Science.gov

Sample records for histocompatibility complex dqb

  1. 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

  2. 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

  3. Spatial variation and low diversity in the major histocompatibility complex in walrus (Odobenus rosmarus)

    USGS Publications Warehouse

    Sonsthagen, Sarah A.; Fales, Krystal; Jay, Chadwick V.; Sage, George K.; Talbot, Sandra L.

    2014-01-01

    Increased global temperature and associated changes to Arctic habitats will likely result in the northward advance of species, including an influx of pathogens novel to the Arctic. How species respond to these immunological challenges will depend in part on the adaptive potential of their immune response system. We compared levels of genetic diversity at a gene associated with adaptive immune response [Class II major histocompatibility complex (MHC), DQB exon 2] between populations of walrus (Odobenus rosmarus), a sea ice-dependent Arctic species. Walrus was represented by only five MHC DQB alleles, with frequency differences observed between Pacific and Atlantic populations. MHC DQB alleles appear to be under balancing selection, and most (80 %; n = 4/5) of the alleles were observed in walruses from both oceans, suggesting broad scale differences in the frequency of exposure and diversity of pathogens may be influencing levels of heterozygosity at DQB in walruses. Limited genetic diversity at MHC, however, suggests that walrus may have a reduced capacity to respond to novel immunological challenges associated with shifts in ecological communities and environmental stressors predicted for changing climates. This is particularly pertinent for walrus, since reductions in summer sea ice may facilitate both northward expansion of marine species and associated pathogens from more temperate regions, and exchange of marine mammals and associated pathogens through the recently opened Northwest Passage between the Atlantic and Pacific Oceans in the Canadian high Arctic.

  4. 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

  5. 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

  6. Major Histocompatibility Complex Heterozygote Superiority during Coinfection

    PubMed Central

    McClelland, Erin E.; Penn, Dustin J.; Potts, Wayne K.

    2003-01-01

    Genes of the major histocompatibility complex (MHC) play a critical role in immune recognition, and many alleles confer susceptibility to infectious and autoimmune diseases. How these deleterious alleles persist in populations is controversial. One hypothesis postulates that MHC heterozygote superiority emerges over multiple infections because MHC-mediated resistance is generally dominant and many allele-specific susceptibilities to pathogens will be masked by the resistant allele in heterozygotes. We tested this hypothesis by using experimental coinfections with Salmonella enterica (serovar Typhimurium C5TS) and Theiler's murine encephalomyelitis virus (TMEV) in MHC-congenic mouse strains where one haplotype was resistant to Salmonella and the other was resistant to TMEV. MHC heterozygotes were superior to both homozygotes in 7 out of 8 comparisons (P = 0.0024), and the mean standardized pathogen load of heterozygotes was reduced by 41% over that of homozygotes (P = 0.01). In contrast, no heterozygote superiority was observed when the MHC haplotype combinations had similar susceptibility profiles to the two pathogens. This is the first experimental evidence for MHC heterozygote superiority against multiple pathogens, a mechanism that would contribute to the evolution of MHC diversity and explain the persistence of alleles conferring susceptibility to disease. PMID:12654829

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Association of DQw7 (DQB1*0301) with ocular cicatricial pemphigoid.

    PubMed Central

    Ahmed, A R; Foster, S; Zaltas, M; Notani, G; Awdeh, Z; Alper, C A; Yunis, E J

    1991-01-01

    Ocular cicatricial pemphigoid (OCP) is an autoimmune blistering disease that affects the conjunctiva and multiple mucous membranes. Class I and II and complement genetic markers of the major histocompatibility complex were studied in 20 Caucasian OCP patients and members of their families. Frequencies of individual alleles and common fixed or extended haplotypes in the patients were compared with those in normal family control haplotypes and with overall normal Caucasian haplotypes. The most striking increase compared with overall controls was noted in HLA-DQw3 (P = 0.006), unassociated with any extended haplotype. All but 1 of the 20 patients carried DQw3 in linkage with HLA-DR4 (increased significantly with P = 0.042 compared with overall normal genotype controls) or DR5. The DQw3, on analysis by restriction fragment length polymorphism in genomic DNA, was, in every instance, DQw7 (3.1, DQB1*0301). The frequency of DQB1*0301 in patient haplotypes compared with overall normal DR4 and DR5 DQw3-bearing haplotypes was statistically significantly increased (P less than 0.003, relative risk = 9.6). The distribution of homozygotes and heterozygotes for DQB1*0301 among the patients was consistent with dominant but not recessive inheritance of DQB1*0301 or a gene, probably a class II allele, in linkage disequilibrium with it as the major histocompatibility complex susceptibility gene for OCP. Images PMID:1763074

  18. 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

  19. 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...

  20. Roles for major histocompatibility complex glycosylation in immune function

    PubMed Central

    Ryan, Sean O.

    2013-01-01

    The major histocompatibility complex (MHC) glycoprotein family, also referred to as human leukocyte antigens, present endogenous and exogenous antigens to T lymphocytes for recognition and response. These molecules play a central role in enabling the immune system to distinguish self from non-self, which is the basis for protective immunity against pathogenic infections and disease while at the same time representing a serious obstacle for tissue transplantation. All known MHC family members, like the majority of secreted, cell surface, and other immune-related molecules, carry asparagine (N)-linked glycans. The immune system has evolved increasing complexity in higher-order organisms along with a more complex pattern of protein glycosylation, a relationship that may contribute to immune function beyond the early protein quality control events in the endoplasmic reticulum that are commonly known. The broad MHC family maintains peptide sequence motifs for glycosylation at sites that are highly conserved across evolution, suggesting importance, yet functional roles for these glycans remain largely elusive. In this review, we will summarize what is known about MHC glycosylation and provide new insight for additional functional roles for this glycoprotein modification in mediating immune responses. PMID:22461020

  1. A temporal analysis shows major histocompatibility complex loci in the Scandinavian wolf population are consistent with neutral evolution.

    PubMed

    Seddon, J M; Ellegren, H

    2004-11-01

    The major histocompatibility complex (MHC) has an integral role in the immune system, and hence diversity at its genes may be of particular importance for the health of populations. In large populations, balancing selection maintains diversity in MHC genes, but theoretical expectations indicate that this form of selection is absent or inefficient in small populations. We examine the level of diversity at three MHC class II loci in the wolf population of Scandinavia, a population naturally recolonized with a genetic contribution from as few as three founders, and in four neighbouring wolf populations. In the Scandinavian wolf population, two alleles were found for each locus and the distribution of alleles is compatible with their linkage into two haplotypes. Changes in the level of heterozygosity over time since recolonization demonstrate the effects of the proposed arrival of an immigrant wolf. The maintenance of diversity is shown to be compatible with a neutral, random allocation of alleles, in conjunction with crossing between packs. A total of 15 DRB1, seven DQA and 10 DQB1 alleles are found in four neighbouring wolf populations, with substantial sharing across populations. Even in these larger populations, bottlenecks and fragmentation with consequent genetic drift are likely to have resulted in few indicators for balancing selection and significant differentiation of populations. PMID:15539354

  2. Major Histocompatibility Complex (MHC) Markers in Conservation Biology

    PubMed Central

    Ujvari, Beata; Belov, Katherine

    2011-01-01

    Human impacts through habitat destruction, introduction of invasive species and climate change are increasing the number of species threatened with extinction. Decreases in population size simultaneously lead to reductions in genetic diversity, ultimately reducing the ability of populations to adapt to a changing environment. In this way, loss of genetic polymorphism is linked with extinction risk. Recent advances in sequencing technologies mean that obtaining measures of genetic diversity at functionally important genes is within reach for conservation programs. A key region of the genome that should be targeted for population genetic studies is the Major Histocompatibility Complex (MHC). MHC genes, found in all jawed vertebrates, are the most polymorphic genes in vertebrate genomes. They play key roles in immune function via immune-recognition and -surveillance and host-parasite interaction. Therefore, measuring levels of polymorphism at these genes can provide indirect measures of the immunological fitness of populations. The MHC has also been linked with mate-choice and pregnancy outcomes and has application for improving mating success in captive breeding programs. The recent discovery that genetic diversity at MHC genes may protect against the spread of contagious cancers provides an added impetus for managing and protecting MHC diversity in wild populations. Here we review the field and focus on the successful applications of MHC-typing for conservation management. We emphasize the importance of using MHC markers when planning and executing wildlife rescue and conservation programs but stress that this should not be done to the detriment of genome-wide diversity. PMID:21954351

  3. Major Histocompatibility Complex (MHC) markers in conservation biology.

    PubMed

    Ujvari, Beata; Belov, Katherine

    2011-01-01

    Human impacts through habitat destruction, introduction of invasive species and climate change are increasing the number of species threatened with extinction. Decreases in population size simultaneously lead to reductions in genetic diversity, ultimately reducing the ability of populations to adapt to a changing environment. In this way, loss of genetic polymorphism is linked with extinction risk. Recent advances in sequencing technologies mean that obtaining measures of genetic diversity at functionally important genes is within reach for conservation programs. A key region of the genome that should be targeted for population genetic studies is the Major Histocompatibility Complex (MHC). MHC genes, found in all jawed vertebrates, are the most polymorphic genes in vertebrate genomes. They play key roles in immune function via immune-recognition and -surveillance and host-parasite interaction. Therefore, measuring levels of polymorphism at these genes can provide indirect measures of the immunological fitness of populations. The MHC has also been linked with mate-choice and pregnancy outcomes and has application for improving mating success in captive breeding programs. The recent discovery that genetic diversity at MHC genes may protect against the spread of contagious cancers provides an added impetus for managing and protecting MHC diversity in wild populations. Here we review the field and focus on the successful applications of MHC-typing for conservation management. We emphasize the importance of using MHC markers when planning and executing wildlife rescue and conservation programs but stress that this should not be done to the detriment of genome-wide diversity. PMID:21954351

  4. 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

  5. Major histocompatibility complex heterozygosity reduces fitness in experimentally infected mice.

    PubMed

    Ilmonen, Petteri; Penn, Dustin J; Damjanovich, Kristy; Morrison, Linda; Ghotbi, Laleh; Potts, Wayne K

    2007-08-01

    It is often suggested that heterozygosity at major histocompatibility complex (MHC) loci confers enhanced resistance to infectious diseases (heterozygote advantage, HA, hypothesis), and overdominant selection should contribute to the evolution of these highly polymorphic genes. The evidence for the HA hypothesis is mixed and mainly from laboratory studies on inbred congenic mice, leaving the importance of MHC heterozygosity for natural populations unclear. We tested the HA hypothesis by infecting mice, produced by crossbreeding congenic C57BL/10 with wild ones, with different strains of Salmonella, both in laboratory and in large population enclosures. In the laboratory, we found that MHC influenced resistance, despite interacting wild-derived background loci. Surprisingly, resistance was mostly recessive rather than dominant, unlike in most inbred mouse strains, and it was never overdominant. In the enclosures, heterozygotes did not show better resistance, survival, or reproductive success compared to homozygotes. On the contrary, infected heterozygous females produced significantly fewer pups than homozygotes. Our results show that MHC effects are not masked on an outbred genetic background, and that MHC heterozygosity provides no immunological benefits when resistance is recessive, and can actually reduce fitness. These findings challenge the HA hypothesis and emphasize the need for studies on wild, genetically diverse species. PMID:17603099

  6. From genome-wide to candidate gene: an investigation of variation at the major histocompatibility complex in common bottlenose dolphins exposed to harmful algal blooms.

    PubMed

    Cammen, Kristina M; Wilcox, Lynsey A; Rosel, Patricia E; Wells, Randall S; Read, Andrew J

    2015-02-01

    The role the major histocompatibility complex (MHC) plays in response to exposure to environmental toxins is relatively poorly understood, particularly in comparison to its well-described role in pathogen immunity. We investigated associations between MHC diversity and resistance to brevetoxins in common bottlenose dolphins (Tursiops truncatus). A previous genome-wide association study investigating an apparent difference in harmful algal bloom (HAB) resistance among dolphin populations in the Gulf of Mexico identified genetic variation associated with survival in close genomic proximity to multiple MHC class II loci. Here, we characterized genetic variation at DQA, DQB, DRA, and DRB loci in dolphins from central-west Florida and the Florida Panhandle, including dolphins that died during HABs and dolphins presumed to have survived HAB exposure. We found that DRB and DQB exhibited patterns of genetic differentiation among geographic regions that differed from neutral microsatellite loci. In addition, genetic differentiation at DRB across multiple pairwise comparisons of live and dead dolphins was greater than differentiation observed at neutral loci. Our findings at these MHC loci did not approach the strength of association with survival previously described for a nearby genetic variant. However, the results provide evidence that selective pressures at the MHC vary among dolphin populations that differ in the frequency of HAB exposure and that the overall composition of DRB variants differs between dolphin survivors and non-survivors of HABs. These results may suggest a potential role of MHC diversity in variable survival of bottlenose dolphins exposed to HABs. PMID:25475909

  7. 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

  8. Excess of homozygosity in the major histocompatibility complex in schizophrenia

    PubMed Central

    Mukherjee, Semanti; Guha, Saurav; Ikeda, Masashi; Iwata, Nakao; Malhotra, Anil K.; Pe'er, Itsik; Darvasi, Ariel; Lencz, Todd

    2014-01-01

    Genome-wide association studies (GWAS) in schizophrenia have focused on additive allelic effects to identify disease risk loci. In order to examine potential recessive effects, we applied a novel approach to identify regions of excess homozygosity in an ethnically homogenous cohort: 904 schizophrenia cases and 1640 controls drawn from the Ashkenazi Jewish (AJ) population. Genome-wide examination of runs of homozygosity identified an excess in cases localized to the major histocompatibility complex (MHC). To refine this signal, we used the recently developed GERMLINE algorithm to identify chromosomal segments shared identical-by-descent (IBD) and compared homozygosity at such segments in cases and controls. We found a significant excess of homozygosity in schizophrenia cases compared with controls in the MHC (P-value = 0.003). An independent replication cohort of 548 schizophrenia cases from Japan and 542 matched healthy controls demonstrated similar effects. The strongest case–control recessive effects (P = 8.81 × 10−8) were localized to a 53-kb region near HLA-A, in a segment encompassing three poorly annotated genes, TRIM10, TRIM15 and TRIM40. At the same time, an adjacent segment in the Class I MHC demonstrated clear additive effects on schizophrenia risk, demonstrating the complexity of association in the MHC and the ability of our IBD approach to refine localization of broad signals derived from conventional GWAS. In sum, homozygosity in the classical MHC region appears to convey significant risk for schizophrenia, consistent with the ecological literature suggesting that homozygosity at the MHC locus may be associated with vulnerability to disease. PMID:24943592

  9. 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

  10. Diversity of MHC DQB and DRB Genes in the Endangered Australian Sea Lion (Neophoca cinerea).

    PubMed

    Lau, Quintin; Chow, Natalie; Gray, Rachael; Gongora, Jaime; Higgins, Damien P

    2015-01-01

    Major histocompatibility complex (MHC) class II molecules have an important role in vertebrate adaptive immunity, being responsible for recognizing, binding, and presenting specific antigenic peptides to T lymphocytes. Here, we study the MHC class II DQB and DRB exon 2 genes of the Australian sea lion (Neophoca cinerea), an endangered pinniped species that experiences high pup mortality. Following characterization of N. cinerea DQB and DRB by molecular cloning, and evaluation of diversity in pups across 2 colonies using variant screening (n = 47), 3 DQB alleles and 10 DRB variants (including 1 pseudogene allele) were identified. The higher diversity at DRB relative to DQB is consistent with other studies in marine mammals. Despite overall lower MHC class II allelic diversity relative to some other pinniped species, we observed similar levels of nucleotide diversity and selection in N. cinerea. In addition, we provide support for recent divergence of MHC class II alleles. The characterization of MHC class II diversity in the Australian sea lion establishes a baseline for further investigation of associations with disease, including endemic hookworm infection, and contributes to the conservation management of this species. PMID:25908666

  11. 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...

  12. Major Histocompatibility Complex and Background Genes in Chickens Influence Susceptibility to High Pathogenicity Avian Influenza Virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chicken’s major histocompatibility complex (MHC) haplotype has profound influence on the resistance or susceptibility to certain pathogens such as B21 MHC haplotype confers resistance to Marek’s disease (MD). However, non-MHC genes are also important in disease resistance. For example, both line...

  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. Olfactory receptor-like genes are located in the human major histocompatibility complex

    SciTech Connect

    Fan, W.; Liu, Y.C.; Parimoo, S.

    1995-05-01

    The murine major histocompatibility complex (MHC) includes sequences that are responsible for haplotype-specific odor types that, in turn, influence mating preference. The authors report that there are several olfactory receptor genes or pseudogenes in the Class I region of the human MHC. At least one of these genes is intact, appears to encode an mRNA, and is quite homologous to a previously reported murine olfactory receptor. 14 refs., 4 figs.

  15. Measuring complexity, nonextensivity and chaos in the DNA sequence of the Major Histocompatibility Complex

    NASA Astrophysics Data System (ADS)

    Pavlos, G. P.; Karakatsanis, L. P.; Iliopoulos, A. C.; Pavlos, E. G.; Xenakis, M. N.; Clark, Peter; Duke, Jamie; Monos, D. S.

    2015-11-01

    We analyze 4 Mb sequences of the Major Histocompatibility Complex (MHC), which is a DNA segment on chromosome 6 with high gene density, controlling many immunological functions and associated with many diseases. The analysis is based on modern theoretical and mathematical tools of complexity theory, such as nonlinear time series analysis and Tsallis non-extensive statistics. The results revealed that the DNA complexity and self-organization can be related to fractional dynamical nonlinear processes with low-dimensional deterministic chaotic and non-extensive statistical character, which generate the DNA sequences under the extremization of Tsallis q-entropy principle. While it still remains an open question as to whether the DNA walk is a fractional Brownian motion (FBM), a static anomalous diffusion process or a non-Gaussian dynamical fractional anomalous diffusion process, the results of this study testify for the latter, providing also a possible explanation for the previously observed long-range power law correlations of nucleotides, as well as the long-range correlation properties of coding and non-coding sequences present in DNA sequences.

  16. 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

  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. Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3.

    PubMed

    Price, P; Santoso, L; Mastaglia, F; Garlepp, M; Kok, C C; Allcock, R; Laing, N

    2004-11-01

    Previous studies of sporadic inclusion body myositis (sIBM) have shown a strong association with HLA-DR3 and other components of the 8.1 ancestral haplotype (AH) (HLA-A1, B8, DR3), where the susceptibility locus has been mapped to the central major histocompatibility complex (MHC) region between HLA-DR and C4. Here, the association with HLA-DR3 and other genes in the central MHC and class II region was further investigated in a group of 42 sIBM patients and in an ethnically similar control group (n = 214), using single-nucleotide polymorphisms and microsatellite screening. HLA-DR3 (marking DRB1*0301 in Caucasians) was associated with sIBM (Fisher's test). However, among HLA-DR3-positive patients and controls, carriage of HLA-DR3 without microsatellite and single-nucleotide polymorphism alleles of the 8.1AH (HLA-A1, B8, DRB3*0101, DRB1*0301, DQB1*0201) was marginally less common in patients. Patients showed no increase in carriage of the 18.2AH (HLA-A30, B18, DRB3*0202, DRB1*0301, DQB1*0201) or HLA-DR3 without the central MHC of the 8.1AH, further arguing against HLA-DRB1 as the direct cause of susceptibility. Genes between HLA-DRB1 and HOX12 require further investigation. BTL-II lies in this region and is expressed in muscle. Carriage of allele 2 (exon 6) was more common in patients. BTL-II(E6)*2 is characteristic of the 35.2AH (HLA-A3, B35, DRB1*01) in Caucasians and HLA-DR1, BTL-II(E6)*2, HOX12*2, RAGE*2 was carried by several patients. The 8.1AH and 35.2AH may confer susceptibility to sIBM independently or share a critical allele. PMID:15496200

  19. 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

  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. 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

  2. Passive Immunotherapy for Retroviral Disease: Influence of Major Histocompatibility Complex Type and T-Cell Responsiveness

    NASA Astrophysics Data System (ADS)

    Hasenkrug, Kim J.; Brooks, Diane M.; Chesebro, Bruce

    1995-11-01

    Administration of virus-specific antibodies is known to be an effective early treatment for some viral infections. Such immunotherapy probably acts by antibody-mediated neutralization of viral infectivity and is often thought to function independently of T-cell-mediated immune responses. In the present experiments, we studied passive antibody therapy using Friend murine leukemia virus complex as a model for an immunosuppressive retroviral disease in adult mice. The results showed that antibody therapy could induce recovery from a well-established retroviral infection. However, the success of therapy was dependent on the presence of both CD4^+ and CD8^+ T lymphocytes. Thus, cell-mediated responses were required for recovery from infection even in the presence of therapeutic levels of antibody. The major histocompatibility type of the mice was also an important factor determining the relative success of antibody therapy in this system, but it was less critical for low-dose than for high-dose infections. Our results imply that limited T-cell responsiveness as dictated by major histocompatibility genes and/or stage of disease may have contributed to previous immunotherapy failures in AIDS patients. Possible strategies to improve the efficacy of future therapies are discussed.

  3. 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.

  4. IMGT/HLA database--a sequence database for the human major histocompatibility complex.

    PubMed

    Robinson, J; Malik, A; Parham, P; Bodmer, J G; Marsh, S G

    2000-03-01

    The IMGT/HLA Database is a specialist database for sequences of the human major histocompatibility (MHC) system. It includes all the HLA sequences officially recognised and named by the WHO Nomenclature Committee for Factors of the HLA System. The database provides users with online tools and facilities for the retrieval and analysis of these sequences. These include allele reports, alignment tools and a detailed database of all source cells. The online IMGT/HLA submission tool allows the submission of both new and confirmatory allele sequences directly to the WHO Nomenclature Committee for Factors of the HLA System. The latest version (release 1.4.1, November 1999) contains 1,015 HLA alleles from over 2,270 component sequences derived from the EMBL/GenBank/DDBJ databases. From its release in December 1998 until December 1999 the IMGT/HLA website received approximately 100,000 hits. The database currently focuses on the human major histocompatibility complex but will be used as a model system to provide specialist databases for the MHC sequences of other species. PMID:10777106

  5. 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

  6. 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

  7. 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

  8. Genetic Variation of Major Histocompatibility Complex and Microsatellite Loci: A Comparison in Bighorn Sheep

    PubMed Central

    Boyce, W. M.; Hedrick, P. W.; Muggli-Cockett, N. E.; Kalinowski, S.; Penedo, MCT.; Ramey-II, R. R.

    1997-01-01

    Examining and comparing genetic variation for major histocompatibility complex (MHC) and microsatellite (MS) loci in the same individuals provides an opportunity to understand the forces influencing genetic variation. We examined five MHC and three MS loci in 235 bighorn sheep (Ovis canadensis) from 14 populations and found that both types of loci were highly variable and were in Hardy-Weinberg proportions. Mean F(ST) values for both markers were very similar and MHC and MS genetic variability was predominantly distributed within rather than among populations. However, analyses of genetic distances and tree topologies revealed different spatial patterns of variation for the two types of loci. Collectively, these results indicated that neutral forces substantially influenced MS and MHC variation, and they provided limited evidence for selection acting on the MHC. PMID:9071595

  9. Quantitative online prediction of peptide binding to the major histocompatibility complex.

    PubMed

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

    2004-01-01

    With its implications for vaccine discovery, the accurate prediction of T cell epitopes is one of the key aspirations of computational vaccinology. We have developed a robust multivariate statistical method, based on partial least squares, for the quantitative prediction of peptide binding to major histocompatibility complexes (MHC), the principal checkpoint on the antigen presentation pathway. As a service to the immunobiology community, we have made a Perl implementation of the method available via a World Wide Web server. We call this server MHCPred. Access to the server is freely available from the URL: http://www.jenner.ac.uk/MHCPred. We have exemplified our method with a model for peptides binding to the common human MHC molecule HLA-B*3501. PMID:14629978

  10. 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

  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. Major histocompatibility complex and host background genes in chickens influence resistance to high pathogenicity avian influenza virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The chicken’s major histocompatibility complex (MHC) haplotype has a profound influence on the resistance or susceptibility to certain pathogens such as B21 MHC haplotype confers resistance to Marek’s disease (MD). However, non-MHC genes are also important in disease resistance. For example, both li...

  13. 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

  14. 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

  15. T cell receptor reversed polarity recognition of a self-antigen major histocompatibility complex.

    PubMed

    Beringer, Dennis X; Kleijwegt, Fleur S; Wiede, Florian; van der Slik, Arno R; Loh, Khai Lee; Petersen, Jan; Dudek, Nadine L; Duinkerken, Gaby; Laban, Sandra; Joosten, Antoinette; Vivian, Julian P; Chen, Zhenjun; Uldrich, Adam P; Godfrey, Dale I; McCluskey, James; Price, David A; Radford, Kristen J; Purcell, Anthony W; Nikolic, Tatjana; Reid, Hugh H; Tiganis, Tony; Roep, Bart O; Rossjohn, Jamie

    2015-11-01

    Central to adaptive immunity is the interaction between the αβ T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR α-chain and β-chain are overlaid with the α-chain and β-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition. PMID:26437244

  16. 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

  17. 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

  18. 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

  19. Sexual selection and the evolutionary dynamics of the major histocompatibility complex

    PubMed Central

    Jan Ejsmond, Maciej; Radwan, Jacek; Wilson, Anthony B.

    2014-01-01

    The genes of the major histocompatibility complex (MHC) are a key component of the adaptive immune system and among the most variable loci in the vertebrate genome. Pathogen-mediated natural selection and MHC-based disassortative mating are both thought to structure MHC polymorphism, but their effects have proven difficult to discriminate in natural systems. Using the first model of MHC dynamics incorporating both survival and reproduction, we demonstrate that natural and sexual selection produce distinctive signatures of MHC allelic diversity with critical implications for understanding host–pathogen dynamics. While natural selection produces the Red Queen dynamics characteristic of host–parasite interactions, disassortative mating stabilizes allele frequencies, damping major fluctuations in dominant alleles and protecting functional variants against drift. This subtle difference generates a complex interaction between MHC allelic diversity and population size. In small populations, the stabilizing effects of sexual selection moderate the effects of drift, whereas pathogen-mediated selection accelerates the loss of functionally important genetic diversity. Natural selection enhances MHC allelic variation in larger populations, with the highest levels of diversity generated by the combined action of pathogen-mediated selection and disassortative mating. MHC-based sexual selection may help to explain how functionally important genetic variation can be maintained in populations of conservation concern. PMID:25339723

  20. High-Resolution Patterns of Meiotic Recombination across the Human Major Histocompatibility Complex

    PubMed Central

    Cullen, Michael; Perfetto, Stephen P.; Klitz, William; Nelson, George; Carrington, Mary

    2002-01-01

    Definitive characteristics of meiotic recombination events over large (i.e., >1 Mb) segments of the human genome remain obscure, yet they are essential for establishing the haplotypic structure of the genome and for efficient mapping of complex traits. We present a high-resolution map of recombination at the kilobase level across a 3.3-Mb interval encompassing the major histocompatibility complex (MHC). Genotyping of 20,031 single sperm from 12 individuals resulted in the identification and fine mapping of 325 recombinant chromosomes within genomic intervals as small as 7 kb. Several principal characteristics of recombination in this region were observed: (1) rates of recombination can differ significantly between individuals; (2) intense hot spots of recombination occur at least every 0.8 Mb but are not necessarily evenly spaced; (3) distribution in the location of recombination events can differ significantly among individuals; (4) between hot spots, low levels of recombination occur fairly evenly across 100-kb segments, suggesting the presence of warm spots of recombination; and (5) specific sequence motifs associate significantly with recombination distribution. These data provide a plausible model for recombination patterns of the human genome overall. PMID:12297984

  1. DNA variation of the mammalian major histocompatibility complex reflects genomic diversity and population history.

    PubMed Central

    Yuhki, N; O'Brien, S J

    1990-01-01

    The major histocompatibility complex (MHC) is a multigene complex of tightly linked homologous genes that encode cell surface antigens that play a key role in immune regulation and response to foreign antigens. In most species, MHC gene products display extreme antigenic polymorphism, and their variability has been interpreted to reflect an adaptive strategy for accommodating rapidly evolving infectious agents that periodically afflict natural populations. Determination of the extent of MHC variation has been limited to populations in which skin grafting is feasible or for which serological reagents have been developed. We present here a quantitative analysis of restriction fragment length polymorphism of MHC class I genes in several mammalian species (cats, rodents, humans) known to have very different levels of genetic diversity based on functional MHC assays and on allozyme surveys. When homologous class I probes were employed, a notable concordance was observed between the extent of MHC restriction fragment variation and functional MHC variation detected by skin grafts or genome-wide diversity estimated by allozyme screens. These results confirm the genetically depauperate character of the African cheetah, Acinonyx jubatus, and the Asiatic lion, Panthera leo persica; further, they support the use of class I MHC molecular reagents in estimating the extent and character of genetic diversity in natural populations. Images PMID:1967831

  2. Evolution of mouse major histocompatibility complex genes borne by t chromosomes.

    PubMed Central

    Figueroa, F; Golubić, M; Nizetić, D; Klein, J

    1985-01-01

    Virtually all wild mouse populations carry t haplotypes that cause embryonic lethality or semilethality, distortion of segregation ratios, suppression of crossing-over, and male sterility. The t complex of genes is located on chromosome 17, closely linked to the H-2, the major histocompatibility complex of the mouse. The t haplotypes differ from each other not only in lethal genes they carry but also in their linked H-2 haplotypes. In this study, we compared the class II H-2 genes present on 31 t chromosomes extracted from wild populations in different parts of the world. The comparison was based on the analysis of DNA fragments obtained after digestion with restriction endonucleases. The results reveal the existence of three major groups of class II alleles representing main branches on the evolutionary tree of the t chromosomes. Alleles within each group are similar if not identical, although they are borne by chromosomes that have been separated in time and space. The presence of similar alleles in Mus musculus and Mus domesticus suggests that some of them may have been separated for more than 1 million years. This must also be the minimal age of the t chromosomes but, because at least two of the three main branches appear to be related in their origin, the actual age of t chromosomes could be much greater. The observations support the proposal that H-2 genes evolve slowly. Images PMID:2986138

  3. Reconsidering the association between the major histocompatibility complex and bipolar disorder.

    PubMed

    Figueiredo, Thalita Cristina; de Oliveira, João Ricardo Mendes

    2012-05-01

    Bipolar disorder (BD) is a cyclical and chronic affective disorder, globally recognized as an important public health problem and characterized by mood changes with recurring phases such as mania and depression. It is considered a complex disease, depending on the interaction of genetic and environmental triggers (stressors factors), but with a poorly known pathogenesis. Recent studies have implicated immune factors in the pathogenesis of BD and more particularly associated with different human major histocompatibility complex (MHC) regions. A major consortium study have recently linked BD to hundreds of variations with stronger associations in the MHC region, such as the rs3130297 SNP, located in the NOTCH4 gene, with an additional overlapping association with schizophrenia. This short review focuses on studies that investigated the association between bipolar disorder and the MHC, and the involvement of the immune system in the pathogenesis of the disease, in order to provide further information for additional diagnostic and therapeutic strategies. Fully understanding the etiology and pathophysiology of BD is extremely important to define new approaches for intervention and prevention, maybe through the modulation of the immune system. PMID:21987052

  4. DNA variation of the mammalian major histocompatibility complex reflects genomic diversity and population history

    SciTech Connect

    Yuhki, Naoya; O'Brien, S.J. )

    1990-01-01

    The major histocompatibility complex (MHC) is a multigene complex of tightly linked homologous genes that encode cell surface antigens that play a key role in immune regulation and response to foreign antigens. In most species, MHC gene products display extreme antigenic polymorphism, and their variability has been interpreted to reflect an adaptive strategy for accommodating rapidly evolving infectious agents that periodically afflict natural populations. Determination of the extent of MHC variation has been limited to populations in which skin grafting is feasible or for which serological reagents have been developed. The authors present here a quantitative analysis of restriction fragment length polymorphism of MHC class I genes in several mammalian species (cats, rodents, humans) known to have very different levels of genetic diversity based on functional MHC assays and on allozyme surveys. When homologous class I probes were employed, a notable concordance was observed between the extent of MHC restriction fragment variation and functional MHC variation detected by skin grafts or genome-wide diversity estimated by allozyme screens. These results confirm the genetically depauperate character of the African cheetah, Acinonyx jubatus, and the Asiatic lion, Panthera leo persica; further, they support the use of class I MHC molecular reagents in estimating the extent and character of genetic diversity in natural populations.

  5. IMGT/HLA Database—a sequence database for the human major histocompatibility complex

    PubMed Central

    Robinson, James; Waller, Matthew J.; Parham, Peter; Bodmer, Julia G.; Marsh, Steven G. E.

    2001-01-01

    The IMGT/HLA Database (www.ebi.ac.uk/imgt/hla/) specialises in sequences of polymorphic genes of the HLA system, the human major histocompatibility complex (MHC). The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and these include the 21 highly polymorphic HLA genes, which influence the outcome of clinical transplantation and confer susceptibility to a wide range of non-infectious diseases. The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. The latest version (release 1.7.0 July 2000) contains 1220 HLA alleles derived from over 2700 component sequences from the EMBL/GenBank/DDBJ databases. The HLA database provides a model which will be extended to provide specialist databases for polymorphic MHC genes of other species. PMID:11125094

  6. IMGT/HLA Database--a sequence database for the human major histocompatibility complex.

    PubMed

    Robinson, J; Waller, M J; Parham, P; Bodmer, J G; Marsh, S G

    2001-01-01

    The IMGT/HLA Database (www.ebi.ac.uk/imgt/hla/) specialises in sequences of polymorphic genes of the HLA system, the human major histocompatibility complex (MHC). The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and these include the 21 highly polymorphic HLA genes, which influence the outcome of clinical transplantation and confer susceptibility to a wide range of non-infectious diseases. The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. The latest version (release 1.7.0 July 2000) contains 1220 HLA alleles derived from over 2700 component sequences from the EMBL/GenBank/DDBJ databases. The HLA database provides a model which will be extended to provide specialist databases for polymorphic MHC genes of other species. PMID:11125094

  7. 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

  8. Alloreactivity and Association of Human Natural Killer Cells with the Major Histocompatibility Complex

    PubMed Central

    Mavoungou, Elie; Sall, Aicha; Poaty-Mavoungou, Virginie; Toure, Fousseyni S.; Yaba, Philippe; Delicat, Andre; Lansoud-Soukate, Joseph

    1999-01-01

    All NK cells potentially lytic for autologous cells but not expressing self-major histocompatibility complex (MHC)-reactive receptors could be eliminated by a negative selection mechanism during ontogeny. This idea is based on the existence of a NK cell subset expressing a specific inhibitory receptor for allogeneic MHC alleles. As ancestral haplotypes of the MHC appear to define identical MHC haplotypes in unrelated individuals, unrelated individuals having the same ancestral haplotype should also have the same NK-defined allospecificities that have been shown to map to the human MHC. To test this prediction, multiple cell lines from unrelated individuals having the same ancestral haplotypes were tested for the NK-defined allospecificities. It was found that cells having the same ancestral haplotypes do have the same NK-defined specificities. Furthermore, the NK-defined phenotype of cells that possess two different ancestral haplotypes can be predicted from the NK-defined phenotypes of unrelated cells that are homozygous for the ancestral haplotypes concerned. Although the group 1 and 2 NK-defined allospecificities can be explained to some extent by HLA-C alleles, evidence is presented that additional genes may modify the phenotype conferred by HLA-C. PMID:10066663

  9. Major Histocompatibility Complex I Expression by Motor Neurons and Its Implication in Amyotrophic Lateral Sclerosis

    PubMed Central

    Nardo, Giovanni; Trolese, Maria Chiara; Bendotti, Caterina

    2016-01-01

    Neuronal expression of major histocompatibility complex I (MHCI)-related molecules in adults and during CNS diseases is involved in the synaptic plasticity and axonal regeneration with mechanisms either dependent or independent of their immune functions. Motor neurons are highly responsive in triggering the expression of MHCI molecules during normal aging or following insults and diseases, and this has implications in the synaptic controls, axonal regeneration, and neuromuscular junction stability of these neurons. We recently reported that MHCI and immunoproteasome are strongly activated in spinal motor neurons and their peripheral motor axon in a mouse model of familial amyotrophic lateral sclerosis (ALS) during the course of the disease. This response was prominent in ALS mice with slower disease progression in which the axonal structure and function was better preserved than in fast-progressing mice. This review summarizes and discusses our observations in the light of knowledge about the possible role of MHCI in motor neurons providing additional insight into the pathophysiology of ALS. PMID:27379008

  10. Major histocompatibility complex variation and mate choice in a lekking bird, the great snipe (Gallinago media).

    PubMed

    Ekblom, R; Saether, S A; Grahn, M; Fiske, P; Kålås, J A; Höglund, J

    2004-12-01

    Genes of the major histocompatibility complex (MHC) play a major part in the activation of the vertebrate immune system. In addition, they also appear to function as cues for mate choice. In mammals especially, several kinds of MHC-dependent mate choice have been hypothesized and observed. These include choice of mates that share no or few alleles with the choosing individual, choice of mates with alleles that differ as much as possible from the choosing individual, choice of heterozygous mates, choice of certain genotypes and choice of rare alleles. We investigated these different aspects of mate choice in relation to MHC in a lekking bird species, the great snipe (Gallinago media). We found no evidence for MHC disassortative mating, no preference for males with many MHC alleles and no preference for rare alleles. However, we did find that some allelic lineages were more often found in males with mating success than in males without mating success. Females do not seem to use themselves as references for the MHC-dependent mate choice, rather they seem to prefer males with certain allele types. We speculate that these alleles may be linked to resistance to common parasites. PMID:15548294

  11. Adaptive tolerance to a pathogenic fungus drives major histocompatibility complex evolution in natural amphibian populations.

    PubMed

    Savage, Anna E; Zamudio, Kelly R

    2016-03-30

    Amphibians have been affected globally by the disease chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), and we are just now beginning to understand how immunogenetic variability contributes to disease susceptibility. Lineages of an expressed major histocompatibility complex (MHC) class II locus involved in acquired immunity are associated with chytridiomycosis susceptibility in controlled laboratory challenge assays. Here, we extend these findings to natural populations that vary both in exposure and response to Bd We find that MHC alleles and supertypes associated with Bd survival in the field show a molecular signal of positive selection, while those associated with susceptibility do not, supporting the hypothesis that heritable Bd tolerance is rapidly evolving. We compare MHC supertypes to neutral loci to demonstrate where selection versus demography is shaping MHC variability. One population with Bd tolerance in nature shows a significant signal of directional selection for the same allele (allele Q) that was significantly associated with survival in an earlier laboratory study. Our findings indicate that selective pressure for Bd survival drives rapid immunogenetic adaptation in some natural populations, despite differences in environment and demography. Our field-based analysis of immunogenetic variation confirms that natural amphibian populations have the evolutionary potential to adapt to chytridiomycosis. PMID:27009220

  12. Major histocompatibility complex peptide ligands as olfactory cues in human body odour assessment

    PubMed Central

    Milinski, Manfred; Croy, Ilona; Hummel, Thomas; Boehm, Thomas

    2013-01-01

    In many animal species, social communication and mate choice are influenced by cues encoded by the major histocompatibility complex (MHC). The mechanism by which the MHC influences sexual selection is a matter of intense debate. In mice, peptide ligands of MHC molecules activate subsets of vomeronasal and olfactory sensory neurons and influence social memory formation; in sticklebacks, such peptides predictably modify the outcome of mate choice. Here, we examine whether this evolutionarily conserved mechanism of interindividual communication extends to humans. In psychometric tests, volunteers recognized the supplementation of their body odour by MHC peptides and preferred ‘self’ to ‘non-self’ ligands when asked to decide whether the modified odour smelled ‘like themselves’ or ‘like their favourite perfume’. Functional magnetic resonance imaging indicated that ‘self’-peptides specifically activated a region in the right middle frontal cortex. Our results suggest that despite the absence of a vomeronasal organ, humans have the ability to detect and evaluate MHC peptides in body odour. This may provide a basis for the sensory evaluation of potential partners during human mate choice. PMID:23345577

  13. Evolutionary relationship between human major histocompatibility complex HLA-DR haplotypes

    SciTech Connect

    Svensson, A.C.; Setterblad, N.; Pihlgren, U.; Rask, L.; Andersson, G.

    1996-09-01

    HLA-DR haplotypes of the human major histocompatibility complex are organized in five different groups. They can be identified based on the serological specificity expressed by the polymorphic DRB1 locus and by the presence of a characteristic set of DRB genes. The nucleotide sequences of introns 4 and 5 of the two DRB genes (DRB1*01 and DRB6*01) from a DR1 haplotype and the three DRB genes (DRB1*15, DRB6*15, and DRB5*15), from a DR51 haplotype were determined. This study identified endogenous retroviral long terminal repeat elements (ERV9 LTR) located at identical positions in intron 5 of the DRB1 genes in both the DR1 and DR51 haplotypes. Phylogenetic analyses revealed a close evolutionary relationship between these two haplotypes. The DRB5 gene, unique for the DR51 haplotype, may have been lost by a recent gene deletion event creating the DR1 haplotype. A model for the evolution of the human DR haplotypes involving separate duplication and contraction events is presented. 55 refs., 5 figs., 2 tabs.

  14. Induction of embryonic major histocompatibility complex antigen expression by gamma-IFN.

    PubMed

    Warner, C M; Almquist, C D; Toulimat, M H; Xu, Y

    1993-07-01

    Preimplantation mouse embryos were incubated in vitro with mouse recombinant gamma-interferon (IFN). The effect of the gamma-IFN on major histocompatibility complex (MHC) class I antigen expression was tested using an ELISA procedure. It was found that there is a doubling of Db antigens and a tripling of Qa-2 antigens on C57BL/6 mouse embryos cultured from the 8-cell stage for 24 h in the presence of 10(5) units/ml gamma-IFN. The effect of gamma-IFN on the rate of preimplantation embryonic development was tested by culturing 2-cell embryos for 48 h and 8-cell embryos for 24 h in the presence of varying concentrations of gamma-IFN up to 10(6) units/ml. Two methods were used to assess the cell number per embryo after the culture period: incorporation of [3H]thymidine into DNA, and direct counting of nuclei in fixed and stained embryos. Both methods showed that treatment with gamma-IFN increases the rate of development of preimplantation mouse embryos. Since rate of preimplantation embryonic development is genetically controlled by the Ped gene, it is suggested that gamma-IFN has a direct effect on the Ped gene phenotype of preimplantation mouse embryos. PMID:8229991

  15. 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

  16. 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.

  17. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex E

    DOE PAGESBeta

    Hansen, Scott G.; Wu, Helen L.; Burwits, Benjamin J.; Hughes, Colette M.; Hammond, Katherine B.; Ventura, Abigail B.; Reed, Jason S.; Gilbride, Roxanne M.; Ainslie, Emily; Morrow, David W.; et al

    2016-02-12

    Major histocompatibility complex (MHC)-E is a highly conserved, ubiquitously expressed, nonclassical, MHC-Ib molecule with limited polymorphism primarily involved in regulation of NK cell reactivity via interaction with NKG2/CD94 receptors. We found that vaccination of rhesus macaques with Rh157.5/.4 gene-deleted rhesus Cytomegalovirus (RhCMV) vectors uniquely diverts MHC-E function to presentation of highly diverse peptide epitopes to CD8α/β+ T cells, approximately 4 distinct epitopes per 100 amino acids, in all tested protein antigens. Computational structural analysis revealed that a relatively stable, open binding groove in MHC-E attains broad peptide binding specificity by imposing a similar backbone configuration on bound peptides with fewmore » restrictions based on amino acid side chains. Since MHC-E is up-regulated on cells infected with HIV/SIV and other persistent viruses to evade NK cell activity, MHC-E-restricted CD8+ T cell responses have the potential to exploit pathogen immune evasion adaptations, a capability that might endow these unconventional responses with superior efficacy.« less

  18. Cryptic female choice favours sperm from major histocompatibility complex-dissimilar males

    PubMed Central

    Løvlie, Hanne; Gillingham, Mark A. F.; Worley, Kirsty; Pizzari, Tommaso; Richardson, David S.

    2013-01-01

    Cryptic female choice may enable polyandrous females to avoid inbreeding or bias offspring variability at key loci after mating. However, the role of these genetic benefits in cryptic female choice remains poorly understood. Female red junglefowl, Gallus gallus, bias sperm use in favour of unrelated males. Here, we experimentally investigate whether this bias is driven by relatedness per se, or by similarity at the major histocompatibility complex (MHC), genes central to vertebrate acquired immunity, where polymorphism is critical to an individual's ability to combat pathogens. Through experimentally controlled natural matings, we confirm that selection against related males' sperm occurs within the female reproductive tract but demonstrate that this is more accurately predicted by MHC similarity: controlling for relatedness per se, more sperm reached the eggs when partners were MHC-dissimilar. Importantly, this effect appeared largely owing to similarity at a single MHC locus (class I minor). Further, the effect of MHC similarity was lost following artificial insemination, suggesting that male phenotypic cues might be required for females to select sperm differentially. These results indicate that postmating mechanisms that reduce inbreeding may do so as a consequence of more specific strategies of cryptic female choice promoting MHC diversity in offspring. PMID:24004935

  19. Major histocompatibility complex diversity influences parasite resistance and innate immunity in sticklebacks.

    PubMed

    Kurtz, Joachim; Kalbe, Martin; Aeschlimann, Peter B; Häberli, Michael A; Wegner, K Mathias; Reusch, Thorsten B H; Milinski, Manfred

    2004-01-22

    Proteins of the major histocompatibility complex (MHC) play a central role in the presentation of antigens to the adaptive immune system. The MHC also influences the odour-based choice of mates in humans and several animal taxa. It has recently been shown that female three-spined sticklebacks (Gasterosteus aculeatus) aim at a moderately high MHC diversity in their offspring when choosing a mate. Do they optimize the immune systems of their offspring? Using three-spined sticklebacks that varied in their individual numbers of MHC class IIB molecules, we tested, experimentally, whether allelic diversity at the MHC influences parasite resistance and immune parameters. We found that sticklebacks with low MHC diversity suffered more from parasite infection after experimental exposure to Schistocephalus solidus tapeworms and Glugea anomala microsporidians. They also showed the highest proportion of granulocytes and the strongest respiratory burst reaction, which are correlates of innate immunity. This indicates a strong activity of the innate immune system after challenge by parasites when MHC diversity is suboptimal. Individuals with very high allelic diversity at the MHC seemed inferior to those with moderately high diversity. Such a pattern is consistent with theoretical expectations of an optimal balance between the number of recognizable antigens and self-tolerance. PMID:15058398

  20. Major histocompatibility complex peptide ligands as olfactory cues in human body odour assessment.

    PubMed

    Milinski, Manfred; Croy, Ilona; Hummel, Thomas; Boehm, Thomas

    2013-03-22

    In many animal species, social communication and mate choice are influenced by cues encoded by the major histocompatibility complex (MHC). The mechanism by which the MHC influences sexual selection is a matter of intense debate. In mice, peptide ligands of MHC molecules activate subsets of vomeronasal and olfactory sensory neurons and influence social memory formation; in sticklebacks, such peptides predictably modify the outcome of mate choice. Here, we examine whether this evolutionarily conserved mechanism of interindividual communication extends to humans. In psychometric tests, volunteers recognized the supplementation of their body odour by MHC peptides and preferred 'self' to 'non-self' ligands when asked to decide whether the modified odour smelled 'like themselves' or 'like their favourite perfume'. Functional magnetic resonance imaging indicated that 'self'-peptides specifically activated a region in the right middle frontal cortex. Our results suggest that despite the absence of a vomeronasal organ, humans have the ability to detect and evaluate MHC peptides in body odour. This may provide a basis for the sensory evaluation of potential partners during human mate choice. PMID:23345577

  1. 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

  2. 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.

  3. 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

  4. Sequence-based evidence for major histocompatibility complex-disassortative mating in a colonial seabird

    PubMed Central

    Juola, Frans A.; Dearborn, Donald C.

    2012-01-01

    The major histocompatibility complex (MHC) is a polymorphic gene family associated with immune defence, and it can play a role in mate choice. Under the genetic compatibility hypothesis, females choose mates that differ genetically from their own MHC genotypes, avoiding inbreeding and/or enhancing the immunocompetence of their offspring. We tested this hypothesis of disassortative mating based on MHC genotypes in a population of great frigatebirds (Fregata minor) by sequencing the second exon of MHC class II B. Extensive haploid cloning yielded two to four alleles per individual, suggesting the amplification of two genes. MHC similarity between mates was not significantly different between pairs that did (n = 4) or did not (n = 42) exhibit extra-pair paternity. Comparing all 46 mated pairs to a distribution based on randomized re-pairings, we observed the following (i): no evidence for mate choice based on maximal or intermediate levels of MHC allele sharing (ii), significantly disassortative mating based on similarity of MHC amino acid sequences, and (iii) no evidence for mate choice based on microsatellite alleles, as measured by either allele sharing or similarity in allele size. This suggests that females choose mates that differ genetically from themselves at MHC loci, but not as an inbreeding-avoidance mechanism. PMID:21613297

  5. Recombination and selection in the major histocompatibility complex of the endangered forest musk deer (Moschus berezovskii).

    PubMed

    Cai, Ruibo; Shafer, Aaron B A; Laguardia, Alice; Lin, Zhenzhen; Liu, Shuqiang; Hu, Defu

    2015-01-01

    The forest musk deer (Moschus berezovskii) is a high elevation species distributed across western China and northern Vietnam. Once abundant, habitat loss and poaching has led to a dramatic decrease in population numbers prompting the IUCN to list the species as endangered. Here, we characterized the genetic diversity of a Major Histocompatibility Complex (MHC) locus and teased apart driving factors shaping its variation. Seven DRB exon 2 alleles were identified among a group of randomly sampled forest musk deer from a captive population in the Sichuan province of China. Compared to other endangered or captive ungulates, forest musk deer have relatively low levels of MHC genetic diversity. Non-synonymous substitutions primarily occurred in the putative peptide-binding region (PBR), with analyses suggesting that recombination and selection has shaped the genetic diversity across the locus. Specifically, inter-allelic recombination generated novel allelic combinations, with evidence for both positive selection acting on the PBR and negative selection on the non-PBR. An improved understanding of functional genetic variability of the MHC will facilitate better design and management of captive breeding programs for this endangered species. PMID:26603338

  6. Structure and function of the non-classical major histocompatibility complex molecule MR1.

    PubMed

    Krovi, S Harsha; Gapin, Laurent

    2016-08-01

    Polymorphic major histocompatibility complex (MHC) molecules play a central role in the vertebrate adaptive immune system. By presenting short peptides derived from pathogen-derived proteins, these "classical" MHC molecules can alert the T cell branch of the immune system of infected cells and clear the pathogen. There exist other "non-classical" MHC molecules, which while similar in structure to classical MHC proteins, are contrasted by their limited polymorphism. While the functions of many class Ib MHC molecules have still to be elucidated, the nature and diversity of antigens (if any) that some of them might present to the immune system is expected to be more restricted and might function as another approach to distinguish self from non-self. The MHC-related 1 (MR1) molecule is a member of this family of non-classical MHC proteins. It was recently shown to present unique antigens in the form of vitamin metabolites found in certain microbes. MR1 is strongly conserved genetically, structurally, and functionally through mammalian evolution, indicating its necessity in ensuring an effective immune system for members of this class. Although MR1 will be celebrating 21 years this year since its discovery, most of our understanding of how this molecule functions has only been uncovered in the past decade. Herein, we discuss where MR1 is expressed, how it selectively is able to bind to its appropriate antigens and how it, then, is able to specifically activate a distinct population of T cells. PMID:27448212

  7. 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

  8. Major histocompatibility complex selection dynamics in pathogen-infected túngara frog (Physalaemus pustulosus) populations.

    PubMed

    Kosch, Tiffany A; Bataille, Arnaud; Didinger, Chelsea; Eimes, John A; Rodríguez-Brenes, Sofia; Ryan, Michael J; Waldman, Bruce

    2016-08-01

    Pathogen-driven selection can favour major histocompatibility complex (MHC) alleles that confer immunological resistance to specific diseases. However, strong directional selection should deplete genetic variation necessary for robust immune function in the absence of balancing selection or challenges presented by other pathogens. We examined selection dynamics at one MHC class II (MHC-II) locus across Panamanian populations of the túngara frog, Physalaemus pustulosus, infected by the amphibian chytrid fungus Batrachochytrium dendrobatidis (Bd). We compared MHC-II diversity in highland túngara frog populations, where amphibian communities have experienced declines owing to Bd, with those in the lowland region that have shown no evidence of decline. Highland region frogs had MHC variants that confer resistance to Bd. Variant fixation appeared to occur by directional selection rather than inbreeding, as overall genetic variation persisted in populations. In Bd-infected lowland sites, however, selective advantage may accrue to individuals with only one Bd-resistance allele, which were more frequent. Environmental conditions in lowlands should be less favourable for Bd infection, which may reduce selection for specific Bd resistance in hosts. Our results suggest that MHC selection dynamics fluctuate in túngara frog populations as a function of the favourability of habitat to pathogen spread and the vulnerability of hosts to infection. PMID:27531158

  9. Individual odor recognition in procellariiform chicks: potential role for the major histocompatibility complex.

    PubMed

    O'Dwyer, Terence W; Nevitt, Gabrielle A

    2009-07-01

    Since the groundbreaking work of Wenzel, Bang, and Grubb in the 1960s, enormous progress has been made toward elucidating the sense of smell in procellariiform seabirds. Although it is now well established that adult procellariiforms use olfaction in many behaviors, such as for foraging, nest relocation, and mate recognition, the olfactory abilities of petrel chicks are less well understood. Recent studies have shown that petrel chicks can recognize prey-related odors and odors associated with their nest before leaving their burrow for the first time. The recognition of burrow odors by petrel chicks is unlikely to be used for homing, and we have suggested that chicks may be learning personal odors associated with the nest's occupants for use later in life in the context of kin recognition or mate choice. The source of personal odors in petrels is unknown. However, in other vertebrates, the major histocompatibility complex influences body odors, which in turn influence mating preferences. It is not currently known whether this highly polymorphic gene region influences body odors and individual recognition in the procellariiforms, but this could be a fruitful area of future research. PMID:19686174

  10. Genetic variation of major histocompatibility complex (MHC) in wild Red Junglefowl (Gallus gallus).

    PubMed

    Nguyen-Phuc, Hoa; Fulton, Janet E; Berres, Mark E

    2016-02-01

    The major histocompatibility complex (MHC) is a multi-family gene cluster that encodes proteins with immuno-responsive function. While studies of MHC in domesticated poultry are relatively common, very little is known about this highly polymorphic locus in wild Red Junglefowl (Gallus gallus), the natural progenitor of domestic chickens. We investigated the diversity of MHC within and among four wild Red Junglefowl populations across diversified natural habitats in South Central Vietnam. Based on a SNP panel of 84 sites spanning 210 Kb of the MHC-B locus, we identified 310 unique haplotypes in 398 chromosomes. None of these haplotypes have been described before and we did not observe any of the wild Red Junglefowl haplotypes in domesticated chickens. Analysis of molecular variance (AMOVA) revealed that 94.51% of observed haplotype variation was accounted for at the within individual level. Little genetic variance was apportioned within and among populations, the latter accounting only for 0.83%. We also found evidence of increased recombination, including numerous hotspots, and limited linkage disequilibrium among the 84 SNP sites. Compared to an average haplotype diversity of 3.55% among seventeen lines of domestic chickens, our results suggest extraordinarily high haplotype diversity remains in wild Red Junglefowl and is consistent with a pattern of balancing selection. Wild Red Junglefowl in Vietnam, therefore, represent a rich resource of natural genomic variation independent from artificial selection. PMID:26839415

  11. Cryptic female choice favours sperm from major histocompatibility complex-dissimilar males.

    PubMed

    Løvlie, Hanne; Gillingham, Mark A F; Worley, Kirsty; Pizzari, Tommaso; Richardson, David S

    2013-10-22

    Cryptic female choice may enable polyandrous females to avoid inbreeding or bias offspring variability at key loci after mating. However, the role of these genetic benefits in cryptic female choice remains poorly understood. Female red junglefowl, Gallus gallus, bias sperm use in favour of unrelated males. Here, we experimentally investigate whether this bias is driven by relatedness per se, or by similarity at the major histocompatibility complex (MHC), genes central to vertebrate acquired immunity, where polymorphism is critical to an individual's ability to combat pathogens. Through experimentally controlled natural matings, we confirm that selection against related males' sperm occurs within the female reproductive tract but demonstrate that this is more accurately predicted by MHC similarity: controlling for relatedness per se, more sperm reached the eggs when partners were MHC--dissimilar. Importantly, this effect appeared largely owing to similarity at a single MHC locus (class I minor). Further, the effect of MHC similarity was lost following artificial insemination, suggesting that male phenotypic cues might be required for females to select sperm differentially. These results indicate that postmating mechanisms that reduce inbreeding may do so as a consequence of more specific strategies of cryptic female choice promoting MHC diversity in offspring. PMID:24004935

  12. Volatile signals of the major histocompatibility complex in male mouse urine.

    PubMed

    Singer, A G; Beauchamp, G K; Yamazaki, K

    1997-03-18

    Variation in the genes of the major histocompatibility complex (MHC) contributes to unique individual odors (odortypes) in mice, as demonstrated by the ability of trained mice in a Y-maze olfactometer to discriminate nearly identical inbred mice that differ genetically only at the MHC (MHC congenic mice), while they cannot distinguish genetically identical inbred mice. Similar distinctions are possible with urine, a substance that is involved in many facets of mouse chemical communication. This paper reports results supporting the hypothesis that the MHC-determined urinary odor is composed of a mixture of volatile carboxylic acids occurring in relative concentrations that are characteristic of the odortype. Y-maze behavioral testing of urine fractions from anion exchange chromatography indicates that volatile acids are necessary and sufficient to convey MHC odortype information. Diethyl ether extracts, which are expected to contain the more volatile, less polar organic acids, were also discriminable in the Y-maze olfactometer. Ether extracts of 12 different urine samples from each of two panels of MHC congenic mice were analyzed by gas chromatography. No compounds unique to urine of either genotype were detected, but compounds did appear to occur in characteristic ratios in most of the samples of each type. Nonparametric statistical analysis of the gas chromatographic data showed that eight of the peaks occurred in significantly different relative concentrations in the congenic samples. One of the peaks was shown to represent phenylacetic acid, which has implications for the mechanism of the MHC specification of odortype. PMID:9122173

  13. 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

  14. Adaptive tolerance to a pathogenic fungus drives major histocompatibility complex evolution in natural amphibian populations

    PubMed Central

    Savage, Anna E.; Zamudio, Kelly R.

    2016-01-01

    Amphibians have been affected globally by the disease chytridiomycosis, caused by the fungus Batrachochytrium dendrobatidis (Bd), and we are just now beginning to understand how immunogenetic variability contributes to disease susceptibility. Lineages of an expressed major histocompatibility complex (MHC) class II locus involved in acquired immunity are associated with chytridiomycosis susceptibility in controlled laboratory challenge assays. Here, we extend these findings to natural populations that vary both in exposure and response to Bd. We find that MHC alleles and supertypes associated with Bd survival in the field show a molecular signal of positive selection, while those associated with susceptibility do not, supporting the hypothesis that heritable Bd tolerance is rapidly evolving. We compare MHC supertypes to neutral loci to demonstrate where selection versus demography is shaping MHC variability. One population with Bd tolerance in nature shows a significant signal of directional selection for the same allele (allele Q) that was significantly associated with survival in an earlier laboratory study. Our findings indicate that selective pressure for Bd survival drives rapid immunogenetic adaptation in some natural populations, despite differences in environment and demography. Our field-based analysis of immunogenetic variation confirms that natural amphibian populations have the evolutionary potential to adapt to chytridiomycosis. PMID:27009220

  15. 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

  16. 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

  17. 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.

  18. 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

  19. Sexual selection explains more functional variation in the mammalian major histocompatibility complex than parasitism

    PubMed Central

    Winternitz, J. C.; Minchey, S. G.; Garamszegi, L. Z.; Huang, S.; Stephens, P. R.; Altizer, S.

    2013-01-01

    Understanding drivers of genetic diversity at the major histocompatibility complex (MHC) is vitally important for predicting how vertebrate immune defence might respond to future selection pressures and for preserving immunogenetic diversity in declining populations. Parasite-mediated selection is believed to be the major selective force generating MHC polymorphism, and while MHC-based mating preferences also exist for multiple species including humans, the general importance of mate choice is debated. To investigate the contributions of parasitism and sexual selection in explaining among-species variation in MHC diversity, we applied comparative methods and meta-analysis across 112 mammal species, including carnivores, bats, primates, rodents and ungulates. We tested whether MHC diversity increased with parasite richness and relative testes size (as an indicator of the potential for mate choice), while controlling for phylogenetic autocorrelation, neutral mutation rate and confounding ecological variables. We found that MHC nucleotide diversity increased with parasite richness for bats and ungulates but decreased with parasite richness for carnivores. By contrast, nucleotide diversity increased with relative testes size for all taxa. This study provides support for both parasite-mediated and sexual selection in shaping functional MHC polymorphism across mammals, and importantly, suggests that sexual selection could have a more general role than previously thought. PMID:23966643

  20. Ancient, highly polymorphic human major histocompatibility complex DQA1 intron sequence

    SciTech Connect

    McGinnis, M.D.; Quinn, D.L.; Lebo, R.V.; Simons, M.J.

    1994-10-01

    A 438 basepair intron 1 sequence adjacent to exon 2 in the human major histocompatibility complex DQA1 gene defined 16 allelic variants in 69 individuals from wide ethnic backgrounds. In contrast, the most variable coding region spanned by the 247 basepair exon 2 defined 11 allelic variants. Our phylogenetic human intron 1 tree derived by the Bootstrap algorithm reflects the same relative allelic relationships as the reported DQA1 exon 2 have cosegregated since divergence of the human races. Comparison of human alleles to a Rhesus monkey DQA1 first intron sequence found only 10 nucleotide substitutions unique to Rhesus, with the other 428 positions (98%) found in at least one human allele. This high degree of homology reflects the evolutionary stability of intron sequences since these two species diverged over 20 million years ago. Because more intron 1 alleles exist than exon 2 alleles, these polymorphic introns can be used to improve tissue typing for transplantation, paternity testing, and forensics and to derive more complete phylogenetic trees. These results suggest that introns represent a previously underutilized polymorphic resource. 42 refs., 3 figs., 1 tab.

  1. Broadly targeted CD8⁺ T cell responses restricted by major histocompatibility complex E.

    PubMed

    Hansen, Scott G; Wu, Helen L; Burwitz, Benjamin J; Hughes, Colette M; Hammond, Katherine B; Ventura, Abigail B; Reed, Jason S; Gilbride, Roxanne M; Ainslie, Emily; Morrow, David W; Ford, Julia C; Selseth, Andrea N; Pathak, Reesab; Malouli, Daniel; Legasse, Alfred W; Axthelm, Michael K; Nelson, Jay A; Gillespie, Geraldine M; Walters, Lucy C; Brackenridge, Simon; Sharpe, Hannah R; López, César A; Früh, Klaus; Korber, Bette T; McMichael, Andrew J; Gnanakaran, S; Sacha, Jonah B; Picker, Louis J

    2016-02-12

    Major histocompatibility complex E (MHC-E) is a highly conserved, ubiquitously expressed, nonclassical MHC class Ib molecule with limited polymorphism that is primarily involved in the regulation of natural killer (NK) cells. We found that vaccinating rhesus macaques with rhesus cytomegalovirus vectors in which genes Rh157.5 and Rh157.4 are deleted results in MHC-E-restricted presentation of highly varied peptide epitopes to CD8αβ(+) T cells, at ~4 distinct epitopes per 100 amino acids in all tested antigens. Computational structural analysis revealed that MHC-E provides heterogeneous chemical environments for diverse side-chain interactions within a stable, open binding groove. Because MHC-E is up-regulated to evade NK cell activity in cells infected with HIV, simian immunodeficiency virus, and other persistent viruses, MHC-E-restricted CD8(+) T cell responses have the potential to exploit pathogen immune-evasion adaptations, a capability that might endow these unconventional responses with superior efficacy. PMID:26797147

  2. 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

  3. Red Queen Processes Drive Positive Selection on Major Histocompatibility Complex (MHC) Genes

    PubMed Central

    Ejsmond, Maciej Jan; Radwan, Jacek

    2015-01-01

    Major Histocompatibility Complex (MHC) genes code for proteins involved in the incitation of the adaptive immune response in vertebrates, which is achieved through binding oligopeptides (antigens) of pathogenic origin. Across vertebrate species, substitutions of amino acids at sites responsible for the specificity of antigen binding (ABS) are positively selected. This is attributed to pathogen-driven balancing selection, which is also thought to maintain the high polymorphism of MHC genes, and to cause the sharing of allelic lineages between species. However, the nature of this selection remains controversial. We used individual-based computer simulations to investigate the roles of two phenomena capable of maintaining MHC polymorphism: heterozygote advantage and host-pathogen arms race (Red Queen process). Our simulations revealed that levels of MHC polymorphism were high and driven mostly by the Red Queen process at a high pathogen mutation rate, but were low and driven mostly by heterozygote advantage when the pathogen mutation rate was low. We found that novel mutations at ABSs are strongly favored by the Red Queen process, but not by heterozygote advantage, regardless of the pathogen mutation rate. However, while the strong advantage of novel alleles increased the allele turnover rate, under a high pathogen mutation rate, allelic lineages persisted for a comparable length of time under Red Queen and under heterozygote advantage. Thus, when pathogens evolve quickly, the Red Queen is capable of explaining both positive selection and long coalescence times, but the tension between the novel allele advantage and persistence of alleles deserves further investigation. PMID:26599213

  4. Does the major histocompatibility complex serve as a specific receptor for Semliki Forest virus?

    PubMed Central

    Oldstone, M B; Tishon, A; Dutko, F J; Kennedy, S I; Holland, J J; Lampert, P W

    1980-01-01

    Murine F9 and PCC4 teratoma cells do not express H-2 major transplantation antigens according to virus-specific T-lymphocyte cytotoxic or serological assays. However, such cells can be infected with and readily replicate many types of viruses (coxsackie B 3, mouse hepatitis, Sindbis, Semliki Forest [SFV], lymphocytic choriomeningitis, Pichinde, vesicular stomatitis, herpes simplex type 1) to the same extent as do murine F12 teratoma cells and mouse embryo fibroblasts, all of which express the H-2 determinants. In contrast, F9 and PCC4 cells are not productively infected with murine cytomegalovirus, whereas F12 and mouse embryo fibroblast cells are. In addition to replicating in H-2-negative murine teratoma cells, SFV replicates in H-2-negative murine lymphoblastoid cells. The ability of SFV to infect cells without H-2 antigens and then to effect viral antigenic expression in the cells' cytoplasm and on their surface with similar kinetics and in equivalent amounts as cells with H-2 antigens indicates that the H-2 receptor is not needed for SFV infection. Daudi cells, which lack HLA antigens, block the replication of SFV. This occurs at some point after receptor binding, as demonstrated by diminished viral mRNA. In addition, a possible membrane defect precludes viral exit in Daudi cells transfected with SFV infectious RNA. These results indicate that a cell's possession of H-2 antigens is not a requirement for SFV infection and that major histocompatibility complex antigens are not specific receptors for this virus. Images PMID:7373708

  5. 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

  6. Major histocompatibility complex loci are associated with susceptibility of Atlantic salmon to infectious hematopoietic necrosis virus

    USGS Publications Warehouse

    Miller, Kristina M.; Winton, James R.; Schulze, Angela D.; Purcell, Maureen K.; Ming, Tobi J.

    2004-01-01

    Infectious hematopoietic necrosis virus (IHNV) is one of the most significant viral pathogens of salmonids and is a leading cause of death among cultured juvenile fish. Although several vaccine strategies have been developed, some of which are highly protective, the delivery systems are still too costly for general use by the aquaculture industry. More cost effective methods could come from the identification of genes associated with IHNV resistance for use in selective breeding. Further, identification of susceptibility genes may lead to an improved understanding of viral pathogenesis and may therefore aid in the development of preventive and therapeutic measures. Genes of the major histocompatibility complex (MHC), involved in the primary recognition of foreign pathogens in the acquired immune response, are associated with resistance to a variety of diseases in vertebrate organisms. We conducted a preliminary analysis of MHC disease association in which an aquaculture strain of Atlantic salmon was challenged with IHNV at three different doses and individual fish were genotyped at three MHC loci using denaturing gradient gel electrophoresis (PCR-DGGE), followed by sequencing of all differentiated alleles. Nine to fourteen alleles per exon-locus were resolved, and alleles potentially associated with resistance or susceptibility were identified. One allele (Sasa-B-04) from a potentially non-classical class I locus was highly associated with resistance to infectious hematopoietic necrosis (p < 0.01). This information can be used to design crosses of specific haplotypes for family analysis of disease associations.

  7. Major histocompatibility complex similarity and sexual selection: different does not always mean attractive.

    PubMed

    Gasparini, Clelia; Congiu, Leonardo; Pilastro, Andrea

    2015-08-01

    Females that mate multiply have the possibility to exert postcopulatory choice and select more compatible sperm to fertilize eggs. Prior work suggests that dissimilarity in major histocompatibility complex (MHC) plays an important role in determining genetic compatibility between partners. Favouring a partner with dissimilar MHC alleles would result in offspring with high MHC diversity and therefore with enhanced survival thanks to increased resistance to pathogens and parasites. The high variability of MHC genes may further allow discrimination against the sperm from related males, reducing offspring homozygosity and inbreeding risk. Despite the large body of work conducted at precopulatory level, the role of MHC similarity between partners at postcopulatory level has been rarely investigated. We used an internal fertilizing fish with high level of multiple matings (Poecilia reticulata) to study whether MHC similarity plays a role in determining the outcome of fertilization when sperm from two males compete for the same set of eggs. We also controlled for genomewide similarity by determining similarity at 10 microsatellite loci. Contrary to prediction, we found that the more MHC-similar male sired more offspring while similarity at the microsatellite loci did not predict the outcome of sperm competition. Our results suggest that MHC discrimination may be involved in avoidance of hybridization or outbreeding rather than inbreeding avoidance. This, coupled with similar findings in salmon, suggests that the preference for MHC-dissimilar mates is far from being unanimous and that pre- and postcopulatory episodes of sexual selection can indeed act in opposite directions. PMID:25940673

  8. Recombination and selection in the major histocompatibility complex of the endangered forest musk deer (Moschus berezovskii)

    PubMed Central

    Cai, Ruibo; Shafer, Aaron B.A.; Laguardia, Alice; Lin, Zhenzhen; Liu, Shuqiang; Hu, Defu

    2015-01-01

    The forest musk deer (Moschus berezovskii) is a high elevation species distributed across western China and northern Vietnam. Once abundant, habitat loss and poaching has led to a dramatic decrease in population numbers prompting the IUCN to list the species as endangered. Here, we characterized the genetic diversity of a Major Histocompatibility Complex (MHC) locus and teased apart driving factors shaping its variation. Seven DRB exon 2 alleles were identified among a group of randomly sampled forest musk deer from a captive population in the Sichuan province of China. Compared to other endangered or captive ungulates, forest musk deer have relatively low levels of MHC genetic diversity. Non-synonymous substitutions primarily occurred in the putative peptide-binding region (PBR), with analyses suggesting that recombination and selection has shaped the genetic diversity across the locus. Specifically, inter-allelic recombination generated novel allelic combinations, with evidence for both positive selection acting on the PBR and negative selection on the non-PBR. An improved understanding of functional genetic variability of the MHC will facilitate better design and management of captive breeding programs for this endangered species. PMID:26603338

  9. 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

  10. Pervasive haplotypic variation in the spliceo-transcriptome of the human major histocompatibility complex.

    PubMed

    Vandiedonck, Claire; Taylor, Martin S; Lockstone, Helen E; Plant, Katharine; Taylor, Jennifer M; Durrant, Caroline; Broxholme, John; Fairfax, Benjamin P; Knight, Julian C

    2011-07-01

    The human major histocompatibility complex (MHC) on chromosome 6p21 is a paradigm for genomics, showing remarkable polymorphism and striking association with immune and non-immune diseases. The complex genomic landscape of the MHC, notably strong linkage disequilibrium, has made resolving causal variants very challenging. A promising approach is to investigate gene expression levels considered as tractable intermediate phenotypes in mapping complex diseases. However, how transcription varies across the MHC, notably relative to specific haplotypes, remains unknown. Here, using an original hybrid tiling and splice junction microarray that includes alternate allele probes, we draw the first high-resolution strand-specific transcription map for three common MHC haplotypes (HLA-A1-B8-Cw7-DR3, HLA-A3-B7-Cw7-DR15, and HLA-A26-B18-Cw5-DR3-DQ2) strongly associated with autoimmune diseases including type 1 diabetes, systemic lupus erythematosus, and multiple sclerosis. We find that haplotype-specific differences in gene expression are common across the MHC, affecting 96 genes (46.4%), most significantly the zing finger protein gene ZFP57. Differentially expressed probes are correlated with polymorphisms between haplotypes, consistent with cis effects that we directly demonstrate for ZFP57 in a cohort of healthy volunteers (P = 1.2 × 10(-14)). We establish that alternative splicing is significantly more frequent in the MHC than genome-wide (72.5% vs. 62.1% of genes, P ≤ 1 × 10(-4)) and shows marked haplotypic differences. We also unmask novel and abundant intergenic transcription involving 31% of transcribed blocks identified. Our study reveals that the renowned MHC polymorphism also manifests as transcript diversity, and our novel haplotype-based approach marks a new step toward identification of regulatory variants involved in the control of MHC-associated phenotypes and diseases. PMID:21628452

  11. A recombinant antibody with the antigen-specific, major histocompatibility complex-restricted specificity of T cells.

    PubMed Central

    Andersen, P S; Stryhn, A; Hansen, B E; Fugger, L; Engberg, J; Buus, S

    1996-01-01

    Specific recognition of peptide/major histocompatibility complex (MHC) molecule complexes by the T-cell receptor is a key reaction in the specific immune response. Antibodies against peptide/MHC complexes would therefore be valuable tools in studying MHC function and T-cell recognition and might lead to novel approaches in immunotherapy. However, it has proven difficult to generate antibodies with the specificity of T cells by conventional hybridoma techniques. Here we report that the phage display technology is a feasible alternative to generate antibodies recognizing specific, predetermined peptide/MHC complexes. Images Fig. 2 PMID:8700842

  12. 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.

  13. High-Density SNP Screening of the Major Histocompatibility Complex in Systemic Lupus Erythematosus Demonstrates Strong Evidence for Independent Susceptibility Regions

    PubMed Central

    Barcellos, Lisa F.; May, Suzanne L.; Ramsay, Patricia P.; Quach, Hong L.; Lane, Julie A.; Nititham, Joanne; Noble, Janelle A.; Taylor, Kimberly E.; Quach, Diana L.; Chung, Sharon A.; Kelly, Jennifer A.; Moser, Kathy L.; Behrens, Timothy W.; Seldin, Michael F.; Thomson, Glenys; Harley, John B.; Gaffney, Patrick M.; Criswell, Lindsey A.

    2009-01-01

    A substantial genetic contribution to systemic lupus erythematosus (SLE) risk is conferred by major histocompatibility complex (MHC) gene(s) on chromosome 6p21. Previous studies in SLE have lacked statistical power and genetic resolution to fully define MHC influences. We characterized 1,610 Caucasian SLE cases and 1,470 parents for 1,974 MHC SNPs, the highly polymorphic HLA-DRB1 locus, and a panel of ancestry informative markers. Single-marker analyses revealed strong signals for SNPs within several MHC regions, as well as with HLA-DRB1 (global p = 9.99×10−16). The most strongly associated DRB1 alleles were: *0301 (odds ratio, OR = 2.21, p = 2.53×10−12), *1401 (OR = 0.50, p = 0.0002), and *1501 (OR = 1.39, p = 0.0032). The MHC region SNP demonstrating the strongest evidence of association with SLE was rs3117103, with OR = 2.44 and p = 2.80×10−13. Conditional haplotype and stepwise logistic regression analyses identified strong evidence for association between SLE and the extended class I, class I, class III, class II, and the extended class II MHC regions. Sequential removal of SLE–associated DRB1 haplotypes revealed independent effects due to variation within OR2H2 (extended class I, rs362521, p = 0.006), CREBL1 (class III, rs8283, p = 0.01), and DQB2 (class II, rs7769979, p = 0.003, and rs10947345, p = 0.0004). Further, conditional haplotype analyses demonstrated that variation within MICB (class I, rs3828903, p = 0.006) also contributes to SLE risk independent of HLA-DRB1*0301. Our results for the first time delineate with high resolution several MHC regions with independent contributions to SLE risk. We provide a list of candidate variants based on biologic and functional considerations that may be causally related to SLE risk and warrant further investigation. PMID:19851445

  14. 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

  15. Major histocompatibility complex linked databases and prediction tools for designing vaccines.

    PubMed

    Singh, Satarudra Prakash; Mishra, Bhartendu Nath

    2016-03-01

    Presently, the major histocompatibility complex (MHC) is receiving considerable interest owing to its remarkable role in antigen presentation and vaccine design. The specific databases and prediction approaches related to MHC sequences, structures and binding/nonbinding peptides have been aggressively developed in the past two decades with their own benchmarks and standards. Before using these databases and prediction tools, it is important to analyze why and how the tools are constructed along with their strengths and limitations. The current review presents insights into web-based immunological bioinformatics resources that include searchable databases of MHC sequences, epitopes and prediction tools that are linked to MHC based vaccine design, including population coverage analysis. In T cell epitope forecasts, MHC class I binding predictions are very accurate for most of the identified MHC alleles. However, these predictions could be further improved by integrating proteasome cleavage (in conjugation with transporter associated with antigen processing (TAP) binding) prediction, as well as T cell receptor binding prediction. On the other hand, MHC class II restricted epitope predictions display relatively low accuracy compared to MHC class I. To date, pan-specific tools have been developed, which not only deliver significantly improved predictions in terms of accuracy, but also in terms of the coverage of MHC alleles and supertypes. In addition, structural modeling and simulation systems for peptide-MHC complexes enable the molecular-level investigation of immune processes. Finally, epitope prediction tools, and their assessments and guidelines, have been presented to immunologist for the design of novel vaccine and diagnostics. PMID:26585361

  16. Assembly and Function of the Major Histocompatibility Complex (MHC) I Peptide-loading Complex Are Conserved Across Higher Vertebrates*

    PubMed Central

    Hinz, Andreas; Jedamzick, Johanna; Herbring, Valentina; Fischbach, Hanna; Hartmann, Jessica; Parcej, David; Koch, Joachim; Tampé, Robert

    2014-01-01

    Antigen presentation to cytotoxic T lymphocytes via major histocompatibility complex class I (MHC I) molecules depends on the heterodimeric transporter associated with antigen processing (TAP). For efficient antigen supply to MHC I molecules in the ER, TAP assembles a macromolecular peptide-loading complex (PLC) by recruiting tapasin. In evolution, TAP appeared together with effector cells of adaptive immunity at the transition from jawless to jawed vertebrates and diversified further within the jawed vertebrates. Here, we compared TAP function and interaction with tapasin of a range of species within two classes of jawed vertebrates. We found that avian and mammalian TAP1 and TAP2 form heterodimeric complexes across taxa. Moreover, the extra N-terminal domain TMD0 of mammalian TAP1 and TAP2 as well as avian TAP2 recruits tapasin. Strikingly, however, only TAP1 and TAP2 from the same taxon can form a functional heterodimeric translocation complex. These data demonstrate that the dimerization interface between TAP1 and TAP2 and the tapasin docking sites for PLC assembly are conserved in evolution, whereas elements of antigen translocation diverged later in evolution and are thus taxon specific. PMID:25320083

  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. Major Histocompatibility Complex, demographic, and environmental predictors of antibody presence in a free-ranging mammal.

    PubMed

    Ruiz-López, María José; Monello, Ryan J; Schuttler, Stephanie G; Lance, Stacey L; Gompper, Matthew E; Eggert, Lori S

    2014-12-01

    Major Histocompatibility Complex (MHC) variability plays a key role in pathogen resistance, but its relative importance compared to environmental and demographic factors that also influence resistance is unknown. We analyzed the MHC II DRB exon 2 for 165 raccoons (Procyon lotor) in Missouri (USA). For each animal we also determined the presence of immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies to two highly virulent pathogens, canine distemper virus (CDV) and parvovirus. We investigated the role of MHC polymorphism and other demographic and environmental factors previously associated with predicting seroconversion. In addition, using an experimental approach, we studied the relative importance of resource availability and contact rates. We found important associations between IgG antibody presence and several MHC alleles and supertypes but not between IgM antibody presence and MHC. No effect of individual MHC diversity was found. For CDV, supertype S8, one allele within S8 (Prlo-DRB(∗)222), and a second allele (Prlo-DRB(∗)204) were positively associated with being IgG+, while supertype S4 and one allele within the supertype (Prlo-DRB(∗)210) were negatively associated with being IgG+. Age, year, and increased food availability were also positively associated with being IgG+, but allele Prlo-DRB(∗)222 was a stronger predictor. For parvovirus, only one MHC allele was negatively associated with being IgG+ and age and site were stronger predictors of seroconversion. Our results show that negative-frequency dependent selection is likely acting on the raccoon MHC and that while the role of MHC in relation to other factors depends on the pathogen of interest, it may be one of the most important factors predicting successful immune response. PMID:25446941

  19. Sequence variation at the major histocompatibility complex locus DQ beta in beluga whales (Delphinapterus leucas)

    PubMed

    Murray, B W; Malik, S; White, B N

    1995-07-01

    Genetic variation at the Major Histocompatibility Complex locus DQ beta was analyzed in 233 beluga whales (Delphinapterus leucas) from seven populations: St. Lawrence Estuary, eastern Beaufort Sea, eastern Chukchi Sea, western Hudson Bay, eastern Hudson Bay, southeastern Baffin Island, and High Arctic and in 12 narwhals (Monodon monoceros) sympatric with the High Arctic beluga population. Variation was assessed by amplification of the exon coding for the peptide binding region via the polymerase chain reaction, followed by either cloning and DNA sequencing or single-stranded conformation polymorphism analysis. Five alleles were found across the beluga populations and one in the narwhal. Pairwise comparisons of these alleles showed a 5:1 ratio of nonsynonymous to synonymous substitutions per site leading to eight amino acid differences, five of which were nonconservative substitutions, centered around positions previously shown to be important for peptide binding. Although the amount of allelic variation is low when compared with terrestrial mammals, the nature of the substitutions in the peptide binding sites indicates an important role for the DQ beta locus in the cellular immune response of beluga whales. Comparisons of allele frequencies among populations show the High Arctic population to be different (P < or = .005) from the other beluga populations surveyed. In these other populations an allele, Dele-DQ beta*0101-2, was found in 98% of the animals, while in the High Arctic it was found in only 52% of the animals. Two other alleles were found at high frequencies in the High Arctic population, one being very similar to the single allele found in narwhal. PMID:7659014

  20. 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

  1. Major histocompatibility complex alleles associated with parasite susceptibility in wild giant pandas.

    PubMed

    Zhang, L; Wu, Q; Hu, Y; Wu, H; Wei, F

    2015-01-01

    Major histocompatibility complex (MHC) polymorphism is thought to be driven by antagonistic coevolution between pathogens and hosts, mediated through either overdominance or frequency-dependent selection. However, investigations under natural conditions are still rare for endangered mammals which often exhibit depleted variation, and the mechanism of selection underlying the maintenance of characteristics remains a considerable debate. In this study, 87 wild giant pandas were used to investigate MHC variation associated with parasite load. With the knowledge of the MHC profile provided by the genomic data of the giant panda, seven DRB1, seven DQA1 and eight DQA2 alleles were identified at each single locus. Positive selection evidenced by a significantly higher number of non-synonymous substitutions per non-synonymous codon site relative to synonymous substitutions per synonymous codon site could only be detected at the DRB1 locus, which leads to the speculation that DRB1 may have a more important role in dealing with parasite infection for pandas. Coprological analyses revealed that 55.17% of individuals exhibited infection with 1-2 helminthes and 95.3% of infected pandas carried Baylisascaris shroederi. Using a generalized linear model, we found that Aime-DRB1*10 was significantly associated with parasite infection, but no resistant alleles could be detected. MHC heterozygosity of the pandas was found to be uncorrelated with the infection status or the infection intensity. These results suggested that the possible selection mechanisms in extant wild pandas may be frequency dependent rather than being determined by overdominance selection. Our findings could guide the candidate selection for the ongoing reintroduction or translocation of pandas. PMID:25248466

  2. 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

  3. 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

  4. Introgression from Domestic Goat Generated Variation at the Major Histocompatibility Complex of Alpine Ibex

    PubMed Central

    Grossen, Christine; Keller, Lukas; Biebach, Iris; Croll, Daniel

    2014-01-01

    The major histocompatibility complex (MHC) is a crucial component of the vertebrate immune system and shows extremely high levels of genetic polymorphism. The extraordinary genetic variation is thought to be ancient polymorphisms maintained by balancing selection. However, introgression from related species was recently proposed as an additional mechanism. Here we provide evidence for introgression at the MHC in Alpine ibex (Capra ibex ibex). At a usually very polymorphic MHC exon involved in pathogen recognition (DRB exon 2), Alpine ibex carried only two alleles. We found that one of these DRB alleles is identical to a DRB allele of domestic goats (Capra aegagrus hircus). We sequenced 2489 bp of the coding and non-coding regions of the DRB gene and found that Alpine ibex homozygous for the goat-type DRB exon 2 allele showed nearly identical sequences (99.8%) to a breed of domestic goats. Using Sanger and RAD sequencing, microsatellite and SNP chip data, we show that the chromosomal region containing the goat-type DRB allele has a signature of recent introgression in Alpine ibex. A region of approximately 750 kb including the DRB locus showed high rates of heterozygosity in individuals carrying one copy of the goat-type DRB allele. These individuals shared SNP alleles both with domestic goats and other Alpine ibex. In a survey of four Alpine ibex populations, we found that the region surrounding the DRB allele shows strong linkage disequilibria, strong sequence clustering and low diversity among haplotypes carrying the goat-type allele. Introgression at the MHC is likely adaptive and introgression critically increased MHC DRB diversity in the genetically impoverished Alpine ibex. Our finding contradicts the long-standing view that genetic variability at the MHC is solely a consequence of ancient trans-species polymorphism. Introgression is likely an underappreciated source of genetic diversity at the MHC and other loci under balancing selection. PMID:24945814

  5. The tammar wallaby major histocompatibility complex shows evidence of past genomic instability

    PubMed Central

    2011-01-01

    Background The major histocompatibility complex (MHC) is a group of genes with a variety of roles in the innate and adaptive immune responses. MHC genes form a genetically linked cluster in eutherian mammals, an organization that is thought to confer functional and evolutionary advantages to the immune system. The tammar wallaby (Macropus eugenii), an Australian marsupial, provides a unique model for understanding MHC gene evolution, as many of its antigen presenting genes are not linked to the MHC, but are scattered around the genome. Results Here we describe the 'core' tammar wallaby MHC region on chromosome 2q by ordering and sequencing 33 BAC clones, covering over 4.5 MB and containing 129 genes. When compared to the MHC region of the South American opossum, eutherian mammals and non-mammals, the wallaby MHC has a novel gene organization. The wallaby has undergone an expansion of MHC class II genes, which are separated into two clusters by the class III genes. The antigen processing genes have undergone duplication, resulting in two copies of TAP1 and three copies of TAP2. Notably, Kangaroo Endogenous Retroviral Elements are present within the region and may have contributed to the genomic instability. Conclusions The wallaby MHC has been extensively remodeled since the American and Australian marsupials last shared a common ancestor. The instability is characterized by the movement of antigen presenting genes away from the core MHC, most likely via the presence and activity of retroviral elements. We propose that the movement of class II genes away from the ancestral class II region has allowed this gene family to expand and diversify in the wallaby. The duplication of TAP genes in the wallaby MHC makes this species a unique model organism for studying the relationship between MHC gene organization and function. PMID:21854592

  6. Microsatellite and major histocompatibility complex variation in an endangered rattlesnake, the Eastern Massasauga (Sistrurus catenatus).

    PubMed

    Jaeger, Collin P; Duvall, Melvin R; Swanson, Bradley J; Phillips, Christopher A; Dreslik, Michael J; Baker, Sarah J; King, Richard B

    2016-06-01

    Genetic diversity is fundamental to maintaining the long-term viability of populations, yet reduced genetic variation is often associated with small, isolated populations. To examine the relationship between demography and genetic variation, variation at hypervariable loci (e.g., microsatellite DNA loci) is often measured. However, these loci are selectively neutral (or near neutral) and may not accurately reflect genomewide variation. Variation at functional trait loci, such as the major histocompatibility complex (MHC), can provide a better assessment of adaptive genetic variation in fragmented populations. We compared patterns of microsatellite and MHC variation across three Eastern Massasauga (Sistrurus catenatus) populations representing a gradient of demographic histories to assess the relative roles of natural selection and genetic drift. Using 454 deep amplicon sequencing, we identified 24 putatively functional MHC IIB exon 2 alleles belonging to a minimum of six loci. Analysis of synonymous and nonsynonymous substitution rates provided evidence of historical positive selection at the nucleotide level, and Tajima's D provided support for balancing selection in each population. As predicted, estimates of microsatellite allelic richness, observed, heterozygosity, and expected heterozygosity varied among populations in a pattern qualitatively consistent with demographic history and abundance. While MHC allelic richness at the population and individual levels revealed similar trends, MHC nucleotide diversity was unexpectedly high in the smallest population. Overall, these results suggest that genetic variation in the Eastern Massasauga populations in Illinois has been shaped by multiple evolutionary mechanisms. Thus, conservation efforts should consider both neutral and functional genetic variation when managing captive and wild Eastern Massasauga populations. PMID:27516858

  7. 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

  8. Fine Mapping Major Histocompatibility Complex Associations in Psoriasis and Its Clinical Subtypes

    PubMed Central

    Okada, Yukinori; Han, Buhm; Tsoi, Lam C.; Stuart, Philip E.; Ellinghaus, Eva; Tejasvi, Trilokraj; Chandran, Vinod; Pellett, Fawnda; Pollock, Remy; Bowcock, Anne M.; Krueger, Gerald G.; Weichenthal, Michael; Voorhees, John J.; Rahman, Proton; Gregersen, Peter K.; Franke, Andre; Nair, Rajan P.; Abecasis, Gonçalo R.; Gladman, Dafna D.; Elder, James T.; de Bakker, Paul I.W.; Raychaudhuri, Soumya

    2014-01-01

    Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C∗06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10−364). Stepwise analysis revealed multiple HLA-C∗06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C∗12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10−8), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (pomnibus = 2.2 × 10−11), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC. PMID:25087609

  9. Fine mapping major histocompatibility complex associations in psoriasis and its clinical subtypes.

    PubMed

    Okada, Yukinori; Han, Buhm; Tsoi, Lam C; Stuart, Philip E; Ellinghaus, Eva; Tejasvi, Trilokraj; Chandran, Vinod; Pellett, Fawnda; Pollock, Remy; Bowcock, Anne M; Krueger, Gerald G; Weichenthal, Michael; Voorhees, John J; Rahman, Proton; Gregersen, Peter K; Franke, Andre; Nair, Rajan P; Abecasis, Gonçalo R; Gladman, Dafna D; Elder, James T; de Bakker, Paul I W; Raychaudhuri, Soumya

    2014-08-01

    Psoriasis vulgaris (PsV) risk is strongly associated with variation within the major histocompatibility complex (MHC) region, but its genetic architecture has yet to be fully elucidated. Here, we conducted a large-scale fine-mapping study of PsV risk in the MHC region in 9,247 PsV-affected individuals and 13,589 controls of European descent by imputing class I and II human leukocyte antigen (HLA) genes from SNP genotype data. In addition, we imputed sequence variants for MICA, an MHC HLA-like gene that has been associated with PsV, to evaluate association at that locus as well. We observed that HLA-C(∗)06:02 demonstrated the lowest p value for overall PsV risk (p = 1.7 × 10(-364)). Stepwise analysis revealed multiple HLA-C(∗)06:02-independent risk variants in both class I and class II HLA genes for PsV susceptibility (HLA-C(∗)12:03, HLA-B amino acid positions 67 and 9, HLA-A amino acid position 95, and HLA-DQα1 amino acid position 53; p < 5.0 × 10(-8)), but no apparent risk conferred by MICA. We further evaluated risk of two major clinical subtypes of PsV, psoriatic arthritis (PsA; n = 3,038) and cutaneous psoriasis (PsC; n = 3,098). We found that risk heterogeneity between PsA and PsC might be driven by HLA-B amino acid position 45 (Pomnibus = 2.2 × 10(-11)), indicating that different genetic factors underlie the overall risk of PsV and the risk of specific PsV subphenotypes. Our study illustrates the value of high-resolution HLA and MICA imputation for fine mapping causal variants in the MHC. PMID:25087609

  10. Major histocompatibility complex alleles associated with parasite susceptibility in wild giant pandas

    PubMed Central

    Zhang, L; Wu, Q; Hu, Y; Wu, H; Wei, F

    2015-01-01

    Major histocompatibility complex (MHC) polymorphism is thought to be driven by antagonistic coevolution between pathogens and hosts, mediated through either overdominance or frequency-dependent selection. However, investigations under natural conditions are still rare for endangered mammals which often exhibit depleted variation, and the mechanism of selection underlying the maintenance of characteristics remains a considerable debate. In this study, 87 wild giant pandas were used to investigate MHC variation associated with parasite load. With the knowledge of the MHC profile provided by the genomic data of the giant panda, seven DRB1, seven DQA1 and eight DQA2 alleles were identified at each single locus. Positive selection evidenced by a significantly higher number of non-synonymous substitutions per non-synonymous codon site relative to synonymous substitutions per synonymous codon site could only be detected at the DRB1 locus, which leads to the speculation that DRB1 may have a more important role in dealing with parasite infection for pandas. Coprological analyses revealed that 55.17% of individuals exhibited infection with 1–2 helminthes and 95.3% of infected pandas carried Baylisascaris shroederi. Using a generalized linear model, we found that Aime-DRB1*10 was significantly associated with parasite infection, but no resistant alleles could be detected. MHC heterozygosity of the pandas was found to be uncorrelated with the infection status or the infection intensity. These results suggested that the possible selection mechanisms in extant wild pandas may be frequency dependent rather than being determined by overdominance selection. Our findings could guide the candidate selection for the ongoing reintroduction or translocation of pandas. PMID:25248466

  11. Sampling strategies for accurate computational inferences of gametic phase across highly polymorphic major histocompatibility complex loci

    PubMed Central

    2011-01-01

    Background Genes of the Major Histocompatibility Complex (MHC) are very popular genetic markers among evolutionary biologists because of their potential role in pathogen confrontation and sexual selection. However, MHC genotyping still remains challenging and time-consuming in spite of substantial methodological advances. Although computational haplotype inference has brought into focus interesting alternatives, high heterozygosity, extensive genetic variation and population admixture are known to cause inaccuracies. We have investigated the role of sample size, genetic polymorphism and genetic structuring on the performance of the popular Bayesian PHASE algorithm. To cover this aim, we took advantage of a large database of known genotypes (using traditional laboratory-based techniques) at single MHC class I (N = 56 individuals and 50 alleles) and MHC class II B (N = 103 individuals and 62 alleles) loci in the lesser kestrel Falco naumanni. Findings Analyses carried out over real MHC genotypes showed that the accuracy of gametic phase reconstruction improved with sample size as a result of the reduction in the allele to individual ratio. We then simulated different data sets introducing variations in this parameter to define an optimal ratio. Conclusions Our results demonstrate a critical influence of the allele to individual ratio on PHASE performance. We found that a minimum allele to individual ratio (1:2) yielded 100% accuracy for both MHC loci. Sampling effort is therefore a crucial step to obtain reliable MHC haplotype reconstructions and must be accomplished accordingly to the degree of MHC polymorphism. We expect our findings provide a foothold into the design of straightforward and cost-effective genotyping strategies of those MHC loci from which locus-specific primers are available. PMID:21615903

  12. 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

  13. Hypoexpression of major histocompatibility complex molecules on Legionella pneumophila phagosomes and phagolysosomes.

    PubMed Central

    Clemens, D L; Horwitz, M A

    1993-01-01

    Legionella pneumophila is a facultative intracellular pathogen that parasitizes host mononuclear phagocytes. Cell-mediated immunity is pivotal to host defense against L. pneumophila, and the infected host cell may play a central role in processing and presenting parasite antigens to lymphocytes mediating cell-mediated immune response. However, in the case of L. pneumophila and intracellular parasites in general, little is known about the intracellular trafficking of parasite antigens, the influence of parasite infection on major histocompatibility complex (MHC) expression, or the relationship of MHC molecules to sites of parasite replication. To learn more about this, we have used flow cytometry to study the expression of HLA-DR by monocytes infected with L. pneumophila and cryosection immunogold electron microscopy to study the distribution of MHC class I and II molecules on L. pneumophila phagosomes. Flow cytometry analysis demonstrated that L. pneumophila infection has little effect on the overall expression of HLA-DR by monocytes. Cryosection immunogold studies revealed abundant staining for MHC class I and II molecules on the plasma membrane of infected monocytes but little or no staining on the membranes of mature L. pneumophila phagosomes. Cryosection immunogold studies of an avirulent mutant of L. pneumophila that, unlike the wild type, does not inhibit phagosome-lysosome fusion and subsequently survives but does not multiply in a phagolysosome yielded similar results. We have previously found that MHC class I and II molecules are excluded from nascent phagosomes during coiling and conventional phagocytosis. The present work demonstrates that MHC molecules do not accumulate appreciably in the L. pneumophila phagosome as it matures and at a point in the life cycle of the organism in which it is replicating and producing immunoprotective T-cell antigens. This suggests that L. pneumophila does not reside in a typical endosomal compartment in the host cell and

  14. The major histocompatibility complex genes impact pain response in DA and DA.1U rats.

    PubMed

    Guo, Yuan; Yao, Fan-Rong; Cao, Dong-Yuan; Li, Li; Wang, Hui-Sheng; Xie, Wen; Zhao, Yan

    2015-08-01

    Our recent studies have shown that the difference in basal pain sensitivity to mechanical and thermal stimulation between Dark-Agouti (DA) rats and a novel congenic DA.1U rats is major histocompatibility complex (MHC) genes dependent. In the present study, we further used DA and DA.1U rats to investigate the role of MHC genes in formalin-induced pain model by behavioral, electrophysiological and immunohistochemical methods. Behavioral results showed biphasic nociceptive behaviors increased significantly following the intraplantar injection of formalin in the hindpaw of DA and DA.1U rats. The main nociceptive behaviors were lifting and licking, especially in DA rats (P<0.001 and P<0.01). The composite pain scores (CPS) in DA rats were significantly higher than those in DA.1U rats in both phases of the formalin test (P<0.01). Electrophysiological results also showed the biphasic increase in discharge rates of C and Aδ fibers of L5 dorsal root in the two strains, and the net change of the discharge rate of DA rats was significantly higher than that of DA.1U rats (P<0.05). The mechanical thresholds decreased after formalin injection in both strains (P<0.01), and the net change in the mechanical threshold in DA was greater than that in DA.1U rats (P<0.05). The expression of RT1-B, representation of MHC class II molecule, in laminae I-II of L4/5 spinal cord in DA rats was significantly higher than that in DA.1U rats in the respective experimental group (P<0.05). These results suggested that both DA and DA.1U rats exhibited nociceptive responses in formalin-induced pain model and DA rats were more sensitive to noxious chemical stimulus than DA.1U rats, indicating that MHC genes might contribute to the difference in pain sensitivity. PMID:25861730

  15. 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

  16. 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

  17. Gene duplication and fragmentation in the zebra finch major histocompatibility complex

    PubMed Central

    2010-01-01

    Background Due to its high polymorphism and importance for disease resistance, the major histocompatibility complex (MHC) has been an important focus of many vertebrate genome projects. Avian MHC organization is of particular interest because the chicken Gallus gallus, the avian species with the best characterized MHC, possesses a highly streamlined minimal essential MHC, which is linked to resistance against specific pathogens. It remains unclear the extent to which this organization describes the situation in other birds and whether it represents a derived or ancestral condition. The sequencing of the zebra finch Taeniopygia guttata genome, in combination with targeted bacterial artificial chromosome (BAC) sequencing, has allowed us to characterize an MHC from a highly divergent and diverse avian lineage, the passerines. Results The zebra finch MHC exhibits a complex structure and history involving gene duplication and fragmentation. The zebra finch MHC includes multiple Class I and Class II genes, some of which appear to be pseudogenes, and spans a much more extensive genomic region than the chicken MHC, as evidenced by the presence of MHC genes on each of seven BACs spanning 739 kb. Cytogenetic (FISH) evidence and the genome assembly itself place core MHC genes on as many as four chromosomes with TAP and Class I genes mapping to different chromosomes. MHC Class II regions are further characterized by high endogenous retroviral content. Lastly, we find strong evidence of selection acting on sites within passerine MHC Class I and Class II genes. Conclusion The zebra finch MHC differs markedly from that of the chicken, the only other bird species with a complete genome sequence. The apparent lack of synteny between TAP and the expressed MHC Class I locus is in fact reminiscent of a pattern seen in some mammalian lineages and may represent convergent evolution. Our analyses of the zebra finch MHC suggest a complex history involving chromosomal fission, gene

  18. Positive selection drives the evolution of a major histocompatibility complex gene in an endangered Mexican salamander species complex.

    PubMed

    Tracy, Karen E; Kiemnec-Tyburczy, Karen M; DeWoody, J Andrew; Parra-Olea, Gabriela; Zamudio, Kelly R

    2015-06-01

    Immune gene evolution can be critical to species survival in the face of infectious disease. In particular, polymorphism in the genes of the major histocompatibility complex (MHC) helps vertebrates combat novel and diverse pathogens by increasing the number of pathogen-derived proteins that can initiate the host's acquired immune response. In this study, we used a combination of presumably adaptive and neutral markers to investigate MHC evolution in populations of five salamander species within the Ambystoma velasci complex, a group consisting of 15 recently diverged species, several of which are endangered. We isolated 31 unique MHC class II β alleles from 75 total individuals from five species in this complex. MHC heterozygosity was significantly lower than expected for all five species, and we found no clear relationship between number of MHC alleles and species range, life history, or level of heterozygosity. We inferred a phylogeny representing the evolutionary history of Ambystoma MHC, with which we found signatures of positive selection on the overall gene, putative peptide-binding residues, and allelic lineages. We identified several instances of trans-species polymorphism, a hallmark of balancing selection observed in other groups of closely related species. In contrast, we did not detect comparable allelic diversity or signatures of selection on neutral loci. Additionally, we identified 17 supertypes among the 44 unique Ambystoma alleles, indicating that these sequences may encode functionally distinct MHC variants. We therefore have strong evidence that positive selection is a major evolutionary force driving patterns of MHC polymorphism in this recently radiated species complex. PMID:25846208

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. 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

  5. Association of DLA-DQB1 alleles with exocrine pancreatic insufficiency in Pembroke Welsh Corgis.

    PubMed

    Evans, J M; Tsai, K L; Starr-Moss, A N; Steiner, J M; Clark, L A

    2015-08-01

    Exocrine pancreatic insufficiency (EPI) is a digestive disorder resulting from the insufficient secretion of enzymes from the pancreas. In dogs, this condition is often attributed to pancreatic acinar atrophy, wherein the enzyme-producing acinar cells are believed to be destroyed through an autoimmune process. Although EPI affects many diverse breeds, to date, molecular studies have been limited to the German Shepherd dog. A recent study of major histocompatibility genes in diseased and healthy German Shepherd dogs identified both risk and protective haplotypes. Herein, we genotyped DLA-DQB1 in Pembroke Welsh Corgis to determine whether dog leukocyte antigen alleles contribute to the pathogenesis of EPI across dog breeds. We evaluated 14 affected and 43 control Pembroke Welsh Corgis, which were selected based on an age of onset similar to German Shepherd dogs. We identified one protective allele (odds ratio = 0.13, P-value = 0.044) and one risk allele (odds ratio = 3.8, P-value = 0.047). As in German Shepherd dogs, the risk allele is a duplication of DLA-DQB1 (alleles DQB1*013:03 and 017:01); however, Pembroke Welsh Corgis have acquired a single polymorphism on DQB1*017:01. Thus, the DLA-DQB1 duplication is a risk allele for EPI in at least two breeds. PMID:26095904

  6. Clarifying the association of genes within the major histocompatibility complex with narcolepsy

    SciTech Connect

    Acton, R.T.; Watson, B.; Rivers, C.

    1994-09-01

    HLA-DR2 and DQwl has been reported to be strongly associated with narcolepsy. The particular phenotype and strength of these associations varies between races. For example DQB*0601 has been reported associated with some African American (AA) narcoleptics while some Caucasian American (CA) narcoleptics do not possess DR2 or DQw1. We have sought to clarify the relationship of MHC genes with narcolepsy in the local CA and AA population. There was no significant difference in the frequency of DR phenotypes in CA or AA narcoleptics compared to race, age, sex and geographic region-matched controls. DR2 was increased in CA cataplexy positive (Cat+) narcoleptics compared to controls (p=0.028, odds ratio (OR)=2.4) and to Cat- narcoleptics (p=<0.001, OR=8.8). DR11 was increased in AA Cat+ narcoleptics compared to controls (p=0.004, OR=11.2) and to Cat- narcoleptics (p=0.002). DQB1*0601 was not significantly associated with narcolepsy in our AA population. We have assessed the frequency of the TNFa (13 alleles, 1.1Mb telomeric to DQ{alpha}), D6S105 (13 alleles, 1kb telomeric of HLA-A), and GLP-1R (19 alleles, 18.5 Mb centromeric of DQ{alpha}), dinucleotide repeats in narcoleptics compared to controls. The TNFa allele 117 was increased in CA Cat+ vs. controls (p=0.003). The GLP-1R allele 144 was increased in CA Cat- vs. controls (p=0.02). In AA narcoleptics, the TNFa allele 109 was significantly increased (p=0.04) along with the D6S105 allele 130 (p=0.02) compared to controls. The D6S105 allele 130 was increased in AA Cat- vs. controls (p=0.03). The GLP-1R allele 154 was significantly decreased in AA Cat+ vs. Cat- (p=0.04). These data suggest that DR and/or DQ genes are not responsible for narcolepsy and that cataplexy is associated with different regions around the MHC in various racial groups.

  7. Ancestral polymorphism at the major histocompatibility complex (MHCIIß) in the Nesospiza bunting species complex and its sister species (Rowettia goughensis)

    PubMed Central

    2012-01-01

    Background The major histocompatibility complex (MHC) is an important component of the vertebrate immune system and is frequently used to characterise adaptive variation in wild populations due to its co-evolution with pathogens. Passerine birds have an exceptionally diverse MHC with multiple gene copies and large numbers of alleles compared to other avian taxa. The Nesospiza bunting species complex (two species on Nightingale Island; one species with three sub-species on Inaccessible Island) represents a rapid adaptive radiation at a small, isolated archipelago, and is thus an excellent model for the study of adaptation and speciation. In this first study of MHC in Nesospiza buntings, we aim to characterize MHCIIß variation, determine the strength of selection acting at this gene region and assess the level of shared polymorphism between the Nesospiza species complex and its putative sister taxon, Rowettia goughensis, from Gough Island. Results In total, 23 unique alleles were found in 14 Nesospiza and 2 R. goughensis individuals encoding at least four presumably functional loci and two pseudogenes. There was no evidence of ongoing selection on the peptide binding region (PBR). Of the 23 alleles, 15 were found on both the islands inhabited by Nesospiza species, and seven in both Nesospiza and Rowettia; indications of shared, ancestral polymorphism. A gene tree of Nesospiza MHCIIß alleles with several other passerine birds shows three highly supported Nesospiza-specific groups. All R. goughensis alleles were shared with Nesospiza, and these alleles were found in all three Nesospiza sequence groups in the gene tree, suggesting that most of the observed variation predates their phylogenetic split. Conclusions Lack of evidence of selection on the PBR, together with shared polymorphism across the gene tree, suggests that population variation of MHCIIß among Nesospiza and Rowettia is due to ancestral polymorphism rather than local selective forces. Weak or no

  8. Mammalian non-classical major histocompatibility complex I and its receptors: Important contexts of gene, evolution, and immunity

    PubMed Central

    Pratheek, B. M.; Nayak, Tapas K.; Sahoo, Subhransu S.; Mohanty, Prafulla K.; Chattopadhyay, Soma; Chakraborty, Ntiya G.; Chattopadhyay, Subhasis

    2014-01-01

    The evolutionary conserved, less-polymorphic, nonclassical major histocompatibility complex (MHC) class I molecules: Qa-1 and its human homologue human leukocyte antigen-E (HLA-E) along with HLA-F, G and H cross-talk with the T-cell receptors and also interact with natural killer T-cells and other lymphocytes. Moreover, these nonclassical MHC molecules are known to interact with CD94/NKG2 heterodimeric receptors to induce immune responses and immune regulations. This dual role of Qa-1/HLA-E in terms of innate and adaptive immunity makes them more interesting. This review highlights the new updates of the mammalian nonclassical MHC-I molecules in terms of their gene organization, evolutionary perspective and their role in immunity. PMID:25400340

  9. 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

  10. Low major histocompatibility complex diversity in the Tasmanian devil predates European settlement and may explain susceptibility to disease epidemics.

    PubMed

    Morris, Katrina; Austin, Jeremy J; Belov, Katherine

    2013-02-23

    The Tasmanian devil (Sarcophilus harrisii) is at risk of extinction owing to the emergence of a contagious cancer known as devil facial tumour disease (DFTD). The emergence and spread of DFTD has been linked to low genetic diversity in the major histocompatibility complex (MHC). We examined MHC diversity in historical and ancient devils to determine whether loss of diversity is recent or predates European settlement in Australia. Our results reveal no additional diversity in historical Tasmanian samples. Mainland devils had common modern variants plus six new variants that are highly similar to existing alleles. We conclude that low MHC diversity has been a feature of devil populations since at least the Mid-Holocene and could explain their tumultuous history of population crashes. PMID:23221872

  11. Low major histocompatibility complex diversity in the Tasmanian devil predates European settlement and may explain susceptibility to disease epidemics

    PubMed Central

    Morris, Katrina; Austin, Jeremy J.; Belov, Katherine

    2013-01-01

    The Tasmanian devil (Sarcophilus harrisii) is at risk of extinction owing to the emergence of a contagious cancer known as devil facial tumour disease (DFTD). The emergence and spread of DFTD has been linked to low genetic diversity in the major histocompatibility complex (MHC). We examined MHC diversity in historical and ancient devils to determine whether loss of diversity is recent or predates European settlement in Australia. Our results reveal no additional diversity in historical Tasmanian samples. Mainland devils had common modern variants plus six new variants that are highly similar to existing alleles. We conclude that low MHC diversity has been a feature of devil populations since at least the Mid-Holocene and could explain their tumultuous history of population crashes. PMID:23221872

  12. 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...

  13. 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

  14. 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.

  15. Characterization, Polymorphism and Selection of Major Histocompatibility Complex (MHC) DAB Genes in Vulnerable Chinese Egret (Egretta eulophotes)

    PubMed Central

    Wang, Zeng; Zhou, Xiaoping; Lin, Qingxian

    2013-01-01

    The major histocompatibility complex (MHC) is an excellent molecular marker for the studies of evolutionary ecology and conservation genetics because it is a family of highly polymorphic genes that play a key role in vertebrate immune response. In this study, the functional genes of MHC Class II B (DAB) were isolated for the first time in a vulnerable species, the Chinese egret (Egrettaeulophotes). Using a full length DNA and cDNA produced by PCR and RACE methods, four potential MHC DAB loci were characterized in the genome of this egret and all four were expressed in liver and blood. At least four copies of the MHC gene complex were similar to two copies of the minimal essential MHC complex of chicken, but are less complex than the multiple copies expressed in passerine species. In MHC polymorphism, 19 alleles of exon 2 were isolated from 48 individuals using PCR. No stop codons or frameshift mutations were found in any of the coding regions. The signatures of positive selection detected in potential peptide-binding regions by Bayesian analysis, suggesting that all of these genes were functional. These data will provide the fundamental basis for further studies to elucidate the mechanisms and significance of MHC molecular adaptation in vulnerable Chinese egret and other ardeids. PMID:24019955

  16. Hard wiring of T cell receptor specificity for the major histocompatibility complex is underpinned by TCR adaptability

    SciTech Connect

    Burrows, Scott R.; Chen, Zhenjun; Archbold, Julia K.; Tynan, Fleur E.; Beddoe, Travis; Kjer-Nielsen, Lars; Miles, John J.; Khanna, Rajiv; Moss, Denis J.; Liu, Yu Chih; Gras, Stephanie; Kostenko, Lyudmila; Brennan, Rebekah M.; Clements, Craig S.; Brooks, Andrew G.; Purcell, Anthony W.; McCluskey, James; Rossjohn, Jamie

    2010-07-07

    {alpha}{beta} T cell receptors (TCRs) are genetically restricted to corecognize peptide antigens bound to self-major histocompatibility complex (pMHC) molecules; however, the basis for this MHC specificity remains unclear. Despite the current dogma, evaluation of the TCR-pMHC-I structural database shows that the nongermline-encoded complementarity-determining region (CDR)-3 loops often contact the MHC-I, and the germline-encoded CDR1 and -2 loops frequently participate in peptide-mediated interactions. Nevertheless, different TCRs adopt a roughly conserved docking mode over the pMHC-I, in which three MHC-I residues (65, 69, and 155) are invariably contacted by the TCR in one way or another. Nonetheless, the impact of mutations at these three positions, either individually or together, was not uniformly detrimental to TCR recognition of pHLA-B*0801 or pHLA-B*3508. Moreover, when TCR-pMHC-I recognition was impaired, this could be partially restored by expression of the CD8 coreceptor. The structure of a TCR-pMHC-I complex in which these three (65, 69, and 155) MHC-I positions were all mutated resulted in shifting of the TCR footprint relative to the cognate complex and formation of compensatory interactions. Collectively, our findings reveal the inherent adaptability of the TCR in maintaining peptide recognition while accommodating changes to the central docking site on the pMHC-I.

  17. 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.

  18. 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

  19. 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

  20. Major histocompatibility complex harbors widespread genotypic variability of non-additive risk of rheumatoid arthritis including epistasis.

    PubMed

    Wei, Wen-Hua; Bowes, John; Plant, Darren; Viatte, Sebastien; Yarwood, Annie; Massey, Jonathan; Worthington, Jane; Eyre, Stephen

    2016-01-01

    Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene's (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P < 2.5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals. PMID:27109064

  1. Major histocompatibility complex harbors widespread genotypic variability of non-additive risk of rheumatoid arthritis including epistasis

    PubMed Central

    Wei, Wen-Hua; Bowes, John; Plant, Darren; Viatte, Sebastien; Yarwood, Annie; Massey, Jonathan; Worthington, Jane; Eyre, Stephen

    2016-01-01

    Genotypic variability based genome-wide association studies (vGWASs) can identify potentially interacting loci without prior knowledge of the interacting factors. We report a two-stage approach to make vGWAS applicable to diseases: firstly using a mixed model approach to partition dichotomous phenotypes into additive risk and non-additive environmental residuals on the liability scale and secondly using the Levene’s (Brown-Forsythe) test to assess equality of the residual variances across genotype groups per marker. We found widespread significant (P < 2.5e-05) vGWAS signals within the major histocompatibility complex (MHC) across all three study cohorts of rheumatoid arthritis. We further identified 10 epistatic interactions between the vGWAS signals independent of the MHC additive effects, each with a weak effect but jointly explained 1.9% of phenotypic variance. PTPN22 was also identified in the discovery cohort but replicated in only one independent cohort. Combining the three cohorts boosted power of vGWAS and additionally identified TYK2 and ANKRD55. Both PTPN22 and TYK2 had evidence of interactions reported elsewhere. We conclude that vGWAS can help discover interacting loci for complex diseases but require large samples to find additional signals. PMID:27109064

  2. 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

  3. Myelin/oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex.

    PubMed

    Pham-Dinh, D; Mattei, M G; Nussbaum, J L; Roussel, G; Pontarotti, P; Roeckel, N; Mather, I H; Artzt, K; Lindahl, K F; Dautigny, A

    1993-09-01

    Myelin/oligodendrocyte glycoprotein (MOG) is found on the surface of myelinating oligodendrocytes and external lamellae of myelin sheaths in the central nervous system, and it is a target antigen in experimental autoimmune encephalomyelitis and multiple sclerosis. We have isolated bovine, mouse, and rat MOG cDNA clones and shown that the developmental pattern of MOG expression in the rat central nervous system coincides with the late stages of myelination. The amino-terminal, extracellular domain of MOG has characteristics of an immunoglobulin variable domain and is 46% and 41% identical with the amino terminus of bovine butyrophilin (expressed in the lactating mammary gland) and B-G antigens of the chicken major histocompatibility complex (MHC), respectively; these proteins thus form a subset of the immunoglobulin superfamily. The homology between MOG and B-G extends beyond their structure and genetic mapping to their ability to induce strong antibody responses and has implications for the role of MOG in pathological, autoimmune conditions. We colocalized the MOG and BT genes to the human MHC on chromosome 6p21.3-p22. The mouse MOG gene was mapped to the homologous band C of chromosome 17, within the M region of the mouse MHC. PMID:8367453

  4. 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.

  5. 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

  6. 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

  7. A single peptide-major histocompatibility complex ligand triggers digital cytokine secretion in CD4(+) T cells.

    PubMed

    Huang, Jun; Brameshuber, Mario; Zeng, Xun; Xie, Jianming; Li, Qi-jing; Chien, Yueh-hsiu; Valitutti, Salvatore; Davis, Mark M

    2013-11-14

    We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4(+) T cell functional sensitivity. We found that naive T cells, T cell blasts, and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of ∼1,000, ∼10,000, and ∼10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4(+) T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell. PMID:24120362

  8. 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

  9. Major histocompatibility complex-unrestricted cytolytic activity of human T cells: analysis of precursor frequency and effector phenotype

    SciTech Connect

    Patel, S.S.; Thiele, D.L.; Lipsky, P.E.

    1987-12-01

    The frequency and phenotype of human T cells that mediate major histocompatibility complex (MHC)-unrestricted cytolysis were analyzed. T cell clones were generated by culturing adherent cell-depleted peripheral blood mononuclear cells at a density of 0.3 cell/well with phytohemagglutinin, recombinant interleukin 2 (rIL-2), and irradiated autologous peripheral blood mononuclear cells and/or Epstein-Barr virus-transformed lymphoblastoid cell lines. All of the 198 clones generated by this method were T cells (CD2/sup +/, CD3/sup +/, CD4/sup +/ or CD2/sup +/, CD3/sup +/, CD8/sup +/) that possessed potent lytic activity against K562, an erythroleukemia line sensitive to lysis by human natural killer cells, and Cur, a renal carcinoma cell line resistant to human natural killer activity. Cytolysis, measured by /sup 51/Cr release, was MHC-unrestricted, since the clones were able to lyse MHC class I or class II negative targets, as well as MHC class I and class II negative targets. Although the clones produced tissue necrosis factor/lymphotoxin-like molecules, lysis of Cur of K562 was not mediated by a soluble factor secreted by the clones. These data indicate that the capacity for MHC-unrestricted tumoricidal activity and expression of NKH1 and CD11b, but not CD 16, are properties common to all or nearly all human peripheral blood-derived T cell clones regardless of CD4 or CD8 phenotype.

  10. 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.

  11. 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

  12. Myelin-oligodendrocyte glycoprotein is a member of a subset of the immunoglobulin superfamily encoded within the major histocompatibility complex

    SciTech Connect

    Pham-Dinh, D.; Dautigny, A. ); Mattei, M.G.; Roeckel, N. ); Nussbaum, J.H.; Roussel, G. ); Pontarotti, P. ); Mather, I.H. ); Artzt, K. ); Lindahl, K.F. )

    1993-09-01

    Myelin/oligodendrocyte glycoprotein (MOG) is found on the surface of myelinating oligodendrocytes and external lamellae of myelin sheaths in the central nervous system, and it is target antigen in experimental autoimmune encephalomyelitis and multiple sclerosis. The authors have isolated bovine, mouse, and rat MOG cDNA clones and shown that the developmental pattern of MOG expression in the rat central nervous system coincides with the late stages of myelination. The amino-terminal, extracellular domain of MOG has characteristics of an immunoglobulin variable domain and is 46% and 41% identical with the amino terminus of bovine butyrophilin (expressed in the lactating mammary gland) and B-G antigens of the chicken major histocompatibility complex (MHC), respectively; these proteins thus form a subset of the immunoglobulin superfamily. The homology between MOG and B-G extends beyond their structure and genetic mapping to their ability to induce strong antibody responses and has implications for the role of MOG in pathological, autoimmune conditions. The authors colocalized the MOG and BT genes to the human MHC on chromosome 6p21.3-p22. The mouse MOG gene was mapped to the homologous band C of chromosome 17, within the M region of the mouse MHC. 38 refs., 6 figs.

  13. 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

  14. Generation of a genomic tiling array of the human Major Histocompatibility Complex (MHC) and its application for DNA methylation analysis

    PubMed Central

    Tomazou, Eleni M; Rakyan, Vardhman K; Lefebvre, Gregory; Andrews, Robert; Ellis, Peter; Jackson, David K; Langford, Cordelia; Francis, Matthew D; Bäckdahl, Liselotte; Miretti, Marcos; Coggill, Penny; Ottaviani, Diego; Sheer, Denise; Murrell, Adele; Beck, Stephan

    2008-01-01

    Background The major histocompatibility complex (MHC) is essential for human immunity and is highly associated with common diseases, including cancer. While the genetics of the MHC has been studied intensively for many decades, very little is known about the epigenetics of this most polymorphic and disease-associated region of the genome. Methods To facilitate comprehensive epigenetic analyses of this region, we have generated a genomic tiling array of 2 Kb resolution covering the entire 4 Mb MHC region. The array has been designed to be compatible with chromatin immunoprecipitation (ChIP), methylated DNA immunoprecipitation (MeDIP), array comparative genomic hybridization (aCGH) and expression profiling, including of non-coding RNAs. The array comprises 7832 features, consisting of two replicates of both forward and reverse strands of MHC amplicons and appropriate controls. Results Using MeDIP, we demonstrate the application of the MHC array for DNA methylation profiling and the identification of tissue-specific differentially methylated regions (tDMRs). Based on the analysis of two tissues and two cell types, we identified 90 tDMRs within the MHC and describe their characterisation. Conclusion A tiling array covering the MHC region was developed and validated. Its successful application for DNA methylation profiling indicates that this array represents a useful tool for molecular analyses of the MHC in the context of medical genomics. PMID:18513384

  15. 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

  16. 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

  17. Gastrointestinal helminths in indigenous and exotic chickens in Vietnam: association of the intensity of infection with the Major Histocompatibility Complex.

    PubMed

    Schou, T W; Permin, A; Juul-Madsen, H R; Sørensen, P; Labouriau, R; Nguyên, T L H; Fink, M; Pham, S L

    2007-04-01

    This study compared the prevalence and intensity of infections of helminths in 2 chicken breeds in Vietnam, the indigenous Ri and the exotic Luong Phuong. Also, possible correlations with the Major Histocompatibility Complex (MHC) were tested. The most prevalent helminths were Ascaridia galli, Heterakis beramporia, Tetrameres mothedai, Capillaria obsignata, Raillietina echinobothrida and Raillietina tetragona. Differences in prevalence and intensity of infection were found between the 2 breeds. Comparing the 2 groups of adult birds, Ri chickens were observed to have higher prevalence and infection intensities of several species of helminths, as well as a higher mean number of helminth species. In contrast, A. galli and C. obsignata were shown to be more prevalent in Luong Phuong chickens. Furthermore, an age-dependent difference was indicated in the group of Ri chickens in which the prevalence and the intensity of infection was higher for the adult than the young chickens for most helminths. The most notable exception was the significantly lower prevalence and intensities of A. galli in the group of adult chickens. In contrast, the prevalence and intensity were very similar in both age groups of Luong Phuong chickens. Using a genetic marker located in the MHC, a statistically significant correlation between several MHC haplotypes and the infection intensity of different helminth species was inferred. This is the first report of an association of MHC haplotype with the intensity of parasite infections in chickens. PMID:17166322

  18. 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

  19. 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

  20. 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

  1. 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

  2. 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

  3. 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

  4. Predictions of T-cell receptor- and major histocompatibility complex-binding sites on staphylococcal enterotoxin C1.

    PubMed Central

    Hoffmann, M L; Jablonski, L M; Crum, K K; Hackett, S P; Chi, Y I; Stauffacher, C V; Stevens, D L; Bohach, G A

    1994-01-01

    We have focused on regions of staphylococcal enterotoxin C1 (SEC1) causing immunomodulation. N-terminal deletion mutants lacking residues 6 through 13 induced T-cell proliferation similar to that induced by native toxin. However, mutants with residues deleted between positions 19 and 33, although nonmitogenic themselves, were able to inhibit both SEC1-induced T-cell proliferation and binding of the native toxin to major histocompatibility complex (MHC) class II. Presumably, these deletions define a part of SEC1 that interacts with the T-cell receptor. Three synthetic peptides containing residues located in a region analogous to the alpha 5 groove of SEC3 had residual mitogenic activity or blocked T-cell proliferation induced by SEC1 and appear to recognize the same site as SEC1 on a receptor for the toxin, presumably MHC class II. We conclude that isolated portions of the SEC1 molecule can retain residual mitogenic activity but that the entire protein is needed to achieve maximal superantigenic stimulation. Our results, together with the results of other investigators, support a model in which SEC1 binds to an alpha helix of MHC class II through a central groove in the toxin and thereby promotes or stabilizes the interaction between antigen-presenting cells and T cells. Images PMID:8039910

  5. Female major histocompatibility complex type affects male testosterone levels and sperm number in the horse (Equus caballus)

    PubMed Central

    Burger, D.; Dolivo, G.; Marti, E.; Sieme, H.; Wedekind, C.

    2015-01-01

    Odours of vertebrates often contain information about the major histocompatibility complex (MHC), and are used in kin recognition, mate choice or female investment in pregnancy. It is, however, still unclear whether MHC-linked signals can also affect male reproductive strategies. We used horses (Equus caballus) to study this question under experimental conditions. Twelve stallions were individually exposed either to an unfamiliar MHC-similar mare and then to an unfamiliar MHC-dissimilar mare, or vice versa. Each exposure lasted over a period of four weeks. Peripheral blood testosterone levels were determined weekly. Three ejaculates each were collected in the week after exposure to both mares (i.e. in the ninth week) to determine mean sperm number and sperm velocity. We found high testosterone levels when stallions were kept close to MHC-dissimilar mares and significantly lower ones when kept close to MHC-similar mares. Mean sperm number per ejaculate (but not sperm velocity) was positively correlated to mean testosterone levels and also affected by the order of presentation of mares: sperm numbers were higher if MHC-dissimilar mares were presented last than if MHC-similar mares were presented last. We conclude that MHC-linked signals influence testosterone secretion and semen characteristics, two indicators of male reproductive strategies. PMID:25904670

  6. 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

  7. Effects of messenger RNA structure and other translational control mechanisms on major histocompatibility complex-I mediated antigen presentation

    PubMed Central

    Murat, Pierre; Tellam, Judy

    2015-01-01

    Effective T-cell surveillance of antigen-presenting cells is dependent on the expression of an array of antigenic peptides bound to major histocompatibility complex (MHC) class I (MHC-I) or class II (MHC-II) molecules. Pathogens co-evolving with their hosts exploit crucial translational regulatory mechanisms in order to evade host immune recognition and thereby sustain their infection. Evasion strategies that downregulate viral protein synthesis and thereby restrict antigen presentation to cytotoxic T-cells through the endogenous MHC-I pathway have been implicated in the pathogenesis of viral-associated malignancies. An understanding of the mechanisms by which messenger RNA (mRNA) structure modulates both viral mRNA translation and the antigen processing machinery to escape immune surveillance, will stimulate the development of alternative therapeutic strategies focused on RNA-directed drugs designed to enhance immune responses against infected cells. In this review, we discuss regulatory aspects of the MHC-I pathway and summarize current knowledge of the role attributed by mRNA structure and other translational regulatory mechanisms in immune evasion. In particular we highlight the impact of recently identified G-quadruplex structures within virally encoded transcripts as unique regulatory signals for translational control and antigen presentation. WIREs RNA 2015, 6:157–171. doi: 10.1002/wrna.1262 PMID:25264139

  8. A complex alloantigen system in Florida sandhill cranes, Grus canadensis pratensis: Evidence for the major histocompatibility (B) system

    USGS Publications Warehouse

    Jarvi, S.I.; Gee, G.F.; Miller, M.M.; Briles, W.E.

    1995-01-01

    The B blood group system constitutes the major histocompatibility complex (Mhc) in birds. The Mhc is a cluster of genes largely devoted to the processing and presentation of antigen. The Mhc is highly polymorphic in many species and, thus, useful in the evaluation of genetic diversity for fitness traits within populations of a variety of animals. Correlations found between particular Mhc haplotypes and resistance to certain diseases emphasize the importance of understanding the functional significance of diversity of the Mhc, particularly in species threatened with extinction. As part of studies focused on genetic diversity in wild birds, serological techniques were used to define a highly polymorphic alloantigen system in seven families of Florida sandhill cranes (Grus canadensis pratensis). The results of analyses with antisera produced within the crane families and with chicken Mhc antigen-specific reagents revealed a single major alloantigen system that is likely the Mhc of the Florida sandhill crane. Preliminary experiments indicate that these crane alloantisera will provide a means of defining .the Mhc in other species of cranes.

  9. Major Histocompatibility Complex I Mediates Immunological Tolerance of the Trophoblast during Pregnancy and May Mediate Rejection during Parturition

    PubMed Central

    Rapacz-Leonard, Anna; Dąbrowska, Małgorzata; Janowski, Tomasz

    2014-01-01

    During pregnancy in larger mammals, the maternal immune system must tolerate the fetus for months while resisting external infection. This tolerance is facilitated by immunological communication between the fetus and the mother, which is mediated by Major Histocompatibility Complex I (MHC I) proteins, by leukocytes, and by the cytokines secreted by the leukocytes. Fetal-maternal immunological communication also supports pregnancy by inducing physiological changes in the mother. If the mother “misunderstands” the signal sent by the fetus during pregnancy, the fetus will be miscarried or delivered preterm. Unlike any other maternal organ, the placenta can express paternal antigens. At parturition, paternal antigens are known to be expressed in cows and may be expressed in horses, possibly so that the maternal immune system will reject the placenta and help to expel it. This review compares fetal-maternal crosstalk that is mediated by the immune system in three species with pregnancies that last for nine months or longer: humans, cattle, and horses. It raises the possibility that immunological communication early in pregnancy may prepare the mother for successful expulsion of fetal membranes at parturition. PMID:24812442

  10. 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.

  11. 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.

  12. 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

  13. Bioorthogonal cleavage and exchange of major histocompatibility complex ligands by employing azobenzene-containing peptides.

    PubMed

    Choo, Joanna A L; Thong, Sock Yue; Yap, Jiawei; van Esch, Wim J E; Raida, Manfred; Meijers, Rob; Lescar, Julien; Verhelst, Steven H L; Grotenbreg, Gijsbert M

    2014-12-01

    Bioorthogonal cleavable linkers are attractive building blocks for compounds that can be manipulated to study biological and cellular processes. Sodium dithionite sensitive azobenzene-containing (Abc) peptides were applied for the temporary stabilization of recombinant MHC complexes, which can then be employed to generate libraries of MHC tetramers after exchange with a novel epitope. This technology represents an important tool for high-throughput studies of disease-specific T cell responses. PMID:25348595

  14. Modeling the structure of bound peptide ligands to major histocompatibility complex

    PubMed Central

    Tong, Joo Chuan; Tan, Tin Wee; Ranganathan, Shoba

    2004-01-01

    In this article, we present a new technique for the rapid and precise docking of peptides to MHC class I and class II receptors. Our docking procedure consists of three steps: (1) peptide residues near the ends of the binding groove are docked by using an efficient pseudo-Brownian rigid body docking procedure followed by (2) loop closure of the intervening backbone structure by satisfaction of spatial constraints, and subsequently, (3) the refinement of the entire backbone and ligand interacting side chains and receptor side chains experiencing atomic clash at the MHC receptor–peptide interface. The method was tested by remodeling of 40 nonredundant complexes of at least 3.00 Å resolution for which three-dimensional structural information is available and independently for docking peptides derived from 15 nonredundant complexes into a single template structure. In the first test, 33 out of 40 MHC class I and class II peptides and in the second test, 11 out of 15 MHC–peptide complexes were modeled with a Cα RMSD < 1.00 Å. PMID:15322290

  15. 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

  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. 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

  18. 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

  19. 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.

  20. A Genome Wide Association Study for Coronary Artery Disease Identifies a Novel Susceptibility Locus in the Major Histocompatibility Complex

    PubMed Central

    Davies, Robert W.; Wells, George A.; Stewart, Alexandre F.R.; Erdmann, Jeanette; Shah, Svati H.; Ferguson, Jane F.; Hall, Alistair S.; Anand, Sonia S.; Burnett, Mary S.; Epstein, Stephen E.; Dandona, Sonny; Chen, Li; Nahrstaedt, Janja; Loley, Christina; König, Inke R.; Kraus, William E.; Granger, Christopher B.; Engert, James C.; Hengstenberg, Christian; Wichmann, H.-Erich; Schreiber, Stefan; Tang, W. H. Wilson; Ellis, Stephen G.; Rader, Daniel J.; Hazen, Stanley L.; Reilly, Muredach P.; Samani, Nilesh J.; Schunkert, Heribert; Roberts, Robert; McPherson, Ruth

    2012-01-01

    Background Recent genome-wide association studies (GWAS) have identified several novel loci that reproducibly associate with CAD and/or MI risk. However, known common CAD risk variants explain only 10% of the predicted genetic heritability of the disease, suggesting that important genetic signals remain to be discovered. Methods and Results We performed a discovery meta-analysis of 5 GWASs involving 13,949 subjects (7123 cases, 6826 controls) imputed at approximately 5 million SNPs using pilot 1000 Genomes based haplotypes. Promising loci were followed up in an additional 5 studies with 11,032 subjects (5211 cases, 5821 controls). A novel CAD locus on chromosome 6p21.3 in the major histocompatibility complex (MHC) between HCG27 and HLA-C was identified and achieved genome wide significance in the combined analysis (rs3869109; pdiscovery=3.3×10−7, preplication=5.3×10−4 pcombined=1.12×10−9). A sub-analysis combining discovery GWASs showed an attenuation of significance when stringent corrections for European population structure were employed (p=4.1×10−10 versus 3.2×10−7) suggesting the observed signal is partly confounded due to population stratification. This gene dense region plays an important role in inflammation, immunity and self cell recognition. To determine whether the underlying association was driven by MHC class I alleles, we statistically imputed common HLA alleles into the discovery subjects; however, no single common HLA type contributed significantly or fully explained the observed association. Conclusion We have identified a novel locus in the MHC associated with CAD. MHC genes regulate inflammation and T cell responses that contribute importantly to the initiation and propagation of atherosclerosis. Further laboratory studies will be required to understand the biological basis of this association and identify the causative allele(s). PMID:22319020

  1. 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

  2. Testing for post-copulatory selection for major histocompatibility complex genotype in a semi-free-ranging primate population.

    PubMed

    Setchell, Joanna M; Abbott, Kristin M; Gonzalez, Jean-Paul; Knapp, Leslie A

    2013-10-01

    A large body of evidence suggests that major histocompatibility complex (MHC) genotype influences mate choice. However, few studies have investigated MHC-mediated post-copulatory mate choice under natural, or even semi-natural, conditions. We set out to explore this question in a large semi-free-ranging population of mandrills (Mandrillus sphinx) using MHC-DRB genotypes for 127 parent-offspring triads. First, we showed that offspring MHC heterozygosity correlates positively with parental MHC dissimilarity suggesting that mating among MHC dissimilar mates is efficient in increasing offspring MHC diversity. Second, we compared the haplotypes of the parental dyad with those of the offspring to test whether post-copulatory sexual selection favored offspring with two different MHC haplotypes, more diverse gamete combinations, or greater within-haplotype diversity. Limited statistical power meant that we could only detect medium or large effect sizes. Nevertheless, we found no evidence for selection for heterozygous offspring when parents share a haplotype (large effect size), genetic dissimilarity between parental haplotypes (we could detect an odds ratio of ≥1.86), or within-haplotype diversity (medium-large effect). These findings suggest that comparing parental and offspring haplotypes may be a useful approach to test for post-copulatory selection when matings cannot be observed, as is the case in many study systems. However, it will be extremely difficult to determine conclusively whether post-copulatory selection mechanisms for MHC genotype exist, particularly if the effect sizes are small, due to the difficulty in obtaining a sufficiently large sample. PMID:23677678

  3. Critical role of the major histocompatibility complex and IL-10 in matrilin-1-induced relapsing polychondritis in mice.

    PubMed

    Hansson, Ann-Sofie; Johansson, Asa C M; Holmdahl, Rikard

    2004-01-01

    Relapsing polychondritis (RP) is an autoimmune disease that affects extra-articular cartilage. Matrilin-1-induced relapsing polychondritis (MIRP) is a model for RP and is useful for studies of the pathogenic mechanisms in this disease. There are indications that the major histocompatibility complex (MHC) class II plays a major role in RP, since DR4+ patients are more commonly affected than controls. We have now addressed the role of the MHC region, as well as the non-MHC contribution, using congenic mouse strains. Of the MHC congenic strains, B10.Q (H2q) was the most susceptible, the B10.P (H2p) and B10.R (H2r) strains developed mild disease, while B10 strains carrying the v, b, f, or u H2 haplotypes were resistant. A slight variation of susceptibility of H2q strains (B10.Q> C3H.Q> DBA/1) was observed and the (B10.Q x DBA/1)F1 was the most susceptible of all strains. Furthermore, macrophages and CD4+ T cells were the most prominent cell types in inflammatory infiltrates of the tracheal cartilage. Macrophages are the major source of many cytokines, such as interleukin-10 (IL-10), which is currently being tested as a therapeutic agent in several autoimmune diseases. We therefore investigated B10.Q mice devoid of IL-10 through gene deletion and found that they developed a significantly more severe disease, with an earlier onset, than their heterozygous littermates. In conclusion, MHC genes, as well as non-MHC genes, are important for MIRP induction, and IL-10 plays a major suppressive role in cartilage inflammation of the respiratory tract. PMID:15380048

  4. Major Histocompatibility Complex Genes Map to Two Chromosomes in an Evolutionarily Ancient Reptile, the Tuatara Sphenodon punctatus

    PubMed Central

    Miller, Hilary C.; O’Meally, Denis; Ezaz, Tariq; Amemiya, Chris; Marshall-Graves, Jennifer A.; Edwards, Scott

    2015-01-01

    Major histocompatibility complex (MHC) genes are a central component of the vertebrate immune system and usually exist in a single genomic region. However, considerable differences in MHC organization and size exist between different vertebrate lineages. Reptiles occupy a key evolutionary position for understanding how variation in MHC structure evolved in vertebrates, but information on the structure of the MHC region in reptiles is limited. In this study, we investigate the organization and cytogenetic location of MHC genes in the tuatara (Sphenodon punctatus), the sole extant representative of the early-diverging reptilian order Rhynchocephalia. Sequencing and mapping of 12 clones containing class I and II MHC genes from a bacterial artificial chromosome library indicated that the core MHC region is located on chromosome 13q. However, duplication and translocation of MHC genes outside of the core region was evident, because additional class I MHC genes were located on chromosome 4p. We found a total of seven class I sequences and 11 class II β sequences, with evidence for duplication and pseudogenization of genes within the tuatara lineage. The tuatara MHC is characterized by high repeat content and low gene density compared with other species and we found no antigen processing or MHC framework genes on the MHC gene-containing clones. Our findings indicate substantial differences in MHC organization in tuatara compared with mammalian and avian MHCs and highlight the dynamic nature of the MHC. Further sequencing and annotation of tuatara and other reptile MHCs will determine if the tuatara MHC is representative of nonavian reptiles in general. PMID:25953959

  5. 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

  6. Major Histocompatibility Complex Genes Map to Two Chromosomes in an Evolutionarily Ancient Reptile, the Tuatara Sphenodon punctatus.

    PubMed

    Miller, Hilary C; O'Meally, Denis; Ezaz, Tariq; Amemiya, Chris; Marshall-Graves, Jennifer A; Edwards, Scott

    2015-07-01

    Major histocompatibility complex (MHC) genes are a central component of the vertebrate immune system and usually exist in a single genomic region. However, considerable differences in MHC organization and size exist between different vertebrate lineages. Reptiles occupy a key evolutionary position for understanding how variation in MHC structure evolved in vertebrates, but information on the structure of the MHC region in reptiles is limited. In this study, we investigate the organization and cytogenetic location of MHC genes in the tuatara (Sphenodon punctatus), the sole extant representative of the early-diverging reptilian order Rhynchocephalia. Sequencing and mapping of 12 clones containing class I and II MHC genes from a bacterial artificial chromosome library indicated that the core MHC region is located on chromosome 13q. However, duplication and translocation of MHC genes outside of the core region was evident, because additional class I MHC genes were located on chromosome 4p. We found a total of seven class I sequences and 11 class II β sequences, with evidence for duplication and pseudogenization of genes within the tuatara lineage. The tuatara MHC is characterized by high repeat content and low gene density compared with other species and we found no antigen processing or MHC framework genes on the MHC gene-containing clones. Our findings indicate substantial differences in MHC organization in tuatara compared with mammalian and avian MHCs and highlight the dynamic nature of the MHC. Further sequencing and annotation of tuatara and other reptile MHCs will determine if the tuatara MHC is representative of nonavian reptiles in general. PMID:25953959

  7. 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

  8. Duplication and population dynamics shape historic patterns of selection and genetic variation at the major histocompatibility complex in rodents

    PubMed Central

    Winternitz, Jamie C; Wares, John P

    2013-01-01

    Genetic variation at the major histocompatibility complex (MHC) is vitally important for wildlife populations to respond to pathogen threats. As natural populations can fluctuate greatly in size, a key issue concerns how population cycles and bottlenecks that could reduce genetic diversity will influence MHC genes. Using 454 sequencing, we characterized genetic diversity at the DRB Class II locus in montane voles (Microtus montanus), a North American rodent that regularly undergoes high-amplitude fluctuations in population size. We tested for evidence of historic balancing selection, recombination, and gene duplication to identify mechanisms maintaining allelic diversity. Counter to our expectations, we found strong evidence of purifying selection acting on the DRB locus in montane voles. We speculate that the interplay between population fluctuations and gene duplication might be responsible for the weak evidence of historic balancing selection and strong evidence of purifying selection detected. To further explore this idea, we conducted a phylogenetically controlled comparative analysis across 16 rodent species with varying demographic histories and MHC duplication events (based on the maximum number of alleles detected per individual). On the basis of phylogenetic generalized linear model-averaging, we found evidence that the estimated number of duplicated loci was positively related to allelic diversity and, surprisingly, to the strength of purifying selection at the DRB locus. Our analyses also revealed that species that had undergone population bottlenecks had lower allelic richness than stable species. This study highlights the need to consider demographic history and genetic structure alongside patterns of natural selection to understand resulting patterns of genetic variation at the MHC. PMID:23789067

  9. 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

  10. 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

  11. Duplication and population dynamics shape historic patterns of selection and genetic variation at the major histocompatibility complex in rodents.

    PubMed

    Winternitz, Jamie C; Wares, John P

    2013-06-01

    Genetic variation at the major histocompatibility complex (MHC) is vitally important for wildlife populations to respond to pathogen threats. As natural populations can fluctuate greatly in size, a key issue concerns how population cycles and bottlenecks that could reduce genetic diversity will influence MHC genes. Using 454 sequencing, we characterized genetic diversity at the DRB Class II locus in montane voles (Microtus montanus), a North American rodent that regularly undergoes high-amplitude fluctuations in population size. We tested for evidence of historic balancing selection, recombination, and gene duplication to identify mechanisms maintaining allelic diversity. Counter to our expectations, we found strong evidence of purifying selection acting on the DRB locus in montane voles. We speculate that the interplay between population fluctuations and gene duplication might be responsible for the weak evidence of historic balancing selection and strong evidence of purifying selection detected. To further explore this idea, we conducted a phylogenetically controlled comparative analysis across 16 rodent species with varying demographic histories and MHC duplication events (based on the maximum number of alleles detected per individual). On the basis of phylogenetic generalized linear model-averaging, we found evidence that the estimated number of duplicated loci was positively related to allelic diversity and, surprisingly, to the strength of purifying selection at the DRB locus. Our analyses also revealed that species that had undergone population bottlenecks had lower allelic richness than stable species. This study highlights the need to consider demographic history and genetic structure alongside patterns of natural selection to understand resulting patterns of genetic variation at the MHC. PMID:23789067

  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. 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

  14. Expression of major histocompatibility complex antigens on mouse brain microvascular endothelial cells in relation to susceptibility to cerebral malaria.

    PubMed Central

    Monso-Hinard, C; Lou, J N; Behr, C; Juillard, P; Grau, G E

    1997-01-01

    The physiopathology of experimental cerebral malaria (CM), an acute neurological complication of Plasmodium berghei ANKA (PbA) infection, involves interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha), two cytokines that are known to modulate major histocompatibility complex (MHC) molecule expression. The aim of this study was to evaluate whether the genetic susceptibility to CM is related to the constitutive or IFN-gamma-induced expression of MHC molecules on brain microvessels. To this end, brain microvascular endothelial cells (B-MVEC) were isolated from CM-susceptible (CM-S, CBA/J) and resistant (CM-R, BALB/c) mice. By flow cytometry, we found that less than 5% of CM-S B-MVEC constitutively expressed MHC class I molecules, in contrast to up to 90% of CM-R B-MVEC. Upon stimulation with IFN-gamma, the percentage of positive cells for MHC class I molecules in CM-S B-MVEC became comparable to CM-R B-MVEC, but a higher fluorescence intensity existed on CM-S B-MVEC compared with CM-R B-MVEC. MHC class II molecules were not constitutively expressed on B-MVEC from either strain. IFN-gamma-induced expression of MHC class II (I-A, I-E) molecules was significantly higher in CM-S than CM-R B-MVEC both in percentage of positive cells and fluorescence intensity. These data demonstrate that absent or low MHC class I and higher inducibility of MHC class II expression on B-MVEC are associated with the genetic susceptibility to CM. Images Figure 4 Figure 5 PMID:9370924

  15. 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

  16. 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

  17. 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

  18. 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.

  19. Association of smoking behavior with an odorant receptor allele telomeric to the human major histocompatibility complex.

    PubMed

    Santos, Pablo Sandro Carvalho; Füst, George; Prohászka, Zoltán; Volz, Armin; Horton, Roger; Miretti, Marcos; Yu, Chack-Yung; Beck, Stephan; Uchanska-Ziegler, Barbara; Ziegler, Andreas

    2008-12-01

    Smoking behavior has been associated in two independent European cohorts with the most common Caucasian human leukocyte antigen (HLA) haplotype (A1-B8-DR3). We aimed to test whether polymorphic members of the two odorant receptor (OR) clusters within the extended HLA complex might be responsible for the observed association, by genotyping a cohort of Hungarian women in which the mentioned association had been found. One hundred and eighty HLA haplotypes from Centre d'Etude du Polymorphisme Humain families were analyzed in silico to identify single-nucleotide polymorphisms (SNPs) within OR genes that are in linkage disequilibrium with the A1-B8-DR3 haplotype, as well as with two other haplotypes indirectly linked to smoking behavior. A nonsynonymous SNP within the OR12D3 gene (rs3749971(T)) was found to be linked to the A1-B8-DR3 haplotype. This polymorphism leads to a (97)Thr --> Ile exchange that affects a putative ligand binding region of the OR12D3 protein. Smoking was found to be associated in the Hungarian cohort with the rs3749971(T) allele (p = 1.05 x 10(-2)), with higher significance than with A1-B8-DR3 (p = 2.38 x 10(-2)). Our results link smoking to a distinct OR allele, and demonstrate that the rs3749971(T) polymorphism is associated with the HLA haplotype-dependent differential recognition of cigarette smoke components, at least among Caucasian women. PMID:18939942

  20. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

    PubMed

    Goldstein, Jacqueline I; Jarskog, L Fredrik; Hilliard, Chris; Alfirevic, Ana; Duncan, Laramie; Fourches, Denis; Huang, Hailiang; Lek, Monkol; Neale, Benjamin M; Ripke, Stephan; Shianna, Kevin; Szatkiewicz, Jin P; Tropsha, Alexander; van den Oord, Edwin J C G; Cascorbi, Ingolf; Dettling, Michael; Gazit, Ephraim; Goff, Donald C; Holden, Arthur L; Kelly, Deanna L; Malhotra, Anil K; Nielsen, Jimmi; Pirmohamed, Munir; Rujescu, Dan; Werge, Thomas; Levy, Deborah L; Josiassen, Richard C; Kennedy, James L; Lieberman, Jeffrey A; Daly, Mark J; Sullivan, Patrick F

    2014-01-01

    Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7 × 10(-14), odds ratio (OR)=0.19, 95% confidence interval (CI)=0.12-0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4 × 10(-10), OR=3.3, 95% CI=2.3-4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG. PMID:25187353

  1. Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles

    PubMed Central

    Goldstein, Jacqueline I; Jarskog, L Fredrik; Hilliard, Chris; Alfirevic, Ana; Duncan, Laramie; Fourches, Denis; Huang, Hailiang; Lek, Monkol; Neale, Benjamin M; Ripke, Stephan; Shianna, Kevin; Szatkiewicz, Jin P; Tropsha, Alexander; van den Oord, Edwin JCG; Cascorbi, Ingolf; Dettling, Michael; Gazit, Ephraim; Goff, Donald C; Holden, Arthur L; Kelly, Deanna L; Malhotra, Anil K; Nielsen, Jimmi; Pirmohamed, Munir; Rujescu, Dan; Werge, Thomas; Levy, Deborah L; Josiassen, Richard C; Kennedy, James L; Lieberman, Jeffrey A; Daly, Mark J; Sullivan, Patrick F

    2014-01-01

    Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7×10−14, odds ratio, OR=0.19, 95% CI 0.12–0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4×10−10, OR=3.3, 95% CI 2.3–4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG. PMID:25187353

  2. 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

  3. Haplotype-specific pattern of association of human major histocompatibility complex with non-Hodgkin's lymphoma outcome.

    PubMed

    Nowak, J; Kalinka-Warzocha, E; Juszczyński, P; Mika-Witkowska, R; Zajko, M; Graczyk-Pol, E; Coiffier, B; Salles, G; Warzocha, K

    2008-01-01

    In the previous studies, some human major histocompatibility complex (MHC) genes such as TNF, LTA and human leukocyte antigen (HLA)-DR2 genes and A1-B8-TNF(-308A) haplotype were implied in non-Hodgkin's lymphoma (NHL) outcome. In the current study, we have assigned most probable six-locus haplotypes determined by HLA-A, -Cw, -B and -DRB1 highly polymorphic genes and non-HLA LTA(+252) and TNF(-308) single nucleotide polymorphisms (SNPs) in 152 NHL Caucasian French patients. We have broadly mapped the MHC region by its component blocks and tagging alleles. Ten frequent (with haplotype frequency >1%) six-locus extended haplotypes (EHs) were revealed in NHL patients. The only two adjacent locus fragment of 8.1 EH associated with shortened freedom from progression (FFP) was B*08-LTA(+252G) (P= 0.0084, RR = 2.45). Interestingly, 305-kbp-long, four-locus fragment of 8.1 EH, Cw*07-B*08-LTA(+252G)-TNF(-308A) block was much strongly associated with shortened FFP (P= 0.00045, RR = 3.26). The analysis of further extended haploblocks comprising five or six loci showed weaker association with outcome measures, suggesting linkage disequilibrium to be the cause of DRB1*03 and A*01 allele associations. In contrast, all fragments of 7.1 EH influenced FFP favorably with top association of TNF(-308G) allele. In multivariate analysis, only Cw*07-B*08-LTA(+252G)-TNF(-308A) and TNF(-308G)-DRB1*01 haplotypes remained predictive for shortened FFP (P= 0.024 and 0.027, respectively) and independent of International Prognostic Index (P= 0.00044). This study reveals that the block composition of EHs may cause important functional differences for NHL outcomes. Further study will be required in NHL patients by fine mapping with dense microsatellite or SNP tags to define susceptibility genes in associating regions. PMID:17971052

  4. 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

  5. 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

  6. 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.

  7. 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

  8. Antitumor Activity of a Monoclonal Antibody Targeting Major Histocompatibility Complex Class I–Her2 Peptide Complexes

    PubMed Central

    2013-01-01

    Background Applications of trastuzumab are limited to breast cancer patients with high Her2-expressing tumors. We developed a T-cell receptor mimic (TCRm) monoclonal antibody (hereafter called RL1B) that targets the Her2-E75 peptide (residues 369–377)–HLA-A2 complex and examined its effects in Her2-expressing cancer cells. Methods RL1B binding affinity was determined by surface plasmon resonance and specificity was demonstrated using Her2 antigen-positive and negative tumor cell lines. Immunohistochemistry was used to assess binding to frozen sections of human carcinomas (n = 3). Antitumor activity mediated by RL1B and trastuzumab against Her2+ tumor cell lines was evaluated using the WST-1 cell viability assay and caspase-3 and poly(ADP-ribose) polymerase cleavage assays. A xenograft mouse model (n = 6 per group) was used to assess RL1B antitumor activity. Mechanisms of RL1B-mediated cytotoxicity were evaluated with confocal microscopy, flow cytometry, and histology. All statistical tests were two-sided. Results RL1B bound with high specificity and affinity to the E75 peptide–HLA-A2 complex in all Her2+ and HLA-A2+ cancer cell lines and human carcinomas. Compared with control antibody, RL1B suppressed growth of low Her2–expressing breast tumors in mice (mean volume, RL1B vs control = 241mm3 vs 1531mm3; P = .0109) and statistically significantly increased mouse survival (P = .0098). It reduced viability compared to control monoclonal antibody–treated cells and statistically significantly increased caspase 3 activation of all Her2+ carcinoma cell lines tested, whereas trastuzumab induced apoptosis only in high Her2–expressing cancer cells. Mechanisms of RL1B cytotoxicity were associated with antibody internalization and intracellular signaling. Conclusion The TCRm RL1B could be a new approach to immunotherapy of Her2-expressing malignancies. PMID:23300219

  9. Functional effects of a natural polymorphism in the transcriptional regulatory sequence of HLA-DQB1.

    PubMed Central

    Beaty, J S; West, K A; Nepom, G T

    1995-01-01

    DNA sequence polymorphism in the genes encoding HLA class II proteins accounts for allelic diversity in antigen recognition and presentation and, thus, in the role of these cell surface glycoproteins as determinants of the scope of the T-cell repertoire. In addition, sequence polymorphism in the promoter-proximal transcriptional regulatory regions of these genes has been described, particularly for the HLA-DQB1 locus, where these differences may contribute to variation in locus- and allele-specific expression. In this study, we measured the effect of such regulatory sequence polymorphism on the expression of endogenous alleles of DQB1 in heterozygous cells. Quantitative reverse transcriptase-mediated PCR analysis showed that expression of the DQB1*0301 allele responded more rapidly to gamma interferon induction than that of DQB1*0302. We have analyzed functional effects of a prominent allelic polymorphism that consists of a TG dinucleotide present between the W and X1 consensus elements in the DQB1*0302 allele but missing in the DQB1*0301 allele. The dominant effect of this polymorphism was to introduce a variation in the spacing between the W and X1 elements of these two alleles. A secondary compensatory effect was specific for the TG dinucleotide itself, which was essential for the binding of a nuclear protein complex to the *0302 regulatory region immediately 5' of the X1 element. Derivatives of the DQB1 5' regulatory region were used to drive expression of the chloramphenicol acetyltransferase gene in transient transfections of human B-lymphoblastoid and gamma interferon-treated melanoma cell lines, demonstrating that the additional spacing between the W and X1 elements caused by the presence of the TG dinucleotide in the *0302 allele resulted in reduced expression compared with that driven by the *0301 fragment; this difference overshadowed an up-regulating effect on expression which corresponded to the binding of the TG-dependent nuclear protein complex. The

  10. 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

  11. 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

  12. Dominant sequences of human major histocompatibility complex conserved extended haplotypes from HLA-DQA2 to DAXX.

    PubMed

    Larsen, Charles E; Alford, Dennis R; Trautwein, Michael R; Jalloh, Yanoh K; Tarnacki, Jennifer L; Kunnenkeri, Sushruta K; Fici, Dolores A; Yunis, Edmond J; Awdeh, Zuheir L; Alper, Chester A

    2014-10-01

    We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight "common" European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population's haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots. PMID:25299700

  13. Dominant Sequences of Human Major Histocompatibility Complex Conserved Extended Haplotypes from HLA-DQA2 to DAXX

    PubMed Central

    Larsen, Charles E.; Alford, Dennis R.; Trautwein, Michael R.; Jalloh, Yanoh K.; Tarnacki, Jennifer L.; Kunnenkeri, Sushruta K.; Fici, Dolores A.; Yunis, Edmond J.; Awdeh, Zuheir L.; Alper, Chester A.

    2014-01-01

    We resequenced and phased 27 kb of DNA within 580 kb of the MHC class II region in 158 population chromosomes, most of which were conserved extended haplotypes (CEHs) of European descent or contained their centromeric fragments. We determined the single nucleotide polymorphism and deletion-insertion polymorphism alleles of the dominant sequences from HLA-DQA2 to DAXX for these CEHs. Nine of 13 CEHs remained sufficiently intact to possess a dominant sequence extending at least to DAXX, 230 kb centromeric to HLA-DPB1. We identified the regions centromeric to HLA-DQB1 within which single instances of eight “common” European MHC haplotypes previously sequenced by the MHC Haplotype Project (MHP) were representative of those dominant CEH sequences. Only two MHP haplotypes had a dominant CEH sequence throughout the centromeric and extended class II region and one MHP haplotype did not represent a known European CEH anywhere in the region. We identified the centromeric recombination transition points of other MHP sequences from CEH representation to non-representation. Several CEH pairs or groups shared sequence identity in small blocks but had significantly different (although still conserved for each separate CEH) sequences in surrounding regions. These patterns partly explain strong calculated linkage disequilibrium over only short (tens to hundreds of kilobases) distances in the context of a finite number of observed megabase-length CEHs comprising half a population's haplotypes. Our results provide a clearer picture of European CEH class II allelic structure and population haplotype architecture, improved regional CEH markers, and raise questions concerning regional recombination hotspots. PMID:25299700

  14. 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

  15. 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

  16. 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

  17. 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

  18. 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

  19. 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

  20. 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

  1. 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

  2. Specific DNA binding to a major histocompatibility complex enhancer sequence by a synthetic 57-residue double zinc finger peptide from a human enhancer binding protein.

    PubMed

    Sakaguchi, K; Appella, E; Omichinski, J G; Clore, G M; Gronenborn, A M

    1991-04-15

    Two 57-residue peptides containing one pair of "zinc fingers" from a human enhancer binding protein were prepared by solid-phase peptide synthesis. One peptide (MBP-DF) contained the native sequence, while the second peptide ([Abu11]MBP-DF) has an alpha-aminobutyric acid residue substituted for a nonconserved cysteine residue at position 11. The peptides were characterized by several chemical and physical methods, and their DNA binding properties were evaluated using gel retardation experiments. Spectroscopic studies demonstrated that addition of metal ions such as zinc and cobalt resulted in specific conformational changes in both peptides, indicating that cysteine-11 does not appear to be involved in metal chelation. One-dimensional 1H NMR studies indicate that a stable folded structure is formed upon addition of zinc, and the chemical shift pattern is consistent with that previously observed for one constituent single finger (Omichinski, J., Clore, G. M., Appella, E., Sakaguchi, K., and Gronenborn, A. M. (1990) Biochemistry 29, 9324-9334). Gel retardation experiments demonstrate that the peptides are capable of interacting with a 15-mer oligonucleotide comprising a portion of the major histocompatibility complex enhancer sequence and that the interaction is zinc-dependent. The dissociation constant for the [Abu11]MBP-DF peptide is 1.4 x 10(-7) M with maximal binding occurring at a zinc-to-peptide ratio of 2 to 1. The binding specificity observed with respect to related enhancer sequences exhibits the same relative order as noted previously for the whole protein. Studies with point mutants of the major histocompatibility complex enhancer binding sequence indicate that the last GC base pair in a four-guanine stretch plays a pivotal role in the interaction between the peptide and DNA. PMID:2016331

  3. 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

  4. 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…

  5. HLA DRB1*DQB1* haplotype in HTLV-I-associated familial infective dermatitis may predict development of HTLV-I-associated myelopathy/tropical spastic paraparesis

    SciTech Connect

    LaGrenade, L.; Miller, W.; Pate, E.; Rodgers-Johnson, P.

    1996-01-02

    A possible causal association between infective dermatitis and HTLV-I infection was reported in 1990 and confirmed in 1992. We now report familial infective dermatitis (ID) occurring in a 26-year-old mother and her 9-year-old son. The mother was first diagnosed with ID in 1969 at the age of 2 years in Dermatology Unit at the University Hospital of the West Indies (U.H.W.I.) in Jamacia. The elder of her 2 sons was diagnosed with ID at the age of 3 years, also at U.H.W.I. Both mother and son are HTLV-I-seropositive. A second, younger son, currently age 2 years, is also HTLV-I-seropositive, but without clinical evidence of ID. Major histocompatibility complex (MHC), class II, human leucocyte antigen (HLA) genotyping documented a shared class II haplotype, DRB1*DQB1* (1101-0301), in the mother and her 2 sons. This same haplotype has been described among Japanese patients with HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP), and has been associated with a possible pathologically heightened immune response to HTLV-I infection. The presence of this haplotype in these familial ID cases with clinical signs of HAM/TSP may have contributed to their risk for development of HAM/TSP. The unaffected, HTLV-I-seropositive, younger son requires close clinical follow-up. 20 refs., 1 fig., 1 tab.

  6. 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.

  7. 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

  8. Identification of Major Histocompatibility Complex-Regulated Body Odorants by Statistical Analysis of a Comparative Gas Chromatography/Mass Spectrometry Experiment

    SciTech Connect

    Willse, Alan R.; Belcher, Ann; Preti, George; Wahl, Jon H.; Thresher, Miranda; Yang, Peter; Yamazaki, Kunio; Beauchamp, Gary

    2005-04-15

    Gas chromatography (GC), combined with mass spectrometry (MS) detection, is a powerful analytical technique that can be used to separate, quantify, and identify volatile compounds in complex mixtures. This paper examines the application of GC-MS in a comparative experiment to identify volatiles that differ in concentration between two groups. A complex mixture might comprise several hundred or even thousands of volatile compounds. Because their number and location in a chromatogram generally are unknown, and because components overlap in populous chromatograms, the statistical problems offer significant challenges beyond traditional two-group screening procedures. We describe a statistical procedure to compare two-dimensional GC-MS profiles between groups, which entails (1) signal processing: baseline correction and peak detection in single ion chromatograms; (2) aligning chromatograms in time; (3) normalizing differences in overall signal intensities; and (4) detecting chromatographic regions that differ between groups. Compared to existing approaches, the proposed method is robust to errors made at earlier stages of analysis, such as missed peaks or slightly misaligned chromatograms. To illustrate the method, we identify differences in GC-MS chromatograms of ether-extracted urine collected from two nearly identical inbred groups of mice, to investigate the relationship between odor and genetics of the major histocompatibility complex.

  9. 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

  10. Loss of T Cell Antigen Recognition Arising from Changes in Peptide and Major Histocompatibility Complex Protein Flexibility: Implications for Vaccine Design

    SciTech Connect

    Insaidoo, Francis K.; Borbulevych, Oleg Y.; Hossain, Moushumi; Santhanagopolan, Sujatha M.; Baxter, Tiffany K.; Baker, Brian M.

    2012-05-08

    Modification of the primary anchor positions of antigenic peptides to improve binding to major histocompatibility complex (MHC) proteins is a commonly used strategy for engineering peptide-based vaccine candidates. However, such peptide modifications do not always improve antigenicity, complicating efforts to design effective vaccines for cancer and infectious disease. Here we investigated the MART-1{sub 27-35} tumor antigen, for which anchor modification (replacement of the position two alanine with leucine) dramatically reduces or ablates antigenicity with a wide range of T cell clones despite significantly improving peptide binding to MHC. We found that anchor modification in the MART-1{sub 27-35} antigen enhances the flexibility of both the peptide and the HLA-A*0201 molecule. Although the resulting entropic effects contribute to the improved binding of the peptide to MHC, they also negatively impact T cell receptor binding to the peptide {center_dot} MHC complex. These results help explain how the 'anchor-fixing' strategy fails to improve antigenicity in this case, and more generally, may be relevant for understanding the high specificity characteristic of the T cell repertoire. In addition to impacting vaccine design, modulation of peptide and MHC flexibility through changes to antigenic peptides may present an evolutionary strategy for the escape of pathogens from immune destruction.