contrast in antitumor efficacy could be due to differences in how dendritic cells process antigen from the two mycobacterial strains for class I presentation. Both strains of mycobacteria caused phenotypic maturation of dendritic cells, but recombinant M. smegmatis infection led to a greater degree of dendritic cell maturation than recombinant M. bovis BCG infection. Antigen from recombinant M. smegmatis was processed and presented as OVA257-264 on Kb molecules by the dendritic cell line DC2.4 but not by bone marrow-derived dendritic cells (BMDC) or splenic dendritic cells. In contrast, antigen from recombinant M. bovis BCG was presented by all three dendritic cell types as long as the mycobacteria were viable. Such presentation was dependent on proteasome function and nascent major histocompatibility complex (MHC) class I molecules in DC2.4 cells but independent of the proteasome and transporter associated with antigen processings (TAP) in BMDC and splenic dendritic cells. These data demonstrate for the first time that antigen vectored by the slow-growing M. bovis BCG but not that vectored by fast-growing, readily destroyed M. smegmatis is processed and presented on MHC class I by in vitro-generated dendritic cells, which has implications for recombinant microbial vaccine development. PMID:15664917

  7. Construction of Soluble Mamu-B*1703, a Class I Major Histocompatibility Complex of Chinese Rhesus Macaques, Monomer and Tetramer Loaded with a Simian Immunodeficiency Virus Peptide

    PubMed Central

    Ouyang, Dongyun; Wang, Xiaoying; He, Xianhui; Xu, Lihui; Shi, Huanjing; Gao, Qi; Guo, He

    2009-01-01

    Chinese-descent rhesus macaques have become more prevalent for HIV infection and vaccine investigation than Indian-origin macaques. Most of the currently available data and reagents such as major histocompatibility complex (MHC) class I tetramers, however, were derived from Indian-origin macaques due to the dominant use of these animals in history. Although there are significant differences in the immunogenetic background between the two macaque populations, they share a few of common MHC class I alleles. We reported in this study the procedure for preparation of a soluble Mamu-B*1703 (a MHC class I molecule of Chinese macaques) monomer and tetramer loaded with a dominant simian immunodeficiency virus (SIV) epitope IW9 (IRYPKTFGW) that was identified to be Mamu-B*1701-restricted in Indian macaques. The DNA fragment encoding the Mamu-B*1703 extracellular domain fused with a BirA substrate peptide (BSP) was amplified from a previously cloned cDNA and inserted into a prokaratic expression vector. In the presence of the antigenic peptide IW9 and light chain β2-microglobulin, the expressed heavy chain was refolded into a soluble monomer. After biotinylation, four monomers were polymerized as a tetramer by phycoerythrin-conjugated streptavidin. The tetramer, having been confirmed to have the right conformation, was a potential tool for investigation of antigen-specific CD8+ T-lymphocytes in SIV vaccine models of Chinese macaques. And our results also suggested that some antigenic peptides reported in Indian-origin macaques could be directly recruited as ligands for construction of Chinese macaque MHC tetramers. PMID:19403061

  8. Cloning and modeling of CD8 beta in the amphibian ambystoma Mexicanum. Evolutionary conserved structures for interactions with major histocompatibility complex (MHC) class I molecules.

    PubMed

    Fellah, Julien S; Tuffèry, Pierre; Etchebest, Catherine; Guillet, Françoise; Bleux, Christian; Charlemagne, Jacques

    2002-04-17

    Mammalian and avian T-cells exhibit a large number of well characterized surface molecules associated with their maturation degree. Very little is known in comparison with T-cell differentiation in ectothermic vertebrates. This is mainly due to the lack of probes to identify T-cell subsets. We cloned and sequenced the first ectothermic CD8 beta DNA complementary to RNA from an amphibian species, the Mexican axolotl. The CD8 beta chain was 30-36% identical with its avian and mammalian homologues. The extracellular V-like domain contained the two typically conserved cysteines and was followed by a J-like sequence containing the canonical Phe-Gly-X-Gly stretch. The connecting peptide was much longer than in other species and contained potential O-glycosylation sites. The axolotl CD8 beta and major histocompatibility complex class I molecules were modeled using human HLA-A2/CD8 alphaalpha complex as template. The backbone conformation of axolotl CD8 beta matched well with the CD8 alpha-2 subunit of the human complex but significant structural differences were located in the CDR1, CDR2 and DE loops. Both axolotl and human class I showed large negative surface potential. The interacting area of the human CD8 alpha chain and of the corresponding region of axolotl CD8 beta had positive electrostatic potential compatible with complexation with the corresponding class I molecules. The presence of a CD8 beta homologue in an amphibian species implies that it was already present in the Devonian ancestor of amphibians and mammals, i.e. more than 400 million years ago. PMID:12034498

  9. Class II Resin Composites: Restorative Options.

    PubMed

    Patel, Minesh; Mehta, Shamir B; Banerji, Subir

    2015-10-01

    Tooth-coloured, resin composite restorations are amongst the most frequently prescribed forms of dental restoration to manage defects in posterior teeth. The attainment of a desirable outcome when placing posterior resin composite restorations requires the clinician to have a good understanding of the benefits (as well as the limitations) posed by this material, together with a sound knowledge of placement technique. Numerous protocols and materials have evolved to assist the dental operator with this type of demanding posterior restoration. With the use of case examples, four techniques available are reported here. CPD/Clinical Relevance: This article explores varying techniques for the restoration of Class II cavities using resin composite. PMID:26685471

  10. Class II virus membrane fusion proteins

    SciTech Connect

    Kielian, Margaret . E-mail: kielian@aecom.yu.edu

    2006-01-05

    Enveloped animal viruses fuse their membrane with a host cell membrane, thus delivering the virus genetic material into the cytoplasm and initiating infection. This critical membrane fusion reaction is mediated by a virus transmembrane protein known as the fusion protein, which inserts its hydrophobic fusion peptide into the cell membrane and refolds to drive the fusion reaction. This review describes recent advances in our understanding of the structure and function of the class II fusion proteins of the alphaviruses and flaviviruses. Inhibition of the fusion protein refolding reaction confirms its importance in fusion and suggests new antiviral strategies for these medically important viruses.

  11. Lateral cephalometric diagnosis of asymmetry in Angle Class II subdivision compared to Class I and II

    PubMed Central

    Meloti, Aparecida Fernanda; Gonçalves, Renata de Cássia; Silva, Ertty; Martins, Lídia Parsekian; dos Santos-Pinto, Ary

    2014-01-01

    Introduction Lateral cephalometric radiographs are traditionally required for orthodontic treatment, yet rarely used to assess asymmetries. Objective The objective of the present study was to use lateral cephalometric radiographs to identify existing skeletal and dentoalveolar morphological alterations in Class II subdivision and to compare them with the existing morphology in Class I and II relationship. Material and Methods Ninety initial lateral cephalometric radiographs of male and female Brazilian children aged between 12 to 15 years old were randomly and proportionally divided into three groups: Group 1 (Class I), Group 2 (Class II) and Group 3 (Class II subdivision). Analysis of lateral cephalometric radiographs included angular measurements, horizontal linear measurements and two indexes of asymmetry that were prepared for this study. Results In accordance with an Index of Dental Asymmetry (IDA), greater mandibular dental asymmetry was identified in Group 3. An Index of Mandibular Asymmetry (IMA) revealed less skeletal and dental mandibular asymmetry in Group 2, greater skeletal mandibular asymmetry in Group 1, and greater mandibular dental asymmetry in Group 3. Conclusion Both IDA and IMA revealed greater mandibular dental asymmetry for Group 3 in comparison to Groups 1 and 2. These results are in accordance with those found by other diagnostic methods, showing that lateral cephalometric radiography is an acceptable method to identify existing skeletal and dentoalveolar morphological alterations in malocclusions. PMID:25279525

  12. Condylar volume and condylar area in class I, class II and class III young adult subjects

    PubMed Central

    2012-01-01

    Aim Aim of this study was to compare the volume and the shape of mandibular condyles in a Caucasian young adult population, with different skeletal pattern. Material and methods 200 Caucasian patients (15–30 years old, 95 male and 105 females) were classified in three groups on the base of ANB angle: skeletal class I (65 patients), skeletal class II (70 patients) and skeletal class III (65 patients). Left and right TMJs of each subject were evaluated independently with CBCT (Iluma). TMJ evaluation included: condylar volume; condylar area; morphological index (MI). Condylar volumes were calculated by using the Mimics software. The condylar volume, the area and the morphological index (MI) were compared among the three groups, by using non-parametric tests. Results The Kruskal-Wallis test and the Mann Whitney test revealed that: no significant difference was observed in the whole sample between the right and the left condylar volume; subjects in skeletal class III showed a significantly higher condylar volume, respect to class I and class II subjects (p < 0.05); significantly lower condylar volume was observed in class II subjects, respect to class I and class III (p < 0.05). In the whole sample condylar volume (699.8 ± 63.07 mm3 in males and 663.5 ± 81.3 mm3 in females; p < 0.01) as well as condylar surface (423.24 ± 63.03 mm2 in males and 389.76 ± 61.15 mm2 in females; p < 0.01) were significantly higher in males than in females. Conclusion Skeletal class appeared to be associated to the mandibular condylar volume and to the mandibular condylar area in the Caucasian orthodontic population. PMID:23241136

  13. Salmonella enterica serovar Typhi live vector vaccines delivered intranasally elicit regional and systemic specific CD8+ major histocompatibility class I-restricted cytotoxic T lymphocytes.

    PubMed

    Pasetti, Marcela F; Salerno-Gonçalves, Rosangela; Sztein, Marcelo B

    2002-08-01

    We investigated the ability of live attenuated Salmonella enterica serovar Typhi strains delivered to mice intranasally to induce specific cytotoxic T-lymphocyte (CTL) responses at regional and systemic levels. Mice immunized with two doses (28 days apart) of Salmonella serovar Typhi strain Ty21a, the licensed oral typhoid vaccine, and genetically attenuated mutants CVD 908 (DeltaaroC DeltaaroD), CVD 915 (DeltaguaBA), and CVD 908-htrA (DeltaaroC DeltaaroD DeltahtrA) induced CTL specific for Salmonella serovar Typhi-infected cells in spleens and cervical lymph nodes. CTL were detected in effector T cells that had been expanded in vitro for 7 days in the presence of Salmonella-infected syngeneic splenocytes. A second round of stimulation further enhanced the levels of specific cytotoxicity. CTL activity was observed in sorted alphabeta+ CD8+ T cells, which were remarkably increased after expansion, but not in CD4+ T cells. CTL from both cervical lymph nodes and spleens failed to recognize Salmonella-infected major histocompatibility complex (MHC)-mismatched cells, indicating that the responses were MHC restricted. Studies in which MHC blocking antibodies were used showed that H-2L(d) was the restriction element. This is the first demonstration that Salmonella serovar Typhi vaccines delivered intranasally elicit CD8+ MHC class I-restricted CTL. The results further support the usefulness of the murine intranasal model for evaluating the immunogenicity of typhoid vaccine candidates at the preclinical level. PMID:12117906

  14. Pulse-chase analysis for studies of MHC class II biosynthesis, maturation, and peptide loading

    PubMed Central

    Hou, Tieying; Rinderknecht, Cornelia H; Hadjinicolaou, Andreas V; Busch, Robert; Mellins, Elizabeth

    2014-01-01

    Pulse-chase analysis is a commonly used technique for studying the synthesis, processing and transport of proteins. Cultured cells expressing proteins of interest are allowed to take up radioactively labeled amino acids for a brief interval (“pulse”), during which all newly synthesized proteins incorporate the label. The cells are then returned to non-radioactive culture medium for various times (“chase”), during which proteins may undergo conformational changes, trafficking, or degradation. Proteins of interest are isolated (usually by immunoprecipitation) and resolved by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and the fate of radiolabeled molecules is examined by autoradiography. This chapter describes a pulse-chase protocol suitable for studies of major histocompatibility complex (MHC) class II biosynthesis and maturation. We discuss how results are affected by the recognition by certain anti-class II antibodies of distinct class II conformations associated with particular biosynthetic states. Our protocol can be adapted to follow the fate of many other endogenously synthesized proteins, including viral or transfected gene products, in cultured cells. PMID:23329504

  15. Mitogen-activated protein kinase ERK1/2 regulates the class II transactivator.

    PubMed

    Voong, Lilien N; Slater, Allison R; Kratovac, Sebila; Cressman, Drew E

    2008-04-01

    The expression of major histocompatibility class II genes is necessary for proper antigen presentation and induction of an immune response. This expression is initiated by the class II transactivator, CIITA. The establishment of the active form of CIITA is controlled by a series of post-translational events, including GTP binding, ubiquitination, and dimerization. However, the role of phosphorylation is less clearly defined as are the consequences of phosphorylation on CIITA activity and the identity of the kinases involved. In this study we show that the extracellular signal-regulated kinases 1 and 2 (ERK1/2) interact directly with CIITA, targeting serine residues in the amino terminus of the protein, including serine 288. Inhibition of this phosphorylation by dominant-negative forms of ERK or by treatment of cells with the ERK inhibitor PD98059 resulted in the increase in CIITA-mediated gene expression from a class II promoter, enhanced the nuclear concentration of CIITA, and impaired its ability to bind to the nuclear export factor, CRM1. In contrast, inhibition of ERK1/2 activity had little effect on serine-to-alanine mutant forms of CIITA. These data suggest a model whereby ERK1/2-mediated phosphorylation of CIITA down-regulates CIITA activity by priming it for nuclear export, thus providing a means for cells to tightly regulate the extent of antigen presentation. PMID:18245089

  16. Susceptibility of amphibians to chytridiomycosis is associated with MHC class II conformation.

    PubMed

    Bataille, Arnaud; Cashins, Scott D; Grogan, Laura; Skerratt, Lee F; Hunter, David; McFadden, Michael; Scheele, Benjamin; Brannelly, Laura A; Macris, Amy; Harlow, Peter S; Bell, Sara; Berger, Lee; Waldman, Bruce

    2015-04-22

    The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) can cause precipitous population declines in its amphibian hosts. Responses of individuals to infection vary greatly with the capacity of their immune system to respond to the pathogen. We used a combination of comparative and experimental approaches to identify major histocompatibility complex class II (MHC-II) alleles encoding molecules that foster the survival of Bd-infected amphibians. We found that Bd-resistant amphibians across four continents share common amino acids in three binding pockets of the MHC-II antigen-binding groove. Moreover, strong signals of selection acting on these specific sites were evident among all species co-existing with the pathogen. In the laboratory, we experimentally inoculated Australian tree frogs with Bd to test how each binding pocket conformation influences disease resistance. Only the conformation of MHC-II pocket 9 of surviving subjects matched those of Bd-resistant species. This MHC-II conformation thus may determine amphibian resistance to Bd, although other MHC-II binding pockets also may contribute to resistance. Rescuing amphibian biodiversity will depend on our understanding of amphibian immune defence mechanisms against Bd. The identification of adaptive genetic markers for Bd resistance represents an important step forward towards that goal. PMID:25808889

  17. Susceptibility of amphibians to chytridiomycosis is associated with MHC class II conformation

    PubMed Central

    Bataille, Arnaud; Cashins, Scott D.; Grogan, Laura; Skerratt, Lee F.; Hunter, David; McFadden, Michael; Scheele, Benjamin; Brannelly, Laura A.; Macris, Amy; Harlow, Peter S.; Bell, Sara; Berger, Lee; Waldman, Bruce

    2015-01-01

    The pathogenic chytrid fungus Batrachochytrium dendrobatidis (Bd) can cause precipitous population declines in its amphibian hosts. Responses of individuals to infection vary greatly with the capacity of their immune system to respond to the pathogen. We used a combination of comparative and experimental approaches to identify major histocompatibility complex class II (MHC-II) alleles encoding molecules that foster the survival of Bd-infected amphibians. We found that Bd-resistant amphibians across four continents share common amino acids in three binding pockets of the MHC-II antigen-binding groove. Moreover, strong signals of selection acting on these specific sites were evident among all species co-existing with the pathogen. In the laboratory, we experimentally inoculated Australian tree frogs with Bd to test how each binding pocket conformation influences disease resistance. Only the conformation of MHC-II pocket 9 of surviving subjects matched those of Bd-resistant species. This MHC-II conformation thus may determine amphibian resistance to Bd, although other MHC-II binding pockets also may contribute to resistance. Rescuing amphibian biodiversity will depend on our understanding of amphibian immune defence mechanisms against Bd. The identification of adaptive genetic markers for Bd resistance represents an important step forward towards that goal. PMID:25808889

  18. Measurement of Peptide Binding to MHC Class II Molecules by Fluorescence Polarization.

    PubMed

    Yin, Liusong; Stern, Lawrence J

    2014-01-01

    Peptide binding to major histocompatibility complex class II (MHCII) molecules is a key process in antigen presentation and CD4+ T cell epitope selection. This unit describes a fairly simple but powerful fluorescence polarization-based binding competition assay to measure peptide binding to soluble recombinant MHCII molecules. The binding of a peptide of interest to MHCII molecules is assessed based on its ability to inhibit the binding of a fluorescence-labeled probe peptide, with the strength of binding characterized as IC50 (concentration required for 50% inhibition of probe peptide binding). Data analysis related to this method is discussed. In addition, this unit includes a support protocol for fluorescence labeling peptide using an amine-reactive probe. The advantage of this protocol is that it allows simple, fast, and high-throughput measurements of binding for a large set of peptides to MHCII molecules. PMID:25081912

  19. Genetic characterization of MHC class II DQB exon 2 variants in gayal (Bos frontalis)

    PubMed Central

    Sun, Yongke; Xi, Dongmei; Li, Guozhi; Hao, Tiantian; Chen, Yuhan; Yang, Yuai

    2014-01-01

    In the present study, exon 2 of major histocompatibility complex (MHC) class II DQB gene from 39 gayals (Bos frontalis) was isolated, characterized and compared with previously reported patterns for other bovidae. It was revealed by sequence analyses that there are 36 DQB exon 2 variants among 39 gayals. These variants exhibited a high degree of nucleotide and amino acid substitutions with most amino acid variations occurring at positions forming the peptide-binding sites (PBS). The DQB loci were analysed for patterns of synonymous (d S) and non-synonymous (d N) substitution. The gayals were observed to be under strong balancing selection in the DQB exon 2 PBS (d N = 0.094, P = 0.001). It appears that this variability among gayals could confer the ability to mount immune responses to a wide variety of peptides or pathogens. PMID:26019566

  20. MHC Class II Antigen Presentation by Dendritic Cells Regulated through Endosomal Sorting

    PubMed Central

    ten Broeke, Toine; Wubbolts, Richard; Stoorvogel, Willem

    2013-01-01

    For the initiation of adaptive immune responses, dendritic cells present antigenic peptides in association with major histocompatibility complex class II (MHCII) to naïve CD4+ T lymphocytes. In this review, we discuss how antigen presentation is regulated through intracellular processing and trafficking of MHCII. Newly synthesized MHCII is chaperoned by the invariant chain to endosomes, where peptides from endocytosed pathogens can bind. In nonactivated dendritic cells, peptide-loaded MHCII is ubiquitinated and consequently sorted by the ESCRT machinery to intraluminal vesicles of multivesicular bodies, ultimately leading to lysosomal degradation. Ubiquitination of newly synthesized MHCII is blocked when dendritic cells are activated, now allowing its transfer to the cell surface. This mode of regulation for MHCII is a prime example of how molecular processing and sorting at multivesicular bodies can determine the expression of signaling receptors at the plasma membrane. PMID:24296169

  1. Expressed MHC class II genes in sea otters (Enhydra lutris) from geographically disparate populations

    USGS Publications Warehouse

    Bowen, L.; Aldridge, B.M.; Miles, A.K.; Stott, J.L.

    2006-01-01

    The major histocompatibility complex (MHC) is central to maintaining the immunologic vigor of individuals and populations. Classical MHC class II genes were targeted for partial sequencing in sea otters (Enhydra lutris) from populations in California, Washington, and Alaska. Sequences derived from sea otter peripheral blood leukocyte mRNAs were similar to those classified as DQA, DQB, DRA, and DRB in other species. Comparisons of the derived amino acid compositions supported the classification of these as functional molecules from at least one DQA, DQB, and DRA locus and at least two DRB loci. While limited in scope, phylogenetic analysis of the DRB peptide-binding region suggested the possible existence of distinct clades demarcated by geographic region. These preliminary findings support the need for additional MHC gene sequencing and expansion to a comprehensive study targeting additional otters. ?? 2006 Blackwell Munksgaard.

  2. The Atlantic Salmon MHC class II alpha and beta promoters are active in mammalian cell lines.

    PubMed

    Vestrheim, O; Lundin, M; Syed, M

    2007-01-01

    The major histocompatibility complex class II (MHCII) genes are only constitutively expressed in certain immune response cells such as B cells, macrophages, dendritic cells and other antigen presenting cells. This cell specific expression pattern and the presence of conserved regions such as the X-, X2-, Y-, and W-boxes make the MHCII promoters especially interesting as vector constructs. We tested whether the Atlantic salmon (Salmo salar L.) MHCII promoters can function in cell lines from other organisms. We found that the salmon MHCII alpha and MHCII beta promoters could drive expression of a LacZ reporter gene in adherent lymphoblast cell lines from dog (DH82) and rabbit (HybL-L). This paper shows that the promoters of Atlantic salmon MHCII alpha and beta genes can function in mammalian cell lines. PMID:17934904

  3. Influence of kinship and MHC class II genotype on visual traits in zebrafish larvae (Danio rerio).

    PubMed

    Hinz, Cornelia; Gebhardt, Katharina; Hartmann, Alexander K; Sigman, Lauren; Gerlach, Gabriele

    2012-01-01

    Kin recognition can drive kin selection and the evolution of social behaviour. In zebrafish (Danio rerio, Hamilton 1822), kin recognition is based on olfactory and visual imprinting processes. If larvae are exposed to visual and chemical cues of kin at day 5 and 6 post fertilization they will recognize kin throughout life, while exposure to non-kin fails to trigger any recognition. Chemical imprinting signals are transcribed by polymorphic genes of the major histocompatibility complex (MHC) code; however, the underlying mechanism for visual imprinting remains unclear. Here we provide evidence for the existence of family-specific differences in morphometry and pigmentation pattern of six day old zebrafish larvae. While rump, tail and body pigmentation were dependent on relatedness, iris pigmentation and morphometry were also influenced by MHC class II genotype. Our study revealed that the MHC not only influences the chemical signature of individuals, but also their visual appearance. PMID:23251449

  4. Rhodococcus equi-Infected Macrophages Are Recognized and Killed by CD8+ T Lymphocytes in a Major Histocompatibility Complex Class I-Unrestricted Fashion

    PubMed Central

    Patton, Kristin M.; McGuire, Travis C.; Fraser, Darrilyn G.; Hines, Stephen A.

    2004-01-01

    The goal of this research was to examine the role of cytotoxic T lymphocytes (CTL) in the control of Rhodococcus equi and specifically to determine if R. equi-specific CD8+ CTL occurred in the blood of immune horses. Equine peripheral blood mononuclear cells stimulated with antigen-presenting cells either infected with R. equi or exposed to soluble R. equi antigen lysed R. equi-infected target cells. Lysis was decreased to background by depletion of either CD2+ or CD3+ cells, indicating that the effector cell had a T-lymphocyte, but not NK cell, phenotype. Stimulation induced an increased percentage of CD8+ T cells in the effector population, and depletion of CD8+ T cells resulted in significantly decreased lysis of infected targets. Killing of R. equi-infected macrophages by effector cells was equally effective against autologous and equine leukocyte antigen A (classical major histocompatibility complex [MHC] class I) mismatched targets. To evaluate potential target antigens, target cells were infected with either virulent (80.6-kb plasmid-containing) or avirulent (plasmid-cured) R. equi. The degree of lysis was not altered by the presence of the plasmid, providing evidence that the virulence plasmid, which is required for survival within macrophages, was not necessary for recognition and killing of R. equi-infected cells. These data indicate that immunocompetent adult horses develop R. equi-specific CD8+ CTL, which may play a role in immunity to R. equi. The apparent lack of restriction via classical MHC class I molecules suggests a novel or nonclassical method of antigen processing and presentation, such as presentation by CD1 or other nonclassical MHC molecules. PMID:15557631

  5. An interferon gamma-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes.

    PubMed Central

    Driggers, P H; Ennist, D L; Gleason, S L; Mak, W H; Marks, M S; Levi, B Z; Flanagan, J R; Appella, E; Ozato, K

    1990-01-01

    Interferons (IFNs) induce transcription of major histocompatibility complex (MHC) class I genes through the conserved IFN consensus sequence (ICS) that contains an IFN response motif shared by many IFN-regulated genes. By screening mouse lambda ZAP expression libraries with the ICS as a probe, we isolated a cDNA clone encoding a protein that binds the ICS, designated ICSBP. Protein blot analysis with labeled oligonucleotide probes showed that ICSBP binds not only the MHC class I ICS but also IFN response motifs of many IFN-regulated genes, as well as a virus-inducible element of the IFN-beta gene. The ICSBP cDNA encodes 424 amino acids and a long 3' untranslated sequence. The N-terminal 115 amino acids correspond to a putative DNA-binding domain and show significant sequence similarity with other cloned IFN response factors (IRF-1 and IRF-2). Because of the structural similarity and shared binding specificity, we conclude that ICSBP is a third member of the IRF gene family, presumably playing a role in IFN- and virus-mediated regulation of many genes. Although IRF-1 and IRF-2 share some similarity in their C-terminal regions, ICSBP shows no similarity to IRF-1 or IRF-2 in this region, suggesting that it is more distantly related. We show that ICSBP mRNA is expressed predominantly in lymphoid tissues and is inducible preferentially by IFN-gamma. The induction by IFN-gamma appears to be predominant in lymphocytes and macrophages, implying that ICSBP plays a regulatory role in cells of the immune system. The presence of multiple factors that bind common IFN response motifs may partly account for the complexity and diversity of IFN action as well as IFN-regulated gene expression. Images PMID:2111015

  6. Positive regulatory domain I binding factor 1 silences class II transactivator expression in multiple myeloma cells.

    PubMed

    Ghosh, N; Gyory, I; Wright, G; Wood, J; Wright, K L

    2001-05-01

    The major histocompatibility complex (MHC) class II transactivator (CIITA) acts as a master switch to activate expression of the genes required for MHC-II antigen presentation. During B-cell to plasma cell differentiation, MHC-II expression is actively silenced, but the mechanism has been unknown. In plasma cell tumors such as multiple myeloma the repression of MHC-II is associated with the loss of CIITA. We have identified that positive regulatory domain I binding factor 1 (PRDI-BF1), a transcriptional repressor, inhibits CIITA expression in multiple myeloma cell lines. Repression of CIITA depends on the DNA binding activity of PRDI-BF1 and its specific binding site in the CIITA promoter. Deletion of a histone deacetylase recruitment domain in PRDI-BF1 does not inhibit repression of CIITA nor does blocking histone deacetylase activity. This is in contrast to PRDI-BF1 repression of the c-myc promoter. Repression of CIITA requires either the N-terminal acidic and conserved PR motif or the proline-rich domain. PRDI-BF1 has been shown to be a key regulator of B-cell and macrophage differentiation. These findings now indicate that PRDI-BF1 has at least two mechanisms of repression whose function is dependent on the nature of the target promoter. Importantly, PRDI-BF1 is defined as the key molecule in silencing CIITA and thus MHC-II in multiple myeloma cells. PMID:11279146

  7. [Orthodontic failures in Class II cases].

    PubMed

    Boileau, Marie-José

    2016-03-01

    In Class II treatment, as with all malformations, therapeutic failure can impact some or all of our treatment aims, whether occlusal, functional or esthetic. Using clinical cases, we will first define the concept of failure and the limits of what is acceptable in these different areas. We will then attempt to determine the main causes underlying our failures in order to better avoid them. An analysis of the literature and of the clinical cases demonstrates that our failures are most often caused by a misevaluation of the amount and direction of residual growth, poor control of the vertical dimension, inadequate management of functional problems, an inadequate position of the maxillary and mandibular incisors. In addition to these major treatment errors, one also encounters insufficient patient cooperation, which needs to be assessed and maintained in order to limit the number of failures and treatment drop-outs. PMID:27083232

  8. Major Histocompatibility Complex Genomics and Human Disease

    PubMed Central

    Trowsdale, John; Knight, Julian C.

    2015-01-01

    Over several decades, various forms of genomic analysis of the human major histocompatibility complex (MHC) have been extremely successful in picking up many disease associations. This is to be expected, as the MHC region is one of the most gene-dense and polymorphic stretches of human DNA. It also encodes proteins critical to immunity, including several controlling antigen processing and presentation. Single-nucleotide polymorphism genotyping and human leukocyte antigen (HLA) imputation now permit the screening of large sample sets, a technique further facilitated by high-throughput sequencing. These methods promise to yield more precise contributions of MHC variants to disease. However, interpretation of MHC-disease associations in terms of the functions of variants has been problematic. Most studies confirm the paramount importance of class I and class II molecules, which are key to resistance to infection. Infection is likely driving the extreme variation of these genes across the human population, but this has been difficult to demonstrate. In contrast, many associations with autoimmune conditions have been shown to be specific to certain class I and class II alleles. Interestingly, conditions other than infections and autoimmunity are also associated with the MHC, including some cancers and neuropathies. These associations could be indirect, owing, for example, to the infectious history of a particular individual and selective pressures operating at the population level. PMID:23875801

  9. The major histocompatibility complex of primates.

    PubMed

    Heise, E R; Cook, D J; Schepart, B S; Manning, C H; McMahan, M R; Chedid, M; Keever, C A

    1987-08-31

    The major histocompatibility complex (MHC) encodes cell surface glycoproteins that function in self-nonself recognition and in allograft rejection. Among primates, the MHC has been well defined only in the human; in the chimpanzee and in two species of macaque monkeys the MHC is less well characterized. Serologic, biochemical and genetic evidence indicates that the basic organization of the MHC linkage group has been phylogenetically conserved. However, the number of genes and their linear relationship on the chromosomes differ between species. Class I MHC loci encode molecules that are the most polymorphic genes known. These molecules are ubiquitous in their tissue distribution and typically are recognized together with nominal antigens by cytotoxic lymphocytes. Class II MHC loci constitute a smaller family of serotypes serving as restricting elements for regulatory T lymphocytes. The distribution of class II antigens is limited mainly to cell types serving immune functions, and their expression is subject to up and down modulation. Class III loci code for components C2, C4 and Factor B (Bf) of the complement system. Interspecies differences in the extent of polymorphism occur, but the significance of this finding in relation to fitness and natural selection is unclear. Detailed information on the structure and regulation of MHC gene expression will be required to understand fully the biologic role of the MHC and the evolutionary relationships between species. Meanwhile, MHC testing has numerous applications to biomedical research, especially in preclinical tissue and organ transplantation studies, the study of disease mechanisms, parentage determination and breeding colony management. In this review, the current status of MHC definition in nonhuman primates will be summarized. Special emphasis is placed on the CyLA system of M. fascicularis which is a major focus in our laboratory. A highly polymorphic cynomolgus MHC has been partially characterized and consists

  10. Salmonella enterica Serovar Typhi Live Vector Vaccines Delivered Intranasally Elicit Regional and Systemic Specific CD8+ Major Histocompatibility Class I-Restricted Cytotoxic T Lymphocytes

    PubMed Central

    Pasetti, Marcela F.; Salerno-Gonçalves, Rosangela; Sztein, Marcelo B.

    2002-01-01

    We investigated the ability of live attenuated Salmonella enterica serovar Typhi strains delivered to mice intranasally to induce specific cytotoxic T-lymphocyte (CTL) responses at regional and systemic levels. Mice immunized with two doses (28 days apart) of Salmonella serovar Typhi strain Ty21a, the licensed oral typhoid vaccine, and genetically attenuated mutants CVD 908 (ΔaroC ΔaroD), CVD 915 (ΔguaBA), and CVD 908-htrA (ΔaroC ΔaroD ΔhtrA) induced CTL specific for Salmonella serovar Typhi-infected cells in spleens and cervical lymph nodes. CTL were detected in effector T cells that had been expanded in vitro for 7 days in the presence of Salmonella-infected syngeneic splenocytes. A second round of stimulation further enhanced the levels of specific cytotoxicity. CTL activity was observed in sorted αβ+ CD8+ T cells, which were remarkably increased after expansion, but not in CD4+ T cells. CTL from both cervical lymph nodes and spleens failed to recognize Salmonella-infected major histocompatibility complex (MHC)-mismatched cells, indicating that the responses were MHC restricted. Studies in which MHC blocking antibodies were used showed that H-2Ld was the restriction element. This is the first demonstration that Salmonella serovar Typhi vaccines delivered intranasally elicit CD8+ MHC class I-restricted CTL. The results further support the usefulness of the murine intranasal model for evaluating the immunogenicity of typhoid vaccine candidates at the preclinical level. PMID:12117906

  11. Equine herpesvirus type 4 UL56 and UL49.5 proteins downregulate cell surface major histocompatibility complex class I expression independently of each other.

    PubMed

    Said, Abdelrahman; Azab, Walid; Damiani, Armando; Osterrieder, Nikolaus

    2012-08-01

    Major histocompatibility complex class I (MHC-I) molecules are critically important in the host defense against various pathogens through presentation of viral peptides to cytotoxic T lymphocytes (CTLs), a process resulting in the destruction of virus-infected cells. Herpesviruses interfere with CTL-mediated elimination of infected cells by various mechanisms, including inhibition of peptide transport and loading, perturbation of MHC-I trafficking, and rerouting and proteolysis of cell surface MHC-I. In this study, we show that equine herpesvirus type 4 (EHV-4) modulates MHC-I cell surface expression through two different mechanisms. First, EHV-4 can lead to a significant downregulation of MHC-I expression at the cell surface through the product of ORF1, a protein expressed with early kinetics from a gene that is homologous to herpes simplex virus 1 UL56. The EHV-4 UL56 protein reduces cell surface MHC-I as early as 4 h after infection. Second, EHV-4 can interfere with MHC-I antigen presentation, starting at 6 h after infection, by inhibition of the transporter associated with antigen processing (TAP) through its UL49.5 protein. Although pUL49.5 has no immediate effect on overall surface MHC-I levels in infected cells, it blocks the supply of antigenic peptides to the endoplasmic reticulum (ER) and transport of peptide-loaded MHC-I to the cell surface. Taken together, our results show that EHV-4 encodes at least two viral immune evasion proteins: pUL56 reduces MHC-I molecules on the cell surface at early times after infection, and pUL49.5 interferes with MHC-I antigen presentation by blocking peptide transport in the ER. PMID:22623773

  12. In silico prediction of peptide binding affinity to class I mouse major histocompatibility complexes: a comparative molecular similarity index analysis (CoMSIA) study.

    PubMed

    Hattotuwagama, Channa K; Doytchinova, Irini A; Flower, Darren R

    2005-01-01

    Current methods for the in silico identification of T cell epitopes (which form the basis of many vaccines, diagnostics, and reagents) rely on the accurate prediction of peptide-major histocompatibility complex (MHC) affinity. A three-dimensional quantitative structure-activity relationship (3D-QSAR) for the prediction of peptide binding to class I MHC molecules was established using the comparative molecular similarity index analysis (CoMSIA) method. Three MHC alleles were studied: H2-D(b), H2-K(b), and H2-K(k). Models were produced for each allele. Each model consisted of five physicochemical descriptors-steric bulk, electrostatic potentials, hydrophobic interactions, and hydrogen-bond donor and hydrogen-bond acceptor abilities. The models have an acceptable level of predictivity: cross-validation leave-one-out statistical terms q2 and SEP (standard error of prediction) ranged between 0.490 and 0.679 and between 0.525 and 0.889, respectively. The non-cross-validated statistical terms r2 and SEE (standard error of estimate) ranged between 0.913 and 0.979 and between 0.167 and 0.248, respectively. The use of coefficient contour maps, which indicate favored and disfavored areas for each position of the MHC-bound peptides, allowed the binding specificity of each allele to be identified, visualized, and understood. The present study demonstrates the effectiveness of CoMSIA as a method for studying peptide-MHC interactions. The peptides used in this study are available on the Internet (http://www.jenner.ac.uk/AntiJen). The partial least-squares method is available commercially in the SYBYL molecular modeling software package. PMID:16180918

  13. Major Histocompatibility Complex Class I Downregulation Induced by Equine Herpesvirus Type 1 pUL56 Is through Dynamin-Dependent Endocytosis

    PubMed Central

    Huang, Teng; Lehmann, Maik J.; Said, Abdelrahman; Ma, Guanggang

    2014-01-01

    ABSTRACT Equine herpesvirus type 1 (EHV-1) downregulates cell surface expression of major histocompatibility complex class I (MHC-I) in infected cells. We have previously shown that pUL56 encoded by the EHV-1 ORF1 gene regulates the process (G. Ma, S. Feineis, N. Osterrieder, and G. R. Van de Walle, J. Virol. 86:3554–3563, 2012, doi:http://dx.doi.org/10.1128/JVI.06994-11). Here, we report that cell surface MHC-I in EHV-1-infected cells is internalized and degraded in the lysosomal compartment in a pUL56-dependent fashion. pUL56-induced MHC-I endocytosis required dynamin and tyrosine kinase but was independent of clathrin and caveolin-1, the main constituents of the clathrin- and raft/caveola-mediated endocytosis pathways, respectively. Downregulation of cell surface MHC-I was significantly inhibited by the ubiquitin-activating enzyme E1 inhibitor PYR41, indicating that ubiquitination is essential for the process. Finally, we show that downregulation is not specific for MHC-I and that other molecules, including CD46 and CD63, are also removed from the cell surface in a pUL56-dependent fashion. IMPORTANCE We show that alphaherpesvirus induces MHC-I downregulation through endocytosis, which is mediated by pUL56. The dynamin-dependent endocytic pathway is responsible for MHC-I internalization in infected cells. Furthermore, we discovered that this endocytic process can be disrupted by the inhibiting ubiquitin-activating E1 enzyme, which is indispensable for ubiquitination. Finally, pUL56 action extends to a number of cell surface molecules that are significant for host immunity. Therefore, the protein may exert a more general immunomodulatory effect. PMID:25165105

  14. Major histocompatibility complex class I-intercellular adhesion molecule-1 association on the surface of target cells: implications for antigen presentation to cytotoxic T lymphocytes.

    PubMed

    Lebedeva, Tatiana; Anikeeva, Nadja; Kalams, Spyros A; Walker, Bruce D; Gaidarov, Ibragim; Keen, James H; Sykulev, Yuri

    2004-12-01

    Polarization and segregation of the T-cell receptor (TCR) and integrins upon productive cytotoxic T-lymphocyte (CTL) target cell encounters are well documented. Much less is known about the redistribution of major histocompatibility complex class I (MHC-I) and intercellular adhesion molecule-1 (ICAM-1) proteins on target cells interacting with CTLs. Here we show that human leucocyte antigen-A2 (HLA-A2) MHC-I and ICAM-1 are physically associated and recovered from both the raft fraction and the fraction of soluble membranes of target cells. Conjugation of target cells with surrogate CTLs, i.e. polystyrene beads loaded with antibodies specific for HLA-A2 and ICAM-1, induced the accumulation of membrane rafts, and beads loaded with ICAM-1-specific antibodies caused the selective recruitment of HLA-A2 MHC-I at the contact area of the target cells. Disruption of raft integrity on target cells led to a release of HLA-A2 and ICAM-1 from the raft fraction, abatement of HLA-A2 polarization, and diminished the ability of target cells bearing viral peptides to induce a Ca(2+) flux in virus-specific CTLs. These data suggest that productive engagement of ICAM-1 on target cells facilitates the polarization of MHC-I at the CTL-target cell interface, augmenting presentation of cognate peptide-MHC (pMHC) complexes to CTLs. We propose that ICAM-1-MHC-I association on the cell membrane is a mechanism that enhances the linkage between antigen recognition and early immunological synapse formation. PMID:15554924

  15. Characterization and 454 pyrosequencing of Major Histocompatibility Complex class I genes in the great tit reveal complexity in a passerine system

    PubMed Central

    2012-01-01

    Background The critical role of Major Histocompatibility Complex (Mhc) genes in disease resistance and their highly polymorphic nature make them exceptional candidates for studies investigating genetic effects on survival, mate choice and conservation. Species that harbor many Mhc loci and high allelic diversity are particularly intriguing as they are potentially under strong selection and studies of such species provide valuable information as to the mechanisms maintaining Mhc diversity. However comprehensive genotyping of complex multilocus systems has been a major challenge to date with the result that little is known about the consequences of this complexity in terms of fitness effects and disease resistance. Results In this study, we genotyped the Mhc class I exon 3 of the great tit (Parus major) from two nest-box breeding populations near Oxford, UK that have been monitored for decades. Characterization of Mhc class I exon 3 was adopted and bidirectional sequencing was carried using the 454 sequencing platform. Full analysis of sequences through a stepwise variant validation procedure allowed reliable typing of more than 800 great tits based on 214,357 reads; from duplicates we estimated the repeatability of typing as 0.94. A total of 862 alleles were detected, and the presence of at least 16 functional loci was shown - the highest number characterized in a wild bird species. Finally, the functional alleles were grouped into 17 supertypes based on their antigen binding affinities. Conclusions We found extreme complexity at the Mhc class I of the great tit both in terms of allelic diversity and gene number. The presence of many functional loci was shown, together with a pseudogene family and putatively non-functional alleles; there was clear evidence that functional alleles were under strong balancing selection. This study is the first step towards an in-depth analysis of this gene complex in this species, which will help understanding how parasite

  16. Deficient Peptide Loading and MHC Class II Endosomal Sorting in a Human Genetic Immunodeficiency Disease: the Chediak-Higashi Syndrome

    PubMed Central

    Faigle, Wolfgang; Raposo, Graça; Tenza, Daniele; Pinet, Valérie; Vogt, Anne B.; Kropshofer, Harald; Fischer, Alain; de Saint-Basile, Geneviève; Amigorena, Sebastian

    1998-01-01

    The Chediak-Higashi syndrome (CHS) is a human recessive autosomal disease caused by mutations in a single gene encoding a protein of unknown function, called lysosomal-trafficking regulator. All cells in CHS patients bear enlarged lysosomes. In addition, T- and natural killer cell cytotoxicity is defective in these patients, causing severe immunodeficiencies. We have analyzed major histocompatibility complex class II functions and intracellular transport in Epstein Barr Virus–transformed B cells from CHS patients. Peptide loading onto major histocompatibility complex class II molecules and antigen presentation are strongly delayed these cells. A detailed electron microscopy analysis of endocytic compartments revealed that only lysosomal multilaminar compartments are enlarged (reaching 1–2 μm), whereas late multivesicular endosomes have normal size and morphology. In contrast to giant multilaminar compartments that bear most of the usual lysosomal markers in these cells (HLA-DR, HLA-DM, Lamp-1, CD63, etc.), multivesicular late endosomes displayed reduced levels of all these molecules, suggesting a defect in transport from the trans-Golgi network and/or early endosomes into late multivesicular endosomes. Further insight into a possible mechanism of this transport defect came from immunolocalizing the lysosomal trafficking regulator protein, as antibodies directed to a peptide from its COOH terminal domain decorated punctated structures partially aligned along microtubules. These results suggest that the product of the Lyst gene is required for sorting endosomal resident proteins into late multivesicular endosomes by a mechanism involving microtubules. PMID:9606205

  17. Giving CD4+ T cells the slip: viral interference with MHC class II-restricted antigen processing and presentation.

    PubMed

    Forsyth, Katherine S; Eisenlohr, Laurence C

    2016-06-01

    Activation of CD4+ T cells through interactions with peptides bound to Major Histocompatibility Complex Class II (MHC-II) molecules is a crucial step in clearance of most pathogens. Consequently, many viruses have evolved ways of blocking this aspect of adaptive immunity, from specific targeting of processing and presentation components to modulation of signaling pathways that regulate peptide presentation in addition to many other host defense mechanisms. Such cases of interference are far less common compared to what has been elucidated in MHC-I processing and presentation. This may be attributable in part to the complexity of MHC-II antigen processing, the scope of which is only now coming to light. PMID:27115617

  18. Secreted Toxoplasma gondii molecules interfere with expression of MHC-II in interferon gamma-activated macrophages.

    PubMed

    Leroux, Louis-Philippe; Dasanayake, Dayal; Rommereim, Leah M; Fox, Barbara A; Bzik, David J; Jardim, Armando; Dzierszinski, Florence S

    2015-04-01

    The obligate intracellular protozoan parasite Toxoplasma gondii interferes with major histocompatibility complex class II antigen presentation to dampen host CD4(+) T cell responses. While it is known that T. gondii inhibits major histocompatibility complex class II gene transcription and expression in infected host cells, the mechanism of this host manipulation is unknown. Here, we show that soluble parasite proteins inhibit IFNγ-induced expression of major histocompatibility complex class II on the surface of the infected cell in a dose-dependent response that was abolished by protease treatment. Subcellular fractionation of T. gondii tachyzoites revealed that the major histocompatibility complex class II inhibitory activity co-partitioned with rhoptries and/or dense granules. However, parasite mutants deleted for single rhoptries or dense granules genes (ROP1, 4/7, 14, 16 and 18 or GRA 2-9 and 12 knock-out strains) retained the ability to inhibit expression of major histocompatibility complex class II. In addition, excreted/secreted antigens released by extracellular tachyzoites displayed immunomodulatory activity characterized by an inhibition of major histocompatibility complex class II expression, and reduced expression and release of TNFα by macrophages. Tandem MS analysis of parasite excreted/secreted antigens generated a list of T. gondii secreted proteins that may participate in major histocompatibility complex class II inhibition and the modulation of host immune functions. PMID:25720921

  19. Equine Herpesvirus 1 Multiply Inserted Transmembrane Protein pUL43 Cooperates with pUL56 in Downregulation of Cell Surface Major Histocompatibility Complex Class I

    PubMed Central

    Huang, Teng; Ma, Guanggang

    2015-01-01

    ABSTRACT Herpesviruses have evolved an array of strategies to counteract antigen presentation by major histocompatibility complex class I (MHC-I). Previously, we identified pUL56 of equine herpesvirus 1 (EHV-1) as one major determinant of the downregulation of cell surface MHC-I (G. Ma, S. Feineis, N. Osterrieder, and G. R. Van de Walle, J. Virol. 86:3554–3563, 2012, http://dx.doi.org/10.1128/JVI.06994-11; T. Huang, M. J. Lehmann, A. Said, G. Ma, and N. Osterrieder, J. Virol. 88:12802–12815, 2014, http://dx.doi.org/10.1128/JVI.02079-14). Since pUL56 was able to exert its function only in the context of virus infection, we hypothesized that pUL56 cooperates with another viral protein. Here, we generated and screened a series of EHV-1 single-gene deletion mutants and found that the pUL43 orthologue was required for downregulation of cell surface MHC-I expression at the same time of infection as when pUL56 exerts its function. We demonstrate that the absence of pUL43 was not deleterious to virus growth and that expression of pUL43 was detectable from 2 h postinfection (p.i.) but decreased after 8 h p.i. due to lysosomal degradation. pUL43 localized within Golgi vesicles and required a unique hydrophilic N-terminal domain to function properly. Finally, coexpression of pUL43 and pUL56 in transfected cells reduced the cell surface expression of MHC-I. This process was dependent on PPxY motifs present in pUL56, suggesting that late domains are required for pUL43- and pUL56-dependent sorting of MHC class I for lysosomal degradation. IMPORTANCE We describe here that the poorly characterized herpesviral protein pUL43 is involved in downregulation of cell surface MHC-I. pUL43 is an early protein and degraded in lysosomes. pUL43 resides in the Golgi vesicles and needs an intact N terminus to induce MHC-I downregulation in infected cells. Importantly, pUL43 and pUL56 cooperate to reduce MHC-I expression on the surface of transfected cells. Our results suggest a model for

  20. A comparison of craniofacial Class I and Class II growth patterns.

    PubMed

    Riesmeijer, Arnold M; Prahl-Andersen, Birte; Mascarenhas, Anna K; Joo, Bert H; Vig, Katherine W L

    2004-04-01

    Longitudinal craniofacial databases, including the Fels Longitudinal Study, the Michigan Growth Study, and the Nijmegen (The Netherlands) Growth Study, were compared for a set of 12 craniofacial measurements on lateral skull cephalograms. The age ranges of the subjects were 7-14 years for females and 9-14 years for males. When we compared the normally distributed databases using multiple comparisons, a small sample test statistic t for differences between means of the databases showed few statistical differences. The databases were therefore pooled, and sex-specific Class I (ANB < 4 degrees), and Class II (ANB > or = 4 degrees) subsamples were analyzed with the same t test. The sizes of these subsamples ranged from 39 to 122 at the different ages. The findings showed that the Class II samples had greater SNA and SN-GoMe angles. Compared with the Class I group, shorter mandibles were found in the younger age groups of the Class II samples. No differences were found in mandibular length (Ar-Gn) and mandibular body length (Go-Gn) in the older Class II groups compared with the Class I groups. These findings indicate that the greater mandibular lengthening in the Class II groups might have contributed to successful Class II treatment in studies in which a Class I group was the control. Because of individual biological variability, the average Class I or Class II growth pattern might not be a realistic assumption or have clinical relevance for individual patients. PMID:15067263

  1. 25 CFR 522.10 - Individually owned class II and class III gaming operations other than those operating on...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 2 2010-04-01 2010-04-01 false Individually owned class II and class III gaming... GAMING COMMISSION, DEPARTMENT OF THE INTERIOR APPROVAL OF CLASS II AND CLASS III ORDINANCES AND RESOLUTIONS SUBMISSION OF GAMING ORDINANCE OR RESOLUTION § 522.10 Individually owned class II and class...

  2. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 18 2012-07-01 2012-07-01 false Definitions for class I and class II controlled substances. 82.3 Section 82.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.3 Definitions for class I and class...

  3. 40 CFR 82.3 - Definitions for class I and class II controlled substances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 40 Protection of Environment 17 2011-07-01 2011-07-01 false Definitions for class I and class II controlled substances. 82.3 Section 82.3 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.3 Definitions for class I and class...

  4. Btn2a2, a T cell immunomodulatory molecule coregulated with MHC class II genes

    PubMed Central

    Sarter, Kerstin; Leimgruber, Elisa; Gobet, Florian; Agrawal, Vishal; Dunand-Sauthier, Isabelle; Barras, Emmanuèle; Mastelic-Gavillet, Béatris; Kamath, Arun; Fontannaz, Paola; Guéry, Leslie; Duraes, Fernanda do Valle; Lippens, Carla; Ravn, Ulla; Santiago-Raber, Marie-Laure; Magistrelli, Giovanni; Fischer, Nicolas; Siegrist, Claire-Anne; Hugues, Stéphanie

    2016-01-01

    Evidence has recently emerged that butyrophilins, which are members of the extended B7 family of co-stimulatory molecules, have diverse functions in the immune system. We found that the human and mouse genes encoding butyrophilin-2A2 (BTN2A2) are regulated by the class II trans-activator and regulatory factor X, two transcription factors dedicated to major histocompatibility complex class II expression, suggesting a role in T cell immunity. To address this, we generated Btn2a2-deficient mice. Btn2a2−/− mice exhibited enhanced effector CD4+ and CD8+ T cell responses, impaired CD4+ regulatory T cell induction, potentiated antitumor responses, and exacerbated experimental autoimmune encephalomyelitis. Altered immune responses were attributed to Btn2a2 deficiency in antigen-presenting cells rather than T cells or nonhematopoietic cells. These results provide the first genetic evidence that BTN2A2 is a co-inhibitory molecule that modulates T cell–mediated immunity. PMID:26809444

  5. Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts.

    PubMed

    Brown, K; Nowocin, A K; Meader, L; Edwards, L A; Smith, R A; Wong, W

    2016-04-01

    Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II(+) cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab')2 fragment of a monoclonal antibody against the donor MHC class II molecule I-A(k) conjugated with the plant-derived ribosomal inactivating protein gelonin. This anti-I-A(k) gelonin immunotoxin depletes I-A(k) expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3(+) cells within donor grafts, diminished donor-specific antibody formation, and delayed rejection of subsequent donor-type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient-orientated immunosuppression. PMID:26799449

  6. HLA class II genes in chronic hepatitis C virus-infection and associated immunological disorders.

    PubMed

    Congia, M; Clemente, M G; Dessi, C; Cucca, F; Mazzoleni, A P; Frau, F; Lampis, R; Cao, A; Lai, M E; De Virgiliis, S

    1996-12-01

    To investigate the factors that may confer susceptibility or protection to hepatitis C virus (HCV) infection and to HCV-associated immunological disorders, we designed two studies on 420 Sardinian transfusion-dependent thalassemia patients followed in our department in Cagliari since 1974. The first one was an epidemiological survey aimed to evaluate the prevalence of HCV infection and HCV-associated immunological disorders. In the second study, the distribution of different HLA class II genes was examined by DNA analysis in 116 HCV positive patients, 30 HCV negative patients, and 606 healthy controls. Three hundred fourteen patients became infected with HCV (74.7%) after 5.6 +/- 2.8 years of regular transfusion program. Mixed cryoglobulinemia, purpura, arthritis, proteinuria, decreased complement levels, rheumatoid factor and anti-GOR, smooth muscle antibody (SMA), anti-nuclear antibody (ANA), and liver, kidney microsome (LKM) autoantibodies were significantly more represented in HCV positive patients than in negative ones (P < .05). A significant increase of HLA class II DR2 subtype (DRB1*1601,DQB1*0502) was observed in a group of 30 HCV negative patients who despite 10.3 +/- 2.2 years in a regular blood transfusion program did not show any evidence of HCV infection (Pc < .0092). Our results represent clear evidence for a relationship between HCV infection and immune extrahepatic abnormalities. A gene(s) located in the human major histocompatibility complex (MHC) region may play an important role in conferring protection against HCV infection. PMID:8938157

  7. Immunotoxin Against a Donor MHC Class II Molecule Induces Indefinite Survival of Murine Kidney Allografts

    PubMed Central

    Brown, K.; Nowocin, A. K.; Meader, L.; Edwards, L. A.; Smith, R. A.

    2016-01-01

    Rejection of donor organs depends on the trafficking of donor passenger leukocytes to the secondary lymphoid organs of the recipient to elicit an immune response via the direct antigen presentation pathway. Therefore, the depletion of passenger leukocytes may be clinically applicable as a strategy to improve graft survival. Because major histocompatibility complex (MHC) class II+ cells are most efficient at inducing immune responses, selective depletion of this population from donor grafts may dampen the alloimmune response and prolong graft survival. In a fully MHC mismatched mouse kidney allograft model, we describe the synthesis of an immunotoxin, consisting of the F(ab′)2 fragment of a monoclonal antibody against the donor MHC class II molecule I‐Ak conjugated with the plant‐derived ribosomal inactivating protein gelonin. This anti–I‐Ak gelonin immunotoxin depletes I‐Ak expressing cells specifically in vitro and in vivo. When given to recipients of kidney allografts, it resulted in indefinite graft survival with normal graft function, presence of Foxp3+ cells within donor grafts, diminished donor‐specific antibody formation, and delayed rejection of subsequent donor‐type skin grafts. Strategies aimed at the donor arm of the immune system using agents such as immunotoxins may be a useful adjuvant to existing recipient‐orientated immunosuppression. PMID:26799449

  8. Prediction of peptides binding to MHC class I and II alleles by temporal motif mining

    PubMed Central

    2013-01-01

    Background MHC (Major Histocompatibility Complex) is a key player in the immune response of most vertebrates. The computational prediction of whether a given antigenic peptide will bind to a specific MHC allele is important in the development of vaccines for emerging pathogens, the creation of possibilities for controlling immune response, and for the applications of immunotherapy. One of the problems that make this computational prediction difficult is the detection of the binding core region in peptides, coupled with the presence of bulges and loops causing variations in the total sequence length. Most machine learning methods require the sequences to be of the same length to successfully discover the binding motifs, ignoring the length variance in both motif mining and prediction steps. In order to overcome this limitation, we propose the use of time-based motif mining methods that work position-independently. Results The prediction method was tested on a benchmark set of 28 different alleles for MHC class I and 27 different alleles for MHC class II. The obtained results are comparable to the state of the art methods for both MHC classes, surpassing the published results for some alleles. The average prediction AUC values are 0.897 for class I, and 0.858 for class II. Conclusions Temporal motif mining using partial periodic patterns can capture information about the sequences well enough to predict the binding of the peptides and is comparable to state of the art methods in the literature. Unlike neural networks or matrix based predictors, our proposed method does not depend on peptide length and can work with both short and long fragments. This advantage allows better use of the available training data and the prediction of peptides of uncommon lengths. PMID:23368521

  9. Efficiency of Class I and Class II malocclusion treatment with four premolar extractions

    PubMed Central

    JANSON, Guilherme; NAKAMURA, Alexandre; BARROS, Sérgio Estelita; BOMBONATTI, Roberto; CHIQUETO, Kelly

    2014-01-01

    Four premolar extractions is a successful protocol to treat Class I malocclusion, but it is a less efficient way when compared with other Class II treatment protocols. Objective: The objective of this study was to evaluate the influence of anteroposterior discrepancy on the success of four premolar extractions protocol. For that, treatment efficiency of Class I and complete Class II malocclusions, treated with four premolar extractions were compared. Methods: A sample of 107 records from 75 Class I (mean age of 13.98 years - group 1) and 32 Class II (mean age of 13.19 years - group 2) malocclusion patients treated with four premolar extractions was selected. The initial and final occlusal status of each patient was evaluated on dental casts with the PAR index. The treatment time was calculated based on the clinical charts, and the treatment efficiency was obtained by the ratio between the percentage of PAR reduction and treatment time. The PAR index and its components, the treatment time and the treatment efficiency of the groups were statistically compared with t tests and Mann-Whitney U-test. Results: The Class II malocclusion patients had a greater final PAR index than Class I malocclusion patients, and similar duration (Class I - 28.95 mo. and Class II - 28.10 mo.) and treatment efficiency. Conclusion: The treatment of the complete Class II malocclusion with four premolar extractions presented worse occlusal results than Class I malocclusion owing to incomplete molar relationship correction. PMID:24918660

  10. A predominant role for the HLA class II region in the association of the MHC region with multiple sclerosis.

    PubMed

    Lincoln, Matthew R; Montpetit, Alexandre; Cader, M Zameel; Saarela, Janna; Dyment, David A; Tiislar, Milvi; Ferretti, Vincent; Tienari, Pentti J; Sadovnick, A Dessa; Peltonen, Leena; Ebers, George C; Hudson, Thomas J

    2005-10-01

    Genetic susceptibility to multiple sclerosis is associated with genes of the major histocompatibility complex (MHC), particularly HLA-DRB1 and HLA-DQB1 (ref. 1). Both locus and allelic heterogeneity have been reported in this genomic region. To clarify whether HLA-DRB1 itself, nearby genes in the region encoding the MHC or combinations of these loci underlie susceptibility to multiple sclerosis, we genotyped 1,185 Canadian and Finnish families with multiple sclerosis (n = 4,203 individuals) with a high-density SNP panel spanning the genes encoding the MHC and flanking genomic regions. Strong associations in Canadian and Finnish samples were observed with blocks in the HLA class II genomic region (P < 4.9 x 10(-13) and P < 2.0 x 10(-16), respectively), but the strongest association was with HLA-DRB1 (P < 4.4 x 10(-17)). Conditioning on either HLA-DRB1 or the most significant HLA class II haplotype block found no additional block or SNP association independent of the HLA class II genomic region. This study therefore indicates that MHC-associated susceptibility to multiple sclerosis is determined by HLA class II alleles, their interactions and closely neighboring variants. PMID:16186814

  11. Immunization with a single major histocompatibility complex class I-restricted cytotoxic T-lymphocyte recognition epitope of herpes simplex virus type 2 confers protective immunity.

    PubMed

    Blaney, J E; Nobusawa, E; Brehm, M A; Bonneau, R H; Mylin, L M; Fu, T M; Kawaoka, Y; Tevethia, S S

    1998-12-01

    We have evaluated the potential of conferring protective immunity to herpes simplex virus type 2 (HSV-2) by selectively inducing an HSV-specific CD8(+) cytotoxic T-lymphocyte (CTL) response directed against a single major histocompatibility complex class I-restricted CTL recognition epitope. We generated a recombinant vaccinia virus (rVV-ES-gB498-505) which expresses the H-2Kb-restricted, HSV-1/2-cross-reactive CTL recognition epitope, HSV glycoprotein B residues 498 to 505 (SSIEFARL) (gB498-505), fused to the adenovirus type 5 E3/19K endoplasmic reticulum insertion sequence (ES). Mucosal immunization of C57BL/6 mice with this recombinant vaccinia virus induced both a primary CTL response in the draining lymph nodes and a splenic memory CTL response directed against HSV gB498-505. To determine the ability of the gB498-505-specific memory CTL response to provide protection from HSV infection, immunized mice were challenged with a lethal dose of HSV-2 strain 186 by the intranasal (i.n.) route. Development of the gB498-505-specific CTL response conferred resistance in 60 to 75% of mice challenged with a lethal dose of HSV-2 and significantly reduced the levels of infectious virus in the brains and trigeminal ganglia of challenged mice. Finally, i.n. immunization of C57BL/6 mice with either a recombinant influenza virus or a recombinant vaccinia virus expressing HSV gB498-505 without the ES was also demonstrated to induce an HSV-specific CTL response and provide protection from HSV infection. This finding confirms that the induction of an HSV-specific CTL response directed against a single epitope is sufficient for conferring protective immunity to HSV. Our findings support the role of CD8(+) T cells in the control of HSV infection of the central nervous system and suggest the potential importance of eliciting HSV-specific mucosal CD8(+) CTL in HSV vaccine design. PMID:9811690

  12. Expression of bovine non-classical major histocompatibility complex class I proteins in mouse P815 and human K562 cells.

    PubMed

    Parasar, Parveen; Wilhelm, Amanda; Rutigliano, Heloisa M; Thomas, Aaron J; Teng, Lihong; Shi, Bi; Davis, William C; Suarez, Carlos E; New, Daniel D; White, Kenneth L; Davies, Christopher J

    2016-08-01

    Major histocompatibility complex class I (MHC-I) proteins can be expressed as cell surface or secreted proteins. To investigate whether bovine non-classical MHC-I proteins are expressed as cell surface or secreted proteins, and to assess the reactivity pattern of monoclonal antibodies with non-classical MHC-I isoforms, we expressed the MHC proteins in murine P815 and human K562 (MHC-I deficient) cells. Following antibiotic selection, stably transfected cell lines were stained with H1A or W6/32 antibodies to detect expression of the MHC-I proteins by flow cytometry. Two non-classical proteins (BoLA-NC1*00501 and BoLA-NC3*00101) were expressed on the cell surface in both cell lines. Surprisingly, the BoLA-NC4*00201 protein was expressed on the cell membrane of human K562 but not mouse P815 cells. Two non-classical proteins (BoLA-NC1*00401, which lacks a transmembrane domain, and BoLA-NC2*00102) did not exhibit cell surface expression. Nevertheless, Western blot analyses demonstrated expression of the MHC-I heavy chain in all transfected cell lines. Ammonium-sulfate precipitation of proteins from culture supernatants showed that BoLA-NC1*00401 was secreted and that all surface expressed proteins where shed from the cell membrane by the transfected cells. Interestingly, the surface expressed MHC-I proteins were present in culture supernatants at a much higher concentration than BoLA-NC1*00401. This comprehensive study shows that bovine non-classical MHC-I proteins BoLA-NC1*00501, BoLA-NC3*00101, and BoLA-NC4*00201 are expressed as surface isoforms with the latter reaching the cell membrane only in K562 cells. Furthermore, it demonstrated that BoLA-NC1*00401 is a secreted isoform and that significant quantities of membrane associated MHC-I proteins can be shed from the cell membrane. PMID:27473990

  13. Role of major histocompatibility complex class I-related molecules A*A5·1 allele in ulcerative colitis in Chinese patients

    PubMed Central

    Lü, Min; Xia, Bing; Ge, Liuqing; Li, Yi; Zhao, Jie; Chen, Fan; Zhou, Feng; Zhang, Xiaolian; Tan, Jinquan

    2009-01-01

    The major histocompatibility complex (MHC) class I-related molecules A (MICA) is a stress-inducible cell surface antigen that is recognized by intestinal epithelial Vδ1 γδ T cells, natural killer (NK) cells and CD8+ T cells with NKG2D receptor participating in the immunological reaction in the intestinal mucosa. The present study aimed to investigate the functions of the MICA*A5.1 allele in the development of ulcerative colitis (UC) in the Chinese population. The microsatellite polymorphisms of MICA were genotyped in 124 unrelated Chinese patients with UC and 172 ethnically matched healthy controls using a semiautomatic fluorescently labelled polymerase chain reaction. MICA*A5.1-expressing Raji cells were generated by gene transfection. Cytotoxicity of NK cells to Raji cells expressing different MICA molecules was detected using the lactate dehydrogenase method. Soluble MICA in the culture supernatant was detected by enzyme-linked immunosorbent assay. The frequency of MICA*A5.1 was significantly higher in UC patients compared with the healthy controls (29·0% versus 17·4%, P= 0·001, corrected P= 0·005, OR = 1·936, 95% CI 1·310–2·863) and the frequency of a MICA*A5.1/A5.1 homozygous genotype was increased in UC patients (18·5% versus 7% in healthy controls, P= 0·0032, corrected P= 0·048, OR = 3·036, 95% CI 1·447–6·372). Raji cells with MICA*A5.1 expression produced more soluble MICA (t = 5·75, P < 0·01) than Raji cells with full-length MICA expression in culture supernatant. Raji cells with MICA*A5.1 expression were more resistant to killing by NK cells than Raji cells with full-length MICA expression. The MICA*A5.1 allele and MICA*A5.1/A5.1 genotype are significantly associated with Chinese UC patients in central China. MICA*A5.1 may play a role in the development of UC by producing more soluble MICA and resistance to NK cells. PMID:19016911

  14. Recognition of the Major Histocompatibility Complex (MHC) Class Ib Molecule H2-Q10 by the Natural Killer Cell Receptor Ly49C.

    PubMed

    Sullivan, Lucy C; Berry, Richard; Sosnin, Natasha; Widjaja, Jacqueline M L; Deuss, Felix A; Balaji, Gautham R; LaGruta, Nicole L; Mirams, Michiko; Trapani, Joseph A; Rossjohn, Jamie; Brooks, Andrew G; Andrews, Daniel M

    2016-09-01

    Murine natural killer (NK) cells are regulated by the interaction of Ly49 receptors with major histocompatibility complex class I molecules (MHC-I). Although the ligands for inhibitory Ly49 were considered to be restricted to classical MHC (MHC-Ia), we have shown that the non-classical MHC molecule (MHC-Ib) H2-M3 was a ligand for the inhibitory Ly49A. Here we establish that another MHC-Ib, H2-Q10, is a bona fide ligand for the inhibitory Ly49C receptor. H2-Q10 bound to Ly49C with a marginally lower affinity (∼5 μm) than that observed between Ly49C and MHC-Ia (H-2K(b)/H-2D(d), both ∼1 μm), and this recognition could be prevented by cis interactions with H-2K in situ To understand the molecular details underpinning Ly49·MHC-Ib recognition, we determined the crystal structures of H2-Q10 and Ly49C bound H2-Q10. Unliganded H2-Q10 adopted a classical MHC-I fold and possessed a peptide-binding groove that exhibited features similar to those found in MHC-Ia, explaining the diverse peptide binding repertoire of H2-Q10. Ly49C bound to H2-Q10 underneath the peptide binding platform to a region that encompassed residues from the α1, α2, and α3 domains, as well as the associated β2-microglobulin subunit. This docking mode was conserved with that previously observed for Ly49C·H-2K(b) Indeed, structure-guided mutation of Ly49C indicated that Ly49C·H2-Q10 and Ly49C·H-2K(b) possess similar energetic footprints focused around residues located within the Ly49C β4-stand and L5 loop, which contact the underside of the peptide-binding platform floor. Our data provide a structural basis for Ly49·MHC-Ib recognition and demonstrate that MHC-Ib represent an extended family of ligands for Ly49 molecules. PMID:27385590

  15. HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations

    PubMed Central

    Ohashi, Marina; Lebedeva, Tatiana; Acuña-Alonzo, Víctor; Yunis, María; Granados-Montiel, Julio; Cruz-Lagunas, Alfredo; Vargas-Alarcón, Gilberto; Rodríguez-Reyna, Tatiana S.; Fernandez-Viña, Marcelo; Granados, Julio; Yunis, Edmond J.

    2013-01-01

    Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/−B and -DRB1/−DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations. PMID:24086347

  16. Characterization of MHC class I and II genes in a subantarctic seabird, the blue petrel, Halobaena caerulea (Procellariiformes).

    PubMed

    Strandh, Maria; Lannefors, Mimi; Bonadonna, Francesco; Westerdahl, Helena

    2011-10-01

    The great polymorphism observed in the major histocompatibility complex (MHC) genes is thought to be maintained by pathogen-mediated selection possibly combined with MHC-disassortative mating, guided by MHC-determined olfactory cues. Here, we partly characterize the MHC class I and II B of the blue petrel, Halobaena caerulea (Procellariiformes), a bird with significant olfactory abilities that lives under presumably low pathogen burdens in Subantarctica. Blue petrels are long-lived, monogamous birds which suggest the necessity of an accurate mate choice process. The species is ancestral to songbirds (Passeriformes; many MHC loci), although not to gamefowls (Galliformes; few MHC loci). Considering the phylogenetic relationships and the low subantarctic pathogen burden, we expected few rather than many MHC loci in the blue petrel. However, when we analysed partial MHC class I and class II B cDNA and gDNA sequences we found evidence for as many as at least eight MHC class I loci and at least two class II B loci. These class I and II B sequences showed classical MHC characteristics, e.g. high nucleotide diversity, especially in putative peptide-binding regions where signatures of positive selection was detected. Trans-species polymorphism was found between MHC class II B sequences of the blue petrel and those of thin-billed prion, Pachyptila belcheri, two species that diverged ∼25 MYA. The observed MHC allele richness in the blue petrel may well serve as a basis for mate choice, especially since olfactory discrimination of MHC types may be possible in this species. PMID:21607694

  17. Engineering of chimeric class II polyhydroxyalkanoate synthases.

    PubMed

    Niamsiri, Nuttawee; Delamarre, Soazig C; Kim, Young-Rok; Batt, Carl A

    2004-11-01

    PHA synthase is a key enzyme involved in the biosynthesis of polyhydroxyalkanoates (PHAs). Using a combinatorial genetic strategy to create unique chimeric class II PHA synthases, we have obtained a number of novel chimeras which display improved catalytic properties. To engineer the chimeric PHA synthases, we constructed a synthetic phaC gene from Pseudomonas oleovorans (phaC1Po) that was devoid of an internal 540-bp fragment. Randomly amplified PCR products (created with primers based on conserved phaC sequences flanking the deleted internal fragment) were generated using genomic DNA isolated from soil and were substituted for the 540-bp internal region. The chimeric genes were expressed in a PHA-negative strain of Ralstonia eutropha, PHB(-)4 (DSM 541). Out of 1,478 recombinant clones screened for PHA production, we obtained five different chimeric phaC1Po genes that produced more PHA than the native phaC1Po. Chimeras S1-71, S4-8, S5-58, S3-69, and S3-44 exhibited 1.3-, 1.4-, 2.0-, 2.1-, and 3.0-fold-increased levels of in vivo activity, respectively. All of the mutants mediated the synthesis of PHAs with a slightly increased molar fraction of 3-hydroxyoctanoate; however, the weight-average molecular weights (Mw) of the PHAs in all cases remained almost the same. Based upon DNA sequence analyses, the various phaC fragments appear to have originated from Pseudomonas fluorescens and Pseudomonas aureofaciens. The amino acid sequence analyses showed that the chimeric proteins had 17 to 20 amino acid differences from the wild-type phaC1Po, and these differences were clustered in the same positions in the five chimeric clones. A threading model of PhaC1Po, developed based on homology of the enzyme to the Burkholderia glumae lipase, suggested that the amino acid substitutions found in the active chimeras were located mostly on the protein model surface. Thus, our combinatorial genetic engineering strategy proved to be broadly useful for improving the catalytic

  18. MHC class II diversity of koala (Phascolarctos cinereus) populations across their range.

    PubMed

    Lau, Q; Jaratlerdsiri, W; Griffith, J E; Gongora, J; Higgins, D P

    2014-10-01

    Major histocompatibility complex class II (MHCII) genes code for proteins that bind and present antigenic peptides and trigger the adaptive immune response. We present a broad geographical study of MHCII DA β1 (DAB) and DB β1 (DBB) variants of the koala (Phascolarctos cinereus; n=191) from 12 populations across eastern Australia, with a total of 13 DAB and 7 DBB variants found. We identified greater MHCII variation and, possibly, additional gene copies in koala populations in the north (Queensland and New South Wales) relative to the south (Victoria), confirmed by STRUCTURE analyses and genetic differentiation using analysis of molecular variance. The higher MHCII diversity in the north relative to south could potentially be attributed to (i) significant founder effect in Victorian populations linked to historical translocation of bottlenecked koala populations and (ii) increased pathogen-driven balancing selection and/or local genetic drift in the north. Low MHCII genetic diversity in koalas from the south could reduce their potential response to disease, although the three DAB variants found in the south had substantial sequence divergence between variants. This study assessing MHCII diversity in the koala with historical translocations in some populations contributes to understanding the effects of population translocations on functional genetic diversity. PMID:24690756

  19. High levels of MHC class II allelic diversity in lake trout from Lake Superior

    USGS Publications Warehouse

    Dorschner, M.O.; Duris, T.; Bronte, C.R.; Burnham-Curtis, M. K.; Phillips, R.B.

    2000-01-01

    Sequence variation in a 216 bp portion of the major histocompatibility complex (MHC) II B1 domain was examined in 74 individual lake trout (Salvelinus namaycush) from different locations in Lake Superior. Forty-three alleles were obtained which encoded 71-72 amino acids of the mature protein. These sequences were compared with previous data obtained from five Pacific salmon species and Atlantic salmon using the same primers. Although all of the lake trout alleles clustered together in the neighbor-joining analysis of amino acid sequences, one amino acid allelic lineage was shared with Atlantic salmon (Salmo salar), a species in another genus which probably diverged from Salvelinus more than 10-20 million years ago. As shown previously in other salmonids, the level of nonsynonymous nucleotide substitution (d(N)) exceeded the level of synonymous substitution (d(S)). The level of nucleotide diversity at the MHC class II B1 locus was considerably higher in lake trout than in the Pacific salmon (genus Oncorhynchus). These results are consistent with the hypothesis that lake trout colonized Lake Superior from more than one refuge following the Wisconsin glaciation. Recent population bottlenecks may have reduced nucleotide diversity in Pacific salmon populations.

  20. Coordinated changes of histone modifications and HDAC mobilization regulate the induction of MHC class II genes by Trichostatin A

    PubMed Central

    2006-01-01

    The deacetylase inhibitor Trichostatin A (TSA) induces the transcription of the Major Histocompatibility Class II (MHC II) DRA gene in a way independent of the master coactivator CIITA. To analyze the molecular mechanisms by which this epigenetic regulator stimulates MHC II expression, we used chromatin immunoprecipitation (ChIP) assays to monitor the alterations in histone modifications that correlate with DRA transcription after TSA treatment. We found that a dramatic increase in promoter linked histone acetylation is followed by an increase in Histone H3 lysine 4 methylation and a decrease of lysine 9 methylation. Fluorescence recovery after photobleaching (FRAP) experiments showed that TSA increases the mobility of HDAC while decreasing the mobility of the class II enhanceosome factor RFX5. These data, in combination with ChIP experiments, indicate that the TSA-mediated induction of DRA transcription involves HDAC relocation and enhanceosome stabilization. In order to gain a genome-wide view of the genes responding to inhibition of deacetylases, we compared the transcriptome of B cells before and after TSA treatment using Affymetrix microarrays. This analysis showed that in addition to the DRA gene, the entire MHC II family and the adjacent histone cluster that are located in chromosome 6p21-22 locus are strongly induced by TSA. A complex pattern of gene reprogramming by TSA involves immune recognition, antiviral, apoptotic and inflammatory pathways and extends the rationale for using Histone Deacetylase Inhibitors (HDACi) to modulate the immune response. PMID:16452299

  1. The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

    PubMed Central

    Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.; Broughton, Sophie E.; Huyton, Trevor; Anderson, Robert P.; McCluskey, James; Rossjohn, Jamie

    2007-01-01

    The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4+ T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8 α-I (EGSFQPSQE), respectively, are reported. PMID:18084083

  2. 78 FR 37114 - Self-Regulation of Class II Gaming

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-06-20

    ... the issuance of a certificate for tribal self-regulation of Class II gaming. 78 FR 20236, April 4..., productivity, innovation, or the ability of U.S.-based enterprises to compete with foreign-based...

  3. Class II barodontalgia: review and report of a case.

    PubMed

    Woodmansey, Karl

    2008-01-01

    Barodontalgia is a rarely reported condition involving changes in ambient pressure resulting in tooth pain. According to Ferjentsik and Aker, Class II barodontalgia is observed in teeth that have pre-existing pulpal disease and an ultimate diagnosis of irreversible pulpitis.1 This article describes a case of Class II barodontalgia that was experienced on a commercial airline flight and reviews current knowledge regarding this phenomenon, including proposed etiologic mechanisms. PMID:21444271

  4. Evolution and Distribution of Class II-Related Endogenous Retroviruses†

    PubMed Central

    Gifford, Robert; Kabat, Peter; Martin, Joanne; Lynch, Clare; Tristem, Michael

    2005-01-01

    Endogenous retroviruses (ERVs) are widespread in vertebrate genomes and have been loosely grouped into “classes” on the basis of their phylogenetic relatedness to the established genera of exogenous retroviruses. Four of these genera—the lentiviruses, alpharetroviruses, betaretroviruses, and deltaretroviruses—form a well-supported clade in retroviral phylogenies, and ERVs that group with these genera have been termed class II ERVs. We used PCR amplification and sequencing of retroviral fragments from more than 130 vertebrate taxa to investigate the evolution of the class II retroviruses in detail. We confirm that class II retroviruses are largely confined to mammalian and avian hosts and provide evidence for a major novel group of avian retroviruses, and we identify additional members of both the alpha- and the betaretrovirus genera. Phylogenetic analyses demonstrated that the avian and mammalian viruses form distinct monophyletic groups, implying that interclass transmission has occurred only rarely during the evolution of the class II retroviruses. In contrast to previous reports, the lentiviruses clustered as sister taxa to several endogenous retroviruses derived from rodents and insectivores. This topology was further supported by the shared loss of both the class II PR-Pol frameshift site and the class II retrovirus G-patch domain. PMID:15858031

  5. Diagnostic features of Angle's Class II div 2 malocclusion

    PubMed Central

    Dodda, Kiran Kumar; Prasad, Singamsetty E. R. V.; Kanuru, Ravi Krishna; Nalluri, Siddhartha; Mittapalli, Radhika; Raghavendra

    2015-01-01

    Statement of Problem: A thorough knowledge of the salient features of malocclusion makes the practitioner to come to a proper diagnosis and to formulate proper mechanotherapy. It also helps to predict the prognosis, prior to the onset of treatment process. Among the various malocclusions, Class II div 2 occurs the least often. The literature review does not clearly describe the classical skeletal and dental features of Angle's Class II div 2 malocclusion. Purpose of Study: The aim of this study is to describe the unique features of Angle's Class II division 2 malocclusion. Materials and Methods: A total of 612 pre-treatment records (study models and cephalograms), with age ranging from 14 to 25 years, were obtained from the hospital records of Drs Sudha and Nageswar Rao Siddhartha Institute of Dental Sciences. Among these samples, 317 were Class II div 1 and 295 were Class II div 2. The lateral cephalograms were analyzed by using Kodak software and the arch width analysis was calculated by using digital vernier calipers. Results: Student's t test was used for the study. On the cephalograms, the vertical skeletal measurements and few of the dental variables showed a significant difference. On the plaster models, the maxillary transverse measurements revealed a notable discrimination between the groups. Conclusion: Angle's Class II div 2 malocclusion has a marked horizontal growth pattern with decreased lower facial thirds, palatally inclined upper anteriors, and remarkably increased transverse maxillary arch dimensions. PMID:26759807

  6. 40 CFR 144.19 - Transitioning from Class II to Class VI.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...) Increase in carbon dioxide injection rates; (3) Decrease in reservoir production rates; (4) Distance... Transitioning from Class II to Class VI. (a) Owners or operators that are injecting carbon dioxide for the... of carbon dioxide at the cessation of injection; (8) The source and properties of injected...

  7. 40 CFR 144.19 - Transitioning from Class II to Class VI.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) Increase in carbon dioxide injection rates; (3) Decrease in reservoir production rates; (4) Distance... Transitioning from Class II to Class VI. (a) Owners or operators that are injecting carbon dioxide for the... of carbon dioxide at the cessation of injection; (8) The source and properties of injected...

  8. 40 CFR 144.19 - Transitioning from Class II to Class VI.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...) Increase in carbon dioxide injection rates; (3) Decrease in reservoir production rates; (4) Distance... Transitioning from Class II to Class VI. (a) Owners or operators that are injecting carbon dioxide for the... of carbon dioxide at the cessation of injection; (8) The source and properties of injected...

  9. Analysis of T-cell hybridomas with an unusual MHC class II-dependent ligand specificity.

    PubMed Central

    Mendiratta, S K; Singh, N; Bal, V; Rath, S

    1996-01-01

    We have characterized two unusual T-cell hybridomas, 1E3 and 3B8, from H-2k mice immunized with I-Ab-transfected L cells (H-2k), that are stimulated by L cells transfected with I-Ab, I-Ak or I-Eb, but not by non-transfected L cells. These hybridomas could not be stimulated by spleen cells from H-2i3, H-2k, H-2b or H-2d mice. Monoclonal anti-I-A antibodies did not block their responses, suggesting that mouse major histocompatibility complex (MHC) class II molecules may be peptide donors rather than restriction elements for them. The stimulation of these hybridomas by fibroblast targets was not blocked by an anti-H-2kk, Dk-specific monoclonal antibody. Lipopolysaccharide (LPS)-activated splenic and peritoneal exudate cells from H-2k, H-2d, H-2i3, H-2b as well as beta 2-microglobulin-deficient, TAP-1-deficient and I-A alpha-deficient H-2b mice stimulated these hybridomas. LPS could also activate a macrophage cell line, but not a B-cell line, to become stimulatory for 1E3. A rat antiserum against untransfected L cells specifically and significantly blocked the response of 1E3. Thus, 1E3 may recognize a conserved murine MHC class II peptide loaded in a TAP-1-independent fashion on a non-classical, monomorphic, beta 2-microglobulin-independent restriction element. PMID:8943720

  10. Mutant MHC class II epitopes drive therapeutic immune responses to cancer

    PubMed Central

    Kreiter, Sebastian; Vormehr, Mathias; van de Roemer, Niels; Diken, Mustafa; Löwer, Martin; Diekmann, Jan; Boegel, Sebastian; Schrörs, Barbara; Vascotto, Fulvia; Castle, John C.; Tadmor, Arbel D.; Schoenberger, Stephen P.; Huber, Christoph; Türeci, Özlem; Sahin, Ugur

    2016-01-01

    Tumour-specific mutations are ideal targets for cancer immunotherapy as they lack expression in healthy tissues and can potentially be recognized as neo-antigens by the mature T-cell repertoire. Their systematic targeting by vaccine approaches, however, has been hampered by the fact that every patient’s tumour possesses a unique set of mutations (‘the mutanome’) that must first be identified. Recently, we proposed a personalized immunotherapy approach to target the full spectrum of a patient’s individual tumour-specific mutations1. Here we show in three independent murine tumour models that a considerable fraction of non-synonymous cancer mutations is immunogenic and that, unexpectedly, the majority of the immunogenic mutanome is recognized by CD4+ T cells. Vaccination with such CD4+ immunogenic mutations confers strong antitumour activity. Encouraged by these findings, we established a process by which mutations identified by exome sequencing could be selected as vaccine targets solely through bioinformatic prioritization on the basis of their expression levels and major histocompatibility complex (MHC) class II-binding capacity for rapid production as synthetic poly-neo-epitope messenger RNA vaccines. We show that vaccination with such polytope mRNA vaccines induces potent tumour control and complete rejection of established aggressively growing tumours in mice. Moreover, we demonstrate that CD4+ T cell neo-epitope vaccination reshapes the tumour microenvironment and induces cytotoxic T lymphocyte responses against an independent immunodominant antigen in mice, indicating orchestration of antigen spread. Finally, we demonstrate an abundance of mutations predicted to bind to MHC class II in human cancers as well by employing the same predictive algorithm on corresponding human cancer types. Thus, the tailored immunotherapy approach introduced here may be regarded as a universally applicable blueprint for comprehensive exploitation of the substantial neo

  11. MHC class II transcription is associated with inflammatory responses in a wild marine mammal.

    PubMed

    Montano-Frías, Jorge E; Vera-Massieu, Camila; Álvarez-Martínez, Roberto; Flores-Morán, Adriana; Acevedo-Whitehouse, Karina

    2016-08-01

    Inflammation is one of the most important non-specific and rapid responses that a vertebrate can elicit in response to damage or a foreign insult. To date, despite increasing evidence that the innate and adaptive branches of immunity are more intricately related than previously thought, few have examined interactions between the Major Histocompatibility Complex (MHC, a polymorphic region of the vertebrate genome that is involved with antigen presentation) and inflammation, and even less is known about these interactions in an eco-immunological context. Here, we examined the effect of MHC class II DRB gene multiplicity and transcription on phytohemagglutinin (PHA)-induced inflammation during the early stages of development of California sea lions. Neither constitutive nor expressed ZacaDRB diversity was found to be associated with pup responses to PHA at any of the stages of pup development. However, for two-month-old pups, those with a specific MHC-DRB locus (ZacaDRB-A) tended to have less efficient responsive inflammation. Transcription of distinct MHC-DRB loci was also linked to PHA-induced inflammation, with patterns that varied markedly between ages, and that suggested that ongoing infectious processes could limit the capacity to respond to a secondary challenge. Life history constraints and physiological processes associated with development of California sea lions, in conjunction with their changing pathogenic environment could explain the observed effects of MHC class II transcription on PHA-induced inflammation. To our knowledge, ours is the first study to examine the importance of expressed vs. constitutive MHC loci on inflammation in a natural population. PMID:27137083

  12. Single-Molecule Motions of MHC Class II Rely on Bound Peptides

    PubMed Central

    Kozono, Haruo; Matsushita, Yufuku; Ogawa, Naoki; Kozono, Yuko; Miyabe, Toshihiro; Sekiguchi, Hiroshi; Ichiyanagi, Kouhei; Okimoto, Noriaki; Taiji, Makoto; Kanagawa, Osami; Sasaki, Yuji C.

    2015-01-01

    The major histocompatibility complex (MHC) class II protein can bind peptides of different lengths in the region outside the peptide-binding groove. Peptide-flanking residues (PFRs) contribute to the binding affinity of the peptide for MHC and change the immunogenicity of the peptide/MHC complex with regard to T cell receptor (TCR). The mechanisms underlying these phenomena are currently unknown. The molecular flexibility of the peptide/MHC complex may be an important determinant of the structures recognized by certain T cells. We used single-molecule x-ray analysis (diffracted x-ray tracking (DXT)) and fluorescence anisotropy to investigate these mechanisms. DXT enabled us to monitor the real-time Brownian motion of the peptide/MHC complex and revealed that peptides without PFRs undergo larger rotational motions than peptides with PFRs. Fluorescence anisotropy further revealed that peptides without PFRs exhibit slightly larger motions on the nanosecond timescale. These results demonstrate that peptides without PFRs undergo dynamic motions in the groove of MHC and consequently are able to assume diverse structures that can be recognized by T cells. PMID:25606683

  13. Design of Peptide Immunotherapies for MHC Class-II-Associated Autoimmune Disorders

    PubMed Central

    2013-01-01

    Autoimmune disorders, that occur when autoreactive immune cells are induced to activate their responses against self-tissues, affect one percent of the world population and represent one of the top 10 leading causes of death. The major histocompatibility complex (MHC) is a principal susceptibility locus for many human autoimmune diseases, in which self-tissue antigens providing targets for pathogenic lymphocytes are bound to HLA molecules encoded by disease-associated alleles. In spite of the attempts to design strategies for inhibition of antigen presentation targeting the MHC-peptide/TCR complex via generation of blocking antibodies, altered peptide ligands (APL), or inhibitors of costimulatory molecules, potent therapies with minimal side effects have yet to be developed. Copaxone (glatiramer acetate, GA) is a random synthetic amino acid copolymer that reduces the relapse rate by about 30% in relapsing-remitting multiple sclerosis (MS) patients. Based on the elucidated binding motifs of Copaxone and of the anchor residues of the immunogenic myelin basic protein (MBP) peptide to HLA-DR molecules, novel copolymers have been designed and proved to be more effective in suppressing MS-like disease in mice. In this report, we describe the rationale for design of second-generation synthetic random copolymers as candidate drugs for a number of MHC class-II-associated autoimmune disorders. PMID:24324511

  14. MHC class II B diversity in blue tits: a preliminary study

    PubMed Central

    Aguilar, Juan Rivero-de; Schut, Elske; Merino, Santiago; Martínez, Javier; Komdeur, Jan; Westerdahl, Helena

    2013-01-01

    In this study, we partly characterize major histocompatibility complex (MHC) class II B in the blue tit (Cyanistes caeruleus). A total of 22 individuals from three different European locations: Spain, The Netherlands, and Sweden were screened for MHC allelic diversity. The MHC genes were investigated using both PCR-based methods and unamplified genomic DNA with restriction fragment length polymorphism (RFLP) and southern blots. A total of 13 different exon 2 sequences were obtained independently from DNA and/or RNA, thus confirming gene transcription and likely functionality of the genes. Nine out of 13 alleles were found in more than one country, and two alleles appeared in all countries. Positive selection was detected in the region coding for the peptide binding region (PBR). A maximum of three alleles per individual was detected by sequencing and the RFLP pattern consisted of 4–7 fragments, indicating a minimum number of 2–4 loci per individual. A phylogenetic analysis, demonstrated that the blue tit sequences are divergent compared to sequences from other passerines resembling a different MHC lineage than those possessed by most passerines studied to date. PMID:23919136

  15. ITAM signaling in dendritic cells controls T helper cell priming by regulating MHC class II recycling

    PubMed Central

    Graham, Daniel B.; Akilesh, Holly M.; Gmyrek, Grzegorz B.; Piccio, Laura; Gilfillan, Susan; Sim, Julia; Belizaire, Roger; Carrero, Javier A.; Wang, Yinan; Blaufuss, Gregory S.; Sandoval, Gabriel; Fujikawa, Keiko; Cross, Anne H.; Russell, John H.; Cella, Marina

    2010-01-01

    Immature dendritic cells (DCs) specialize in antigen capture and maintain a highly dynamic pool of intracellular major histocompatibility complex class II (MHCII) that continuously recycles from peptide loading compartments to the plasma membrane and back again. This process facilitates sampling of environmental antigens for presentation to T helper cells. Here, we show that a signaling pathway mediated by the DC immunoreceptor tyrosine-based activation motif (ITAM)–containing adaptors (DAP12 and FcRγ) and Vav family guanine nucleotide exchange factors controls the half-life of surface peptide-MHCII (pMHCII) complexes and is critical for CD4 T-cell triggering in vitro. Strikingly, mice with disrupted DC ITAMs show defective T helper cell priming in vivo and are protected from experimental autoimmune encephalitis. Mechanistically, we show that deficiency in ITAM signaling results in increased pMHCII internalization, impaired recycling, and an accumulation of ubiquitinated MHCII species that are prematurely degraded in lysosomes. We propose a novel mechanism for control of T helper cell priming. PMID:20634378

  16. MHC class II compatibility in aborted fetuses and term infants of couples with recurrent spontaneous abortion.

    PubMed

    Ober, C; Steck, T; van der Ven, K; Billstrand, C; Messer, L; Kwak, J; Beaman, K; Beer, A

    1993-12-01

    Maternal-fetal histocompatibility for alleles at HLA class II loci, HLA-DQA1 and HLA-DQB1, was examined in 40 abortuses and 31 liveborn children of 68 couples with a history of idiopathic recurrent spontaneous abortion (RSAB) who underwent leukocyte immunization prior to the index pregnancy. Significantly more couples with RSAB shared two HLA-DQA1 alleles as compared with fertile control couples (0.18 vs. 0.03, respectively; P = 0.031). There were no differences in HLA sharing between couples with RSAB who experienced a repeat abortion in the index pregnancy as compared with couples with RSAB who were delivered of a liveborn child. Non-significant deficits of abortuses who were compatible for alleles at the HLA-DQA1 (6 observed vs. 8.5 expected; P = 0.225) and the HLA-DQB1 (7 observed vs. 9.2 expected; P = 0.254) loci were observed. A significant deficit of HLA-DQA1 compatible liveborn children was observed (1 observed vs. 5.5 expected; P = 0.0069). The overall deficit of HLA-DQA1 compatible fetuses (7 observed vs. 14.0 expected; P = 0.0018) after approximately 8 weeks gestation suggests that HLA-DQA1 compatible fetuses may be aborted early in pregnancy, prior to the time when fetal tissue can be recovered for genetic studies. PMID:8207709

  17. Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro

    PubMed Central

    2014-01-01

    Introduction The horse is a valuable species to assess the effect of allogeneic mesenchymal stromal cells (MSCs) in regenerative treatments. No studies to date have examined recipient response to major histocompatibility complex (MHC)-mismatched equine MSCs. The purposes of this study were to immunophenotype MSCs from horses of known MHC haplotype and to compare the immunogenicity of MSCs with differing MHC class II expression. Methods MSCs and peripheral blood leukocytes (PBLs) were obtained from Thoroughbred horses (n = 10) of known MHC haplotype (ELA-A2, -A3, and -A9 homozygotes). MSCs were cultured through P8; cells from each passage (P2 to P8) were cryopreserved until used. Immunophenotyping of MHC class I and II, CD44, CD29, CD90, LFA-1, and CD45RB was performed by using flow cytometry. Tri-lineage differentiation assays were performed to confirm MSC multipotency. Recombinant equine IFN-γ was used to stimulate MHC class II negative MSCs in culture, after which expression of MHC class II was re-examined. To assess the ability of MHC class II negative or positive MSCs to stimulate an immune response, modified one-way mixed leukocyte reactions (MLRs) were performed by using MHC-matched and mismatched responder PBLs and stimulator PBLs or MSCs. Proliferation of gated CFSE-labeled CD3+ responder T cells was evaluated via CFSE attenuation by using flow cytometry and reported as the number of cells in the proliferating T-cell gate. Results MSCs varied widely in MHC class II expression despite being homogenous in terms of “stemness” marker expression and ability to undergo trilineage differentiation. Stimulation of MHC class II negative MSCs with IFN-γ resulted in markedly increased expression of MHC class II. MLR results revealed that MHC-mismatched MHC class II-positive MSCs caused significantly increased responder T-cell proliferation compared with MHC-mismatched MHC class II-negative and MHC-matched MSCs, and equivalent to that of the positive control of

  18. PowerScope a Class II corrector - A case report.

    PubMed

    Paulose, Joby; Antony, Palathottungal Joseph; Sureshkumar, Brijesh; George, Susha Mariam; Mathew, Manu Mundackal; Sebastian, Joseph

    2016-01-01

    Managing mild to moderate Class II malocclusion is a one of the common and major challenges to orthodontists. Class II discrepancies with mandibular deficiency during active growth are usually treated by myofunctional appliances. Fixed functional appliances evolved due to the noncompliance with conventional myofunctional appliances. This case report illustrates the efficiency of PowerScope in correction of skeletal Class II with mandibular deficiency in a patient aged 13 years who has reported to the department with a chief complaint of forwardly placed upper front teeth. This case with functional jaw retrusion was treated initially with MBT 0.022" prescription followed by PowerScope. Pre-, mid- and post-treatment cephalograms were obtained, and cephalometric analysis was performed. Stable and successful results were obtained with a substantial improvement in facial profile, skeletal jaw relationship, and overall esthetic appearance of the patient. A significant forward displacement of the mandible was the principal element for successful correction of Class II malocclusion. PowerScope provides the best results for Class II management, thus enables us to treat such cases by a nonextraction approach rather than contemplating extractions. PMID:27307671

  19. The role of charge and multiple faces of the CD8 alpha/alpha homodimer in binding to major histocompatibility complex class I molecules: support for a bivalent model.

    PubMed Central

    Giblin, P A; Leahy, D J; Mennone, J; Kavathas, P B

    1994-01-01

    The CD8 dimer interacts with the alpha 3 domain of major histocompatibility complex class I molecules through two immunoglobulin variable-like domains. In this study a crystal structure-informed mutational analysis has been performed to identify amino acids in the CD8 alpha/alpha homodimer that are likely to be involved in binding to class I. Several key residues are situated on the top face of the dimer within loops analogous to the complementarity-determining regions (CDRs) of immunoglobulin. In addition, other important amino acids are located in the A and B beta-strands on the sides of the dimer. The potential involvement of amino acids on both the top and the side faces of the molecule is consistent with a bivalent model for the interaction between a single CD8 alpha/alpha homodimer and two class I molecules and may have important implications for signal transduction in class I-expressing cells. This study also demonstrates a role for the positive surface potential of CD8 in class I binding and complements previous work demonstrating the importance of a negatively charged loop on the alpha 3 domain of class I for CD8 alpha/alpha-class I interaction. We propose a model whereby residues located on the CDR-like loops of the CD8 homodimer interact with the alpha 3 domain of MHC class I while amino acids on the side of the molecule containing the A and B beta-strands contact the alpha 2 domain of class I. Images PMID:8127870

  20. In vitro digestion with proteases producing MHC class II ligands.

    PubMed

    Tohmé, Mira; Maschalidi, Sophia; Manoury, Bénédicte

    2013-01-01

    Proteases generate peptides that bind to MHC class II molecules to interact with a wide diversity of CD4(+) T cells. They are expressed in dedicated organelles: endosomes and lysosomes of professional antigen presenting cells (pAPCs) such as B cells, macrophages, and dendritic cells. The identification of endosomal proteases which produce antigenic peptides is important, for example, for better vaccination and to prevent autoimmune diseases. Here, we describe a panel of technics (in vitro digestion assays of protein with recombinant proteases or purified endosomes/lysosomes, T cell stimulation) to monitor the production of MHC class II ligands. PMID:23329510

  1. Highly Pathogenic Simian Immunodeficiency Virus mne Variants That Emerge during the Course of Infection Evolve Enhanced Infectivity and the Ability To Downregulate CD4 but Not Class I Major Histocompatibility Complex Antigens

    PubMed Central

    Patel, Parul G.; Yu Kimata, Monica T.; Biggins, Julia E.; Wilson, Joelle M.; Kimata, Jason T.

    2002-01-01

    The replicative, cytopathic, and antigenic properties of simian immunodeficiency virus (SIV) variants influence its replication efficiency in vivo. To further define the viral properties and determinants that may be important for high-level replication in vivo and progression to AIDS, we compared a minimally pathogenic SIVmne molecular clone with two highly pathogenic variants cloned from late stages of infection. Both variants had evolved greater infectivity than the parental clone due to mutations in nef. Interestingly, a pol determinant in one of the highly pathogenic variants also contributed to its increased infectivity. Furthermore, because replication in vivo may also be influenced by the ability of a virus to evade the cellular immune response of the host, we examined whether the variants were more capable of downregulating surface expression of class I major histocompatibility complex (MHC). Decreased MHC class I expression was not observed in cells infected with any of the viruses. Furthermore, the Nef proteins of the highly pathogenic variants only slightly reduced surface MHC class I expression in transfected cells, although they efficiently downregulated CD4. Together, these data demonstrate that mutations which can enhance viral infectivity, as well as CD4 downregulation, may be important for efficient replication of SIV in the host. However, Nef-mediated reduction of MHC class I expression does not appear to be critical for the increased in vivo replicative ability of highly pathogenic late variants. PMID:12050354

  2. Intranasal antigen targeting to MHC class II molecules primes local IgA and serum IgG antibody responses in mice.

    PubMed

    Snider, D P; Underdown, B J; McDermott, M R

    1997-03-01

    Covalent conjugates of hen egg lysozyme (HEL) and anti-major histocompatibility complex (MHC) class II monoclonal antibodies (mAb) were used to immunize mice intranasally. Three weeks after intranasal (IN) priming, mice responded rapidly to IN challenge with a mixture of HEL and cholera toxin (CT), by producing large titres of anti-HEL IgA and IgG1 antibody in serum, and IgA antibody in nasal secretions. No secondary response to HEL plus CT occurred in mice that received no priming or mice primed with HEL alone. The secondary serum IgG antibody response was dominated by the IgG1 subclass. HEL combined with CT adjuvant worked much better than HEL alone in producing the secondary response. Control conjugates, containing an IgG isotype-matched mAb without specificity for mouse tissues, provided poor priming. Mice expressing MHC class II molecules, to which the anti-MHC II mAb could not bind, produced a weak antibody response compared with those that expressed the appropriate. MHC class II molecule. Our results demonstrate that immunotargeting to MHC class II molecules via the IN route allows priming of the local IgA and circulating IgG antibody, and indicate that this technique is a feasible approach for delivery of subunit vaccines in the upper respiratory tract. PMID:9155636

  3. Towards a systems understanding of MHC class I and MHC class II antigen presentation.

    PubMed

    Neefjes, Jacques; Jongsma, Marlieke L M; Paul, Petra; Bakke, Oddmund

    2011-12-01

    The molecular details of antigen processing and presentation by MHC class I and class II molecules have been studied extensively for almost three decades. Although the basic principles of these processes were laid out approximately 10 years ago, the recent years have revealed many details and provided new insights into their control and specificity. MHC molecules use various biochemical reactions to achieve successful presentation of antigenic fragments to the immune system. Here we present a timely evaluation of the biology of antigen presentation and a survey of issues that are considered unresolved. The continuing flow of new details into our understanding of the biology of MHC class I and class II antigen presentation builds a system involving several cell biological processes, which is discussed in this Review. PMID:22076556

  4. An engineered class I transfer RNA with a class II tertiary fold.

    PubMed Central

    Nissan, T A; Oliphant, B; Perona, J J

    1999-01-01

    Structure-based engineering of the tertiary fold of Escherichia coli tRNA(Gln)2 has enabled conversion of this transfer RNA to a class II structure while retaining recognition properties of a class I glutamine tRNA. The new tRNA possesses the 20-nt variable stem-loop of Thermus thermophilus tRNA(Ser). Enlargement of the D-loop appears essential to maintaining a stable tertiary structure in this species, while rearrangement of a base triple in the augmented D-stem is critical for efficient glutaminylation. These data provide new insight into structural determinants distinguishing the class I and class II tRNA folds, and demonstrate a marked sensitivity of glutaminyl-tRNA synthetase to alteration of tRNA tertiary structure. PMID:10094311

  5. 77 FR 4714 - Self-Regulation of Class II Gaming

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-01-31

    ...This action proposes to amend the NIGC's self-regulation regulations to tailor the self-regulating qualifying criteria to a tribe's regulation of class II gaming activity and more clearly define and streamline the self-regulation certification process. By tailoring the self-regulating qualifying criteria to the capabilities of a tribe's regulatory body, and by clarifying and streamlining the......

  6. MHC class II DR allelic diversity in bighorn sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We hypothesized that decreased diversity and/or unique polymorphisms in MHC class II alleles of bighorn sheep (BHS, Ovis canadensis) are responsible for lower titer of antibodies against Mannheimia haemolytica leukotoxin, in comparison to domestic sheep (DS, Ovis aries). To test this hypothesis, DRA...

  7. 49 CFR 238.317 - Class II brake test.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Class II brake test. 238.317 Section 238.317 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION PASSENGER EQUIPMENT SAFETY STANDARDS Inspection, Testing, and Maintenance Requirements for Tier I Passenger Equipment...

  8. 18 CFR 415.21 - Class II projects.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 18 Conservation of Power and Water Resources 2 2012-04-01 2012-04-01 false Class II projects. 415.21 Section 415.21 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION... flooded, would pollute the waters of the basin or threaten damage to off-site areas, including,...

  9. 18 CFR 415.21 - Class II projects.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 18 Conservation of Power and Water Resources 2 2013-04-01 2012-04-01 true Class II projects. 415.21 Section 415.21 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION... flooded, would pollute the waters of the basin or threaten damage to off-site areas, including,...

  10. 18 CFR 415.21 - Class II projects.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 18 Conservation of Power and Water Resources 2 2014-04-01 2014-04-01 false Class II projects. 415.21 Section 415.21 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION... flooded, would pollute the waters of the basin or threaten damage to off-site areas, including,...

  11. 18 CFR 415.21 - Class II projects.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 18 Conservation of Power and Water Resources 2 2011-04-01 2011-04-01 false Class II projects. 415.21 Section 415.21 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION... flooded, would pollute the waters of the basin or threaten damage to off-site areas, including,...

  12. 18 CFR 415.21 - Class II projects.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 18 Conservation of Power and Water Resources 2 2010-04-01 2010-04-01 false Class II projects. 415.21 Section 415.21 Conservation of Power and Water Resources DELAWARE RIVER BASIN COMMISSION... flooded, would pollute the waters of the basin or threaten damage to off-site areas, including,...

  13. 14 CFR 21.223 - Class II provisional airworthiness certificates.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Class II provisional airworthiness certificates. 21.223 Section 21.223 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION, DEPARTMENT OF... the aircraft has been issued to the manufacturer. (c) The applicant must submit a statement by...

  14. H2-M3 Major Histocompatibility Complex Class Ib-Restricted CD8 T Cells Induced by Salmonella enterica Serovar Typhimurium Infection Recognize Proteins Released by Salmonella Serovar Typhimurium

    PubMed Central

    Ugrinovic, S.; Brooks, C. G.; Robson, J.; Blacklaws, B. A.; Hormaeche, C. E.; Robinson, J. H.

    2005-01-01

    Salmonella enterica serovar Typhimurium causes a typhoid-like disease in mice which has been studied extensively as a model for typhoid fever in humans. CD8 T cells contribute to protection against S. enterica serovar Typhimurium in mice, but little is known about the specificity and major histocompatibility complex (MHC) restriction of the response. We report here that CD8 T-cell lines derived from S. enterica serovar Typhimurium-infected BALB/c mice lysed bone marrow macrophages infected with S. enterica serovar Typhimurium or pulsed with proteins from S. enterica serovar Typhimurium culture supernatants. Cytoxicity was beta-2-microglobulin dependent and largely TAP dependent, although not MHC class Ia restricted, as target cells of several different MHC haplotypes were lysed. The data suggested the participation of class Ib MHC molecules although no evidence for the presence of Qa1-restricted T cells could be found, unlike in previous reports. Instead, the T-cell lines lysed H2-M3-transfected fibroblasts infected with S. enterica serovar Typhimurium SL3261 or treated with Salmonella culture supernatants. Thus, this report increases the number of MHC class Ib antigen-presenting molecules known for Salmonella antigens to three: Qa-1, HLA-E, and now H2-M3. It also expands the range of pathogens that induce H2-M3-restricted CD8 T cells to include an example of gram-negative bacteria. PMID:16299293

  15. Intermediate number of major histocompatibility complex class IIB length variants relates to enlarged perivisceral fat deposits in the blunt-head cichlid Tropheus moorii.

    PubMed

    Hablützel, P I; Vanhove, M P M; Grégoir, A F; Hellemans, B; Volckaert, F A M; Raeymaekers, J A M

    2014-10-01

    Studying the genetic basis of host-parasite interactions represents an outstanding opportunity to observe eco-evolutionary processes. Established candidates for such studies in vertebrates are immunogenes of the major histocompatibility complex (MHC). The MHC has been reported to reach high intra- and interindividual diversity, and a diverse MHC might be advantageous when facing infections from multiple parasites. However, other studies indicated that individuals with an intermediate number of MHC alleles are less infected with parasites or have other fitness advantages. In this study, we assessed the optimal number of MHC alleles in the blunt-head cichlid Tropheus moorii from Lake Tanganyika. We investigated the influence of the interindividual variation in number of MHC length variants on parasite infection and body condition, measured by the amount of perivisceral fat reserves. Surprisingly, there was no correlation between parasite infection and number of MHC length variants or perivisceral fat deposits. However, the individual number of MHC length variants significantly correlated with the amount of perivisceral fat deposits in males, suggesting that male individuals with an intermediate number of alleles might be able to use their fat reserves more efficiently. PMID:25201492

  16. The diversity of major histocompatibility complex class II DRB1 gene in sheep breeds from Xinjiang, China.

    PubMed

    Polat, M; Aida, Y; Takeshima, S-N; Aniwashi, J; Halik, M

    2015-01-01

    Exon 2 of the ovine leukocyte antigen OLA-DRB1 locus was examined in sheep from the Xinjiang Karakul Ram and Bashibai populations, and three generations of hybrids were derived from a cross between Bashibai and Altai Argali wild sheep. This identified 12 novel alleles and 30 previously reported alleles. A neighbor-joining tree of the amino acid sequences of these 42 alleles revealed allelic clusters shared across the study populations. There were significant differences in allelic frequency between Karakul Ram and Bashibai sheep. DRB1*K18cC was the most frequent allele in Kararul Ram with a frequency of 21.2%, while DRB1*2F10c8 (13.2%) and DRB1*0803 (13.2%) were the most frequent alleles found in Bashibai sheep; the alleles DRB1*2F16c2, DRB1*1601, and DRB1*0803 occurred most frequently in F1, F2, and F3 populations, with frequencies of 17.6%, 14.3%, and 20%, respectively. Although many alleles were shared by Bashibai and hybrid sheep, some alleles differed between them, especially in the F1 generation of the Bashibai × Altai Argali cross. The hybrid-specific alleles indicated the introgression of Altai Argali alleles into hybrid flocks. A population tree based on the OLA-DRB1 allelic frequency in each population indicated that the Bashibai sheep and three hybrid populations were similar, with Karakul Ram being genetically distinct. PMID:25430475

  17. 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

  18. Effect of HLA Class I and Class II Alleles on Progression From Autoantibody Positivity to Overt Type 1 Diabetes in Children With Risk-Associated Class II Genotypes

    PubMed Central

    Lipponen, Kati; Gombos, Zsofia; Kiviniemi, Minna; Siljander, Heli; Lempainen, Johanna; Hermann, Robert; Veijola, Riitta; Simell, Olli; Knip, Mikael; Ilonen, Jorma

    2010-01-01

    OBJECTIVE Class II alleles define the main HLA effect on type 1 diabetes, but there is an independent effect of certain class I alleles. Class II and class I molecules are differently involved in the initiation and effector phases of the immune response, suggesting that class I alleles would be important determinants in the rate of β-cell destruction. To test this hypothesis we analyzed the role of HLA class I and class II gene polymorphisms in the progression from diabetes-associated autoimmunity to clinical disease. RESEARCH DESIGN AND METHODS The effect of HLA-DR-DQ haplotypes and a panel of class I HLA-A and -B alleles on the progression from autoantibody seroconversion to clinical diabetes was studied in 249 children persistently positive for at least one biochemical diabetes-associated autoantibody in addition to islet cell autoantibody. RESULTS The progression to clinical disease was separately analyzed after the appearance of the first and the second persistent biochemical autoantibody using Cox regression. Multivariate analysis demonstrated a significant protective effect of the A*03 allele (odds ratio [OR] 0.61, P = 0.042 after the first and OR 0.55, P = 0.027 after the second autoantibody), whereas the B*39 allele had a promoting effect after seroconversion for the second autoantibody (OR 2.4, P = 0.014). When children with the DR3/DR4 genotype were separately analyzed, HLA-B*39 had a strong effect (OR 6.6, P = 0.004 and OR 7.5, P = 0.007, after the appearance of the first and the second autoantibody, respectively). The protective effect of A*03 was seen only among children without the DR3/DR4 combination. CONCLUSIONS These results confirm that class I alleles affect the progression of diabetes-associated autoimmunity and demonstrate interactions between class I and class II alleles. PMID:20739684

  19. Infectious diseases and immunity: special reference to major histocompatibility complex.

    PubMed Central

    Singh, N.; Agrawal, S.; Rastogi, A. K.

    1997-01-01

    Human leukocyte antigens (HLAs) are an inherent system of alloantigens, which are the products of genes of the major histocompatibility complex (MHC). These genes span a region of approximately 4 centimorgans on the short arm of human chromosome 6 at band p 21.3 and encode the HLA class I and class II antigens, which play a central role in cell-to-cell interaction in the immune system. These antigens interact with the antigen-specific cell surface receptors of T lymphocytes (TCR) thus causing activation of the lymphocytes and the resulting immune response. Class I antigens restrict cytotoxic T-cell (CD8+) function thus killing viral infected targets, while class II antigens are involved in presentation of exogenous antigens to T-helper cells (CD4+) by antigen presenting cells (APC). The APC processes the antigens, and the immunogenic peptide is then presented at the cell surface along with the MHC molecule for recognition by the TCR. Since the MHC molecules play a central role in regulating the immune response, they may have an important role in controlling resistance and susceptibility to diseases. In this review we have highlighted studies conducted to look for an association between HLA and infectious diseases; such studies have had a variable degree of success because the pathogenesis of different diseases varies widely, and most diseases have a polygenic etiology. PMID:9126443

  20. Major histocompatibility complex differentiation in Sacramento River chinook salmon.

    PubMed Central

    Kim, T J; Parker, K M; Hedrick, P W

    1999-01-01

    The chinook salmon of the Sacramento River, California, have been reduced to a fraction of their former abundance because of human impact and use of the river system. Here we examine the genetic variation at a major histocompatibility complex class II exon in the four Sacramento chinook salmon runs. Examination of the alleles found in these and other chinook salmon revealed nucleotide patterns consistent with selection for amino acid replacement at the putative antigen-binding sites. We found a significant amount of variation in each of the runs, including the federally endangered winter run. All of the samples were in Hardy-Weinberg proportions. A significant amount of genetic differentiation between runs was revealed by several measures of differentiation. Winter run was the most genetically divergent, while the spring, late-fall, and fall runs were less differentiated. PMID:10049927

  1. Novel Mutants Define Genes Required for the Expression of Human Histocompatibility Leukocyte Antigen DM: Evidence for Loci on Human Chromosome 6p

    PubMed Central

    Fling, Steven P.; Rak, Jennifer; Muczynski, Kimberly A.; Arp, Benjamin; Pious, Donald

    1997-01-01

    We and others have shown that the products of the HLA-DM locus are required for the intracellular assembly of major histocompatibility complex class II molecules with cognate peptides for antigen presentation. HLA-DM heterodimers mediate the dissociation of invariant chain (Ii)-derived class II–associated Ii peptides (CLIP) from class II molecules and facilitate the loading of class II molecules with antigenic peptides. Here we describe novel APC mutants with defects in the formation of class II–peptide complexes. These mutants express class II molecules which are conformationally altered, and an aberrantly high percentage of these class II molecules are associated with Ii-derived CLIP. This phenotype resembles that of DM null mutants. However, we show that the defects in two of these new mutants do not map to the DM locus. Nevertheless, our evidence suggests that the antigen processing defective phenotype in these mutants results from deficient DM expression. These mutants thus appear to define genes in which mutations have differential effects on the expression of conventional class II molecules and DM molecules. Our data are most consistent with these factors mapping to human chromosome 6p. Previous data have suggested that the expression of DM and class II genes are coordinately regulated. The results reported here suggest that DM and class II can also be differentially regulated, and that this differential regulation has significant effects on class II–restricted antigen processing. PMID:9348304

  2. NetMHCIIpan-3.0, a common pan-specific MHC class II prediction method including all three human MHC class II isotypes, HLA-DR, HLA-DP and HLA-DQ

    PubMed Central

    Karosiene, Edita; Rasmussen, Michael; Blicher, Thomas; Lund, Ole; Buus, Søren; Nielsen, Morten

    2013-01-01

    Major histocompatibility complex class II (MHCII) molecules play an important role in cell-mediated immunity. They present specific peptides derived from endosomal proteins for recognition by T helper cells. The identification of peptides that bind to MHCII molecules is therefore of great importance for understanding the nature of immune responses and identifying T cell epitopes for the design of new vaccines and immunotherapies. Given the large number of MHC variants, and the costly experimental procedures needed to evaluate individual peptide–MHC interactions, computational predictions have become particularly attractive as first-line methods in epitope discovery. However, only a few so-called pan-specific prediction methods capable of predicting binding to any MHC molecule with known protein sequence are currently available, and all of them are limited to HLA-DR. Here, we present the first pan-specific method capable of predicting peptide binding to any HLA class II molecule with a defined protein sequence. The method employs a strategy common for HLA-DR, HLA-DP and HLA-DQ molecules to define the peptide-binding MHC environment in terms of a pseudo sequence. This strategy allows the inclusion of new molecules even from other species. The method was evaluated in several benchmarks and demonstrates a significant improvement over molecule-specific methods as well as the ability to predict peptide binding of previously uncharacterised MHCII molecules. To the best of our knowledge, the NetMHCIIpan-3.0 method is the first pan-specific predictor covering all HLA class II molecules with known sequences including HLA-DR, HLA-DP, and HLA-DQ. The NetMHCpan-3.0 method is available at http://www.cbs.dtu.dk/services/NetMHCIIpan-3.0. PMID:23900783

  3. In vitro analysis of a primary, major histocompatibility complex (MHC)-restricted, cytotoxic T-lymphocyte response to avian leukosis virus (ALV), using target cells expressing MHC class I cDNA inserted into a recombinant ALV vector.

    PubMed

    Thacker, E L; Fulton, J E; Hunt, H D

    1995-10-01

    The interaction between the major histocompatibility complex (MHC) and cytotoxic T lymphocytes (CTLs) is an important component of the host's resistance to viral infections and tumor formation. In this study, an avian leukosis virus (ALV) vector system, RCASBP, expressing MHC chicken class I (B-F) cDNA was used to develop target cells expressing the chicken class I glycoproteins complexed with ALV antigens on the cell surface. Peripheral blood from chickens inoculated with ALV was shown to contain antigen-specific, MHC-restricted, CD8+ effector CTLs, using a 51Cr release assay utilizing the RCASBP B-F target cells. The stimulated effector cells were also predominantly alpha beta T-cell receptor-positive (TCR2) T cells. The CTL response varied between two haplotypes of chickens which differed in their response to Rous sarcoma virus (RSV)-induced tumors. Chickens with the B21 haplotype which regress RSV-induced tumors showed maximal cytolytic activity, while chickens with the B13 haplotype which do not regress RSV-induced tumors had minimal to no cytolytic activity. In addition to assessing the CTL response to ALV, the creation of MHC-specific immortal target cell lines will be extremely useful in evaluating CTL responses to other viral disease in chickens. PMID:7666545

  4. Positive selection of invariant V alpha 14+ T cells by non-major histocompatibility complex-encoded class I-like molecules expressed on bone marrow-derived cells.

    PubMed Central

    Adachi, Y; Koseki, H; Zijlstra, M; Taniguchi, M

    1995-01-01

    V alpha 14+ T cells are a unique subset expressing an invariant T-cell antigen receptor alpha chain encoded by V alpha 14 and J alpha 281 gene fragments with a 1-nt N region. Most invariant V alpha 14+ T cells develop in extrathymic organs, independent of thymus, and expand at a high frequency in various mouse strains regardless of major histocompatibility complex (MHC) haplotype. In this paper, we show that the positive selection of invariant V alpha 14+ T cells requires a beta 2-microglobulin-associated MHC class I-like molecule not linked to the MHC on chromosome 17. This was determined by linkage analysis on DNA from recombinant mice generated by crossing a C57BL/6 mouse with a wild mouse, Mus musculus molossinus, that is negative for invariant V alpha 14 TCR expression. However, the peptide transporter TAP1 is not necessary for positive selection of invariant V alpha 14+ T cells, indicating the direct recognition of the MHC class I-like molecule without peptide by the invariant V alpha 14 TCR. Further, experiments with bone marrow-chimeric mice show that invariant V alpha 14+ T cells in the periphery are selected by bone marrow cells, suggesting a unique lineage of V alpha 14+ T cells differentiated through a selection process distinct from that of conventional alpha beta TCR+ T cells. Images Fig. 1 Fig. 2 Fig. 3 PMID:7862661

  5. In silico identification of supertypes for class II MHCs.

    PubMed

    Doytchinova, Irini A; Flower, Darren R

    2005-06-01

    The development of epitope-based vaccines, which have wide population coverage, is greatly complicated by MHC polymorphism. The grouping of alleles into supertypes, on the basis of common structural and functional features, addresses this problem directly. In the present study we applied a combined bioinformatics approach, based on analysis of both protein sequence and structure, to identify similarities in the peptide binding sites of 2225 human class II MHC molecules, and thus define supertypes and supertype fingerprints. Two chemometric techniques were used: hierarchical clustering using three-dimensional Comparative Similarity Indices Analysis fields and nonhierarchical k-means clustering using sequence-based z-descriptors. An average consensus of 84% was achieved, i.e., 1872 of 2225 class II molecules were classified in the same supertype by both techniques. Twelve class II supertypes were defined: five DRs, three DQs, and four DPs. The HLA class II supertypes and their fingerprints given in parenthesis are DR1 (Trp(9beta)), DR3 (Glu(9beta), Gln(70beta), and Gln/Arg(74beta)), DR4 (Glu(9beta), Gln/Arg(70beta), and Glu/Ala(74beta)), DR5 (Glu(9beta), Asp(70beta)), and DR9 (Lys/Gln(9beta)); DQ1 (Ala/Gly(86beta)), DQ2 (Glu(86beta), Lys(71beta)), and DQ3 (Glu(86beta), Thr/Asp(71beta)); DPw1 (Asp(84beta) and Lys(69beta)), DPw2 (Gly/Val(84beta) and Glu(69beta)), DPw4 (Gly/Val(84beta) and Lys(69beta)), and DPw6 (Asp(84beta) and Glu(69beta)). Apart from the good agreement between known binding motifs and our classification, several new supertypes, and corresponding thematic binding motifs, were also defined. PMID:15905552

  6. Cylindrical bubbles and blobs from a Class II Hydrophobin

    NASA Astrophysics Data System (ADS)

    Russo, Paul; Pham, Michael; Blalock, Brad

    2012-02-01

    Cerato ulmin is a class II hydrophobin. In aqueous suspensions, it easily forms cylindrical air bubbles and cylindrical oil blobs. The conditions for formation of these unusual structures will be discussed, along with scattering and microscopic investigations of their remarkable stability. Possible applications in diverse fields including polymer synthesis and oil spill remediation will be considered. Acknowledgment is made to Dr. Wayne C. Richards of the Canadian Forest Service for the gift of Cerato ulmin.

  7. Molecular characterization of MHC class II in the Australian invasive cane toad reveals multiple splice variants.

    PubMed

    Lillie, Mette; Cui, Jian; Shine, Richard; Belov, Katherine

    2016-07-01

    The cane toad has gained notoriety for its invasion across the Australian landscape, with significant impacts on the native Australian fauna. The invasion has accelerated over time, with invading cane toads adapted for highly dispersive traits. This, however, has come at the cost of the immune system, with lower investment in some immune functions. To investigate the cane toad's immunogenetics, we characterized four major histocompatibility complex (MHC) class IIA and three MHC class IIB loci. Preliminary observations suggest very low allelic diversity at all loci. We also observed various splice isoforms. One isoform seen at one class IIA and two class IIB loci was missing exon 2, which is essential to peptide binding and presentation. The other isoform, observed at a class IIA locus, is likely to be a soluble MHC product. These results may suggest a significant role of alternative splicing of MHC loci in the Australian cane toad. PMID:27233954

  8. Extraordinary MHC class II B diversity in a non-passerine, wild bird: the Eurasian Coot Fulica atra (Aves: Rallidae)

    PubMed Central

    Alcaide, Miguel; Muñoz, Joaquin; Martínez-de la Puente, Josué; Soriguer, Ramón; Figuerola, Jordi

    2014-01-01

    The major histocompatibility complex (MHC) hosts the most polymorphic genes ever described in vertebrates. The MHC triggers the adaptive branch of the immune response, and its extraordinary variability is considered an evolutionary consequence of pathogen pressure. The last few years have witnessed the characterization of the MHC multigene family in a large diversity of bird species, unraveling important differences in its polymorphism, complexity, and evolution. Here, we characterize the first MHC class II B sequences isolated from a Rallidae species, the Eurasian Coot Fulica atra. A next-generation sequencing approach revealed up to 265 alleles that translated into 251 different amino acid sequences (β chain, exon 2) in 902 individuals. Bayesian inference identified up to 19 codons within the presumptive peptide-binding region showing pervasive evidence of positive, diversifying selection. Our analyses also detected a significant excess of high-frequency segregating sites (average Tajima's D = 2.36, P < 0.05), indicative of balancing selection. We found one to six different alleles per individual, consistent with the occurrence of at least three MHC class II B gene duplicates. However, the genotypes comprised of three alleles were by far the most abundant in the population investigated (49.4%), followed by those with two (29.6%) and four (17.5%) alleles. We suggest that these proportions are in agreement with the segregation of MHC haplotypes differing in gene copy number. The most widespread segregating haplotypes, according to our findings, would contain one single gene or two genes. The MHC class II of the Eurasian Coot is a valuable system to investigate the evolutionary implications of gene copy variation and extensive variability, the greatest ever found, to the best of our knowledge, in a wild population of a non-passerine bird. PMID:24683452

  9. Characterization of expressed class II MHC sequences in the banner-tailed kangaroo rat (Dipodomys spectabilis) reveals multiple DRB loci.

    PubMed

    Busch, Joseph D; Waser, Peter M; DeWoody, J Andrew

    2008-11-01

    Genes of the major histocompatibility complex (MHC) are exceptionally polymorphic due to the combined effects of natural and sexual selection. Most research in wild populations has focused on the second exon of a single class II locus (DRB), but complete gene sequences can provide an illuminating backdrop for studies of intragenic selection, recombination, and organization. To this end, we characterized class II loci in the banner-tailed kangaroo rat (Dipodomys spectabilis). Seven DRB-like sequences (provisionally named MhcDisp-DRB*01 through *07) were isolated from spleen cDNA and most likely comprise > or =5 loci; this multiformity is quite unlike the situation in muroid rodents such as Mus, Rattus, and Peromyscus. In silico translation revealed the presence of important structural residues for glycosylation sites, salt bonds, and CD4+ T-cell recognition. Amino-acid distances varied widely among the seven sequences (2-34%). Nuclear DNA sequences from the Disp-DRB*07 locus (approximately 10 kb) revealed a conventional exon/intron structure as well as a number of microsatellites and short interspersed nuclear elements (B4, Alu, and IDL-Geo subfamilies). Rates of nucleotide substitution at Disp-DRB*07 are similar in both exons and introns (pi = 0.015 and 0.012, respectively), which suggests relaxed selection and may indicate that this locus is an expressed pseudogene. Finally, we performed BLASTn searches against Dipodomys ordii genomic sequences (unassembled reads) and find 90-97% nucleotide similarity between the two kangaroo rat species. Collectively, these data suggest that class II diversity in heteromyid rodents is based on polylocism and departs from the muroid architecture. PMID:18836711

  10. MHC Class II haplotypes of Colombian Amerindian tribes

    PubMed Central

    Yunis, Juan J.; Yunis, Edmond J.; Yunis, Emilio

    2013-01-01

    We analyzed 1041 individuals belonging to 17 Amerindian tribes of Colombia, Chimila, Bari and Tunebo (Chibcha linguistic family), Embera, Waunana (Choco linguistic family), Puinave and Nukak (Maku-Puinave linguistic families), Cubeo, Guanano, Tucano, Desano and Piratapuyo (Tukano linguistic family), Guahibo and Guayabero (Guayabero Linguistic Family), Curripaco and Piapoco (Arawak linguistic family) and Yucpa (Karib linguistic family). for MHC class II haplotypes (HLA-DRB1, DQA1, DQB1). Approximately 90% of the MHC class II haplotypes found among these tribes are haplotypes frequently encountered in other Amerindian tribes. Nonetheless, striking differences were observed among Chibcha and non-Chibcha speaking tribes. The DRB1*04:04, DRB1*04:11, DRB1*09:01 carrying haplotypes were frequently found among non-Chibcha speaking tribes, while the DRB1*04:07 haplotype showed significant frequencies among Chibcha speaking tribes, and only marginal frequencies among non-Chibcha speaking tribes. Our results suggest that the differences in MHC class II haplotype frequency found among Chibcha and non-Chibcha speaking tribes could be due to genetic differentiation in Mesoamerica of the ancestral Amerindian population into Chibcha and non-Chibcha speaking populations before they entered into South America. PMID:23885196

  11. Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC Class II-dependent manner.

    PubMed

    Kasper, Katherine J; Zeppa, Joseph J; Wakabayashi, Adrienne T; Xu, Stacey X; Mazzuca, Delfina M; Welch, Ian; Baroja, Miren L; Kotb, Malak; Cairns, Ewa; Cleary, P Patrick; Haeryfar, S M Mansour; McCormick, John K

    2014-05-01

    Establishing the genetic determinants of niche adaptation by microbial pathogens to specific hosts is important for the management and control of infectious disease. Streptococcus pyogenes is a globally prominent human-specific bacterial pathogen that secretes superantigens (SAgs) as 'trademark' virulence factors. SAgs function to force the activation of T lymphocytes through direct binding to lateral surfaces of T cell receptors and class II major histocompatibility complex (MHC-II) molecules. S. pyogenes invariably encodes multiple SAgs, often within putative mobile genetic elements, and although SAgs are documented virulence factors for diseases such as scarlet fever and the streptococcal toxic shock syndrome (STSS), how these exotoxins contribute to the fitness and evolution of S. pyogenes is unknown. Here we show that acute infection in the nasopharynx is dependent upon both bacterial SAgs and host MHC-II molecules. S. pyogenes was rapidly cleared from the nasal cavity of wild-type C57BL/6 (B6) mice, whereas infection was enhanced up to ∼10,000-fold in B6 mice that express human MHC-II. This phenotype required the SpeA superantigen, and vaccination with an MHC -II binding mutant toxoid of SpeA dramatically inhibited infection. Our findings indicate that streptococcal SAgs are critical for the establishment of nasopharyngeal infection, thus providing an explanation as to why S. pyogenes produces these potent toxins. This work also highlights that SAg redundancy exists to avoid host anti-SAg humoral immune responses and to potentially overcome host MHC-II polymorphisms. PMID:24875883

  12. Spectral energy distribution analysis of class I and class II FU Orionis stars

    SciTech Connect

    Gramajo, Luciana V.; Gómez, Mercedes; Rodón, Javier A. E-mail: mercedes@oac.uncor.edu

    2014-06-01

    FU Orionis stars (FUors) are eruptive pre-main sequence objects thought to represent quasi-periodic or recurring stages of enhanced accretion during the low-mass star-forming process. We characterize the sample of known and candidate FUors in a homogeneous and consistent way, deriving stellar and circumstellar parameters for each object. We emphasize the analysis in those parameters that are supposed to vary during the FUor stage. We modeled the spectral energy distributions of 24 of the 26 currently known FUors, using the radiative transfer code of Whitney et al. We compare our models with those obtained by Robitaille et al. for Taurus class II and I sources in quiescence periods by calculating the cumulative distribution of the different parameters. FUors have more massive disks: we find that ∼80% of the disks in FUors are more massive than any Taurus class II and I sources in the sample. Median values for the disk mass accretion rates are ∼10{sup –7} M {sub ☉} yr{sup –1} versus ∼10{sup –5} M {sub ☉} yr{sup –1} for standard young stellar objects (YSOs) and FUors, respectively. While the distributions of envelope mass accretion rates for class I FUors and standard class I objects are similar, FUors, on average, have higher envelope mass accretion rates than standard class II and class I sources. Most FUors (∼70%) have envelope mass accretion rates above 10{sup –7} M {sub ☉} yr{sup –1}. In contrast, 60% of the classical YSO sample has an accretion rate below this value. Our results support the current scenario in which changes experimented by the circumstellar disk explain the observed properties of these stars. However, the increase in the disk mass accretion rate is smaller than theoretically predicted, although in good agreement with previous determinations.

  13. Spectrum of MHC Class II Variability in Darwin’s Finches and Their Close Relatives

    PubMed Central

    Sato, Akie; Tichy, Herbert; Grant, Peter R.; Grant, B. Rosemary; Sato, Tetsuji; O’hUigin, Colm

    2011-01-01

    The study describes >400 major histocompatibility complex (MHC) class II B exon 2 and 114 intron 2 sequences of 36 passerine bird species, 13 of which belong to the group of Darwin’s finches (DFs) and the remaining 23 to close or more distant relatives of DFs in Central and South America. The data set is analyzed by a combination of judiciously selected statistical methods. The analysis reveals that reliable information concerning MHC organization, including the assignment of sequences to loci, and evolution, as well as the process of species divergence, can be obtained in the absence of genomic sequence data, if the analysis is taken several steps beyond the standard phylogenetic tree construction approach. The main findings of the present study are these: The MHC class II B region of the passerine birds is as elaborate in its organization, divergence, and genetic diversity as the MHC of the eutherian mammals, specifically the primates. Hence, the reported simplicity of the fowl MHC is an oddity. With the help of appropriate markers, the divergence of the MHC genes can be traced deep in the phylogeny of the bird taxa. Transspecies polymorphism is rampant at many of the bird MHC loci. In this respect, the DFs behave as if they were a single, genetically undifferentiated population. There is thus far no indication of alleles that could be considered species, genus, or even DF group specific. The implication of these findings is that DFs are in the midst of adaptive radiations, in which morphological differentiation into species is running ahead of genetic differentiation in genetic systems such as the MHC or the mitochondrial DNA. The radiations are so young that there has not been enough time to sort out polymorphisms at most of the loci among the morphologically differentiating species. These findings parallel those on Lake Victoria haplochromine fishes. Several of the DF MHC allelic lineages can be traced back to the MHC genes of the species Tiaris obscura

  14. Trans-species polymorphism and selection in the MHC class II DRA genes of domestic sheep.

    PubMed

    Ballingall, Keith T; Rocchi, Mara S; McKeever, Declan J; Wright, Frank

    2010-01-01

    Highly polymorphic genes with central roles in lymphocyte mediated immune surveillance are grouped together in the major histocompatibility complex (MHC) in higher vertebrates. Generally, across vertebrate species the class II MHC DRA gene is highly conserved with only limited allelic variation. Here however, we provide evidence of trans-species polymorphism at the DRA locus in domestic sheep (Ovis aries). We describe variation at the Ovar-DRA locus that is far in excess of anything described in other vertebrate species. The divergent DRA allele (Ovar-DRA*0201) differs from the sheep reference sequences by 20 nucleotides, 12 of which appear non-synonymous. Furthermore, DRA*0201 is paired with an equally divergent DRB1 allele (Ovar-DRB1*0901), which is consistent with an independent evolutionary history for the DR sub-region within this MHC haplotype. No recombination was observed between the divergent DRA and B genes in a range of breeds and typical levels of MHC class II DR protein expression were detected at the surface of leukocyte populations obtained from animals homozygous for the DRA*0201, DRB1*0901 haplotype. Bayesian phylogenetic analysis groups Ovar-DRA*0201 with DRA sequences derived from species within the Oryx and Alcelaphus genera rather than clustering with other ovine and caprine DRA alleles. Tests for Darwinian selection identified 10 positively selected sites on the branch leading to Ovar-DRA*0201, three of which are predicted to be associated with the binding of peptide antigen. As the Ovis, Oryx and Alcelaphus genera have not shared a common ancestor for over 30 million years, the DRA*0201 and DRB1*0901 allelic pair is likely to be of ancient origin and present in the founding population from which all contemporary domestic sheep breeds are derived. The conservation of the integrity of this unusual DR allelic pair suggests some selective advantage which is likely to be associated with the presentation of pathogen antigen to T-cells and the

  15. Trans-Species Polymorphism and Selection in the MHC Class II DRA Genes of Domestic Sheep

    PubMed Central

    Ballingall, Keith T.; Rocchi, Mara S.; McKeever, Declan J.; Wright, Frank

    2010-01-01

    Highly polymorphic genes with central roles in lymphocyte mediated immune surveillance are grouped together in the major histocompatibility complex (MHC) in higher vertebrates. Generally, across vertebrate species the class II MHC DRA gene is highly conserved with only limited allelic variation. Here however, we provide evidence of trans-species polymorphism at the DRA locus in domestic sheep (Ovis aries). We describe variation at the Ovar-DRA locus that is far in excess of anything described in other vertebrate species. The divergent DRA allele (Ovar-DRA*0201) differs from the sheep reference sequences by 20 nucleotides, 12 of which appear non-synonymous. Furthermore, DRA*0201 is paired with an equally divergent DRB1 allele (Ovar-DRB1*0901), which is consistent with an independent evolutionary history for the DR sub-region within this MHC haplotype. No recombination was observed between the divergent DRA and B genes in a range of breeds and typical levels of MHC class II DR protein expression were detected at the surface of leukocyte populations obtained from animals homozygous for the DRA*0201, DRB1*0901 haplotype. Bayesian phylogenetic analysis groups Ovar-DRA*0201 with DRA sequences derived from species within the Oryx and Alcelaphus genera rather than clustering with other ovine and caprine DRA alleles. Tests for Darwinian selection identified 10 positively selected sites on the branch leading to Ovar-DRA*0201, three of which are predicted to be associated with the binding of peptide antigen. As the Ovis, Oryx and Alcelaphus genera have not shared a common ancestor for over 30 million years, the DRA*0201 and DRB1*0901 allelic pair is likely to be of ancient origin and present in the founding population from which all contemporary domestic sheep breeds are derived. The conservation of the integrity of this unusual DR allelic pair suggests some selective advantage which is likely to be associated with the presentation of pathogen antigen to T-cells and the

  16. Medical devices; reclassification of three anesthesiology preamendments class III devices into class II. Final rule.

    PubMed

    2001-11-15

    The Food and Drug Administration (FDA) is reclassifying three anesthesiology preamendments devices from class III (premarket approval) into class II (special controls). FDA is also identifying the special controls that the agency believes will reasonably ensure the safety and effectiveness of the devices. This reclassification is being undertaken on the agency's own initiative based on new information under the Federal Food, Drug, and Cosmetic Act (the act), as amended by the Safe Medical Devices Act of 1990 and the FDA Modernization Act of 1997. PMID:11776278

  17. Major histocompatibility complex locus DRA polymorphism in the endangered Sorraia horse and related breeds.

    PubMed

    Luís, C; Cothran, E G; Oom, M M; Bailey, E

    2005-02-01

    The major histocompatibility complex (MHC) genes play well-defined roles in eliciting immune responses and combating infectious diseases. This genetic system is among the most polymorphic. The extent of genetic variation within a population has been directly correlated with fitness for many traits. The MHC class II locus DRA polymorphism was analysed in the endangered Sorraia horse, two other Portuguese and four New World horse breeds considered to be historically close to the Sorraia. Comparison of the Sorraia with other breeds demonstrated less MHC variation among Sorraia horses. If DRA polymorphism provides greater disease resistance, selective breeding to increase MHC polymorphism may increase fitness of this population. PMID:16130491

  18. Class II Division 1 in New Dimension: Role of Posterior Transverse Interarch Discrepancy in Class II Division 1 Malocclusion During the Mixed Dentition Period

    PubMed Central

    Garg, Deepanshu; Mahajan, Neeraj; Bansal, Samriti; Sawhney, Anshul; Kaur, Jasvir; Tripathi, Shashank; Malaviya, Neha

    2015-01-01

    Introduction Posterior transverse discrepancy as seen in some cases of Class II Division 1 malocclusion in mixed dentition period can be related to typical skeletofacial characteristics. These features when studied early in the mixed dentition period give a clear view of the desired appropriate treatment plan in a particular case. Aim The purpose of this study was to establish a simple method to determine the posterior (intermolar) transverse discrepancy and craniofacial skeletal features between the dental arches during the mixed dentition in a sample of Class II Division 1 patients to provide diagnostic and therapeutic guidance in the early approach. Materials and Methods A sample of 60 Class II Division 1 patients in mixed dention that were divided into 30 Class II Division 1 patients with posterior transverse interarch discrepancy {Class II (I) PTID group} and 30 Class II Division 1 patients without posterior transverse interarch discrepancy {Class II (I) NPTID group}. Thirty Class I subjects in mixed dentition were included as control. Results The skeletal features of the Class II group without PTID are those of the skeletal Class II associated with ‘anatomic’ mandibular retrusion (due to a micrognathic mandible) and those of the Class II group with PTID as skeletal Class II associated with only a ‘functional’ mandibular retrusion (due to a posteriorly displaced mandible of normal size). Conclusion This study confirmed the role of occlusion in the control of maxillomandibular skeletal relationships.The treatment strategies could be planned on the basis of the transverse component of Class II Division 1 groups in the mixed dentition period. PMID:26417555

  19. Escape in One of Two Cytotoxic T-Lymphocyte Epitopes Bound by a High-Frequency Major Histocompatibility Complex Class I Molecule, Mamu-A*02: a Paradigm for Virus Evolution and Persistence?

    PubMed Central

    Vogel, Thorsten U.; Friedrich, Thomas C.; O'Connor, David H.; Rehrauer, William; Dodds, Elizabeth J.; Hickman, Heather; Hildebrand, William; Sidney, John; Sette, Alessandro; Hughes, Austin; Horton, Helen; Vielhuber, Kathy; Rudersdorf, Richard; de Souza, Ivna P.; Reynolds, Matthew R.; Allen, Todd M.; Wilson, Nancy; Watkins, David I.

    2002-01-01

    It is now accepted that an effective vaccine against AIDS must include effective cytotoxic-T-lymphocyte (CTL) responses. The simian immunodeficiency virus (SIV)-infected rhesus macaque is the best available animal model for AIDS, but analysis of macaque CTL responses has hitherto focused mainly on epitopes bound by a single major histocompatibility complex (MHC) class I molecule, Mamu-A*01. The availability of Mamu-A*01-positive macaques for vaccine studies is therefore severely limited. Furthermore, it is becoming clear that different CTL responses are able to control immunodeficiency virus replication with varying success, making it a priority to identify and analyze CTL responses restricted by common MHC class I molecules other than Mamu-A*01. Here we describe two novel epitopes derived from SIV, one from Gag (Gag71-79 GY9), and one from the Nef protein (Nef159-167 YY9). Both epitopes are bound by the common macaque MHC class I molecule, Mamu-A*02. The sequences of these two eptiopes are consistent with the molecule's peptide-binding motif, which we have defined by elution of natural ligands from Mamu-A*02. Strikingly, we found evidence for the selection of escape variant viruses by CTL specific for Nef159-167 YY9 in 6 of 6 Mamu-A*02-positive animals. In contrast, viral sequences encoding the Gag71-79 GY9 epitope remained intact in each animal. This situation is reminiscent of Mamu-A*01-restricted CTL that recognize Tat28-35 SL8, which reproducibly selects for escape variants during acute infection, and Gag181-189 CM9, which does not. Differential selection by CTL may therefore be a paradigm of immunodeficiency virus infection. PMID:12388723

  20. Lysis of pig endothelium by IL-2 activated human natural killer cells is inhibited by swine and human major histocompatibility complex (MHC) class I gene products.

    PubMed

    Itescu, S; Artrip, J H; Kwiatkowski, P A; Wang, S F; Minanov, O P; Morgenthau, A S; Michler, R E

    1997-01-01

    We have previously described a form of xenograft rejection, mediated by natural killer (NK) cells, occurring in pig-to-primate organ transplants beyond the period of antibody-mediated hyperacute rejection. In this study, two distinct NK activation pathways were identified as mechanisms of pig aortic endotheliual cell (PAEC) lysis by human NK cells. Using an antibody-dependent cellular cytotoxicity (ADCC) assay, a progressive increase in human NK lysis of PAEC was observed following incubation with human IgG at increasing serum titer. In the absence of IgG, a second mechanism of PAEC lysis by human NK cells was observed following activation with IL-2. IL-2 activation of human NK cells increased lysis of PAEC by over 3-fold compared with ADCC. These results indicate that IL-2 activation of human NK cells induces significantly higher levels of lytic activity than does conventional ADCC involving IgG and FcRIII. We next investigated the role of MHC class I molecules in the regulation of NK lysis following IL-2 activation. PAEC expression of SLA class I molecules was increased by up to 75% by treatment with human TNFa. Following treatment with TNFa at 1 u/ml, IL-2 activated human NK lysis of PAEC was inhibited at every effector:target (E:T) ratio tested. Maximal effect occurred at an E:T ratio of 10:1, with TNFa inhibiting specific lysis by 59% (p < 0.01). Incubation with an anti-SLA class I Mab, but not IgG isotype control, abrogated the protective effects of TNFa on NK lysis of PAEC, suggesting direct inhibitory effects of SLA class I molecules on human NK function. To investigate whether human MHC class I molecules might have similar effects on human NK lysis of PAEC, further experiments were performed using a soluble peptide derived from the alpha-helical region of HLA-B7. Incubation with the HLA-B7 derived peptide significantly reduced the IL-2 activated NK lytic activity against PAEC in a dose-dependent fashion. Maximal effect occurred at a concentration of 10 mg

  1. Impact of Viral Dose and Major Histocompatibility Complex Class IB Haplotype on Viral Outcome in Mauritian Cynomolgus Monkeys Vaccinated with Tat upon Challenge with Simian/Human Immunodeficiency Virus SHIV89.6P ▿ †

    PubMed Central

    Cafaro, Aurelio; Bellino, Stefania; Titti, Fausto; Maggiorella, Maria Teresa; Sernicola, Leonardo; Wiseman, Roger W.; Venzon, David; Karl, Julie A.; O'Connor, David; Monini, Paolo; Robert-Guroff, Marjorie; Ensoli, Barbara

    2010-01-01

    The effects of the challenge dose and major histocompatibility complex (MHC) class IB alleles were analyzed in 112 Mauritian cynomolgus monkeys vaccinated (n = 67) or not vaccinated (n = 45) with Tat and challenged with simian/human immunodeficiency virus (SHIV) 89.6Pcy243. In the controls, the challenge dose (10 to 20 50% monkey infectious doses [MID50]) or MHC did not affect susceptibility to infection, peak viral load, or acute CD4 T-cell loss, whereas in the chronic phase of infection, the H1 haplotype correlated with a high viral load (P = 0.0280) and CD4 loss (P = 0.0343). Vaccination reduced the rate of infection acquisition at 10 MID50 (P < 0.0001), and contained acute CD4 loss at 15 MID50 (P = 0.0099). Haplotypes H2 and H6 were correlated with increased susceptibility (P = 0.0199) and resistance (P = 0.0087) to infection, respectively. Vaccination also contained CD4 depletion (P = 0.0391) during chronic infection, independently of the challenge dose or haplotype. PMID:20554774

  2. Evaluation depth of the curve of Spee in class I, class II, and class III malocclusion: A cross sectional study

    PubMed Central

    Nayar, Sanjna; Dinakarsamy, V.; Santhosh, S.

    2015-01-01

    Occlusal plane is an essential consideration when multiple long-span posterior restorations are designed. When restorations are added to an existing tooth arrangement characterized by rotated, tipped, or extruded teeth, excursive interferences may be incorporated, resulting in detrimental squeal. The curve of Spee, which exists in the ideal natural dentition, allows harmony to exist between the anterior tooth and condylar guidance. This curve exists in the sagittal plane and is the best viewed from a lateral aspect. It permits total posterior disclusion on mandibular protrusion, given proper anterior tooth guidance. It is unclear that whether the curve of Spee is a description of the occlusal surface of each arch separately or in maximal intercuspation. The purpose of this study was to examine the differences in the depth of curve of Spee between the class I, class II, class III and to investigate the relationship of depth of curve of Spee with over jet, over-bite. PMID:26015764

  3. Class II HLA interactions modulate genetic risk for multiple sclerosis

    PubMed Central

    Dilthey, Alexander T; Xifara, Dionysia K; Ban, Maria; Shah, Tejas S; Patsopoulos, Nikolaos A; Alfredsson, Lars; Anderson, Carl A; Attfield, Katherine E; Baranzini, Sergio E; Barrett, Jeffrey; Binder, Thomas M C; Booth, David; Buck, Dorothea; Celius, Elisabeth G; Cotsapas, Chris; D’Alfonso, Sandra; Dendrou, Calliope A; Donnelly, Peter; Dubois, Bénédicte; Fontaine, Bertrand; Fugger, Lars; Goris, An; Gourraud, Pierre-Antoine; Graetz, Christiane; Hemmer, Bernhard; Hillert, Jan; Kockum, Ingrid; Leslie, Stephen; Lill, Christina M; Martinelli-Boneschi, Filippo; Oksenberg, Jorge R; Olsson, Tomas; Oturai, Annette; Saarela, Janna; Søndergaard, Helle Bach; Spurkland, Anne; Taylor, Bruce; Winkelmann, Juliane; Zipp, Frauke; Haines, Jonathan L; Pericak-Vance, Margaret A; Spencer, Chris C A; Stewart, Graeme; Hafler, David A; Ivinson, Adrian J; Harbo, Hanne F; Hauser, Stephen L; De Jager, Philip L; Compston, Alastair; McCauley, Jacob L; Sawcer, Stephen; McVean, Gil

    2016-01-01

    Association studies have greatly refined the understanding of how variation within the human leukocyte antigen (HLA) genes influences risk of multiple sclerosis. However, the extent to which major effects are modulated by interactions is poorly characterized. We analyzed high-density SNP data on 17,465 cases and 30,385 controls from 11 cohorts of European ancestry, in combination with imputation of classical HLA alleles, to build a high-resolution map of HLA genetic risk and assess the evidence for interactions involving classical HLA alleles. Among new and previously identified class II risk alleles (HLA-DRB1*15:01, HLA-DRB1*13:03, HLA-DRB1*03:01, HLA-DRB1*08:01 and HLA-DQB1*03:02) and class I protective alleles (HLA-A*02:01, HLA-B*44:02, HLA-B*38:01 and HLA-B*55:01), we find evidence for two interactions involving pairs of class II alleles: HLA-DQA1*01:01–HLA-DRB1*15:01 and HLA-DQB1*03:01–HLA-DQB1*03:02. We find no evidence for interactions between classical HLA alleles and non-HLA risk-associated variants and estimate a minimal effect of polygenic epistasis in modulating major risk alleles. PMID:26343388

  4. HLA Class I and Class II Associations with ESRD in Saudi Arabian Population

    PubMed Central

    Hamdi, Nuha Mahmoud; Al-Hababi, Fadel Hassan; Eid, Amr Ekhlas

    2014-01-01

    Background Chronic renal failure (CRF) leads in the majority of instances to end stage renal disease (ESRD) requiring renal replacement therapy. Our interest was to evaluate the possible associations of HLA class I and class II antigens with ESRD independent of other factors, in Saudi Arabia population. Methodology A retrospective study to determine the HLA class I and class II polymorphisms and their association with ESRD, was performed on 350 patients with ESRD, and 105 healthy unrelated control. Patients and control groups were typed by SSOP lumenix techniques. The alleles positively associated to the ESRD were: HLA-B*15, B*18, B*49 - DRB1*03, negatively associated alleles were A*26, HLA-B*39, B*50. The haplotypes positively associated with ESRD were: HLA-A*01-DRB1*13 and HLA-A*30-DRBI*03. The negatively associated haplotypes were: HLA-A*02-B*39, A*02-B*50, A*24-B*35, A*24-B*58, A*24-DRB1*16, A*68-DRB1*04, A*02-DQB1*03, A*29-DQB1*02, A*29-DOB1*05 and B*27-DRB1*07 and the last one is the most significant protective haplotypes. Conclusion The high Relative Risk (RR) observed and its statistical correlation reflect the strength of the described association between HLA antigens and ESRD. PMID:25380295

  5. 78 FR 24061 - Minimum Technical Standards for Class II Gaming Systems and Equipment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-24

    ... ensuring the integrity of electronic Class II games and aids. 73 FR 60508, Oct. 10, 2008. The technical... Class II gaming system; and to clarify the term ``alternate standard.'' 77 FR 58473, Sept. 21, 2012. In... control standards (MICS) for Class II gaming. 77 FR 58708, Sept. 21, 2012. Similar to the part...

  6. 25 CFR 522.5 - Disapproval of a class II ordinance.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 2 2010-04-01 2010-04-01 false Disapproval of a class II ordinance. 522.5 Section 522.5 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR APPROVAL OF CLASS II AND CLASS III ORDINANCES AND RESOLUTIONS SUBMISSION OF GAMING ORDINANCE OR RESOLUTION § 522.5 Disapproval of a class...

  7. Degradation, Promoter Recruitment and Transactivation Mediated by the Extreme N-Terminus of MHC Class II Transactivator CIITA Isoform III

    PubMed Central

    Ethier, Sylvain; Gaudreau, Luc; Steimle, Viktor

    2016-01-01

    Multiple relationships between ubiquitin-proteasome mediated protein turnover and transcriptional activation have been well documented, but the underlying mechanisms are still poorly understood. One way to induce degradation is via ubiquitination of the N-terminal α-amino group of proteins. The major histocompatibility complex (MHC) class II transactivator CIITA is the master regulator of MHC class II gene expression and we found earlier that CIITA is a short-lived protein. Using stable and transient transfections of different CIITA constructs into HEK-293 and HeLa cell lines, we show here that the extreme N-terminal end of CIITA isoform III induces both rapid degradation and transactivation. It is essential that this sequence resides at the N-terminal end of the protein since blocking of the N-terminal end with an epitope-tag stabilizes the protein and reduces transactivation potential. The first ten amino acids of CIITA isoform III act as a portable degron and transactivation sequence when transferred as N-terminal extension to truncated CIITA constructs and are also able to destabilize a heterologous protein. The same is observed with the N-terminal ends of several known N-terminal ubiquitination substrates, such as Id2, Cdt1 and MyoD. Arginine and proline residues within the N-terminal ends contribute to rapid turnover. The N-terminal end of CIITA isoform III is responsible for efficient in vivo recruitment to the HLA-DRA promoter and increased interaction with components of the transcription machinery, such as TBP, p300, p400/Domino, the 19S ATPase S8, and the MHC-II promoter binding complex RFX. These experiments reveal a novel function of free N-terminal ends of proteins in degradation-dependent transcriptional activation. PMID:26871568

  8. Degradation, Promoter Recruitment and Transactivation Mediated by the Extreme N-Terminus of MHC Class II Transactivator CIITA Isoform III.

    PubMed

    Beaulieu, Yves B; Leon Machado, Jorge A; Ethier, Sylvain; Gaudreau, Luc; Steimle, Viktor

    2016-01-01

    Multiple relationships between ubiquitin-proteasome mediated protein turnover and transcriptional activation have been well documented, but the underlying mechanisms are still poorly understood. One way to induce degradation is via ubiquitination of the N-terminal α-amino group of proteins. The major histocompatibility complex (MHC) class II transactivator CIITA is the master regulator of MHC class II gene expression and we found earlier that CIITA is a short-lived protein. Using stable and transient transfections of different CIITA constructs into HEK-293 and HeLa cell lines, we show here that the extreme N-terminal end of CIITA isoform III induces both rapid degradation and transactivation. It is essential that this sequence resides at the N-terminal end of the protein since blocking of the N-terminal end with an epitope-tag stabilizes the protein and reduces transactivation potential. The first ten amino acids of CIITA isoform III act as a portable degron and transactivation sequence when transferred as N-terminal extension to truncated CIITA constructs and are also able to destabilize a heterologous protein. The same is observed with the N-terminal ends of several known N-terminal ubiquitination substrates, such as Id2, Cdt1 and MyoD. Arginine and proline residues within the N-terminal ends contribute to rapid turnover. The N-terminal end of CIITA isoform III is responsible for efficient in vivo recruitment to the HLA-DRA promoter and increased interaction with components of the transcription machinery, such as TBP, p300, p400/Domino, the 19S ATPase S8, and the MHC-II promoter binding complex RFX. These experiments reveal a novel function of free N-terminal ends of proteins in degradation-dependent transcriptional activation. PMID:26871568

  9. [Histocompatibility HLA system of man. Considerations in the light of current concepts. IV. Soluble HLA class I antigens (sHLA-I)].

    PubMed

    Kedzierska, A; Turowski, G

    2001-01-01

    Soluble class I human leukocyte antigens (sHLA) have been detected in serum, sweat, lymphatic fluid, urine and cerebrospinal fluid. The levels vary among different individuals and are significantly affected by inflammatory diseases and organ rejection. This article discusses the clinical significance of levels of serum HLA class I antigens, both in patients with viral diseases and following organ transplantation, as well as the potential involvement of such antigens in the immune response. The potential use of sHLA in clinical medicine is far-reaching. sHLA-peptide complexes may find wide application, particularly for the treatment recipients. Although further in vivo studies are required, available data show the efficacy of sHLA to regulate T-cell function. PMID:11868249

  10. Reproductive failure and the major histocompatibility complex

    SciTech Connect

    Jin, K.; Gill, T.J. III; Ho, H.N.

    1995-06-01

    The association between HLA sharing and recurrent spontaneous abortion (RSA) was tested in 123 couples and the association between HLA sharing, and the outcome of treatment for unexplained infertility by in vitro fertilization (IVF) was tested in 76 couples, by using a new shared-allele test in order to identify more precisely the region of the major histocompatibility complex (MHC) influencing these reproductive defects. The shared-allele test circumvents the problem of rare alleles at HLA loci and at the same time provides a substantial gain in power over the simple {chi}{sup 2} test. Two statistical methods, a corrected homogeneity test and a bootstrap approach, were developed to compare the allele frequencies at each of the HLA-A, HLA-B, HLA-DR, and HLA-DQ loci; they were not statistically different amount the three patient groups and the control group. There was a significant excess of HLA-DR sharing in couples with RSA and a significant excess of HLA-DQ sharing in couples with unexplained infertility who failed treatment by IVF. These findings indicate that genes located in different parts of the class II region of the MHC affect different aspects of reproduction and strongly suggest that the sharing of HLA antigens per se is not the mechanism involved in the reproductive defects. The segment of the MHC that has genes affecting reproduction also has genes associated with different autoimmune diseases, and this juxtaposition may explain the association between reproductive defects and autoimmune diseases. 58 refs., 1 fig., 7 tabs.

  11. Adenovirus E3/19K Promotes Evasion of NK Cell Recognition by Intracellular Sequestration of the NKG2D Ligands Major Histocompatibility Complex Class I Chain-Related Proteins A and B▿

    PubMed Central

    McSharry, Brian P.; Burgert, Hans-Gerhard; Owen, Douglas P.; Stanton, Richard J.; Prod'homme, Virginie; Sester, Martina; Koebernick, Katja; Groh, Veronika; Spies, Thomas; Cox, Steven; Little, Ann-Margaret; Wang, Eddie C. Y.; Tomasec, Peter; Wilkinson, Gavin W. G.

    2008-01-01

    The adenovirus (Ad) early transcription unit 3 (E3) encodes multiple immunosubversive functions that are presumed to facilitate the establishment and persistence of infection. Indeed, the capacity of E3/19K to inhibit transport of HLA class I (HLA-I) to the cell surface, thereby preventing peptide presentation to CD8+ T cells, has long been recognized as a paradigm for viral immune evasion. However, HLA-I downregulation has the potential to render Ad-infected cells vulnerable to natural killer (NK) cell recognition. Furthermore, expression of the immediate-early Ad gene E1A is associated with efficient induction of ligands for the key NK cell-activating receptor NKG2D. Here we show that while infection with wild-type Ad enhances synthesis of the NKG2D ligands, major histocompatibility complex class I chain-related proteins A and B (MICA and MICB), their expression on the cell surface is actively suppressed. Both MICA and MICB are retained within the endoplasmic reticulum as immature endoglycosidase H-sensitive forms. By analyzing a range of cell lines and viruses carrying mutated versions of the E3 gene region, E3/19K was identified as the gene responsible for this activity. The structural requirements within E3/19K necessary to sequester MICA/B and HLA-I are similar. In functional assays, deletion of E3/19K rendered Ad-infected cells more sensitive to NK cell recognition. We report the first NK evasion function in the Adenoviridae and describe a novel function for E3/19K. Thus, E3/19K has a dual function: inhibition of T-cell recognition and NK cell activation. PMID:18287244

  12. Pseudomonas aeruginosa Cif Protein Enhances the Ubiquitination and Proteasomal Degradation of the Transporter Associated with Antigen Processing (TAP) and Reduces Major Histocompatibility Complex (MHC) Class I Antigen Presentation*

    PubMed Central

    Bomberger, Jennifer M.; Ely, Kenneth H.; Bangia, Naveen; Ye, Siying; Green, Kathy A.; Green, William R.; Enelow, Richard I.; Stanton, Bruce A.

    2014-01-01

    Cif (PA2934), a bacterial virulence factor secreted in outer membrane vesicles by Pseudomonas aeruginosa, increases the ubiquitination and lysosomal degradation of some, but not all, plasma membrane ATP-binding cassette transporters (ABC), including the cystic fibrosis transmembrane conductance regulator and P-glycoprotein. The goal of this study was to determine whether Cif enhances the ubiquitination and degradation of the transporter associated with antigen processing (TAP1 and TAP2), members of the ABC transporter family that play an essential role in antigen presentation and intracellular pathogen clearance. Cif selectively increased the amount of ubiquitinated TAP1 and increased its degradation in the proteasome of human airway epithelial cells. This effect of Cif was mediated by reducing USP10 deubiquitinating activity, resulting in increased polyubiquitination and proteasomal degradation of TAP1. The reduction in TAP1 abundance decreased peptide antigen translocation into the endoplasmic reticulum, an effect that resulted in reduced antigen available to MHC class I molecules for presentation at the plasma membrane of airway epithelial cells and recognition by CD8+ T cells. Cif is the first bacterial factor identified that inhibits TAP function and MHC class I antigen presentation. PMID:24247241

  13. Human B lymphoblastoid cells contain distinct patterns of cathepsin activity in endocytic compartments and regulate MHC class II transport in a cathepsin S-independent manner.

    PubMed

    Lautwein, Alfred; Kraus, Marianne; Reich, Michael; Burster, Timo; Brandenburg, J; Overkleeft, Herman S; Schwarz, Gerold; Kammer, Winfried; Weber, Ekkehard; Kalbacher, Hubert; Nordheim, Alfred; Driessen, Christoph

    2004-05-01

    Endocytic proteolysis represents a major functional component of the major histocompatibility complex class II antigen-presentation machinery. Although transport and assembly of class II molecules in the endocytic compartment are well characterized, we lack information about the pattern of endocytic protease activity along this pathway. Here, we used chemical tools that visualize endocytic proteases in an activity-dependent manner in combination with subcellular fractionation to dissect the subcellular distribution of the major cathepsins (Cat) CatS, CatB, CatH, CatD, CatC, and CatZ as well as the asparagine-specific endoprotease (AEP) in human B-lymphoblastoid cells (BLC). Endocytic proteases were distributed in two distinct patterns: CatB and CatZ were most prominent in early and late endosomes but absent from lysosomes, and CatH, CatS, CatD, CatC, and AEP distributed between late endosomes and lysosomes, suggesting that CatB and CatZ might be involved in the initial proteolytic attack on a given antigen. The entire spectrum of protease activity colocalized with human leukocyte antigen-DM and the C-terminal and N-terminal processing of invariant chain (Ii) in late endosomes. CatS was active in all endocytic compartments. Surprisingly and in contrast with results from dendritic cells, inhibition of CatS activity by leucine-homophenylalanine-vinylsulfone-phenol prevented N-terminal processing of Ii but did not alter the subcellular trafficking or surface delivery of class II complexes, as deferred from pulse-chase analysis in combination with subcellular fractionation and biotinylation of cell-surface protein. Thus, BLC contain distinct activity patterns of proteases in endocytic compartments and regulate the intracellular transport and surface-delivery of class II in a CatS-independent manner. PMID:14966190

  14. MHC2SKpan: a novel kernel based approach for pan-specific MHC class II peptide binding prediction

    PubMed Central

    2013-01-01

    Background Computational methods for the prediction of Major Histocompatibility Complex (MHC) class II binding peptides play an important role in facilitating the understanding of immune recognition and the process of epitope discovery. To develop an effective computational method, we need to consider two important characteristics of the problem: (1) the length of binding peptides is highly flexible; and (2) MHC molecules are extremely polymorphic and for the vast majority of them there are no sufficient training data. Methods We develop a novel string kernel MHC2SK (MHC-II String Kernel) method to measure the similarities among peptides with variable lengths. By considering the distinct features of MHC-II peptide binding prediction problem, MHC2SK differs significantly from the recently developed kernel based method, GS (Generic String) kernel, in the way of computing similarities. Furthermore, we extend MHC2SK to MHC2SKpan for pan-specific MHC-II peptide binding prediction by leveraging the binding data of various MHC molecules. Results MHC2SK outperformed GS in allele specific prediction using a benchmark dataset, which demonstrates the effectiveness of MHC2SK. Furthermore, we evaluated the performance of MHC2SKpan using various benckmark data sets from several different perspectives: Leave-one-allele-out (LOO), 5-fold cross validation as well as independent data testing. MHC2SKpan has achieved comparable performance with NetMHCIIpan-2.0 and outperformed NetMHCIIpan-1.0, TEPITOPEpan and MultiRTA, being statistically significant. MHC2SKpan can be freely accessed at http://datamining-iip.fudan.edu.cn/service/MHC2SKpan/index.html. PMID:24564280

  15. Structural Basis for the Recognition of Mutant Self by a Tumor-Specific, MHC Class II-Restricted T Cell Receptor

    SciTech Connect

    Deng,L.; Langley, R.; Brown, P.; Xu, G.; Teng, L.; Wang, Q.; Gonzales, M.; Callender, G.; Nishimura, M.; et al.

    2007-01-01

    Structural studies of complexes of T cell receptor (TCR) and peptide-major histocompatibility complex (MHC) have focused on TCRs specific for foreign antigens or native self. An unexplored category of TCRs includes those specific for self determinants bearing alterations resulting from disease, notably cancer. We determined here the structure of a human melanoma-specific TCR (E8) bound to the MHC molecule HLA-DR1 and an epitope from mutant triosephosphate isomerase. The structure had features intermediate between 'anti-foreign' and autoimmune TCR-peptide-MHC class II complexes that may reflect the hybrid nature of altered self. E8 manifested very low affinity for mutant triosephosphate isomerase-HLA-DR1 despite the highly tumor-reactive properties of E8 cells. A second TCR (G4) had even lower affinity but underwent peptide-specific formation of dimers, suggesting this as a mechanism for enhancing low-affinity TCR-peptide-MHC interactions for T cell activation.

  16. Medical devices; reclassification of six cardiovascular preamendments class III devices into class II. Final rule.

    PubMed

    2001-04-10

    The Food and Drug Administration (FDA) is reclassifying six cardiovascular pre amendments devices from class III (pre market approval) into class II (special controls). FDA is also identifying the special controls that the agency believes will reasonably ensure the safety and effectiveness of the devices. This reclassification is being undertaken on the agency's own initiative based on new information under the Federal Food, Drug, and Cosmetic Act (the act), as amended by the Safe Medical Devices Act of 1990 and the Food and Drug Administration Modernization Act of 1997. The agency is also revising the identification of one of the devices subject to this rule to simplify the classification regulation and is correcting a typographical error that was incorporated into the regulations. PMID:11721689

  17. Evaluation and Comparison of Intermaxillary Tooth Size Discrepancy among Class I, Class II Division 1, and Class III Subjects Using Bolton’s Analysis: An in vitro Study

    PubMed Central

    Prasanna, A Lakshmi; Venkatramana, V; Aryasri, A Srikanth; Katta, Anil Kumar; Santhanakrishnan, K; Maheshwari, Uma

    2015-01-01

    Aim: The aim of the present study was to evaluation and comparison of intermaxillary tooth size discrepancy among Class I, Class II division 1, and Class III subjects using Bolton’s analysis. Materials and Methods: The pre-treatment casts were selected from the records of patients attending the Department of Orthodontics of Meenakshi Ammal Dental College, Chennai. The sample consists of 180 pre-treatment casts with both sexes evenly distributed with 60 casts in each type of malocclusion, i.e., Class I, Class II div 1, and Class III malocclusion. The sample was selected according to angles classification. All patients were Indian nationals, between the age group of 12 to 20 years and Bolton’s analysis done on all the casts. Results: Statistically no significant difference in all types of malocclusion except anterior Bolton’s discrepancy in Class III. Conclusion: Mean Bolton’s anterior ratio for angles Class III subjects was significantly greater than for Class I and Class II subjects. When Bolton’s overall ratio was compared there was no statistically significant difference among Class I, Class II div 1, and Class III malocclusions. PMID:26435619

  18. CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity.

    PubMed

    Morris, David L; Oatmen, Kelsie E; Mergian, Taleen A; Cho, Kae Won; DelProposto, Jennifer L; Singer, Kanakadurga; Evans-Molina, Carmella; O'Rourke, Robert W; Lumeng, Carey N

    2016-06-01

    Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4(+) T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of conventional CD4(+) T cells (Tconv: CD3(+)CD4(+)Foxp3(-)) in visceral fat compared with wild-type mice. By contrast, the number of regulatory CD4(+) T cells (Treg: CD3(+)CD4(+)Foxp3(+)) in lean and obese fat was similar between wild-type and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesity-induced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4(+) T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice. PMID:26658005

  19. Central nervous system-specific consequences of simian immunodeficiency virus Gag escape from major histocompatibility complex class I-mediated control.

    PubMed

    Beck, Sarah E; Queen, Suzanne E; Viscidi, Raphael; Johnson, Darius; Kent, Stephen J; Adams, Robert J; Tarwater, Patrick M; Mankowski, Joseph L

    2016-08-01

    In the fourth decade of the HIV epidemic, the relationship between host immunity and HIV central nervous system (CNS) disease remains incompletely understood. Using a simian immunodeficiency virus (SIV)/macaque model, we examined CNS outcomes in pigtailed macaques expressing the MHC class I allele Mane-A1*084:01 which confers resistance to SIV-induced CNS disease and induces the prototypic viral escape mutation Gag K165R. Insertion of gag K165R into the neurovirulent clone SIV/17E-Fr reduced viral replication in vitro compared to SIV/17E-Fr. We also found lower cerebrospinal fluid (CSF), but not plasma, viral loads in macaques inoculated with SIV/17E-Fr K165R versus those inoculated with wildtype. Although escape mutation K165R was genotypically stable in plasma, it rapidly reverted to wildtype Gag KP9 in both CSF and in microglia cultures. We induced robust Gag KP9-specific CTL tetramer responses by vaccinating Mane-A*084:01-positive pigtailed macaques with a Gag KP9 virus-like particle (VLP) vaccine. Upon SIV/17E-Fr challenge, vaccinated animals had lower SIV RNA in CSF compared to unvaccinated controls, but showed no difference in plasma viral loads. These data clearly demonstrate that viral fitness in the CNS is distinct from the periphery and underscores the necessity of understanding the consequences of viral escape in CNS disease with the advent of new therapeutic vaccination strategies. PMID:26727909

  20. Structure of an α-Helical Peptide and Lipopeptide Bound to the Nonclassical Major Histocompatibility Complex (MHC) Class I Molecule CD1d.

    PubMed

    Girardi, Enrico; Wang, Jing; Zajonc, Dirk M

    2016-05-13

    Mouse CD1d is a nonclassical MHC molecule able to present lipids and glycolipids to a specialized subset of T cells known as natural killer T cells. The antigens presented by CD1d have been shown to cover a broad range of chemical structures and to follow precise rules determining the potency of the antigen in the context of T cell activation. Together with lipids, initial reports suggested that CD1d can also bind and present hydrophobic peptides with (F/W)XX(I/L/M)XXW. However, the exact location of peptide binding and the molecular basis for the required motif are currently unknown. Here we present the crystal structure of the first peptide identified to bind CD1d, p99, and show that it binds in the antigen-binding groove of CD1d in a manner compatible with its presentation to T cell receptors. Interestingly, the peptide adopts an α-helical conformation, which orients the motif residues toward its deep binding groove, therefore explaining the molecular requirements for peptide binding. Moreover, we demonstrate that a lipopeptide version of the same peptide is able to bind CD1d in a similar conformation, identifying another class of molecules binding this antigen-presenting molecule. PMID:27006394

  1. Trans-species polymorphism of the Mhc class II DRB-like gene in banded penguins (genus Spheniscus).

    PubMed

    Kikkawa, Eri F; Tsuda, Tomi T; Sumiyama, Daisuke; Naruse, Taeko K; Fukuda, Michio; Kurita, Masanori; Wilson, Rory P; LeMaho, Yvon; Miller, Gary D; Tsuda, Michio; Murata, Koichi; Kulski, Jerzy K; Inoko, Hidetoshi

    2009-05-01

    The Major Histocompatibility Complex (Mhc) class II DRB locus of vertebrates is highly polymorphic and some alleles may be shared between closely related species as a result of balancing selection in association with resistance to parasites. In this study, we developed a new set of PCR primers to amplify, clone, and sequence overlapping portions of the Mhc class II DRB-like gene from the 5'UTR end to intron 3, including exons 1, 2, and 3 and introns 1 and 2 in four species (20 Humboldt, six African, five Magellanic, and three Galapagos penguins) of penguin from the genus Spheniscus (Sphe). Analysis of gene sequence variation by the neighbor-joining method of 21 Sphe sequences and 20 previously published sequences from four other penguin species revealed overlapping clades within the Sphe species, but species-specific clades for the other penguin species. The overlap of the DRB-like gene sequence variants between the four Sphe species suggests that, despite their allopatric distribution, the Sphe species are closely related and that some shared DRB1 alleles may have undergone a trans-species inheritance because of balancing selection and/or recent rapid speciation. The new primers and PCR assays that we have developed for the identification of the DRB1 DNA and protein sequence variations appear to be useful for the characterization of the molecular evolution of the gene in closely related Penguin species and might be helpful for the assessment of the genetic health and the management of the conservation and captivity of these endangered species. PMID:19319519

  2. Rotation of the upper first molar in Class I, II, and III patients

    PubMed Central

    de Oliveira Viganó, Cristiane; da Rocha, Viviane Ekerman; Junior, Laerte Ribeiro Menezes; Paranhos, Luiz Renato; Ramos, Adilson Luiz

    2016-01-01

    Objective: The aim of this study was to evaluate the mean rotation of the upper first molar (U1st M) in cast models from nontreated patients presenting: Class I, skeletal Class II, dental Class II, and skeletal Class III, comparing with Class I orthodontically treated patients. Materials and Methods: One hundred cast models were evaluated with five groups, composed of nontreated Class I (n = 20), dental Class II (n = 20), skeletal Class II (n = 20), skeletal Class III (n = 20), and treated Class I (n = 20). Measurements were taken from photocopies of the upper arches. The angle formed between a line crossing the mesiopalatal and the distal-buccalcusps of the U1st M and a line traced on mid palatal junction were measured in all samples. Results: One-way variance analysis showed that dental Class II group presented great mean rotation of the 1st molar (x = 78.95°, SD = 6.19) (P < 0.05), and in 85% of the patients from this group this angle was higher than 73°. Conclusions: The skeletal Class II and skeletal Class III groups showed similar mean position of the 1st molar, presenting rotation in approximately 50% of the patients. It can be concluded that upper molar rotation occurs mainly in dental Class II patients and shows higher mesial rotation angle. PMID:27011741

  3. Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell-specific MHC class II expression.

    PubMed

    Rubino, Stephen J; Geddes, Kaoru; Magalhaes, Joao G; Streutker, Catherine; Philpott, Dana J; Girardin, Stephen E

    2013-11-01

    The enteric pathogen Citrobacter rodentium induces a mucosal IL-17 response in CD4(+) T helper (Th17) cells that is dependent on the Nod-like receptors Nod1 and Nod2. Here, we sought to determine whether this early Th17 response required antigen presentation by major histocompatibility complex class II (MHCII) for full induction. At early phases of C. rodentium infection, we observed that the intestinal mucosal Th17 response was fully blunted in irradiated mice reconstituted with MHCII-deficient (MHCII(-/-) →WT) hematopoietic cells. Surprisingly, we also observed a substantial increase in the relative frequency of IL-17(+) CD8(+) CD4(-) TCR-β(+) cells (Tc17 cells) and FOXP3(+) CD8(+) CD4(-) TCR-β(+) cells in the lamina propria and intraepithelial lymphocyte compartment of MHCII(-/-) →WT mice compared with that in WT→WT counterparts. Moreover, MHCII(-/-) →WT mice displayed increased susceptibility, increased bacterial translocation to deeper organs, and more severe colonic histopathology after infection with C. rodentium. Finally, a similar phenotype was observed in mice deficient for CIITA, a transcriptional regulator of MHCII expression. Together, these results indicate that MHCII is required to mount early mucosal Th17 responses to an enteric pathogen, and that MHCII regulates the induction of atypical CD8(+) T-cell subsets, such as Tc17 cells and FOXP3(+) CD8(+) cells, in vivo. PMID:23881368

  4. Heligmosomoides polygyrus infection is associated with lower MHC class II gene expression in Apodemus flavicollis: indication for immune suppression?

    PubMed

    Axtner, Jan; Sommer, Simone

    2011-12-01

    Due to their key role in recognizing foreign antigens and triggering the subsequent immune response the genes of the major histocompatibility complex (MHC) provide a potential target for parasites to attack in order to evade detection and expulsion from the host. A diminished MHC gene expression results in less activated T cells and might serve as a gateway for pathogens and parasites. Some parasites are suspected to be immune suppressors and promote co-infections of other parasites even in other parts of the body. In our study we found indications that the gut dwelling nematode Heligmosomoides polygyrus might exert a systemic immunosuppressive effect in yellow-necked mice (Apodemus flavicollis). The amount of hepatic MHC class II DRB gene RNA transcripts in infected mice was negatively associated with infection intensity with H. polygyrus. The hepatic expression of immunosuppressive cytokines, such as transforming growth factor β and interleukin 10 was not associated with H. polygyrus infection. We did not find direct positive associations of H. polygyrus with other helminth species. But the prevalence and infection intensity of the nematodes Syphacia stroma and Trichuris muris were higher in multiple infected individuals. Furthermore, our data indicated antagonistic effects in the helminth community of A. flavicollis as cestode infection correlated negatively with H. polygyrus and helminth species richness. Our study shows that expression analyses of immune relevant genes can also be performed in wildlife, opening new aspects and possibilities for future ecological and evolutionary research. PMID:21983561

  5. Constitutive and inducible expression of HLA class II determinants by human osteoblast-like cells in vitro.

    PubMed Central

    Skjødt, H; Hughes, D E; Dobson, P R; Russell, R G

    1990-01-01

    Activated immune cells release cytokines which modulate the activity of bone cells in vitro. Expression of major histocompatibility complex (HLA in humans) class II determinants on bone surface cells may be important in local immune cell activation. In this study, expression of HLA-DR and DQ by cultured human bone cells (HBC) derived from normal trabecular bone surfaces was assessed by fluorescence-activated cell sorter (FACS) analysis and immunoperoxidase techniques using monoclonal antibodies. A subset of HBC (10-30%) expressed DR constitutively while 5-15% displayed DQ during long-term culture. HBC lacked a number of monocyte and lymphocyte markers. In addition, both DR+ and DR- HBC (FACS separated) produced osteocalcin stimulated by 1,25-dihydroxyvitamin D2 (1,25(OH)2D3). This suggests that both phenotypes belong to the osteoblast lineage. The number of DR+ HBC was increased by interferon-gamma (IFN gamma; 40-95% DR+ cells) whereas DQ+ HBC remained unchanged or was slightly increased (5-20% DQ+ cells). Moreover, 1,25(OH)2D3 enhanced IFN gamma-induced DR expression and at high concentration (10(-7) M) augmented DR expression by itself. Other major osteotropic factors, parathyroid hormone, interleukin 1, and calcitonin, did not affect HBC DR expression. The findings suggest that HBC may participate in activation of the immune system and that some osteotropic factors may regulate this function. PMID:2110190

  6. Structural Basis for the Presentation of Tumor-Associated MHC Class II-Restricted Phosphopeptides to CD4+ T Cells

    SciTech Connect

    Li, Y.; Depontieu, F; Sidney, J; Salay, T; Engelhard, V; Hunt, D; Sette, A; Topalian, S; Mariuzza, R

    2010-01-01

    Dysregulated protein phosphorylation is a hallmark of malignant transformation. Transformation can generate major histocompatibility complex (MHC)-bound phosphopeptides that are differentially displayed on tumor cells for specific recognition by T cells. To understand how phosphorylation alters the antigenic identity of self-peptides and how MHC class II molecules present phosphopeptides for CD4{sup +} T-cell recognition, we determined the crystal structure of a phosphopeptide derived from melanoma antigen recognized by T cells-1 (pMART-1), selectively expressed by human melanomas, in complex with HLA-DR1. The structure revealed that the phosphate moiety attached to the serine residue at position P5 of pMART-1 is available for direct interactions with T-cell receptor (TCR) and that the peptide N-terminus adopts an unusual conformation orienting it toward TCR. This structure, combined with measurements of peptide affinity for HLA-DR1 and of peptide-MHC recognition by pMART-1-specific T cells, suggests that TCR recognition is focused on the N-terminal portion of pMART-1. This recognition mode appears to be distinct from that of foreign antigen complexes but is remarkably reminiscent of the way autoreactive TCRs engage self- or altered self-peptides, consistent with the tolerogenic nature of tumor-host immune interactions.

  7. Removable functional appliances effective in patients with Class II malocclusions.

    PubMed

    Madurantakam, Parthasarathy

    2016-03-01

    Data sourcesMedline (Pubmed), Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Google Scholar, Web of Science, Evidence-based Medicine, Scopus, LILACS database, Ovid database, Bibliografia Brasileira de Odontolgogia, Bandolier, Atypon Link, African Journals Online, ProQuest, Conference Paper Index, German National Library of Medicine, metaRegister of Controlled Trials.Study selectionRandomised Controlled Trials (RCT) or prospective Controlled Clinical Trials (pCCT) in patients with Class II malocclusions that compared at least one removable functional appliance (RFA) with a non-intervention control. Primary outcomes were angular measurements of skeletal, dental and soft tissue changes as measured by lateral cephalographs.Data extraction and synthesisTwo reviewers independently extracted data and assessed risk of bias. A third author assessed bias across studies. Pooling of data was done if similar control groups were used and if the same angular cephalometric measurements were reported. A random-effects model was used to analyse pooled estimates and results were expressed as mean differences (MDs) and 95% confidence intervals (CI). The extent and impact of heterogeneity was assessed.ResultsData were pooled from seventeen studies (seven RCTs and ten pCCT) involving 1031 patients with a mean age of 10.6 years. Most of the RCTs were associated with high risk of bias while most of the pCCTs were without serious methodological limitations. RFA treatment in Class II malocclusions was shown to have a statistically significant short-term effect on skeletal, dental and soft tissue relationships when compared to untreated controls. There is a minimal reduction of SNA (MD=-0.26 degree/year, 95% CI=-0.44 to -0.12 degree/year), minimal increase of SNB (MD=0.62 degree/year, 95% CI=0.36 to 0.88 degree/year) and a small decrease in ANB (MD= -1.14degree/year, 95% CI=-1.52 to 0.77 degree/year). Maxillary incisors were significantly

  8. Comprehensive analysis of cooperative gene mutations between class I and class II in de novo acute myeloid leukemia.

    PubMed

    Ishikawa, Yuichi; Kiyoi, Hitoshi; Tsujimura, Akane; Miyawaki, Shuichi; Miyazaki, Yasushi; Kuriyama, Kazutaka; Tomonaga, Masao; Naoe, Tomoki

    2009-08-01

    Acute myeloid leukemia (AML) has been thought to be the consequence of two broad complementation classes of mutations: class I and class II. However, overlap-mutations between them or within the same class and the position of TP53 mutation are not fully analyzed. We comprehensively analyzed the FLT3, cKIT, N-RAS, C/EBPA, AML1, MLL, NPM1, and TP53 mutations in 144 newly diagnosed de novo AML. We found 103 of 165 identified mutations were overlapped with other mutations, and most overlap-mutations consisted of class I and class II mutations. Although overlap-mutations within the same class were found in seven patients, five of them additionally had the other class mutation. These results suggest that most overlap-mutations within the same class might be the consequence of acquiring an additional mutation after the completion both of class I and class II mutations. However, mutated genes overlapped with the same class were limited in N-RAS, TP53, MLL-PTD, and NPM1, suggesting the possibility that these irregular overlap-mutations might cooperatively participate in the development of AML. Notably, TP53 mutation was overlapped with both class I and class II mutations, and associated with morphologic multilineage dysplasia and complex karyotype. The genotype consisting of complex karyotype and TP53 mutation was an unfavorable prognostic factor in entire AML patients, indicating this genotype generates a disease entity in de novo AML. These results collectively suggest that TP53 mutation might be a functionally distinguishable class of mutation. PMID:19309322

  9. Identification of peptides fromm foot-and-mouth disease virus structural proteins bound by class I swine leucocyte antigen (SLA) alleles, SLA-1*0401 and SLA-2*0401

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The analysis of peptide binding to porcine major histocompatibility complex (MHC) class I molecules has not been extensively performed. Critical to understanding the adaptive immune response of swine to infection is characterization of Swine Leucocyte Antigens (SLA) class I and class II peptide bind...

  10. 25 CFR 522.11 - Individually owned class II gaming operations operating on September 1, 1986.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 25 Indians 2 2010-04-01 2010-04-01 false Individually owned class II gaming operations operating on September 1, 1986. 522.11 Section 522.11 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR APPROVAL OF CLASS II AND CLASS III ORDINANCES AND RESOLUTIONS SUBMISSION OF...

  11. MHC-class-II are expressed in a subpopulation of human neural stem cells in vitro in an IFNγ-independent fashion and during development.

    PubMed

    Vagaska, B; New, S E P; Alvarez-Gonzalez, C; D'Acquisto, F; Gomez, S G; Bulstrode, N W; Madrigal, A; Ferretti, P

    2016-01-01

    Expression of major histocompatibility antigens class-2 (MHC-II) under non-inflammatory conditions is not usually associated with the nervous system. Comparative analysis of immunogenicity of human embryonic/fetal brain-derived neural stem cells (hNSCs) and human mesenchymal stem cells with neurogenic potential from umbilical cord (UC-MSCs) and paediatric adipose tissue (ADSCs), while highlighting differences in their immunogenicity, led us to discover subsets of neural cells co-expressing the neural marker SOX2 and MHC-II antigen in vivo during human CNS development. MHC-II proteins in hNSCs are functional, and differently regulated upon differentiation along different lineages. Mimicking an inflammatory response using the inflammatory cytokine IFNγ induced MHC-II up-regulation in both astrocytes and hNSCs, but not in UC-MSCs and ADSCs, either undifferentiated or differentiated, though IFNγ receptor expression was comparable. Together, hypoimmunogenicity of both UC-MSCs and ADSCs supports their suitability for allogeneic therapy, while significant immunogenicity of hNSCs and their progeny may at least in part underlie negative effects reported in some patients following embryonic neural cell grafts. Crucially, we show for the first time that MHC-II expression in developing human brains is not restricted to microglia as previously suggested, but is present in discrete subsets of neural progenitors and appears to be regulated independently of inflammatory stimuli. PMID:27080443

  12. MHC-class-II are expressed in a subpopulation of human neural stem cells in vitro in an IFNγ–independent fashion and during development

    PubMed Central

    Vagaska, B.; New, S. E. P.; Alvarez-Gonzalez, C.; D’Acquisto, F.; Gomez, S. G.; Bulstrode, N. W.; Madrigal, A.; Ferretti, P.

    2016-01-01

    Expression of major histocompatibility antigens class-2 (MHC-II) under non-inflammatory conditions is not usually associated with the nervous system. Comparative analysis of immunogenicity of human embryonic/fetal brain-derived neural stem cells (hNSCs) and human mesenchymal stem cells with neurogenic potential from umbilical cord (UC-MSCs) and paediatric adipose tissue (ADSCs), while highlighting differences in their immunogenicity, led us to discover subsets of neural cells co-expressing the neural marker SOX2 and MHC-II antigen in vivo during human CNS development. MHC-II proteins in hNSCs are functional, and differently regulated upon differentiation along different lineages. Mimicking an inflammatory response using the inflammatory cytokine IFNγ induced MHC-II up-regulation in both astrocytes and hNSCs, but not in UC-MSCs and ADSCs, either undifferentiated or differentiated, though IFNγ receptor expression was comparable. Together, hypoimmunogenicity of both UC-MSCs and ADSCs supports their suitability for allogeneic therapy, while significant immunogenicity of hNSCs and their progeny may at least in part underlie negative effects reported in some patients following embryonic neural cell grafts. Crucially, we show for the first time that MHC-II expression in developing human brains is not restricted to microglia as previously suggested, but is present in discrete subsets of neural progenitors and appears to be regulated independently of inflammatory stimuli. PMID:27080443

  13. 40 CFR 82.70 - Nonessential Class II products and exceptions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... designated as class II in 40 CFR part 82, appendix B to subpart A) are identified as being nonessential and... 21 CFR 2.125(e); (ii) Lubricants, coatings or cleaning fluids for electrical or electronic equipment... aerosol product or other pressurized dispenser which contains a class II substance: (1) Including but...

  14. Whole blood transcriptional profiling reveals significant down-regulation of human leukocyte antigen class I and II genes in essential thrombocythemia, polycythemia vera and myelofibrosis.

    PubMed

    Skov, Vibe; Riley, Caroline Hasselbalch; Thomassen, Mads; Larsen, Thomas Stauffer; Jensen, Morten K; Bjerrum, Ole Weis; Kruse, Torben A; Hasselbalch, Hans Carl

    2013-10-01

    Gene expression profiling studies in the Philadelphia-negative chronic myeloproliferative neoplasms have revealed significant deregulation of several immune and inflammation genes that might be of importance for clonal evolution due to defective tumor immune surveillance. Other mechanisms might be down-regulation of major histocompatibility (MHC) class I and II genes, which are used by tumor cells to escape antitumor T-cell-mediated immune responses. We have performed whole blood transcriptional profiling of genes encoding human leukocyte antigen (HLA) class I and II molecules, β2-microglobulin and members of the antigen processing machinery of HLA class I molecules (LMP2, LMP7, TAP1, TAP2 and tapasin). The findings of significant down-regulation of several of these genes may possibly be of major importance for defective tumor immune surveillance. Since up-regulation of HLA genes is recorded during treatment with epigenome modulating agents (DNA-hypomethylators and DNA-hyperacetylators [histone deacetylase inhibitors]) and interferon-α2, our findings call for prospective transcriptional studies of HLA genes during treatment with these agents. PMID:23302045

  15. The production and crystallization of the human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 complexed with deamidated gliadin peptides implicated in coeliac disease

    SciTech Connect

    Henderson, Kate N.; Reid, Hugh H.; Borg, Natalie A.; Broughton, Sophie E.; Huyton, Trevor; Anderson, Robert P.; McCluskey, James; Rossjohn, Jamie

    2007-12-01

    The production and crystallization of human leukocyte antigen class II molecules HLA-DQ2 and HLA-DQ8 in complex with deamidated gliadin peptides is reported. Crystals of HLA-DQ2{sup PQPELPYPQ} diffracted to 3.9 Å, while the HLA-DQ8{sup EGSFQPSQE} crystals diffracted to 2.1 Å, allowing structure determination by molecular replacement. The major histocompatibility complex (MHC) class II molecules HLA-DQ2 and HLA-DQ8 are key risk factors in coeliac disease, as they bind deamidated gluten peptides that are subsequently recognized by CD4{sup +} T cells. Here, the production and crystallization of both HLA-DQ2 and HLA-DQ8 in complex with the deamidated gliadin peptides DQ2 α-I (PQPELPYPQ) and DQ8 α-I (EGSFQPSQE), respectively, are reported.

  16. Multipotent adult germ-line stem cells, like other pluripotent stem cells, can be killed by cytotoxic T lymphocytes despite low expression of major histocompatibility complex class I molecules

    PubMed Central

    Dressel, Ralf; Guan, Kaomei; Nolte, Jessica; Elsner, Leslie; Monecke, Sebastian; Nayernia, Karim; Hasenfuss, Gerd; Engel, Wolfgang

    2009-01-01

    Background Multipotent adult germ-line stem cells (maGSCs) represent a new pluripotent cell type that can be derived without genetic manipulation from spermatogonial stem cells (SSCs) present in adult testis. Similarly to induced pluripotent stem cells (iPSCs), they could provide a source of cellular grafts for new transplantation therapies of a broad variety of diseases. To test whether these stem cells can be rejected by the recipients, we have analyzed whether maGSCs and iPSCs can become targets for cytotoxic T lymphocytes (CTL) or whether they are protected, as previously proposed for embryonic stem cells (ESCs). Results We have observed that maGSCs can be maintained in prolonged culture with or without leukemia inhibitory factor and/or feeder cells and still retain the capacity to form teratomas in immunodeficient recipients. They were, however, rejected in immunocompetent allogeneic recipients, and the immune response controlled teratoma growth. We analyzed the susceptibility of three maGSC lines to CTL in comparison to ESCs, iPSCs, and F9 teratocarcinoma cells. Major histocompatibility complex (MHC) class I molecules were not detectable by flow cytometry on these stem cell lines, apart from low levels on one maGSC line (maGSC Stra8 SSC5). However, using a quantitative real time PCR analysis H2K and B2m transcripts were detected in all pluripotent stem cell lines. All pluripotent stem cell lines were killed in a peptide-dependent manner by activated CTLs derived from T cell receptor transgenic OT-I mice after pulsing of the targets with the SIINFEKL peptide. Conclusion Pluripotent stem cells, including maGSCs, ESCs, and iPSCs can become targets for CTLs, even if the expression level of MHC class I molecules is below the detection limit of flow cytometry. Thus they are not protected against CTL-mediated cytotoxicity. Therefore, pluripotent cells might be rejected after transplantation by this mechanism if specific antigens are presented and if specific

  17. Comparison of Class II HLA antigen expression in normal and carcinomatous human breast cells

    SciTech Connect

    Bernard, D.J.; Maurizis, J.C.; Chassagne, J.; Chollet, P.; Plagne, R.

    1985-03-01

    Class II HLA antigen expression in breast carcinoma and normal breast gland cells was compared using a method more accurate than immunofluorescence. This new method involves labeling membrane proteins with /sup 131/I and the anti-Class II HLA monoclonal antibody with /sup 125/I. The isolation and purification of the doubly labeled (/sup 125/I-/sup 131/I) immune complex was performed by affinity chromatography and chromatofocusing successively. When the specific activity of glycoproteins is known, the amount of glycoprotein which bind specifically to the anti-Class II HLA monoclonal antibody can be deduced. In breast carcinoma cells, 1.5 to 2% of the purified glycoproteins bind specifically to the monoclonal antibody, whereas less than 0.3% of normal breast gland cells binds. In contrast, leukemic cells, of which 80 to 90% possess Class II HLA antigens, 2 to 3% of Class II HLA glycoproteins bind specifically with the anti-Class II HLA monoclonal antibody.

  18. Active site nanospace of aminoacyl tRNA synthetase: difference between the class I and class II synthetases.

    PubMed

    Dutta, Saheb; Choudhury, Kaberi; Banik, Sindrila Dutta; Nandi, Nilashis

    2014-03-01

    The present work is aimed at understanding the origin of the difference in the molecular organization of the active site nanospaces of the class I and class II aminoacyl tRNA synthetases (aaRSs) which are tunnel-like structures. The active site encloses the cognate amino acid (AA) and the adenosine triphosphate (ATP) to carry out aminoacylation reaction. Comparison of the structures of the active site of the class I and class II (aaRSs) shows that the nanodimensional tunnels are curved in opposite directions in the two classes. We investigated the origin of this difference using quantum mechanical computation of electrostatic potential (ESP) of substrates, surrounding residues and ions, using Atoms in Molecule (AIM) Theory and charge population analysis. We show that the difference is principally due to the variation in the spatial charge distribution of ATP in the two classes which correspond to extended and bent conformations of ATP. The present computation shows that the most feasible pathway for nucleophilic attack to alphaP is oppositely directed for class I and class II aaRSs. The available crystal structures show that the cognate AA is indeed located along the channel favorable for nucleophilic attack as predicted by the ESP analysis. It is also shown that the direction of the channel changes its orientation when the orientation of ATP is changed from extended to a bent like structure. We further used the AIM theory to confirm the direction of the approach of AA in each case and the results corroborate the results from the ESP analysis. The opposite curvatures of the active site nanospaces in class I and class II aaRSs are related with the influence of the charge distributions of the extended and bent conformations of ATP, respectively. The results of the computation of electrostatic potential by successive addition of active site residues show that their roles on the reaction are similar in both classes despite the difference in the organization of the

  19. Quantification of HLA class II-specific memory B cells in HLA-sensitized individuals.

    PubMed

    Karahan, Gonca E; de Vaal, Yvonne J H; Roelen, Dave L; Buchli, Rico; Claas, Frans H J; Heidt, Sebastiaan

    2015-03-01

    For the quantification of HLA-specific memory B cells from peripheral blood of sensitized individuals, a limited number of methods are available. However, none of these are capable of detecting memory B cells directed at HLA class II molecules. Since the majority of antibodies that occur after transplantation appear to be specific for HLA class II, our aim was to develop an assay to detect and quantify HLA class II-specific memory B cells from peripheral blood. By using biotinylated soluble HLA class II molecules as detection agent, we were able to develop an HLA class II-specific memory B cell ELISPOT assay. The assay was validated using B cell-derived hybridomas that produce human monoclonal antibodies directed at specific HLA class II molecules. In pregnancy-immunized females, we found memory B cell frequencies ranging from 25 to 756 spots per 10(6) B cells specific for the immunizing paternal HLA class II molecules, whereas in non-immunized males no significant spot formation was detected. Here, we present a novel ELISPOT assay for quantifying HLA class II-specific memory B cells from peripheral blood. This technique provides a unique tool for monitoring the HLA class II-specific memory B cell pool in sensitized transplant recipients. PMID:25636565

  20. MHC class II allosteric site drugs: new immunotherapeutics for malignant, infectious and autoimmune diseases.

    PubMed

    Xu, M; Li, J; Gulfo, J V; Von Hofe, E; Humphreys, R E

    2001-01-01

    The discovery of the interactions of the 'Ii-Key' segment of the Ii protein with the major histocmpatibility complex (MHC) Class II allosteric site, which is adjacent to the antigenic peptide-binding site, creates therapeutic opportunities by regulating the antigenic peptide binding to MHC class II molecules. The binding of Ii-Key to the MHC class II allosteric site loosens the hold of the MHC Class II 'clamshell' on antigenic peptides and leads to highly efficient antigenic peptide charging to or releasing from the MHC class II antigenic peptide-binding groove. Ii-Key peptide-induced spilling of bound antigenic peptide, or replacement with inert blockers, leads to 'inert immunosuppression'. Highly efficient replacement of ambient with vaccine peptides by Ii-Key permits 'active immunosuppression' for antigen-specific control of autoimmune diseases in the absence of cytokines or adjuvants. On the other hand, active immunization against cancer or infectious disease can result from epitope replacement mediated by Ii-Key and accompanied by cytokines or other adjuvants. Finally, linking the Ii-Key peptide through a simple polymethylene bridge to an antigenic sequence vastly increases the potency of MHC Class II peptide vaccines. In summary, the discovery of the MHC class II allosteric site allows one to increase the efficiency of MHC class II-related, antigenic epitope-specific therapy for malignant, infectious, and autoimmune diseases. The focus of this review is on the mechanism and potential clinical use of such novel allosteric site-directed, Ii-key drugs. PMID:11439146

  1. Expression of major histocompatibility antigens in human chronic pancreatitis.

    PubMed

    Jalleh, R P; Gilbertson, J A; Williamson, R C; Slater, S D; Foster, C S

    1993-10-01

    T-lymphocytic infiltration of the exocrine pancreas and liver in patients with chronic pancreatitis has suggested that cell mediated immune mechanisms may play a part in the pathogenesis of this disease. As expression of major histocompatibility (MHC) antigens is a prerequisite for organ specific autoimmunity, the expression of HLA class I (beta 2-microglobulin) and class II (HLA-DR) determinants have been analysed, together with the presence of T-lymphocytes, in 93 patients (64 men and 29 women, mean age 40.6 years) having an operation for chronic pancreatitis. Ethanol (63 patients), recurrent acute pancreatitis (12), congenital lesions (2), and unknown (16) were suggested to be the causes of the disease. Immunohistochemical staining of formalin fixed and paraffin wax embedded tissue sections used conventional immunohistochemical techniques with specific anti-serum samples. No MHC expression was identified in 10 histologically normal pancreatic control specimens or in four cases of chronic pancreatitis secondary to obstruction by neuroendocrine tumours within the head of the pancreas. beta 2-microglobulin expression by pancreatic exocrine epithelial cells was seen in 76 chronic pancreatitis specimens (82%) while HLA-DR was present in 61 (66%). Simultaneous expression of both class I and II determinants was seen in 53 (57%) of cases. MHC determinant expression was not found in 10 cases (11%) of chronic pancreatitis. In the positive specimens, expression was confined to ductal and ductular (interlobular and intralobular) epithelium with no staining of acinar cells. Staining was not related to the suspected cause of the disease or age. T-lymphocytes were more prominent in chronic pancreatitis mean (SEM) (131 (15) cells per high powered field) than controls (5 (1), p < 0.01). Aberrant MHC expression by exocrine pancreatic epithelial cells occurring in the presence of an appreciable T-cell infiltration confirmed that the appropriate cellular conditions were present for

  2. OGLE II Eclipsing Binaries In The LMC: Analysis With Class

    NASA Astrophysics Data System (ADS)

    Devinney, Edward J.; Prsa, A.; Guinan, E. F.; DeGeorge, M.

    2011-01-01

    The Eclipsing Binaries (EBs) via Artificial Intelligence (EBAI) Project is applying machine learning techniques to elucidate the nature of EBs. Previously, Prsa, et al. applied artificial neural networks (ANNs) trained on physically-realistic Wilson-Devinney models to solve the light curves of the 1882 detached EBs in the LMC discovered by the OGLE II Project (Wyrzykowski, et al.) fully automatically, bypassing the need for manually-derived starting solutions. A curious result is the non-monotonic distribution of the temperature ratio parameter T2/T1, featuring a subsidiary peak noted previously by Mazeh, et al. in an independent analysis using the EBOP EB solution code (Tamuz, et al.). To explore this and to gain a fuller understanding of the multivariate EBAI LMC observational plus solutions data, we have employed automatic clustering and advanced visualization (CAV) techniques. Clustering the OGLE II data aggregates objects that are similar with respect to many parameter dimensions. Measures of similarity for example, could include the multidimensional Euclidean Distance between data objects, although other measures may be appropriate. Applying clustering, we find good evidence that the T2/T1 subsidiary peak is due to evolved binaries, in support of Mazeh et al.'s speculation. Further, clustering suggests that the LMC detached EBs occupying the main sequence region belong to two distinct classes. Also identified as a separate cluster in the multivariate data are stars having a Period-I band relation. Derekas et al. had previously found a Period-K band relation for LMC EBs discovered by the MACHO Project (Alcock, et al.). We suggest such CAV techniques will prove increasingly useful for understanding the large, multivariate datasets increasingly being produced in astronomy. We are grateful for the support of this research from NSF/RUI Grant AST-05-75042 f.

  3. Pseudomycoicidin, a Class II Lantibiotic from Bacillus pseudomycoides

    PubMed Central

    Basi-Chipalu, Shradha; Dischinger, Jasmin; Josten, Michaele; Szekat, Christiane; Zweynert, Annegret; Sahl, Hans-Georg

    2015-01-01

    Lantibiotics are ribosomally synthesized antimicrobial peptides with substantial posttranslational modifications. They are characterized by the unique amino acids lanthionine and methyllanthionine, which are introduced by dehydration of Ser/Thr residues and linkage of the resulting dehydrated amino acids with Cys residues. BLAST searches using the mersacidin biosynthetic enzyme (MrsM) in the NCBI database revealed a new class II lantibiotic gene cluster in Bacillus pseudomycoides DSM 12442. Production of an antimicrobial substance with activity against Gram-positive bacteria was detectable in a cell wash extract of this strain. The substance was partially purified, and mass spectrometric analysis predicted a peptide of 2,786 Da in the active fraction. In order to characterize the putative lantibiotic further, heterologous expression of the predicted biosynthetic genes was performed in Escherichia coli. Coexpression of the prepeptide (PseA) along with the corresponding modification enzyme (PseM) resulted in the production of a modified peptide with the corresponding mass, carrying four out of eight possible dehydrations and supporting the presence of four thioether and one disulfide bridge. After the proteolytic removal of the leader, the core peptide exhibited antimicrobial activity. In conclusion, pseudomycoicidin is a novel lantibiotic with antimicrobial activity that was heterologously produced in E. coli. PMID:25769830

  4. Structural hierarchy in molecular films of two class II hydrophobins.

    PubMed

    Paananen, Arja; Vuorimaa, Elina; Torkkeli, Mika; Penttilä, Merja; Kauranen, Martti; Ikkala, Olli; Lemmetyinen, Helge; Serimaa, Ritva; Linder, Markus B

    2003-05-13

    Hydrophobins are highly surface-active proteins that are specific to filamentous fungi. They function as coatings on various fungal structures, enable aerial growth of hyphae, and facilitate attachment to surfaces. Little is known about their structures and structure-function relationships. In this work we show highly organized surface layers of hydrophobins, representing the most detailed structural study of hydrophobin films so far. Langmuir-Blodgett films of class II hydrophobins HFBI and HFBII from Trichoderma reesei were prepared and analyzed by atomic force microscopy. The films showed highly ordered two-dimensional crystalline structures. By combining our recent results on small-angle X-ray scattering of hydrophobin solutions, we found that the unit cells in the films have dimensions similar to those of tetrameric aggregates found in solutions. Further analysis leads to a model in which the building blocks of the two-dimensional crystals are shape-persistent supramolecules consisting of four hydrophobin molecules. The results also indicate functional and structural differences between HFBI and HFBII that help to explain differences in their properties. The possibility that the highly organized surface assemblies of hydrophobins could allow a route for manufacturing functional surfaces is suggested. PMID:12731866

  5. Performance assessment for the class L-II disposal facility

    SciTech Connect

    1997-03-01

    This draft radiological performance assessment (PA) for the proposed Class L-II Disposal Facility (CIIDF) on the Oak Ridge Reservation (ORR) has been prepared to demonstrate compliance with the requirements of the US Department of Energy Order 5820.2A. This PA considers the disposal of low-level radioactive wastes (LLW) over the operating life of the facility and the long-term performance of the facility in providing protection to public health and the environment. The performance objectives contained in the order require that the facility be managed to accomplish the following: (1) Protect public health and safety in accordance with standards specified in environmental health orders and other DOE orders. (2) Ensure that external exposure to the waste and concentrations of radioactive material that may be released into surface water, groundwater, soil, plants, and animals results in an effective dose equivalent (EDE) that does not exceed 25 mrem/year to a member of the public. Releases to the atmosphere shall meet the requirements of 40 CFR Pt. 61. Reasonable effort should be made to maintain releases of radioactivity in effluents to the general environment as low as reasonably achievable. (1) Ensure that the committed EDEs received by individual who inadvertently may intrude into the facility after the loss of active institutional control (100 years) will not exceed 100 mrem/year for continuous exposure of 500 mrem for a single acute exposure. (4) Protect groundwater resources, consistent with federal, state, and local requirements.

  6. Decreased expression of human class II antigens on monocytes from patients with acquired immune deficiency syndrome. Increased expression with interferon-gamma.

    PubMed Central

    Heagy, W; Kelley, V E; Strom, T B; Mayer, K; Shapiro, H M; Mandel, R; Finberg, R

    1984-01-01

    The expression of HLA-DR (a class II histocompatibility antigen) on monocytes isolated from the peripheral blood of normal individuals and patients with acquired immune deficiency syndrome (AIDS) was investigated by the use of dual fluorescent staining and cytofluorometry. In animal models the absence of class II positive monocytes is linked to a failure of T cells to respond to antigens. We now report that patients with AIDS have a paucity of HLA-DR+ monocytes. The percentage of HLA-DR+ monocytes among eight normal individuals ranged from 49.3 to 95.0%+, and only one individual had less than 50% HLA-DR+ monocytes. HLA-DR expression on monocytes from homosexual male patients with lymphadenopathy was similar to that of normal subjects (range, 58.0 to 97.4%+). In contrast, seven of nine patients with AIDS had less than 50% HLA-DR+ monocytes (range, 13.4 to 78.8%+). The in vitro incubation of monocytes from AIDS patients with cloned human interferon-gamma resulted in an increase of the expression of HLA-DR to near normal levels. PMID:6439741

  7. 40 CFR Figure C-2 to Subpart C of... - Illustration of the Slope and Intercept Limits for Class II and Class III PM2.5 Candidate...

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 6 2012-07-01 2012-07-01 false Illustration of the Slope and Intercept Limits for Class II and Class III PM2.5 Candidate Equivalent Methods C Figure C-2 to Subpart C of Part 53... of the Slope and Intercept Limits for Class II and Class III PM2.5 Candidate Equivalent...

  8. 14 CFR 21.331 - Issue of airworthiness approval tags for Class II products.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Issue of airworthiness approval tags for Class II products. 21.331 Section 21.331 Aeronautics and Space FEDERAL AVIATION ADMINISTRATION... Approvals § 21.331 Issue of airworthiness approval tags for Class II products. (a) An applicant is...

  9. 14 CFR 21.83 - Requirements for issue and amendment of Class II provisional type certificates.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 14 Aeronautics and Space 1 2010-01-01 2010-01-01 false Requirements for issue and amendment of Class II provisional type certificates. 21.83 Section 21.83 Aeronautics and Space FEDERAL AVIATION... Type Certificates § 21.83 Requirements for issue and amendment of Class II provisional...

  10. 40 CFR 147.1851 - State-administered program-Class II wells.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Oklahoma § 147.1851 State-administered program—Class II wells. The UIC program for Class II wells in the State of Oklahoma, including the lands of the Five Civilized Tribes, but not including those on other Indian lands, is the program administered by the Oklahoma Corporation Commission approved by EPA...

  11. 40 CFR 147.1851 - State-administered program-Class II wells.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Oklahoma § 147.1851 State-administered program—Class II wells. The UIC program for Class II wells in the State of Oklahoma, including the lands of the Five Civilized Tribes, but not including those on other Indian lands, is the program administered by the Oklahoma Corporation Commission approved by EPA...

  12. 40 CFR 147.1851 - State-administered program-Class II wells.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Oklahoma § 147.1851 State-administered program—Class II wells. The UIC program for Class II wells in the State of Oklahoma, including the lands of the Five Civilized Tribes, but not including those on other Indian lands, is the program administered by the Oklahoma Corporation Commission approved by EPA...

  13. 40 CFR 147.1851 - State-administered program-Class II wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Oklahoma § 147.1851 State-administered program—Class II wells. The UIC program for Class II wells in the State of Oklahoma, including the lands of the Five Civilized Tribes, but not including those on other Indian lands, is the program administered by the Oklahoma Corporation Commission approved by EPA...

  14. 40 CFR 144.22 - Existing Class II enhanced recovery and hydrocarbon storage wells.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... and hydrocarbon storage wells. 144.22 Section 144.22 Protection of Environment ENVIRONMENTAL... of Underground Injection by Rule § 144.22 Existing Class II enhanced recovery and hydrocarbon storage wells. (a) An existing Class II enhanced recovery or hydrocarbon storage injection well is authorized...

  15. 40 CFR 144.22 - Existing Class II enhanced recovery and hydrocarbon storage wells.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... and hydrocarbon storage wells. 144.22 Section 144.22 Protection of Environment ENVIRONMENTAL... of Underground Injection by Rule § 144.22 Existing Class II enhanced recovery and hydrocarbon storage wells. (a) An existing Class II enhanced recovery or hydrocarbon storage injection well is authorized...

  16. 40 CFR 144.22 - Existing Class II enhanced recovery and hydrocarbon storage wells.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... and hydrocarbon storage wells. 144.22 Section 144.22 Protection of Environment ENVIRONMENTAL... of Underground Injection by Rule § 144.22 Existing Class II enhanced recovery and hydrocarbon storage wells. (a) An existing Class II enhanced recovery or hydrocarbon storage injection well is authorized...

  17. 40 CFR 144.22 - Existing Class II enhanced recovery and hydrocarbon storage wells.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... and hydrocarbon storage wells. 144.22 Section 144.22 Protection of Environment ENVIRONMENTAL... of Underground Injection by Rule § 144.22 Existing Class II enhanced recovery and hydrocarbon storage wells. (a) An existing Class II enhanced recovery or hydrocarbon storage injection well is authorized...

  18. 40 CFR 144.22 - Existing Class II enhanced recovery and hydrocarbon storage wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... and hydrocarbon storage wells. 144.22 Section 144.22 Protection of Environment ENVIRONMENTAL... of Underground Injection by Rule § 144.22 Existing Class II enhanced recovery and hydrocarbon storage wells. (a) An existing Class II enhanced recovery or hydrocarbon storage injection well is authorized...

  19. 40 CFR 82.15 - Prohibitions for class II controlled substances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... person for that substance under the authority of this subpart at that time in that control period, unless... use production allowances to produce a quantity of class II controlled substance unless that person... class II controlled substance for which EPA has apportioned baseline production and...

  20. 40 CFR 82.15 - Prohibitions for class II controlled substances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 18 2012-07-01 2012-07-01 false Prohibitions for class II controlled substances. 82.15 Section 82.15 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.15 Prohibitions for class II...

  1. 40 CFR 82.15 - Prohibitions for class II controlled substances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 18 2013-07-01 2013-07-01 false Prohibitions for class II controlled substances. 82.15 Section 82.15 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.15 Prohibitions for class II...

  2. 40 CFR 82.16 - Phaseout schedule of class II controlled substances.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 18 2013-07-01 2013-07-01 false Phaseout schedule of class II controlled substances. 82.16 Section 82.16 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.16 Phaseout schedule of class II...

  3. 40 CFR 82.16 - Phaseout schedule of class II controlled substances.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 40 Protection of Environment 18 2012-07-01 2012-07-01 false Phaseout schedule of class II controlled substances. 82.16 Section 82.16 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.16 Phaseout schedule of class II...

  4. 40 CFR 147.851 - State-administered program-Class II wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... Kansas § 147.851 State-administered program—Class II wells. The UIC program for Class II wells in the State of Kansas, except those on Indian lands as described in § 147.860, is the program administered by the Kansas Corporation Commission and the Kansas Department of Health and Environment, approved by...

  5. 38 CFR 17.162 - Eligibility for Class II dental treatment without rating action.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... dental treatment without rating action. 17.162 Section 17.162 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Dental Services § 17.162 Eligibility for Class II dental treatment without rating action. When an application has been made for class II dental treatment under §...

  6. 38 CFR 17.162 - Eligibility for Class II dental treatment without rating action.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... dental treatment without rating action. 17.162 Section 17.162 Pensions, Bonuses, and Veterans' Relief DEPARTMENT OF VETERANS AFFAIRS MEDICAL Dental Services § 17.162 Eligibility for Class II dental treatment without rating action. When an application has been made for class II dental treatment under §...

  7. 40 CFR 82.23 - Transfers of allowances of class II controlled substances.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... class II controlled substance being converted multiplied by the quotient of the ozone depletion potential of the first class II controlled substance divided by the ozone depletion potential of the second... (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption...

  8. 40 CFR 82.23 - Transfers of allowances of class II controlled substances.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... class II controlled substance being converted multiplied by the quotient of the ozone depletion potential of the first class II controlled substance divided by the ozone depletion potential of the second... (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption...

  9. 40 CFR 147.2100 - State-administered program-Class II wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... South Dakota § 147.2100 State-administered program—Class II wells. The UIC program for Class II wells in the State of South Dakota, except those on Indian lands, is the program administered by the South... part of the applicable UIC program under the SDWA for the State of South Dakota. This incorporation...

  10. 40 CFR 147.2100 - State-administered program-Class II wells.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... South Dakota § 147.2100 State-administered program—Class II wells. The UIC program for Class II wells in the State of South Dakota, except those on Indian lands, is the program administered by the South... part of the applicable UIC program under the SDWA for the State of South Dakota. This incorporation...

  11. 40 CFR 147.2100 - State-administered program-Class II wells.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... South Dakota § 147.2100 State-administered program—Class II wells. The UIC program for Class II wells in the State of South Dakota, except those on Indian lands, is the program administered by the South... part of the applicable UIC program under the SDWA for the State of South Dakota. This incorporation...

  12. 40 CFR 147.2100 - State-administered program-Class II wells.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... South Dakota § 147.2100 State-administered program—Class II wells. The UIC program for Class II wells in the State of South Dakota, except those on Indian lands, is the program administered by the South... part of the applicable UIC program under the SDWA for the State of South Dakota. This incorporation...

  13. 40 CFR 147.1600 - State-administered program-Class II wells.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... New Mexico § 147.1600 State-administered program—Class II wells. The UIC program for Class II wells in the State of New Mexico, except for those on Indian lands, is the program administered by the New... reference and made a part of the applicable UIC program under the SDWA for the State of New Mexico....

  14. 40 CFR 147.1600 - State-administered program-Class II wells.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... New Mexico § 147.1600 State-administered program—Class II wells. The UIC program for Class II wells in the State of New Mexico, except for those on Indian lands, is the program administered by the New... reference and made a part of the applicable UIC program under the SDWA for the State of New Mexico....

  15. 40 CFR 147.1600 - State-administered program-Class II wells.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... New Mexico § 147.1600 State-administered program—Class II wells. The UIC program for Class II wells in the State of New Mexico, except for those on Indian lands, is the program administered by the New... reference and made a part of the applicable UIC program under the SDWA for the State of New Mexico....

  16. 40 CFR 147.1600 - State-administered program-Class II wells.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... New Mexico § 147.1600 State-administered program—Class II wells. The UIC program for Class II wells in the State of New Mexico, except for those on Indian lands, is the program administered by the New... reference and made a part of the applicable UIC program under the SDWA for the State of New Mexico....

  17. 40 CFR 147.300 - State-administered program-Class II wells.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... Director of the OFR in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies may be obtained at the... Colorado Assistant Attorney General to the Acting Regional Counsel, EPA Region VIII, “Re: Class II Well...: Class II Well Injection Control Program of Colorado Oil and Gas Conservation Commission”, April 29,...

  18. 40 CFR 147.300 - State-administered program-Class II wells.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... Director of the OFR in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies may be obtained at the... Colorado Assistant Attorney General to the Acting Regional Counsel, EPA Region VIII, “Re: Class II Well...: Class II Well Injection Control Program of Colorado Oil and Gas Conservation Commission”, April 29,...

  19. 40 CFR 147.300 - State-administered program-Class II wells.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... Director of the OFR in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies may be obtained at the... Colorado Assistant Attorney General to the Acting Regional Counsel, EPA Region VIII, “Re: Class II Well...: Class II Well Injection Control Program of Colorado Oil and Gas Conservation Commission”, April 29,...

  20. 40 CFR 147.300 - State-administered program-Class II wells.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... Director of the OFR in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies may be obtained at the... Colorado Assistant Attorney General to the Acting Regional Counsel, EPA Region VIII, “Re: Class II Well...: Class II Well Injection Control Program of Colorado Oil and Gas Conservation Commission”, April 29,...

  1. 46 CFR 128.220 - Class II non-vital systems-materials and pressure design.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... SUPPLY VESSELS MARINE ENGINEERING: EQUIPMENT AND SYSTEMS Materials and Pressure Design § 128.220 Class II non-vital systems—materials and pressure design. (a) Except as provided by §§ 128.230, 128.240, and... 46 Shipping 4 2011-10-01 2011-10-01 false Class II non-vital systems-materials and pressure...

  2. 46 CFR 128.220 - Class II non-vital systems-materials and pressure design.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 46 Shipping 4 2013-10-01 2013-10-01 false Class II non-vital systems-materials and pressure design. 128.220 Section 128.220 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OFFSHORE SUPPLY VESSELS MARINE ENGINEERING: EQUIPMENT AND SYSTEMS Materials and Pressure Design § 128.220 Class II non-vital systems—materials and...

  3. 76 FR 53817 - Minimum Internal Control Standards for Class II Gaming

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-08-30

    ... National Indian Gaming Commission 25 CFR Parts 542 and 543 Minimum Internal Control Standards for Class II... delay of the effective date on the final rule for Minimum Internal Control Standards for Class II Gaming... the final rule published October 10, 2008 (73 FR 60492), delayed October 9, 2009 (74 FR 52138)...

  4. 40 CFR 82.16 - Phaseout schedule of class II controlled substances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 40 Protection of Environment 18 2014-07-01 2014-07-01 false Phaseout schedule of class II controlled substances. 82.16 Section 82.16 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls § 82.16 Phaseout schedule of class II...

  5. 40 CFR 147.1600 - State-administered program-Class II wells.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... New Mexico § 147.1600 State-administered program—Class II wells. The UIC program for Class II wells in the State of New Mexico, except for those on Indian lands, is the program administered by the New Mexico Energy and Minerals Department, Oil Conservation Division, approved by EPA pursuant to...

  6. HLA class I and class II haplotypes in admixed families from several regions of Mexico.

    PubMed

    Barquera, Rodrigo; Zúñiga, Joaquín; Hernández-Díaz, Raquel; Acuña-Alonzo, Victor; Montoya-Gama, Karla; Moscoso, Juan; Torres-García, Diana; García-Salas, Claudia; Silva, Beatriz; Cruz-Robles, David; Arnaiz-Villena, Antonio; Vargas-Alarcón, Gilberto; Granados, Julio

    2008-02-01

    We studied HLA class I and class II alleles in 191 Mexican families (381 non-related individuals) to directly obtain the HLA-A/B/DRB1/DQB1 haplotypes and their linkage disequilibrium (LD). The most frequent HLA haplotypes observed were: A*02-B*39-DRB1*04-DQB1*0302, A*02-B*35-DRB1*04-DQB1*0302, A*68-B*39-DRB1*04-DQB1*0302, A*02-B*35-DRB1*08-DQB1*04, A*33-B*1402-DRB1*01-DQB1*05, and A*24-B*35-DRB1*04-DQB1*0302. The four most common haplotypes found by our study involve those previously reported in Amerindian populations. LD analysis of HLA-A-B and HLA-B-DRB1 loci showed significant associations between A29(19)-B44(12), A33(19)-B65(14), A1-B8, A26(19)-B44(12), A24(9)-B61(40), B65(14)-DR1, B8-DR17(3), B44(12)-DR7, B7-DR15(2), and B39(16)-DR4. Also, all DRB1-DQB1 associations showed significant LD values. Admixture estimations using a trihybrid model showed that Mexicans from the State of Sinaloa (Northern Mexico) have a greater proportion of European genetic component compared with Mexicans from the Central area of Mexico, who have a greater percentage of Amerindian genes. Our results are important for future comparative genetic studies of different Mexican ethnic groups with special relevance to disease association and transplantation studies. PMID:17904223

  7. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas.

    PubMed

    Brown, P J; Wong, K K; Felce, S L; Lyne, L; Spearman, H; Soilleux, E J; Pedersen, L M; Møller, M B; Green, T M; Gascoyne, D M; Banham, A H

    2016-03-01

    The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco-Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients. PMID:26500140

  8. FOXP1 suppresses immune response signatures and MHC class II expression in activated B-cell-like diffuse large B-cell lymphomas

    PubMed Central

    Brown, P J; Wong, K K; Felce, S L; Lyne, L; Spearman, H; Soilleux, E J; Pedersen, L M; Møller, M B; Green, T M; Gascoyne, D M; Banham, A H

    2016-01-01

    The FOXP1 (forkhead box P1) transcription factor is a marker of poor prognosis in diffuse large B-cell lymphoma (DLBCL). Here microarray analysis of FOXP1-silenced DLBCL cell lines identified differential regulation of immune response signatures and major histocompatibility complex class II (MHC II) genes as some of the most significant differences between germinal center B-cell (GCB)-like DLBCL with full-length FOXP1 protein expression versus activated B-cell (ABC)-like DLBCL expressing predominantly short FOXP1 isoforms. In an independent primary DLBCL microarray data set, multiple MHC II genes, including human leukocyte antigen DR alpha chain (HLA-DRA), were inversely correlated with FOXP1 transcript expression (P<0.05). FOXP1 knockdown in ABC-DLBCL cells led to increased cell-surface expression of HLA-DRA and CD74. In R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone)-treated DLBCL patients (n=150), reduced HLA-DRA (<90% frequency) expression correlated with inferior overall survival (P=0.0003) and progression-free survival (P=0.0012) and with non-GCB subtype stratified by the Hans, Choi or Visco–Young algorithms (all P<0.01). In non-GCB DLBCL cases with <90% HLA-DRA, there was an inverse correlation with the frequency (P=0.0456) and intensity (P=0.0349) of FOXP1 expression. We propose that FOXP1 represents a novel regulator of genes targeted by the class II MHC transactivator CIITA (MHC II and CD74) and therapeutically targeting the FOXP1 pathway may improve antigen presentation and immune surveillance in high-risk DLBCL patients. PMID:26500140

  9. Fish oil disrupts MHC class II lateral organization on the B-cell side of the immunological synapse independent of B-T cell adhesion.

    PubMed

    Rockett, Benjamin Drew; Melton, Mark; Harris, Mitchel; Bridges, Lance C; Shaikh, Saame Raza

    2013-11-01

    Fish oil-enriched long chain n-3 polyunsaturated fatty acids disrupt the molecular organization of T-cell proteins in the immunological synapse. The impact of fish oil derived n-3 fatty acids on antigen-presenting cells, particularly at the animal level, is unknown. We previously demonstrated B-cells isolated from mice fed with fish oil-suppressed naïve CD4(+) T-cell activation. Therefore, here we determined the mechanistic effects of fish oil on murine B-cell major histocompatibility complex (MHC) class II molecular distribution using a combination of total internal reflection fluorescence, Förster resonance energy transfer and confocal imaging. Fish oil had no impact on presynaptic B-cell MHC II clustering. Upon conjugation with transgenic T-cells, fish-oil suppressed MHC II accumulation at the immunological synapse. As a consequence, T-cell protein kinase C theta (PKCθ) recruitment to the synapse was also diminished. The effects were independent of changes in B-T cell adhesion, as measured with microscopy, flow cytometry and static cell adhesion assays with select immune ligands. Given that fish oil can reorganize the membrane by lowering membrane cholesterol levels, we then compared the results with fish oil to cholesterol depletion using methyl-B-cyclodextrin (MβCD). MβCD treatment of B-cells suppressed MHC II and T-cell PKCθ recruitment to the immunological synapse, similar to fish oil. Overall, the results reveal commonality in the mechanism by which fish oil manipulates protein lateral organization of B-cells compared to T-cells. Furthermore, the data establish MHC class II lateral organization on the B-cell side of the immunological synapse as a novel molecular target of fish oil. PMID:23791516

  10. Comparison of occlusal contact areas of class I and class II molar relationships at finishing using three-dimensional digital models

    PubMed Central

    Lee, Hyejoon; Kim, Minji

    2015-01-01

    Objective This study compared occlusal contact areas of ideally planned set-up and accomplished final models against the initial in class I and II molar relationships at finishing. Methods Evaluations were performed for 41 post-orthodontic treatment cases, of which 22 were clinically diagnosed as class I and the remainder were diagnosed as full cusp class II. Class I cases had four first premolars extracted, while class II cases had maxillary first premolars extracted. Occlusal contact areas were measured using a three-dimensional scanner and RapidForm 2004. Independent t-tests were used to validate comparison values between class I and II finishings. Repeated measures analysis of variance was used to compare initial, set up, and final models. Results Molars from cases in the class I finishing for the set-up model showed significantly greater contact areas than those from class II finishing (p < 0.05). The final model class I finishing showed significantly larger contact areas for the second molars (p < 0.05). The first molars of the class I finishing for the final model showed a tendency to have larger contact areas than those of class II finishing, although the difference was not statistically significant (p = 0.078). Conclusions In set-up models, posterior occlusal contact was better in class I than in class II finishing. In final models, class I finishing tended to have larger occlusal contact areas than class II finishing. PMID:26023539

  11. An ATF/CREB binding motif is required for aberrant constitutive expression of the MHC class II DR alpha promoter and activation by SV40 T-antigen.

    PubMed Central

    Cox, P M; Goding, C R

    1992-01-01

    Constitutive expression of major histocompatibility complex class II (MHC II) antigens normally occurs in B-lymphocytes and antigen presenting cells of the monocyte/macrophage lineage. However, many malignant tumours and transformed cells express these proteins aberrantly. We demonstrate here that the MHC II DR alpha promoter is constitutively active both in the SV40 large T antigen transformed cell line, COS, and in CV1 cells from which they are derived. As an approach to understanding the molecular mechanisms underlying aberrant DR alpha expression we have examined the cis- and trans-acting requirements for DR alpha transcription in these cell types. Electrophoretic mobility shift assays showed that the region immediately 3' to the X-box was bound by a member of the ATF/CREB family of transcription factors. Using deletions and point mutations in the DR alpha promoter we demonstrate that, in contrast to B-cells, the octamer motif and conserved X- and Y-boxes make only a minor contribution to promoter function while single point mutations in the ATF/CREB motif reduced transcription up to 20-fold. In addition, we show that the DR alpha promoter is activated by SV40 large T-antigen and that activation requires an intact ATF/CREB motif. Similar data were obtained using B16 melanoma cells. These results suggest that the ATF/CREB motif may be a target for transcription deregulation in several transformed cell types. Images PMID:1329030

  12. 25 CFR 547.8 - What are the minimum technical software standards applicable to Class II gaming systems?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... OF CLASS II GAMES § 547.8 What are the minimum technical software standards applicable to Class II... of Class II games. (a) Player interface displays. (1) If not otherwise provided to the player, the player interface shall display the following: (i) The purchase or wager amount; (ii) Game results;...

  13. 25 CFR 547.8 - What are the minimum technical software standards applicable to Class II gaming systems?

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... OF CLASS II GAMES § 547.8 What are the minimum technical software standards applicable to Class II... of Class II games. (a) Player interface displays. (1) If not otherwise provided to the player, the player interface shall display the following: (i) The purchase or wager amount; (ii) Game results;...

  14. 25 CFR 547.8 - What are the minimum technical software standards applicable to Class II gaming systems?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... OF CLASS II GAMES § 547.8 What are the minimum technical software standards applicable to Class II... of Class II games. (a) Player interface displays. (1) If not otherwise provided to the player, the player interface shall display the following: (i) The purchase or wager amount; (ii) Game results;...

  15. Phenotypic Diversity in Caucasian Adults with Moderate to Severe Class II Malocclusion

    PubMed Central

    Moreno Uribe, Lina M.; Howe, Sara C.; Kummet, Colleen; Vela, Kaci C.; Dawson, Deborah V.; Southard, Thomas E.

    2014-01-01

    INTRODUCTION Class II malocclusion affects about 15 % of the US population and is characterized by a convex profile and occlusion disharmonies. The specific etiological mechanisms resulting in the range of Class II dento-skeletal combinations observed is not yet understood. Most studies describing the class II phenotypic diversity have utilized moderate sample sizes or have focused on younger individuals that later in life may outgrow their class II discrepancies; such a focus may also preclude the visualization of adult class II features. The majority have utilized simple correlation methods resulting in phenotypes that may not be generalizable to different samples and thus may not be suitable for studies of malocclusion etiology. The purpose of this study is to address these knowledge gaps by capturing the maximum phenotypic variation present in a large Caucasian sample of class II individuals selected with strict eligibility criteria and rigorously standardized multivariate reduction analyses. METHODS Sixty-three lateral cephalometric variables were measured from pre-treatment records of 309 Class II Caucasian adults (82 males, 227 females; ages 16–60 years). Principal component analysis (PCA) and cluster analysis were used to generate comprehensive phenotypes in an effort to identify the most homogeneous groups of individuals reducing heterogeneity and improving the power of future malocclusion etiology studies. RESULTS PCA resulted in 7 principal components that accounted for 81% of the variation. The first three components represented variation on mandibular rotation, upper incisor angulation and mandibular length, respectively. The cluster analysis identified 5 distinct Class II phenotypes. CONCLUSIONS A comprehensive spectrum of Class II phenotypic definitions was obtained that could be generalized to other samples advancing our efforts to the identification of etiological factors underlying Class II malocclusion. PMID:24582022

  16. Minor histocompatibility antigens on canine hemopoietic progenitor cells.

    PubMed

    Weber, Martin; Lange, Claudia; Günther, Wolfgang; Franz, Monika; Kremmer, Elisabeth; Kolb, Hans-Jochem

    2003-06-15

    Adoptive immunotherapy with CTL against minor histocompatibility Ags (mHA) provides a promising way to treat leukemia relapse in allogeneic chimeras. Here we describe the in vitro generation of CTL against mHA in the dog. We tested their inhibitory effect on the growth of hemopoietic progenitor cells stimulated by hemopoietic growth factors in a 4-day suspension culture. CTL were produced by coculture of donor PBMC with bone marrow-derived dendritic cells (DCs). These DCs were characterized by morphology, high expression of MHC class II and CD1a, and the absence of the monocyte-specific marker CD14. Characteristically these cells stimulated allogeneic lymphocytes (MLR) and, after pulsing with a foreign Ag (keyhole limpet hemocyanin), autologous T cells. CTL were generated either ex vivo by coculture with DCs of DLA-identical littermates or in vivo by immunization of the responder with DCs obtained from a DLA-identical littermate. In suspension culture assays the growth of hemopoietic progenitor cells was inhibited in 53% of DLA-identical littermate combinations. In canine families mHA segregated with DLA as restriction elements. One-way reactivity against mHA was found in five littermate combinations. In two cases mHA might be Y chromosome associated, in three cases autosomally inherited alleles were detected. We conclude that CTL can be produced in vitro and in vivo against mHA on canine hemopoietic progenitor cells using bone marrow-derived DCs. PMID:12794111

  17. The Oropharyngeal Airway in Young Adults with Skeletal Class II and Class III Deformities: A 3-D Morphometric Analysis

    PubMed Central

    Jayaratne, Yasas Shri Nalaka; Zwahlen, Roger Arthur

    2016-01-01

    Objectives 1) To determine the accuracy and reliability of an automated anthropometric measurement software for the oropharyngeal airway and 2) To compare the anthropometric dimensions of the oropharyngeal airway in skeletal class II and III deformity patients. Methods Cone-beam CT (CBCT) scans of 62 patients with skeletal class II or III deformities were used for this study. Volumetric, linear and surface area measurements retroglossal (RG) and retropalatal (RP) compartments of the oropharyngeal airway was measured with the 3dMDVultus software. Accuracy of automated anthropometric pharyngeal airway measurements was assessed using an airway phantom. Results The software was found to be reasonably accurate for measuring dimensions of air passages. The total oropharyngeal volume was significantly greater in the skeletal class III deformity group (16.7 ± 9.04 mm3) compared with class II subjects (11.87 ± 4.01 mm3). The average surface area of both the RG and RP compartments were significantly larger in the class III deformity group. The most constricted area in the RG and RP airway was significantly larger in individuals with skeletal class III deformity. The anterior-posterior (AP) length of this constriction was significantly greater in skeletal class III individuals in both compartments, whereas the width of the constriction was not significantly different between the two groups in both compartments. The RP compartment was larger but less uniform than the RG compartment in both skeletal deformities. Conclusion Significant differences were observed in morphological characteristics of the oropharyngeal airway in individuals with skeletal class II and III deformities. This information may be valuable for surgeons in orthognathic treatment planning, especially for mandibular setback surgery that might compromise the oropharyngeal patency. PMID:26901313

  18. Dissection of the role of MHC class II A and E genes in autoimmune susceptibility in murine lupus models with intragenic recombination.

    PubMed

    Zhang, Danqing; Fujio, Keishi; Jiang, Yi; Zhao, Jingyuan; Tada, Norihiro; Sudo, Katsuko; Tsurui, Hiromichi; Nakamura, Kazuhiro; Yamamoto, Kazuhiko; Nishimura, Hiroyuki; Shira, Toshikazu; Hirose, Sachiko

    2004-09-21

    Systemic lupus erythematosus (SLE) is a multigenic autoimmune disease, and the major histocompatibility complex (MHC) class II polymorphism serves as a key genetic element. In SLE-prone (NZB x NZW)F(1) mice, the MHC H-2(d/z) heterozygosity (H-2(d) of NZB and H-2(z) of NZW) has a strong impact on disease; thus, congenic H-2(d/d) homozygous F(1) mice do not develop severe disease. In this study, we used Ea-deficient intra-H-2 recombination to establish A(d/d)-congenic (NZB x NZW)F(1) mice, with or without E molecule expression, and dissected the role of class II A and E molecules. Here we found that A(d/d) homozygous F(1) mice lacking E molecules developed severe SLE similar to that seen in wild-type F1 mice, including lupus nephritis, autoantibody production, and spontaneously occurring T cell activation. Additional evidence revealed that E molecules prevent the disease in a dose-dependent manner; however, the effect is greatly influenced by the haplotype of A molecules, because wild-type H-2(d/z) F(1) mice develop SLE, despite E molecule expression. Studies on the potential of dendritic cells to present a self-antigen chromatin indicated that dendritic cells from wild-type F(1) mice induced a greater response of chromatin-specific T cells than did those from A(d/d) F(1) mice, irrespective of the presence or absence of E molecules, suggesting that the self-antigen presentation is mediated by A, but not by E, molecules. Our mouse models are useful for analyzing the molecular mechanisms by which MHC class II regions regulate the process of autoimmune responses. PMID:15361580

  19. Structure and evolution of a new avian MHC class II B gene in a sub-Antarctic seabird, the thin-billed prion (Procellariiformes: Pachyptila belcheri).

    PubMed

    Silva, Mónica C; Edwards, Scott V

    2009-03-01

    The major histocompatibility complex encodes molecules that present foreign peptides to T cells of the immune system. The peptide binding region (PBR) of these molecules is among the most polymorphic regions found in vertebrate taxa. Genomic cloning approaches are improving our understanding of the evolution of this multigene family in nonmodel avian groups. By building a cosmid library, a new MHC class II B gene, Pabe-DAB1, was isolated and characterized at the genomic level in a sub-Antarctic seabird, the thin-billed prion (Pachyptila belcheri). Pabe-DAB1 exhibits the hallmark structural features of functional MHC class II loci. Direct sequencing of the PBR encoding exon in a panel of prions revealed significantly higher levels of genetic diversity compared to two noncoding neutral loci, with most alleles differing by at least one replacement substitution in the peptide binding codons. We estimated evolutionary dynamics for Pabe-DAB1 using a variety of Bayesian and other approaches. Evidence for balancing selection comes from a spatially variable ratio of nonsynonymous-to-synonymous substitutions (mean d (N)/d (S) = 2.87) in the PBR, with sites predicted to be functionally relevant exhibiting the highest omega values. We estimate the population recombination rate to be approximately 0.3 per site per generation, indicating an important role for recombination in generating polymorphism at this locus. Pabe-DAB1 is among the few avian class II loci characterized at the genomic level and with a known intron-exon structure, a feature that greatly facilitated the amplification and sequencing of a single MHC locus in this species. PMID:19209378

  20. Differential regulation of expression of the MHC class II molecules RT1.B and RT1.D on rat B lymphocytes: effects of interleukin-4, interleukin-13 and interferon-gamma.

    PubMed Central

    Roos, A; Schilder-Tol, E J; Chand, M A; Claessen, N; Lakkis, F G; Pascual, D W; Weening, J J; Aten, J

    1998-01-01

    Susceptibility to induction of both T helper 1- (Th1) and Th2-mediated autoimmunity is multifactorial and involves genetic linkage to the major histocompatibility complex (MHC) class II haplotype. Brown Norway (BN) rats exposed to mercuric chloride develop a Th2-dependent systemic autoimmunity, whereas Lewis rats, which are highly susceptible to Th1-mediated autoimmunity, develop immune suppression after mercuric chloride exposure. Exposure to mercuric chloride is known to enhance B-lymphocyte expression of the MHC class II molecule RT1.B, predominantly in BN rats. We demonstrate that, in contrast, expression of RT1.D was unmodified on these B cells, whereas both RT1.B and RT1.D were up-regulated on epithelial cells. Regulation of B-cell MHC class II isotype expression was further studied in vitro, using BN rat lymph node (LN) cells. Interleukin-4 (IL-4) strongly enhanced B-cell expression of RT1.B (2.8-fold), whereas RT1.D expression was only slightly, although significantly, modified (1.2-fold). B cells from Lewis rats showed a similar IL-4-induced enhancement of RT1.B expression (2.5-fold), whereas, in contrast, RT1.D expression was unmodified. Exposure of LN cells from BN rats to interferon-gamma induced a moderate increase of B-cell MHC class II expression, predominantly of RT1.B. Strong and rapid enhancement of B-cell RT1.D expression was observed after stimulation by phorbol 12-myristate 13-acetate and ionomycin. Rat IL-13 did not modify B-cell MHC class II expression; however, it induced typical morphological changes in peritoneal macrophages. These experiments demonstrate isotype-specific and strain-dependent regulation of MHC class II expression on rat B lymphocytes, which may be of pathophysiological relevance for the strain-dependent susceptibility for Th1- or Th2-mediated autoimmunity. Images Figure 1 Figure 5 PMID:9536116

  1. A novel high-wear-resistant glass-ionomer cement for class I and class II restorations.

    PubMed

    Zhao, Jun; Weng, Yiming; Xie, Dong

    2009-02-01

    This study reports the results of an evaluation on the in vitro wear of a newly developed experimental light-cured glass-ionomer cement composed of the synthesized six-arm star-shape poly(acrylic acid) and Fuji II LC glass fillers. The resin composite P-60, as well as glass-ionomer cements Fuji II and Fuji II LC, were used for comparison. All specimens were conditioned in distilled water at 37 degrees C for 1 d prior to testing. The experimental cement exhibited statistically the same wear-resistance to abrasion as P-60, but the wear-resistance was 14 times higher for the experimental cement than for Fuji II and Fuji II LC. Furthermore, the experimental cement showed a degree of wear-resistance to attrition that was 1.4 times higher than both Fuji II and Fuji II LC but six times lower than that of P-60. Impressively, after 1 month of aging the experimental cement was able to compete with P-60 in wear-resistance to attrition, showing a degree of wear depth that was only 1.3 times more than that of P-60. It appears that this novel cement is a clinically attractive dental restorative that can be potentially used for high-wear sites such as class I and class II restorations. PMID:19196323

  2. Non-neutral evolution and reciprocal monophyly of two expressed Mhc class II B genes in Leach's storm-petrel.

    PubMed

    Dearborn, Donald C; Gager, Andrea B; Gilmour, Morgan E; McArthur, Andrew G; Hinerfeld, Douglas A; Mauck, Robert A

    2015-02-01

    The major histocompatibility complex (Mhc) is subject to pathogen-mediated balancing selection and can link natural selection with mate choice. We characterized two Mhc class II B loci in Leach's storm-petrel, Oceanodroma leucorhoa, focusing on exon 2 which encodes the portion of the protein that binds pathogen peptides. We amplified and sequenced exon 2 with locus-specific nested PCR and Illumina MiSeq using individually barcoded primers. Repeat genotyping of 78 single-locus genotypes produced identical results in 77 cases (98.7%). Sequencing of messenger RNA (mRNA) from three birds confirmed expression of both loci, consistent with the observed absence of stop codons or frameshifts in all alleles. In 48 birds, we found 9 and 12 alleles at the two loci, respectively, and all 21 alleles translated to unique amino acid sequences. Unlike many studies of duplicated Mhc genes, alleles of the two loci clustered into monophyletic groups. Consistent with this phylogenetic result, interlocus gene conversion appears to have affected only two short fragments of the exon. As predicted under a paradigm of pathogen-mediated selection, comparison of synonymous and non-synonymous substitution rates found evidence of a history of positive selection at putative peptide binding sites. Overall, the results suggest that the gene duplication event leading to these two loci is not recent and that point mutations and positive selection on the peptide binding sites may be the predominant forces acting on these genes. Characterization of these loci sets the stage for population-level work on the evolutionary ecology of Mhc in this species. PMID:25416539

  3. Multiple sclerosis: a role for astroglia in active demyelination suggested by class II MHC expression and ultrastructural study.

    PubMed

    Lee, S C; Moore, G R; Golenwsky, G; Raine, C S

    1990-03-01

    Central nervous system (CNS) tissue was studied by immunocytochemistry and electron microscopy from three cases of multiple sclerosis (MS) in which evidence of ongoing myelin breakdown could be documented. The study focussed upon the role of glial cells in the pathogenesis of demyelination. In acute MS, demyelination involved the vesicular dissolution of myelin from intact axons and a paucity of fibrillary astrogliosis. Foamy macrophages, many of them probably derived from transformed and recently proliferated microglia, contained recognizable myelin debris and lipid droplets and were abundant throughout the lesions. These cells formed the major phagocytic population and stained positively for class II major histocompatibility complex antigens (HLA-DR; Ia). In acute MS lesions, rounded astrocytes were encountered which possessed membrane-bound compartments enclosing phagocytosed fragments of myelin basic protein-positive debris. Despite the superficial resemblance of these cells to foamy macrophages, the presence of intermediate filaments, glycogen granules and diffuse glial fibrillary acidic protein positivity supported an astroglial identity. Astrocyte processes were involved in myelin removal and invested recently demyelinated axons. Hypertrophic fibrous astrocytes were common in chronic active lesions, were capable of myelin degradation and on occasion, contained myelin debris attached to clathrin-coated pits. These astrocytes were sometimes Ia+. Oligodendrocytes were depleted from the center of active lesions but were numerous at the lesion margin, suggesting survival and proliferation. They stained positively for myelin-associated glycoprotein, a marker for immature oligodendrocytes. However, they were invariably Ia-. The findings confirm and further support a role for the astrocyte as both an antigen presenting cell and a phagocyte in the CNS during MS. PMID:2307980

  4. Correction of Class II malocclusion and soft tissue profile in an adult patient

    PubMed Central

    Gaur, Aditi; Maheshwari, Sandhya; Verma, Sanjeev Kumar

    2016-01-01

    Treatment of Class II malocclusion in nongrowing individuals is a challenging situation for the clinician. Class II malocclusion with bialveolar protrusion often dictates premolar extractions with maximum anchorage. The present article describes the case of an adult female with skeletal Class II malocclusion, bimaxillary protrusion, increased overjet, deep bite, lip protrusion, everted lower lip, deep mentolabial sulcus, and lip incompetence. To correct the malocclusion, all four first premolars were extracted. Direct anchorage from miniscrews was used for retraction of the anterior segment. The mandibular buccal segment was protracted into the extraction space using Class II mechanics. Ideal Class I canine and molar relation were achieved in 24 months. There was a significant improvement in facial profile and smile esthetics of the patient.

  5. Inflammatory bowel disease associations with HLA Class II genes

    SciTech Connect

    Castro, R.; Yang, H.; Targan, S.

    1994-09-01

    A PCR-SSOP assay has been used to analyze HLA-Class II DRB1 and DQB1 alleles in 378 Caucasians from a population in Southern California. The data has been analyzed separately for the Ashkenasi Jews and non-Jewish patients (n=286) and controls (n=92). Two common clinical forms of inflammatory bowel disease (IBD) have been studied: ulcerative colitis (UC) and Crohn`s disease (CD). In CD, we observed a susceptible effect with the rare DR1 allele - DRB*0103 [O.R.=4.56; 95% CI (0.96, 42.97); p=0.03]; a trend for an increase in DRB1*0103 was also observed in UC patients. A susceptible effect with DRB1*1502 [O.R.=5.20; 95% CI (1.10, 48.99); p=0.02] was observed in non-Jewish UC patients. This susceptible effect was restricted to UC ANCA-positive (antineutrophil cytoplasmic antibodies) patients. In addition, a significant association with DRB1*1101-DQB1*0301 [O.R.=9.46; 95% CI (1.30, 413.87); p=0.01] was seen with UC among non-Jewish patients: this haplotype was increased with CD among non-Jewish patients. Two protective haplotypes were detected among CD non-Jewish patients: DRB1*1301-DQB1*0603 [O.R.=0.34; 95% CI (0.09, 1.09); p=0.04], and DRB*0404-DQB1*0302 [O.R.=<0.08; 95% CI (0.0, 0.84); p=0.01]. When the same data were analyzed at the serology level, we observed a positive association in UC with DR2 [O.R.6.77; 95% CI (2.47, 22.95); p=2 x 10{sup -4}], and a positive association in CD with DR1 [O.R.=2.63; 95% CI (1.14, 6.62); p=0.01] consistent with previous reports. Thus, some IBD disease associations appear to be common to both UC and CD, while some are unique to one disease.

  6. Fixed or removable function appliances for Class II malocclusions.

    PubMed

    Madurantakam, Parthasarathy

    2016-06-01

    Data sourcesEmbase, Cochrane Central Register of Controlled Trials, Medline (Pubmed), Web of Science, Google Scholar, Scopus, LILACS database and bibliographies of clinical trials encountered during search. There was no restriction on language or date during search.Study selectionRandomised Controlled Trials (RCTs) and Controlled Clinical Trials (CCT) in patients with Class II malocclusions that compared at least one fixed functional appliance with at least one removable functional appliance (RFA) in children below 16 years of age. Primary outcomes were clinical and lateral cephalometric measurements and the duration of treatment. Secondary outcomes included patient experiences of treatment, quality of life measures and harms arising during treatment as well as costs of both treatments.Data extraction and synthesisThe titles and abstracts of all studies identified through the search were assessed independently and in duplicate by two review authors. Disagreements about included studies were resolved through discussion with the third author. Heterogeneity was assessed using customised forms and risk of bias using a Cochrane Collaboration tool. A meta-analysis was planned for studies at low risk of bias with similar comparisons reporting the same outcome.ResultsTwo RCTs and two CCTs that met the inclusion/exclusion criteria were included in the final analysis. Risk of bias assessment indicated three trials were at high risk while one was unclear. Consequently, the included trials were deemed to be inappropriate for meta-analysis (MA).Two studies with 282 participants evaluated Twin Block with fixed Herbst appliance and reported significant improvements in anterior-posterior skeletal discrepancy, mandibular length and reduction of overjet with both appliances. While one study reported significantly shorter treatment duration in Herbst appliance, the other study did not find any difference. Herbst appliance had better compliance, less dropouts but more emergency visits

  7. Searching for the Right Way to Begin Class: Part II

    ERIC Educational Resources Information Center

    Lawry, John D.

    2012-01-01

    Part I, "Searching for the Right Way to Begin Class," described the various iterations of beginning class rituals the author used over the years. Those rituals began with a prayer to the Holy Spirit as was required at the Catholic women's college Marymount in Tarrytown, New York, where he first taught out of graduate school in 1965. That was…

  8. HLA Class II Antigen Expression in Colorectal Carcinoma Tumors as a Favorable Prognostic Marker12

    PubMed Central

    Sconocchia, Giuseppe; Eppenberger-Castori, Serenella; Zlobec, Inti; Karamitopoulou, Eva; Arriga, Roberto; Coppola, Andrea; Caratelli, Sara; Spagnoli, Giulio Cesare; Lauro, Davide; Lugli, Alessandro; Han, Junyi; Iezzi, Giandomenica; Ferrone, Cristina; Ferlosio, Amedeo; Tornillo, Luigi; Droeser, Raoul; Rossi, Piero; Attanasio, Antonio; Ferrone, Soldano; Terracciano, Luigi

    2014-01-01

    The goal of this study was to determine the frequency of HLA class II antigen expression in colorectal carcinoma (CRC) tumors, its association with the clinical course of the disease, and the underlying mechanism(s). Two tissue microarrays constructed with 220 and 778 CRC tumors were stained with HLA-DR, DQ, and DP antigen-specific monoclonal antibody LGII-612.14, using the immunoperoxidase staining technique. The immunohistochemical staining results were correlated with the clinical course of the disease. The functional role of HLA class II antigens expressed on CRC cells was analyzed by investigating their in vitro interactions with immune cells. HLA class II antigens were expressed in about 25% of the 220 and 21% of the 778 tumors analyzed with an overall frequency of 23%. HLA class II antigens were detected in 19% of colorectal adenomas. Importantly, the percentage of stained cells and the staining intensity were significantly lower than those detected in CRC tumors. However, HLA class II antigen staining was weakly detected only in 5.4% of 37 normal mucosa tissues. HLA class II antigen expression was associated with a favorable clinical course of the disease. In vitro stimulation with interferon gamma (IFNγ) induced HLA class II antigen expression on two of the four CRC cell lines tested. HLA class II antigen expression on CRC cells triggered interleukin-1β (IL-1β) production by resting monocytes. HLA class II antigen expression in CRC tumors is a favorable prognostic marker. This association may reflect stimulation of IL-1β production by monocytes. PMID:24563618

  9. Drift Rather than Selection Dominates MHC Class II Allelic Diversity Patterns at the Biogeographical Range Scale in Natterjack Toads Bufo calamita

    PubMed Central

    Zeisset, Inga; Beebee, Trevor J. C.

    2014-01-01

    Study of major histocompatibility complex (MHC) loci has gained great popularity in recent years, partly due to their function in protecting vertebrates from infections. This is of particular interest in amphibians on account of major threats many species face from emergent diseases such as chytridiomycosis. In this study we compare levels of diversity in an expressed MHC class II locus with neutral genetic diversity at microsatellite loci in natterjack toad (Bufo (Epidalea) calamita) populations across the whole of the species’ biogeographical range. Variation at both classes of loci was high in the glacial refugium areas (REF) and much lower in postglacial expansion areas (PGE), especially in range edge populations. Although there was clear evidence that the MHC locus was influenced by positive selection in the past, congruence with the neutral markers suggested that historical demographic events were the main force shaping MHC variation in the PGE area. Both neutral and adaptive genetic variation declined with distance from glacial refugia. Nevertheless, there were also some indications from differential isolation by distance and allele abundance patterns that weak effects of selection have been superimposed on the main drift effect in the PGE zone. PMID:24937211

  10. Dual MHC class I and class II restriction of a single T cell receptor: distinct modes of tolerance induction by two classes of autoantigens.

    PubMed

    Arsov, I; Vukmanović, S

    1999-02-15

    In the final stages of thymic development, immature T cells undergo three distinct processes (positive selection, negative selection, and lineage commitment) that all depend on interactions of thymocyte TCRs with MHC molecules. It is currently thought that TCRs are preferentially restricted by either MHC class I or class II molecules. In this report, we present direct evidence that the TCR previously described as H-Y/H-2Db specific cross-reacts with H-2IAb if expressed in CD4+ cells. We also demonstrate an increase in thymocyte numbers in H-Y TCR-trangenic mice deficient in MHC class II, suggesting a relatively discrete form of negative selection by MHC class II compared with that induced by H-Y/H-2Db. We propose that inability to generate CD4+ T cells expressing H-Y TCR in different experimental settings may be due to tolerance to self-MHC class II. These results, therefore, support an intriguing possibility that tolerance to self may influence and/or interfere with the outcome of the lineage commitment. PMID:9973472

  11. 25 CFR 547.10 - What are the minimum standards for Class II gaming system critical events?

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 25 Indians 2 2013-04-01 2013-04-01 false What are the minimum standards for Class II gaming system... are the minimum standards for Class II gaming system critical events? (a) Fault events. (1) The following are fault events that must be capable of being recorded by the Class II gaming system:...

  12. 25 CFR 547.10 - What are the minimum standards for Class II gaming system critical events?

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 25 Indians 2 2014-04-01 2014-04-01 false What are the minimum standards for Class II gaming system... are the minimum standards for Class II gaming system critical events? (a) Fault events. (1) The following are fault events that must be capable of being recorded by the Class II gaming system:...

  13. 25 CFR 547.6 - What are the minimum technical standards for enrolling and enabling Class II gaming system...

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... and enabling Class II gaming system components? 547.6 Section 547.6 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR HUMAN SERVICES MINIMUM TECHNICAL STANDARDS FOR GAMING EQUIPMENT USED... enabling Class II gaming system components? (a) General requirements. Class II gaming systems shall...

  14. Immunogenicity of HLA Class I and II Double Restricted Influenza A-Derived Peptides

    PubMed Central

    Pedersen, Sara Ram; Christensen, Jan Pravsgaard; Buus, Søren; Rasmussen, Michael; Korsholm, Karen Smith; Nielsen, Morten; Claesson, Mogens Helweg

    2016-01-01

    The aim of the present study was to identify influenza A-derived peptides which bind to both HLA class I and -II molecules and by immunization lead to both HLA class I and class II restricted immune responses. Eight influenza A-derived 9-11mer peptides with simultaneous binding to both HLA-A*02:01 and HLA-DRB1*01:01 molecules were identified by bioinformatics and biochemical technology. Immunization of transgenic HLA-A*02:01/HLA-DRB1*01:01 mice with four of these double binding peptides gave rise to both HLA class I and class II restricted responses by CD8 and CD4 T cells, respectively, whereas four of the double binding peptides did result in HLA-A*02:01 restricted responses only. According to their cytokine profile, the CD4 T cell responses were of the Th2 type. In influenza infected mice, we were unable to detect natural processing in vivo of the double restricted peptides and in line with this, peptide vaccination did not decrease virus titres in the lungs of intranasally influenza challenged mice. Our data show that HLA class I and class II double binding peptides can be identified by bioinformatics and biochemical technology. By immunization, double binding peptides can give rise to both HLA class I and class I restricted responses, a quality which might be of potential interest for peptide-based vaccine development. PMID:26731261

  15. 40 CFR 82.23 - Transfers of allowances of class II controlled substances.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... (CONTINUED) AIR PROGRAMS (CONTINUED) PROTECTION OF STRATOSPHERIC OZONE Production and Consumption Controls... quantity of the transferor's class II consumption allowances, production allowances, export production... EPA; and (G) For trades of consumption allowances, production allowances, export production...

  16. 46 CFR 128.220 - Class II non-vital systems-materials and pressure design.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... SUPPLY VESSELS MARINE ENGINEERING: EQUIPMENT AND SYSTEMS Materials and Pressure Design § 128.220 Class II... a corrosion-resistant material and, if ferrous, be hot-dip galvanized or be at least of...

  17. An adult with a severe Class II division 1 malocclusion: Frances' case.

    PubMed

    Clark, J D; Kerr, W J; Davis, M H

    1998-04-01

    This article describes treatment options for an adult with a severe Class II division 1 malocclusion. The opinions of British orthodontists, as obtained through the CASES project, are summarized and the patient's actual treatment is discussed. PMID:9791204

  18. Correction of an adult Class II division 2 individual using fixed functional appliance: A noncompliance approach.

    PubMed

    Basavaraddi, Shrinivas; Gandedkar, Narayan H; Belludi, Anup; Patil, Anand

    2016-01-01

    This case report describes the application of fixed functional appliance in the treatment of an adult female having Class II division 2 malocclusion with retroclination of upper incisors. Fixed functional appliance was used to correct the overjet after the uprighting of upper incisors. Fixed functional appliance was fitted on a rigid rectangular arch wire. Application of fixed functional appliance achieved a good Class I molar relationship along with Class I canine relationship with normal overjet and overbite. Fixed functional appliance is effective in the treatment of Class II malocclusions, even in adult patients, and can serve as an alternate choice of treatment instead of orthognathic surgery. This is a case; wherein, fixed functional appliance was successfully used to relieve deep bite and overjet that was ensued after leveling and aligning. We demonstrate that fixed functional appliance can act as a "noncompliant corrector" and use of Class II elastics can be avoided. PMID:27041908

  19. Correction of an adult Class II division 2 individual using fixed functional appliance: A noncompliance approach

    PubMed Central

    Basavaraddi, Shrinivas; Gandedkar, Narayan H.; Belludi, Anup; Patil, Anand

    2016-01-01

    This case report describes the application of fixed functional appliance in the treatment of an adult female having Class II division 2 malocclusion with retroclination of upper incisors. Fixed functional appliance was used to correct the overjet after the uprighting of upper incisors. Fixed functional appliance was fitted on a rigid rectangular arch wire. Application of fixed functional appliance achieved a good Class I molar relationship along with Class I canine relationship with normal overjet and overbite. Fixed functional appliance is effective in the treatment of Class II malocclusions, even in adult patients, and can serve as an alternate choice of treatment instead of orthognathic surgery. This is a case; wherein, fixed functional appliance was successfully used to relieve deep bite and overjet that was ensued after leveling and aligning. We demonstrate that fixed functional appliance can act as a “noncompliant corrector” and use of Class II elastics can be avoided. PMID:27041908

  20. Quantification of the configuration factor in Class I and II cavities and simulated cervical erosions.

    PubMed

    de la Macorra, J C; Gomez-Fernandez, S

    1996-03-01

    The configuration factor of adhesive cavities is defined as the ratio of the restoration's bonded to unbonded (free) surfaces. Such a configuration factor was described, on ideal cavities, as having a potential value in predicting the behaviour of the restorations, because it is related to the restoration's capacity for relieving stress by flow. The aim of this study was to measure the configuration factor value for real Class I and II cavities and simulated cervical erosions prepared in molars. Ten Class I, five Class II cavities and seven cervical erosions were analysed using a computerised digitising system. The configuration factor values found were 4.03 +/- 0.33 for Class I cavities, 1.85 +/- 0.59 for Class II cavities and 1.10 +/- 0.09 for simulated cervical erosions (P < 0.01). PMID:9171011

  1. Class II Division 1 Malocclusion Treated with a Cervical-Pull Headgear: A Case Report.

    PubMed

    Shah, Ankit H

    2016-01-01

    Orthodontic treatment for skeletal Class II malocclusion was undertaken with the aim ofachieving orthopedic correction by modifying the growth pattern. A case of Class II, Division 1 malocclusion in the late mixed dentition was corrected to a Class I molar relationship by primarily using cervical-pull headgear. Cephalometric analysis indicated a reduction in the maxillo-mandibular discrepancy (ANB°) due to the correction of a skeletal Class II malocclusion to a Class I occlusion. The superimposition demonstrated that this was achieved by favorable growth of the mandible, control of maxillary first molars in an antero-posterior direction and retraction of maxillary incisors. Proclination of mandibular incisors was reduced. Significant improvement in the soft-tissue profile was noted. PMID:27319037

  2. Data on HLA class I/II profile in Brazilian pemphigus patients.

    PubMed

    Franco Brochado, Maria José; Nascimento, Daniela Francisca; Saloum Deghaide, Neifi Hassan; Donadi, Eduardo Antonio; Roselino, Ana Maria

    2016-09-01

    Pemphigus are blistering autoimmune diseases related with genetic and environmental factors. Here we describe HLA genotyping in pemphigus patients. First, we review the HLA class I/II data on pemphigus reported in Brazilian samples and then present the HLA class I (-A, -B, -C) and class II (-DRB1, -DQA1, -DQB1) alleles related to susceptibility/resistance to pemphigus by comparing 86 patients with pemphigus foliaceus, 83 patients with pemphigus vulgaris, and 1592 controls from the northeastern region of the state of São Paulo, Southeastern Brazil. The data presented here are related to the manuscript "Differential HLA class I and class II associations in Pemphigus Foliaceus and Pemphigus Vulgaris patients from a prevalent Southeastern Brazilian region" Brochado et al. (2016) [1]. PMID:27331116

  3. MHC class II antigen presentation pathway in murine tumours: tumour evasion from immunosurveillance?

    PubMed Central

    Walter, W; Lingnau, K; Schmitt, E; Loos, M; Maeurer, M J

    2000-01-01

    Qualitative differences in the MHC class II antigen processing and presentation pathway may be instrumental in shaping the CD4+ T cell response directed against tumour cells. Efficient loading of many MHC class II alleles with peptides requires the assistance of H2-M, a heterodimeric MHC class II-like molecule. In contrast to the HLA-DM region in humans, the β-chain locus is duplicated in mouse, with the H2-Mb1 (Mb1β-chain distal to H2-Mb2 (Mb2) and the H2-Ma (Ma) α-chain gene). Here, we show that murine MHC class II and H2-M genes are coordinately regulated in murine tumour cell lines by T helper cell 1 (IFN-γ) and T helper cell 2 (IL-4 or IL-10) cytokines in the presence of the MHC class II-specific transactivator CIITA as determined by mRNA expression and Western blot analysis. Furthermore, Mαβ1 and Mαβ2 heterodimers are differentially expressed in murine tumour cell lines of different histology. Both H2-M isoforms promote equally processing and presentation of native protein antigens to H2-Ad- and H2-Ed-restricted CD4+ T cells. Murine tumour cell lines could be divided into three groups: constitutive MHC class II and CIITA expression; inducible MHC class II and CIITA expression upon IFN-γ-treatment; and lack of constitutive and IFN-γ-inducible MHC class II and CIITA expression. These differences may impact on CD4+ T cell recognition of cancer cells in murine tumour models. © 2000 Cancer Research Campaign PMID:11027433

  4. Total distalization of the maxillary arch in a patient with skeletal Class II malocclusion.

    PubMed

    Choi, Yoon Jeong; Lee, Jong-Suk; Cha, Jung-Yul; Park, Young-Chel

    2011-06-01

    In nongrowing patients with skeletal Class II malocclusion, premolar extraction or maxillary molar distalization can be used as camouflage treatment. Orthodontic miniscrew implants are widely used for this purpose because they do not produce undesirable reciprocal effects and do not depend on the patient's cooperation. This article reports on maxillary molar distalization by using miniscrew implants to correct a Class II problem. The main considerations of molar distalization treatment with miniscrew implants are discussed. PMID:21640890

  5. Wide tissue distribution of axolotl class II molecules occurs independently of thyroxin.

    PubMed

    Völk, H; Charlemagne, J; Tournefier, A; Ferrone, S; Jost, R; Parisot, R; Kaufman, J

    1998-04-01

    Unlike most salamanders, the Mexican axolotl (Ambystoma mexicanum) fails to produce enough thyroxin to undergo anatomical metamorphosis, although a "cryptic metamorphosis" involving a change from fetal to adult hemoglobins has been described. To understand to what extent the development of the axolotl hemopoietic system is linked to anatomical metamorphosis, we examined the appearance and thyroxin dependence of class II molecules on thymus, blood, and spleen cells, using both flow cytometry and biosynthetic labeling followed by immunoprecipitation. Class II molecules are present on B cells as early as 7 weeks after hatching, the first time analyzed. At this time, most thymocytes, all T cells, and all erythrocytes lack class II molecules, but first thymocytes at 17 weeks, then T cells at 22 weeks, and finally erythrocytes at 26-27 weeks virtually all bear class II molecules. Class II molecules and adult hemoglobin appear at roughly the same time in erythrocytes. These data are most easily explained by populations of class II-negative cells being replaced by populations of class II-positive cells, and they show that the hemopoietic system matures at a variety of times unrelated to the increase of thyroxin that drives anatomical metamorphosis. We found that administration of thyroxin during axolotl ontogeny does not accelerate or otherwise affect the acquisition of class II molecules, nor does administration of drugs that inhibit thyroxin (sodium perchlorate, thiourea, methimazole, and 1-methyl imidazole) retard or abolish this acquisition, suggesting that the programs for anatomical metamorphosis and some aspects of hemopoietic development are entirely separate. PMID:9510551

  6. 46 CFR 128.210 - Class II vital systems-materials.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 46 Shipping 4 2011-10-01 2011-10-01 false Class II vital systems-materials. 128.210 Section 128.210 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OFFSHORE SUPPLY VESSELS MARINE ENGINEERING: EQUIPMENT AND SYSTEMS Materials and Pressure Design § 128.210 Class II vital systems—materials. Except as provided by §§ 128.230...

  7. Establishment of major histocompatibility complex homozygous gnotobiotic miniature swine colony for xenotransplantation.

    PubMed

    Hwang, Jeong Ho; Gupta, Mukesh Kumar; Park, Chan Kyu; Kim, Yoon Berm; Lee, Hoon Taek

    2015-04-01

    To overcome shortages of human donor organs for organ failure patients, we made a commitment to develop gnotobiotic miniature swine as an alternative organ donor source for xenotransplantation. For this, we have constructed an absolute barrier-sustained gnotobiotic facility. Pregnant sows of gnotobiotic miniature swine, were procured and germfree piglets were obtained by hysterectomy. These were maintained in germfree isolators for about 4 weeks, deprived of colostrum and were fed sterilized soybean milk. They were associated with di-flora, anaerobic Lactobacillus sp. and Streptococcus sp. After confirmation of successful associations, gnotobiotic piglets were transferred into the facility aseptically. The piglets are maintained on high-efficiency particle air-filtered air in and out; maintaining constant room air pressure of 33 ± 3 mmAq, and sterile water and diet. In 10 sessions of hysterectomy, 18 male and 32 female piglets were obtained of which piglets (M six, F eight) died within 5 days. Among live piglets, piglets (M eight, F 12) were confirmed to be germfree by microbiological monitoring. For research of xenotransplantation, one consistent experimental result was essential. Therefore, major histocompatibility complex class II which related innate immunity, homozygotic gnotobiotic miniature swine was developed. As a result, genotyping revealed 14 individuals to be homozygous for major histocompatibility complex class II (DRB, DQB) as 0301, three individuals were homozygous as 0201 and each of two were homozygous for DQB as 0701 and DRB as 0404, respectively. Genetic modifications and immunological research for ideal alternative organ sources are in progress. PMID:25491717

  8. Sequences, Annotation and Single Nucleotide Polymorphism of the Major Histocompatibility Complex in the Domestic Cat

    PubMed Central

    Yuhki, Naoya; Mullikin, James C.; Beck, Thomas; Stephens, Robert; O'Brien, Stephen J.

    2008-01-01

    Two sequences of major histocompatibility complex (MHC) regions in the domestic cat, 2.976 and 0.362 Mbps, which were separated by an ancient chromosome break (55–80 MYA) and followed by a chromosomal inversion were annotated in detail. Gene annotation of this MHC was completed and identified 183 possible coding regions, 147 human homologues, possible functional genes and 36 pseudo/unidentified genes) by GENSCAN and BLASTN, BLASTP RepeatMasker programs. The first region spans 2.976 Mbp sequence, which encodes six classical class II antigens (three DRA and three DRB antigens) lacking the functional DP, DQ regions, nine antigen processing molecules (DOA/DOB, DMA/DMB, TAPASIN, and LMP2/LMP7,TAP1/TAP2), 52 class III genes, nineteen class I genes/gene fragments (FLAI-A to FLAI-S). Three class I genes (FLAI-H, I-K, I-E) may encode functional classical class I antigens based on deduced amino acid sequence and promoter structure. The second region spans 0.362 Mbp sequence encoding no class I genes and 18 cross-species conserved genes, excluding class I, II and their functionally related/associated genes, namely framework genes, including three olfactory receptor genes. One previously identified feline endogenous retrovirus, a baboon retrovirus derived sequence (ECE1) and two new endogenous retrovirus sequences, similar to brown bat endogenous retrovirus (FERVmlu1, FERVmlu2) were found within a 140 Kbp interval in the middle of class I region. MHC SNPs were examined based on comparisons of this BAC sequence and MHC homozygous 1.9× WGS sequences and found that 11,654 SNPs in 2.84 Mbp (0.00411 SNP per bp), which is 2.4 times higher rate than average heterozygous region in the WGS (0.0017 SNP per bp genome), and slightly higher than the SNP rate observed in human MHC (0.00337 SNP per bp). PMID:18629345

  9. Type 1 Diabetes in the Spanish Population: additional factors to Class II HLA-DR3 and -DR4

    PubMed Central

    Urcelay, Elena; Santiago, José L; de la Calle, Hermenegildo; Martínez, Alfonso; Méndez, Julián; Ibarra, José M; Maluenda, Carlos; Fernández-Arquero, Miguel; de la Concha, Emilio G

    2005-01-01

    Background The Major Histocompatibility Complex is the main genetic contributor to susceptibility to type 1 diabetes (T1D); genome-wide scans have consistently mapped increased predisposition to this region. The highest disease risk has been associated with HLA-DR3 and HLA-DR4. In particular, the DR3-positive ancestral haplotype 18.2 was reported as highly diabetogenic. We aimed to corroborate whether this haplotype increases the susceptibility conferred by the DQ2-DR3 alleles in a Mediterranean population. We also searched for additional susceptibility factors to the classic DQ2-DR3 and DQ8-DR4. Results Genetic MHC markers were analysed in a case-control study with 302 T1D patients and 529 ethnically matched controls. DR3-TNFa1b5 carrier rate was significantly higher in DR3-positive heterozygous T1D patients than in DR3-positive heterozygous controls (p = 0.0019; odds ratio OR [95% confidence interval CI] = 2.26 [1.3–3.93]). This data was confirmed analysing the allelic frequency, which includes the information corresponding to the DR3-homozygous individuals (p = 0.001; OR = 2.09) and by using the Arlequin software to check the DR3-positive haplotypes (p = 0.004;OR = 1.93). The present results provide strong evidence of a second susceptibility region in the ancestral haplotype 18.2 in the Spanish population. Moreover, we searched for T1D susceptibility factors in addition to the MHC classical ones, within the DR2-DQ6/DR3-DQ2/DR4-DQ8 negative population. Several genetic markers in both MHC class II (DQA1*0101-DQB1*0501 [p = 0.007;OR = 2.81], DQA1*0201-DQB1*0202 [p = 0.03; OR = 2.35]) and III (TNFa2b1 [p = 0.01 OR = 2.74], BAT-2*2 [p = 0.004; OR = 3.19]) were found. These different alleles associated with T1D were not independent and we observed linkage disequilibrium among them leading us to describe two new risk haplotypes (DQA1*0101-DQB1*0501-TNFa2b1 and DQA1*0201-DQB1*0202- BAT-2*2). Finally, we studied a T1D susceptibility/protection marker located in

  10. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 8 2013-10-01 2013-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class...

  11. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 8 2012-10-01 2012-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class...

  12. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 8 2011-10-01 2011-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class...

  13. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 8 2014-10-01 2014-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class...

  14. 49 CFR 1150.35 - Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Procedures and relevant dates-transactions that involve creation of Class I or Class II carriers. 1150.35 Section 1150.35 Transportation Other Regulations.... 10901 § 1150.35 Procedures and relevant dates—transactions that involve creation of Class I or Class...

  15. 25 CFR 522.4 - Approval requirements for class II ordinances.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... Section 522.4 Indians NATIONAL INDIAN GAMING COMMISSION, DEPARTMENT OF THE INTERIOR APPROVAL OF CLASS II AND CLASS III ORDINANCES AND RESOLUTIONS SUBMISSION OF GAMING ORDINANCE OR RESOLUTION § 522.4 Approval... in and responsibility for the conduct of any gaming operation unless it elects to allow...

  16. 46 CFR 128.220 - Class II non-vital systems-materials and pressure design.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 46 Shipping 4 2012-10-01 2012-10-01 false Class II non-vital systems-materials and pressure design. 128.220 Section 128.220 Shipping COAST GUARD, DEPARTMENT OF HOMELAND SECURITY (CONTINUED) OFFSHORE SUPPLY VESSELS MARINE ENGINEERING: EQUIPMENT AND SYSTEMS Materials and Pressure Design § 128.220 Class...

  17. Alveolar bone thickness and lower incisor position in skeletal Class I and Class II malocclusions assessed with cone-beam computed tomography

    PubMed Central

    Ucar, Faruk Izzet; Buyuk, Suleyman Kutalmis; Ozer, Torun; Uysal, Tancan

    2013-01-01

    Objective To evaluate lower incisor position and bony support between patients with Class II average- and high-angle malocclusions and compare with the patients presenting Class I malocclusions. Methods CBCT records of 79 patients were divided into 2 groups according to sagittal jaw relationships: Class I and II. Each group was further divided into average- and high-angle subgroups. Six angular and 6 linear measurements were performed. Independent samples t-test, Kruskal-Wallis, and Dunn post-hoc tests were performed for statistical comparisons. Results Labial alveolar bone thickness was significantly higher in Class I group compared to Class II group (p = 0.003). Lingual alveolar bone angle (p = 0.004), lower incisor protrusion (p = 0.007) and proclination (p = 0.046) were greatest in Class II average-angle patients. Spongious bone was thinner (p = 0.016) and root apex was closer to the labial cortex in high-angle subgroups when compared to the Class II average-angle subgroup (p = 0.004). Conclusions Mandibular anterior bony support and lower incisor position were different between average- and high-angle Class II patients. Clinicians should be aware that the range of lower incisor movement in high-angle Class II patients is limited compared to average- angle Class II patients. PMID:23814708

  18. 40 CFR 82.70 - Nonessential Class II products and exceptions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... designated as class II in 40 CFR part 82, appendix B to subpart A) are identified as being nonessential and... 21 CFR 2.125(e); (ii) Lubricants, coatings or cleaning fluids for electrical or electronic equipment... equipment used for non-residential applications; and (viii) Wasp and hornet sprays for use near...

  19. 40 CFR 82.70 - Nonessential Class II products and exceptions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... designated as class II in 40 CFR part 82, appendix B to subpart A) are identified as being nonessential and... 21 CFR 2.125(e); (ii) Lubricants, coatings or cleaning fluids for electrical or electronic equipment... equipment used for non-residential applications; and (viii) Wasp and hornet sprays for use near...

  20. 40 CFR 82.70 - Nonessential Class II products and exceptions.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... designated as class II in 40 CFR part 82, appendix B to subpart A) are identified as being nonessential and... 21 CFR 2.125(e); (ii) Lubricants, coatings or cleaning fluids for electrical or electronic equipment... equipment used for non-residential applications; and (viii) Wasp and hornet sprays for use near...

  1. 40 CFR 82.70 - Nonessential Class II products and exceptions.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... designated as class II in 40 CFR part 82, appendix B to subpart A) are identified as being nonessential and... 21 CFR 2.125(e); (ii) Lubricants, coatings or cleaning fluids for electrical or electronic equipment... equipment used for non-residential applications; and (viii) Wasp and hornet sprays for use near...

  2. Pathognomonic features of Angle's Class II division 2 malocclusion: A comparative cephalometric and arch width study

    PubMed Central

    Prasad, Singamsetty E.R.V.; Indukuri, Ravikishore Reddy; Singh, Rupesh; Nooney, Anitha; Palagiri, Firoz Babu; Narayana, Veera

    2014-01-01

    Background: A thorough knowledge of the salient features of malocclusion helps the clinician in arriving at a proper diagnosis and treatment plan, and also to predict the prognosis, prior to the onset of treatment process. Among the four classes of Angle's classification of malocclusion, Class II division 2 occurs with the least frequency. There is still continuing debate in the literature whether the Class II division 2 patients ascribe the pathognomonic skeletal and dental features. Aim of the study: The aim of this study is to describe the unique features of Angle's Class II division 2 malocclusion to differentiate it from Angle's Class II division 1 malocclusion. Materials and Methods: A total of 582 pre-treatment records (study models and cephalograms), with the age of patients ranging from 15 to 22 years, were obtained from the hospital records of Vishnu Dental College, Bhimavaram and Geetam's Dental College, Visakhapatnam. Out of these, 11 pre-treatment records were excluded because of lack of clarity. In the rest of the sample, 283 were Class II division 1 and 288 were Class II division 2. The lateral cephalograms were analyzed by using digiceph and the arch width analysis was done based on the anatomical points described by Staley et al. and Sergl et al. Results: An intergroup evaluation was done by using unpaired Student's “t” test. The skeletal vertical parameters, dental parameters, and the maxillary arch width parameters revealed a statistically significant difference between the two groups of malocclusion. Conclusion: Angle's Class II division 2 malocclusion has a pronounced horizontal growth pattern with decreased lower anterior facial height, retroclined upper anteriors, and significantly increased maxillary arch width parameters. PMID:25558449

  3. Comparative genome organization of the major histocompatibility complex: lessons from the Felidae.

    PubMed

    O'Brien, S J; Yuhki, N

    1999-02-01

    The mammalian major histocompatibility complex (MHC) has taught both immunologists and evolutionary biologists a great deal about the patterns and processes that have led to immune defenses. Driven principally by human and mouse studies, comparative MHC projects among other mammalian species offer certain advantages in connecting MHC genome characters to natural situations. We have studied the MHC in the domestic cat and in several wild species of Felidae. Our observations affirm class I and class II homology with other mammalian orders, derivative gene duplications during the Felidae radiation, abundant persistent trans-species allele polymorphism, recombination-derived amino acid motifs, and inverted ratios of non-synonymous to silent substitutions in the MHC peptide-binding regions, consistent with overdominant selection in class I and II genes. MHC diversity as quantified in population studies is a powerful barometer of historic demographic reduction for several endangered species including cheetahs, Asiatic lions, Florida panthers and tigers. In two cases (Florida panther and cheetah), reduced MHC variation may be contributing to uniform population sensitivity to emerging infectious pathogens. The Felidae species, nearly all endangered and monitored for conservation concerns, have allowed a glimpse of species adaptation, mediated by MHC divergence, using comparative inferences drawn from human and mouse models. PMID:10319256

  4. Donor MHC class II antigen is essential for induction of transplantation tolerance by bone marrow cells.

    PubMed

    Umemura, A; Monaco, A P; Maki, T

    2000-05-01

    Posttransplant infusion of donor bone marrow cells (BMC) induces tolerance to allografts in adult mice, dogs, nonhuman primates, and probably humans. Here we used a mouse skin allograft model and an allogeneic radiation chimera model to examine the role of MHC Ags in tolerance induction. Infusion of MHC class II Ag-deficient (CIID) BMC failed to prolong C57BL/6 (B6) skin grafts in ALS- and rapamycin-treated B10.A mice, whereas wild-type B6 or MHC class I Ag-deficient BMC induced prolongation. Removal of class II Ag-bearing cells from donor BMC markedly reduced the tolerogenic effect compared with untreated BMC, although graft survival was significantly longer in mice given depleted BMC than that in control mice given no BMC. Infusion of CIID BMC into irradiated syngeneic B6 or allogeneic B10.A mice produced normal lymphoid cell reconstitution including CD4+ T cells except for the absence of class II Ag-positive cells. However, irradiated B10.A mice reconstituted with CIID BMC rejected all B6 and a majority of CIID skin grafts despite continued maintenance of high degree chimerism. B10.A mice reconstituted with B6 BMC maintained chimerism and accepted both B6 and CIID skin grafts. Thus, expression of MHC class II Ag on BMC is essential for allograft tolerance induction and peripheral chimerism with cells deficient in class II Ag does not guarantee allograft acceptance. PMID:10779744

  5. Class II HDAC Inhibition Hampers Hepatic Stellate Cell Activation by Induction of MicroRNA-29

    PubMed Central

    Mannaerts, Inge; Eysackers, Nathalie; Onyema, Oscar O.; Van Beneden, Katrien; Valente, Sergio; Mai, Antonello; Odenthal, Margarete; van Grunsven, Leo A.

    2013-01-01

    Background The conversion of a quiescent vitamin A storing hepatic stellate cell (HSC) to a matrix producing, contractile myofibroblast-like activated HSC is a key event in the onset of liver disease following injury of any aetiology. Previous studies have shown that class I histone deacetylases (HDACs) are involved in the phenotypical changes occurring during stellate cell activation in liver and pancreas. Aims In the current study we investigate the role of class II HDACs during HSC activation. Methods We characterized the expression of the class II HDACs freshly isolated mouse HSCs. We inhibited HDAC activity by selective pharmacological inhibition with MC1568, and by repressing class II HDAC gene expression using specific siRNAs. Results Inhibition of HDAC activity leads to a strong reduction of HSC activation markers α-SMA, lysyl oxidase and collagens as well as an inhibition of cell proliferation. Knock down experiments showed that HDAC4 contributes to HSC activation by regulating lysyl oxidase expression. In addition, we observed a strong up regulation of miR-29, a well-known anti-fibrotic miR, upon treatment with MC1568. Our in vivo work suggests that a successful inhibition of class II HDACs could be promising for development of future anti-fibrotic compounds. Conclusions In conclusion, the use of MC1568 has enabled us to identify a role for class II HDACs regulating miR-29 during HSC activation. PMID:23383282

  6. BIITE: A Tool to Determine HLA Class II Epitopes from T Cell ELISpot Data

    PubMed Central

    Boelen, Lies; O’Neill, Patrick K.; Quigley, Kathryn J.; Reynolds, Catherine J.; Maillere, Bernard; Robinson, John H.; Lertmemongkolchai, Ganjana; Altmann, Daniel M.; Boyton, Rosemary J.; Asquith, Becca

    2016-01-01

    Activation of CD4+ T cells requires the recognition of peptides that are presented by HLA class II molecules and can be assessed experimentally using the ELISpot assay. However, even given an individual’s HLA class II genotype, identifying which class II molecule is responsible for a positive ELISpot response to a given peptide is not trivial. The two main difficulties are the number of HLA class II molecules that can potentially be formed in a single individual (3–14) and the lack of clear peptide binding motifs for class II molecules. Here, we present a Bayesian framework to interpret ELISpot data (BIITE: Bayesian Immunogenicity Inference Tool for ELISpot); specifically BIITE identifies which HLA-II:peptide combination(s) are immunogenic based on cohort ELISpot data. We apply BIITE to two ELISpot datasets and explore the expected performance using simulations. We show this method can reach high accuracies, depending on the cohort size and the success rate of the ELISpot assay within the cohort. PMID:26953935

  7. Successful treatment of Class II malocclusion with bidental protrusion using standard edgewise prescription.

    PubMed

    Ayaz, Mohd; Kharbanda, Om Prakash

    2016-01-01

    This case report deals with the successful orthodontic treatment of a 14-year-old female patient having Class II malocclusion with bidental protrusion using standard edgewise prescription. She reported with forwardly placed upper front teeth and difficulty in closing lips. She had prognathic maxilla, retrognathic mandible, and full cusp Class II molar and canine relation bilaterally with overjet of 7 mm. She was in cervical vertebrae maturation indicator Stage IV. The case was treated by fixed extraction mechanotherapy. Interarch Class II mechanics was used to retract the upper incisor and to mesialize the lower molars. Simultaneously, Class I mechanics was used to upright lower incisors. Tip back bend, curve of Spee, and extra palatal root torque were incorporated in upper archwire to maintain molars in upright position and prevent extrusion and deepening of bite, respectively. There was satisfactory improvement in facial profile at the end of 24 months. After a follow-up of 6 months, occlusion was stable. PMID:27041906

  8. Successful treatment of Class II malocclusion with bidental protrusion using standard edgewise prescription

    PubMed Central

    Ayaz, Mohd; Kharbanda, Om Prakash

    2016-01-01

    This case report deals with the successful orthodontic treatment of a 14-year-old female patient having Class II malocclusion with bidental protrusion using standard edgewise prescription. She reported with forwardly placed upper front teeth and difficulty in closing lips. She had prognathic maxilla, retrognathic mandible, and full cusp Class II molar and canine relation bilaterally with overjet of 7 mm. She was in cervical vertebrae maturation indicator Stage IV. The case was treated by fixed extraction mechanotherapy. Interarch Class II mechanics was used to retract the upper incisor and to mesialize the lower molars. Simultaneously, Class I mechanics was used to upright lower incisors. Tip back bend, curve of Spee, and extra palatal root torque were incorporated in upper archwire to maintain molars in upright position and prevent extrusion and deepening of bite, respectively. There was satisfactory improvement in facial profile at the end of 24 months. After a follow-up of 6 months, occlusion was stable. PMID:27041906

  9. Upregulation and induction of surface antigens with special reference to MHC class II expression in microglia in postnatal rat brain following intravenous or intraperitoneal injections of lipopolysaccharide.

    PubMed Central

    Xu, J; Ling, E A

    1994-01-01

    The effects of bacterial lipopolysaccharide (LPS) on the expression of surface antigens including major histocompatibility complex (MHC) and complement type 3 (CR3) receptors on microglial cells in the corpus callosum in postnatal rat brain were investigated. When LPS was injected intravenously (i.v.) in 1-d-old rats, the immunostaining of callosal amoeboid microglial cells with OX-18 directed against MHC class I antigen was enhanced 24 h after the injection in comparison with the controls. The expression of MHC class II (Ia) antigen on the same cell type as shown by its immunoreactivity with OX-6 was also elicited especially after 2 intraperitoneal (i.p.) injections of LPS. Thus 7 d after a single i.p. injection of LPS into 1-d-old rats, only a few OX-6 positive cells showing a moderate staining reaction were observed in the corpus callosum. The immunoreactivity diminished 14 d after the injection. However, in rats receiving 2 successive i.p. injections of LPS at 1 and 4 d of age and killed 7 d after the 1st injection, a significant number of intensely stained OX-6 positive amoeboid microglial cells were observed in the corpus callosum. The expression of MHC class II antigens induced by 2 injections of LPS was sustained at least until d 14 when the callosal ramified microglial cells, known to be derived from gradual metamorphic transformation of amoeboid microglia, still exhibited intense immunoreactivity with OX-6. The effect of LPS on the expression of CR3 on amoeboid microglial cells was not obvious after a single injection, but the immunoreactivity with OX-42 was also augmented in rats given 2 i.p. administration of LPS into rats at 1 an 4 d of age. It is concluded from this study that the expression of MHC class I and class II antigens on amoeboid microglial cells in corpus callosum was upregulated and induced respectively after i.v. or i.p. injection of LPS into early postnatal rats. Although relatively fewer in number when compared with OX-18 and OX-42

  10. Molecular analysis of human leukocyte antigen class I and class II allele frequencies and haplotype distribution in Pakistani population

    PubMed Central

    Moatter, T.; Aban, M.; Tabassum, S.; Shaikh, U.; Pervez, S.

    2010-01-01

    AIM: Distribution of HLA class I and II alleles and haplotype was studied in Pakistani population and compared with the data reported for Caucasoid, Africans, Orientals and Arab populations. MATERIALS AND METHODS: HLA class I and II polymorphisms in 1000 unrelated Pakistani individuals was studied using sequence-specific primers and polymerase chain reaction and assay. RESULTS: The most frequent class I alleles observed were A*02, B*35 and CW*07, with frequencies of 19.2, 13.7 and 20%, respectively. Fifteen distinct HLA-DRB1 alleles and eight HLA-DQB1 alleles were recognized. The most frequently observed DRB1 alleles which represented more than 60% of the subjects were DRB1 *03, *07, *11 and *15. The rare DRB1 alleles detected in this study were HLADRB1 *08 and *09, having frequencies of 0.9 and 1.7%, respectively. In addition, at DRB1-DQB1 loci there were 179 different haplotypes and 285 unique genotypes and the most common haplotype was DRB1*15-DQB1*06 which represented 17% of the total DRB1-DQB1 haplotypes. In our population, haplotype A*33-B*58-Cw*03 comprised 2.8% of the total class I haplotypes observed. This haplotype was seen only in the oriental populations and has not been reported in the African or European Caucasoid. CONCLUSION: Our study showed a close similarity of HLA class I and II alleles with that of European Caucasoid and Orientals. In Pakistani population, two rare loci and three haplotypes were identified, whereas haplotypes characteristic of Caucasians, Africans and Orientals were also found, suggesting an admixture of different races due to migration to and from this region. PMID:21206703

  11. Major Histocompatibility Complex and Malaria: Focus on Plasmodium vivax Infection

    PubMed Central

    Lima-Junior, Josué da Costa; Pratt-Riccio, Lilian Rose

    2016-01-01

    The importance of host and parasite genetic factors in malaria resistance or susceptibility has been investigated since the middle of the last century. Nowadays, of all diseases that affect man, malaria still plays one of the highest levels of selective pressure on human genome. Susceptibility to malaria depends on exposure profile, epidemiological characteristics, and several components of the innate and adaptive immune system that influences the quality of the immune response generated during the Plasmodium lifecycle in the vertebrate host. But it is well known that the parasite’s enormous capacity of genetic variation in conjunction with the host genetics polymorphism is also associated with a wide spectrum of susceptibility degrees to complicated or severe forms of the disease. In this scenario, variations in genes of the major histocompatibility complex (MHC) associated with host resistance or susceptibility to malaria have been identified and used as markers in host–pathogen interaction studies, mainly those evaluating the impact on the immune response, acquisition of resistance, or increased susceptibility to infection or vulnerability to disease. However, due to the intense selective pressure, number of cases, and mortality rates, the majority of the reported associations reported concerned Plasmodium falciparum malaria. Studies on the MHC polymorphism and its association with Plasmodium vivax, which is the most widespread Plasmodium and the most prevalent species outside the African continent, are less frequent but equally important. Despite punctual contributions, there are accumulated evidences of human genetic control in P. vivax infection and disease. Herein, we review the current knowledge in the field of MHC and derived molecules (HLA Class I, Class II, TNF-α, LTA, BAT1, and CTL4) regarding P. vivax malaria. We discuss particularly the results of P. vivax studies on HLA class I and II polymorphisms in relation to host susceptibility, naturally

  12. HLA-G and MHC Class II Protein Expression in Diffuse Large B-Cell Lymphoma.

    PubMed

    Jesionek-Kupnicka, Dorota; Bojo, Marcin; Prochorec-Sobieszek, Monika; Szumera-Ciećkiewicz, Anna; Jabłońska, Joanna; Kalinka-Warzocha, Ewa; Kordek, Radzisław; Młynarski, Wojciech; Robak, Tadeusz; Warzocha, Krzysztof; Lech-Maranda, Ewa

    2016-06-01

    The expression of human leukocyte antigen-G (HLA-G) and HLA class II protein was studied by immunohistochemical staining of lymph nodes from 148 patients with diffuse large B-cell lymphoma (DLBCL) and related to the clinical course of the disease. Negative HLA-G expression was associated with a lower probability of achieving a complete remission (p = 0.04). Patients with negative HLA-G expression tended towards a lower 3-year overall survival (OS) rate compared to those with positive expression of HLA-G (p = 0.08). When restricting the analysis to patients receiving chemotherapy with rituximab, the estimated 3-year OS rate of patients with positive HLA-G expression was 73.3 % compared with 47.5 % (p = 0.03) in those with negative expression. Patients with negative HLA class II expression presented a lower 3-year OS rate compared to subjects with positive expression (p = 0.04). The loss of HLA class II expression (p = 0.05) and belonging to the intermediate high/high IPI risk group (p = 0.001) independently increased the risk of death. HLA class II expression also retained its prognostic value in patients receiving rituximab; the 3-year OS rate was 65.3 % in patients with positive HLA class II expression versus 29.6 % (p = 0.04) in subjects that had loss of HLA class II expression. To our knowledge, for the first time, the expression of HLA-G protein in DLBCL and its association with the clinical course of the disease was demonstrated. Moreover, the link between losing HLA class II protein expression and poor survival of patients treated with immunochemotherapy was confirmed. PMID:26667793

  13. Assessment of upper airways measurements in patients with mandibular skeletal Class II malocclusion

    PubMed Central

    Silva, Nayanna Nadja e; Lacerda, Rosa Helena Wanderley; Silva, Alexandre Wellos Cunha; Ramos, Tania Braga

    2015-01-01

    Objective: Mandibular Class II malocclusions seem to interfere in upper airways measurements. The aim of this study was to assess the upper airways measurements of patients with skeletal Class II malocclusion in order to investigate the association between these measurements and the position and length of the mandible as well as mandibular growth trend, comparing the Class II group with a Class I one. Methods: A total of 80 lateral cephalograms from 80 individuals aged between 10 and 17 years old were assessed. Forty radiographs of Class I malocclusion individuals were matched by age with forty radiographs of individuals with mandibular Class II malocclusion. McNamara Jr., Ricketts, Downs and Jarabak's measurements were used for cephalometric evaluation. Data were submitted to descriptive and inferential statistical analysis by means of SPSS 20.0 statistical package. Student's t-test, Pearson correlation and intraclass correlation coefficient were used. A 95% confidence interval and 5% significance level were adopted to interpret the results. Results: There were differences between groups. Oropharynx and nasopharynx sizes as well as mandibular position and length were found to be reduced in Class II individuals. There was a statistically significant positive correlation between the size of the oropharynx and Xi-Pm, Co-Gn and SNB measurements. In addition, the size of the nasopharynx was found to be correlated with Xi-Pm, Co-Gn, facial depth, SNB, facial axis and FMA. Conclusion: Individuals with mandibular Class II malocclusion were shown to have upper airways measurements diminished. There was a correlation between mandibular length and position and the size of oropharynx and nasopharynx. PMID:26560826

  14. Transport of Streptococcus pneumoniae Capsular Polysaccharide in MHC Class II Tubules

    PubMed Central

    Stephen, Tom Li; Fabri, Mario; Groneck, Laura; Röhn, Till A; Hafke, Helena; Robinson, Nirmal; Rietdorf, Jens; Schrama, David; Becker, Jürgen C; Plum, Georg; Krönke, Martin; Kropshofer, Harald; Kalka-Moll, Wiltrud M

    2007-01-01

    Bacterial capsular polysaccharides are virulence factors and are considered T cell–independent antigens. However, the capsular polysaccharide Sp1 from Streptococcus pneumoniae serotype 1 has been shown to activate CD4+ T cells in a major histocompatibility complex (MHC) class II–dependent manner. The mechanism of carbohydrate presentation to CD4+ T cells is unknown. We show in live murine dendritic cells (DCs) that Sp1 translocates from lysosomal compartments to the plasma membrane in MHCII-positive tubules. Sp1 cell surface presentation results in reduction of self-peptide presentation without alteration of the MHCII self peptide repertoire. In DM-deficient mice, retrograde transport of Sp1/MHCII complexes resulting in T cell–dependent immune responses to the polysaccharide in vitro and in vivo is significantly reduced. The results demonstrate the capacity of a bacterial capsular polysaccharide antigen to use DC tubules as a vehicle for its transport as an MHCII/saccharide complex to the cell surface for the induction of T cell activation. Furthermore, retrograde transport requires the functional role of DM in self peptide–carbohydrate exchange. These observations open new opportunities for the design of vaccines against microbial encapsulated pathogens. PMID:17367207

  15. MHC class II transactivator represses human IL-4 gene transcription by interruption of promoter binding with CBP/p300, STAT6 and NFAT1 via histone hypoacetylation

    PubMed Central

    Zhou, Xiaorong; Jiang, Yang; Lu, Liming; Ding, Qing; Jiao, Zhijun; Zhou, Yun; Xin, Lijun; Chou, Kuang-Yen

    2007-01-01

    In addition to its property of enhancing major histocompatibility complex (MHC) class II expression, the class II transactivator (CIITA) was recently demonstrated to be involved in T helper type 1/type 2 (Th1/Th2) differentiation by regulating interleukin-4 (IL-4) gene transcription. There was however, controversy regarding whether CIITA promotes or suppresses IL-4 expression in the experiments with transgenic mice. To clarify the discrepancy by using simpler experimental systems, human Jurkat T cells that express IL-4 but not interferon-γ, even if stimulated with phorbol 12-myristate 13-acetate plus ionomycin, were used for CIITA transfection. Significant suppression of IL-4 gene expression was demonstrated. Simultaneously, histones H3 and H4 in the IL-4 promoter were hypoacetylated. The suppression could be totally reversed by the histone deacetylatase inhibitor trichostatin A. Furthermore, the IL-4 expression was determined in primarily established human Th1/Th2 cells to which CIITA small interference RNA (siRNA) had been introduced. A substantially increased level of IL-4 was recorded in the CIITA siRNA-transfected Th1 cells, which was in parallel with significantly enhanced acetylation in histone H3 of the IL-4 promoter. Chromatin immunoprecipitation analysis indicated that CIITA abrogated the binding of coactivator CBP/p300 and transcription factors STAT6/NFAT1 to IL-4 promoter in the CIITA-transfected cells. In conclusion, CIITA was active in the repression of transcription activation of human IL-4 gene in both the T-cell line and the primary human CD4 T cells by preventing transcription factors from binding to IL-4 promoter through histone hypoacetylation. Our data confirm a potential significant role of CIITA in controlling Th1/Th2 differentiation via modulation of IL-4 gene activation. PMID:17645498

  16. 40 CFR 144.19 - Transitioning from Class II to Class VI.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... primary purpose of long-term storage into an oil and gas reservoir must apply for and obtain a Class VI... must consider the following: (1) Increase in reservoir pressure within the injection zone(s); (2) Increase in carbon dioxide injection rates; (3) Decrease in reservoir production rates; (4)...

  17. MHC class II variation in a rare and ecological specialist mouse lemur reveals lower allelic richness and contrasting selection patterns compared to a generalist and widespread sympatric congener.

    PubMed

    Pechouskova, Eva; Dammhahn, Melanie; Brameier, Markus; Fichtel, Claudia; Kappeler, Peter M; Huchard, Elise

    2015-04-01

    The polymorphism of immunogenes of the major histocompatibility complex (MHC) is thought to influence the functional plasticity of immune responses and, consequently, the fitness of populations facing heterogeneous pathogenic pressures. Here, we evaluated MHC variation (allelic richness and divergence) and patterns of selection acting on the two highly polymorphic MHC class II loci (DRB and DQB) in the endangered primate Madame Berthe's mouse lemur (Microcebus berthae). Using 454 pyrosequencing, we examined MHC variation in a total of 100 individuals sampled over 9 years in Kirindy Forest, Western Madagascar, and compared our findings with data obtained previously for its sympatric congener, the grey mouse lemur (Microcebus murinus). These species exhibit a contrasting ecology and demography that were expected to affect MHC variation and molecular signatures of selection. We found a lower allelic richness concordant with its low population density, but a similar level of allelic divergence and signals of historical selection in the rare feeding specialist M. berthae compared to the widespread generalist M. murinus. These findings suggest that demographic factors may exert a stronger influence than pathogen-driven selection on current levels of allelic richness in M. berthae. Despite a high sequence similarity between the two congeners, contrasting selection patterns detected at DQB suggest its potential functional divergence. This study represents a first step toward unravelling factors influencing the adaptive divergence of MHC genes between closely related but ecologically differentiated sympatric lemurs and opens new questions regarding potential functional discrepancy that would explain contrasting selection patterns detected at DQB. PMID:25687337

  18. Genetic Variation at Exon 2 of the MHC Class II DQB Locus in Blue Whale (Balaenoptera musculus) from the Gulf of California

    PubMed Central

    Moreno-Santillán, Diana D.; Lacey, Eileen A.; Gendron, Diane; Ortega, Jorge

    2016-01-01

    The genes of the Major Histocompatibility Complex (MHC) play an important role in the vertebrate immune response and are among the most polymorphic genes known in vertebrates. In some marine mammals, MHC genes have been shown to be characterized by low levels of polymorphism compared to terrestrial taxa; this reduction in variation is often explained as a result of lower pathogen pressures in marine habitats. To determine if this same reduction in variation applies to the migratory population of blue whales (Balaenoptera musculus) that occurs in the Gulf of California, we genotyped a 172 bp fragment of exon 2 of the MHC Class II DQB locus for 80 members of this population. Twenty-two putatively functional DQB allotypes were identified, all of which were homologous with DQB sequences from other cetacean species. Up to 5 putative alleles per individual were identified, suggesting that gene duplication has occurred at this locus. Rates of non-synonymous to synonymous substitutions (ω) and maximum likelihood analyses of models of nucleotide variation provided potential evidence of ongoing positive selection at this exon. Phylogenetic analyses of DQB alleles from B. musculus and 16 other species of cetaceans revealed trans-specific conservation of MHC variants, suggesting that selection has acted on this locus over prolonged periods of time. Collectively our findings reveal that immunogenic variation in blue whales is comparable to that in terrestrial mammals, thereby providing no evidence that marine taxa are subject to reduced pathogen-induced selective pressures. PMID:26761201

  19. Genetic variation of the MHC class II DRB genes in the Japanese weasel, Mustela itatsi, endemic to Japan, compared with the Siberian weasel, Mustela sibirica.

    PubMed

    Nishita, Y; Abramov, A V; Kosintsev, P A; Lin, L-K; Watanabe, S; Yamazaki, K; Kaneko, Y; Masuda, R

    2015-12-01

    Major histocompatibility complex (MHC) genes encode proteins that play a critical role in vertebrate immune system and are highly polymorphic. To further understand the molecular evolution of the MHC genes, we compared MHC class II DRB genes between the Japanese weasel (Mustela itatsi), a species endemic to Japan, and the Siberian weasel (Mustela sibirica), a closely related species on the continent. We sequenced a 242-bp region of DRB exon 2, which encodes antigen-binding sites (ABS), and found 24 alleles from 31 M. itatsi individuals and 17 alleles from 21 M. sibirica individuals, including broadly distributed, species-specific and/or geographically restricted alleles. Our results suggest that pathogen-driven balancing selection have acted to maintain the diversity in the DRB genes. For predicted ABS, nonsynonymous substitutions exceeded synonymous substitutions, also indicating positive selection, which was not seen at non-ABS. In a Bayesian phylogenetic tree, two M. sibirica DRB alleles were basal to the rest of the sequences from mustelid species and may represent ancestral alleles. Trans-species polymorphism was evident between many mustelid DRB alleles, especially between M. itatsi and M. sibirica. These two Mustela species divided about 1.7 million years ago, but still share many MHC alleles, indicative of their close phylogenetic relationship. PMID:26593752

  20. Genetic Variation at Exon 2 of the MHC Class II DQB Locus in Blue Whale (Balaenoptera musculus) from the Gulf of California.

    PubMed

    Moreno-Santillán, Diana D; Lacey, Eileen A; Gendron, Diane; Ortega, Jorge

    2016-01-01

    The genes of the Major Histocompatibility Complex (MHC) play an important role in the vertebrate immune response and are among the most polymorphic genes known in vertebrates. In some marine mammals, MHC genes have been shown to be characterized by low levels of polymorphism compared to terrestrial taxa; this reduction in variation is often explained as a result of lower pathogen pressures in marine habitats. To determine if this same reduction in variation applies to the migratory population of blue whales (Balaenoptera musculus) that occurs in the Gulf of California, we genotyped a 172 bp fragment of exon 2 of the MHC Class II DQB locus for 80 members of this population. Twenty-two putatively functional DQB allotypes were identified, all of which were homologous with DQB sequences from other cetacean species. Up to 5 putative alleles per individual were identified, suggesting that gene duplication has occurred at this locus. Rates of non-synonymous to synonymous substitutions (ω) and maximum likelihood analyses of models of nucleotide variation provided potential evidence of ongoing positive selection at this exon. Phylogenetic analyses of DQB alleles from B. musculus and 16 other species of cetaceans revealed trans-specific conservation of MHC variants, suggesting that selection has acted on this locus over prolonged periods of time. Collectively our findings reveal that immunogenic variation in blue whales is comparable to that in terrestrial mammals, thereby providing no evidence that marine taxa are subject to reduced pathogen-induced selective pressures. PMID:26761201

  1. A population response analysis approach to assign class II HLA-epitope restrictions

    PubMed Central

    Arlehamn, Cecilia S. Lindestam; Huang, Huang; Davis, Mark M.; McKinney, Denise M.; Scriba, Thomas Jens; Sidney, John; Peters, Bjoern; Sette, Alessandro

    2015-01-01

    Identification of the specific HLA locus and allele presenting an epitope for recognition by specific T cell receptors (HLA restriction) is necessary to fully characterize the immune response to antigens. Experimental determination of HLA restriction is complex and technically challenging. As an alternative, the restricting HLA locus and allele can be inferred by genetic association, utilizing response data in an HLA typed population. However, simple odds ratio calculations can be problematic when dealing with large numbers of subjects and antigens and because the same epitope can be presented by multiple alleles (epitope promiscuity). Here, we develop a tool, denominated Restrictor Analysis Tool for Epitopes (RATE), to extract inferred restriction from HLA class II -typed epitope responses. This automated method infers HLA class II restriction from large datasets of T cell responses in HLA class II typed subjects by calculating Odds Ratios and relative frequencies from simple data tables. The program is validated by 1. Analyzing data of previously determined HLA restrictions. 2. Experimentally determining in selected individuals new HLA restrictions using HLA transfected cell lines 3. Predicting HLA restriction of particular peptides, and showing that corresponding HLA class II tetramers efficiently bind to epitope specific T cells. We further design a specific iterative algorithm to account for promiscuous recognition by calculation of Odds Ratio values for combinations of different HLA molecules while incorporating predicted HLA binding affinity. The RATE program streamlines the prediction of HLA class II restriction across multiple T cell epitopes and HLA types. PMID:25948811

  2. Use of MHC class II tetramers to investigate CD4+ T cell responses: problems and solutions.

    PubMed

    Cecconi, Virginia; Moro, Monica; Del Mare, Sara; Dellabona, Paolo; Casorati, Giulia

    2008-11-01

    MHC-class I tetramers technology enabled the characterization of peptide-specific T cells at the single cell level in a variety of studies. Several laboratories have also developed MHC-class II multimers to characterize Ag-specific CD4+ T cells. However, the generation and use of MHC-class II multimers seems more problematic than that of MHC-I multimers. We have generated HLA-DR*1101 tetramers in a versatile empty form, which can be loaded after purification with peptides of interest. We discuss the impact of critical biological and structural parameters for the optimal staining of Ag-specific CD4+ T cells using HLA-DR*1101 tetramers, such as: (i) activation state of CD4+ T cells; (ii) membrane trafficking in the target CD4+ T cells; (iii) binding characteristics of the loaded CD4 epitope. Our data indicate that reorganization of TCR on the plasma membrane upon CD4+ T cell activation, as well as an homogenous binding frame of the CD4 epitopes to the soluble HLA-DR monomer, are critical for a stable TCR/MHC-class II tetramer interaction. These factors, together with the low frequencies and affinities of specific CD4+ T cells, explain the need for in vitro expansion or ex vivo enrichment of specific T cells for the optimal visualization with MHC-class II tetramers. PMID:18612991

  3. Class II G Protein-Coupled Receptors and Their Ligands in Neuronal Function and Protection

    PubMed Central

    Martin, Bronwen; de Maturana, Rakel Lopez; Brenneman, Randall; Walent, Tom; Mattson, Mark P.; Maudsley, Stuart

    2008-01-01

    G protein-coupled receptors (GPCRs) play pivotal roles in regulating the function and plasticity of neuronal circuits in the nervous system. Among the myriad of GPCRs expressed in neural cells, class II GPCRs which couples predominantly to the Gs–adenylate cyclase–cAMP signaling pathway, have recently received considerable attention for their involvement in regulating neuronal survival. Neuropeptides that activate class II GPCRs include secretin, glucagon-like peptides (GLP-1 and GLP-2), growth hormone-releasing hormone (GHRH), pituitary adenylate cyclase activating peptide (PACAP), corticotropin-releasing hormone (CRH), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH), and calcitonin-related peptides. Studies of patients and animal and cell culture models, have revealed possible roles for class II GPCRs signaling in the pathogenesis of several prominent neurodegenerative conditions including stroke, Alzheimer's, Parkinson's, and Huntington's diseases. Many of the peptides that activate class II GPCRs promote neuron survival by increasing the resistance of the cells to oxidative, metabolic, and excitotoxic injury. A better understanding of the cellular and molecular mechanisms by which class II GPCRs signaling modulates neuronal survival and plasticity will likely lead to novel therapeutic interventions for neurodegenerative disorders. PMID:16052036

  4. MHC class II proteins contain a potential binding site for the verotoxin receptor glycolipid CD77.

    PubMed

    George, T; Boyd, B; Price, M; Lingwood, C; Maloney, M

    2001-11-01

    Globotriaosyl ceramide or CD77 functions as a cell surface receptor for toxins of the Shiga toxin/verotoxin family and as a marker for germinal center stage B-cells. The B-cell protein CD19 and the interferon-alpha receptor possess verotoxin-like amino acid sequences in their extracellular domains, and CD77 has been shown to function in CD19-mediated adhesion and interferon-induced growth inhibition. The Burkitt's lymphoma cell line, Daudi, is similar to germinal center B-cells in their expression of CD77, CD19 and MHC class II molecules. Using the multiple sequence alignment program, ClustalW, we have identified a verotoxin-like amino acid sequence on the beta-chain of human and murine MHC class II molecules. Binding of CD77 at this site could modulate the peptide-binding properties of these MHC class II molecules. Using Western blot analysis of whole cell extracts, we found that CD77-positive Daudi cells have higher levels of HLA-D proteins than VT500 cells, a Daudi-derived CD77-deficient mutant cell line. In contrast, MHC class II-mediated adhesion and surface expression are similar in the two cell lines. Therefore, CD77 could play a functional or regulatory role in MHC class II-mediated functions specifically relating to antigen presentation by B-cells to T helper cells. PMID:11838965

  5. PowerScope a Class II corrector – A case report

    PubMed Central

    Paulose, Joby; Antony, Palathottungal Joseph; Sureshkumar, Brijesh; George, Susha Mariam; Mathew, Manu Mundackal; Sebastian, Joseph

    2016-01-01

    Managing mild to moderate Class II malocclusion is a one of the common and major challenges to orthodontists. Class II discrepancies with mandibular deficiency during active growth are usually treated by myofunctional appliances. Fixed functional appliances evolved due to the noncompliance with conventional myofunctional appliances. This case report illustrates the efficiency of PowerScope in correction of skeletal Class II with mandibular deficiency in a patient aged 13 years who has reported to the department with a chief complaint of forwardly placed upper front teeth. This case with functional jaw retrusion was treated initially with MBT 0.022” prescription followed by PowerScope. Pre-, mid- and post-treatment cephalograms were obtained, and cephalometric analysis was performed. Stable and successful results were obtained with a substantial improvement in facial profile, skeletal jaw relationship, and overall esthetic appearance of the patient. A significant forward displacement of the mandible was the principal element for successful correction of Class II malocclusion. PowerScope provides the best results for Class II management, thus enables us to treat such cases by a nonextraction approach rather than contemplating extractions. PMID:27307671

  6. Evaluation of Pharyngeal Space in Different Combinations of Class II Skeletal Malocclusion

    PubMed Central

    Soni, Jay; Shyagali, Tarulatha R.; Bhayya, Deepak P.; Shah, Romil

    2015-01-01

    Objectives: The study was aimed to evaluate the pharyngeal airway linear measurements of untreated skeletal class II subjects with normal facial vertical pattern in prognathic maxilla with orthognathic mandible and orthognathic maxilla with retrognathic mandible. Materials and method: the sample comprised of lateral Cephalograms of two groups (30 each) of class II malocclusion variants. Group 1 comprised of class II malocclusion with prognathic maxilla and orthognathic mandible, whereas group 2 comprised of class II malocclusion with orthognathic maxilla and retrognathic mandible. Each group was traced for the linear measurements of the pharyngeal airway like the oropharynx, nasopharynx and soft palate. The obtained data was subjected to independent t test and the Mann Whitney test to check the difference between the two groups and within the groups respectively. Results: there was significant difference between all the linear measurements at the soft palate region and the distance between the tip of soft palate to its counter point on the pharyngeal wall in oropharynx region (p-ppm). Conclusion: the pharyngeal airway for class II malocclusion with various combination in an average growth pattern adult showed significant difference. The present results suggested, that the pharyngeal airway space might be the etiological factor for different sagittal growth pattern of the jaws and probable usage of different growth modification appliance can influence the pharyngeal airway. PMID:26635436

  7. Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor. alpha. : Relevance to genetic predisposition to systemic lupus erythematosus

    SciTech Connect

    Jacob, C.O.; Fronek, Z.; Koo, M.; McDevitt, H.O. ); Lewis, G.C. ); Hansen, J.A. )

    1990-02-01

    The authors report on the production of tumor necrosis factor (TNF)-{alpha} and TNF-{beta} by mitogen-activated peripheral blood lymphocytes or enriched monocyte subpopulations from human leukocyte antigen (HLA)-typed healthy subjects. The results indicate that HLA-DR2- and DQw1-positive donors frequently exhibit low production of TNF-{alpha}, whereas DR3- and DR4-positive subjects show high levels of TNF-{alpha} production. No correlation between TNF-{alpha} levels and HLA-A, -B, and -C genotype was found. The relevance of this quantitative polymorphism to the genetic predisposition to lupus nephritis in systemic lupus erythematosus (SLE) patients was investigated. DR2, DQw1-positive SLE patients show low levels of TNF-{alpha} inducibility; this genotype is also associated with an increased incidence of lupus nephritis. DR3-positive SLE patients, on the other hand, are not predisposed to nephritis, and these patients have high TNF-{alpha} production. DR4 haplotype is associated with high TNF-{alpha} inducibility and is negatively correlated with lupus nephritis. These data may help explain the strong association between HLA-DR2, DQw1 in SLE patients and their susceptibility to nephritis.

  8. Lack of association between Behçet's disease and major histocompatibility complex class II antigens in an ethnically diverse North American Caucasoid patient group.

    PubMed

    Moore, S B; O'Duffy, J D

    1986-08-01

    A group of 25 North American Caucasoid patients with well defined Behcet's disease were serologically typed for HLA-DR and DQw antigens. No significant associations were seen when results were compared with a group of 73 normal Caucasoid controls tested concomitantly. PMID:3772926

  9. Narcolepsy: Autoimmunity, Effector T Cell Activation Due to Infection, or T Cell Independent, Major Histocompatibility Complex Class II Induced Neuronal Loss?

    ERIC Educational Resources Information Center

    Fontana, Adriano; Gast, Heidemarie; Reith, Walter; Recher, Mike; Birchler, Thomas; Bassetti, Claudio L.

    2010-01-01

    Human narcolepsy with cataplexy is a neurological disorder, which develops due to a deficiency in hypocretin producing neurons in the hypothalamus. There is a strong association with human leucocyte antigens HLA-DR2 and HLA-DQB1*0602. The disease typically starts in adolescence. Recent developments in narcolepsy research support the hypothesis of…

  10. Association of the bovine leukocyte antigen major histocompatibility complex class II DRB3*4401 allele with host resistance to the Lone Star Tick, Amblyomma americanum

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The MHC of cattle, known as the bovine leukocyte antigen (BoLA) complex, plays an integral role in disease and parasite susceptibility, and immune responsiveness of the host. While susceptibility to tick infestation in cattle is believed to be heritable, genes that may be responsible for the manife...

  11. The Use of Peptide–Major-Histocompatibility-Complex Multimers in Type 1 Diabetes Mellitus

    PubMed Central

    Gojanovich, Greg S; Murray, Sabrina L; Buntzman, Adam S; Young, Ellen F; Vincent, Benjamin G; Hess, Paul R; DVM

    2012-01-01

    Major histocompatibility complex (MHC) class I and MHC class II molecules present short peptides that are derived from endogenous and exogenous proteins, respectively, to cognate T-cell receptors (TCRs) on the surface of T cells. The exquisite specificity with which T cells recognize particular peptide–major-histocompatibility-complex (pMHC) combinations has permitted development of soluble pMHC multimers that bind exclusively to selected T-cell populations. Because the pathogenesis of type 1 diabetes mellitus (T1DM) is driven largely by islet-reactive T-cell activity that causes β-cell death, these reagents are useful tools for studying and, potentially, for treating this disease. When coupled to fluorophores or paramagnetic nanoparticles, pMHC multimers have been used to visualize the expansion and islet invasion of T-cell effectors during diabetogenesis. Administration of pMHC multimers to mice has been shown to modulate T-cell responses by signaling through the TCR or by delivering a toxic moiety that deletes the targeted T cell. In the nonobese diabetic mouse model of T1DM, a pMHC-I tetramer coupled to a potent ribosome-inactivating toxin caused long-term elimination of a specific diabetogenic cluster of differentiation 8+ T-cell population from the pancreatic islets and delayed the onset of diabetes. This review will provide an overview of the development and use of pMHC multimers, particularly in T1DM, and describe the therapeutic promise these reagents have as an antigen-specific means of ameliorating deleterious T-cell responses in this autoimmune disease. PMID:22768881

  12. 25 CFR 547.9 - What are the minimum technical standards for Class II gaming system accounting functions?

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... OF CLASS II GAMES § 547.9 What are the minimum technical standards for Class II gaming system... digits to accommodate the design of the game. (3) Accounting data displayed to the player may be... audit, configuration, recall and test modes; or (ii) Temporarily, during entertaining displays of...

  13. 25 CFR 547.9 - What are the minimum technical standards for Class II gaming system accounting functions?

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... OF CLASS II GAMES § 547.9 What are the minimum technical standards for Class II gaming system... digits to accommodate the design of the game. (3) Accounting data displayed to the player may be... audit, configuration, recall and t