Differences in meiotic recombination rates in childhood acute lymphoblastic leukemia at an MHC class II hotspot close to disease associated haplotypes.

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Pamela Thompson

Full Text Available Childhood Acute Lymphoblastic Leukemia (ALL is a malignant lymphoid disease of which B-cell precursor- (BCP and T-cell- (T ALL are subtypes. The role of alleles encoded by major histocompatibility loci (MHC have been examined in a number of previous studies and results indicating weak, multi-allele associations between the HLA-DPB1 locus and BCP-ALL suggested a role for immunosusceptibility and possibly infection. Two independent SNP association studies of ALL identified loci approximately 37 kb from one another and flanking a strong meiotic recombination hotspot (DNA3, adjacent to HLA-DOA and centromeric of HLA-DPB1. To determine the relationship between this observation and HLA-DPB1 associations, we constructed high density SNP haplotypes of the 316 kb region from HLA-DMB to COL11A2 in childhood ALL and controls using a UK GWAS data subset and the software PHASE. Of four haplotype blocks identified, predicted haplotypes in Block 1 (centromeric of DNA3 differed significantly between BCP-ALL and controls (P = 0.002 and in Block 4 (including HLA-DPB1 between T-ALL and controls (P = 0.049. Of specific common (>5% haplotypes in Block 1, two were less frequent in BCP-ALL, and in Block 4 a single haplotype was more frequent in T-ALL, compared to controls. Unexpectedly, we also observed apparent differences in ancestral meiotic recombination rates at DNA3, with BCP-ALL showing increased and T-ALL decreased levels compared to controls. In silico analysis using LDsplit sotware indicated that recombination rates at DNA3 are influenced by flanking loci, including SNPs identified in childhood ALL association studies. The observed differences in rates of meiotic recombination at this hotspot, and potentially others, may be a characteristic of childhood leukemia and contribute to disease susceptibility, alternatively they may reflect interactions between ALL-associated haplotypes in this region.

Characterization of 47 MHC class I sequences in Filipino cynomolgus macaques

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Campbell, Kevin J.; Detmer, Ann M.; Karl, Julie A.; Wiseman, Roger W.; Blasky, Alex J.; Hughes, Austin L.; Bimber, Benjamin N.; O’Connor, Shelby L.; O’Connor, David H.

2009-01-01

Cynomolgus macaques (Macaca fascicularis) provide increasingly common models for infectious disease research. Several geographically distinct populations of these macaques from Southeast Asia and the Indian Ocean island of Mauritius are available for pathogenesis studies. Though host genetics may profoundly impact results of such studies, similarities and differences between populations are often overlooked. In this study we identified 47 full-length MHC class I nucleotide sequences in 16 cynomolgus macaques of Filipino origin. The majority of MHC class I sequences characterized (39 of 47) were unique to this regional population. However, we discovered eight sequences with perfect identity and six sequences with close similarity to previously defined MHC class I sequences from other macaque populations. We identified two ancestral MHC haplotypes that appear to be shared between Filipino and Mauritian cynomolgus macaques, notably a Mafa-B haplotype that has previously been shown to protect Mauritian cynomolgus macaques against challenge with a simian/human immunodeficiency virus, SHIV89.6P. We also identified a Filipino cynomolgus macaque MHC class I sequence for which the predicted protein sequence differs from Mamu-B*17 by a single amino acid. This is important because Mamu-B*17 is strongly associated with protection against simian immunodeficiency virus (SIV) challenge in Indian rhesus macaques. These findings have implications for the evolutionary history of Filipino cynomolgus macaques as well as for the use of this model in SIV/SHIV research protocols. PMID:19107381

The role of MHC haplotypes H2d/H2b in mouse resistance/susceptibility to cyst formation is influenced by the lineage of infective Toxoplasma gondii strain

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Marianne G. Resende

2008-03-01

Full Text Available Toxoplasma gondii strains displaying the Type I/III genotype are associated with acquired ocular toxoplasmosis in humans. Here, we used a mice model to characterize some immunological mechanisms involved in host resistance to infection with such strains. We have chosen the Type I/III strains D8, G2 and P-Br, which cause a chronic infection in mice that resembles human toxoplamosis. Mice deficient of molecules MyD88, IFN-gamma, and IL-12 were susceptible to all three parasite strains. This finding indicates the importance of innate mechanisms in controlling infection. On the other hand, MHC haplotype did not influenced resistance/susceptibility; since mice lineages displaying a same genetic background but different MHC haplotypes (H2b or H2d developed similar mortality and cyst numbers after infection with those strains. In contrast, the C57BL/6 genetic background, and not MHC haplotype, was critical for development of intestinal inflammation caused by any of the studied strains. Finally, regarding effector mechanisms, weobserved that B and CD8+ T lymphocytes controlled survival,whereas the inducible nitric oxide synthase influenced cyst numbers in brains of mice infected with Type I/III strains. These findings are relevant to further understanding of the immunologic mechanisms involved in host protection and pathogenesis during infection with T. gondii.Cepas de Toxoplasma gondii que apresentam o genótipo I/III são associadas a toxoplasmose ocular adquirida em humanos. No presente trabalho, nós utilizamos um modelo da doença em camundongos para caracterizar mecanismos imunológicos envolvidos na resistência do hospedeiro à infecção por aquelas cepas. Escolhemos as cepas D8, G2 e P-Br, que causam infecção crônica em camundongos, semelhante à toxoplasmose humana. Camundongos deficientes em MyD88, IFN-G e IL-12 foram susceptíveis a infecções com todas as três linhagens do parasita. Esses dados indicam a importância de mecanismos

High levels of diversity characterize mandrill (Mandrillus sphinx) Mhc-DRB sequences.

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Abbott, Kristin M; Wickings, E Jean; Knapp, Leslie A

2006-08-01

The major histocompatibility complex (MHC) is highly polymorphic in most primate species studied thus far. The rhesus macaque (Macaca mulatta) has been studied extensively and the Mhc-DRB region demonstrates variability similar to humans. The extent of MHC diversity is relatively unknown for other Old World monkeys (OWM), especially among genera other than Macaca. A molecular survey of the Mhc-DRB region in mandrills (Mandrillus sphinx) revealed extensive variability, suggesting that other OWMs may also possess high levels of Mhc-DRB polymorphism. In the present study, 33 Mhc-DRB loci were identified from only 13 animals. Eleven were wild-born and presumed to be unrelated and two were captive-born twins. Two to seven different sequences were identified for each individual, suggesting that some mandrills may have as many as four Mhc-DRB loci on a single haplotype. From these sequences, representatives of at least six Mhc-DRB loci or lineages were identified. As observed in other primates, some new lineages may have arisen through the process of gene conversion. These findings indicate that mandrills have Mhc-DRB diversity not unlike rhesus macaques and humans.

Peptide motifs of the single dominantly expressed class I molecule explain the striking MHC-determined response to Rous sarcoma virus in chickens

DEFF Research Database (Denmark)

Wallny, Hans-Joachim; Avila, David; Hunt, Lawrence G.

2006-01-01

Compared with the MHC of typical mammals, the chicken MHC is smaller and simpler, with only two class I genes found in the B12 haplotype. We make five points to show that there is a single-dominantly expressed class I molecule that can have a strong effect on MHC function. First, we find only one...

Horse cDNA clones encoding two MHC class I genes

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Barbis, D.P.; Maher, J.K.; Stanek, J.; Klaunberg, B.A.; Antczak, D.F.

1994-12-31

Two full-length clones encoding MHC class I genes were isolated by screening a horse cDNA library, using a probe encoding in human HLA-A2.2Y allele. The library was made in the pcDNA1 vector (Invitrogen, San Diego, CA), using mRNA from peripheral blood lymphocytes obtained from a Thoroughbred stallion (No. 0834) homozygous for a common horse MHC haplotype (ELA-A2, -B2, -D2; Antczak et al. 1984; Donaldson et al. 1988). The clones were sequenced, using SP6 and T7 universal primers and horse-specific oligonucleotides designed to extend previously determined sequences.

Identification of SIV Nef CD8(+) T cell epitopes restricted by a MHC class I haplotype associated with lower viral loads in a macaque AIDS model.

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Nomura, Takushi; Yamamoto, Hiroyuki; Takahashi, Naofumi; Naruse, Taeko K; Kimura, Akinori; Matano, Tetsuro

2014-07-25

Virus-specific CD8(+) T-cell responses are crucial for the control of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) replication. Multiple studies on HIV-infected individuals and SIV-infected macaques have indicated association of several major histocompatibility complex class I (MHC-I) genotypes with lower viral loads and delayed AIDS progression. Understanding of the viral control mechanism associated with these MHC-I genotypes would contribute to the development of intervention strategy for HIV control. We have previously reported a rhesus MHC-I haplotype, 90-120-Ia, associated with lower viral loads after SIVmac239 infection. Gag206-216 and Gag241-249 epitope-specific CD8(+) T-cell responses have been shown to play a central role in the reduction of viral loads, whereas the effect of Nef-specific CD8(+) T-cell responses induced in all the 90-120-Ia(+) macaques on SIV replication remains unknown. Here, we identified three CD8(+) T-cell epitopes, Nef9-19, Nef89-97, and Nef193-203, associated with 90-120-Ia. Nef9-19 and Nef193-203 epitope-specific CD8(+) T-cell responses frequently selected for mutations resulting in viral escape from recognition by these CD8(+) T cells, indicating that these CD8(+) T cells exert strong suppressive pressure on SIV replication. Results would be useful for elucidation of the viral control mechanism associated with 90-120-Ia. Copyright © 2014 Elsevier Inc. All rights reserved.

Mapping the genetic diversity of HLA haplotypes in the Japanese populations

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Saw, Woei-Yuh; Liu, Xuanyao; Khor, Chiea-Chuen; Takeuchi, Fumihiko; Katsuya, Tomohiro; Kimura, Ryosuke; Nabika, Toru; Ohkubo, Takayoshi; Tabara, Yasuharu; Yamamoto, Ken; Yokota, Mitsuhiro; Akiyama, Koichi; Asano, Hiroyuki; Asayama, Kei; Haga, Toshikazu; Hara, Azusa; Hirose, Takuo; Hosaka, Miki; Ichihara, Sahoko; Imai, Yutaka; Inoue, Ryusuke; Ishiguro, Aya; Isomura, Minoru; Isono, Masato; Kamide, Kei; Kato, Norihiro; Katsuya, Tomohiro; Kikuya, Masahiro; Kohara, Katsuhiko; Matsubara, Tatsuaki; Matsuda, Ayako; Metoki, Hirohito; Miki, Tetsuro; Murakami, Keiko; Nabika, Toru; Nakatochi, Masahiro; Ogihara, Toshio; Ohnaka, Keizo; Ohkubo, Takayoshi; Rakugi, Hiromi; Satoh, Michihiro; Shiwaku, Kunihiro; Sugimoto, Ken; Tabara, Yasuharu; Takami, Yoichi; Takayanagi, Ryoichi; Takeuchi, Fumihiko; Tsubota-Utsugi, Megumi; Yamamoto, Ken; Yamamoto, Koichi; Yamasaki, Masayuki; Yasui, Daisaku; Yokota, Mitsuhiro; Teo, Yik-Ying; Kato, Norihiro

2015-01-01

Japan has often been viewed as an Asian country that possesses a genetically homogenous community. The basis for partitioning the country into prefectures has largely been geographical, although cultural and linguistic differences still exist between some of the districts/prefectures, especially between Okinawa and the mainland prefectures. The Major Histocompatibility Complex (MHC) region has consistently emerged as the most polymorphic region in the human genome, harbouring numerous biologically important variants; nevertheless the presence of population-specific long haplotypes hinders the imputation of SNPs and classical HLA alleles. Here, we examined the extent of genetic variation at the MHC between eight Japanese populations sampled from Okinawa, and six other prefectures located in or close to the mainland of Japan, specifically focusing at the haplotypes observed within each population, and what the impact of any variation has on imputation. Our results indicated that Okinawa was genetically farther to the mainland Japanese than were Gujarati Indians from Tamil Indians, while the mainland Japanese from six prefectures were more homogeneous than between northern and southern Han Chinese. The distribution of haplotypes across Japan was similar, although imputation was most accurate for Okinawa and several mainland prefectures when population-specific panels were used as reference. PMID:26648100

An integrated tool to study MHC region: accurate SNV detection and HLA genes typing in human MHC region using targeted high-throughput sequencing.

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Hongzhi Cao

Full Text Available The major histocompatibility complex (MHC is one of the most variable and gene-dense regions of the human genome. Most studies of the MHC, and associated regions, focus on minor variants and HLA typing, many of which have been demonstrated to be associated with human disease susceptibility and metabolic pathways. However, the detection of variants in the MHC region, and diagnostic HLA typing, still lacks a coherent, standardized, cost effective and high coverage protocol of clinical quality and reliability. In this paper, we presented such a method for the accurate detection of minor variants and HLA types in the human MHC region, using high-throughput, high-coverage sequencing of target regions. A probe set was designed to template upon the 8 annotated human MHC haplotypes, and to encompass the 5 megabases (Mb of the extended MHC region. We deployed our probes upon three, genetically diverse human samples for probe set evaluation, and sequencing data show that ∼97% of the MHC region, and over 99% of the genes in MHC region, are covered with sufficient depth and good evenness. 98% of genotypes called by this capture sequencing prove consistent with established HapMap genotypes. We have concurrently developed a one-step pipeline for calling any HLA type referenced in the IMGT/HLA database from this target capture sequencing data, which shows over 96% typing accuracy when deployed at 4 digital resolution. This cost-effective and highly accurate approach for variant detection and HLA typing in the MHC region may lend further insight into immune-mediated diseases studies, and may find clinical utility in transplantation medicine research. This one-step pipeline is released for general evaluation and use by the scientific community.

T lymphocytes from irradiation chimeras repopulated with 13-day fetal liver cells recognize antigens only in association with self-MHC products

International Nuclear Information System (INIS)

Nisbet-Brown, E.; Diener, E.

1986-01-01

The restriction specificities of maturing thymocytes are determined by the Class II MHC antigens expressed by non-lymphoid thymic tissues. The proliferative response of mature T lymphocytes to antigen-presenting cells (APC) and antigen requires that the APC express the same MHC antigens as the thymus in which the T cells differentiated. Thus, in the two-way bone marrow chimera [A + B----(A x B)F1], T lymphocyte populations of A and B haplotypes have each acquired the potential to recognize antigens associated with either parental haplotype. In spite of the large body of work on MHC restriction, we still do not have a clear understanding of the mechanisms which impose self restriction. The chimeric model systems used previously to study MHC restriction have used adult bone marrow cells as the source of lymphoid precursors. During normal ontogeny, T cells are derived from precursors in the fetal liver and we felt that a direct comparison of T cells from fetal liver and bone marrow-repopulated animals would shed light on the development of MHC restriction specificities during T cell ontogeny in the thymus or prethymically. We found that parental T lymphocyte populations isolated from two-way fetal liver chimeras cooperated only with syngeneic APC, while those from bone marrow chimeras cooperated with APC of either parental haplotype. This suggests that fetal liver and bone marrow may not be equivalent sources of stem cells. Our results may be due to fundamental differences between thymocyte precursors in fetal liver and bone marrow, including the time course of their expression of T cell receptor gene products

Peptide-binding motifs of two common equine class I MHC molecules in Thoroughbred horses.

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Bergmann, Tobias; Lindvall, Mikaela; Moore, Erin; Moore, Eugene; Sidney, John; Miller, Donald; Tallmadge, Rebecca L; Myers, Paisley T; Malaker, Stacy A; Shabanowitz, Jeffrey; Osterrieder, Nikolaus; Peters, Bjoern; Hunt, Donald F; Antczak, Douglas F; Sette, Alessandro

2017-05-01

Quantitative peptide-binding motifs of MHC class I alleles provide a valuable tool to efficiently identify putative T cell epitopes. Detailed information on equine MHC class I alleles is still very limited, and to date, only a single equine MHC class I allele, Eqca-1*00101 (ELA-A3 haplotype), has been characterized. The present study extends the number of characterized ELA class I specificities in two additional haplotypes found commonly in the Thoroughbred breed. Accordingly, we here report quantitative binding motifs for the ELA-A2 allele Eqca-16*00101 and the ELA-A9 allele Eqca-1*00201. Utilizing analyses of endogenously bound and eluted ligands and the screening of positional scanning combinatorial libraries, detailed and quantitative peptide-binding motifs were derived for both alleles. Eqca-16*00101 preferentially binds peptides with aliphatic/hydrophobic residues in position 2 and at the C-terminus, and Eqca-1*00201 has a preference for peptides with arginine in position 2 and hydrophobic/aliphatic residues at the C-terminus. Interestingly, the Eqca-16*00101 motif resembles that of the human HLA A02-supertype, while the Eqca-1*00201 motif resembles that of the HLA B27-supertype and two macaque class I alleles. It is expected that the identified motifs will facilitate the selection of candidate epitopes for the study of immune responses in horses.

Haplotype Analysis Discriminates Genetic Risk for DR3-Associated Endocrine Autoimmunity and Helps Define Extreme Risk for Addison’s Disease

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Baker, Peter R.; Baschal, Erin E.; Fain, Pam R.; Triolo, Taylor M.; Nanduri, Priyaanka; Siebert, Janet C.; Armstrong, Taylor K.; Babu, Sunanda R.; Rewers, Marian J.; Gottlieb, Peter A.; Barker, Jennifer M.; Eisenbarth, George S.

2010-01-01

Context: Multiple autoimmune disorders (e.g. Addison’s disease, type 1 diabetes, celiac disease) are associated with HLA-DR3, but it is likely that alleles of additional genes in linkage disequilibrium with HLA-DRB1 contribute to disease. Objective: The objective of the study was to characterize major histocompatability complex (MHC) haplotypes conferring extreme risk for autoimmune Addison’s disease (AD). Design, Setting, and Participants: Eighty-six 21-hydroxylase autoantibody-positive, nonautoimmune polyendocrine syndrome type 1, Caucasian individuals collected from 1992 to 2009 with clinical AD from 68 families (12 multiplex and 56 simplex) were genotyped for HLA-DRB1, HLA-DQB1, MICA, HLA-B, and HLA-A as well as high density MHC single-nucleotide polymorphism (SNP) analysis for 34. Main Outcome Measures: AD and genotype were measured. Result: Ninety-seven percent of the multiplex individuals had both HLA-DR3 and HLA-B8 vs. 60% of simplex AD patients (P = 9.72 × 10−4) and 13% of general population controls (P = 3.00 × 10−19). The genotype DR3/DR4 with B8 was present in 85% of AD multiplex patients, 24% of simplex patients, and 1.5% of control individuals (P = 4.92 × 10−191). The DR3-B8 haplotype of AD patients had HLA-A1 less often (47%) than controls (81%, P = 7.00 × 10−5) and type 1 diabetes patients (73%, P = 1.93 × 10−3). Analysis of 1228 SNPs across the MHC for individuals with AD revealed a shorter conserved haplotype (3.8) with the loss of the extended conserved 3.8.1 haplotype approximately halfway between HLA-B and HLA-A. Conclusion: Extreme risk for AD, especially in multiplex families, is associated with haplotypic DR3 variants, in particular a portion (3.8) but not all of the conserved 3.8.1 haplotype. PMID:20631027

A haplotype regression approach for genetic evaluation using sequences from the 1000 bull genomes Project

International Nuclear Information System (INIS)

Lakhssassi, K.; González-Recio, O.

2017-01-01

Haplotypes from sequencing data may improve the prediction accuracy in genomic evaluations as haplotypes are in stronger linkage disequilibrium with quantitative trait loci than markers from SNP chips. This study focuses first, on the creation of haplotypes in a population sample of 450 Holstein animals, with full-sequence data from the 1000 bull genomes project; and second, on incorporating them into the whole genome prediction model. In total, 38,319,258 SNPs (and indels) from Next Generation Sequencing were included in the analysis. After filtering variants with minor allele frequency (MAF< 0.025) 13,912,326 SNPs were available for the haplotypes extraction with findhap.f90. The number of SNPs in the haploblocks was on average 924 SNP (166,552 bp). Unique haplotypes were around 97% in all chromosomes and were ignored leaving 153,428 haplotypes. Estimated haplotypes had a large contribution to the total variance of genomic estimated breeding values for kilogram of protein, Global Type Index, Somatic Cell Score and Days Open (between 32 and 99.9%). Haploblocks containing haplotypes with large effects were selected by filtering for each trait, haplotypes whose effect was larger/lower than the mean plus/minus 3 times the standard deviation (SD) and 1 SD above the mean of the haplotypes effect distribution. Results showed that filtering by 3 SD would not be enough to capture a large proportion of genetic variance, whereas filtering by 1 SD could be useful but model convergence should be considered. Additionally, sequence haplotypes were able to capture additional genetic variance to the polygenic effect for traits undergoing lower selection intensity like fertility and health traits.

A haplotype regression approach for genetic evaluation using sequences from the 1000 bull genomes Project

Energy Technology Data Exchange (ETDEWEB)

Lakhssassi, K.; González-Recio, O.

2017-07-01

Haplotypes from sequencing data may improve the prediction accuracy in genomic evaluations as haplotypes are in stronger linkage disequilibrium with quantitative trait loci than markers from SNP chips. This study focuses first, on the creation of haplotypes in a population sample of 450 Holstein animals, with full-sequence data from the 1000 bull genomes project; and second, on incorporating them into the whole genome prediction model. In total, 38,319,258 SNPs (and indels) from Next Generation Sequencing were included in the analysis. After filtering variants with minor allele frequency (MAF< 0.025) 13,912,326 SNPs were available for the haplotypes extraction with findhap.f90. The number of SNPs in the haploblocks was on average 924 SNP (166,552 bp). Unique haplotypes were around 97% in all chromosomes and were ignored leaving 153,428 haplotypes. Estimated haplotypes had a large contribution to the total variance of genomic estimated breeding values for kilogram of protein, Global Type Index, Somatic Cell Score and Days Open (between 32 and 99.9%). Haploblocks containing haplotypes with large effects were selected by filtering for each trait, haplotypes whose effect was larger/lower than the mean plus/minus 3 times the standard deviation (SD) and 1 SD above the mean of the haplotypes effect distribution. Results showed that filtering by 3 SD would not be enough to capture a large proportion of genetic variance, whereas filtering by 1 SD could be useful but model convergence should be considered. Additionally, sequence haplotypes were able to capture additional genetic variance to the polygenic effect for traits undergoing lower selection intensity like fertility and health traits.

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo.

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Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A; Holcomb, Cherie; Rastrou, Melinda; Erlich, Henry; Tengesdal, Isak W; Dagna, Lorenzo; Neff, C Preston; Palmer, Brent E; Spritz, Richard A; Dinarello, Charles A

2016-02-02

Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.

The analysis of APOL1 genetic variation and haplotype diversity provided by 1000 Genomes project.

Science.gov (United States)

Peng, Ting; Wang, Li; Li, Guisen

2017-08-11

The APOL1 gene variants has been shown to be associated with an increased risk of multiple kinds of diseases, particularly in African Americans, but not in Caucasians and Asians. In this study, we explored the single nucleotide polymorphism (SNP) and haplotype diversity of APOL1 gene in different races provided by 1000 Genomes project. Variants of APOL1 gene in 1000 Genome Project were obtained and SNPs located in the regulatory region or coding region were selected for genetic variation analysis. Total 2504 individuals from 26 populations were classified as four groups that included Africa, Europe, Asia and Admixed populations. Tag SNPs were selected to evaluate the haplotype diversities in the four populations by HaploStats software. APOL1 gene was surrounded by some of the most polymorphic genes in the human genome, variation of APOL1 gene was common, with up to 613 SNP (1000 Genome Project reported) and 99 of them (16.2%) with MAF ≥ 1%. There were 79 SNPs in the URR and 92 SNPs in 3'UTR. Total 12 SNPs in URR and 24 SNPs in 3'UTR were considered as common variants with MAF ≥ 1%. It is worth noting that URR-1 was presents lower frequencies in European populations, while other three haplotypes taken an opposite pattern; 3'UTR presents several high-frequency variation sites in a short segment, and the differences of its haplotypes among different population were significant (P < 0.01), UTR-1 and UTR-5 presented much higher frequency in African population, while UTR-2, UTR-3 and UTR-4 were much lower. APOL1 coding region showed that two SNP of G1 with higher frequency are actually pull down the haplotype H-1 frequency when considering all populations pooled together, and the diversity among the four populations be widen by the G1 two mutation (P 1  = 3.33E-4 vs P 2  = 3.61E-30). The distributions of APOL1 gene variants and haplotypes were significantly different among the different populations, in either regulatory or coding regions. It could provide

Identification, inheritance, and linkage of B-G-like and MHC class I genes in cranes

Science.gov (United States)

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

1999-01-01

We identified B-G-like genes in the whooping and Florida sandhill cranes and linked them to the major histocompatibility complex (MHC). We evaluated the inheritance of B-G-like genes in families of whooping and Florida sandhill cranes using restriction fragment patterns (RFPs). Two B-G-like genes, designated wcbgl and wcbg2, were located within 8 kb of one another. The fully sequenced wcbg2 gene encodes a B-G IgV-like domain, an additional Ig-like domain, a transmembrane domain, and a single heptad domain typical of '-helical coiled coils. Patterns of restriction fragments in DNA from the whooping crane and from a number of other species indicate that the B-G-like gene families of cranes are large with diverse sequences. Segregation of RFPs in families of Florida sandhill cranes provide evidence for genetic polymorphism in the B-G-like genes. The restriction fragments generally segregated in concert with MHC haplotypes assigned by serological typing and by single stranded conformational polymorphism (SSCP) assays based in the second exon of the crane MHC class I genes. This study supports the concept of a long-term association of polymorphic B-G-like genes with the MHC. It also establishes SSCP as a means for evaluating MHC genetic variability in cranes.

Identification, inheritance, and linkage of B-G-like and MHC class I genes in cranes.

Science.gov (United States)

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

1999-01-01

We identified B-G-like genes in the whooping and Florida sandhill cranes and linked them to the major histocompatibility complex (MHC). We evaluated the inheritance of B-G-like genes in families of whooping and Florida sandhill cranes using restriction fragment patterns (RFPs). Two B-G-like genes, designated wcbg1 and wcbg2, were located within 8 kb of one another. The fully sequenced wcbg2 gene encodes a B-G IgV-like domain, an additional Ig-like domain, a transmembrane domain, and a single heptad domain typical of alpha-helical coiled coils. Patterns of restriction fragments in DNA from the whooping crane and from a number of other species indicate that the B-G-like gene families of cranes are large with diverse sequences. Segregation of RFPs in families of Florida sandhill cranes provide evidence for genetic polymorphism in the B-G-like genes. The restriction fragments generally segregated in concert with MHC haplotypes assigned by serological typing and by single stranded conformational polymorphism (SSCP) assays based in the second exon of the crane MHC class I genes. This study supports the concept of a long-term association of polymorphic B-G-like genes with the MHC. It also establishes SSCP as a means for evaluating MHC genetic variability in cranes.

Extensive shared polymorphism at non-MHC immune genes in recently diverged North American prairie grouse

Science.gov (United States)

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

2018-01-01

Gene polymorphisms shared between recently diverged species are thought to be widespread and most commonly reflect introgression from hybridization or retention of ancestral polymorphism through incomplete lineage sorting. Shared genetic diversity resulting from incomplete lineage sorting is usually maintained for a relatively short period of time, but under strong balancing selection it may persist for millions of years beyond species divergence (balanced trans-species polymorphism), as in the case of the major histocompatibility complex (MHC) genes. However, balancing selection is much less likely to act on non-MHC immune genes. The aim of this study was to investigate the patterns of shared polymorphism and selection at non-MHC immune genes in five grouse species from Centrocercus and Tympanuchus genera. For this purpose, we genotyped five non-MHC immune genes that do not interact directly with pathogens, but are involved in signaling and regulate immune cell growth. In contrast to previous studies with MHC, we found no evidence for balancing selection or balanced trans-species polymorphism among the non-MHC immune genes. No haplotypes were shared between genera and in most cases more similar allelic variants sorted by genus. Between species within genera, however, we found extensive shared polymorphism, which was most likely attributable to introgression or incomplete lineage sorting following recent divergence and large ancestral effective population size (i.e., weak genetic drift). Our study suggests that North American prairie grouse may have attained relatively low degree of reciprocal monophyly at nuclear loci and reinforces the rarity of balancing selection in non-MHC immune genes.

Alternative haplotypes of antigen processing genes in zebrafish diverged early in vertebrate evolution

Science.gov (United States)

McConnell, Sean C.; Hernandez, Kyle M.; Wcisel, Dustin J.; Kettleborough, Ross N.; Stemple, Derek L.; Andrade, Jorge; de Jong, Jill L. O.

2016-01-01

Antigen processing and presentation genes found within the MHC are among the most highly polymorphic genes of vertebrate genomes, providing populations with diverse immune responses to a wide array of pathogens. Here, we describe transcriptome, exome, and whole-genome sequencing of clonal zebrafish, uncovering the most extensive diversity within the antigen processing and presentation genes of any species yet examined. Our CG2 clonal zebrafish assembly provides genomic context within a remarkably divergent haplotype of the core MHC region on chromosome 19 for six expressed genes not found in the zebrafish reference genome: mhc1uga, proteasome-β 9b (psmb9b), psmb8f, and previously unknown genes psmb13b, tap2d, and tap2e. We identify ancient lineages for Psmb13 within a proteasome branch previously thought to be monomorphic and provide evidence of substantial lineage diversity within each of three major trifurcations of catalytic-type proteasome subunits in vertebrates: Psmb5/Psmb8/Psmb11, Psmb6/Psmb9/Psmb12, and Psmb7/Psmb10/Psmb13. Strikingly, nearby tap2 and MHC class I genes also retain ancient sequence lineages, indicating that alternative lineages may have been preserved throughout the entire MHC pathway since early diversification of the adaptive immune system ∼500 Mya. Furthermore, polymorphisms within the three MHC pathway steps (antigen cleavage, transport, and presentation) are each predicted to alter peptide specificity. Lastly, comparative analysis shows that antigen processing gene diversity is far more extensive than previously realized (with ancient coelacanth psmb8 lineages, shark psmb13, and tap2t and psmb10 outside the teleost MHC), implying distinct immune functions and conserved roles in shaping MHC pathway evolution throughout vertebrates. PMID:27493218

Polymorphisms in the F8 gene and MHC-II variants as risk factors for the development of inhibitory anti-factor VIII antibodies during the treatment of hemophilia a: a computational assessment.

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Gouri Shankar Pandey

Full Text Available The development of neutralizing anti-drug-antibodies to the Factor VIII protein-therapeutic is currently the most significant impediment to the effective management of hemophilia A. Common non-synonymous single nucleotide polymorphisms (ns-SNPs in the F8 gene occur as six haplotypes in the human population (denoted H1 to H6 of which H3 and H4 have been associated with an increased risk of developing anti-drug antibodies. There is evidence that CD4+ T-cell response is essential for the development of anti-drug antibodies and such a response requires the presentation of the peptides by the MHC-class-II (MHC-II molecules of the patient. We measured the binding and half-life of peptide-MHC-II complexes using synthetic peptides from regions of the Factor VIII protein where ns-SNPs occur and showed that these wild type peptides form stable complexes with six common MHC-II alleles, representing 46.5% of the North American population. Next, we compared the affinities computed by NetMHCIIpan, a neural network-based algorithm for MHC-II peptide binding prediction, to the experimentally measured values and concluded that these are in good agreement (area under the ROC-curve of 0.778 to 0.972 for the six MHC-II variants. Using a computational binding predictor, we were able to expand our analysis to (a include all wild type peptides spanning each polymorphic position; and (b consider more MHC-II variants, thus allowing for a better estimation of the risk for clinical manifestation of anti-drug antibodies in the entire population (or a specific sub-population. Analysis of these computational data confirmed that peptides which have the wild type sequence at positions where the polymorphisms associated with haplotypes H3, H4 and H5 occur bind MHC-II proteins significantly more than a negative control. Taken together, the experimental and computational results suggest that wild type peptides from polymorphic regions of FVIII constitute potential T-cell epitopes

A new polymorphic and multicopy MHC gene family related to nonmammalian class I

Energy Technology Data Exchange (ETDEWEB)

Leelayuwat, C.; Degli-Esposti, M.A.; Abraham, L.J. [Univ. of Western Australia, Perth (Australia); Townend, D.C. [Sir Charles Gairdner Hospital, Perth (Australia); Dawkins, R.L. [Royal Perth Hospital, Perth (Australia)]|[Univ. of Western Australia, Perth (Australia)]|[Sir Charles Gairdner Hospital, Perth (Australia)

1994-12-31

The authors have used genomic analysis to characterize a region of the central major histocompatibility complex (MHC) spanning {approximately} 300 kilobases (kb) between TNF and HLA-B. This region has been suggested to carry genetic factors relevant to the development of autoimmune diseases such as myasthenia gravis (MG) and insulin dependent diabetes mellitus (IDDM). Genomic sequence was analyzed for coding potential, using two neural network programs, GRAIL and GeneParser. A genomic probe, JAB, containing putative coding sequences (PERB11) located 60 kb centromeric of HLA-B, was used for northern analysis of human tissues. Multiple transcripts were detected. Southern analysis of genomic DNA and overlapping YAC clones, covering the region from BAT1 to HLA-F, indicated that there are at least five copies of PERB11, four of which are located within this region of the MHC. The partial cDNA sequence of PERB11 was obtained from poly-A RNA derived from skeletal muscle. The putative amino acid sequence of PERB11 shares {approximately} 30% identity to MHC class I molecules from various species, including reptiles, chickens, and frogs, as well as to other MHC class I-like molecules, such as the IgG FcR of the mouse and rat and the human Zn-{alpha}2-glycoprotein. From direct comparison of amino acid sequences, it is concluded that PERB11 is a distinct molecule more closely related to nonmammalian than known mammalian MHC class I molecules. Genomic sequence analysis of PERB11 from five MHC ancestral haplotypes (AH) indicated that the gene is polymorphic at both DNA and protein level. The results suggest that the authors have identified a novel polymorphic gene family with multiple copies within the MHC. 48 refs., 10 figs., 2 tabs.

Increased projection of MHC and tumor antigens in murine B16-BL6 melanoma induced by hydrostatic pressure and chemical crosslinking.

Science.gov (United States)

Ramakrishna, V; Eisenthal, A; Skornick, Y; Shinitzky, M

1993-05-01

The B16-BL6 melanoma, like most spontaneously arising tumors, is poorly immunogenic and expresses low levels of major histocompatibility complex (MHC) antigens. Treatment of cells of this tumor in vitro by hydrostatic pressure in the presence of adenosine 2',3'-dialdehyde (oxAdo), a membrane-impermeant crosslinker, caused elevated projection of MHC and a specific tumor antigen as demonstrated by flow-cytometric analysis. Maximum projection of both the MHC and the tumor antigens could be reached by application of 1200 atm for 15 min in the presence of 20 mM oxAdo. It is not yet clear whether this passive increase in availability of antigens on the cell surface originated from a dormant pool of antigens in the plasma membrane or from pressure-induced fusion of antigen-rich intracellular organelles (e.g. the endoplasmic reticulum). The immunogenic properties of the antigen-enriched B16-BL6 cells are described in the following paper.

LDSplitDB: a database for studies of meiotic recombination hotspots in MHC using human genomic data.

Science.gov (United States)

Guo, Jing; Chen, Hao; Yang, Peng; Lee, Yew Ti; Wu, Min; Przytycka, Teresa M; Kwoh, Chee Keong; Zheng, Jie

2018-04-20

Meiotic recombination happens during the process of meiosis when chromosomes inherited from two parents exchange genetic materials to generate chromosomes in the gamete cells. The recombination events tend to occur in narrow genomic regions called recombination hotspots. Its dysregulation could lead to serious human diseases such as birth defects. Although the regulatory mechanism of recombination events is still unclear, DNA sequence polymorphisms have been found to play crucial roles in the regulation of recombination hotspots. To facilitate the studies of the underlying mechanism, we developed a database named LDSplitDB which provides an integrative and interactive data mining and visualization platform for the genome-wide association studies of recombination hotspots. It contains the pre-computed association maps of the major histocompatibility complex (MHC) region in the 1000 Genomes Project and the HapMap Phase III datasets, and a genome-scale study of the European population from the HapMap Phase II dataset. Besides the recombination profiles, related data of genes, SNPs and different types of epigenetic modifications, which could be associated with meiotic recombination, are provided for comprehensive analysis. To meet the computational requirement of the rapidly increasing population genomics data, we prepared a lookup table of 400 haplotypes for recombination rate estimation using the well-known LDhat algorithm which includes all possible two-locus haplotype configurations. To the best of our knowledge, LDSplitDB is the first large-scale database for the association analysis of human recombination hotspots with DNA sequence polymorphisms. It provides valuable resources for the discovery of the mechanism of meiotic recombination hotspots. The information about MHC in this database could help understand the roles of recombination in human immune system. DATABASE URL: http://histone.scse.ntu.edu.sg/LDSplitDB.

MHC motif viewer

DEFF Research Database (Denmark)

Rapin, Nicolas Philippe Jean-Pierre; Hoof, Ilka; Lund, Ole

2008-01-01

. Algorithms that predict which peptides MHC molecules bind have recently been developed and cover many different alleles, but the utility of these algorithms is hampered by the lack of tools for browsing and comparing the specificity of these molecules. We have, therefore, developed a web server, MHC motif....... A special viewing feature, MHC fight, allows for display of the specificity of two different MHC molecules side by side. We show how the web server can be used to discover and display surprising similarities as well as differences between MHC molecules within and between different species. The MHC motif...

HLA diversity in the 1000 genomes dataset.

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Pierre-Antoine Gourraud

Full Text Available The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation by sequencing at a level that should allow the genome-wide detection of most variants with frequencies as low as 1%. However, in the major histocompatibility complex (MHC, only the top 10 most frequent haplotypes are in the 1% frequency range whereas thousands of haplotypes are present at lower frequencies. Given the limitation of both the coverage and the read length of the sequences generated by the 1000 Genomes Project, the highly variable positions that define HLA alleles may be difficult to identify. We used classical Sanger sequencing techniques to type the HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 genes in the available 1000 Genomes samples and combined the results with the 103,310 variants in the MHC region genotyped by the 1000 Genomes Project. Using pairwise identity-by-descent distances between individuals and principal component analysis, we established the relationship between ancestry and genetic diversity in the MHC region. As expected, both the MHC variants and the HLA phenotype can identify the major ancestry lineage, informed mainly by the most frequent HLA haplotypes. To some extent, regions of the genome with similar genetic or similar recombination rate have similar properties. An MHC-centric analysis underlines departures between the ancestral background of the MHC and the genome-wide picture. Our analysis of linkage disequilibrium (LD decay in these samples suggests that overestimation of pairwise LD occurs due to a limited sampling of the MHC diversity. This collection of HLA-specific MHC variants, available on the dbMHC portal, is a valuable resource for future analyses of the role of MHC in population and disease studies.

Expression, refolding and preliminary X-ray crystallographic analysis of equine MHC class I molecule complexed with an EIAV-Env CTL epitope

International Nuclear Information System (INIS)

Yao, Shugang; Qi, Jianxun; Liu, Jun; Chen, Rong; Pan, Xiaocheng; Li, Xiaoying; Gao, Feng; Xia, Chun

2011-01-01

The equine MHC class I molecule was crystallized in complex with β 2 -microglobulin and a CTL epitope and X-ray diffraction data were collected to 2.3 Å resolution. In order to clarify the structure and the peptide-presentation characteristics of the equine major histocompatibility complex (MHC) class I molecule, a complex of equine MHC class I molecule (ELA-A1 haplotype, 7-6 allele) with mouse β 2 -microglobulin and the cytotoxic T lymphocyte (CTL) epitope Env-RW12 (RVEDVTNTAEYW) derived from equine infectious anaemia virus (EIAV) envelope protein (residues 195–206) was refolded and crystallized. The crystal, which belonged to space group P2 1 , diffracted to 2.3 Å resolution and had unit-cell parameters a = 82.5, b = 71.4, c = 99.8 Å, β = 102.9°. The crystal structure contained two molecules in the asymmetric unit. These results should help to determine the first equine MHC class I molecule structure presenting an EIAV CTL epitope

Trans-species polymorphism and selection in the MHC class II DRA genes of domestic sheep.

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Keith T Ballingall

Full Text Available Highly polymorphic genes with central roles in lymphocyte mediated immune surveillance are grouped together in the major histocompatibility complex (MHC in higher vertebrates. Generally, across vertebrate species the class II MHC DRA gene is highly conserved with only limited allelic variation. Here however, we provide evidence of trans-species polymorphism at the DRA locus in domestic sheep (Ovis aries. We describe variation at the Ovar-DRA locus that is far in excess of anything described in other vertebrate species. The divergent DRA allele (Ovar-DRA*0201 differs from the sheep reference sequences by 20 nucleotides, 12 of which appear non-synonymous. Furthermore, DRA*0201 is paired with an equally divergent DRB1 allele (Ovar-DRB1*0901, which is consistent with an independent evolutionary history for the DR sub-region within this MHC haplotype. No recombination was observed between the divergent DRA and B genes in a range of breeds and typical levels of MHC class II DR protein expression were detected at the surface of leukocyte populations obtained from animals homozygous for the DRA*0201, DRB1*0901 haplotype. Bayesian phylogenetic analysis groups Ovar-DRA*0201 with DRA sequences derived from species within the Oryx and Alcelaphus genera rather than clustering with other ovine and caprine DRA alleles. Tests for Darwinian selection identified 10 positively selected sites on the branch leading to Ovar-DRA*0201, three of which are predicted to be associated with the binding of peptide antigen. As the Ovis, Oryx and Alcelaphus genera have not shared a common ancestor for over 30 million years, the DRA*0201 and DRB1*0901 allelic pair is likely to be of ancient origin and present in the founding population from which all contemporary domestic sheep breeds are derived. The conservation of the integrity of this unusual DR allelic pair suggests some selective advantage which is likely to be associated with the presentation of pathogen antigen to T

Genetic variation and selection of MHC class I loci differ in two congeneric frogs.

Science.gov (United States)

Kiemnec-Tyburczy, Karen M; Tracy, Karen E; Lips, Karen R; Zamudio, Kelly R

2018-04-01

Major histocompatibility complex (MHC) genes encode proteins in the acquired immune response pathway that often show distinctive selection-driven patterns in wild vertebrate populations. We examined genetic variation and signatures of selection in the MHC class I alpha 1 (A1)- and alpha 2 (A2)-domain encoding exons of two frog congeners [Agalychnis callidryas (n = 20) and A. lemur (n = 20)] from a single locality in Panama. We also investigated how historical demographic processes may have impacted MHC genetic diversity by analyzing a neutral mitochondrial marker. We found that both MHC domains were highly variable in both species, with both species likely expressing three loci. Our analyses revealed different signatures of selection between the two species, most notably that the A. callidryas A2 domain had experienced positive selection while the A2 domain of A. lemur had not. Diversifying selection acted on the same number of A1 and A2 allelic lineages, but on a higher percentage of A1 sites compared to A2 sites. Neutrality tests of mitochondrial haplotypes predominately indicated that the two species were at genetic equilibrium when the samples were collected. In addition, two historical tests of demography indicated both species have had relatively stable population sizes over the past 100,000 years; thus large population size changes are unlikely to have greatly influenced MHC diversity in either species during this time period. In conclusion, our results suggest that the impact of selection on MHC diversity varied between these two closely related species, likely due to a combination of distinct ecological conditions and past pathogenic pressures.

Comparative genomic analysis of the MHC: the evolution of class I duplication blocks, diversity and complexity from shark to man.

Science.gov (United States)

Kulski, Jerzy K; Shiina, Takashi; Anzai, Tatsuya; Kohara, Sakae; Inoko, Hidetoshi

2002-12-01

The major histocompatibility complex (MHC) genomic region is composed of a group of linked genes involved functionally with the adaptive and innate immune systems. The class I and class II genes are intrinsic features of the MHC and have been found in all the jawed vertebrates studied so far. The MHC genomic regions of the human and the chicken (B locus) have been fully sequenced and mapped, and the mouse MHC sequence is almost finished. Information on the MHC genomic structures (size, complexity, genic and intergenic composition and organization, gene order and number) of other vertebrates is largely limited or nonexistent. Therefore, we are mapping, sequencing and analyzing the MHC genomic regions of different human haplotypes and at least eight nonhuman species. Here, we review our progress with these sequences and compare the human MHC structure with that of the nonhuman primates (chimpanzee and rhesus macaque), other mammals (pigs, mice and rats) and nonmammalian vertebrates such as birds (chicken and quail), bony fish (medaka, pufferfish and zebrafish) and cartilaginous fish (nurse shark). This comparison reveals a complex MHC structure for mammals and a relatively simpler design for nonmammalian animals with a hypothetical prototypic structure for the shark. In the mammalian MHC, there are two to five different class I duplication blocks embedded within a framework of conserved nonclass I and/or nonclass II genes. With a few exceptions, the class I framework genes are absent from the MHC of birds, bony fish and sharks. Comparative genomics of the MHC reveal a highly plastic region with major structural differences between the mammalian and nonmammalian vertebrates. Additional genomic data are needed on animals of the reptilia, crocodilia and marsupial classes to find the origins of the class I framework genes and examples of structures that may be intermediate between the simple and complex MHC organizations of birds and mammals, respectively.

New chicken Rfp-Y haplotypes on the basis of MHC class II RFLP and MLC analyses

DEFF Research Database (Denmark)

Juul-Madsen, H R; Zoorob, R; Auffray, C

1997-01-01

New chicken Rfp-Y haplotypes were determined by the use of restriction fragment length polymorphism (RFLP) and mixed lymphocyte culture (MLC) in four different chicken haplotypes, B15, B19, B21, B201. The RFLP polymorphism was mapped to the Rfp-Y system by the use of a subclone (18.1) which maps...... near a polymorphic lectin gene located in the Rfp-Y system and DNA from families with known segregation of the implicated RFLP polymorphism. For the first time it is shown that major histocompatibility complex class II genes in the Rfp-Y system have functional implications. Sequence information...

Determination of haplotypes at structurally complex regions using emulsion haplotype fusion PCR.

Science.gov (United States)

Tyson, Jess; Armour, John A L

2012-12-11

Genotyping and massively-parallel sequencing projects result in a vast amount of diploid data that is only rarely resolved into its constituent haplotypes. It is nevertheless this phased information that is transmitted from one generation to the next and is most directly associated with biological function and the genetic causes of biological effects. Despite progress made in genome-wide sequencing and phasing algorithms and methods, problems assembling (and reconstructing linear haplotypes in) regions of repetitive DNA and structural variation remain. These dynamic and structurally complex regions are often poorly understood from a sequence point of view. Regions such as these that are highly similar in their sequence tend to be collapsed onto the genome assembly. This is turn means downstream determination of the true sequence haplotype in these regions poses a particular challenge. For structurally complex regions, a more focussed approach to assembling haplotypes may be required. In order to investigate reconstruction of spatial information at structurally complex regions, we have used an emulsion haplotype fusion PCR approach to reproducibly link sequences of up to 1kb in length to allow phasing of multiple variants from neighbouring loci, using allele-specific PCR and sequencing to detect the phase. By using emulsion systems linking flanking regions to amplicons within the CNV, this led to the reconstruction of a 59kb haplotype across the DEFA1A3 CNV in HapMap individuals. This study has demonstrated a novel use for emulsion haplotype fusion PCR in addressing the issue of reconstructing structural haplotypes at multiallelic copy variable regions, using the DEFA1A3 locus as an example.

Determination of haplotypes at structurally complex regions using emulsion haplotype fusion PCR

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Tyson Jess

2012-12-01

Full Text Available Abstract Background Genotyping and massively-parallel sequencing projects result in a vast amount of diploid data that is only rarely resolved into its constituent haplotypes. It is nevertheless this phased information that is transmitted from one generation to the next and is most directly associated with biological function and the genetic causes of biological effects. Despite progress made in genome-wide sequencing and phasing algorithms and methods, problems assembling (and reconstructing linear haplotypes in regions of repetitive DNA and structural variation remain. These dynamic and structurally complex regions are often poorly understood from a sequence point of view. Regions such as these that are highly similar in their sequence tend to be collapsed onto the genome assembly. This is turn means downstream determination of the true sequence haplotype in these regions poses a particular challenge. For structurally complex regions, a more focussed approach to assembling haplotypes may be required. Results In order to investigate reconstruction of spatial information at structurally complex regions, we have used an emulsion haplotype fusion PCR approach to reproducibly link sequences of up to 1kb in length to allow phasing of multiple variants from neighbouring loci, using allele-specific PCR and sequencing to detect the phase. By using emulsion systems linking flanking regions to amplicons within the CNV, this led to the reconstruction of a 59kb haplotype across the DEFA1A3 CNV in HapMap individuals. Conclusion This study has demonstrated a novel use for emulsion haplotype fusion PCR in addressing the issue of reconstructing structural haplotypes at multiallelic copy variable regions, using the DEFA1A3 locus as an example.

Sequence of a complete chicken BG haplotype shows dynamic expansion and contraction of two gene lineages with particular expression patterns

DEFF Research Database (Denmark)

Salomonsen, Jan; Chattaway, John A.; Chan, Andrew C. Y.

2014-01-01

complex (MHC), and show striking association with particular autoimmune diseases. In chickens, BG genes encode homologues with somewhat different domain organisation. Only a few BG genes have been characterised, one involved in actin-myosin interaction in the intestinal brush border, and another...... implicated in resistance to viral diseases. We characterise all BG genes in B12 chickens, finding a multigene family organised as tandem repeats in the BG region outside the MHC, a single gene in the MHC (the BF-BL region), and another single gene on a different chromosome. There is a precise cell and tissue...... many hybrid genes, suggesting recombination and/or deletion as major evolutionary forces. We identify BG genes in the chicken whole genome shotgun sequence, as well as by comparison to other haplotypes by fibre fluorescence in situ hybridisation, confirming dynamic expansion and contraction within...

Insights into HLA-G genetics provided by worldwide haplotype diversity

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Erick C Castelli

2014-10-01

Full Text Available Human Leucocyte Antigen G (HLA-G belongs to the family of nonclassical HLA class I genes, located within the major histocompatibility complex (MHC. HLA-G has been the target of most recent research regarding the function of class I nonclassical genes. The main features that distinguish HLA-G from classical class I genes are: a limited protein variability; b alternative splicing generating several membrane bound and soluble isoforms; c short cytoplasmic tail; d modulation of immune response (immune tolerance; e restricted expression to certain tissues. In the present work, we describe the HLA-G gene structure and address the HLA-G variability and haplotype diversity among several populations around the world, considering each of its major segments (promoter, coding and 3’untranslated regions. For this purpose, we developed a pipeline to reevaluate the 1000Genomes data and recover miscalled or missing genotypes and haplotypes. It became clear that the overall structure of the HLA-G molecule has been maintained during the evolutionary process and that most of the variation sites found in the HLA-G coding region are either coding synonymous or intronic mutations. In addition, only a few frequent and divergent extended haplotypes are found when the promoter, coding and 3’ untranslated regions are evaluated together. The divergence is particularly evident for the regulatory regions. The population comparisons confirmed that most of the HLA-G variability has originated before human dispersion from Africa and that the allele and haplotype frequencies have probably been shaped by strong selective pressures.

Ia-restricted B-B cell interaction. I. The MHC haplotype of bone marrow cells present during B cell ontogeny dictates the self-recognition specificity of B cells in the polyclonal B cell activation by a B cell differentiation factor, B151-TRF2

International Nuclear Information System (INIS)

Ono, S.; Takahama, Y.; Hamaoka, T.

1987-01-01

We have demonstrated that B cell recognition of Ia molecules is involved in polyclonal B cell differentiation by B151-TRF2. The present study was undertaken to examine the Ia recognition specificity of B151-TRF2-responsive B cells in fully major histocompatibility complex (MHC)-allogeneic P1----P2, semiallogeneic P1----(P1 x P2)F1, and double donor (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 radiation bone marrow chimeras. The B cells from both P1----P2 and P1----(P1 x P2)F1 chimeras could give rise to in vitro immunoglobulin M-producing cells upon stimulation with B151-TRF2 comparable in magnitude to that of normal P1 B cells, and their responses were inhibited by anti-I-AP1 but not by anti-I-AP2 monoclonal antibody even in the presence of mitomycin C-treated T cell-depleted P2 spleen cells as auxiliary cells. In contrast, the B151-TRF2 responses of P1 B cells isolated from both (P1 + P2)----(P1 x P2)F1 and (P1 + P2)----P1 double bone marrow chimeras became sensitive to the inhibition of not only anti-I-AP1 but also anti-I-AP2 monoclonal antibody only when the culture was conducted in the presence of P2 auxiliary cells, demonstrating that they adaptively differentiate to recognize as self-structures allogeneic as well as syngeneic Ia molecules. Moreover, the experiments utilizing B cells from H-2-congenic mice and B cell hybridoma clones as auxiliary cells revealed that B151-TRF2-responsive B cells recognize Ia molecules expressed on B cells. Taken together, these results demonstrate that B151-TRF2-responsive B cells recognize Ia molecules expressed by B cells as self-structures and that their self-recognition specificity is dictated by the MHC haplotype of bone marrow cells present during the B cell ontogeny but not by the MHC haplotype of a radiation-resistant host environment

HLA alleles and HLA-B27 haplotypes associated with susceptibility and severity of ankylosing spondylitis in a Portuguese population.

Science.gov (United States)

Pimentel-Santos, F M; Matos, M; Ligeiro, D; Mourão, A F; Ribeiro, C; Costa, J; Santos, H; Barcelos, A; Pinto, P; Cruz, M; Sousa, E; Santos, R A; Fonseca, J E; Trindade, H; Guedes-Pinto, H; Branco, J C

2013-12-01

Human leukocyte antigen (HLA)-B27 is the mostly known major histocompatibility complex (MHC) gene associated with ankylosing spondylitis (AS). Nonetheless, there is substantial evidence that other MHC genes appear to be associated with the disease, although it has not yet been established whether these associations are driven by direct associations or by linkage disequilibrium (LD) mechanisms. We aimed to investigate the contributions of HLA class I and II alleles and B27-haplotypes for AS in a case-control study. A total of 188 HLA-B27 AS cases and 189 HLA-B27 healthy controls were selected and typed for HLA class I and II by the Luminex polymerase chain reaction-sequence specific oligonucleotide probe (PCR-SSOP) method. Allelic and haplotypic distributions were estimated by maximum likelihood method using Arlequin v3.11 and statistical analysis were performed by Stata10.1. No associations were found between non-HLA-B27 loci and AS susceptibility, but several associations were observed for phenotypic features of the disease. DRB1*08 was identified as a risk factor for uveitis and DQB1*04 seems to provide protection for AS severity (functional, metrological and radiological indexes). A*02/B27/C*02/DRB1*01/DQB1*05 [P<0.0001; odds ratio (OR) = 39.06; 95% confidence interval (CI) (2.34-651)] is the only haplotype that seems to confer susceptibility to AS. Moreover, the haplotype A*02/B27/C*01/DRB1*08/DQB1*04 seems to provide protection for disease functional and radiological repercussions. Our findings are compatible with the hypothesis that other genes within the HLA region besides HLA-B27 might play some role in AS susceptibility and severity. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Differential regulation of expression of the MHC class II molecules RT1.B and RT1.D on rat B lymphocytes: effects of interleukin-4, interleukin-13 and interferon-gamma

NARCIS (Netherlands)

Roos, A.; Schilder-Tol, E. J.; Chand, M. A.; Claessen, N.; Lakkis, F. G.; Pascual, D. W.; Weening, J. J.; Aten, J.

1998-01-01

Susceptibility to induction of both T helper 1- (Th1) and Th2-mediated autoimmunity is multifactorial and involves genetic linkage to the major histocompatibility complex (MHC) class II haplotype. Brown Norway (BN) rats exposed to mercuric chloride develop a Th2-dependent systemic autoimmunity,

iHAP – integrated haplotype analysis pipeline for characterizing the haplotype structure of genes

Directory of Open Access Journals (Sweden)

Lim Yun Ping

2006-12-01

Full Text Available Abstract Background The advent of genotype data from large-scale efforts that catalog the genetic variants of different populations have given rise to new avenues for multifactorial disease association studies. Recent work shows that genotype data from the International HapMap Project have a high degree of transferability to the wider population. This implies that the design of genotyping studies on local populations may be facilitated through inferences drawn from information contained in HapMap populations. Results To facilitate analysis of HapMap data for characterizing the haplotype structure of genes or any chromosomal regions, we have developed an integrated web-based resource, iHAP. In addition to incorporating genotype and haplotype data from the International HapMap Project and gene information from the UCSC Genome Browser Database, iHAP also provides capabilities for inferring haplotype blocks and selecting tag SNPs that are representative of haplotype patterns. These include block partitioning algorithms, block definitions, tag SNP definitions, as well as SNPs to be "force included" as tags. Based on the parameters defined at the input stage, iHAP performs on-the-fly analysis and displays the result graphically as a webpage. To facilitate analysis, intermediate and final result files can be downloaded. Conclusion The iHAP resource, available at http://ihap.bii.a-star.edu.sg, provides a convenient yet flexible approach for the user community to analyze HapMap data and identify candidate targets for genotyping studies.

MHC protocols

National Research Council Canada - National Science Library

Powis, Stephen H; Vaughan, Robert W

2003-01-01

... because it contains genes encoding components of the complement pathway. The entire human MHC has recently been sequenced (1) and each subregion is now known to contain many other genes, a number of which have immunological functions. The study of polymorphism within the MHC is well established, because the region contains the highly polymorphic HLA genes. HLA polym...

Thymic repopulation following intrathymic injection of mouse bone marrow cells in MHC matched and mismatched recipients

International Nuclear Information System (INIS)

Chervenak, R.

1986-01-01

T cell precursors (pre-T cells) have traditionally been detected by their ability to repopulate the thymus of heavily irradiated mice following intravenous injection. Recently, Goldschneider et. al. developed an assay system which involves the direct injection of pre-T cells into the thymus. The authors used this technique to evaluate the ability of bone marrow cells to repopulate thymuses in various donor-host strain combinations. Sub-lethally irradiated (600R) mice were injected intrathymically with 2 x 10 6 bone marrow cells which differed from the recipient with respect to their Thy 1 allotype. The percentage of thymus cells expressing either the donor or recipient type Thy 1 marker was determined 14 to 21 days after injection. These experiments showed that in MHC matched donor-host combinations (AKR/cum → AKR/J and CBA/J → AKR/J), cells derived from the donor inoculum accounted for 40% to 75% of the total thymus population. MHC mismatched donor-host combinations (C57BL/6J → AKR/J and Balb/c → AKR/J) resulted in significantly less donor-type repopulation of the thymus. In these cases, donor repopulation typically ranged from 0% to 4%. The ability of the pre-T cells detected by intrathymic injection to proliferate in the thymic environment, therefore, appears to be influenced by the MHC. This may reflect commitment of pre-T cells to MHC haplotype recognition prior to their migration to the thymus

Major histocompatibility complex (MHC) class III genetics in two Amerindian tribes from southern Brazil: the Kaingang and the Guarani.

Science.gov (United States)

Weg-Remers, S; Brenden, M; Schwarz, E; Witzel, K; Schneider, P M; Guerra, L K; Rehfeldt, I R; Lima, M T; Hartmann, D; Petzl-Erler, M L; de Messias, I J; Mauff, G

1997-10-01

Population genetic studies of the major histocompatibility complex (MHC) class III region, comprising C2, BF and C4 phenotypes, and molecular genetic data are rarely available for populations other than Caucasoids. We have investigated three Amerindian populations from Southern Brazil: 131 Kaingang from Ivaí (KIV), 111 Kaingang (KRC) and 100 Guarani (GRC) from Rio das Cobras. Extended MHC haplotypes were derived after standard C2, BF, C4 phenotyping and restriction fragment length polymorphism (RFLP) analysis with TaqI, together with HLA data published previously by segregation analysis. C2 and BF frequencies corresponded to other Amerindian populations. C4B*Q0 frequency was high in the GRC (0.429) but low in the Kaingang. Unusual C4 alleles were found, viz. C4A*58, A*55 and C4B*22 (presumably non-Amerindian) and aberrant C4A*3 of Amerindian origin occurring with a frequency of 0.223 in the GRC. C4A*3 bands of homo- and heterozygous individuals carrying this variant were Rodgers 1 positive and Chido 1,3 positive, showed a C4A specific lysis type and a C4A like alpha-chain. Polymerase chain reaction studies and sequencing showed that this is based on a C4A*3 duplication with a regular C4A*3 and a partially converted C4A*0304 carrying the C4B specific epitopes Ch 6 and Ch 1,3. Associations of class III haplotypes with particular RFLP patterns were similar to those reported for Caucasoids. The previously described association between combined C4A and CYP21P deletions and the 6.4 kb TaqI fragment was not seen in these Amerindians. This fragment occurred within a regular two locus gene structure in the Kaingang, representing a "short" gene at C4 locus I. C4 and CYP21 duplications were frequently observed. The distribution of extended MHC haplotypes provides evidence for a close relationship between the KIV and KRC and a larger genetic distance between the two Kaingang groups and the GRC.

MPID-T2: a database for sequence-structure-function analyses of pMHC and TR/pMHC structures.

Science.gov (United States)

Khan, Javed Mohammed; Cheruku, Harish Reddy; Tong, Joo Chuan; Ranganathan, Shoba

2011-04-15

Sequence-structure-function information is critical in understanding the mechanism of pMHC and TR/pMHC binding and recognition. A database for sequence-structure-function information on pMHC and TR/pMHC interactions, MHC-Peptide Interaction Database-TR version 2 (MPID-T2), is now available augmented with the latest PDB and IMGT/3Dstructure-DB data, advanced features and new parameters for the analysis of pMHC and TR/pMHC structures. http://biolinfo.org/mpid-t2. shoba.ranganathan@mq.edu.au Supplementary data are available at Bioinformatics online.

Rejection of class I MHC-deficient haemopoietic cells by irradiated MHC-matched mice

International Nuclear Information System (INIS)

Bix, M.; Nanshih Liao; Raulet, D.; Zijlstra, M.; Loring, J.; Jaenisch, R.

1991-01-01

Irradiated MHC-heterozygous mice often reject bone marrow cells transplanted from one of the homozygous parental strains, a phenomenon ('hybrid resistance') that appears to violate the laws of transplantation. Rejection of parental and allogeneic marrow cells also differs from conventional T cell-mediated rejection mechanisms as it is effected by NK1.1 + cells. To account for the unusual specificity of bone marrow rejection, it has been proposed that NK1.1 + cells destroy marrow cells that fail to express the full complement of self MHC class I (MHC-I) molecules. We show here that NK1.1 + cells in normal mice reject haemopoietic transplants from mice that are deficient for normal cell-surface MHC-I expression because of a targeted mutation in the β 2 -microglobulin gene. These findings demonstrate that deficient expression of MHC-I molecules renders marrow cells susceptible to rejection. (author)

Mapping Haplotype-haplotype Interactions with Adaptive LASSO

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Li Ming

2010-08-01

Full Text Available Abstract Background The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it presents daunting challenges in statistical modeling and testing of the interaction effects, largely due to the complicated higher order epistatic complexity. Results In this article, we propose a new strategy in modeling haplotype-haplotype interactions under the penalized logistic regression framework with adaptive L1-penalty. We consider interactions of sequence variants between haplotype blocks. The adaptive L1-penalty allows simultaneous effect estimation and variable selection in a single model. We propose a new parameter estimation method which estimates and selects parameters by the modified Gauss-Seidel method nested within the EM algorithm. Simulation studies show that it has low false positive rate and reasonable power in detecting haplotype interactions. The method is applied to test haplotype interactions involved in mother and offspring genome in a small for gestational age (SGA neonates data set, and significant interactions between different genomes are detected. Conclusions As demonstrated by the simulation studies and real data analysis, the approach developed provides an efficient tool for the modeling and testing of haplotype interactions. The implementation of the method in R codes can be

Structural properties of MHC class II ligands, implications for the prediction of MHC class II epitopes.

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Kasper Winther Jørgensen

2010-12-01

Full Text Available Major Histocompatibility class II (MHC-II molecules sample peptides from the extracellular space allowing the immune system to detect the presence of foreign microbes from this compartment. Prediction of MHC class II ligands is complicated by the open binding cleft of the MHC class II molecule, allowing binding of peptides extending out of the binding groove. Furthermore, only a few HLA-DR alleles have been characterized with a sufficient number of peptides (100-200 peptides per allele to derive accurate description of their binding motif. Little work has been performed characterizing structural properties of MHC class II ligands. Here, we perform one such large-scale analysis. A large set of SYFPEITHI MHC class II ligands covering more than 20 different HLA-DR molecules was analyzed in terms of their secondary structure and surface exposure characteristics in the context of the native structure of the corresponding source protein. We demonstrated that MHC class II ligands are significantly more exposed and have significantly more coil content than other peptides in the same protein with similar predicted binding affinity. We next exploited this observation to derive an improved prediction method for MHC class II ligands by integrating prediction of MHC- peptide binding with prediction of surface exposure and protein secondary structure. This combined prediction method was shown to significantly outperform the state-of-the-art MHC class II peptide binding prediction method when used to identify MHC class II ligands. We also tried to integrate N- and O-glycosylation in our prediction methods but this additional information was found not to improve prediction performance. In summary, these findings strongly suggest that local structural properties influence antigen processing and/or the accessibility of peptides to the MHC class II molecule.

Major histocompatibility complex-linked immune response of young chickens vaccinated with an attenuated live infectious bursal disease virus vaccine followed by an infection

DEFF Research Database (Denmark)

Juul-Madsen, Helle; Nielsen, O.L.; Krogh-Maibom, T.

2002-01-01

The influence of the MHC on infectious bursal disease virus (IBDV) vaccine response in chickens was investigated in three different chicken lines containing four different MHC haplotypes. Two MHC haplotypes were present in all three lines with one haplotype (1319) shared between the lines. Line I...... further contains the BW1 haplotype isolated from a Red jungle Fowl. Line 131 further contains the B131 haplotype isolated from a meat-type chicken, Finally, Line 21 further contains the international B21 haplotype. The chickens were vaccinated with live attenuated commercial IBDV vaccine at 3 wk of age...

MHC Class II epitope predictive algorithms

DEFF Research Database (Denmark)

Nielsen, Morten; Lund, Ole; Buus, S

2010-01-01

Major histocompatibility complex class II (MHC-II) molecules sample peptides from the extracellular space, allowing the immune system to detect the presence of foreign microbes from this compartment. To be able to predict the immune response to given pathogens, a number of methods have been...... developed to predict peptide-MHC binding. However, few methods other than the pioneering TEPITOPE/ProPred method have been developed for MHC-II. Despite recent progress in method development, the predictive performance for MHC-II remains significantly lower than what can be obtained for MHC-I. One reason...

Immunotherapy of MHC class I-deficient tumors

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan

2010-01-01

Roč. 6, č. 10 (2010), s. 1577-1589 ISSN 1479-6694 R&D Projects: GA ČR GA301/07/1410; GA ČR GAP301/10/2174; GA AV ČR IAA500520807; GA AV ČR IAA500520605 EU Projects: European Commission(XE) 18933 - CLINIGENE Institutional research plan: CEZ:AV0Z50520514 Keywords : tumor vaccine * MHC class I expression * antigen presenting machinery Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.455, year: 2010

The MHC motif viewer: a visualization tool for MHC binding motifs

DEFF Research Database (Denmark)

Rapin, Nicolas; Hoof, Ilka; Lund, Ole

2010-01-01

is hampered by the lack of tools for browsing and comparing specificity of these molecules. We have developed a Web server, MHC Motif Viewer, which allows the display of the binding motif for MHC class I proteins for human, chimpanzee, rhesus monkey, mouse, and swine, as well as HLA-DR protein sequences...

MHC class II expression in lung cancer.

Science.gov (United States)

He, Yayi; Rozeboom, Leslie; Rivard, Christopher J; Ellison, Kim; Dziadziuszko, Rafal; Yu, Hui; Zhou, Caicun; Hirsch, Fred R

2017-10-01

Immunotherapy is an exciting development in lung cancer research. In this study we described major histocompatibility complex (MHC) Class II protein expression in lung cancer cell lines and patient tissues. We studied MHC Class II (DP, DQ, DR) (CR3/43, Abcam) protein expression in 55 non-small cell lung cancer (NSCLC) cell lines, 42 small cell lung cancer (SCLC) cell lines and 278 lung cancer patient tissues by immunohistochemistry (IHC). Seven (12.7%) NSCLC cell lines were positive for MHC Class II. No SCLC cell lines were found to be MHC Class II positive. We assessed 139 lung cancer samples available in the Hirsch Lab for MHC Class II. There was no positive MHC Class II staining on SCLC tumor cells. MHC Class II expression on TILs in SCLC was significantly lower than that on TILs in NSCLC (P＜0.001). MHC Class II was also assessed in an additional 139 NSCLC tumor tissues from Medical University of Gdansk, Poland. Patients with positive staining of MHC Class II on TILs had longer regression-free survival (RFS) and overall survival (OS) than those whose TILs were MHC Class II negative (2.980 years, 95% CI 1.628-4.332 vs. 1.050 years, 95% CI 0.556-1.554, P=0.028) (3.230 years, 95% CI 2.617-3.843 vs. 1.390 years, 95% CI 0.629-2.151, P=0.014). MHC Class II was expressed both in NSCLC cell lines and tissues. However, MHC Class II was not detected in SCLC cell lines or tissue tumor cells. MHC Class II expression was lower on SCLC TILs than on NSCLC TILs. Loss of expression of MHC Class II on SCLC tumor cells and reduced expression on SCLC TILs may be a means of escaping anti-cancer immunity. Higher MHC Class II expression on TILs was correlated with better prognosis in patients with NSCLC. Copyright © 2017. Published by Elsevier B.V.

Immunization with MHC class I-negative but not -positive HPV16-associated tumour cells inhibits growth of MHC class I-negative tumours

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan; Šímová, Jana; Indrová, Marie; Bieblová, Jana; Přibylová, Hana; Moravcová, Simona; Jandlová, Táňa; Bubeník, Jan

2007-01-01

Roč. 30, č. 4 (2007), s. 1011-1017 ISSN 1019-6439 R&D Projects: GA MZd NR7807 EU Projects: European Commission(XE) 18933 - CLINIGENE Grant - others:Liga proti rakovině, Praha(CZ) XX Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV16 * MHC class I-deficient tumours * immunologic crossreaction Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.295, year: 2007

MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo

OpenAIRE

Cavalli, Giulio; Hayashi, Masahiro; Jin, Ying; Yorgov, Daniel; Santorico, Stephanie A.; Holcomb, Cherie; Rastrou, Melinda; Erlich, Henry; Tengesdal, Isak W.; Dagna, Lorenzo; Neff, C. Preston; Palmer, Brent E.; Spritz, Richard A.; Dinarello, Charles A.

2016-01-01

Vitiligo is a classic autoimmune disease genetically associated with SNPs in the MHC class II region. To date, the impact of HLA molecules on autoimmunity has focused on structural diversity of antigen presentation. Here, we describe the properties of a 47-nucleotide high-risk haplotype of three SNPs within an intergenic “super-enhancer” located between the HLA-DRB1 and HLA-DQA1 genes, localized by a genome-wide association study of 2,853 subjects with vitiligo. Monocytes from healthy subject...

Peptide-binding motif prediction by using phage display library for SasaUBA*0301, a resistance haplotype of MHC class I molecule from Atlantic Salmon (Salmo salar)

DEFF Research Database (Denmark)

Zhao, Heng; Hermsen, Trudi; Stet, Rene J M

2008-01-01

The structure of the peptide-binding specificity of major histocompatibility complex (MHC) class I has been analyzed extensively in human and mouse. For fish, there are no crystallographic models of MHC molecules, neither are there data on the peptide-binding specificity. In this study, we descri...... and there is a significant association between MHC polymorphism and the disease resistance. Therefore, our study might contribute to designing a peptide vaccine against this viral disease....... class I molecule might have a very similar binding motif at the C-terminus compared with a known mouse class I molecule H2-Kb which has L, or I, V, M at p8. Previous work showed that Atlantic Salmon carrying the allele SasaUBA*0301 are resistant to infectious Salmon aneamia virus...

Improved pan-specific MHC class I peptide-binding predictions using a novel representation of the MHC-binding cleft environment

DEFF Research Database (Denmark)

Carrasco Pro, S.; Zimic, M.; Nielsen, Morten

2014-01-01

of the current state-of-the-art methods for MHC class I is NetMHCpan, which has a core ingredient for the representation of the MHC class I molecule using a pseudo-sequence representation of the binding cleft amino acid environment. New and large MHC-peptide-binding data sets are constantly being made available...... of different MHC data sets including human leukocyte antigen (HLA), non-human primates (chimpanzee, macaque and gorilla) and other animal alleles (cattle, mouse and swine). From these constructs, we showed that by focusing on MHC sequence positions found to be polymorphic across the MHC molecules used to train...

Patterns of genetic differentiation at MHC class I genes and microsatellites identify conservation units in the giant panda.

Science.gov (United States)

Zhu, Ying; Wan, Qiu-Hong; Yu, Bin; Ge, Yun-Fa; Fang, Sheng-Guo

2013-10-22

Evaluating patterns of genetic variation is important to identify conservation units (i.e., evolutionarily significant units [ESUs], management units [MUs], and adaptive units [AUs]) in endangered species. While neutral markers could be used to infer population history, their application in the estimation of adaptive variation is limited. The capacity to adapt to various environments is vital for the long-term survival of endangered species. Hence, analysis of adaptive loci, such as the major histocompatibility complex (MHC) genes, is critical for conservation genetics studies. Here, we investigated 4 classical MHC class I genes (Aime-C, Aime-F, Aime-I, and Aime-L) and 8 microsatellites to infer patterns of genetic variation in the giant panda (Ailuropoda melanoleuca) and to further define conservation units. Overall, we identified 24 haplotypes (9 for Aime-C, 1 for Aime-F, 7 for Aime-I, and 7 for Aime-L) from 218 individuals obtained from 6 populations of giant panda. We found that the Xiaoxiangling population had the highest genetic variation at microsatellites among the 6 giant panda populations and higher genetic variation at Aime-MHC class I genes than other larger populations (Qinling, Qionglai, and Minshan populations). Differentiation index (FST)-based phylogenetic and Bayesian clustering analyses for Aime-MHC-I and microsatellite loci both supported that most populations were highly differentiated. The Qinling population was the most genetically differentiated. The giant panda showed a relatively higher level of genetic diversity at MHC class I genes compared with endangered felids. Using all of the loci, we found that the 6 giant panda populations fell into 2 ESUs: Qinling and non-Qinling populations. We defined 3 MUs based on microsatellites: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. We also recommended 3 possible AUs based on MHC loci: Qinling, Minshan-Qionglai, and Daxiangling-Xiaoxiangling-Liangshan. Furthermore, we recommend

MHC and Evolution in Teleosts

OpenAIRE

Grimholt, Unni

2016-01-01

Major histocompatibility complex (MHC) molecules are key players in initiating immune responses towards invading pathogens. Both MHC class I and class II genes are present in teleosts, and, using phylogenetic clustering, sequences from both classes have been classified into various lineages. The polymorphic and classical MHC class I and class II gene sequences belong to the U and A lineages, respectively. The remaining class I and class II lineages contain nonclassical gene sequences that, de...

Tumour MHC class I downregulation and immunotherapy (Review)

Czech Academy of Sciences Publication Activity Database

Bubeník, Jan

2003-01-01

Roč. 10, č. 6 (2003), s. 2005-2008 ISSN 1021-335X R&D Projects: GA MZd NC7148; GA ČR GA301/01/0985; GA AV ČR IAA5052203 Institutional research plan: CEZ:AV0Z5052915 Keywords : tumour vaccines * MHC class I downregulation Subject RIV: FD - Oncology ; Hematology Impact factor: 1.256, year: 2003

Innate lymphoid cells and the MHC.

Science.gov (United States)

Robinette, M L; Colonna, M

2016-01-01

Innate lymphoid cells (ILCs) are a new class of immune cells that include natural killer (NK) cells and appear to be the innate counterparts to CD4(+) helper T cells and CD8(+) cytotoxic T cells based on developmental and functional similarities. Like T cells, both NK cells and other ILCs also show connections to the major histocompatibility complex (MHC). In human and mouse, NK cells recognize and respond to classical and nonclassical MHC I molecules as well as structural homologues, whereas mouse ILCs have recently been shown to express MHC II. We describe the history of MHC I recognition by NK cells and discuss emerging roles for MHC II expression by ILC subsets, making comparisons between both mouse and human when possible. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Immunotherapy of MHC class I-deficient tumours and epigenetic upregulation of MHC class I molecules on tumour cells

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan; Manning, Jasper; Indrová, Marie; Přibylová, Hana; Bieblová, Jana; Šímová, Jana; Bubeník, Jan

2007-01-01

Roč. 20, Suppl. 1 (2007), S29-S29 ISSN 1107-3756. [World Congress on Advances in Oncology /12./ and International Symposium on Molecular Medicine /10./. 11.10.2007-12.10.2007, Hernissos] R&D Projects: GA ČR GA301/04/0492; GA ČR GA301/07/1410 Institutional research plan: CEZ:AV0Z50520514 Keywords : Immunotherapy * MHC I-deficient tumours * epigenetics Subject RIV: EB - Genetics ; Molecular Biology

Understanding TR binding to pMHC complexes: how does a TR scan many pMHC complexes yet preferentially bind to one.

Directory of Open Access Journals (Sweden)

Javed Mohammed Khan

Full Text Available Understanding the basis of the binding of a T cell receptor (TR to the peptide-MHC (pMHC complex is essential due to the vital role it plays in adaptive immune response. We describe the use of computed binding (free energy (BE, TR paratope, pMHC epitope, molecular surface electrostatic potential (MSEP and calculated TR docking angle (θ to analyse 61 TR/pMHC crystallographic structures to comprehend TR/pMHC interaction. In doing so, we have successfully demonstrated a novel/rational approach for θ calculation, obtained a linear correlation between BE and θ without any "codon" or amino acid preference, provided an explanation for TR ability to scan many pMHC ligands yet specifically bind one, proposed a mechanism for pMHC recognition by TR leading to T cell activation and illustrated the importance of the peptide in determining TR specificity, challenging the "germline bias" theory.

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

Energy Technology Data Exchange (ETDEWEB)

Crew, M.D.; Bates, L.M. [Univ. of Arkansas for Medical Sciences, Little Rock, AR (United States)

1996-09-01

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

MHC Class II and Non-MHC Class II Genes Differentially Influence Humoral Immunity to Bacillus anthracis Lethal Factor and Protective Antigen

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Judith A. James

2012-12-01

Full Text Available Anthrax Lethal Toxin consists of Protective Antigen (PA and Lethal Factor (LF, and current vaccination strategies focus on eliciting antibodies to PA. In human vaccination, the response to PA can vary greatly, and the response is often directed toward non-neutralizing epitopes. Variable vaccine responses have been shown to be due in part to genetic differences in individuals, with both MHC class II and other genes playing roles. Here, we investigated the relative contribution of MHC class II versus non-MHC class II genes in the humoral response to PA and LF immunization using three immunized strains of inbred mice: A/J (H-2k at the MHC class II locus, B6 (H-2b, and B6.H2k (H-2k. IgG antibody titers to LF were controlled primarily by the MHC class II locus, whereas IgG titers to PA were strongly influenced by the non-MHC class II genetic background. Conversely, the humoral fine specificity of reactivity to LF appeared to be controlled primarily through non-MHC class II genes, while the specificity of reactivity to PA was more dependent on MHC class II. Common epitopes, reactive in all strains, occurred in both LF and PA responses. These results demonstrate that MHC class II differentially influences humoral immune responses to LF and PA.

Haplotype assembly in polyploid genomes and identical by descent shared tracts.

Science.gov (United States)

Aguiar, Derek; Istrail, Sorin

2013-07-01

Genome-wide haplotype reconstruction from sequence data, or haplotype assembly, is at the center of major challenges in molecular biology and life sciences. For complex eukaryotic organisms like humans, the genome is vast and the population samples are growing so rapidly that algorithms processing high-throughput sequencing data must scale favorably in terms of both accuracy and computational efficiency. Furthermore, current models and methodologies for haplotype assembly (i) do not consider individuals sharing haplotypes jointly, which reduces the size and accuracy of assembled haplotypes, and (ii) are unable to model genomes having more than two sets of homologous chromosomes (polyploidy). Polyploid organisms are increasingly becoming the target of many research groups interested in the genomics of disease, phylogenetics, botany and evolution but there is an absence of theory and methods for polyploid haplotype reconstruction. In this work, we present a number of results, extensions and generalizations of compass graphs and our HapCompass framework. We prove the theoretical complexity of two haplotype assembly optimizations, thereby motivating the use of heuristics. Furthermore, we present graph theory-based algorithms for the problem of haplotype assembly using our previously developed HapCompass framework for (i) novel implementations of haplotype assembly optimizations (minimum error correction), (ii) assembly of a pair of individuals sharing a haplotype tract identical by descent and (iii) assembly of polyploid genomes. We evaluate our methods on 1000 Genomes Project, Pacific Biosciences and simulated sequence data. HapCompass is available for download at http://www.brown.edu/Research/Istrail_Lab/. Supplementary data are available at Bioinformatics online.

Split tolerance in nude mice transplanted with 2'-deoxyguanosine-treated allogeneic thymus lobes

International Nuclear Information System (INIS)

Suzuki, G.; Moriyama, T.; Takeuchi, Y.; Kawase, Y.; Habu, S.

1989-01-01

To elucidate the acquisition of self tolerance in the thymus, full-allogeneic thymic chimeras were constructed. Athymic C3H and BALB/c nude mice were reconstituted with the thymic lobes of BALB/c and B10.BR fetuses, respectively, that were organ cultured for 5 days in the presence of 2'-deoxyguanosine. T cells in these chimeras were tolerized to the host MHC in both MLR and CTL assays. In contrast, T cells in the chimeras exhibited split tolerance for the thymic MHC haplotype. CTL specific for class I MHC of the thymic haplotype were generated not only from the peripheral T cells of the chimeras but also from thymocytes re-populated in the engrafted thymic lobes. However, T cells in these chimeras responded poorly to the class II MHC of the thymic haplotype in a standard MLR assay. In a syngeneic MLR culture upon stimulation with enriched APC of the thymic haplotype, only 22 to 48% of the responses were mediated by CD4+ cells, and proliferations of CD4- cells were prominent. There were no haplotype-specific suppressor cells detected which would cause the unresponsiveness to the thymic class II MHC. These results indicated that the thymic lobes treated with 2'-deoxyguanosine were defective in the ability to induce the transplantation tolerance for the class I MHC expressed on the thymus, although the same thymic lobes were able to induce the transplantation tolerance for the thymic class II MHC

Epitopes associated with MHC restriction site of T cells. III. I-J epitope on MHC-restricted T helper cells

International Nuclear Information System (INIS)

Asano, Y.; Nakayama, T.; Kubo, M.; Yagi, J.; Tada, T.

1987-01-01

I-J epitopes were found to be associated with the functional site of the class II MHC-restricted helper T (Th) cells: Virtually all of the H-2k-restricted Th cell function of H-2kxbF1 T cells was inhibited by the anti-I-Jk mAb, leaving the H-2b-restricted function unaffected. The I-Jk epitope was inducible in Th cells of different genotype origin according to the environmental class II antigens present in the early ontogeny of T cells. Although above results suggested that I-J is the structure reflecting the inducible MHC restriction specificity, further studies revealed some interesting controversies: First, the I-J phenotype did not always correlate with the class II restriction specificity, e.g., I-Ab-restricted Th from 5R was I-Jk-positive, whereas I-Ak-restricted Th of 4R was not. Second, there was no trans expression of parental I-J phenotypes and restriction specificities in F1 Th, e.g., the I-J phenotype was detected only on I-Ab-restricted Th of (4R X 5R)F1, whereas it was absent on I-Ak-restricted Th. This strict linkage between the restriction specificity and I-J phenotype was also found on Th cells developed in bone marrow chimera constructed with intra-H-2-recombinant mice. The expression of I-Jk was always associated with the restriction specificity of the relevant host. Thus, the restriction specificity of Th cells followed the host type, and the I-J expression on Th was exactly the same as that expressed by the host haplotype. These results indicate that I-J is an isomorphic structure adaptively expressed on Th cells that is involved in the unidirectional regulatory cell interactions, and that the polymorphism cannot be explained merely by the restriction specificity of the conventional T cell receptor heterodimer

NLRC5: a newly discovered MHC class I transactivator (CITA)

OpenAIRE

Meissner, Torsten B.; Li, Amy; Kobayashi, Koichi S.

2011-01-01

Major histocompatibility complex (MHC) class I and class II are crucial for the function of the human adaptive immune system. An NLR protein, CIITA (MHC class II transactivator), is a master regulator of MHC class II gene expression as well as of some of the genes involved in MHC class II antigen presentation. It has recently been discovered that another member of the NLR protein family, NLRC5, transcriptionally activates MHC class I genes, and thus acts as “CITA” (MHC class I transactivator)...

MHC class IIB Exon 2 Polymorphism in the Grey Partridge (Perdix perdix) is shaped by selection, recombination and gene conversion

Czech Academy of Sciences Publication Activity Database

Promerová, Marta; Králová, Tereza; Bryjová, Anna; Albrecht, Tomáš; Bryja, Josef

2013-01-01

Roč. 8, č. 7 (2013), e69135 E-ISSN 1932-6203 R&D Projects: GA ČR GA206/08/1281 Institutional support: RVO:68081766 Keywords : major histocompatibility complex (MHC) * snipe Gallinago-media * Class-I genes * minimal-essential-MHC Subject RIV: EG - Zoology Impact factor: 3.534, year: 2013

Comparative genome analyses reveal distinct structure in the saltwater crocodile MHC.

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Weerachai Jaratlerdsiri

Full Text Available The major histocompatibility complex (MHC is a dynamic genome region with an essential role in the adaptive immunity of vertebrates, especially antigen presentation. The MHC is generally divided into subregions (classes I, II and III containing genes of similar function across species, but with different gene number and organisation. Crocodylia (crocodilians are widely distributed and represent an evolutionary distinct group among higher vertebrates, but the genomic organisation of MHC within this lineage has been largely unexplored. Here, we studied the MHC region of the saltwater crocodile (Crocodylus porosus and compared it with that of other taxa. We characterised genomic clusters encompassing MHC class I and class II genes in the saltwater crocodile based on sequencing of bacterial artificial chromosomes. Six gene clusters spanning ∼452 kb were identified to contain nine MHC class I genes, six MHC class II genes, three TAP genes, and a TRIM gene. These MHC class I and class II genes were in separate scaffold regions and were greater in length (2-6 times longer than their counterparts in well-studied fowl B loci, suggesting that the compaction of avian MHC occurred after the crocodilian-avian split. Comparative analyses between the saltwater crocodile MHC and that from the alligator and gharial showed large syntenic areas (>80% identity with similar gene order. Comparisons with other vertebrates showed that the saltwater crocodile had MHC class I genes located along with TAP, consistent with birds studied. Linkage between MHC class I and TRIM39 observed in the saltwater crocodile resembled MHC in eutherians compared, but absent in avian MHC, suggesting that the saltwater crocodile MHC appears to have gene organisation intermediate between these two lineages. These observations suggest that the structure of the saltwater crocodile MHC, and other crocodilians, can help determine the MHC that was present in the ancestors of archosaurs.

Primordial linkage of β2-microglobulin to the MHC.

Science.gov (United States)

Ohta, Yuko; Shiina, Takashi; Lohr, Rebecca L; Hosomichi, Kazuyoshi; Pollin, Toni I; Heist, Edward J; Suzuki, Shingo; Inoko, Hidetoshi; Flajnik, Martin F

2011-03-15

β2-Microglobulin (β2M) is believed to have arisen in a basal jawed vertebrate (gnathostome) and is the essential L chain that associates with most MHC class I molecules. It contains a distinctive molecular structure called a constant-1 Ig superfamily domain, which is shared with other adaptive immune molecules including MHC class I and class II. Despite its structural similarity to class I and class II and its conserved function, β2M is encoded outside the MHC in all examined species from bony fish to mammals, but it is assumed to have translocated from its original location within the MHC early in gnathostome evolution. We screened a nurse shark bacterial artificial chromosome library and isolated clones containing β2M genes. A gene present in the MHC of all other vertebrates (ring3) was found in the bacterial artificial chromosome clone, and the close linkage of ring3 and β2M to MHC class I and class II genes was determined by single-strand conformational polymorphism and allele-specific PCR. This study satisfies the long-held conjecture that β2M was linked to the primordial MHC (Ur MHC); furthermore, the apparent stability of the shark genome may yield other genes predicted to have had a primordial association with the MHC specifically and with immunity in general.

Colonizing the world in spite of reduced MHC variation

Science.gov (United States)

Gangoso, L.; Alcaide, M.; Grande, J.M.; Muñoz, J.; Talbot, Sandra L.; Sonsthagen, Sarah A.; Sage, Kevin; Figuerola, J.

2012-01-01

Reduced immune gene diversity is thought to negatively affect the capacity of organisms to adapt to pathogen challenges, which represent a major force in natural selection. Genes of the Major Histocompatibility Complex (MHC) are the most widely invoked adaptive loci in conservation biology, and have become the most popular genetic markers to investigate pathogen-host interactions in vertebrates. Although MHC genes are the most polymorphic genes described in the vertebrate genome, the extent to which MHC diversity determines the long-term persistence of populations is, unclear and often debated, as recent studies have documented the occurrence of natural populations thriving even after a depletion of MHC diversity caused by genetic drift. Here, we show that some phylogenetically related species belonging to the Falco genus (Aves: Falconidae) present a dramatically low MHC variability that has not precluded, nevertheless, the successful colonization of almost all existing regions and habitats worldwide. We found evidence for two remarkably different patterns of MHC variation within the genus. While kestrels show a high MHC variation according to the general theory, falcons exhibit an ancestrally low intra- and inter-specific MHC allelic diversity. We provide compelling evidence that this pattern is not caused by the degeneration of functional genes into pseudogenes, the inadvertent analyses of paralogous MHC genes, or the devastating action of genetic drift. Instead, our results strongly support the idea of an evolutionary transition driven and maintained by natural selection from primarily highly variable towards low polymorphic, but functional and expressed, MHC genes with species-specific pathogen-recognition capabilities.

C57BL/6 mice need MHC class II Aq to develop collagen-induced arthritis dependent on autoreactive T cells.

Science.gov (United States)

Bäcklund, Johan; Li, Cuiqin; Jansson, Erik; Carlsen, Stefan; Merky, Patrick; Nandakumar, Kutty-Selva; Haag, Sabrina; Ytterberg, Jimmy; Zubarev, Roman A; Holmdahl, Rikard

2013-07-01

Collagen-induced arthritis (CIA) has traditionally been performed in MHC class II A(q)-expressing mice, whereas most genetically modified mice are on the C57BL/6 background (expressing the b haplotype of the major histocompatibility complex (MHC) class II region). However, C57BL/6 mice develop arthritis after immunisation with chicken-derived collagen type II (CII), but arthritis susceptibility has been variable, and the immune specificity has not been clarified. To establish a CIA model on the C57BL/6 background with a more predictable and defined immune response to CII. Both chicken and rat CII were arthritogenic in C57BL/6 mice provided they were introduced with high doses of Mycobacterium tuberculosis adjuvant. However, contaminating pepsin was strongly immunogenic and was essential for arthritis development. H-2(b)-restricted T cell epitopes on chicken or rat CII could not be identified, but expression of A(q) on the C57BL/6 background induced T cell response to the CII260-270 epitope, and also prolonged the arthritis to be more chronic. The putative (auto)antigen and its arthritogenic determinants in C57BL/6 mice remains undisclosed, questioning the value of the model for addressing T cell-driven pathological pathways in arthritis. To circumvent this impediment, we recommend MHC class II congenic C57BL/6N.Q mice, expressing A(q), with which T cell determinants have been thoroughly characterised.

Effects of Single Nucleotide Polymorphism Marker Density on Haplotype Block Partition

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Sun Ah Kim

2016-12-01

Full Text Available Many researchers have found that one of the most important characteristics of the structure of linkage disequilibrium is that the human genome can be divided into non-overlapping block partitions in which only a small number of haplotypes are observed. The location and distribution of haplotype blocks can be seen as a population property influenced by population genetic events such as selection, mutation, recombination and population structure. In this study, we investigate the effects of the density of markers relative to the full set of all polymorphisms in the region on the results of haplotype partitioning for five popular haplotype block partition methods: three methods in Haploview (confidence interval, four gamete test, and solid spine, MIG++ implemented in PLINK 1.9 and S-MIG++. We used several experimental datasets obtained by sampling subsets of single nucleotide polymorphism (SNP markers of chromosome 22 region in the 1000 Genomes Project data and also the HapMap phase 3 data to compare the results of haplotype block partitions by five methods. With decreasing sampling ratio down to 20% of the original SNP markers, the total number of haplotype blocks decreases and the length of haplotype blocks increases for all algorithms. When we examined the marker-independence of the haplotype block locations constructed from the datasets of different density, the results using below 50% of the entire SNP markers were very different from the results using the entire SNP markers. We conclude that the haplotype block construction results should be used and interpreted carefully depending on the selection of markers and the purpose of the study.

Molecular Genotype Identification of Different Chickens: Major Histocompatibility Complex

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Hongzhi Wang

2014-09-01

Full Text Available Chicken is a main poultry in China. Molecular breeding for disease resistance plays an important role in the control of diseases, especially infectious diseases. Choice of genes for disease resistance is the key technology of molecular breeding. The major histocompatibility complex (MHC is of great interest to poultry breeding scientists for its extraordinary polymorphism and close relation with traits of resistance against infectious diseases. The MHC-B haplotype plays an important role in the study of disease resistance in chicken. The traditional chicken MHC-B haplotype is commonly defined by serologic reactions of erythrocytes and the majority of studies have been conducted in Leghorn and broiler but study about other chicken breeds is little. In this study, firstly, the microsatellite marker LEI0258 which is located within the MHC was sequenced by using target sequence capture assay in different chicken breeds, and then according to the number of repeated structures and polymorphic sequences in microsatellite, sequence information for the region defined by LEI0258 was obtained for different haplotypes. Afterwards, we identified the relation between MHC-B haplotypes and disease resistance. Collectively, these observed results provided the reference data for disease-resistant breeding association with blood type and for further study of MHC gene function in poultry.

IMGT unique numbering for MHC groove G-DOMAIN and MHC superfamily (MhcSF) G-LIKE-DOMAIN

DEFF Research Database (Denmark)

Lefranc, Marie-Paule; Duprat, E.; Kaas, Quentin

2005-01-01

IMGT, the international ImMunoGeneTics information system® (http://imgt.cines.fr) provides a common access to expertly annotated data on the genome, proteome, genetics and structure of immunoglobulins (IG), T cell receptors (TR), major histocompatibility complex (MHC), and related proteins...

Haplotype-Based Genotyping in Polyploids

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Josh P. Clevenger

2018-04-01

Full Text Available Accurate identification of polymorphisms from sequence data is crucial to unlocking the potential of high throughput sequencing for genomics. Single nucleotide polymorphisms (SNPs are difficult to accurately identify in polyploid crops due to the duplicative nature of polyploid genomes leading to low confidence in the true alignment of short reads. Implementing a haplotype-based method in contrasting subgenome-specific sequences leads to higher accuracy of SNP identification in polyploids. To test this method, a large-scale 48K SNP array (Axiom Arachis2 was developed for Arachis hypogaea (peanut, an allotetraploid, in which 1,674 haplotype-based SNPs were included. Results of the array show that 74% of the haplotype-based SNP markers could be validated, which is considerably higher than previous methods used for peanut. The haplotype method has been implemented in a standalone program, HAPLOSWEEP, which takes as input bam files and a vcf file and identifies haplotype-based markers. Haplotype discovery can be made within single reads or span paired reads, and can leverage long read technology by targeting any length of haplotype. Haplotype-based genotyping is applicable in all allopolyploid genomes and provides confidence in marker identification and in silico-based genotyping for polyploid genomics.

Methods for MHC genotyping in non-model vertebrates.

Science.gov (United States)

Babik, W

2010-03-01

Genes of the major histocompatibility complex (MHC) are considered a paradigm of adaptive evolution at the molecular level and as such are frequently investigated by evolutionary biologists and ecologists. Accurate genotyping is essential for understanding of the role that MHC variation plays in natural populations, but may be extremely challenging. Here, I discuss the DNA-based methods currently used for genotyping MHC in non-model vertebrates, as well as techniques likely to find widespread use in the future. I also highlight the aspects of MHC structure that are relevant for genotyping, and detail the challenges posed by the complex genomic organization and high sequence variation of MHC loci. Special emphasis is placed on designing appropriate PCR primers, accounting for artefacts and the problem of genotyping alleles from multiple, co-amplifying loci, a strategy which is frequently necessary due to the structure of the MHC. The suitability of typing techniques is compared in various research situations, strategies for efficient genotyping are discussed and areas of likely progress in future are identified. This review addresses the well established typing methods such as the Single Strand Conformation Polymorphism (SSCP), Denaturing Gradient Gel Electrophoresis (DGGE), Reference Strand Conformational Analysis (RSCA) and cloning of PCR products. In addition, it includes the intriguing possibility of direct amplicon sequencing followed by the computational inference of alleles and also next generation sequencing (NGS) technologies; the latter technique may, in the future, find widespread use in typing complex multilocus MHC systems. © 2009 Blackwell Publishing Ltd.

MHC class I down-regulation: Tumour escape from immune surveillance? (Review)

Czech Academy of Sciences Publication Activity Database

Bubeník, Jan

2004-01-01

Roč. 25, č. 2 (2004), s. 487-491 ISSN 1019-6439 R&D Projects: GA MZd NC7148; GA ČR GA301/04/0492; GA AV ČR IAA5052203 Institutional research plan: CEZ:AV0Z5052915 Keywords : MHC class I- tumour cells * immune surveillance Subject RIV: EC - Immunology Impact factor: 3.056, year: 2004

Prediction of antigenic epitopes and MHC binders of neurotoxin ...

African Journals Online (AJOL)

PRECIOUS

2009-12-01

Dec 1, 2009 ... scorpion chlorotoxin-like short-chain neurotoxins (SCNs). *Corresponding ... Protein sequence analysis. Here we ... MHC/peptide binding is a log-transformed value related to the IC50 values in nM ..... porter. Adducts of MHC and peptide complexes are the ligands for T cell receptors (TCR) (Table-1). MHC.

Sympatric and allopatric divergence of MHC genes in threespine stickleback.

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Blake Matthews

2010-06-01

Full Text Available Parasites can strongly affect the evolution of their hosts, but their effects on host diversification are less clear. In theory, contrasting parasite communities in different foraging habitats could generate divergent selection on hosts and promote ecological speciation. Immune systems are costly to maintain, adaptable, and an important component of individual fitness. As a result, immune system genes, such as those of the Major Histocompatibility Complex (MHC, can change rapidly in response to parasite-mediated selection. In threespine stickleback (Gasterosteus aculeatus, as well as in other vertebrates, MHC genes have been linked with female mating preference, suggesting that divergent selection acting on MHC genes might influence speciation. Here, we examined genetic variation at MHC Class II loci of sticklebacks from two lakes with a limnetic and benthic species pair, and two lakes with a single species. In both lakes with species pairs, limnetics and benthics differed in their composition of MHC alleles, and limnetics had fewer MHC alleles per individual than benthics. Similar to the limnetics, the allopatric population with a pelagic phenotype had few MHC alleles per individual, suggesting a correlation between MHC genotype and foraging habitat. Using a simulation model we show that the diversity and composition of MHC alleles in a sympatric species pair depends on the amount of assortative mating and on the strength of parasite-mediated selection in adjacent foraging habitats. Our results indicate parallel divergence in the number of MHC alleles between sympatric stickleback species, possibly resulting from the contrasting parasite communities in littoral and pelagic habitats of lakes.

Stepwise threshold clustering: a new method for genotyping MHC loci using next-generation sequencing technology.

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William E Stutz

Full Text Available Genes of the vertebrate major histocompatibility complex (MHC are of great interest to biologists because of their important role in immunity and disease, and their extremely high levels of genetic diversity. Next generation sequencing (NGS technologies are quickly becoming the method of choice for high-throughput genotyping of multi-locus templates like MHC in non-model organisms. Previous approaches to genotyping MHC genes using NGS technologies suffer from two problems:1 a "gray zone" where low frequency alleles and high frequency artifacts can be difficult to disentangle and 2 a similar sequence problem, where very similar alleles can be difficult to distinguish as two distinct alleles. Here were present a new method for genotyping MHC loci--Stepwise Threshold Clustering (STC--that addresses these problems by taking full advantage of the increase in sequence data provided by NGS technologies. Unlike previous approaches for genotyping MHC with NGS data that attempt to classify individual sequences as alleles or artifacts, STC uses a quasi-Dirichlet clustering algorithm to cluster similar sequences at increasing levels of sequence similarity. By applying frequency and similarity based criteria to clusters rather than individual sequences, STC is able to successfully identify clusters of sequences that correspond to individual or similar alleles present in the genomes of individual samples. Furthermore, STC does not require duplicate runs of all samples, increasing the number of samples that can be genotyped in a given project. We show how the STC method works using a single sample library. We then apply STC to 295 threespine stickleback (Gasterosteus aculeatus samples from four populations and show that neighboring populations differ significantly in MHC allele pools. We show that STC is a reliable, accurate, efficient, and flexible method for genotyping MHC that will be of use to biologists interested in a variety of downstream applications.

MHCcluster, a method for functional clustering of MHC molecules

DEFF Research Database (Denmark)

Thomsen, Martin Christen Frølund; Lundegaard, Claus; Buus, Søren

2013-01-01

The identification of peptides binding to major histocompatibility complexes (MHC) is a critical step in the understanding of T cell immune responses. The human MHC genomic region (HLA) is extremely polymorphic comprising several thousand alleles, many encoding a distinct molecule. The potentially...... binding specificity. The method has a flexible web interface that allows the user to include any MHC of interest in the analysis. The output consists of a static heat map and graphical tree-based visualizations of the functional relationship between MHC variants and a dynamic TreeViewer interface where...

[Construction of haplotype and haplotype block based on tag single nucleotide polymorphisms and their applications in association studies].

Science.gov (United States)

Gu, Ming-liang; Chu, Jia-you

2007-12-01

Human genome has structures of haplotype and haplotype block which provide valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to complex diseases. Haplotype block can be divided into discrete blocks of limited haplotype diversity. In each block, a small fraction of ptag SNPsq can be used to distinguish a large fraction of the haplotypes. These tag SNPs can be potentially useful for construction of haplotype and haplotype block, and association studies in complex diseases. There are two general classes of methods to construct haplotype and haplotype blocks based on genotypes on large pedigrees and statistical algorithms respectively. The author evaluate several construction methods to assess the power of different association tests with a variety of disease models and block-partitioning criteria. The advantages, limitations and applications of each method and the application in the association studies are discussed equitably. With the completion of the HapMap and development of statistical algorithms for addressing haplotype reconstruction, ideas of construction of haplotype based on combination of mathematics, physics, and computer science etc will have profound impacts on population genetics, location and cloning for susceptible genes in complex diseases, and related domain with life science etc.

Genomic sequence of 'Candidatus Liberibacter solanacearum' haplotype C and its comparison with haplotype A and B genomes.

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Jinhui Wang

Full Text Available Haplotypes A and B of 'Candidatus Liberibacter solanacearum' (CLso are associated with diseases of solanaceous plants, especially Zebra chip disease of potato, and haplotypes C, D and E are associated with symptoms on apiaceous plants. To date, one complete genome of haplotype B and two high quality draft genomes of haplotype A have been obtained for these unculturable bacteria using metagenomics from the psyllid vector Bactericera cockerelli. Here, we present the first genomic sequences obtained for the carrot-associated CLso. These two genomic sequences of haplotype C, FIN114 (1.24 Mbp and FIN111 (1.20 Mbp, were obtained from carrot psyllids (Trioza apicalis harboring CLso. Genomic comparisons between the haplotypes A, B and C revealed that the genome organization differs between these haplotypes, due to large inversions and other recombinations. Comparison of protein-coding genes indicated that the core genome of CLso consists of 885 ortholog groups, with the pan-genome consisting of 1327 ortholog groups. Twenty-seven ortholog groups are unique to CLso haplotype C, whilst 11 ortholog groups shared by the haplotypes A and B, are not found in the haplotype C. Some of these ortholog groups that are not part of the core genome may encode functions related to interactions with the different host plant and psyllid species.

Simulation of Major Histocompatibility Complex (MHC Structure and Peptide Loading into an MHC Binding Pocket with Teachers’Hands

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Mojtaba Sankian

2013-10-01

Full Text Available Molecular understanding of three-dimensional (3D peptide: MHC models require both basic knowledge of computational modeling and skilled visual perception, which are not possessed by all students. The present model aims to simulate MHC molecular structure with the hands and make a profound impression on the students.

NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8-11.

Science.gov (United States)

Lundegaard, Claus; Lamberth, Kasper; Harndahl, Mikkel; Buus, Søren; Lund, Ole; Nielsen, Morten

2008-07-01

NetMHC-3.0 is trained on a large number of quantitative peptide data using both affinity data from the Immune Epitope Database and Analysis Resource (IEDB) and elution data from SYFPEITHI. The method generates high-accuracy predictions of major histocompatibility complex (MHC): peptide binding. The predictions are based on artificial neural networks trained on data from 55 MHC alleles (43 Human and 12 non-human), and position-specific scoring matrices (PSSMs) for additional 67 HLA alleles. As only the MHC class I prediction server is available, predictions are possible for peptides of length 8-11 for all 122 alleles. artificial neural network predictions are given as actual IC(50) values whereas PSSM predictions are given as a log-odds likelihood scores. The output is optionally available as download for easy post-processing. The training method underlying the server is the best available, and has been used to predict possible MHC-binding peptides in a series of pathogen viral proteomes including SARS, Influenza and HIV, resulting in an average of 75-80% confirmed MHC binders. Here, the performance is further validated and benchmarked using a large set of newly published affinity data, non-redundant to the training set. The server is free of use and available at: http://www.cbs.dtu.dk/services/NetMHC.

Complex Mhc-based mate choice in a wild passerine

Science.gov (United States)

Bonneaud, Camille; Chastel, Olivier; Federici, Pierre; Westerdahl, Helena; Sorci, Gabriele

2006-01-01

The extreme polymorphism of the vertebrate major histocompatibility complex (Mhc) is famous for protecting hosts against constantly evolving pathogens. Mate choice is often evoked as a means of maintaining Mhc variability through avoidance of partners with similar Mhc alleles or preference for heterozygotes. Evidence for these two hypotheses mostly comes from studies on humans and laboratory mice. Here, we tested these hypotheses in a wild outbred population of house sparrows (Passer domesticus). Females were not more or less closely related to the males they paired with when considering neutral genetic variation. However, males failed to form breeding pairs when they had too few Mhc alleles and when they were too dissimilar from females at Mhc loci (i.e. had no common alleles). Furthermore, pairs did not form at random as Mhc diversity positively correlated in mating pairs. These results suggest that mate choice evolves in response to (i) benefits in terms of parasite resistance acquired from allelic diversity, and (ii) costs associated with the disruption of co-adapted genes. PMID:16600889

ER stress affects processing of MHC class I-associated peptides

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Meloche Sylvain

2009-02-01

Full Text Available Abstract Background Viral infection and neoplastic transformation trigger endoplasmic reticulum (ER stress. Thus, a large proportion of the cells that must be recognized by the immune system are stressed cells. Cells respond to ER stress by launching the unfolded protein response (UPR. The UPR regulates the two key processes that control major histocompatibility complex class I (MHC I-peptide presentation: protein synthesis and degradation. We therefore asked whether and how the UPR impinges on MHC I-peptide presentation. Results We evaluated the impact of the UPR on global MHC I expression and on presentation of the H2Kb-associated SIINFEKL peptide. EL4 cells stably transfected with vectors coding hen egg lysozyme (HEL-SIINFEKL protein variants were stressed with palmitate or exposed to glucose deprivation. UPR decreased surface expression of MHC I but did not affect MHC I mRNA level nor the total amount of intracellular MHC I proteins. Impaired MHC I-peptide presentation was due mainly to reduced supply of peptides owing to an inhibition of overall protein synthesis. Consequently, generation of H2Kb-SIINFEKL complexes was curtailed during ER stress, illustrating how generation of MHC I peptide ligands is tightly coupled to ongoing protein synthesis. Notably, the UPR-induced decline of MHC I-peptide presentation was more severe when the protein source of peptides was localized in the cytosol than in the ER. This difference was not due to changes in the translation rates of the precursor proteins but to increased stability of the cytosolic protein during ER stress. Conclusion Our results demonstrate that ER stress impairs MHC I-peptide presentation, and that it differentially regulates expression of ER- vs. cytosol-derived peptides. Furthermore, this work illustrates how ER stress, a typical feature of infected and malignant cells, can impinge on cues for adaptive immune recognition.

Are molecular haplotypes worth the time and expense? A cost-effective method for applying molecular haplotypes.

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Mark A Levenstien

2006-08-01

Full Text Available Because current molecular haplotyping methods are expensive and not amenable to automation, many researchers rely on statistical methods to infer haplotype pairs from multilocus genotypes, and subsequently treat these inferred haplotype pairs as observations. These procedures are prone to haplotype misclassification. We examine the effect of these misclassification errors on the false-positive rate and power for two association tests. These tests include the standard likelihood ratio test (LRTstd and a likelihood ratio test that employs a double-sampling approach to allow for the misclassification inherent in the haplotype inference procedure (LRTae. We aim to determine the cost-benefit relationship of increasing the proportion of individuals with molecular haplotype measurements in addition to genotypes to raise the power gain of the LRTae over the LRTstd. This analysis should provide a guideline for determining the minimum number of molecular haplotypes required for desired power. Our simulations under the null hypothesis of equal haplotype frequencies in cases and controls indicate that (1 for each statistic, permutation methods maintain the correct type I error; (2 specific multilocus genotypes that are misclassified as the incorrect haplotype pair are consistently misclassified throughout each entire dataset; and (3 our simulations under the alternative hypothesis showed a significant power gain for the LRTae over the LRTstd for a subset of the parameter settings. Permutation methods should be used exclusively to determine significance for each statistic. For fixed cost, the power gain of the LRTae over the LRTstd varied depending on the relative costs of genotyping, molecular haplotyping, and phenotyping. The LRTae showed the greatest benefit over the LRTstd when the cost of phenotyping was very high relative to the cost of genotyping. This situation is likely to occur in a replication study as opposed to a whole-genome association study.

Mouse Nkrp1-Clr gene cluster sequence and expression analyses reveal conservation of tissue-specific MHC-independent immunosurveillance.

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Qiang Zhang

Full Text Available The Nkrp1 (Klrb1-Clr (Clec2 genes encode a receptor-ligand system utilized by NK cells as an MHC-independent immunosurveillance strategy for innate immune responses. The related Ly49 family of MHC-I receptors displays extreme allelic polymorphism and haplotype plasticity. In contrast, previous BAC-mapping and aCGH studies in the mouse suggest the neighboring and related Nkrp1-Clr cluster is evolutionarily stable. To definitively compare the relative evolutionary rate of Nkrp1-Clr vs. Ly49 gene clusters, the Nkrp1-Clr gene clusters from two Ly49 haplotype-disparate inbred mouse strains, BALB/c and 129S6, were sequenced. Both Nkrp1-Clr gene cluster sequences are highly similar to the C57BL/6 reference sequence, displaying the same gene numbers and order, complete pseudogenes, and gene fragments. The Nkrp1-Clr clusters contain a strikingly dissimilar proportion of repetitive elements compared to the Ly49 clusters, suggesting that certain elements may be partly responsible for the highly disparate Ly49 vs. Nkrp1 evolutionary rate. Focused allelic polymorphisms were found within the Nkrp1b/d (Klrb1b, Nkrp1c (Klrb1c, and Clr-c (Clec2f genes, suggestive of possible immune selection. Cell-type specific transcription of Nkrp1-Clr genes in a large panel of tissues/organs was determined. Clr-b (Clec2d and Clr-g (Clec2i showed wide expression, while other Clr genes showed more tissue-specific expression patterns. In situ hybridization revealed specific expression of various members of the Clr family in leukocytes/hematopoietic cells of immune organs, various tissue-restricted epithelial cells (including intestinal, kidney tubular, lung, and corneal progenitor epithelial cells, as well as myocytes. In summary, the Nkrp1-Clr gene cluster appears to evolve more slowly relative to the related Ly49 cluster, and likely regulates innate immunosurveillance in a tissue-specific manner.

NLRC5: a key regulator of MHC class I-dependent immune responses.

Science.gov (United States)

Kobayashi, Koichi S; van den Elsen, Peter J

2012-12-01

The expression of MHC class I molecules is crucial for the initiation and regulation of adaptive immune responses against pathogens. NOD-, LRR- and CARD-containing 5 (NLRC5) was recently identified as a specific transactivator of MHC class I genes (CITA). NLRC5 and the master regulator for MHC class II genes, class II transactivator (CIITA), interact with similar MHC promoter-bound factors. Here, we provide a broad overview of the molecular mechanisms behind MHC class I transcription and the role of the class I transactivator NLRC5 in MHC class I-dependent immune responses.

A hybrid approach for predicting promiscuous MHC class I restricted ...

Indian Academy of Sciences (India)

Prakash

2006-09-15

Sep 15, 2006 ... with existing MHC binder prediction methods for alleles studied by both ... in locating the promiscuous MHC binding regions from antigen sequence. ... Artificial neural network; MHC class I alleles; promiscuous binders; ... this problem by developing methods for prediction for ... In case equal number of.

Peptide-selective inrichment of MHC II-peptide complexes in tetraspan microdomains distinct from lipid rafts

Czech Academy of Sciences Publication Activity Database

Kropshofer, H.; Spindeldreher, S.; Rohn, T. A.; Platania, N.; Grygar, C.; Wolpl, A.; Langen, H.; Hořejší, Václav; Vogt, A. B.

2002-01-01

Roč. 3, č. 1 (2002), s. 61-68 ISSN 1529-2908 R&D Projects: GA MŠk LN00A026 Keywords : Microdomain * tetraspan proteins * MHC class II Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 27.868, year: 2002

Neuronal MHC Class I Expression Is Regulated by Activity Driven Calcium Signaling.

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Dan Lv

Full Text Available MHC class I (MHC-I molecules are important components of the immune system. Recently MHC-I have been reported to also play important roles in brain development and synaptic plasticity. In this study, we examine the molecular mechanism(s underlying activity-dependent MHC-I expression using hippocampal neurons. Here we report that neuronal expression level of MHC-I is dynamically regulated during hippocampal development after birth in vivo. Kainic acid (KA treatment significantly increases the expression of MHC-I in cultured hippocampal neurons in vitro, suggesting that MHC-I expression is regulated by neuronal activity. In addition, KA stimulation decreased the expression of pre- and post-synaptic proteins. This down-regulation is prevented by addition of an MHC-I antibody to KA treated neurons. Further studies demonstrate that calcium-dependent protein kinase C (PKC is important in relaying KA simulation activation signals to up-regulated MHC-I expression. This signaling cascade relies on activation of the MAPK pathway, which leads to increased phosphorylation of CREB and NF-κB p65 while also enhancing the expression of IRF-1. Together, these results suggest that expression of MHC-I in hippocampal neurons is driven by Ca2+ regulated activation of the MAPK signaling transduction cascade.

Absence of linkage between MHC and a gene involved in susceptibility to human schistosomiasis

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Chiarella J.M.

1998-01-01

Full Text Available Six hundred million people are at risk of infection by Schistosoma mansoni. MHC haplotypes have been reported to segregate with susceptibility to schistosomiasis in murine models. In humans, a major gene related to susceptibility/resistance to infection by S. mansoni (SM1 and displaying the mean fecal egg count as phenotype was detected by segregation analysis. This gene displayed a codominant mode of inheritance with an estimated frequency of 0.20-0.25 for the deleterious allele and accounted for more than 50% of the variance of infection levels. To determine if the SM1 gene segregates with the human MHC chromosomal region, we performed a linkage study by the lod score method. We typed for HLA-A, B, C, DR and DQ antigens in 11 informative families from an endemic area for schistosomiasis in Bahia, Brazil, by the microlymphocytotoxicity technique. HLA-DR typing by the polymerase chain reaction with sequence-specific primers (PCR-SSP and HLA-DQ were confirmed by PCR-sequence-specific oligonucleotide probes (PCR-SSOP. The lod scores for the different q values obtained clearly indicate that there is no physical linkage between HLA and SM1 genes. Thus, susceptibility or resistance to schistosomiasis, as defined by mean fecal egg count, is not primarily dependent on the host's HLA profile. However, if the HLA molecule plays an important role in specific immune responses to S. mansoni, this may involve the development of the different clinical aspects of the disease such as granuloma formation and development of hepatosplenomegaly.

The C-terminal amino acid of the MHC-I heavy chain is critical for binding to Derlin-1 in human cytomegalovirus US11-induced MHC-I degradation.

Science.gov (United States)

Cho, Sunglim; Kim, Bo Young; Ahn, Kwangseog; Jun, Youngsoo

2013-01-01

Derlin-1 plays a critical role in endoplasmic reticulum-associated protein degradation (ERAD) of a particular subset of proteins. Although it is generally accepted that Derlin-1 mediates the export of ERAD substrates from the ER to the cytosol, little is known about how Derlin-1 interacts with these substrates. Human cytomegalovirus (HCMV) US11 exploits Derlin-1-dependent ERAD to degrade major histocompatibility complex class I (MHC-I) molecules and evade immune surveillance. US11 requires the cytosolic tail of the MHC-I heavy chain to divert MHC-I molecules into the ERAD pathway for degradation; however, the underlying mechanisms remain unknown. Here, we show that the cytosolic tail of the MHC-I heavy chain, although not required for interaction with US11, is required for tight binding to Derlin-1 and thus for US11-induced dislocation of the MHC-I heavy chain to the cytosol for proteasomal degradation. Surprisingly, deletion of a single C-terminal amino acid from the cytosolic tail disrupted the interaction between MHC-I molecules and Derlin-1, rendering mutant MHC-I molecules resistant to US11-induced degradation. Consistently, deleting the C-terminal cytosolic region of Derlin-1 prevented it from binding to MHC-I molecules. Taken together, these results suggest that the cytosolic region of Derlin-1 is involved in ERAD substrate binding and that this interaction is critical for the Derlin-1-mediated dislocation of the MHC-I heavy chain to the cytosol during US11-induced MHC-I degradation.

Chemotherapy, IL-12 gene therapy and combined adjuvant therapy of HPV 16-associated MHC class I-proficient and -deficient tumours

Czech Academy of Sciences Publication Activity Database

Indrová, Marie; Bieblová, Jana; Jandlová, Táňa; Vonka, V.; Pajtasz-Piasecka, E.; Reiniš, Milan

2006-01-01

Roč. 28, č. 1 (2006), s. 253-260 ISSN 1019-6439 R&D Projects: GA MZd(CZ) NR7807; GA MZd(CZ) NR8004 Grant - others:Ministry of Scientific Research Information Society Technologies(PL) PBZ-KBN-091/PO5/2003 Institutional research plan: CEZ:AV0Z50520514 Keywords : HPV 16 * MHC class I-deficient and MHC class I-proficient tumour cells * CMRTD Subject RIV: EC - Immunology Impact factor: 2.556, year: 2006

MHC Intratumoral Heterogeneity May Predict Cancer Progression and Response to Immunotherapy

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Irene Romero

2018-01-01

Full Text Available An individual tumor can present intratumoral phenotypic heterogeneity, containing tumor cells with different phenotypes that do not present irreversible genetic alterations. We have developed a mouse cancer model, named GR9, derived from a methylcholanthrene-induced fibrosarcoma that was adapted to tissue culture and cloned into different tumor cell lines. The clones showed diverse MHC-I phenotypes, ranging from highly positive to weakly positive MHC-I expression. These MHC-I alterations are due to reversible molecular mechanisms, because surface MHC-I could be recovered by IFN-γ treatment. Cell clones with high MHC-I expression demonstrated low local oncogenicity and high spontaneous metastatic capacity, whereas MHC-I-low clones showed high local oncogenicity and no spontaneous metastatic capacity. Although MHC-I-low clones did not metastasize, they produced MHC-I-positive dormant micrometastases controlled by the host immune system, i.e., in a state of immunodormancy. The metastatic capacity of each clone was directly correlated with the host T-cell subpopulations; thus, a strong decrease in cytotoxic and helper T lymphocytes was observed in mice with numerous metastases derived from MHC-I positive tumor clones but a strong increase was observed in those with dormant micrometastases. Immunotherapy was administered to the hosts after excision of the primary tumor, producing a recovery in their immune status and leading to the complete eradication of overt spontaneous metastases or their decrease. According to these findings, the combination of MHC-I surface expression in primary tumor and metastases with host T-cell subsets may be a decisive indicator of the clinical outcome and response to immunotherapy in metastatic disease, allowing the identification of responders to this approach.

Fine-mapping analysis of the MHC region for vitiligo based on a new Han-MHC reference panel.

Science.gov (United States)

Yang, Chao; Wu, Juan; Zhang, Xuelei; Wen, Leilei; Sun, Jingying; Cheng, Yuyan; Tang, Xianfa; Liang, Bo; Chen, Gang; Zhou, Fusheng; Cui, Yong; Zhang, Anping; Zhang, Xuejun; Zheng, Xiaodong; Yang, Sen; Sun, Liangdan

2018-03-30

Vitiligo is an immune-related disease with patchy depigmentation of skin and hair caused by selective destruction of melanocytes. In recent decades, many studies have shown the association between vitiligo and HLA genes; however, the results of Han Chinese are scarce. In this study, we performed a fine-mapping analysis of the MHC region in 2818 Han Chinese subjects through a widely used HLA imputation method with a newly built large-scale Han-MHC reference panel. Three new four-digit HLA alleles (HLA-DQB1 ∗ 02:02, HLA-DQA1 ∗ 02:01 and HLA-DPB1 ∗ 17:01) were identified to be associated with the risk of vitiligo, and four previously reported alleles were confirmed. Further conditional analysis revealed that two important variants, HLA-DQβ1 amino acid position 135 (OR = 1.79, P = 1.87 × 10 -11 ) and HLA-B amino acid positions 45-46 (OR = 1.44, P = 5.61 × 10 -11 ), conferred most of the MHC associations. Three-dimension ribbon models showed that the former is located within the β2 domain of the HLA-DQβ1 molecule, and the latter lies in the α1 domain of the HLA-B molecule, while both are involved in specific antigen presenting process. Finally, we summarized all significant signals in the MHC region to clarify their complex relationships, and 8.60% of phenotypic variance could be explained based on all reported variants in Han Chinese so far. Our findings highlight the complex genetic architecture of the MHC region for vitiligo in Han Chinese population and expand our understanding of the roles of HLA coding variants in the etiology of vitiligo. Copyright © 2018. Published by Elsevier B.V.

Virus encoded MHC-like decoys diversify the inhibitory KIR repertoire.

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Paola Carrillo-Bustamante

Full Text Available Natural killer (NK cells are circulating lymphocytes that play an important role in the control of viral infections and tumors. Their functions are regulated by several activating and inhibitory receptors. A subset of these receptors in human NK cells are the killer immunoglobulin-like receptors (KIRs, which interact with the highly polymorphic MHC class I molecules. One important function of NK cells is to detect cells that have down-regulated MHC expression (missing-self. Because MHC molecules have non polymorphic regions, their expression could have been monitored with a limited set of monomorphic receptors. Surprisingly, the KIR family has a remarkable genetic diversity, the function of which remains poorly understood. The mouse cytomegalovirus (MCMV is able to evade NK cell responses by coding "decoy" molecules that mimic MHC class I. This interaction was suggested to have driven the evolution of novel NK cell receptors. Inspired by the MCMV system, we develop an agent-based model of a host population infected with viruses that are able to evolve MHC down-regulation and decoy molecules. Our simulations show that specific recognition of MHC class I molecules by inhibitory KIRs provides excellent protection against viruses evolving decoys, and that the diversity of inhibitory KIRs will subsequently evolve as a result of the required discrimination between host MHC molecules and decoy molecules.

MHC class I dowregulation, tumour escape from immune surveillance and design of therapeutic strategies

Czech Academy of Sciences Publication Activity Database

Bubeník, Jan

2005-01-01

Roč. 51, č. 1 (2005), s. 1-2 ISSN 0015-5500 R&D Projects: GA ČR GA301/04/0492; GA MZd NR7807 Institutional research plan: CEZ:AV0Z50520514 Keywords : MHC class I * immune surveillance * immunotherapy Subject RIV: EC - Immunology Impact factor: 0.719, year: 2005

MHC class II B diversity in blue tits : A preliminary study

NARCIS (Netherlands)

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

In this study, we partly characterize major histocompatibility complex (MHC) class II B in the blue tit (Cyanistes caeruleus). A total of 22 individuals from three different European locations: Spain, The Netherlands, and Sweden were screened for MHC allelic diversity. The MHC genes were

Cheetah paradigm revisited: MHC diversity in the world's largest free-ranging population.

Science.gov (United States)

Castro-Prieto, Aines; Wachter, Bettina; Sommer, Simone

2011-04-01

For more than two decades, the cheetah (Acinonyx jubatus) has been considered a paradigm of disease vulnerability associated with low genetic diversity, particularly at the immune genes of the major histocompatibility complex (MHC). Cheetahs have been used as a classic example in numerous conservation genetics textbooks as well as in many related scientific publications. However, earlier studies used methods with low resolution to quantify MHC diversity and/or small sample sizes. Furthermore, high disease susceptibility was reported only for captive cheetahs, whereas free-ranging cheetahs show no signs of infectious diseases and a good general health status. We examined whether the diversity at MHC class I and class II-DRB loci in 149 Namibian cheetahs was higher than previously reported using single-strand conformation polymorphism analysis, cloning, and sequencing. MHC genes were examined at the genomic and transcriptomic levels. We detected ten MHC class I and four class II-DRB alleles, of which nine MHC class I and all class II-DRB alleles were expressed. Phylogenetic analyses and individual genotypes suggested that the alleles belong to four MHC class I and three class II-DRB putative loci. Evidence of positive selection was detected in both MHC loci. Our study indicated that the low number of MHC class I alleles previously observed in cheetahs was due to a smaller sample size examined. On the other hand, the low number of MHC class II-DRB alleles previously observed in cheetahs was further confirmed. Compared with other mammalian species including felids, cheetahs showed low levels of MHC diversity, but this does not seem to influence the immunocompetence of free-ranging cheetahs in Namibia and contradicts the previous conclusion that the cheetah is a paradigm species of disease vulnerability.

Sex-specific selection for MHC variability in Alpine chamois

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Schaschl Helmut

2012-02-01

Full Text Available Abstract Background In mammals, males typically have shorter lives than females. This difference is thought to be due to behavioural traits which enhance competitive abilities, and hence male reproductive success, but impair survival. Furthermore, in many species males usually show higher parasite burden than females. Consequently, the intensity of selection for genetic factors which reduce susceptibility to pathogens may differ between sexes. High variability at the major histocompatibility complex (MHC genes is believed to be advantageous for detecting and combating the range of infectious agents present in the environment. Increased heterozygosity at these immune genes is expected to be important for individual longevity. However, whether males in natural populations benefit more from MHC heterozygosity than females has rarely been investigated. We investigated this question in a long-term study of free-living Alpine chamois (Rupicapra rupicapra, a polygynous mountain ungulate. Results Here we show that male chamois survive significantly (P = 0.022 longer if heterozygous at the MHC class II DRB locus, whereas females do not. Improved survival of males was not a result of heterozygote advantage per se, as background heterozygosity (estimated across twelve microsatellite loci did not change significantly with age. Furthermore, reproductively active males depleted their body fat reserves earlier than females leading to significantly impaired survival rates in this sex (P Conclusions Increased MHC class II DRB heterozygosity with age in males, suggests that MHC heterozygous males survive longer than homozygotes. Reproductively active males appear to be less likely to survive than females most likely because of the energetic challenge of the winter rut, accompanied by earlier depletion of their body fat stores, and a generally higher parasite burden. This scenario renders the MHC-mediated immune response more important for males than for females

MHC class I status of tumours and design of immunotherapeutic strategies

Czech Academy of Sciences Publication Activity Database

Bubeník, Jan; Vonka, V.

2003-01-01

Roč. 90, 2-3 (2003), s. 177-178 ISSN 0165-2478 R&D Projects: GA MZd NC7148; GA MZd NC3707; GA MZd NC6957; GA MZd NC7552; GA ČR GA301/01/0985; GA AV ČR IAA5052203 Institutional research plan: CEZ:AV0Z5052915 Keywords : MHC * beta2-mikroglobulin * immunotherapeutic strategies Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.710, year: 2003

MHC class II polymorphisms, autoreactive T-cells and autoimmunity

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Sue eTsai

2013-10-01

Full Text Available Major histocompatibility complex (MHC genes, also known as human leukocyte antigen genes (HLA in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D, Multiple Sclerosis (MS, and Rheumatoid arthritis (RA, among others (Todd and Wicker, 2001;MacKay et al., 2002;Hafler et al., 2007. Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T cell repertoires of the host towards autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development towards a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development towards non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

Semi-empirical quantum evaluation of peptide - MHC class II binding

Science.gov (United States)

González, Ronald; Suárez, Carlos F.; Bohórquez, Hugo J.; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2017-01-01

Peptide presentation by the major histocompatibility complex (MHC) is a key process for triggering a specific immune response. Studying peptide-MHC (pMHC) binding from a structural-based approach has potential for reducing the costs of investigation into vaccine development. This study involved using two semi-empirical quantum chemistry methods (PM7 and FMO-DFTB) for computing the binding energies of peptides bonded to HLA-DR1 and HLA-DR2. We found that key stabilising water molecules involved in the peptide binding mechanism were required for finding high correlation with IC50 experimental values. Our proposal is computationally non-intensive, and is a reliable alternative for studying pMHC binding interactions.

MHC class II+ (HLA-DP-like) cells in the cow reproductive tract: II. Immunolocalization of MHC class II+ cells in oviduct and vagina.

Science.gov (United States)

Eren, U; Kum, S; Sandikçi, M; Eren, V; Ilhan, F

2009-08-01

The aim of this study was to determine and examine the distribution of major frequency MHC II+ cells in the oviduct and vagina of cows during the oestrous and dioestrus phases. Right oviduct (ampulla, isthmus) and vaginal samples taken from a total of twenty seven multiparous cows were used. Tissue samples were processed to obtain both cryostat and paraffin sections. Sections were stained immunocytochemically using StreptABC method using a specific monoclonal antibody to MHC II+ cell population. Intra-epithelial and subepithelial areas along with lamina propria, muscularis mucosae and serosa of both ampulla and isthmus and intra-epithelial/subepithelial areas and mucosae of vagina were examined for the presence of MHC II+ cells. The density of immune positive cells was determined using a subjective scoring system. MHC II+ cells were demonstrated in all areas examined in both oestrus and dioestrus. In oestrus, the density of MHC II+ cells decreased in subepithelial areas (in between the epithelial cells and the basal membrane) of isthmus, whereas the density of immune positive cells was increased in muscularis mucosae of isthmus (P < 0.05), lamina propria and muscularis mucosae of ampulla (P < 0.05) as well as in the mucosae of vagina (P MHC II+ cells observed in the oviduct and vagina increases in the majority of areas examined due to the effect of oestrogen.

MHC class II deficiency: Report of a novel mutation and special review.

Science.gov (United States)

Farrokhi, S; Shabani, M; Aryan, Z; Zoghi, S; Krolo, A; Boztug, K; Rezaei, N

The MHC II deficiency is a rare autosomal recessive primary immunodeficiency syndrome with increased susceptibility to respiratory and gastrointestinal infections, failure to thrive and early mortality. This syndrome is caused by mutations in transcription regulators of the MHC II gene and results in development of blind lymphocytes due to the lack of indicatory MHC II molecules. Despite homogeneity of clinical manifestations of patients with MHC II deficiency, the genetic defects underlying this disease are heterogeneous. Herein, we report an Iranian patient with MHC II deficiency harbouring a novel mutation in RFXANK and novel misleading clinical features. He had ataxic gait and dysarthria from 30 months of age. Epidemiology, clinical and immunological features, therapeutic options and prognosis of patients with MHC II are reviewed in this paper. Copyright © 2017 SEICAP. Published by Elsevier España, S.L.U. All rights reserved.

Factor IX gene haplotypes in Amerindians.

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Franco, R F; Araújo, A G; Zago, M A; Guerreiro, J F; Figueiredo, M S

1997-02-01

We have determined the haplotypes of the factor IX gene for 95 Indians from 5 Brazilian Amazon tribes: Wayampí, Wayana-Apalaí, Kayapó, Arára, and Yanomámi. Eight polymorphisms linked to the factor IX gene were investigated: MseI (at 5', nt -698), BamHI (at 5', nt -561), DdeI (intron 1), BamHI (intron 2), XmnI (intron 3), TaqI (intron 4), MspI (intron 4), and HhaI (at 3', approximately 8 kb). The results of the haplotype distribution and the allele frequencies for each of the factor IX gene polymorphisms in Amerindians were similar to the results reported for Asian populations but differed from results for other ethnic groups. Only five haplotypes were identified within the entire Amerindian study population, and the haplotype distribution was significantly different among the five tribes, with one (Arára) to four (Wayampí) haplotypes being found per tribe. These findings indicate a significant heterogeneity among the Indian tribes and contrast with the homogeneous distribution of the beta-globin gene cluster haplotypes but agree with our recent findings on the distribution of alpha-globin gene cluster haplotypes and the allele frequencies for six VNTRs in the same Amerindian tribes. Our data represent the first study of factor IX-associated polymorphisms in Amerindian populations and emphasizes the applicability of these genetic markers for population and human evolution studies.

The systems biology of MHC class II antigen presentation

NARCIS (Netherlands)

Paul, Petra

2012-01-01

Major histocompatibility class II molecules (MHC class II) are one of the key regulators of adaptive immunity because of their specific expression by professional antigen presenting cells (APC). They present peptides derived from endocytosed material to T helper lymphocytes. Consequently, MHC class

MHC2NNZ: A novel peptide binding prediction approach for HLA DQ molecules

Science.gov (United States)

Xie, Jiang; Zeng, Xu; Lu, Dongfang; Liu, Zhixiang; Wang, Jiao

2017-07-01

The major histocompatibility complex class II (MHC-II) molecule plays a crucial role in immunology. Computational prediction of MHC-II binding peptides can help researchers understand the mechanism of immune systems and design vaccines. Most of the prediction algorithms for MHC-II to date have made large efforts in human leukocyte antigen (HLA, the name of MHC in Human) molecules encoded in the DR locus. However, HLA DQ molecules are equally important and have only been made less progress because it is more difficult to handle them experimentally. In this study, we propose an artificial neural network-based approach called MHC2NNZ to predict peptides binding to HLA DQ molecules. Unlike previous artificial neural network-based methods, MHC2NNZ not only considers sequence similarity features but also captures the chemical and physical properties, and a novel method incorporating these properties is proposed to represent peptide flanking regions (PFR). Furthermore, MHC2NNZ improves the prediction accuracy by combining with amino acid preference at more specific positions of the peptides binding core. By evaluating on 3549 peptides binding to six most frequent HLA DQ molecules, MHC2NNZ is demonstrated to outperform other state-of-the-art MHC-II prediction methods.

Detecting structure of haplotypes and local ancestry

Science.gov (United States)

We present a two-layer hidden Markov model to detect the structure of haplotypes for unrelated individuals. This allows us to model two scales of linkage disequilibrium (one within a group of haplotypes and one between groups), thereby taking advantage of rich haplotype information to infer local an...

NetMHC-3.0: accurate web accessible predictions of human, mouse and monkey MHC class I affinities for peptides of length 8-11

DEFF Research Database (Denmark)

Lundegaard, Claus; Lamberth, K; Harndahl, M

2008-01-01

NetMHC-3.0 is trained on a large number of quantitative peptide data using both affinity data from the Immune Epitope Database and Analysis Resource (IEDB) and elution data from SYFPEITHI. The method generates high-accuracy predictions of major histocompatibility complex (MHC): peptide binding...

An MHC class I immune evasion gene of Marek׳s disease virus.

Science.gov (United States)

Hearn, Cari; Preeyanon, Likit; Hunt, Henry D; York, Ian A

2015-01-15

Marek׳s disease virus (MDV) is a widespread α-herpesvirus of chickens that causes T cell tumors. Acute, but not latent, MDV infection has previously been shown to lead to downregulation of cell-surface MHC class I (Virology 282:198-205 (2001)), but the gene(s) involved have not been identified. Here we demonstrate that an MDV gene, MDV012, is capable of reducing surface expression of MHC class I on chicken cells. Co-expression of an MHC class I-binding peptide targeted to the endoplasmic reticulum (bypassing the requirement for the TAP peptide transporter) partially rescued MHC class I expression in the presence of MDV012, suggesting that MDV012 is a TAP-blocking MHC class I immune evasion protein. This is the first unique non-mammalian MHC class I immune evasion gene identified, and suggests that α-herpesviruses have conserved this function for at least 100 million years. Copyright © 2014 Elsevier Inc. All rights reserved.

A Genome-wide multidimensional RNAi screen reveals pathways controlling MHC class II antigen presentation

NARCIS (Netherlands)

Paul, Petra; van den Hoorn, Tineke; Jongsma, Marlieke L. M.; Bakker, Mark J.; Hengeveld, Rutger; Janssen, Lennert; Cresswell, Peter; Egan, David A.; van Ham, Marieke; ten Brinke, Anja; Ovaa, Huib; Beijersbergen, Roderick L.; Kuijl, Coenraad; Neefjes, Jacques

2011-01-01

MHC class II molecules (MHC-II) present peptides to T helper cells to facilitate immune responses and are strongly linked to autoimmune diseases. To unravel processes controlling MHC-II antigen presentation, we performed a genome-wide flow cytometry-based RNAi screen detecting MHC-II expression and

The Intensity of Human Body Odors and the MHC: Should We Expect a Link?

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Claus Wedekind

2006-01-01

Full Text Available It is now well established that genes within the major histocompatibility complex (MHC somehow affect the production of body odors in several vertebrates, including humans. Here we discuss whether variation in the intensity of body odors may be influenced by the MHC. In order to examine this question, we have to control for MHC-linked odor perception on the smeller's side. Such a control is necessary because the perception of pleasantness and intensity seem to be confounded, and the causalities are still unsolved. It has previously been found that intense odors are scored as less pleasant if the signaler and the receiver are of MHC-dissimilar type, but not if they are of MHC similar type. We argue, and first data suggest, that an effect of the degree of MHC-heterozygosity and odor intensity is likely (MHC-homozygotes may normally smell more intense, while there is currently no strong argument for other possible links between the MHC and body odor intensity.

Y-chromosome STR haplotypes in Somalis

DEFF Research Database (Denmark)

Hallenberg, Charlotte; Simonsen, Bo; Sanchez Sanchez, Juan Jose

2005-01-01

A total of 201 males from Somalia were typed for the Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 with the PowerPlex Y kit (Promega). A total of 96 different haplotypes were observed and the haplotype diversity was 0.9715. The ......A total of 201 males from Somalia were typed for the Y-chromosome STRs DYS19, DYS385a/b, DYS389-I, DYS389-II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439 with the PowerPlex Y kit (Promega). A total of 96 different haplotypes were observed and the haplotype diversity was 0...

Functional recombinant MHC class II molecules and high-throughput peptide-binding assays

DEFF Research Database (Denmark)

Justesen, Sune; Harndahl, Mikkel; Lamberth, Kasper

2009-01-01

BACKGROUND: Molecules of the class II major histocompability complex (MHC-II) specifically bind and present exogenously derived peptide epitopes to CD4+ T helper cells. The extreme polymorphism of the MHC-II hampers the complete analysis of peptide binding. It is also a significant hurdle......-II molecules and accompanying HTS peptide-binding assay were successfully developed for nine different MHC-II molecules including the DPA1*0103/DPB1*0401 (DP401) and DQA1*0501/DQB1*0201, where both alpha and beta chains are polymorphic, illustrating the advantages of producing the two chains separately....... CONCLUSION: We have successfully developed versatile MHC-II resources, which may assist in the generation of MHC class II -wide reagents, data, and tools....

Haplotyping Problem, A Clustering Approach

International Nuclear Information System (INIS)

Eslahchi, Changiz; Sadeghi, Mehdi; Pezeshk, Hamid; Kargar, Mehdi; Poormohammadi, Hadi

2007-01-01

Construction of two haplotypes from a set of Single Nucleotide Polymorphism (SNP) fragments is called haplotype reconstruction problem. One of the most popular computational model for this problem is Minimum Error Correction (MEC). Since MEC is an NP-hard problem, here we propose a novel heuristic algorithm based on clustering analysis in data mining for haplotype reconstruction problem. Based on hamming distance and similarity between two fragments, our iterative algorithm produces two clusters of fragments; then, in each iteration, the algorithm assigns a fragment to one of the clusters. Our results suggest that the algorithm has less reconstruction error rate in comparison with other algorithms

Estimating haplotype effects for survival data.

Science.gov (United States)

Scheike, Thomas H; Martinussen, Torben; Silver, Jeremy D

2010-09-01

Genetic association studies often investigate the effect of haplotypes on an outcome of interest. Haplotypes are not observed directly, and this complicates the inclusion of such effects in survival models. We describe a new estimating equations approach for Cox's regression model to assess haplotype effects for survival data. These estimating equations are simple to implement and avoid the use of the EM algorithm, which may be slow in the context of the semiparametric Cox model with incomplete covariate information. These estimating equations also lead to easily computable, direct estimators of standard errors, and thus overcome some of the difficulty in obtaining variance estimators based on the EM algorithm in this setting. We also develop an easily implemented goodness-of-fit procedure for Cox's regression model including haplotype effects. Finally, we apply the procedures presented in this article to investigate possible haplotype effects of the PAF-receptor on cardiovascular events in patients with coronary artery disease, and compare our results to those based on the EM algorithm. © 2009, The International Biometric Society.

The effect of genealogy-based haplotypes on genomic prediction

DEFF Research Database (Denmark)

Edriss, Vahid; Fernando, Rohan L.; Su, Guosheng

2013-01-01

on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. Methods A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using...... local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (pi) of the haplotype covariates had zero effect......, i.e. a Bayesian mixture method. Results About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some...

Contrasting patterns of selection between MHC I and II across populations of Humboldt and Magellanic penguins.

Science.gov (United States)

Sallaberry-Pincheira, Nicole; González-Acuña, Daniel; Padilla, Pamela; Dantas, Gisele P M; Luna-Jorquera, Guillermo; Frere, Esteban; Valdés-Velásquez, Armando; Vianna, Juliana A

2016-10-01

The evolutionary and adaptive potential of populations or species facing an emerging infectious disease depends on their genetic diversity in genes, such as the major histocompatibility complex (MHC). In birds, MHC class I deals predominantly with intracellular infections (e.g., viruses) and MHC class II with extracellular infections (e.g., bacteria). Therefore, patterns of MHC I and II diversity may differ between species and across populations of species depending on the relative effect of local and global environmental selective pressures, genetic drift, and gene flow. We hypothesize that high gene flow among populations of Humboldt and Magellanic penguins limits local adaptation in MHC I and MHC II, and signatures of selection differ between markers, locations, and species. We evaluated the MHC I and II diversity using 454 next-generation sequencing of 100 Humboldt and 75 Magellanic penguins from seven different breeding colonies. Higher genetic diversity was observed in MHC I than MHC II for both species, explained by more than one MHC I loci identified. Large population sizes, high gene flow, and/or similar selection pressures maintain diversity but limit local adaptation in MHC I. A pattern of isolation by distance was observed for MHC II for Humboldt penguin suggesting local adaptation, mainly on the northernmost studied locality. Furthermore, trans-species alleles were found due to a recent speciation for the genus or convergent evolution. High MHC I and MHC II gene diversity described is extremely advantageous for the long-term survival of the species.

Cutting Edge: Impaired MHC Class I Expression in Mice Deficient for Nlrc5/CITA

OpenAIRE

Biswas, Amlan; Meissner, Torsten B.; Taro Kawai,; Kobayashi, Koichi S.

2012-01-01

MHC class I and class II are crucial for the adaptive immune system. Although regulation of MHC class II expression by CIITA (class II transactivator) has long been recognized, the mechanism of MHC class I transactivation has been largely unknown until the recent discovery of NLRC5/CITA. Here we show using Nlrc5-deficient mice that NLRC5 is required for both constitutive and inducible MHC class I expression. Loss of Nlrc5 resulted in severe reduction in the expression of MHC class I and relat...

Complex assembly, crystallization and preliminary X-ray crystallographic studies of duck MHC class I molecule

International Nuclear Information System (INIS)

Zhang, Jianhua; Chen, Yong; Gao, Feng; Chen, Weihong; Qi, Jianxun; Xia, Chun

2009-01-01

Using a peptide derived from H5N1, a complex of duck MHC class I molecule (DuMHC I) with duck β 2 -microglobulin (Duβ 2 m) was assembled and crystallized. Initial structure analysis indicated that the crystals did not contain the complete DuMHC I complex but instead contained DuMHC I α3-domain and Duβ 2 m subunits. In order to understand the biological properties of the immune systems of waterfowl and to establish a system for structural studies of duck class I major histocompatibility complex (DuMHC I), a complex of DuMHC I with duck β 2 -microglobulin (Duβ 2 m) and the peptide AEIEDLIF (AF8) derived from H5N1 NP residues 251–258 was assembled. The complex was crystallized; the crystals belonged to space group C222 1 , with unit-cell parameters a = 54.7, b = 72.4, c = 102.2 Å, and diffracted to 2.3 Å resolution. Matthews coefficient calculation and initial structure determination by molecular replacement showed that the crystals did not contain the whole DuMHC I complex, but instead contained the DuMHC I α3 domain and a Duβ2m molecule (DuMHC I α3+β2m). Another complex of DuMHC I with the peptide IDWFDGKE derived from a chicken fusion protein also generated the same results. The stable structure of DuMHC I α3+β2m may reflect some unique characteristics of DuMHC I and pave the way for novel MHC structure-related studies in the future

Low genetic variation in the MHC class II DRB gene and MHC-linked microsatellites in endangered island populations of the leopard cat (Prionailurus bengalensis) in Japan.

Science.gov (United States)

Saka, Toshinori; Nishita, Yoshinori; Masuda, Ryuichi

2018-02-01

Isolated populations of the leopard cat (Prionailurus bengalensis) on Tsushima and Iriomote islands in Japan are classified as subspecies P. b. euptilurus and P. b. iriomotensis, respectively. Because both populations have decreased to roughly 100, an understanding of their genetic diversity is essential for conservation. We genotyped MHC class II DRB exon 2 and MHC-linked microsatellite loci to evaluate the diversity of MHC genes in the Tsushima and Iriomote cat populations. We detected ten and four DRB alleles in these populations, respectively. A phylogenetic analysis showed DRB alleles from both populations to be closely related to those in other felid DRB lineages, indicating trans-species polymorphism. The MHC-linked microsatellites were more polymorphic in the Tsushima than in the Iriomote population. The MHC diversity of both leopard cat populations is much lower than in the domestic cat populations on these islands, probably due to inbreeding associated with founder effects, geographical isolation, or genetic drift. Our results predict low resistance of the two endangered populations to new pathogens introduced to the islands.

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

Science.gov (United States)

Denzin, Lisa K; Cresswell, Peter

2013-01-01

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

A comprehensive literature review of haplotyping software and methods for use with unrelated individuals

Directory of Open Access Journals (Sweden)

Salem Rany M

2005-03-01

Full Text Available Abstract Interest in the assignment and frequency analysis of haplotypes in samples of unrelated individuals has increased immeasurably as a result of the emphasis placed on haplotype analyses by, for example, the International HapMap Project and related initiatives. Although there are many available computer programs for haplotype analysis applicable to samples of unrelated individuals, many of these programs have limitations and/or very specific uses. In this paper, the key features of available haplotype analysis software for use with unrelated individuals, as well as pooled DNA samples from unrelated individuals, are summarised. Programs for haplotype analysis were identified through keyword searches on PUBMED and various internet search engines, a review of citations from retrieved papers and personal communications, up to June 2004. Priority was given to functioning computer programs, rather than theoretical models and methods. The available software was considered in light of a number of factors: the algorithm(s used, algorithm accuracy, assumptions, the accommodation of genotyping error, implementation of hypothesis testing, handling of missing data, software characteristics and web-based implementations. Review papers comparing specific methods and programs are also summarised. Forty-six haplotyping programs were identified and reviewed. The programs were divided into two groups: those designed for individual genotype data (a total of 43 programs and those designed for use with pooled DNA samples (a total of three programs. The accuracy of programs using various criteria are assessed and the programs are categorised and discussed in light of: algorithm and method, accuracy, assumptions, genotyping error, hypothesis testing, missing data, software characteristics and web implementation. Many available programs have limitations (eg some cannot accommodate missing data and/or are designed with specific tasks in mind (eg estimating

Leukemia prevention and long-term survival of AKR mice transplanted with MHC-matched or MHC-mismatched bone marrow

International Nuclear Information System (INIS)

Longley, R.E.; Good, R.A.

1986-01-01

The current studies were designed to evaluate the effectiveness of marrow transplantation within and outside the major histocompatibility complex (MHC) on the long-term survival and occurrence of spontaneous leukemia in AKR mice. AKR mice, which were lethally irradiated and received MHC-matched marrow from CBA/J mice (CBA----AKR), never developed leukemia and were alive and remained healthy for up to 280 days post-transplant. These long-term surviving chimeras possessed substantial immune vigor when both cell-mediated and humoral responses were tested. Lethally irradiated AKR mice, which had received MHC-mismatched marrow (anti-Thy-1.2 treated or nontreated) from C57BL/6J mice (B6----AKR), never developed leukemia and survived up to 170 days post-transplant. However, both groups of these chimeras began dying 180 to 270 days post-transplant due to a disease process which could not be readily identified. Histological analysis of B6----AKR chimeras revealed severe lymphoid cell depletion in thymus and spleen; however, none of these chimeras exhibited classical features of acute graft versus host disease. Concanavalin A mitogenesis, primary antibody responses to sheep red blood cells and the production of interleukin 2 (IL-2) were suppressed in B6----AKR chimeras. IL-2 treatment of B6----AKR chimeras was shown to partially correct these deficiencies without stimulating mixed lymphocyte responsiveness to donor or host lymphocytes. These studies indicate that the use of MHC-mismatched marrow for the prevention of spontaneous AKR leukemia may rely on augmentative IL-2 therapy for complete immune reconstitution of leukemia-free chimeras

Social pairing of Seychelles warblers under reduced constraints: MHC, neutral heterozygosity, and age.

Science.gov (United States)

Wright, David J; Brouwer, Lyanne; Mannarelli, Maria-Elena; Burke, Terry; Komdeur, Jan; Richardson, David S

2016-01-01

The prevalence and significance of precopulatory mate choice remains keenly debated. The major histocompatibility complex (MHC) plays a key role in vertebrate adaptive immunity, and variation at the MHC influences individual survival. Although MHC-dependent mate choice has been documented in certain species, many other studies find no such pattern. This may be, at least in part, because in natural systems constraints may reduce the choices available to individuals and prevent full expression of underlying preferences. We used translocations to previously unoccupied islands to experimentally reduce constraints on female social mate choice in the Seychelles warbler ( Acrocephalus sechellensis ), a species in which patterns of MHC-dependent extrapair paternity (EPP), but not social mate choice, have been observed. We find no evidence of MHC-dependent social mate choice in the new populations. Instead, we find that older males and males with more microsatellite heterozygosity are more likely to have successfully paired. Our data cannot resolve whether these patterns in pairing were due to male-male competition or female choice. However, our research does suggest that female Seychelles warblers do not choose social mates using MHC class I to increase fitness. It may also indicate that the MHC-dependent EPP observed in the source population is probably due to mechanisms other than female precopulatory mate choice based on MHC cues.

Founder haplotype analysis of Fanconi anemia in the Korean population finds common ancestral haplotypes for a FANCG variant.

Science.gov (United States)

Park, Joonhong; Kim, Myungshin; Jang, Woori; Chae, Hyojin; Kim, Yonggoo; Chung, Nack-Gyun; Lee, Jae-Wook; Cho, Bin; Jeong, Dae-Chul; Park, In Yang; Park, Mi Sun

2015-05-01

A common ancestral haplotype is strongly suggested in the Korean and Japanese patients with Fanconi anemia (FA), because common mutations have been frequently found: c.2546delC and c.3720_3724delAAACA of FANCA; c.307+1G>C, c.1066C>T, and c.1589_1591delATA of FANCG. Our aim in this study was to investigate the origin of these common mutations of FANCA and FANCG. We genotyped 13 FA patients consisting of five FA-A patients and eight FA-G patients from the Korean FA population. Microsatellite markers used for haplotype analysis included four CA repeat markers which are closely linked with FANCA and eight CA repeat markers which are contiguous with FANCG. As a result, Korean FA-A patients carrying c.2546delC or c.3720_3724delAAACA did not share the same haplotypes. However, three unique haplotypes carrying c.307+1G>C, c.1066C > T, or c.1589_1591delATA, that consisted of eight polymorphic loci covering a flanking region were strongly associated with Korean FA-G, consistent with founder haplotypes reported previously in the Japanese FA-G population. Our finding confirmed the common ancestral haplotypes on the origins of the East Asian FA-G patients, which will improve our understanding of the molecular population genetics of FA-G. To the best of our knowledge, this is the first report on the association between disease-linked mutations and common ancestral haplotypes in the Korean FA population. © 2015 John Wiley & Sons Ltd/University College London.

pH dependence of MHC class I-restricted peptide presentation

DEFF Research Database (Denmark)

Stryhn, A; Pedersen, L O; Romme, T

1996-01-01

The function of MHC class I molecules is to bind and present antigenic peptides to cytotoxic T cells. Here, we report that class I-restricted peptide presentation is strongly pH dependent. The presentation of some peptides was enhanced at acidic pH, whereas the presentation of others was inhibited....... Biochemical peptide-MHC class I binding assays demonstrated that peptide-MHC class I complexes are more stable at neutral pH than at acidic pH. We suggest that acid-dependent peptide dissociation can generate empty class I molecules and that the resulting binding potential can be exploited by a subset...

Statistical deconvolution of enthalpic energetic contributions to MHC-peptide binding affinity

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Drew Michael GB

2006-03-01

Full Text Available Abstract Background MHC Class I molecules present antigenic peptides to cytotoxic T cells, which forms an integral part of the adaptive immune response. Peptides are bound within a groove formed by the MHC heavy chain. Previous approaches to MHC Class I-peptide binding prediction have largely concentrated on the peptide anchor residues located at the P2 and C-terminus positions. Results A large dataset comprising MHC-peptide structural complexes was created by re-modelling pre-determined x-ray crystallographic structures. Static energetic analysis, following energy minimisation, was performed on the dataset in order to characterise interactions between bound peptides and the MHC Class I molecule, partitioning the interactions within the groove into van der Waals, electrostatic and total non-bonded energy contributions. Conclusion The QSAR techniques of Genetic Function Approximation (GFA and Genetic Partial Least Squares (G/PLS algorithms were used to identify key interactions between the two molecules by comparing the calculated energy values with experimentally-determined BL50 data. Although the peptide termini binding interactions help ensure the stability of the MHC Class I-peptide complex, the central region of the peptide is also important in defining the specificity of the interaction. As thermodynamic studies indicate that peptide association and dissociation may be driven entropically, it may be necessary to incorporate entropic contributions into future calculations.

Characterization of MHC class I in a long distance migratory wader, the Icelandic black-tailed godwit.

Science.gov (United States)

Pardal, Sara; Drews, Anna; Alves, José A; Ramos, Jaime A; Westerdahl, Helena

2017-07-01

The major histocompatibility complex (MHC) encodes proteins that are central for antigen presentation and pathogen elimination. MHC class I (MHC-I) genes have attracted a great deal of interest among researchers in ecology and evolution and have been partly characterized in a wide range of bird species. So far, the main focus has been on species within the bird orders Galliformes and Passeriformes, while Charadriiformes remain vastly underrepresented with only two species studied to date. These two Charadriiformes species exhibit striking differences in MHC-I characteristics and MHC-I diversity. We therefore set out to study a third species within Charadriiformes, the Icelandic subspecies of black-tailed godwits (Limosa limosa islandica). This subspecies is normally confined to parasite-poor environments, and we hence expected low MHC diversity. MHC-I was partially characterized first using Sanger sequencing and then using high-throughput sequencing (MiSeq) in 84 individuals. We verified 47 nucleotide alleles in open reading frame with classical MHC-I characteristics, and each individual godwit had two to seven putatively classical MHC alleles. However, in contrast to previous MHC-I data within Charadriiformes, we did not find any evidence of alleles with low sequence diversity, believed to represent non-classical MHC genes. The diversity and divergence of the godwits MHC-I genes to a large extent fell between the previous estimates within Charadriiformes. However, the MHC genes of the migratory godwits had few sites subject to positive selection, and one possible explanation could be a low exposure to pathogens.

Ubiquitination regulates MHC class II-peptide complex retention and degradation in dendritic cells

OpenAIRE

Walseng, Even; Furuta, Kazuyuki; Bosch, Berta; Weih, Karis A.; Matsuki, Yohei; Bakke, Oddmund; Ishido, Satoshi; Roche, Paul A.

2010-01-01

The expression and turnover of MHC class II-peptide complexes (pMHC-II) on the surface of dendritic cells (DCs) is essential for their ability to activate CD4 T cells efficiently. The half-life of surface pMHC-II is significantly greater in activated (mature) DCs than in resting (immature) DCs, but the molecular mechanism leading to this difference remains unknown. We now show that ubiquitination of pMHC-II by the E3 ubiquitin ligase membrane-associated RING-CH 1 (March-I) regulates surface e...

Leukocyte Ig-Like Receptors – a model for MHC class I disease associations

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Rachel Louise Allen

2016-07-01

Full Text Available MHC class I (MHC-I polymorphisms are associated with the outcome of some viral infections and autoimmune diseases. MHC-I proteins present antigenic peptides and are recognised by receptors on Natural Killer cells and Cytotoxic T lymphocytes, thus enabling the immune system to detect self-antigens and eliminate targets lacking self or expressing foreign antigens. Recognition of MHC-I, however, extends beyond receptors on cytotoxic leukocytes. Members of the Leukocyte Ig-like receptor (LILR family are expressed on monocytic cells and can recognise both classical and non-classical MHC-I alleles. Despite their relatively broad specificity when compared to the T Cell Receptor or Killer Ig-like Receptors, variations in the strength of LILR binding between different MHC-I alleles have recently been shown to correlate with control of HIV infection. We suggest that LILR recognition may mediate MHC-I disease association in a manner that does not depend on a binary discrimination of self/non-self by cytotoxic cells. Instead, the effects of LILR activity following engagement by MHC-I may represent a degrees of self model, whereby strength of binding to different alleles determines the degree of influence exerted by these receptors on immune cell functions. LILR are expressed by myelomonocytic cells and lymphocytes, extending their influence across antigen presenting cell subsets including dendritic cells, macrophages and B cells. They have been identified as important players in the response to infection, inflammatory diseases and cancer, with recent literature to indicate that MHC-I recognition by these receptors and consequent allelic effects could extend an influence beyond the immune system.

Estimating haplotype effects for survival data

DEFF Research Database (Denmark)

Scheike, Thomas; Martinussen, Torben; Silver, J

2010-01-01

Genetic association studies often investigate the effect of haplotypes on an outcome of interest. Haplotypes are not observed directly, and this complicates the inclusion of such effects in survival models. We describe a new estimating equations approach for Cox's regression model to assess haplo...

Dimeric MHC-peptides inserted into an immunoglobulin scaffold as new immunotherapeutic agents

Science.gov (United States)

Goldberg, Burt; Bona, Constantin

2011-01-01

Abstract The interactions of the T cell receptor (TCR) with cognate MHC-peptide and co-stimulatory molecules expressed at surface of antigen presenting cells (APC) leads to activation or tolerance of T cells. The development of molecular biological tools allowed for the preparation of soluble MHC-peptide molecules as surrogate for the APC. A decade ago a monomeric class II MHC molecule in which the peptide was covalently linked to β-chain of class II molecule was generated. This type of molecule had a low-binding affinity and did not cause the multimerization of TCR. The requirement of multimerization of TCR led to development of a new class of reagents, chimeric peptides covalently linked to MHC that was dimerized via Fc fragment of an immunoglobulin and linked to 3′ end of the β-chain of MHC class II molecule. These soluble dimerized MHC-peptide chimeric molecules display high affinity for the TCR and caused multimerization of TCR without processing by an APC. Because dimeric molecules are devoid of co-stimulatory molecules interacting with CD28, a second signal, they induce anergy rather the activation of T cells. In this review, we compare the human and murine dimerized MHC class II-peptides and their effect on CD4+ T cells, particularly the generation of T regulatory cells, which make these chimeric molecules an appealing approach for the treatment of autoimmune diseases. PMID:21435177

Establishment of a quantitative ELISA capable of determining peptide - MHC class I interaction

DEFF Research Database (Denmark)

Sylvester-Hvid, C; Kristensen, N; Blicher, T

2002-01-01

dependent manner. Here, we exploit the availability of these molecules to generate a quantitative ELISA-based assay capable of measuring the affinity of the interaction between peptide and MHC-I. This assay is simple and sensitive, and one can easily envisage that the necessary reagents, standards......Many different assays for measuring peptide-MHC interactions have been suggested over the years. Yet, there is no generally accepted standard method available. We have recently generated preoxidized recombinant MHC class I molecules (MHC-I) which can be purified to homogeneity under denaturing...

Structure of a Pheromone Receptor-Associated Mhc Molecule With An Open And Empty Groove

Energy Technology Data Exchange (ETDEWEB)

Olson, R.; Huey-Tubman, K.E.; Dulac, C.; Bjorkman, P.J.; /Caltech /Harvard U.

2006-10-06

Neurons in the murine vomeronasal organ (VNO) express a family of class Ib major histocompatibility complex (MHC) proteins (M10s) that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

Structure of a pheromone receptor-associated MHC molecule with an open and empty groove.

Directory of Open Access Journals (Sweden)

2005-08-01

Full Text Available Neurons in the murine vomeronasal organ (VNO express a family of class Ib major histocompatibility complex (MHC proteins (M10s that interact with the V2R class of VNO receptors. This interaction may play a direct role in the detection of pheromonal cues that initiate reproductive and territorial behaviors. The crystal structure of M10.5, an M10 family member, is similar to that of classical MHC molecules. However, the M10.5 counterpart of the MHC peptide-binding groove is open and unoccupied, revealing the first structure of an empty class I MHC molecule. Similar to empty MHC molecules, but unlike peptide-filled MHC proteins and non-peptide-binding MHC homologs, M10.5 is thermally unstable, suggesting that its groove is normally occupied. However, M10.5 does not bind endogenous peptides when expressed in mammalian cells or when offered a mixture of class I-binding peptides. The F pocket side of the M10.5 groove is open, suggesting that ligands larger than 8-10-mer class I-binding peptides could fit by extending out of the groove. Moreover, variable residues point up from the groove helices, rather than toward the groove as in classical MHC structures. These data suggest that M10s are unlikely to provide specific recognition of class I MHC-binding peptides, but are consistent with binding to other ligands, including proteins such as the V2Rs.

Schwann cells promote post-traumatic nerve inflammation and neuropathic pain through MHC class II.

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Hartlehnert, Maike; Derksen, Angelika; Hagenacker, Tim; Kindermann, David; Schäfers, Maria; Pawlak, Mathias; Kieseier, Bernd C; Meyer Zu Horste, Gerd

2017-10-02

The activation of T helper cells requires antigens to be exposed on the surface of antigen presenting cells (APCs) via MHC class II (MHC-II) molecules. Expression of MHC-II is generally limited to professional APCs, but other cell types can express MHC-II under inflammatory conditions. However, the importance of these conditional APCs is unknown. We and others have previously shown that Schwann cells are potentially conditional APCs, but the functional relevance of MHC-II expression by Schwann cells has not been studied in vivo. Here, we conditionally deleted the MHC-II β-chain from myelinating Schwann cells in mice and investigated how this influenced post-traumatic intraneural inflammation and neuropathic pain using the chronic constriction injury (CCI) model. We demonstrate that deletion of MHC-II in myelinating Schwann cells reduces thermal hyperalgesia and, to a lesser extent, also diminishes mechanical allodynia in CCI in female mice. This was accompanied by a reduction of intraneural CD4+ T cells and greater preservation of preferentially large-caliber axons. Activation of T helper cells by MHC-II on Schwann cells thus promotes post-traumatic axonal loss and neuropathic pain. Hence, we provide experimental evidence that Schwann cells gain antigen-presenting function in vivo and modulate local immune responses and diseases in the peripheral nerves.

Peptide and Peptide-Dependent Motions in MHC Proteins: Immunological Implications and Biophysical Underpinnings

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Cory M. Ayres

2017-08-01

Full Text Available Structural biology of peptides presented by class I and class II MHC proteins has transformed immunology, impacting our understanding of fundamental immune mechanisms and allowing researchers to rationalize immunogenicity and design novel vaccines. However, proteins are not static structures as often inferred from crystallographic structures. Their components move and breathe individually and collectively over a range of timescales. Peptides bound within MHC peptide-binding grooves are no exception and their motions have been shown to impact recognition by T cell and other receptors in ways that influence function. Furthermore, peptides tune the motions of MHC proteins themselves, which impacts recognition of peptide/MHC complexes by other proteins. Here, we review the motional properties of peptides in MHC binding grooves and discuss how peptide properties can influence MHC motions. We briefly review theoretical concepts about protein motion and highlight key data that illustrate immunological consequences. We focus primarily on class I systems due to greater availability of data, but segue into class II systems as the concepts and consequences overlap. We suggest that characterization of the dynamic “energy landscapes” of peptide/MHC complexes and the resulting functional consequences is one of the next frontiers in structural immunology.

MHC Class II and Non-MHC Class II Genes Differentially Influence Humoral Immunity to Bacillus anthracis Lethal Factor and Protective Antigen

OpenAIRE

Garman, Lori; Dumas, Eric K.; Kurella, Sridevi; Hunt, Jonathan J.; Crowe, Sherry R.; Nguyen, Melissa L.; Cox, Philip M.; James, Judith A.; Farris, A. Darise

2012-01-01

Anthrax Lethal Toxin consists of Protective Antigen (PA) and Lethal Factor (LF), and current vaccination strategies focus on eliciting antibodies to PA. In human vaccination, the response to PA can vary greatly, and the response is often directed toward non-neutralizing epitopes. Variable vaccine responses have been shown to be due in part to genetic differences in individuals, with both MHC class II and other genes playing roles. Here, we investigated the relative contribution of MHC class I...

Tapasin-related protein TAPBPR is an additional component of the MHC class I presentation pathway

DEFF Research Database (Denmark)

Boyle, Louise H; Hermann, Clemens; Boname, Jessica M

2013-01-01

Tapasin is an integral component of the peptide-loading complex (PLC) important for efficient peptide loading onto MHC class I molecules. We investigated the function of the tapasin-related protein, TAPBPR. Like tapasin, TAPBPR is widely expressed, IFN-γ-inducible, and binds to MHC class I coupled...... with β2-microglobulin in the endoplasmic reticulum. In contrast to tapasin, TAPBPR does not bind ERp57 or calreticulin and is not an integral component of the PLC. β2-microglobulin is essential for the association between TAPBPR and MHC class I. However, the association between TAPBPR and MHC class I...... occurs in the absence of a functional PLC, suggesting peptide is not required. Expression of TAPBPR decreases the rate of MHC class I maturation through the secretory pathway and prolongs the association of MHC class I on the PLC. The TAPBPR:MHC class I complex trafficks through the Golgi apparatus...

The effect of using genealogy-based haplotypes for genomic prediction.

Science.gov (United States)

Edriss, Vahid; Fernando, Rohan L; Su, Guosheng; Lund, Mogens S; Guldbrandtsen, Bernt

2013-03-06

Genomic prediction uses two sources of information: linkage disequilibrium between markers and quantitative trait loci, and additive genetic relationships between individuals. One way to increase the accuracy of genomic prediction is to capture more linkage disequilibrium by regression on haplotypes instead of regression on individual markers. The aim of this study was to investigate the accuracy of genomic prediction using haplotypes based on local genealogy information. A total of 4429 Danish Holstein bulls were genotyped with the 50K SNP chip. Haplotypes were constructed using local genealogical trees. Effects of haplotype covariates were estimated with two types of prediction models: (1) assuming that effects had the same distribution for all haplotype covariates, i.e. the GBLUP method and (2) assuming that a large proportion (π) of the haplotype covariates had zero effect, i.e. a Bayesian mixture method. About 7.5 times more covariate effects were estimated when fitting haplotypes based on local genealogical trees compared to fitting individuals markers. Genealogy-based haplotype clustering slightly increased the accuracy of genomic prediction and, in some cases, decreased the bias of prediction. With the Bayesian method, accuracy of prediction was less sensitive to parameter π when fitting haplotypes compared to fitting markers. Use of haplotypes based on genealogy can slightly increase the accuracy of genomic prediction. Improved methods to cluster the haplotypes constructed from local genealogy could lead to additional gains in accuracy.

Cis-acting mutation and duplication: History of molecular evolution in a P450 haplotype responsible for insecticide resistance in Culex quinquefasciatus.

Science.gov (United States)

Itokawa, Kentaro; Komagata, Osamu; Kasai, Shinji; Masada, Masahiro; Tomita, Takashi

2011-07-01

A cytochrome P450 gene, Cyp9m10, is more than 200-fold overexpressed in a pyrethroid resistant strain of Culex quinquefasciatus, JPal-per. The haplotype of this strain contains two copies of Cyp9m10 resulted from recent tandem duplication. In this study, we discovered and isolated a Cyp9m10 haplotype closely related to this duplicated Cyp9m10 haplotype from JHB, a strain used for the recent genome project for this mosquito species. The isolated haplotype (JHB-NIID-B haplotype) shared the same insertion of a transposable element upstream of the coding region with JPal-per strain but not duplicated. The JHB-NIID-B haplotype was considered to have diverged from the JPal-per lineage just before the duplication event. Cyp9m10 was moderately overexpressed in larvae with the JHB-NIID-B haplotype. The overexpressions in JHB-NIID-B and JPal-per haplotypes were developmentally regulated in similar pattern indicating both haplotypes share a common cis-acting mutation responsible for the overexpressions. The isolated moderately overexpressed haplotype conferred resistance, however, its efficacy was relatively small. We hypothesized that the first cis-acting mutation modified the consequence of the subsequent duplication in JPal-per lineage to confer stronger phenotypic effect than that if it occurred before the first cis-acting mutation. Copyright © 2011 Elsevier Ltd. All rights reserved.

H pylori receptor MHC class II contributes to the dynamic gastric epithelial apoptotic response

Science.gov (United States)

Bland, David A; Suarez, Giovanni; Beswick, Ellen J; Sierra, Johanna C; Reyes, Victor E

2006-01-01

AIM: To investigate the role of MHC class II in the modulation of gastric epithelial cell apoptosis induced by H pylori infection. METHODS: After stimulating a human gastric epithelial cell line with bacteria or agonist antibodies specific for MHC class II and CD95, the quantitation of apoptotic and anti-apoptotic events, including caspase activation, BCL-2 activation, and FADD recruitment, was performed with a fluorometric assay, a cytometric bead array, and confocal microscopy, respectively. RESULTS: Pretreatment of N87 cells with the anti-MHC class II IgM antibody RFD1 resulted in a reduction in global caspase activation at 24 h of H pylori infection. When caspase 3 activation was specifically measured, crosslinking of MHC class II resulted in a marked reduced caspase activation, while simple ligation of MHC class II did not. Crosslinking of MHC class II also resulted in an increased activation of the anti-apoptosis molecule BCL-2 compared to simple ligation. Confocal microscope analysis demonstrated that the pretreatment of gastric epithelial cells with a crosslinking anti-MHC class II IgM blocked the recruitment of FADD to the cell surface. CONCLUSION: The results presented here demonstrate that the ability of MHC class II to modulate gastric epithelial apoptosis is at least partially dependent on its crosslinking. Furthermore, while previous research has demonstrated that MHC class II signaling can be pro-apoptotic during extended ligation, we have shown that the crosslinking of this molecule has anti-apoptotic effects during the earlier time points of H pylori infection. This effect is possibly mediated by the ability of MHC class II to modulate the activation of the pro-apoptotic receptor Fas by blocking the recruitment of the accessory molecule FADD, and this delay in apoptosis induction could allow for prolonged cytokine secretion by H pylori-infected gastric epithelial cells. PMID:16981259

Gene transfer preferentially selects MHC class I positive tumour cells and enhances tumour immunogenicity.

Science.gov (United States)

Hacker, Ulrich T; Schildhauer, Ines; Barroso, Margarita Céspedes; Kofler, David M; Gerner, Franz M; Mysliwietz, Josef; Buening, Hildegard; Hallek, Michael; King, Susan B S

2006-05-01

The modulated expression of MHC class I on tumour tissue is well documented. Although the effect of MHC class I expression on the tumorigenicity and immunogenicity of MHC class I negative tumour cell lines has been rigorously studied, less is known about the validity of gene transfer and selection in cell lines with a mixed MHC class I phenotype. To address this issue we identified a C26 cell subline that consists of distinct populations of MHC class I (H-2D/K) positive and negative cells. Transient transfection experiments using liposome-based transfer showed a lower transgene expression in MHC class I negative cells. In addition, MHC class I negative cells were more sensitive to antibiotic selection. This led to the generation of fully MHC class I positive cell lines. In contrast to C26 cells, all transfectants were rejected in vivo and induced protection against the parental tumour cells in rechallenge experiments. Tumour cell specificity of the immune response was demonstrated in in vitro cytokine secretion and cytotoxicity assays. Transfectants expressing CD40 ligand and hygromycin phosphotransferase were not more immunogenic than cells expressing hygromycin resistance alone. We suggest that the MHC class I positive phenotype of the C26 transfectants had a bearing on their immunogenicity, because selected MHC class I positive cells were more immunogenic than parental C26 cells and could induce specific anti-tumour immune responses. These data demonstrate that the generation of tumour cell transfectants can lead to the selection of subpopulations that show an altered phenotype compared to the parental cell line and display altered immunogenicity independent of selection marker genes or other immune modulatory genes. Our results show the importance of monitoring gene transfer in the whole tumour cell population, especially for the evaluation of in vivo therapies targeted to heterogeneous tumour cell populations.

ParaHaplo 3.0: A program package for imputation and a haplotype-based whole-genome association study using hybrid parallel computing

Directory of Open Access Journals (Sweden)

Kamatani Naoyuki

2011-05-01

Full Text Available Abstract Background Use of missing genotype imputations and haplotype reconstructions are valuable in genome-wide association studies (GWASs. By modeling the patterns of linkage disequilibrium in a reference panel, genotypes not directly measured in the study samples can be imputed and used for GWASs. Since millions of single nucleotide polymorphisms need to be imputed in a GWAS, faster methods for genotype imputation and haplotype reconstruction are required. Results We developed a program package for parallel computation of genotype imputation and haplotype reconstruction. Our program package, ParaHaplo 3.0, is intended for use in workstation clusters using the Intel Message Passing Interface. We compared the performance of ParaHaplo 3.0 on the Japanese in Tokyo, Japan and Han Chinese in Beijing, and Chinese in the HapMap dataset. A parallel version of ParaHaplo 3.0 can conduct genotype imputation 20 times faster than a non-parallel version of ParaHaplo. Conclusions ParaHaplo 3.0 is an invaluable tool for conducting haplotype-based GWASs. The need for faster genotype imputation and haplotype reconstruction using parallel computing will become increasingly important as the data sizes of such projects continue to increase. ParaHaplo executable binaries and program sources are available at http://en.sourceforge.jp/projects/parallelgwas/releases/.

Strategies for haplotype-based association mapping in complex pedigreed populations

DEFF Research Database (Denmark)

Boleckova, J; Christensen, Ole Fredslund; Sørensen, Peter

2012-01-01

In association mapping, haplotype-based methods are generally regarded to provide higher power and increased precision than methods based on single markers. For haplotype-based association mapping most studies use a fixed haplotype effect in the model. However, an increase in haplotype length inc...

Low MHC variation in the endangered Galápagos penguin (Spheniscus mendiculus).

Science.gov (United States)

Bollmer, Jennifer L; Vargas, F Hernán; Parker, Patricia G

2007-07-01

The major histocompatibility complex (MHC) is one of the most polymorphic regions of the genome, likely due to balancing selection acting to maintain alleles over time. Lack of MHC variability has been attributed to factors such as genetic drift in small populations and relaxed selection pressure. The Galápagos penguin (Spheniscus mendiculus), endemic to the Galápagos Islands, is the only penguin that occurs on the equator. It relies upon cold, nutrient-rich upwellings and experiences severe population declines when ocean temperatures rise during El Niño events. These bottlenecks, occurring in an already small population, have likely resulted in reduced genetic diversity in this species. In this study, we used MHC class II exon 2 sequence data from a DRB1-like gene to characterize the amount of genetic variation at the MHC in 30 Galápagos penguins, as well as one Magellanic penguin (S. magellanicus) and two king penguins (Aptenodytes patagonicus), and compared it to that in five other penguin species for which published data exist. We found that the Galápagos penguin had the lowest MHC diversity (as measured by number of polymorphic sites and average divergence among alleles) of the eight penguin species studied. A phylogenetic analysis showed that Galápagos penguin MHC sequences are most closely related to Humboldt penguin (Spheniscus humboldti) sequences, its putative sister species based on other loci. An excess of non-synonymous mutations and a pattern of trans-specific evolution in the neighbor-joining tree suggest that selection is acting on the penguin MHC.

Ligation of MHC class I molecules on peripheral blood T lymphocytes induces new phenotypes and functions

DEFF Research Database (Denmark)

Bregenholt, S; Röpke, M; Skov, S

1996-01-01

of T cell-mediated cytotoxicity. Immediately following MHC-I ligation, the T cells responded with increased protein tyrosine phosphorylation, with new bands appearing in the SDS-PAGE. Exposure of T cells to immobilized anti-MHC-I Ab for 24 h induced an increased surface expression of the TCR/CD3 and CD......28 molecules. MHC-I-induced proliferation of purified T cells was dependent on cellular interactions with non-T cells. Under certain conditions, in which MHC-I was ligated by picogram concentrations of immobilized anti-MHC-I Ab, anti-TCR/CD3 Ab-induced proliferation of T cells was strongly inhibited....... These data clearly demonstrate that ligation of the MHC-I complex on T cells may induce both positive and negative signals. Since the physiologic ligands for MHC-I molecules are TCR and the CD8 molecules, our data may suggest that MHC-I molecules are instrumental in cellular interactions between T cells....

NLRC5/MHC class I transactivator is a target for immune evasion in cancer.

Science.gov (United States)

Yoshihama, Sayuri; Roszik, Jason; Downs, Isaac; Meissner, Torsten B; Vijayan, Saptha; Chapuy, Bjoern; Sidiq, Tabasum; Shipp, Margaret A; Lizee, Gregory A; Kobayashi, Koichi S

2016-05-24

Cancer cells develop under immune surveillance, thus necessitating immune escape for successful growth. Loss of MHC class I expression provides a key immune evasion strategy in many cancers, although the molecular mechanisms remain elusive. MHC class I transactivator (CITA), known as "NLRC5" [NOD-like receptor (NLR) family, caspase recruitment (CARD) domain containing 5], has recently been identified as a critical transcriptional coactivator of MHC class I gene expression. Here we show that the MHC class I transactivation pathway mediated by CITA/NLRC5 constitutes a target for cancer immune evasion. In all the 21 tumor types we examined, NLRC5 expression was highly correlated with the expression of MHC class I, with cytotoxic T-cell markers, and with genes in the MHC class I antigen-presentation pathway, including LMP2/LMP7, TAP1, and β2-microglobulin. Epigenetic and genetic alterations in cancers, including promoter methylation, copy number loss, and somatic mutations, were most prevalent in NLRC5 among all MHC class I-related genes and were associated with the impaired expression of components of the MHC class I pathway. Strikingly, NLRC5 expression was significantly associated with the activation of CD8(+) cytotoxic T cells and patient survival in multiple cancer types. Thus, NLRC5 constitutes a novel prognostic biomarker and potential therapeutic target of cancers.

Pan-specific prediction of peptide-MHC Class I complex stability, a correlate of T cell immunogenicity

DEFF Research Database (Denmark)

Rasmussen, Michael; Fenoy, Emilio; Harndahl, Mikkel

2016-01-01

Binding of peptides to MHC class I (MHC-I) molecules is the most selective event in the processing and presentation of Ags to CTL, and insights into the mechanisms that govern peptide-MHC-I binding should facilitate our understanding of CTL biology. Peptide-MHC-I interactions have traditionally b...

One-pot, mix-and-read peptide-MHC tetramers

DEFF Research Database (Denmark)

Leisner, Christian Valdemar Vinge; Loeth, Nina; Lamberth, Kasper

2008-01-01

BACKGROUND: Cytotoxic T Lymphocytes (CTL) recognize complexes of peptide ligands and Major Histocompatibility Complex (MHC) class I molecules presented at the surface of Antigen Presenting Cells (APC). Detection and isolation of CTL's are of importance for research on CTL immunity, and development...... molecules can be refolded in vitro, tetramerized with streptavidin, and used for specific T cell staining-all in a one-pot reaction without any intervening purification steps. CONCLUSIONS/SIGNIFICANCE: We have developed an efficient "one-pot, mix-and-read" strategy for peptide-MHC tetramer generation...

Exosomal cancer immunotherapy is independent of MHC molecules on exosomes.

Science.gov (United States)

Hiltbrunner, Stefanie; Larssen, Pia; Eldh, Maria; Martinez-Bravo, Maria-Jose; Wagner, Arnika K; Karlsson, Mikael C I; Gabrielsson, Susanne

2016-06-21

Peptide-loaded exosomes are promising cancer treatment vehicles; however, moderate T cell responses in human clinical trials indicate a need to further understand exosome-induced immunity. We previously demonstrated that antigen-loaded exosomes carry whole protein antigens and require B cells for inducing antigen-specific T cells. Therefore, we investigated the relative importance of exosomal major histocompatibility complex (MHC) class I for the induction of antigen-specific T cell responses and tumour protection. We show that ovalbumin-loaded dendritic cell-derived exosomes from MHCI-/- mice induce antigen-specific T cells at the same magnitude as wild type exosomes. Furthermore, exosomes lacking MHC class I, as well as exosomes with both MHC class I and II mismatch, induced tumour infiltrating T cells and increased overall survival to the same extent as syngeneic exosomes in B16 melanoma. In conclusion, T cell responses are independent of exosomal MHC/peptide complexes if whole antigen is present. This establishes the prospective of using impersonalised exosomes, and will greatly increase the feasibility of designing exosome-based vaccines or therapeutic approaches in humans.

Role of major histocompatibility complex class II in the development of autoimmune type 1 diabetes and thyroiditis in rats

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Yokoi, N; Hidaka, S; Tanabe, S; Ohya, M; Ishima, M; Takagi, Y; Masui, N; Seino, S

2012-01-01

Although the MHC class II ‘u' haplotype is strongly associated with type 1 diabetes (T1D) in rats, the role of MHC class II in the development of tissue-specific autoimmune diseases including T1D and autoimmune thyroiditis remains unclear. To clarify this, we produced a congenic strain carrying MHC class II ‘a' and ‘u' haplotypes on the Komeda diabetes-prone (KDP) genetic background. The u/u homozygous animals developed T1D similar to the original KDP rat; a/u heterozygous animals did develop T1D but with delayed onset and low frequency. In contrast, none of the a/a homozygous animals developed T1D; about half of the animals with a/u heterozygous or a/a homozygous genotypes showed autoimmune thyroiditis. To investigate the role of genetic background in the development of thyroiditis, we also produced a congenic strain carrying Cblb mutation of the KDP rat on the PVG.R23 genetic background (MHC class II ‘a' haplotype). The congenic rats with homozygous Cblb mutation showed autoimmune thyroiditis without T1D and slight to severe alopecia, a clinical symptom of hypothyroidism such as Hashimoto's thyroiditis. These data indicate that MHC class II is involved in the tissue-specific development of autoimmune diseases, including T1D and thyroiditis. PMID:21918539

Identification of the cognate peptide-MHC target of T cell receptors using molecular modeling and force field scoring

DEFF Research Database (Denmark)

Lanzarotti, Esteban; Marcatili, Paolo; Nielsen, Morten

2018-01-01

Interactions of T cell receptors (TCR) to peptides in complex with MHC (p:MHC) are key features that mediate cellular immune responses. While MHC binding is required for a peptide to be presented to T cells, not all MHC binders are immunogenic. The interaction of a TCR to the p:MHC complex holds...... terms. Building a benchmark of TCR:p:MHC complexes where epitopes and non-epitopes are modelled using state-of-the-art molecular modelling tools, scoring p:MHC to a given TCR using force-fields, optimized in a cross-validation setup to evaluate TCR inter atomic interactions involved with each p:MHC, we...... and model the TCR:p:MHC complex structure. In summary, we conclude that it is possible to identify the TCR cognate target among different candidate peptides by using a force-field based model, and believe this works could lay the foundation for future work within prediction of TCR:p:MHC interactions....

The whole genome sequences and experimentally phased haplotypes of over 100 personal genomes.

Science.gov (United States)

Mao, Qing; Ciotlos, Serban; Zhang, Rebecca Yu; Ball, Madeleine P; Chin, Robert; Carnevali, Paolo; Barua, Nina; Nguyen, Staci; Agarwal, Misha R; Clegg, Tom; Connelly, Abram; Vandewege, Ward; Zaranek, Alexander Wait; Estep, Preston W; Church, George M; Drmanac, Radoje; Peters, Brock A

2016-10-11

Since the completion of the Human Genome Project in 2003, it is estimated that more than 200,000 individual whole human genomes have been sequenced. A stunning accomplishment in such a short period of time. However, most of these were sequenced without experimental haplotype data and are therefore missing an important aspect of genome biology. In addition, much of the genomic data is not available to the public and lacks phenotypic information. As part of the Personal Genome Project, blood samples from 184 participants were collected and processed using Complete Genomics' Long Fragment Read technology. Here, we present the experimental whole genome haplotyping and sequencing of these samples to an average read coverage depth of 100X. This is approximately three-fold higher than the read coverage applied to most whole human genome assemblies and ensures the highest quality results. Currently, 114 genomes from this dataset are freely available in the GigaDB repository and are associated with rich phenotypic data; the remaining 70 should be added in the near future as they are approved through the PGP data release process. For reproducibility analyses, 20 genomes were sequenced at least twice using independent LFR barcoded libraries. Seven genomes were also sequenced using Complete Genomics' standard non-barcoded library process. In addition, we report 2.6 million high-quality, rare variants not previously identified in the Single Nucleotide Polymorphisms database or the 1000 Genomes Project Phase 3 data. These genomes represent a unique source of haplotype and phenotype data for the scientific community and should help to expand our understanding of human genome evolution and function.

Predicted MHC peptide binding promiscuity explains MHC class I 'hotspots' of antigen presentation defined by mass spectrometry eluted ligand data.

Science.gov (United States)

Jappe, Emma Christine; Kringelum, Jens; Trolle, Thomas; Nielsen, Morten

2018-02-15

Peptides that bind to and are presented by MHC class I and class II molecules collectively make up the immunopeptidome. In the context of vaccine development, an understanding of the immunopeptidome is essential, and much effort has been dedicated to its accurate and cost-effective identification. Current state-of-the-art methods mainly comprise in silico tools for predicting MHC binding, which is strongly correlated with peptide immunogenicity. However, only a small proportion of the peptides that bind to MHC molecules are, in fact, immunogenic, and substantial work has been dedicated to uncovering additional determinants of peptide immunogenicity. In this context, and in light of recent advancements in mass spectrometry (MS), the existence of immunological hotspots has been given new life, inciting the hypothesis that hotspots are associated with MHC class I peptide immunogenicity. We here introduce a precise terminology for defining these hotspots and carry out a systematic analysis of MS and in silico predicted hotspots. We find that hotspots defined from MS data are largely captured by peptide binding predictions, enabling their replication in silico. This leads us to conclude that hotspots, to a great degree, are simply a result of promiscuous HLA binding, which disproves the hypothesis that the identification of hotspots provides novel information in the context of immunogenic peptide prediction. Furthermore, our analyses demonstrate that the signal of ligand processing, although present in the MS data, has very low predictive power to discriminate between MS and in silico defined hotspots. © 2018 John Wiley & Sons Ltd.

Induction of protective immunity against MHC class I-deficient, HPV16-associated tumours with peptide and dendritic cell-based vaccines

Czech Academy of Sciences Publication Activity Database

Reiniš, Milan; Štěpánek, Ivan; Šímová, Jana; Bieblová, Jana; Přibylová, Hana; Indrová, Marie; Bubeník, Jan

2010-01-01

Roč. 36, č. 3 (2010), s. 545-551 ISSN 1019-6439 R&D Projects: GA AV ČR IAA500520605; GA AV ČR IAA500520807 EU Projects: European Commission(XE) 18933 - CLINIGENE Institutional research plan: CEZ:AV0Z50520514 Keywords : MHC class I-deficient tumours * CpG oligodeoxynucleotides * human papilloma virus Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.571, year: 2010

Haplotype-based stratification of Huntington's disease.

Science.gov (United States)

Chao, Michael J; Gillis, Tammy; Atwal, Ranjit S; Mysore, Jayalakshmi Srinidhi; Arjomand, Jamshid; Harold, Denise; Holmans, Peter; Jones, Lesley; Orth, Michael; Myers, Richard H; Kwak, Seung; Wheeler, Vanessa C; MacDonald, Marcy E; Gusella, James F; Lee, Jong-Min

2017-11-01

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by expansion of a CAG trinucleotide repeat in HTT, resulting in an extended polyglutamine tract in huntingtin. We and others have previously determined that the HD-causing expansion occurs on multiple different haplotype backbones, reflecting more than one ancestral origin of the same type of mutation. In view of the therapeutic potential of mutant allele-specific gene silencing, we have compared and integrated two major systems of HTT haplotype definition, combining data from 74 sequence variants to identify the most frequent disease-associated and control chromosome backbones and revealing that there is potential for additional resolution of HD haplotypes. We have used the large collection of 4078 heterozygous HD subjects analyzed in our recent genome-wide association study of HD age at onset to estimate the frequency of these haplotypes in European subjects, finding that common genetic variation at HTT can distinguish the normal and CAG-expanded chromosomes for more than 95% of European HD individuals. As a resource for the HD research community, we have also determined the haplotypes present in a series of publicly available HD subject-derived fibroblasts, induced pluripotent cells, and embryonic stem cells in order to facilitate efforts to develop inclusive methods of allele-specific HTT silencing applicable to most HD patients. Our data providing genetic guidance for therapeutic gene-based targeting will significantly contribute to the developments of rational treatments and implementation of precision medicine in HD.

Approximation properties of haplotype tagging

Directory of Open Access Journals (Sweden)

Dreiseitl Stephan

2006-01-01

Full Text Available Abstract Background Single nucleotide polymorphisms (SNPs are locations at which the genomic sequences of population members differ. Since these differences are known to follow patterns, disease association studies are facilitated by identifying SNPs that allow the unique identification of such patterns. This process, known as haplotype tagging, is formulated as a combinatorial optimization problem and analyzed in terms of complexity and approximation properties. Results It is shown that the tagging problem is NP-hard but approximable within 1 + ln((n2 - n/2 for n haplotypes but not approximable within (1 - ε ln(n/2 for any ε > 0 unless NP ⊂ DTIME(nlog log n. A simple, very easily implementable algorithm that exhibits the above upper bound on solution quality is presented. This algorithm has running time O((2m - p + 1 ≤ O(m(n2 - n/2 where p ≤ min(n, m for n haplotypes of size m. As we show that the approximation bound is asymptotically tight, the algorithm presented is optimal with respect to this asymptotic bound. Conclusion The haplotype tagging problem is hard, but approachable with a fast, practical, and surprisingly simple algorithm that cannot be significantly improved upon on a single processor machine. Hence, significant improvement in computatational efforts expended can only be expected if the computational effort is distributed and done in parallel.

Circumvention of MHC class II restriction by genetic immunization.

Science.gov (United States)

Schuler, K; Lu, C; Chang, H D; Croft, M; Zanetti, M; Gerloni, M

2001-11-12

The fate of T cell responses to peptide-based vaccination is subject to constraints by the major histocompatibility complex (MHC), MHC restriction. Using as a model system of T and B cell epitopes from the circumsporozoite protein of Plasmodium falciparum malaria parasite, we show that vaccination by somatic transgene immunization readily primes Balb/c mice (H-2(d)) a strain previously reported to be non-responder to immunization with a synthetic peptide vaccine encompassing these epitopes. Following genetic vaccination Balb/c mice developed a primary T cell response comparable to that of the responder strain C57Bl/6 (H-2(b)). Following booster immunization on day 45 Balb/c mice responded with a typical T cell memory response. Priming induced the formation of specific antibodies, which rose sharply after booster immunization. These findings suggests that genetic immunization can circumvent MHC class II restriction.

The importance of immune gene variability (MHC in evolutionary ecology and conservation

Directory of Open Access Journals (Sweden)

Sommer Simone

2005-10-01

Full Text Available Abstract Genetic studies have typically inferred the effects of human impact by documenting patterns of genetic differentiation and levels of genetic diversity among potentially isolated populations using selective neutral markers such as mitochondrial control region sequences, microsatellites or single nucleotide polymorphism (SNPs. However, evolutionary relevant and adaptive processes within and between populations can only be reflected by coding genes. In vertebrates, growing evidence suggests that genetic diversity is particularly important at the level of the major histocompatibility complex (MHC. MHC variants influence many important biological traits, including immune recognition, susceptibility to infectious and autoimmune diseases, individual odours, mating preferences, kin recognition, cooperation and pregnancy outcome. These diverse functions and characteristics place genes of the MHC among the best candidates for studies of mechanisms and significance of molecular adaptation in vertebrates. MHC variability is believed to be maintained by pathogen-driven selection, mediated either through heterozygote advantage or frequency-dependent selection. Up to now, most of our knowledge has derived from studies in humans or from model organisms under experimental, laboratory conditions. Empirical support for selective mechanisms in free-ranging animal populations in their natural environment is rare. In this review, I first introduce general information about the structure and function of MHC genes, as well as current hypotheses and concepts concerning the role of selection in the maintenance of MHC polymorphism. The evolutionary forces acting on the genetic diversity in coding and non-coding markers are compared. Then, I summarise empirical support for the functional importance of MHC variability in parasite resistance with emphasis on the evidence derived from free-ranging animal populations investigated in their natural habitat. Finally, I

Prion gene haplotypes of U.S. cattle

Directory of Open Access Journals (Sweden)

Harhay Gregory P

2006-11-01

Full Text Available Abstract Background Bovine spongiform encephalopathy (BSE is a fatal neurological disorder characterized by abnormal deposits of a protease-resistant isoform of the prion protein. Characterizing linkage disequilibrium (LD and haplotype networks within the bovine prion gene (PRNP is important for 1 testing rare or common PRNP variation for an association with BSE and 2 interpreting any association of PRNP alleles with BSE susceptibility. The objective of this study was to identify polymorphisms and haplotypes within PRNP from the promoter region through the 3'UTR in a diverse sample of U.S. cattle genomes. Results A 25.2-kb genomic region containing PRNP was sequenced from 192 diverse U.S. beef and dairy cattle. Sequence analyses identified 388 total polymorphisms, of which 287 have not previously been reported. The polymorphism alleles define PRNP by regions of high and low LD. High LD is present between alleles in the promoter region through exon 2 (6.7 kb. PRNP alleles within the majority of intron 2, the entire coding sequence and the untranslated region of exon 3 are in low LD (18.0 kb. Two haplotype networks, one representing the region of high LD and the other the region of low LD yielded nineteen different combinations that represent haplotypes spanning PRNP. The haplotype combinations are tagged by 19 polymorphisms (htSNPS which characterize variation within and across PRNP. Conclusion The number of polymorphisms in the prion gene region of U.S. cattle is nearly four times greater than previously described. These polymorphisms define PRNP haplotypes that may influence BSE susceptibility in cattle.

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

Science.gov (United States)

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

2011-10-01

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

Gapped sequence alignment using artificial neural networks: application to the MHC class I system

DEFF Research Database (Denmark)

Andreatta, Massimo; Nielsen, Morten

2016-01-01

. On this relatively simple system, we developed a sequence alignment method based on artificial neural networks that allows insertions and deletions in the alignment. Results: We show that prediction methods based on alignments that include insertions and deletions have significantly higher performance than methods...... trained on peptides of single lengths. Also, we illustrate how the location of deletions can aid the interpretation of the modes of binding of the peptide-MHC, as in the case of long peptides bulging out of the MHC groove or protruding at either terminus. Finally, we demonstrate that the method can learn...... the length profile of different MHC molecules, and quantified the reduction of the experimental effort required to identify potential epitopes using our prediction algorithm. Availability and implementation: The NetMHC-4.0 method for the prediction of peptide-MHC class I binding affinity using gapped...

Immunotherapy augments the effect of 5-azacytidine on HPV16-associated tumours with different MHC class I-expression status

Czech Academy of Sciences Publication Activity Database

Šímová, Jana; Polláková, Veronika; Indrová, Marie; Mikyšková, Romana; Bieblová, Jana; Štěpánek, Ivan; Bubeník, Jan; Reiniš, Milan

2011-01-01

Roč. 105, č. 10 (2011), s. 1533-1541 ISSN 0007-0920 R&D Projects: GA ČR GA301/07/1410; GA ČR GAP301/10/2174; GA ČR GA301/09/1024 EU Projects: European Commission(XE) 18933 - CLINIGENE Institutional research plan: CEZ:AV0Z50520514 Keywords : 5-azacytidine * MHC class I downregulation * tumour chemoimmunotherapy Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.042, year: 2011

NK1.1+ cells are important for the development of protective immunity against MHC I-deficient, HPV16-associated tumours

Czech Academy of Sciences Publication Activity Database

Indrová, Marie; Šímová, Jana; Bieblová, Jana; Bubeník, Jan; Reiniš, Milan

2011-01-01

Roč. 25, č. 1 (2011), s. 281-288 ISSN 1021-335X R&D Projects: GA AV ČR IAA500520807 Grant - others:EU-FP6-NOE(XE) Project 018933 Institutional research plan: CEZ:AV0Z50520514 Keywords : MHC class I-deficient tumours * CD8+, CD4+, NK1.1+cell subpopulations * interferon gamma Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.835, year: 2011

Crystal structure of a TAPBPR–MHC I complex reveals the mechanism of peptide editing in antigen presentation

Energy Technology Data Exchange (ETDEWEB)

Jiang, Jiansheng; Natarajan, Kannan; Boyd, Lisa F.; Morozov, Giora I.; Mage, Michael G.; Margulies, David H. (NIH); (Hebrew)

2017-10-12

Central to CD8+ T cell–mediated immunity is the recognition of peptide–major histocompatibility complex class I (p–MHC I) proteins displayed by antigen-presenting cells. Chaperone-mediated loading of high-affinity peptides onto MHC I is a key step in the MHC I antigen presentation pathway. However, the structure of MHC I with a chaperone that facilitates peptide loading has not been determined. We report the crystal structure of MHC I in complex with the peptide editor TAPBPR (TAP-binding protein–related), a tapasin homolog. TAPBPR remodels the peptide-binding groove of MHC I, resulting in the release of low-affinity peptide. Changes include groove relaxation, modifications of key binding pockets, and domain adjustments. This structure captures a peptide-receptive state of MHC I and provides insights into the mechanism of peptide editing by TAPBPR and, by analogy, tapasin.

Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies.

Science.gov (United States)

Berglund, A K; Schnabel, L V

2017-07-01

Allogeneic mesenchymal stem cells (MSCs) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex (MHC)-mismatched MSCs are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. To determine if cytotoxic anti-MHC antibodies generated in vivo following MHC-mismatched MSC injections are capable of initiating complement-dependent cytotoxicity of MSCs. Experimental controlled study. Antisera previously collected at Days 0, 7, 14 and 21 post-injection from 4 horses injected with donor MHC-mismatched equine leucocyte antigen (ELA)-A2 haplotype MSCs and one control horse injected with donor MHC-matched ELA-A2 MSCs were utilised in this study. Antisera were incubated with ELA-A2 MSCs before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA-A2 peripheral blood leucocytes (PBLs) were used in the assays as a positive control. Antisera from all 4 horses injected with MHC-mismatched MSCs contained antibodies that caused the death of ELA-A2 haplotype MSCs in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post-injection. MSC death was consistently equivalent to that of ELA-A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC-matched MSCs did not contain cytotoxic ELA-A2 antibodies at any of the time points examined. This study examined MSC death in vitro only and utilized antisera from a small number of horses. The cytotoxic antibody response induced in recipient horses following injection with donor MHC-mismatched MSCs is capable of killing donor MSCs in vitro. These results suggest that the use of allogeneic MHC-mismatched MSCs must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death. © 2016 The

Antibody Stabilization of Peptide–MHC Multimers Reveals Functional T Cells Bearing Extremely Low-Affinity TCRs

DEFF Research Database (Denmark)

Tungatt, Katie; Bianchi, Valentina; Crowther, Michael D

2015-01-01

Fluorochrome-conjugated peptide-MHC (pMHC) multimers are commonly used in combination with flow cytometry for direct ex vivo visualization and characterization of Ag-specific T cells, but these reagents can fail to stain cells when TCR affinity and/or TCR cell-surface density are low. pMHC multim...

In Vivo Characterization of Human APOA5 Haplotypes

Energy Technology Data Exchange (ETDEWEB)

Ahituv, Nadav; Akiyama, Jennifer; Chapman-Helleboid, Audrey; Fruchart, Jamila; Pennacchio, Len A.

2006-10-01

Increased plasma triglycerides concentrations are an independent risk factor for cardiovascular disease. Numerous studies support a reproducible genetic association between two minor haplotypes in the human apolipoprotein A5 gene (APOA5) and increased plasma triglyceride concentrations. We thus sought to investigate the effect of these minor haplotypes (APOA5*2 and APOA5*3) on ApoAV plasma levels through the precise insertion of single-copy intact APOA5 haplotypes at a targeted location in the mouse genome. While we found no difference in the amount of human plasma ApoAV in mice containing the common APOA5*1 and minor APOA5*2 haplotype, the introduction of the single APOA5*3 defining allele (19W) resulted in 3-fold lower ApoAV plasma levels consistent with existing genetic association studies. These results indicate that S19W polymorphism is likely to be functional and explain the strong association of this variant with plasma triglycerides supporting the value of sensitive in vivo assays to define the functional nature of human haplotypes.

Evolution of MHC class I genes in the European badger (Meles meles)

NARCIS (Netherlands)

Sin, Yung Wa; Dugdale, Hannah L.; Newman, Chris; Macdonald, David W.; Burke, Terry

The major histocompatibility complex (MHC) plays a central role in the adaptive immune system and provides a good model with which to understand the evolutionary processes underlying functional genes. Trans-species polymorphism and orthology are both commonly found in MHC genes; however, mammalian

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

Science.gov (United States)

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

2013-07-01

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

Disentangling the roles of natural selection and genetic drift in shaping variation at MHC immunity genes.

Science.gov (United States)

Sutton, Jolene T; Nakagawa, Shinichi; Robertson, Bruce C; Jamieson, Ian G

2011-11-01

The major histocompatibility complex (MHC) forms an integral component of the vertebrate immune response and, due to strong selection pressures, is one of the most polymorphic regions of the entire genome. Despite over 15 years of research, empirical studies offer highly contradictory explanations of the relative roles of different evolutionary forces, selection and genetic drift, acting on MHC genes during population bottlenecks. Here, we take a meta-analytical approach to quantify the results of studies into the effects of bottlenecks on MHC polymorphism. We show that the consequences of selection acting on MHC loci prior to a bottleneck event, combined with drift during the bottleneck, will result in overall loss of MHC polymorphism that is ∼15% greater than loss of neutral genetic diversity. These results are counter to general expectations that selection should maintain MHC polymorphism, but do agree with the results of recent simulation models and at least two empirical studies. Notably, our results suggest that negative frequency-dependent selection could be more important than overdominance for maintaining high MHC polymorphism in pre-bottlenecked populations. © 2011 Blackwell Publishing Ltd.

Contrasting patterns of selection between MHC I and II across populations of Humboldt and Magellanic penguins

OpenAIRE

Sallaberry?Pincheira, Nicole; Gonz?lez?Acu?a, Daniel; Padilla, Pamela; Dantas, Gisele P. M.; Luna?Jorquera, Guillermo; Frere, Esteban; Vald?s?Vel?squez, Armando; Vianna, Juliana A.

2016-01-01

Abstract The evolutionary and adaptive potential of populations or species facing an emerging infectious disease depends on their genetic diversity in genes, such as the major histocompatibility complex (MHC). In birds, MHC class I deals predominantly with intracellular infections (e.g., viruses) and MHC class II with extracellular infections (e.g., bacteria). Therefore, patterns of MHC I and II diversity may differ between species and across populations of species depending on the relative e...

Interferon beta 1, an intermediate in the tumor necrosis factor alpha- induced increased MHC class I expression and an autocrine regulator of the constitutive MHC class I expression

OpenAIRE

1987-01-01

In conclusion, our observations indicate that the constitutive MHC class I expression is regulated by autocrine production of IFN-beta 1. TNF-alpha acts as an enhancer of the autocrine production of IFN-beta 1, and consequently as an enhancer of the MHC class I expression and viral protection.

Evolution of MHC class I in the Order Crocodylia

DEFF Research Database (Denmark)

Jaratlerdsiri, Weerachai; Isberg, Sally R; Higgins, Damien P

2014-01-01

have mostly focused on model species. However, the investigation of this region in non-avian reptiles is still in its infancy. To provide insights into the evolutionary mechanisms that have shaped the diversity of this region in the Order Crocodylia, we investigated MHC class I exon 3, intron 3...... events of gene duplication, particularly in Crocodilidae. These findings enhance our understanding of MHC class I evolution and provide a preliminary framework for comparative studies of other non-avian reptiles as well as diversity assessment within Crocodylia....

Orf virus interferes with MHC class I surface expression by targeting vesicular transport and Golgi

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Rohde Jörg

2012-07-01

Full Text Available Abstract Background The Orf virus (ORFV, a zoonotic Parapoxvirus, causes pustular skin lesions in small ruminants (goat and sheep. Intriguingly, ORFV can repeatedly infect its host, despite the induction of a specific immunity. These immune modulating and immune evading properties are still unexplained. Results Here, we describe that ORFV infection of permissive cells impairs the intracellular transport of MHC class I molecules (MHC I as a result of structural disruption and fragmentation of the Golgi apparatus. Depending on the duration of infection, we observed a pronounced co-localization of MHC I and COP-I vesicular structures as well as a reduction of MHC I surface expression of up to 50%. These subversion processes are associated with early ORFV gene expression and are accompanied by disturbed carbohydrate trimming of post-ER MHC I. The MHC I population remaining on the cell surface shows an extended half-life, an effect that might be partially controlled also by late ORFV genes. Conclusions The presented data demonstrate that ORFV down-regulates MHC I surface expression in infected cells by targeting the late vesicular export machinery and the structure and function of the Golgi apparatus, which might aid to escape cellular immune recognition.

Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values

NARCIS (Netherlands)

Calus, M.P.L.; Meuwissen, T.H.E.; Windig, J.J.; Knol, E.F.; Schrooten, C.; Vereijken, A.L.J.; Veerkamp, R.F.

2009-01-01

The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD) probabilities between haplotypes, various haplotype definitions were tested i.e.

Mate choice for nonadditive genetic benefits correlate with MHC dissimilarity in the rose bitterling (Rhodeus ocellatus)

Czech Academy of Sciences Publication Activity Database

Agbali, M.; Reichard, Martin; Bryjová, Anna; Bryja, Josef; Smith, C.

2010-01-01

Roč. 64, č. 6 (2010), s. 1683-1696 ISSN 0014-3820 R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/09/1163 Institutional research plan: CEZ:AV0Z60930519 Keywords : Additive genetic benefit * female mate choice * genetic compatibility * good genes * mate choice * MHC * nonadditive genetic benefit * olfactory cues * Rhodeus ocellatus * sexual selection Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.659, year: 2010

No evidence for the effect of MHC on male mating success in the brown bear.

Science.gov (United States)

Kuduk, Katarzyna; Babik, Wieslaw; Bellemain, Eva; Valentini, Alice; Zedrosser, Andreas; Taberlet, Pierre; Kindberg, Jonas; Swenson, Jon E; Radwan, Jacek

2014-01-01

Mate choice is thought to contribute to the maintenance of the spectacularly high polymorphism of the Major Histocompatibility Complex (MHC) genes, along with balancing selection from parasites, but the relative contribution of the former mechanism is debated. Here, we investigated the association between male MHC genotype and mating success in the brown bear. We analysed fragments of sequences coding for the peptide-binding region of the highly polymorphic MHC class I and class II DRB genes, while controlling for genome-wide effects using a panel of 18 microsatellite markers. Male mating success did not depend on the number of alleles shared with the female or amino-acid distance between potential mates at either locus. Furthermore, we found no indication of female mating preferences for MHC similarity being contingent on the number of alleles the females carried. Finally, we found no significant association between the number of MHC alleles a male carried and his mating success. Thus, our results provided no support for the role of mate choice in shaping MHC polymorphism in the brown bear.

Natural selection on MHC IIβ in parapatric lake and stream stickleback: Balancing, divergent, both or neither?

Science.gov (United States)

Stutz, William E; Bolnick, Daniel I

2017-09-01

Major histocompatibility complex (MHC) genes encode proteins that play a central role in vertebrates' adaptive immunity to parasites. MHC loci are among the most polymorphic in vertebrates' genomes, inspiring many studies to identify evolutionary processes driving MHC polymorphism within populations and divergence between populations. Leading hypotheses include balancing selection favouring rare alleles within populations, and spatially divergent selection. These hypotheses do not always produce diagnosably distinct predictions, causing many studies of MHC to yield inconsistent or ambiguous results. We suggest a novel strategy to distinguish balancing vs. divergent selection on MHC, taking advantage of natural admixture between parapatric populations. With divergent selection, individuals with immigrant alleles will be more infected and less fit because they are susceptible to novel parasites in their new habitat. With balancing selection, individuals with locally rare immigrant alleles will be more fit (less infected). We tested these contrasting predictions using three-spine stickleback from three replicate pairs of parapatric lake and stream habitats. We found numerous positive and negative associations between particular MHC IIβ alleles and particular parasite taxa. A few allele-parasite comparisons supported balancing selection, and others supported divergent selection between habitats. But, there was no overall tendency for fish with immigrant MHC alleles to be more or less heavily infected. Instead, locally rare MHC alleles (not necessarily immigrants) were associated with heavier infections. Our results illustrate the complex relationship between MHC IIβ allelic variation and spatially varying multispecies parasite communities: different hypotheses may be concurrently true for different allele-parasite combinations. © 2017 John Wiley & Sons Ltd.

MHC-Dependent Mate Selection within 872 Spousal Pairs of European Ancestry from the Health and Retirement Study

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Zhen Qiao

2018-01-01

Full Text Available Disassortative mating refers to the phenomenon in which individuals with dissimilar genotypes and/or phenotypes mate with one another more frequently than would be expected by chance. Although the existence of disassortative mating is well established in plant and animal species, the only documented example of negative assortment in humans involves dissimilarity at the major histocompatibility complex (MHC locus. Previous studies investigating mating patterns at the MHC have been hampered by limited sample size and contradictory findings. Inspired by the sparse and conflicting evidence, we investigated the role that the MHC region played in human mate selection using genome-wide association data from 872 European American spouses from the Health and Retirement Study (HRS. First, we treated the MHC region as a whole, and investigated genomic similarity between spouses using three levels of genomic variation: single-nucleotide polymorphisms (SNPs, classical human leukocyte antigen (HLA alleles (both four-digit and two-digit classifications, and amino acid polymorphisms. The extent of MHC dissimilarity between spouses was assessed using a permutation approach. Second, we investigated fine scale mating patterns by testing for deviations from random mating at individual SNPs, HLA genes, and amino acids in HLA molecules. Third, we assessed how extreme the spousal relatedness at the MHC region was compared to the rest of the genome, to distinguish the MHC-specific effects from genome-wide effects. We show that neither the MHC region, nor any single SNPs, classic HLA alleles, or amino acid polymorphisms within the MHC region, were significantly dissimilar between spouses relative to non-spouse pairs. However, dissimilarity in the MHC region was extreme relative to the rest of genome for both spousal and non-spouse pairs. Despite the long-standing controversy, our analyses did not support a significant role of MHC dissimilarity in human mate choice.

Haplotype inference in general pedigrees with two sites

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Doan Duong D

2011-04-01

Full Text Available Abstract Background Genetic disease studies investigate relationships between changes in chromosomes and genetic diseases. Single haplotypes provide useful information for these studies but extracting single haplotypes directly by biochemical methods is expensive. A computational method to infer haplotypes from genotype data is therefore important. We investigate the problem of computing the minimum number of recombination events for general pedigrees with two sites for all members. Results We show that this NP-hard problem can be parametrically reduced to the Bipartization by Edge Removal problem and therefore can be solved by an O(2k · n2 exact algorithm, where n is the number of members and k is the number of recombination events. Conclusions Our work can therefore be useful for genetic disease studies to track down how changes in haplotypes such as recombinations relate to genetic disease.

Thermodynamics of T cell receptor – peptide/MHC interactions: progress and opportunities

Science.gov (United States)

Armstrong, Kathryn M.; Insaidoo, Francis K.; Baker, Brian M.

2013-01-01

αβ T cell receptors (TCR) recognize peptide antigens presented by class I or class II major histocompatibility complex molecules (pMHC). Here we review the use of thermodynamic measurements in the study of TCR-pMHC interactions, with attention to the diversity in binding thermodynamics and how this is related to the variation in TCR-pMHC interfaces. We show that there is no enthalpic or entropic signature for TCR binding; rather, enthalpy and entropy changes vary in a compensatory manner that reflects a narrow free energy window for the interactions that have been characterized. Binding enthalpy and entropy changes do not correlate with structural features such as buried surface area or the number of hydrogen bonds within TCR-pMHC interfaces, possibly reflecting the myriad of contributors to binding thermodynamics, but likely also reflecting a reliance on van’t Hoff over calorimetric measurements and the unaccounted influence of equilibria linked to binding. TCR-pMHC binding heat capacity changes likewise vary considerably. In some cases the heat capacity changes are consistent with conformational differences between bound and free receptors, but there is little data indicating these conformational differences represent the need to organize commonly disordered CDR loops. In this regard, we discuss how thermodynamics may provide additional insight into conformational changes occurring upon TCR binding. Finally, we highlight opportunities for the further use of thermodynamic measurements in the study of TCR-pMHC interactions, not only for understanding TCR binding in general, but for understanding specifics of individual interactions and the engineering of T cell receptors with desired molecular recognition properties. PMID:18496839

Real-time, high-throughput measurements of peptide-MHC-I dissociation using a scintillation proximity assay

DEFF Research Database (Denmark)

Harndahl, Mikkel; Rasmussen, Michael; Røder, Gustav Andreas

2011-01-01

and it is well suited for high-throughput screening. To exemplify this, we screened a panel of 384 high-affinity peptides binding to the MHC class I molecule, HLA-A*02:01, and observed the rates of dissociation that ranged from 0.1h to 46h depending on the peptide used.......Efficient presentation of peptide-MHC class I complexes to immune T cells depends upon stable peptide-MHC class I interactions. Theoretically, determining the rate of dissociation of a peptide-MHC class I complexes is straightforward; in practical terms, however, generating the accurate and closely...... timed data needed to determine the rate of dissociation is not simple. Ideally, one should use a homogenous assay involving an inexhaustible and label-free assay principle. Here, we present a homogenous, high-throughput peptide-MHC class I dissociation assay, which by and large fulfill these ideal...

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

DEFF Research Database (Denmark)

Pedersen, Lasse Eggers; Harndahl, Mikkel; Rasmussen, Michael

2011-01-01

a HLA-I molecule (HLA-A*11:01), thereby generating recombinant human/swine chimeric MHC-I molecules as well as the intact SLA-1*0401 molecule. Biochemical peptide-binding assays and positional scanning combinatorial peptide libraries were used to analyze the peptide-binding motifs of these molecules....... A pan-specific predictor of peptide–MHC-I binding, NetMHCpan, which was originally developed to cover the binding specificities of all known HLA-I molecules, was successfully used to predict the specificities of the SLA-1*0401 molecule as well as the porcine/human chimeric MHC-I molecules. These data......In all vertebrate animals, CD8+ cytotoxic T lymphocytes (CTLs) are controlled by major histocompatibility complex class I (MHC-I) molecules. These are highly polymorphic peptide receptors selecting and presenting endogenously derived epitopes to circulating CTLs. The polymorphism of the MHC...

A comparative analysis of viral peptides presented by contemporary human and chimpanzee MHC class I molecules

NARCIS (Netherlands)

van Deutekom, Hanneke W. M.; Hoof, Ilka; Bontrop, Ronald E.; Keşmir, Can

2011-01-01

Genetic factors such as the MHC influence the immunocompetence of an individual. MHC genes are the most polymorphic genes in primates, which is often interpreted as an adaptation to establish good T cell responses to a wide range of (evolving) pathogens. Chimpanzee MHC (Patr) genes are less

TLR signals induce phagosomal MHC-I delivery from the endosomal recycling compartment to allow cross-presentation

NARCIS (Netherlands)

Nair-Gupta, Priyanka; Baccarini, Alessia; Tung, Navpreet; Seyffer, Fabian; Florey, Oliver; Huang, Yunjie; Banerjee, Meenakshi; Overholtzer, Michael; Roche, Paul A.; Tampé, Robert; Brown, Brian D.; Amsen, Derk; Whiteheart, Sidney W.; Blander, J. Magarian

2014-01-01

Adaptation of the endoplasmic reticulum (ER) pathway for MHC class I (MHC-I) presentation in dendritic cells enables cross-presentation of peptides derived from phagocytosed microbes, infected cells, or tumor cells to CD8 T cells. How these peptides intersect with MHC-I molecules remains poorly

Structure and expression of MHC class Ib genes of the central M region in rat and mouse: M4, M5, and M6.

Science.gov (United States)

Lambracht-Washington, Doris; Moore, Yuki F; Wonigeit, Kurt; Lindahl, Kirsten Fischer

2008-04-01

The M region at the telomeric end of the murine major histocompatibility complex (MHC) contains class I genes that are highly conserved in rat and mouse. We have sequenced a cosmid clone of the LEW rat strain (RT1 haplotype) containing three class I genes, RT1.M6-1, RT1.M4, and RT1.M5. The sequences of allelic genes of the BN strain (RT1n haplotype) were obtained either from cDNAs or genomic clones. For the coding parts of the genes few differences were found between the two RT1 haplotypes. In LEW, however, only RT1.M5 and RT1.M6 have open reading frames; whereas in BN all three genes were intact. In line with the findings in BN, transcription was found for all three rat genes in several tissues from strain Sprague Dawley. Protein expression in transfectants could be demonstrated for RT1.M6-1 using the monoclonal antibody OX18. By sequencing of transcripts obtained by RT-PCR, a second, transcribed M6 gene, RT1.M6-2, was discovered, which maps next to RT1.M6-1 outside of the region covered by the cosmid. In addition, alternatively spliced forms for RT1.M5 and RT1.M6 were detected. Of the orthologous mouse genes, H2-M4, H2-M5, and H2-M6, only H2-M5 has an open reading frame. Other important differences between the corresponding parts of the M region of the two species are insertion of long LINE repeats, duplication of RT1.M6, and the inversion of RT1.M5 in the rat. This demonstrates substantial evolutionary dynamics in this region despite conservation of the class I gene sequences themselves.

New design of MHC class II tetramers to accommodate fundamental principles of antigen presentation.

Science.gov (United States)

Landais, Elise; Romagnoli, Pablo A; Corper, Adam L; Shires, John; Altman, John D; Wilson, Ian A; Garcia, K Christopher; Teyton, Luc

2009-12-15

Direct identification and isolation of Ag-specific T cells became possible with the development of MHC tetramers, based on fluorescent avidins displaying biotinylated peptide-MHC complexes. This approach, extensively used for MHC class I-restricted T cells, has met very limited success with class II peptide-MHC complex tetramers (pMHCT-2) for the detection of CD4(+)-specific T cells. In addition, a very large number of these reagents, although capable of specifically activating T cells after being coated on solid support, is still unable to stain. To try to understand this puzzle and design usable tetramers, we examined each parameter critical for the production of pMHCT-2 using the I-A(d)-OVA system as a model. Through this process, the geometry of peptide-MHC display by avidin tetramers was examined, as well as the stability of rMHC molecules. However, we discovered that the most important factor limiting the reactivity of pMHCT-2 was the display of peptides. Indeed, long peptides, as presented by MHC class II molecules, can be bound to I-A/HLA-DQ molecules in more than one register, as suggested by structural studies. This mode of anchorless peptide binding allows the selection of a broader repertoire on single peptides and should favor anti-infectious immune responses. Thus, beyond the technical improvements that we propose, the redesign of pMHCT-2 will give us the tools to evaluate the real size of the CD4 T cell repertoire and help us in the production and testing of new vaccines.

A new mathematical modeling for pure parsimony haplotyping problem.

Science.gov (United States)

Feizabadi, R; Bagherian, M; Vaziri, H R; Salahi, M

2016-11-01

Pure parsimony haplotyping (PPH) problem is important in bioinformatics because rational haplotyping inference plays important roles in analysis of genetic data, mapping complex genetic diseases such as Alzheimer's disease, heart disorders and etc. Haplotypes and genotypes are m-length sequences. Although several integer programing models have already been presented for PPH problem, its NP-hardness characteristic resulted in ineffectiveness of those models facing the real instances especially instances with many heterozygous sites. In this paper, we assign a corresponding number to each haplotype and genotype and based on those numbers, we set a mixed integer programing model. Using numbers, instead of sequences, would lead to less complexity of the new model in comparison with previous models in a way that there are neither constraints nor variables corresponding to heterozygous nucleotide sites in it. Experimental results approve the efficiency of the new model in producing better solution in comparison to two state-of-the art haplotyping approaches. Copyright © 2016 Elsevier Inc. All rights reserved.

Systematic Characterisation of Cellular Localisation and Expression Profiles of Proteins Containing MHC Ligands

DEFF Research Database (Denmark)

Juncker, Agnieszka; Larsen, Mette Voldby; Weinhold, Nils

2009-01-01

Background: Presentation of peptides on Major Histocompatibility Complex (MHC) molecules is the cornerstone in immune system activation and increased knowledge of the characteristics of MHC ligands and their source proteins is highly desirable. Methodology/Principal Finding: In the present large......-scale study, we used a large data set of proteins containing experimentally identified MHC class I or II ligands and examined the proteins according to their expression profiles at the mRNA level and their Gene Ontology (GO) classification within the cellular component ontology. Proteins encoded by highly...

Negative relationships between cellular immune response, Mhc class II heterozygosity and secondary sexual trait in the montane water vole

Czech Academy of Sciences Publication Activity Database

Charbonnel, N.; Bryja, Josef; Galan, M.; Deter, J.; Tollenaere, C.; Chaval, Y.; Morand, S.; Cosson, J.-F.

2010-01-01

Roč. 3, č. 3 (2010), s. 279-290 ISSN 1752-4571 EU Projects: European Commission(XE) 10284 - EDEN Institutional research plan: CEZ:AV0Z60930519 Keywords : abundance cycles * Dqa and Drb * immunocompetence handicap * Mhc class II genes * parasite-mediated balancing selection * sexual selection Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.145, year: 2010

Do polymorphisms and haplotypes of mismatch repair genes modulate risk of sporadic colorectal cancer?

Czech Academy of Sciences Publication Activity Database

Tulupová, Elena; Kumar, R.; Hánová, Monika; Slyšková, Jana; Pardini, Barbara; Poláková, Veronika; Naccarati, Alessio; Vodičková, Ludmila; Novotný, J.; Halamková, J.; Hemminki, K.; Vodička, Pavel

2008-01-01

Roč. 648, 1-2 (2008), s. 40-45 ISSN 0027-5107 R&D Projects: GA ČR GA310/07/1430 Institutional research plan: CEZ:AV0Z50390512; CEZ:AV0Z50390703 Keywords : DNA mismatch repair * Genetic polymorphism * Haplotype analysis Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.198, year: 2008

NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction

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Lund Ole

2009-09-01

Full Text Available Abstract Background The major histocompatibility complex (MHC molecule plays a central role in controlling the adaptive immune response to infections. MHC class I molecules present peptides derived from intracellular proteins to cytotoxic T cells, whereas MHC class II molecules stimulate cellular and humoral immunity through presentation of extracellularly derived peptides to helper T cells. Identification of which peptides will bind a given MHC molecule is thus of great importance for the understanding of host-pathogen interactions, and large efforts have been placed in developing algorithms capable of predicting this binding event. Results Here, we present a novel artificial neural network-based method, NN-align that allows for simultaneous identification of the MHC class II binding core and binding affinity. NN-align is trained using a novel training algorithm that allows for correction of bias in the training data due to redundant binding core representation. Incorporation of information about the residues flanking the peptide-binding core is shown to significantly improve the prediction accuracy. The method is evaluated on a large-scale benchmark consisting of six independent data sets covering 14 human MHC class II alleles, and is demonstrated to outperform other state-of-the-art MHC class II prediction methods. Conclusion The NN-align method is competitive with the state-of-the-art MHC class II peptide binding prediction algorithms. The method is publicly available at http://www.cbs.dtu.dk/services/NetMHCII-2.0.

The Intensity of Human Body Odors and the MHC: Should We Expect a Link?

OpenAIRE

Claus Wedekind; Thomas Seebeck; Florence Bettens; Alexander J. Paepke

2006-01-01

It is now well established that genes within the major histocompatibility complex (MHC) somehow affect the production of body odors in several vertebrates, including humans. Here we discuss whether variation in the intensity of body odors may be influenced by the MHC. In order to examine this question, we have to control for MHC-linked odor perception on the smeller's side. Such a control is necessary because the perception of pleasantness and intensity seem to be confounded, a...

Inferring mechanisms of copy number change from haplotype structures at the human DEFA1A3 locus.

Science.gov (United States)

Black, Holly A; Khan, Fayeza F; Tyson, Jess; Al Armour, John

2014-07-21

The determination of structural haplotypes at copy number variable regions can indicate the mechanisms responsible for changes in copy number, as well as explain the relationship between gene copy number and expression. However, obtaining spatial information at regions displaying extensive copy number variation, such as the DEFA1A3 locus, is complex, because of the difficulty in the phasing and assembly of these regions. The DEFA1A3 locus is intriguing in that it falls within a region of high linkage disequilibrium, despite its high variability in copy number (n = 3-16); hence, the mechanisms responsible for changes in copy number at this locus are unclear. In this study, a region flanking the DEFA1A3 locus was sequenced across 120 independent haplotypes with European ancestry, identifying five common classes of DEFA1A3 haplotype. Assigning DEFA1A3 class to haplotypes within the 1000 Genomes project highlights a significant difference in DEFA1A3 class frequencies between populations with different ancestry. The features of each DEFA1A3 class, for example, the associated DEFA1A3 copy numbers, were initially assessed in a European cohort (n = 599) and replicated in the 1000 Genomes samples, showing within-class similarity, but between-class and between-population differences in the features of the DEFA1A3 locus. Emulsion haplotype fusion-PCR was used to generate 61 structural haplotypes at the DEFA1A3 locus, showing a high within-class similarity in structure. Structural haplotypes across the DEFA1A3 locus indicate that intra-allelic rearrangement is the predominant mechanism responsible for changes in DEFA1A3 copy number, explaining the conservation of linkage disequilibrium across the locus. The identification of common structural haplotypes at the DEFA1A3 locus could aid studies into how DEFA1A3 copy number influences expression, which is currently unclear.

Structural requirements for the interaction between class II MHC molecules and peptide antigens

DEFF Research Database (Denmark)

Sette, A; Buus, S; Appella, E

1990-01-01

of binding, it is possible to define certain structural features of peptides that are associated with the capacity to bind to a particular MHC specificity (IA(d) or IE(d)); 3) IA(d) and IE(d) molecules recognize different and independent structures on the antigen molecule; 4) only about 10% of the single...... IA(d) and IE(d) molecules and their peptide ligands, we found that some structural characteristics apply to both antigen-MHC interactions. In particular, we found: 1) each MHC molecule is capable of binding many unrelated peptides through the same peptide-binding site; 2) despite this permissiveness...... amino acid substitutions tested on two IA(d)- and IE(d)-binding peptides had significant effect on their MHC-binding capacities, while over 80% of these substitutions significantly impaired T cell recognition of the Ia-peptide complex; 5) based on the segregation between residues that are crucial for T...

A haplotype specific to North European wheat (Triticum aestivum L.)

Czech Academy of Sciences Publication Activity Database

Tsombalova, J.; Karafiátová, Miroslava; Vrána, Jan; Kubaláková, Marie; Peusa, H.; Jakobson, I.; Jarve, M.; Valárik, Miroslav; Doležel, Jaroslav; Jarve, K.

2017-01-01

Roč. 64, č. 4 (2017), s. 653-664 ISSN 0925-9864 R&D Projects: GA MŠk(CZ) LO1204; GA ČR(CZ) GA14-07164S Institutional support: RVO:61389030 Keywords : bread wheat * genetic diversity * polyploid wheat * introgression lines * molecular analysis * tetraploid wheat * hexaploid wheat * powdery mildew * spelta l. * map * Common wheat * Triticum aestivum L * Spelt * Triticum spelta L * Chromosome 4A * Zero alleles * Haplotype * Linkage disequilibrium Subject RIV: EB - Genetics ; Molecular Biology OBOR OECD: Plant sciences, botany Impact factor: 1.294, year: 2016

Identification of MHC class II restricted T‐cell‐mediated reactivity against MHC class I binding Mycobacterium tuberculosis peptides

DEFF Research Database (Denmark)

Wang, Mingjun; Tang, Sheila Tuyet; Stryhn, Anette

2011-01-01

Major histocompatibility complex (MHC) class I restricted cytotoxic T lymphocytes (CTL) are known to play an important role in the control of Mycobacterium tuberculosis infection so identification of CTL epitopes from M. tuberculosis is of importance for the development of effective peptide...

Improved methods for predicting peptide binding affinity to MHC class II molecules.

Science.gov (United States)

Jensen, Kamilla Kjaergaard; Andreatta, Massimo; Marcatili, Paolo; Buus, Søren; Greenbaum, Jason A; Yan, Zhen; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

2018-01-06

Major histocompatibility complex class II (MHC-II) molecules are expressed on the surface of professional antigen-presenting cells where they display peptides to T helper cells, which orchestrate the onset and outcome of many host immune responses. Understanding which peptides will be presented by the MHC-II molecule is therefore important for understanding the activation of T helper cells and can be used to identify T-cell epitopes. We here present updated versions of two MHC-II-peptide binding affinity prediction methods, NetMHCII and NetMHCIIpan. These were constructed using an extended data set of quantitative MHC-peptide binding affinity data obtained from the Immune Epitope Database covering HLA-DR, HLA-DQ, HLA-DP and H-2 mouse molecules. We show that training with this extended data set improved the performance for peptide binding predictions for both methods. Both methods are publicly available at www.cbs.dtu.dk/services/NetMHCII-2.3 and www.cbs.dtu.dk/services/NetMHCIIpan-3.2. © 2018 John Wiley & Sons Ltd.

HapCol: Accurate and Memory-efficient Haplotype Assembly from Long Reads

NARCIS (Netherlands)

Y. Pirola (Yuri); S. Zaccaria (Simone); R. Dondi (Riccardo); G.W. Klau (Gunnar); N. Pisanti (Nadia); P. Bonizzoni (Paola)

2015-01-01

htmlabstractMotivation: Haplotype assembly is the computational problem of reconstructing haplotypes in diploid organisms and is of fundamental importance for characterizing the effects of single-nucleotide polymorphisms on the expression of phenotypic traits. Haplotype assembly highly benefits from

The MHC molecules of nonmammalian vertebrates

DEFF Research Database (Denmark)

Kaufman, J; Skjoedt, K; Salomonsen, J

1990-01-01

class II distribution. The axolotl has a very poor immune response (as though there are no helper T cells), a wide class II distribution and, for most animals, no cell surface class I molecule. It would be enlightening to understand both the mechanisms for the regulation of the MHC molecules during...

Signal peptide-dependent inhibition of MHC class I heavy chain translation by rhesus cytomegalovirus.

Directory of Open Access Journals (Sweden)

Colin J Powers

2008-10-01

Full Text Available The US2-11 region of human and rhesus cytomegalovirus encodes a conserved family of glycoproteins that inhibit MHC-I assembly with viral peptides, thus preventing cytotoxic T cell recognition. Since HCMV lacking US2-11 is no longer able to block assembly and transport of MHC-I, we examined whether this is also observed for RhCMV lacking the corresponding region. Unexpectedly, recombinant RhCMV lacking US2-11 was still able to inhibit MHC-I expression in infected fibroblasts, suggesting the presence of an additional MHC-I evasion mechanism. Progressive deletion analysis of RhCMV-specific genomic regions revealed that MHC-I expression is fully restored upon additional deletion of rh178. The protein encoded by this RhCMV-specific open reading frame is anchored in the endoplasmic reticulum membrane. In the presence of rh178, RhCMV prevented MHC-I heavy chain (HC expression, but did not inhibit mRNA transcription or association of HC mRNA with translating ribosomes. Proteasome inhibitors stabilized a HC degradation intermediate in the absence of rh178, but not in its presence, suggesting that rh178 prevents completion of HC translation. This interference was signal sequence-dependent since replacing the signal peptide with that of CD4 or murine HC rendered human HCs resistant to rh178. We have identified an inhibitor of antigen presentation encoded by rhesus cytomegalovirus unique in both its lack of homology to any other known protein and in its mechanism of action. By preventing signal sequence-dependent HC translocation, rh178 acts prior to US2, US3 and US11 which attack MHC-I proteins after protein synthesis is completed. Rh178 is the first viral protein known to interfere at this step of the MHC-I pathway, thus taking advantage of the conserved nature of HC leader peptides, and represents a new mechanism of translational interference.

Selection, diversity and evolutionary patterns of the MHC class II DAB in free-ranging Neotropical marsupials

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Otten Celine

2008-06-01

Full Text Available Abstract Background Research on the genetic architecture and diversity of the MHC has focused mainly on eutherian mammals, birds and fish. So far, studies on model marsupials used in laboratory investigations indicated very little or even no variation in MHC class II genes. However, natural levels of diversity and selection are unknown in marsupials as studies on wild populations are virtually absent. We used two endemic South American mouse opossums, Gracilinanus microtarsus and Marmosops incanus, to investigate characteristic features of MHC selection. This study is the first investigation of MHC selection in free-ranging Neotropical marsupials. In addition, the evolutionary history of MHC lineages within the group of marsupials was examined. Results G. microtarsus showed extensive levels of MHC diversity within and among individuals as 47 MHC-DAB alleles and high levels of sequence divergence were detected at a minimum of four loci. Positively selected codon sites were identified, of which most were congruent with human antigen binding sites. The diversity in M. incanus was rather low with only eight observed alleles at presumably two loci. However, these alleles also revealed high sequence divergence. Again, positive selection was identified on specific codon sites, all congruent with human ABS and with positively selected sites observed in G. microtarsus. In a phylogenetic comparison alleles of M. incanus interspersed widely within alleles of G. microtarsus with four alleles being present in both species. Conclusion Our investigations revealed extensive MHC class II polymorphism in a natural marsupial population, contrary to previous assumptions. Furthermore, our study confirms for the first time in marsupials the presence of three characteristic features common at MHC loci of eutherian mammals, birds and fish: large allelic sequence divergence, positive selection on specific sites and trans-specific polymorphism.

Quantifying the importance of pMHC valency, total pMHC dose and frequency on nanoparticle therapeutic efficacy.

Science.gov (United States)

Sugarman, Jordan; Tsai, Sue; Santamaria, Pere; Khadra, Anmar

2013-05-01

Nanoparticles (NPs) coated with β-cell-specific peptide major histocompatibility complex (pMHC) class I molecules can effectively restore normoglycemia in spontaneously diabetic nonobese diabetic mice. They do so by expanding pools of cognate memory autoreactive regulatory CD8+ T cells that arise from naive low-avidity T-cell precursors to therapeutic levels. Here we develop our previously constructed mathematical model to explore the effects of compound design parameters (NP dose and pMHC valency) on therapeutic efficacy with the underlying hypothesis that the functional correlates of the therapeutic response (expansion of autoregulatory T cells and deletion of autoantigen-loaded antigen-presenting cells by these T cells) are biphasic. We show, using bifurcation analysis, that the model exhibits a 'resonance'-like behavior for a given range of NP dose in which bistability between the healthy state (possessing zero level of effector T-cell population) and autoimmune state (possessing elevated level of the same population) disappears. A heterogeneous population of model mice subjected to several treatment protocols under these new conditions is conducted to quantify both the average percentage of autoregulatory T cells in responsive and nonresponsive model mice, and the average valency-dependent minimal optimal dose needed for effective therapy. Our results reveal that a moderate increase (≥1.6-fold) in the NP-dependent expansion rate of autoregulatory T-cell population leads to a significant increase in the efficacy and the area corresponding to the effective treatment regimen, provided that NP dose ≥8 μg. We expect the model developed here to generalize to other autoimmune diseases and serve as a computational tool to understand and optimize pMHC-NP-based therapies.

Fine haplotype structure of a chromosome 17 region in the laboratory and wild mouse

Czech Academy of Sciences Publication Activity Database

Trachtulec, Zdeněk; Vlček, Čestmír; Mihola, Ondřej; Gregorová, Soňa; Fotopulosová, Vladana; Forejt, Jiří

2008-01-01

Roč. 178, č. 3 (2008), s. 1777-1784 ISSN 0016-6731 R&D Projects: GA AV ČR IAA5052406; GA ČR GA301/05/0738; GA MŠk(CZ) 1M0520 Institutional research plan: CEZ:AV0Z50520514 Keywords : haplotype * hybrid sterility Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 4.002, year: 2008

HapCol : Accurate and memory-efficient haplotype assembly from long reads

NARCIS (Netherlands)

Pirola, Yuri; Zaccaria, Simone; Dondi, Riccardo; Klau, Gunnar W.; Pisanti, Nadia; Bonizzoni, Paola

2016-01-01

Motivation: Haplotype assembly is the computational problem of reconstructing haplotypes in diploid organisms and is of fundamental importance for characterizing the effects of single-nucleotide polymorphisms on the expression of phenotypic traits. Haplotype assembly highly benefits from the advent

Mineralocorticoid receptor haplotype, oral contraceptives and emotional information processing.

Science.gov (United States)

Hamstra, D A; de Kloet, E R; van Hemert, A M; de Rijk, R H; Van der Does, A J W

2015-02-12

Oral contraceptives (OCs) affect mood in some women and may have more subtle effects on emotional information processing in many more users. Female carriers of mineralocorticoid receptor (MR) haplotype 2 have been shown to be more optimistic and less vulnerable to depression. To investigate the effects of oral contraceptives on emotional information processing and a possible moderating effect of MR haplotype. Cross-sectional study in 85 healthy premenopausal women of West-European descent. We found significant main effects of oral contraceptives on facial expression recognition, emotional memory and decision-making. Furthermore, carriers of MR haplotype 1 or 3 were sensitive to the impact of OCs on the recognition of sad and fearful faces and on emotional memory, whereas MR haplotype 2 carriers were not. Different compounds of OCs were included. No hormonal measures were taken. Most naturally cycling participants were assessed in the luteal phase of their menstrual cycle. Carriers of MR haplotype 2 may be less sensitive to depressogenic side-effects of OCs. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

Genome-wide haplotype analysis of cis expression quantitative trait loci in monocytes.

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Sophie Garnier

Full Text Available In order to assess whether gene expression variability could be influenced by several SNPs acting in cis, either through additive or more complex haplotype effects, a systematic genome-wide search for cis haplotype expression quantitative trait loci (eQTL was conducted in a sample of 758 individuals, part of the Cardiogenics Transcriptomic Study, for which genome-wide monocyte expression and GWAS data were available. 19,805 RNA probes were assessed for cis haplotypic regulation through investigation of ~2,1 × 10(9 haplotypic combinations. 2,650 probes demonstrated haplotypic p-values >10(4-fold smaller than the best single SNP p-value. Replication of significant haplotype effects were tested for 412 probes for which SNPs (or proxies that defined the detected haplotypes were available in the Gutenberg Health Study composed of 1,374 individuals. At the Bonferroni correction level of 1.2 × 10(-4 (~0.05/412, 193 haplotypic signals replicated. 1000 G imputation was then conducted, and 105 haplotypic signals still remained more informative than imputed SNPs. In-depth analysis of these 105 cis eQTL revealed that at 76 loci genetic associations were compatible with additive effects of several SNPs, while for the 29 remaining regions data could be compatible with a more complex haplotypic pattern. As 24 of the 105 cis eQTL have previously been reported to be disease-associated loci, this work highlights the need for conducting haplotype-based and 1000 G imputed cis eQTL analysis before commencing functional studies at disease-associated loci.

The role of NK1.1+ cells in the protection against MHC class I+ HPV16-associated tumours

Czech Academy of Sciences Publication Activity Database

Šímová, Jana; Bubeník, Jan; Bieblová, Jana; Jandlová, Táňa

2004-01-01

Roč. 50, č. 6 (2004), s. 200-202 ISSN 0015-5500 R&D Projects: GA AV ČR IAA5052203; GA AV ČR KSK5011112; GA MZd NC7148; GA MZd NR7807 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * MHC class I expression * NK1.1+ cells Subject RIV: EC - Immunology Impact factor: 0.507, year: 2004

IRF-4-mediated CIITA transcription is blocked by KSHV encoded LANA to inhibit MHC II presentation.

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Qiliang Cai

2013-10-01

Full Text Available Peptides presentation to T cells by MHC class II molecules is of importance in initiation of immune response to a pathogen. The level of MHC II expression directly influences T lymphocyte activation and is often targeted by various viruses. Kaposi's sarcoma-associated herpesvirus (KSHV encoded LANA is known to evade MHC class I peptide processing, however, the effect of LANA on MHC class II remains unclear. Here, we report that LANA down-regulates MHC II expression and presentation by inhibiting the transcription of MHC II transactivator (CIITA promoter pIII and pIV in a dose-dependent manner. Strikingly, although LANA knockdown efficiently disrupts the inhibition of CIITA transcripts from its pIII and pIV promoter region, the expression of HLA-DQβ but no other MHC II molecules was significantly restored. Moreover, we revealed that the presentation of HLA-DQβ enhanced by LANA knockdown did not help LANA-specific CD4+ T cell recognition of PEL cells, and the inhibition of CIITA by LANA is independent of IL-4 or IFN-γ signaling but dependent on the direct interaction of LANA with IRF-4 (an activator of both the pIII and pIV CIITA promoters. This interaction dramatically blocked the DNA-binding ability of IRF-4 on both pIII and pIV promoters. Thus, our data implies that LANA can evade MHC II presentation and suppress CIITA transcription to provide a unique strategy of KSHV escape from immune surveillance by cytotoxic T cells.

MHC class I is functionally associated with antigen receptors in human T and B lymphomas

DEFF Research Database (Denmark)

Pedersen, Anders Elm; Jacoby, B F; Skov, S

1996-01-01

lines the increase in [Ca2+]i after MHC-I cross-linking caused upregulation of CD69, an early marker of activation. When studying the effect of MHC-I cross-linking on the TCR- and B cell antigen receptor (BCR)- mediated increase in [Ca2+]i, respectively, we observed that MHC-I had a costimulatory effect...... on the TCR-mediated increase in [Ca2+]i in Jurkat cells but not on the anti-IgM-mediated activity of Solubo cells. Studies of subpopulations of Jurkat and Solubo cells expressing different levels of MHC-I on their cell surfaces revealed that the TCR- and BCR-mediated increases in [Ca2+]i, respectively, were...

Extremely high MHC class I variation in a population of a long-distance migrant, the Scarlet Rosefinch (Carpodacus erythrinus)

Czech Academy of Sciences Publication Activity Database

Promerová, Marta; Albrecht, Tomáš; Bryja, Josef

2009-01-01

Roč. 61, č. 6 (2009), s. 451-461 ISSN 0093-7711 R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/06/0851; GA MŠk LC06073 Institutional research plan: CEZ:AV0Z60930519 Keywords : MHC class I * scarlet rosefinch * positive selection * recombination Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.988, year: 2009

Tolerance to MHC class II disparate allografts through genetic modification of bone marrow

Science.gov (United States)

Jindra, Peter T.; Tripathi, Sudipta; Tian, Chaorui; Iacomini, John; Bagley, Jessamyn

2012-01-01

Induction of molecular chimerism through genetic modification of bone marrow is a powerful tool for the induction of tolerance. Here we demonstrate for the first time that expression of an allogeneic MHC class II gene in autologous bone marrow cells, resulting in a state of molecular chimerism, induces tolerance to MHC class II mismatched skin grafts, a stringent test of transplant tolerance. Reconstitution of recipients with syngeneic bone marrow transduced with retrovirus encoding H-2I-Ab (I-Ab) resulted the long-term expression of the retroviral gene product on the surface of MHC class II-expressing bone marrow derived cell types. Mechanistically, tolerance was maintained by the presence of regulatory T cells, which prevented proliferation and cytokine production by alloreactive host T cells. Thus, the introduction of MHC class II genes into bone marrow derived cells through genetic engineering results in tolerance. These results have the potential to extend the clinical applicability of molecular chimerism for tolerance induction. PMID:22833118

Mineralocorticoid receptor haplotype, estradiol, progesterone and emotional information processing.

Science.gov (United States)

Hamstra, Danielle A; de Kloet, E Ronald; Quataert, Ina; Jansen, Myrthe; Van der Does, Willem

2017-02-01

Carriers of MR-haplotype 1 and 3 (GA/CG; rs5522 and rs2070951) are more sensitive to the influence of oral contraceptives (OC) and menstrual cycle phase on emotional information processing than MR-haplotype 2 (CA) carriers. We investigated whether this effect is associated with estradiol (E2) and/or progesterone (P4) levels. Healthy MR-genotyped premenopausal women were tested twice in a counterbalanced design. Naturally cycling (NC) women were tested in the early-follicular and mid-luteal phase and OC-users during OC-intake and in the pill-free week. At both sessions E2 and P4 were assessed in saliva. Tests included implicit and explicit positive and negative affect, attentional blink accuracy, emotional memory, emotion recognition, and risky decision-making (gambling). MR-haplotype 2 homozygotes had higher implicit happiness scores than MR-haplotype 2 heterozygotes (p=0.031) and MR-haplotype 1/3 carriers (pemotion recognition test than MR-haplotype 1/3 (p=0.001). Practice effects were observed for most measures. The pattern of correlations between information processing and P4 or E2 differed between sessions, as well as the moderating effects of the MR genotype. In the first session the MR-genotype moderated the influence of P4 on implicit anxiety (sr=-0.30; p=0.005): higher P4 was associated with reduction in implicit anxiety, but only in MR-haplotype 2 homozygotes (sr=-0.61; p=0.012). In the second session the MR-genotype moderated the influence of E2 on the recognition of facial expressions of happiness (sr=-0.21; p=0.035): only in MR-haplotype 1/3 higher E2 was correlated with happiness recognition (sr=0.29; p=0.005). In the second session higher E2 and P4 were negatively correlated with accuracy in lag2 trials of the attentional blink task (pemotional information processing. This moderating effect may depend on the novelty of the situation. Copyright © 2016 Elsevier Ltd. All rights reserved.

Haplotype phasing and inheritance of copy number variants in nuclear families.

Science.gov (United States)

Palta, Priit; Kaplinski, Lauris; Nagirnaja, Liina; Veidenberg, Andres; Möls, Märt; Nelis, Mari; Esko, Tõnu; Metspalu, Andres; Laan, Maris; Remm, Maido

2015-01-01

DNA copy number variants (CNVs) that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i) phase normal and CNV-carrying haplotypes in the copy number variable regions, ii) resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii) infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.

Haplotype phasing and inheritance of copy number variants in nuclear families.

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Priit Palta

Full Text Available DNA copy number variants (CNVs that alter the copy number of a particular DNA segment in the genome play an important role in human phenotypic variability and disease susceptibility. A number of CNVs overlapping with genes have been shown to confer risk to a variety of human diseases thus highlighting the relevance of addressing the variability of CNVs at a higher resolution. So far, it has not been possible to deterministically infer the allelic composition of different haplotypes present within the CNV regions. We have developed a novel computational method, called PiCNV, which enables to resolve the haplotype sequence composition within CNV regions in nuclear families based on SNP genotyping microarray data. The algorithm allows to i phase normal and CNV-carrying haplotypes in the copy number variable regions, ii resolve the allelic copies of rearranged DNA sequence within the haplotypes and iii infer the heritability of identified haplotypes in trios or larger nuclear families. To our knowledge this is the first program available that can deterministically phase null, mono-, di-, tri- and tetraploid genotypes in CNV loci. We applied our method to study the composition and inheritance of haplotypes in CNV regions of 30 HapMap Yoruban trios and 34 Estonian families. For 93.6% of the CNV loci, PiCNV enabled to unambiguously phase normal and CNV-carrying haplotypes and follow their transmission in the corresponding families. Furthermore, allelic composition analysis identified the co-occurrence of alternative allelic copies within 66.7% of haplotypes carrying copy number gains. We also observed less frequent transmission of CNV-carrying haplotypes from parents to children compared to normal haplotypes and identified an emergence of several de novo deletions and duplications in the offspring.

Predicting peptides binding to MHC class II molecules using multi-objective evolutionary algorithms

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Feng Lin

2007-11-01

Full Text Available Abstract Background Peptides binding to Major Histocompatibility Complex (MHC class II molecules are crucial for initiation and regulation of immune responses. Predicting peptides that bind to a specific MHC molecule plays an important role in determining potential candidates for vaccines. The binding groove in class II MHC is open at both ends, allowing peptides longer than 9-mer to bind. Finding the consensus motif facilitating the binding of peptides to a MHC class II molecule is difficult because of different lengths of binding peptides and varying location of 9-mer binding core. The level of difficulty increases when the molecule is promiscuous and binds to a large number of low affinity peptides. In this paper, we propose two approaches using multi-objective evolutionary algorithms (MOEA for predicting peptides binding to MHC class II molecules. One uses the information from both binders and non-binders for self-discovery of motifs. The other, in addition, uses information from experimentally determined motifs for guided-discovery of motifs. Results The proposed methods are intended for finding peptides binding to MHC class II I-Ag7 molecule – a promiscuous binder to a large number of low affinity peptides. Cross-validation results across experiments on two motifs derived for I-Ag7 datasets demonstrate better generalization abilities and accuracies of the present method over earlier approaches. Further, the proposed method was validated and compared on two publicly available benchmark datasets: (1 an ensemble of qualitative HLA-DRB1*0401 peptide data obtained from five different sources, and (2 quantitative peptide data obtained for sixteen different alleles comprising of three mouse alleles and thirteen HLA alleles. The proposed method outperformed earlier methods on most datasets, indicating that it is well suited for finding peptides binding to MHC class II molecules. Conclusion We present two MOEA-based algorithms for finding motifs

Beta-globin gene cluster haplotypes of Amerindian populations from the Brazilian Amazon region.

Science.gov (United States)

Guerreiro, J F; Figueiredo, M S; Zago, M A

1994-01-01

We have determined the beta-globin cluster haplotypes for 80 Indians from four Brazilian Amazon tribes: Kayapó, Wayampí, Wayana-Apalaí, and Arára. The results are analyzed together with 20 Yanomámi previously studied. From 2 to 4 different haplotypes were identified for each tribe, and 7 of the possible 32 haplotypes were found in a sample of 172 chromosomes for which the beta haplotypes were directly determined or derived from family studies. The haplotype distribution does not differ significantly among the five populations. The two most common haplotypes in all tribes were haplotypes 2 and 6, with average frequencies of 0.843 and 0.122, respectively. The genetic affinities between Brazilian Indians and other human populations were evaluated by estimates of genetic distance based on haplotype data. The lowest values were observed in relation to Asians, especially Chinese, Polynesians, and Micronesians.

Immune escape phenotype of HPV16-associated tumours: MHC class I expression changes during progression and therapy

Czech Academy of Sciences Publication Activity Database

Mikyšková, Romana; Bubeník, Jan; Vonka, V.; Šmahel, M.; Indrová, Marie; Bieblová, Jana; Šímová, Jana; Jandlová, Táňa

2005-01-01

Roč. 26, č. 2 (2005), s. 521-527 ISSN 1019-6439 R&D Projects: GA MZd(CZ) NC7148; GA MZd(CZ) NR8004; GA MZd(CZ) NR7807; GA ČR(CZ) GA301/04/0492; GA AV ČR(CZ) IAA5052203 Institutional research plan: CEZ:AV0Z5052915 Keywords : HPV16 * MHC class I- tumour cells * CTLs Subject RIV: EC - Immunology Impact factor: 2.681, year: 2005

Variation in MHC genotypes in two populations of house sparrow (Passer domesticus) with different population histories.

Science.gov (United States)

Borg, Asa Alexandra; Pedersen, Sindre Andre; Jensen, Henrik; Westerdahl, Helena

2011-10-01

Small populations are likely to have a low genetic ability for disease resistance due to loss of genetic variation through inbreeding and genetic drift. In vertebrates, the highest genetic diversity of the immune system is located at genes within the major histocompatibility complex (MHC). Interestingly, parasite-mediated selection is thought to potentially maintain variation at MHC loci even in populations that are monomorphic at other loci. Therefore, general loss of genetic variation in the genome may not necessarily be associated with low variation at MHC loci. We evaluated inter- and intrapopulation variation in MHC genotypes between an inbred (Aldra) and a relatively outbred population (Hestmannøy) of house sparrows (Passer domesticus) in a metapopulation at Helgeland, Norway. Genomic (gDNA) and transcribed (cDNA) alleles of functional MHC class I and IIB loci, along with neutral noncoding microsatellite markers, were analyzed to obtain relevant estimates of genetic variation. We found lower allelic richness in microsatellites in the inbred population, but high genetic variation in MHC class I and IIB loci in both populations. This suggests that also the inbred population could be under balancing selection to maintain genetic variation for pathogen resistance.

A spatial haplotype copying model with applications to genotype imputation.

Science.gov (United States)

Yang, Wen-Yun; Hormozdiari, Farhad; Eskin, Eleazar; Pasaniuc, Bogdan

2015-05-01

Ever since its introduction, the haplotype copy model has proven to be one of the most successful approaches for modeling genetic variation in human populations, with applications ranging from ancestry inference to genotype phasing and imputation. Motivated by coalescent theory, this approach assumes that any chromosome (haplotype) can be modeled as a mosaic of segments copied from a set of chromosomes sampled from the same population. At the core of the model is the assumption that any chromosome from the sample is equally likely to contribute a priori to the copying process. Motivated by recent works that model genetic variation in a geographic continuum, we propose a new spatial-aware haplotype copy model that jointly models geography and the haplotype copying process. We extend hidden Markov models of haplotype diversity such that at any given location, haplotypes that are closest in the genetic-geographic continuum map are a priori more likely to contribute to the copying process than distant ones. Through simulations starting from the 1000 Genomes data, we show that our model achieves superior accuracy in genotype imputation over the standard spatial-unaware haplotype copy model. In addition, we show the utility of our model in selecting a small personalized reference panel for imputation that leads to both improved accuracy as well as to a lower computational runtime than the standard approach. Finally, we show our proposed model can be used to localize individuals on the genetic-geographical map on the basis of their genotype data.

Direct binding of autoimmune disease related T cell epitopes to purified Lewis rat MHC class II molecules

DEFF Research Database (Denmark)

Joosten, I; Wauben, M H; Holewijn, M C

1994-01-01

New strategies applied in the treatment of experimental autoimmune disease models involve blocking or modulation of MHC-peptide-TCR interactions either at the level of peptide-MHC interaction or, alternatively, at the level of T cell recognition. In order to identify useful competitor peptides one...... characteristics of the Lewis rat MHC class II RT1.B1 molecule. We have now developed a biochemical binding assay which enables competition studies in which the relative MHC binding affinity of a set of non-labelled peptides can be assessed while employing detection of biotinylated marker peptides...

It's the peptide-MHC affinity, stupid.

Science.gov (United States)

Kammertoens, Thomas; Blankenstein, Thomas

2013-04-15

Adoptively transferred T cells can reject large established tumors, but recurrence due to escape variants frequently occurs. In this issue of Cancer Cell, Engels et al. demonstrate that the affinity of the target peptide to the MHC molecule determines whether large tumors will relapse following adoptive T cell therapy. Copyright © 2013 Elsevier Inc. All rights reserved.

Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells.

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Beatriz Suárez-Alvarez

2010-04-01

Full Text Available Human embryonic stem cells (hESCs are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored.We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM components and NKG2D ligands (NKG2D-L in hESCs, induced pluripotent stem cells (iPSCs and NTera2 (NT2 teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1 and tapasin (TPN components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of beta2-microglobulin (beta2m light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and beta2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs. Absence of HLA-DR and HLA-G expression was regulated by DNA methylation.Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance.

Epigenetic Mechanisms Regulate MHC and Antigen Processing Molecules in Human Embryonic and Induced Pluripotent Stem Cells

Science.gov (United States)

Suárez-Álvarez, Beatriz; Rodriguez, Ramón M.; Calvanese, Vincenzo; Blanco-Gelaz, Miguel A.; Suhr, Steve T.; Ortega, Francisco; Otero, Jesus; Cibelli, Jose B.; Moore, Harry; Fraga, Mario F.; López-Larrea, Carlos

2010-01-01

Background Human embryonic stem cells (hESCs) are an attractive resource for new therapeutic approaches that involve tissue regeneration. hESCs have exhibited low immunogenicity due to low levels of Mayor Histocompatibility Complex (MHC) class-I and absence of MHC class-II expression. Nevertheless, the mechanisms regulating MHC expression in hESCs had not been explored. Methodology/Principal Findings We analyzed the expression levels of classical and non-classical MHC class-I, MHC class-II molecules, antigen-processing machinery (APM) components and NKG2D ligands (NKG2D-L) in hESCs, induced pluripotent stem cells (iPSCs) and NTera2 (NT2) teratocarcinoma cell line. Epigenetic mechanisms involved in the regulation of these genes were investigated by bisulfite sequencing and chromatin immunoprecipitation (ChIP) assays. We showed that low levels of MHC class-I molecules were associated with absent or reduced expression of the transporter associated with antigen processing 1 (TAP-1) and tapasin (TPN) components in hESCs and iPSCs, which are involved in the transport and load of peptides. Furthermore, lack of β2-microglobulin (β2m) light chain in these cells limited the expression of MHC class I trimeric molecule on the cell surface. NKG2D ligands (MICA, MICB) were observed in all pluripotent stem cells lines. Epigenetic analysis showed that H3K9me3 repressed the TPN gene in undifferentiated cells whilst HLA-B and β2m acquired the H3K4me3 modification during the differentiation to embryoid bodies (EBs). Absence of HLA-DR and HLA-G expression was regulated by DNA methylation. Conclusions/Significance Our data provide fundamental evidence for the epigenetic control of MHC in hESCs and iPSCs. Reduced MHC class I and class II expression in hESCs and iPSCs can limit their recognition by the immune response against these cells. The knowledge of these mechanisms will further allow the development of strategies to induce tolerance and improve stem cell allograft acceptance

Analysis of DR4 haplotypes in insulin dependent diabetes (IDD)

International Nuclear Information System (INIS)

Monos, D.S.; Radka, S.F.; Zmijewski, C.M.; Kamoun, M.

1986-01-01

Population studies indicate that HLA-DR4 is implicated in the susceptibility of IDD. However, biochemical characterization of the serologically defined DR4 haplotype from normal individuals revealed five DR4 and three DQW3 molecular forms. Hence, in this study, they investigated the heterogeneity of the DR4 haplotype, using B-lymphoblastoid cell lines (B-LCL) generated from patients with IDD and seropositive for DR4. Class II molecules, metabolically labeled with 35 S-methionine, were immunoprecipitated with monoclonal antibodies specific for DR(L243), DQ(N297), DQW3(IVD12) or DR and DQ(SG465) and analyzed by two-dimensional polyacrylamide gel electrophoresis (2D-PAGE). The isoelectrofocusing (IEF) conditions employed in this study allow representation only of the DR4 haplotype from either DR3/4 or DR4/4 cell lines. The analysis of six different DR4 haplotypes from seven IDD patients, revealed the presence of two DR4 β and two DQW3 β chains. Three of the six DR4 β haplotypes analyzed shared the same DR4 β chain and three others shared a different one. Additionally five of the six haplotypes shared a different one. Additionally five of the six haplotypes shared the same DQW3 β chain and only one was carrying a different one. Different combinations of the two DR4 and two DQW3 β chains constitute three distinct patterns of DR4 haplotypes. These results suggest the prevalence of a DQW3 β chain in the small sample of IDD patients studied. Studies of a large number of patients should clarify whether IDD is associated with unique variants of DR4 or DQW3 β chains

MHC Region and Its Related Disease Study

DEFF Research Database (Denmark)

Cao, Hongzhi

The major histocompatibility complex (MHC) is one of the most gene dense regions in the human genome and many disorders, including primary immune deficiencies, autoimmune conditions, infections, cancers and mental disorder have been found to be associated with this region. However, due to a high ...

MHC Expression on Spleen Lymphocyte Subsets in Genetically Resistant and Susceptible Chickens Infected with Marek's Disease Virus

DEFF Research Database (Denmark)

Dalgaard, Tina; Bøving, Mette K.; Handberg, Kurt

2009-01-01

cytometry for MHC surface expression. In the spleen, constitutive MHC class I surface expression was found to be highest in homozygous B19, lowest in homozygous B21, and intermediate in heterozygous B19/B21 animals. This was observed on CD4(+), CD8(+), and Bu-1(+) splenic lymphocytes. Chickens of all three...... genotypes were subjected to infection with MD virus (GA strain) and spleen samples from infected as well as MHC-matched negative controls were analyzed at 1, 4, and 8 wk post-infection (p.i.). It was observed that MDV induced an increase in MHC class I expression late in the infection. Thus, MHC class I...... was increased on the surface of CD4(+) cells from infected chickens of all genotypes at 4 and 8 wk p.i. compared with negative controls. Also, MHC class I expression was increased on CD8(+) cells from infected chickens of all genotypes at 4 and 8 wk p.i., except for the homozygous B19 animals, that showed...

Occurrence of extra-pair paternity is connected to social male’s MHC-variability in the scarlet rosefinch Carpodacus erythrinus

Czech Academy of Sciences Publication Activity Database

Promerová, Marta; Vinkler, Michal; Bryja, Josef; Poláková, Radka; Schnitzer, J.; Munclinger, P.; Albrecht, Tomáš

2011-01-01

Roč. 42, č. 1 (2011), s. 5-10 ISSN 0908-8857 R&D Projects: GA AV ČR IAA600930608; GA ČR GA206/06/0851; GA MŠk LC06073 Institutional research plan: CEZ:AV0Z60930519 Keywords : scarlet rosefinch * Major Histocompatibility Complex (MHC) * mate choice decisions * good genes * sexual selection Subject RIV: EG - Zoology Impact factor: 2.280, year: 2011

MHC I stabilizing potential of computer-designed octapeptides.

Science.gov (United States)

Wisniewska, Joanna M; Jäger, Natalie; Freier, Anja; Losch, Florian O; Wiesmüller, Karl-Heinz; Walden, Peter; Wrede, Paul; Schneider, Gisbert; Hiss, Jan A

2010-01-01

Experimental results are presented for 180 in silico designed octapeptide sequences and their stabilizing effects on the major histocompatibility class I molecule H-2K(b). Peptide sequence design was accomplished by a combination of an ant colony optimization algorithm with artificial neural network classifiers. Experimental tests yielded nine H-2K(b) stabilizing and 171 nonstabilizing peptides. 28 among the nonstabilizing octapeptides contain canonical motif residues known to be favorable for MHC I stabilization. For characterization of the area covered by stabilizing and non-stabilizing octapeptides in sequence space, we visualized the distribution of 100,603 octapeptides using a self-organizing map. The experimental results present evidence that the canonical sequence motives of the SYFPEITHI database on their own are insufficient for predicting MHC I protein stabilization.

MHC I Stabilizing Potential of Computer-Designed Octapeptides

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Joanna M. Wisniewska

2010-01-01

Full Text Available Experimental results are presented for 180 in silico designed octapeptide sequences and their stabilizing effects on the major histocompatibility class I molecule H-2Kb. Peptide sequence design was accomplished by a combination of an ant colony optimization algorithm with artificial neural network classifiers. Experimental tests yielded nine H-2Kb stabilizing and 171 nonstabilizing peptides. 28 among the nonstabilizing octapeptides contain canonical motif residues known to be favorable for MHC I stabilization. For characterization of the area covered by stabilizing and non-stabilizing octapeptides in sequence space, we visualized the distribution of 100,603 octapeptides using a self-organizing map. The experimental results present evidence that the canonical sequence motives of the SYFPEITHI database on their own are insufficient for predicting MHC I protein stabilization.

Effects of the number of markers per haplotype and clustering of haplotypes on the accuracy of QTL mapping and prediction of genomic breeding values

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Schrooten Chris

2009-01-01

Full Text Available Abstract The aim of this paper was to compare the effect of haplotype definition on the precision of QTL-mapping and on the accuracy of predicted genomic breeding values. In a multiple QTL model using identity-by-descent (IBD probabilities between haplotypes, various haplotype definitions were tested i.e. including 2, 6, 12 or 20 marker alleles and clustering base haplotypes related with an IBD probability of > 0.55, 0.75 or 0.95. Simulated data contained 1100 animals with known genotypes and phenotypes and 1000 animals with known genotypes and unknown phenotypes. Genomes comprising 3 Morgan were simulated and contained 74 polymorphic QTL and 383 polymorphic SNP markers with an average r2 value of 0.14 between adjacent markers. The total number of haplotypes decreased up to 50% when the window size was increased from two to 20 markers and decreased by at least 50% when haplotypes related with an IBD probability of > 0.55 instead of > 0.95 were clustered. An intermediate window size led to more precise QTL mapping. Window size and clustering had a limited effect on the accuracy of predicted total breeding values, ranging from 0.79 to 0.81. Our conclusion is that different optimal window sizes should be used in QTL-mapping versus genome-wide breeding value prediction.

Vaccination against lymphocytic choriomeningitis virus infection in MHC class II-deficient mice

DEFF Research Database (Denmark)

Holst, Peter Johannes; Christensen, Jan Pravsgaard; Thomsen, Allan Randrup

2011-01-01

response could be elicited in MHC class II-deficient mice by vaccination with adenovirus encoding lymphocytic choriomeningitis virus (LCMV) glycoprotein tethered to MHC class II-associated invariant chain. Moreover, the response induced conferred significant cytolytic CD8(+) T cell-mediated protection...... against challenge with a high dose of the invasive clone 13 strain of LCMV. In contrast, vaccination with adenovirus encoding unlinked LCMV glycoprotein induced weak virus control in the absence of CD4(+) T cells, and mice may die of increased immunopathology associated with incomplete protection. Acute...... mortality was not observed in any vaccinated mice following infection with the less-invasive Traub strain. However, LCMV Traub infection caused accelerated late mortality in unvaccinated MHC class II-deficient mice; in this case, we observed a strong trend toward delayed mortality in vaccinated mice...

Automated benchmarking of peptide-MHC class I binding predictions

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Trolle, Thomas; Metushi, Imir G.; Greenbaum, Jason A.; Kim, Yohan; Sidney, John; Lund, Ole; Sette, Alessandro; Peters, Bjoern; Nielsen, Morten

2015-01-01

Motivation: Numerous in silico methods predicting peptide binding to major histocompatibility complex (MHC) class I molecules have been developed over the last decades. However, the multitude of available prediction tools makes it non-trivial for the end-user to select which tool to use for a given task. To provide a solid basis on which to compare different prediction tools, we here describe a framework for the automated benchmarking of peptide-MHC class I binding prediction tools. The framework runs weekly benchmarks on data that are newly entered into the Immune Epitope Database (IEDB), giving the public access to frequent, up-to-date performance evaluations of all participating tools. To overcome potential selection bias in the data included in the IEDB, a strategy was implemented that suggests a set of peptides for which different prediction methods give divergent predictions as to their binding capability. Upon experimental binding validation, these peptides entered the benchmark study. Results: The benchmark has run for 15 weeks and includes evaluation of 44 datasets covering 17 MHC alleles and more than 4000 peptide-MHC binding measurements. Inspection of the results allows the end-user to make educated selections between participating tools. Of the four participating servers, NetMHCpan performed the best, followed by ANN, SMM and finally ARB. Availability and implementation: Up-to-date performance evaluations of each server can be found online at http://tools.iedb.org/auto_bench/mhci/weekly. All prediction tool developers are invited to participate in the benchmark. Sign-up instructions are available at http://tools.iedb.org/auto_bench/mhci/join. Contact: mniel@cbs.dtu.dk or bpeters@liai.org Supplementary information: Supplementary data are available at Bioinformatics online. PMID:25717196

Constitutive MHC class I molecules negatively regulate TLR-triggered inflammatory responses via the Fps-SHP-2 pathway.

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Xu, Sheng; Liu, Xingguang; Bao, Yan; Zhu, Xuhui; Han, Chaofeng; Zhang, Peng; Zhang, Xuemin; Li, Weihua; Cao, Xuetao

2012-04-22

The molecular mechanisms that fine-tune Toll-like receptor (TLR)-triggered innate inflammatory responses remain to be fully elucidated. Major histocompatibility complex (MHC) molecules can mediate reverse signaling and have nonclassical functions. Here we found that constitutively expressed membrane MHC class I molecules attenuated TLR-triggered innate inflammatory responses via reverse signaling, which protected mice from sepsis. The intracellular domain of MHC class I molecules was phosphorylated by the kinase Src after TLR activation, then the tyrosine kinase Fps was recruited via its Src homology 2 domain to phosphorylated MHC class I molecules. This led to enhanced Fps activity and recruitment of the phosphatase SHP-2, which interfered with TLR signaling mediated by the signaling molecule TRAF6. Thus, constitutive MHC class I molecules engage in crosstalk with TLR signaling via the Fps-SHP-2 pathway and control TLR-triggered innate inflammatory responses.

MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus

Science.gov (United States)

2012-01-01

Background The major histocompatibility complex (MHC) genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus). Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus) from 12 local populations. Results Among 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes) and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected. Conclusions The low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other endangered mammalian

MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus

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Yasukochi Yoshiki

2012-11-01

Full Text Available Abstract Background The major histocompatibility complex (MHC genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus. Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus from 12 local populations. Results Among 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected. Conclusions The low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other

MHC class II DQB diversity in the Japanese black bear, Ursus thibetanus japonicus.

Science.gov (United States)

Yasukochi, Yoshiki; Kurosaki, Toshifumi; Yoneda, Masaaki; Koike, Hiroko; Satta, Yoko

2012-11-29

The major histocompatibility complex (MHC) genes are one of the most important genetic systems in the vertebrate immune response. The diversity of MHC genes may directly influence the survival of individuals against infectious disease. However, there has been no investigation of MHC diversity in the Asiatic black bear (Ursus thibetanus). Here, we analyzed 270-bp nucleotide sequences of the entire exon 2 region of the MHC DQB gene by using 188 samples from the Japanese black bear (Ursus thibetanus japonicus) from 12 local populations. Among 185 of 188 samples, we identified 44 MHC variants that encoded 31 different amino acid sequences (allotypes) and one putative pseudogene. The phylogenetic analysis suggests that MHC variants detected from the Japanese black bear are derived from the DQB locus. One of the 31 DQB allotypes, Urth-DQB*01, was found to be common to all local populations. Moreover, this allotype was shared between the black bear on the Asian continent and the Japanese black bear, suggesting that Urth-DQB*01 might have been maintained in the ancestral black bear population for at least 300,000 years. Our findings, from calculating the ratio of non-synonymous to synonymous substitutions, indicate that balancing selection has maintained genetic variation of peptide-binding residues at the DQB locus of the Japanese black bear. From examination of genotype frequencies among local populations, we observed a considerably lower level of observed heterozygosity than expected. The low level of observed heterozygosity suggests that genetic drift reduced DQB diversity in the Japanese black bear due to a bottleneck event at the population or species level. The decline of DQB diversity might have been accelerated by the loss of rare variants that have been maintained by negative frequency-dependent selection. Nevertheless, DQB diversity of the black bear appears to be relatively high compared with some other endangered mammalian species. This result suggests that

TLR4-HMGB1 signaling pathway affects the inflammatory reaction of autoimmune myositis by regulating MHC-I.

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Wan, Zemin; Zhang, Xiujuan; Peng, Anping; He, Min; Lei, Zhenhua; Wang, Yunxiu

2016-12-01

To analyze the effects of TLR4 on the expression of the HMGB1, MHC-I and downstream cytokines IL-6 and TNF-α, and to investigate the biological role of the TLR4-HMGB1 signaling pathway in the development of the autoimmune myositis. We built mice models with experimental autoimmune myositis (EAM) and used the inverted screen experiment to measure their muscle endurance; we also examined inflammatory infiltration of muscle tissues after HE staining; and we assessed the expression of MHC-I using immunohistochemistry. In addition, peripheral blood mononuclear cells (PBMC) were extracted and flow cytometry was utilized to detect the effect of IFN-γ on the expression of MHC-I. Furthermore, PBMCs were treated with IFN-γ, anti-TLR4, anti-HMGB1 and anti-MHC-I. Real-time PCR and western blotting were employed to examine the expressions of TLR4, HMGB1 and MHC-I in different groups. The ELISA method was also utilized to detect the expression of the downstream cytokines TNF-α and IL-6. The expressions of TLR4, HMGB1 and MHC-I in muscle tissues from mice with EAM were significantly higher than those in the control group (all Pmyositis inflammation by regulating the expression of MHC-I and other pro-inflammatory cytokines. Copyright © 2016 Elsevier B.V. All rights reserved.

HUBUNGAN ANTARA PERTUMBUHAN DENGAN KEBERADAAN GEN TAHAN PENYAKIT MAJOR HISTOCOMPATIBILITY COMPLEX (MHC PADA IKAN MAS (Cyprinus carpio

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Erma Primanita Hayuningtyas

2016-04-01

Full Text Available Wabah penyakit koi herpes virus (KHV di Indonesia yang terjadi sejak tahun 2002 merupakan salah satu faktor yang memicu kemerosotan produksi ikan mas budidaya. Pembentukan strain unggul ikan mas tahan KHV dapat menjadi solusi bagi permasalahan tersebut. Pemilihan genotip ikan mas tahan KHV dengan marka molekuler gen major histocompatibility complex class II (MHC-II, khususnya pada alel Cyca DAB 1*05 akan membantu dalam kegiatan seleksi. Penelitian ini bertujuan untuk mengetahui keberadaan gen MHC-II pada populasi dasar G0 ikan mas strain Rajadanu dan hubungannya dengan pertumbuhan (bobot. Metode deteksi keberadaan gen MHC-II pada dua kelompok ikan dengan ukuran berbeda dilakukan dengan teknik PCR. Hubungan antara pertumbuhan ikan mas dengan persentase kemunculan gen MHC-II dianalisis dengan menggunakan program SPSS (Statistical Package for the Social Sciences, sehingga diperoleh korelasi di antara keduanya. Hasil penelitian menunjukkan bahwa hubungan antara pertumbuhan dengan persentase keberadaan gen MHC-II berkorelasi negatif dengan nilai R = -0,742. Hal ini mengindikasikan bahwa semakin cepat pertumbuhan populasi ikan mas maka semakin sedikit persentase individu yang mempunyai gen MHC-II pada setiap populasi ikan mas. Sehingga populasi ikan mas yang pertumbuhannya lambat memiliki tingkat persentase positif MHC-II lebih tinggi (85,71%-100% dibandingkan populasi ikan mas yang pertumbuhannya cepat (42,86%-85,71%.

The prognostic role of classical and nonclassical MHC class I expression in endometrial cancer

NARCIS (Netherlands)

Bijen, C.B.; Bantema-Joppe, E.J.; de Jong, Renske; Leffers, N.; Mourits, M.J.; Eggink, Henk F.; van der Zee, A.G.; Hollema, H.; de Bock, G.H.; Nijman, H.W.

2010-01-01

The aim of this study was to investigate classical MHC class I and nonclassical MHC (human leukocyte antigen-G [HLA-GJ) expression in a large cohort of patients with endometrial cancer, to determine the prognostic value of these cell surface markers and their relation with clinicopathological

Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method.

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Nielsen, Morten; Lundegaard, Claus; Lund, Ole

2007-07-04

Antigen presenting cells (APCs) sample the extra cellular space and present peptides from here to T helper cells, which can be activated if the peptides are of foreign origin. The peptides are presented on the surface of the cells in complex with major histocompatibility class II (MHC II) molecules. Identification of peptides that bind MHC II molecules is thus a key step in rational vaccine design and developing methods for accurate prediction of the peptide:MHC interactions play a central role in epitope discovery. The MHC class II binding groove is open at both ends making the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC) and three mouse H2-IA alleles. The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR), we demonstrate a consistent gain in predictive performance by favoring binding registers with a minimum PFR length of two amino acids. Visualizing the binding motif as obtained by the SMM-align and TEPITOPE methods highlights a series of fundamental discrepancies between the two predicted motifs. For the DRB1*1302 allele for instance, the TEPITOPE method favors basic amino acids at most anchor positions, whereas the SMM-align method identifies a preference for hydrophobic or neutral amino acids at the anchors. The SMM-align method was shown to outperform other

Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method

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Lund Ole

2007-07-01

Full Text Available Abstract Background Antigen presenting cells (APCs sample the extra cellular space and present peptides from here to T helper cells, which can be activated if the peptides are of foreign origin. The peptides are presented on the surface of the cells in complex with major histocompatibility class II (MHC II molecules. Identification of peptides that bind MHC II molecules is thus a key step in rational vaccine design and developing methods for accurate prediction of the peptide:MHC interactions play a central role in epitope discovery. The MHC class II binding groove is open at both ends making the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC and three mouse H2-IA alleles. Results The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR, we demonstrate a consistent gain in predictive performance by favoring binding registers with a minimum PFR length of two amino acids. Visualizing the binding motif as obtained by the SMM-align and TEPITOPE methods highlights a series of fundamental discrepancies between the two predicted motifs. For the DRB1*1302 allele for instance, the TEPITOPE method favors basic amino acids at most anchor positions, whereas the SMM-align method identifies a preference for hydrophobic or neutral amino acids at the anchors. Conclusion

Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo.

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Pezzanite, Lynn M; Fortier, Lisa A; Antczak, Douglas F; Cassano, Jennifer M; Brosnahan, Margaret M; Miller, Donald; Schnabel, Lauren V

2015-04-12

This study tested the hypothesis that Major Histocompatibility Complex (MHC) incompatible equine mesenchymal stromal cells (MSCs) would induce cytotoxic antibodies to donor MHC antigens in recipient horses after intradermal injection. No studies to date have explored recipient antibody responses to allogeneic donor MSC transplantation in the horse. This information is critical because the horse is a valuable species for assessing the safety and efficacy of MSC treatment prior to human clinical application. Six MHC heterozygote horses were identified as non-ELA-A2 haplotype by microsatellite typing and used as allogeneic MHC-mismatched MSC recipients. MHC homozygote horses of known ELA-A2 haplotype were used as MSC and peripheral blood leukocyte (PBL) donors. One MHC homozygote horse of the ELA-A2 haplotype was the recipient of ELA-A2 donor MSCs as an MHC-matched control. Donor MSCs, which were previously isolated and immunophenotyped, were thawed and culture expanded to achieve between 30x10(6) and 50x10(6) cells for intradermal injection into the recipient's neck. Recipient serum was collected and tested for the presence of anti-donor antibodies prior to MSC injection and every 7 days after MSC injection for the duration of the 8-week study using the standard two-stage lymphocyte microcytotoxicity dye-exclusion test. In addition to anti-ELA-A2 antibodies, recipient serum was examined for the presence of cross-reactive antibodies including anti-ELA-A3 and anti-RBC antibodies. All MHC-mismatched recipient horses produced anti-ELA-A2 antibodies following injection of ELA-A2 MSCs and developed a wheal at the injection site that persisted for the duration of the experiment. Anti-ELA-A2 antibody responses were varied both in terms of strength and timing. Four recipient horses had high-titered anti-ELA-A2 antibody responses resulting in greater than 80% donor PBL death in the microcytotoxicity assays and one of these horses also developed antibodies that cross

MHC and non-MHC genes regulate elimination of lymphocytic choriomeningitis virus and antiviral cytotoxic T lymphocyte and delayed-type hypersensitivity mediating T lymphocyte activity in parallel

DEFF Research Database (Denmark)

Thomsen, Allan Randrup; Marker, O

1989-01-01

with regard to all three parameters was recessive, indicating that natural tolerance is not the mechanism explaining non-MHC dependent low responsiveness in this system. The implications of these findings are discussed with specific reference to the role of MHC genes in controlling resistance to infectious......, indicating that both H-2 and non-H-2 genes may influence the elimination of this virus. Differences in virus spread prior to appearance of the immune response could not explain the observed differences in clearance rate. On the other hand, inefficient clearance always correlated with low T cell...

The Missing Link in Epstein-Barr Virus Immune Evasion: the BDLF3 Gene Induces Ubiquitination and Downregulation of Major Histocompatibility Complex Class I (MHC-I) and MHC-II.

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Quinn, Laura L; Williams, Luke R; White, Claire; Forrest, Calum; Zuo, Jianmin; Rowe, Martin

2016-01-01

The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8(+) cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8(+) cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8(+) cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4(+) cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8(+) and CD4(+) T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner. Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8(+) T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8(+) T cells specific for

A new 500 kb haplotype associated with high CD8+ T-lymphocyte numbers predicts a less severe expression of hereditary hemochromatosis

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Mascarenhas Cláudia

2008-11-01

Full Text Available Abstract Background Hereditary Hemochromatosis(HH is a common genetic disorder of iron overload where the large majority of patients are homozygous for one ancestral mutation in the HFE gene. In spite of this remarkable genetic homogeneity, the condition is clinically heterogeneous, varying from a severe disease to an asymptomatic phenotype with only abnormal biochemical parameters. The recent recognition of the variable penetrance of the HH mutation in different large population studies demands the need to search for new modifiers of its phenotypic expression. The present study follows previous observations that MHC class-I linked genetic markers, associated with the setting of CD8+ T-lymphocyte numbers, could be clinically relevant modifiers of the phenotypic expression in HH, and aimed to find new markers that could be used as more reliable prognostic variables. Methods Haplotype analysis, including seven genetic markers within a 1 Mb region around the microsatellite D6S105 was performed in a group of 56 previously characterized C282Y homozygous Portuguese patients. Parameters analyzed in this study were total body iron stores, clinical manifestations related with HH and immunological parameters (total lymphocyte numbers, CD4+ and CD8+ T-lymphocyte numbers. An independent group of 10 C282Y homozygous patients from Vancouver, Canada, were also included in this study and analyzed for the same parameters. Results A highly conserved ancestral haplotype defined by the SNP markers PGBD1-A, ZNF193-A, ZNF165-T (designated as A-A-T was found associated with both abnormally low CD8+ T-lymphocyte numbers and the development of a severe clinical expression of HH. In a small proportion of patients, another conserved haplotype defined by the SNP markers PGBD1-G, ZNF193-G, ZNF165-G (designated as G-G-G was found associated with high CD8+ T-lymphocyte numbers and a milder clinical expression. Remarkably, the two conserved haplotypes defined in Portuguese

The peptide-receptive transition state of MHC-1 molecules: Insight from structure and molecular dynamics

Energy Technology Data Exchange (ETDEWEB)

Robinson H.; Mage, M.; Dolan, M.; Wang, R.; Boyd, L.; Revilleza, M.; Natarajan, K.; Myers, N.; Hansen, T.; Margulies, D.

2012-05-01

MHC class I (MHC-I) proteins of the adaptive immune system require antigenic peptides for maintenance of mature conformation and immune function via specific recognition by MHC-I-restricted CD8(+) T lymphocytes. New MHC-I molecules in the endoplasmic reticulum are held by chaperones in a peptide-receptive (PR) transition state pending release by tightly binding peptides. In this study, we show, by crystallographic, docking, and molecular dynamics methods, dramatic movement of a hinged unit containing a conserved 3(10) helix that flips from an exposed 'open' position in the PR transition state to a 'closed' position with buried hydrophobic side chains in the peptide-loaded mature molecule. Crystallography of hinged unit residues 46-53 of murine H-2L(d) MHC-I H chain, complexed with mAb 64-3-7, demonstrates solvent exposure of these residues in the PR conformation. Docking and molecular dynamics predict how this segment moves to help form the A and B pockets crucial for the tight peptide binding needed for stability of the mature peptide-loaded conformation, chaperone dissociation, and Ag presentation.

Honey bee-inspired algorithms for SNP haplotype reconstruction problem

Science.gov (United States)

PourkamaliAnaraki, Maryam; Sadeghi, Mehdi

2016-03-01

Reconstructing haplotypes from SNP fragments is an important problem in computational biology. There have been a lot of interests in this field because haplotypes have been shown to contain promising data for disease association research. It is proved that haplotype reconstruction in Minimum Error Correction model is an NP-hard problem. Therefore, several methods such as clustering techniques, evolutionary algorithms, neural networks and swarm intelligence approaches have been proposed in order to solve this problem in appropriate time. In this paper, we have focused on various evolutionary clustering techniques and try to find an efficient technique for solving haplotype reconstruction problem. It can be referred from our experiments that the clustering methods relying on the behaviour of honey bee colony in nature, specifically bees algorithm and artificial bee colony methods, are expected to result in more efficient solutions. An application program of the methods is available at the following link. http://www.bioinf.cs.ipm.ir/software/haprs/

HERC1 polymorphisms: population-specific variations in haplotype composition.

Science.gov (United States)

Yuasa, Isao; Umetsu, Kazuo; Nishimukai, Hiroaki; Fukumori, Yasuo; Harihara, Shinji; Saitou, Naruya; Jin, Feng; Chattopadhyay, Prasanta K; Henke, Lotte; Henke, Jürgen

2009-08-01

Human HERC1 is one of six HERC proteins and may play an important role in intracellular membrane trafficking. The human HERC1 gene is suggested to have been affected by local positive selection. To assess the global frequency distributions of coding and non-coding single nucleotide polymorphisms (SNPs) in the HERC1 gene, we developed a new simultaneous genotyping method for four SNPs, and applied this method to investigate 1213 individuals from 12 global populations. The results confirmed remarked differences in the allele and haplotype frequencies between East Asian and non-East Asian populations. One of the three common haplotypes observed was found to be characteristic of East Asians, who showed a relatively uniform distribution of haplotypes. Information on haplotypes would be useful for testing the function of polymorphisms in the HERC1 gene. This is the first study to investigate the distribution of HERC1 polymorphisms in various populations. (c) 2009 John Wiley & Sons, Ltd.

De novo assembly of a haplotype-resolved human genome.

Science.gov (United States)

Cao, Hongzhi; Wu, Honglong; Luo, Ruibang; Huang, Shujia; Sun, Yuhui; Tong, Xin; Xie, Yinlong; Liu, Binghang; Yang, Hailong; Zheng, Hancheng; Li, Jian; Li, Bo; Wang, Yu; Yang, Fang; Sun, Peng; Liu, Siyang; Gao, Peng; Huang, Haodong; Sun, Jing; Chen, Dan; He, Guangzhu; Huang, Weihua; Huang, Zheng; Li, Yue; Tellier, Laurent C A M; Liu, Xiao; Feng, Qiang; Xu, Xun; Zhang, Xiuqing; Bolund, Lars; Krogh, Anders; Kristiansen, Karsten; Drmanac, Radoje; Drmanac, Snezana; Nielsen, Rasmus; Li, Songgang; Wang, Jian; Yang, Huanming; Li, Yingrui; Wong, Gane Ka-Shu; Wang, Jun

2015-06-01

The human genome is diploid, and knowledge of the variants on each chromosome is important for the interpretation of genomic information. Here we report the assembly of a haplotype-resolved diploid genome without using a reference genome. Our pipeline relies on fosmid pooling together with whole-genome shotgun strategies, based solely on next-generation sequencing and hierarchical assembly methods. We applied our sequencing method to the genome of an Asian individual and generated a 5.15-Gb assembled genome with a haplotype N50 of 484 kb. Our analysis identified previously undetected indels and 7.49 Mb of novel coding sequences that could not be aligned to the human reference genome, which include at least six predicted genes. This haplotype-resolved genome represents the most complete de novo human genome assembly to date. Application of our approach to identify individual haplotype differences should aid in translating genotypes to phenotypes for the development of personalized medicine.

Can Selective MHC Downregulation Explain the Specificity and Genetic Diversity of NK Cell Receptors?

NARCIS (Netherlands)

Carrillo-Bustamante, Paola; Kesmir, Can; de Boer, Rob J

2015-01-01

Natural killer (NK) cells express inhibiting receptors (iNKRs), which specifically bind MHC-I molecules on the surface of healthy cells. When the expression of MHC-I on the cell surface decreases, which might occur during certain viral infections and cancer, iNKRs lose inhibiting signals and the

An accurate clone-based haplotyping method by overlapping pool sequencing.

Science.gov (United States)

Li, Cheng; Cao, Changchang; Tu, Jing; Sun, Xiao

2016-07-08

Chromosome-long haplotyping of human genomes is important to identify genetic variants with differing gene expression, in human evolution studies, clinical diagnosis, and other biological and medical fields. Although several methods have realized haplotyping based on sequencing technologies or population statistics, accuracy and cost are factors that prohibit their wide use. Borrowing ideas from group testing theories, we proposed a clone-based haplotyping method by overlapping pool sequencing. The clones from a single individual were pooled combinatorially and then sequenced. According to the distinct pooling pattern for each clone in the overlapping pool sequencing, alleles for the recovered variants could be assigned to their original clones precisely. Subsequently, the clone sequences could be reconstructed by linking these alleles accordingly and assembling them into haplotypes with high accuracy. To verify the utility of our method, we constructed 130 110 clones in silico for the individual NA12878 and simulated the pooling and sequencing process. Ultimately, 99.9% of variants on chromosome 1 that were covered by clones from both parental chromosomes were recovered correctly, and 112 haplotype contigs were assembled with an N50 length of 3.4 Mb and no switch errors. A comparison with current clone-based haplotyping methods indicated our method was more accurate. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

ZAP-70 and p72syk are signaling response elements through MHC class II molecules

DEFF Research Database (Denmark)

Kanner, S B; Grosmaire, L S; Blake, J

1995-01-01

Ligation of major histocompatibility complex (MHC) class II antigens expressed on antigen-activated human CD4+ T-lymphocytes induces early signal transduction events including the activation of tyrosine kinases, the tyrosine phosphorylation of phospholipase-C gamma 1 and the mobilization...... of intracellular calcium. Similar responses have been observed in B-cells following stimulation of MHC class II molecules, including the increased production of intracellular cAMP. In this report, we demonstrate that the ZAP-70 tyrosine kinase is a responsive signaling element following cross-linking of HLA...... by herbimycin A. MHC class II ligation on B-lymphocytes resulted in cell death, which was both qualitatively distinct from Fas-induced apoptosis and partially protected by herbimycin A pretreatment. Thus, ligation of MHC class II molecules expressed on human lymphocytes stimulates the ZAP-70/p72syk family...

Genetic relationships among native americans based on beta-globin gene cluster haplotype frequencies

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Rita de Cassia Mousinho-Ribeiro

2003-01-01

Full Text Available The distribution of b-globin gene haplotypes was studied in 209 Amerindians from eight tribes of the Brazilian Amazon: Asurini from Xingú, Awá-Guajá, Parakanã, Urubú-Kaapór, Zoé, Kayapó (Xikrin from the Bacajá village, Katuena, and Tiriyó. Nine different haplotypes were found, two of which (n. 11 and 13 had not been previously identified in Brazilian indigenous populations. Haplotype 2 (+ - - - - was the most common in all groups studied, with frequencies varying from 70% to 100%, followed by haplotype 6 (- + + - +, with frequencies between 7% and 18%. The frequency distribution of the b-globin gene haplotypes in the eighteen Brazilian Amerindian populations studied to date is characterized by a reduced number of haplotypes (average of 3.5 and low levels of heterozygosity and intrapopulational differentiation, with a single clearly predominant haplotype in most tribes (haplotype 2. The Parakanã, Urubú-Kaapór, Tiriyó and Xavante tribes constitute exceptions, presenting at least four haplotypes with relatively high frequencies. The closest genetic relationships were observed between the Brazilian and the Colombian Amerindians (Wayuu, Kamsa and Inga, and, to a lesser extent, with the Huichol of Mexico. North-American Amerindians are more differentiated and clearly separated from all other tribes, except the Xavante, from Brazil, and the Mapuche, from Argentina. A restricted pool of ancestral haplotypes may explain the low diversity observed among most present-day Brazilian and Colombian Amerindian groups, while interethnic admixture could be the most important factor to explain the high number of haplotypes and high levels of diversity observed in some South-American and most North-American tribes.

De novo transcriptome assembly facilitates characterisation of fast-evolving gene families, MHC class I in the bank vole (Myodes glareolus).

Science.gov (United States)

Migalska, M; Sebastian, A; Konczal, M; Kotlík, P; Radwan, J

2017-04-01

The major histocompatibility complex (MHC) plays a central role in the adaptive immune response and is the most polymorphic gene family in vertebrates. Although high-throughput sequencing has increasingly been used for genotyping families of co-amplifying MHC genes, its potential to facilitate early steps in the characterisation of MHC variation in nonmodel organism has not been fully explored. In this study we evaluated the usefulness of de novo transcriptome assembly in characterisation of MHC sequence diversity. We found that although de novo transcriptome assembly of MHC I genes does not reconstruct sequences of individual alleles, it does allow the identification of conserved regions for PCR primer design. Using the newly designed primers, we characterised MHC I sequences in the bank vole. Phylogenetic analysis of the partial MHC I coding sequence (2-4 exons) of the bank vole revealed a lack of orthology to MHC I of other Cricetidae, consistent with the high gene turnover of this region. The diversity of expressed alleles was characterised using ultra-deep sequencing of the third exon that codes for the peptide-binding region of the MHC molecule. High allelic diversity was demonstrated, with 72 alleles found in 29 individuals. Interindividual variation in the number of expressed loci was found, with the number of alleles per individual ranging from 5 to 14. Strong signatures of positive selection were found for 8 amino acid sites, most of which are inferred to bind antigens in human MHC, indicating conservation of structure despite rapid sequence evolution.

Updated listing of haplotypes at the human phenylalanine hydroxylase (PAH) locus

Energy Technology Data Exchange (ETDEWEB)

Eisensmith, R.C.; Woo, S.L.C. (Baylor College of Medicine, Houston, TX (United States))

1992-12-01

Analysis of mutant PAH chromosomes has identified approximately 60 different single-base substitutions and deletions within the PAH locus. Nearly all of these molecular lesions are in strong linkage disequilibrium with specific RFLP haplotypes in different ethnic populations. Thus, haplotype analysis is not only useful for diagnostic purposes but is proving to be a valuable tool in population genetic studies of the origin and spread of phenylketonuria alleles in human populations. PCR-based methods have been developed to detect six of the eight polymorphic restriction sites used for determination of RFLP haplotypes at the PAH locus. A table of the proposed expanded haplotypes is given.

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

International Nuclear Information System (INIS)

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

1986-01-01

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

Fitchi: haplotype genealogy graphs based on the Fitch algorithm.

Science.gov (United States)

Matschiner, Michael

2016-04-15

: In population genetics and phylogeography, haplotype genealogy graphs are important tools for the visualization of population structure based on sequence data. In this type of graph, node sizes are often drawn in proportion to haplotype frequencies and edge lengths represent the minimum number of mutations separating adjacent nodes. I here present Fitchi, a new program that produces publication-ready haplotype genealogy graphs based on the Fitch algorithm. http://www.evoinformatics.eu/fitchi.htm : michaelmatschiner@mac.com Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Axotomy induces MHC class I antigen expression on rat nerve cells

DEFF Research Database (Denmark)

Maehlen, J; Schröder, H D; Klareskog, L

1988-01-01

Immunomorphological staining demonstrates that class I major histocompatibility complex (MHC)-coded antigen expression can be selectively induced on otherwise class I-negative rat nerve cells by peripheral axotomy. Induction of class I as well as class II antigen expression was simultaneously seen...... on non-neural cells in the immediate vicinity of the injured nerve cells. As nerve regeneration after axotomy includes growth of new nerve cell processes and formation of new nerve cell contacts, the present findings raise the question of a role for MHC-coded molecules in cell-cell interactions during...... nerve cell growth....

Prediction of the binding affinities of peptides to class II MHC using a regularized thermodynamic model

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Mittelmann Hans D

2010-01-01

Full Text Available Abstract Background The binding of peptide fragments of extracellular peptides to class II MHC is a crucial event in the adaptive immune response. Each MHC allotype generally binds a distinct subset of peptides and the enormous number of possible peptide epitopes prevents their complete experimental characterization. Computational methods can utilize the limited experimental data to predict the binding affinities of peptides to class II MHC. Results We have developed the Regularized Thermodynamic Average, or RTA, method for predicting the affinities of peptides binding to class II MHC. RTA accounts for all possible peptide binding conformations using a thermodynamic average and includes a parameter constraint for regularization to improve accuracy on novel data. RTA was shown to achieve higher accuracy, as measured by AUC, than SMM-align on the same data for all 17 MHC allotypes examined. RTA also gave the highest accuracy on all but three allotypes when compared with results from 9 different prediction methods applied to the same data. In addition, the method correctly predicted the peptide binding register of 17 out of 18 peptide-MHC complexes. Finally, we found that suboptimal peptide binding registers, which are often ignored in other prediction methods, made significant contributions of at least 50% of the total binding energy for approximately 20% of the peptides. Conclusions The RTA method accurately predicts peptide binding affinities to class II MHC and accounts for multiple peptide binding registers while reducing overfitting through regularization. The method has potential applications in vaccine design and in understanding autoimmune disorders. A web server implementing the RTA prediction method is available at http://bordnerlab.org/RTA/.

Modes of salmonid MHC class I and II evolution differ from the primate paradigm

NARCIS (Netherlands)

Shum, B.P.; Guethlein, L.; Flodin, L.R.; Adkison, M.A.; Hedrick, R.P.; Nehring, R.B.; Stet, R.J.M.; Secombes, C.; Parham, P.

2001-01-01

Rainbow trout (Oncorhynchus mykiss) and brown trout (Salmo trutta) represent two salmonid genera separated for 15-20 million years. cDNA sequences were determined for the classical MHC class I heavy chain gene UBA and the MHC class II β-chain gene DAB from 15 rainbow and 10 brown trout. Both genes

New recombinants within the MHC (B-complex) of the chicken

DEFF Research Database (Denmark)

Koch, C; Skjødt, K; Toivanen, A

1983-01-01

In a search for genetic recombinations within the major histocompatibility complex (MHC) of the chicken, the B-complex, the offspring from matings between heterozygous B15/B21 and B4/B6 animals were analysed by red cell agglutination. Among the progeny, 8,912 informative typings were performed...... followed B-F/B-L. The mapping distance between the two loci B-F and B-G is in the range of 0.04 centimorgan. The lack of recombinants separating individual B-F loci in this study and in the studies of others might indicate that chicken MHC is less complex than those of mammalian species, but alternative...

Dimensional Anxiety Mediates Linkage of GABRA2 Haplotypes With Alcoholism

Science.gov (United States)

Enoch, Mary-Anne; Schwartz, Lori; Albaugh, Bernard; Virkkunen, Matti; Goldman, David

2015-01-01

The GABAAα2 receptor gene (GABRA2) modulates anxiety and stress response. Three recent association studies implicate GABRA2 in alcoholism, however in these papers both common, opposite-configuration haplotypes in the region distal to intron3 predict risk. We have now replicated the GABRA2 association with alcoholism in 331 Plains Indian men and women and 461 Finnish Caucasian men. Using a dimensional measure of anxiety, harm avoidance (HA), we also found that the association with alcoholism is mediated, or moderated, by anxiety. Nine SNPs were genotyped revealing two haplotype blocks. Within the previously implicated block 2 region, we identified the two common, opposite-configuration risk haplotypes, A and B. Their frequencies differed markedly in Finns and Plains Indians. In both populations, most block 2 SNPs were significantly associated with alcoholism. The associations were due to increased frequencies of both homozygotes in alcoholics, indicating the possibility of alcoholic subtypes with opposite genotypes. Congruently, there was no significant haplotype association. Using HA as an indicator variable for anxiety, we found haplotype linkage to alcoholism with high and low dimensional anxiety, and to HA itself, in both populations. High HA alcoholics had the highest frequency of the more abundant haplotype (A in Finns, B in Plains Indians); low HA alcoholics had the highest frequency of the less abundant haplotype (B in Finns, A in Plains Indians) (Finns: P α0.007, OR α2.1, Plains Indians: P α0.040, OR α1.9). Non-alcoholics had intermediate frequencies. Our results suggest that within the distal GABRA2 region is a functional locus or loci that may differ between populations but that alters risk for alcoholism via the mediating action of anxiety. PMID:16874763

Deep convolutional neural networks for pan-specific peptide-MHC class I binding prediction.

Science.gov (United States)

Han, Youngmahn; Kim, Dongsup

2017-12-28

Computational scanning of peptide candidates that bind to a specific major histocompatibility complex (MHC) can speed up the peptide-based vaccine development process and therefore various methods are being actively developed. Recently, machine-learning-based methods have generated successful results by training large amounts of experimental data. However, many machine learning-based methods are generally less sensitive in recognizing locally-clustered interactions, which can synergistically stabilize peptide binding. Deep convolutional neural network (DCNN) is a deep learning method inspired by visual recognition process of animal brain and it is known to be able to capture meaningful local patterns from 2D images. Once the peptide-MHC interactions can be encoded into image-like array(ILA) data, DCNN can be employed to build a predictive model for peptide-MHC binding prediction. In this study, we demonstrated that DCNN is able to not only reliably predict peptide-MHC binding, but also sensitively detect locally-clustered interactions. Nonapeptide-HLA-A and -B binding data were encoded into ILA data. A DCNN, as a pan-specific prediction model, was trained on the ILA data. The DCNN showed higher performance than other prediction tools for the latest benchmark datasets, which consist of 43 datasets for 15 HLA-A alleles and 25 datasets for 10 HLA-B alleles. In particular, the DCNN outperformed other tools for alleles belonging to the HLA-A3 supertype. The F1 scores of the DCNN were 0.86, 0.94, and 0.67 for HLA-A*31:01, HLA-A*03:01, and HLA-A*68:01 alleles, respectively, which were significantly higher than those of other tools. We found that the DCNN was able to recognize locally-clustered interactions that could synergistically stabilize peptide binding. We developed ConvMHC, a web server to provide user-friendly web interfaces for peptide-MHC class I binding predictions using the DCNN. ConvMHC web server can be accessible via http://jumong.kaist.ac.kr:8080/convmhc

HLA-G Haplotypes Are Differentially Associated with Asthmatic Features

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Camille Ribeyre

2018-02-01

Full Text Available Human leukocyte antigen (HLA-G, a HLA class Ib molecule, interacts with receptors on lymphocytes such as T cells, B cells, and natural killer cells to influence immune responses. Unlike classical HLA molecules, HLA-G expression is not found on all somatic cells, but restricted to tissue sites, including human bronchial epithelium cells (HBEC. Individual variation in HLA-G expression is linked to its genetic polymorphism and has been associated with many pathological situations such as asthma, which is characterized by epithelium abnormalities and inflammatory cell activation. Studies reported both higher and equivalent soluble HLA-G (sHLA-G expression in different cohorts of asthmatic patients. In particular, we recently described impaired local expression of HLA-G and abnormal profiles for alternatively spliced isoforms in HBEC from asthmatic patients. sHLA-G dosage is challenging because of its many levels of polymorphism (dimerization, association with β2-microglobulin, and alternative splicing, thus many clinical studies focused on HLA-G single-nucleotide polymorphisms as predictive biomarkers, but few analyzed HLA-G haplotypes. Here, we aimed to characterize HLA-G haplotypes and describe their association with asthmatic clinical features and sHLA-G peripheral expression and to describe variations in transcription factor (TF binding sites and alternative splicing sites. HLA-G haplotypes were differentially distributed in 330 healthy and 580 asthmatic individuals. Furthermore, HLA-G haplotypes were associated with asthmatic clinical features showed. However, we did not confirm an association between sHLA-G and genetic, biological, or clinical parameters. HLA-G haplotypes were phylogenetically split into distinct groups, with each group displaying particular variations in TF binding or RNA splicing sites that could reflect differential HLA-G qualitative or quantitative expression, with tissue-dependent specificities. Our results, based on a

Genetics of chloroquine-resistant malaria: a haplotypic view

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Gauri Awasthi

2013-12-01

Full Text Available The development and rapid spread of chloroquine resistance (CQR in Plasmodium falciparum have triggered the identification of several genetic target(s in the P. falciparum genome. In particular, mutations in the Pfcrt gene, specifically, K76T and mutations in three other amino acids in the region adjoining K76 (residues 72, 74, 75 and 76, are considered to be highly related to CQR. These various mutations form several different haplotypes and Pfcrt gene polymorphisms and the global distribution of the different CQR- Pfcrt haplotypes in endemic and non-endemic regions of P. falciparum malaria have been the subject of extensive study. Despite the fact that the Pfcrt gene is considered to be the primary CQR gene in P. falciparum , several studies have suggested that this may not be the case. Furthermore, there is a poor correlation between the evolutionary implications of the Pfcrt haplotypes and the inferred migration of CQR P. falciparum based on CQR epidemiological surveillance data. The present paper aims to clarify the existing knowledge on the genetic basis of the different CQR- Pfcrt haplotypes that are prevalent in worldwide populations based on the published literature and to analyse the data to generate hypotheses on the genetics and evolution of CQR malaria.

MHC class II molecules and tumour immunotherapy

International Nuclear Information System (INIS)

Oven, I.

2005-01-01

Background. Tumour immunotherapy attempts to use the specificity and capability of the immune system to kill malignant cells with a minimum damage to normal tissue. Increasing knowledge of the identity of tumour antigens should help us design more effective therapeutic vaccines. Increasing evidence has demonstrated that MHC class II molecules and CD4+ T cells play important roles in generating and maintaining antitumour immune responses in animal models. These data suggest that it may be necessary to involve both CD4+ and CD8+ T cells for more effective antitumour therapy. Novel strategies have been developed for enhancing T cell responses against cancer by prolonging antigen presentation of dendritic cells to T cells, by the inclusion of MHC class II-restricted tumour antigens and by genetically modifying tumour cells to present antigen to T lymphocytes directly. Conclusions. Vaccines against cancers aim to induce tumour-specific effector T cells that can reduce tumour mass and induce development of tumour-specific T cell memory, that can control tumour relapse. (author)

Haplotype association analysis of human disease traits using genotype data of unrelated individuals

DEFF Research Database (Denmark)

Tan, Qihua; Christiansen, Lene; Christensen, Kaare

2005-01-01

unphased multi-locus genotype data, ranging from the early approach by the simple gene-counting method to the recent work using the generalized linear model. However, these methods are either confined to case – control design or unable to yield unbiased point and interval estimates of haplotype effects....... Based on the popular logistic regression model, we present a new approach for haplotype association analysis of human disease traits. Using haplotype-based parameterization, our model infers the effects of specific haplotypes (point estimation) and constructs confidence interval for the risks...... on the well-known logistic regression model is a useful tool for haplotype association analysis of human disease traits....

Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease

NARCIS (Netherlands)

Gutierrez-Achury, Javier; Zhernakova, Alexandra; Pulit, Sara L.; Trynka, Gosia; Hunt, Karen A.; Romanos, Jihane; Raychaudhuri, Soumya; van Heel, David A.; Wijmenga, Cisca; de Balcker, Paul I. W.

Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region. We fine mapped the MHC association signal to identify additional risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles and

Peptide specific expansion of CD8(+) T cells by recombinant plate bound MHC/peptide complexes

DEFF Research Database (Denmark)

Schmidt, Esben G W; Buus, Soren; Thorn, Mette

2009-01-01

to in vitro T cell stimulation was investigated. By use of an antigenic peptide derived from the cytomegalovirus (CMVp) we tested the stimulatory efficacy of recombinant plate bound MHC molecules (PB-MHC), being immobilized in culture plates. A single stimulation of non-adherent peripheral blood mononuclear...

Multiple parasites mediate balancing selection at two MHC class II genes in the fossorial water vole: insights from multivariate analyses and population genetics

Czech Academy of Sciences Publication Activity Database

Tollenaere, C.; Bryja, Josef; Galan, M.; Cadet, P.; Deter, J.; Chaval, Y.; Berthier, K.; Ribas Salvador, A.; Voutilainen, L.; Laakkonen, J.; Henttonen, H.; Cosson, J.-F.; Charbonnel, N.

2008-01-01

Roč. 21, č. 5 (2008), s. 1307-1320 ISSN 1010-061X EU Projects: European Commission(XE) 10284 - EDEN Institutional research plan: CEZ:AV0Z60930519 Keywords : co-inertia * DQA and DRB MHC gen es * immunogenetics * multivariate analysis * parasite-mediated balancing selection Subject RIV: EB - Gen etics ; Molecular Biology Impact factor: 3.471, year: 2008

Patterns of evolution of MHC class II genes of crows (Corvus suggest trans-species polymorphism

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John A. Eimes

2015-03-01

Full Text Available A distinguishing characteristic of genes that code for the major histocompatibility complex (MHC is that alleles often share more similarity between, rather than within species. There are two likely mechanisms that can explain this pattern: convergent evolution and trans-species polymorphism (TSP, in which ancient allelic lineages are maintained by balancing selection and retained by descendant species. Distinguishing between these two mechanisms has major implications in how we view adaptation of immune genes. In this study we analyzed exon 2 of the MHC class IIB in three passerine bird species in the genus Corvus: jungle crows (Corvus macrorhynchos japonensis American crows (C. brachyrhynchos and carrion crows (C. corone orientalis. Carrion crows and American crows are recently diverged, but allopatric, sister species, whereas carrion crows and jungle crows are more distantly related but sympatric species, and possibly share pathogens linked to MHC IIB polymorphisms. These patterns of evolutionary divergence and current geographic ranges enabled us to test for trans-species polymorphism and convergent evolution of the MHC IIB in crows. Phylogenetic reconstructions of MHC IIB sequences revealed several well supported interspecific clusters containing all three species, and there was no biased clustering of variants among the sympatric carrion crows and jungle crows. The topologies of phylogenetic trees constructed from putatively selected sites were remarkably different than those constructed from putatively neutral sites. In addition, trees constructed using non-synonymous substitutions from a continuous fragment of exon 2 had more, and generally more inclusive, supported interspecific MHC IIB variant clusters than those constructed from the same fragment using synonymous substitutions. These phylogenetic patterns suggest that recombination, especially gene conversion, has partially erased the signal of allelic ancestry in these species. While

Immunogenetic Management Software: a new tool for visualization and analysis of complex immunogenetic datasets.

Science.gov (United States)

Johnson, Z P; Eady, R D; Ahmad, S F; Agravat, S; Morris, T; Else, J; Lank, S M; Wiseman, R W; O'Connor, D H; Penedo, M C T; Larsen, C P; Kean, L S

2012-04-01

Here we describe the Immunogenetic Management Software (IMS) system, a novel web-based application that permits multiplexed analysis of complex immunogenetic traits that are necessary for the accurate planning and execution of experiments involving large animal models, including nonhuman primates. IMS is capable of housing complex pedigree relationships, microsatellite-based MHC typing data, as well as MHC pyrosequencing expression analysis of class I alleles. It includes a novel, automated MHC haplotype naming algorithm and has accomplished an innovative visualization protocol that allows users to view multiple familial and MHC haplotype relationships through a single, interactive graphical interface. Detailed DNA and RNA-based data can also be queried and analyzed in a highly accessible fashion, and flexible search capabilities allow experimental choices to be made based on multiple, individualized and expandable immunogenetic factors. This web application is implemented in Java, MySQL, Tomcat, and Apache, with supported browsers including Internet Explorer and Firefox on Windows and Safari on Mac OS. The software is freely available for distribution to noncommercial users by contacting Leslie.kean@emory.edu. A demonstration site for the software is available at http://typing.emory.edu/typing_demo , user name: imsdemo7@gmail.com and password: imsdemo.

Additional file 4: of MHC class II expression and potential antigen-presenting cells in the retina during experimental autoimmune uveitis

OpenAIRE

Lipski, Deborah; Dewispelaere, RÊmi; Foucart, Vincent; Caspers, Laure; Defrance, Matthieu; Bruyns, Catherine; Willermain, François

2017-01-01

Figure S4. MHC class II expression in the retina during classical EAU. Three weeks after immunization, eye cryosections were prepared and stained for MHC class II (green) and IBA1 (red) or endoglin (magenta) detection. Cell nuclei were stained with Hoechst (blue). Each picture was chosen as representative of an experiment conducted on six or more animals. A. MHC class II and IBA1 expression. B. MHC class II and endoglin expression. (PPTX 7276 kb)

Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method

DEFF Research Database (Denmark)

Nielsen, Morten; Lundegaard, Claus; Lund, Ole

2007-01-01

the correct alignment of a peptide in the binding groove a crucial part of identifying the core of an MHC class II binding motif. Here, we present a novel stabilization matrix alignment method, SMM-align, that allows for direct prediction of peptide:MHC binding affinities. The predictive performance...... of the method is validated on a large MHC class II benchmark data set covering 14 HLA-DR (human MHC) and three mouse H2-IA alleles. RESULTS: The predictive performance of the SMM-align method was demonstrated to be superior to that of the Gibbs sampler, TEPITOPE, SVRMHC, and MHCpred methods. Cross validation...... between peptide data set obtained from different sources demonstrated that direct incorporation of peptide length potentially results in over-fitting of the binding prediction method. Focusing on amino terminal peptide flanking residues (PFR), we demonstrate a consistent gain in predictive performance...

Chronic inflammatory state in sickle cell anemia patients is associated with HBB(*)S haplotype.

Science.gov (United States)

Bandeira, Izabel C J; Rocha, Lillianne B S; Barbosa, Maritza C; Elias, Darcielle B D; Querioz, José A N; Freitas, Max Vitor Carioca; Gonçalves, Romélia P

2014-02-01

The chronic inflammatory state in sickle cell anemia (SCA) is associated with several factors such as the following: endothelial damage; increased production of reactive oxygen species; hemolysis; increased expression of adhesion molecules by leukocytes, erythrocytes, and platelets; and increased production of proinflammatory cytokines. Genetic characteristics affecting the clinical severity of SCA include variations in the hemoglobin F (HbF) level, coexistence of alpha-thalassemia, and the haplotype associated with the HbS gene. The different haplotypes of SCA are Bantu, Benin, Senegal, Cameroon, and Arab-Indian. These haplotypes are associated with ethnic groups and also based on the geographical origin. Studies have shown that the Bantu haplotype is associated with higher incidence of clinical complications than the other haplotypes and is therefore considered to have the worst prognosis. This study aimed to evaluate the profile of the proinflammatory cytokines interleukin-6, tumor necrosis factor-α, and interleukin-17 in patients with SCA and also to assess the haplotypes associated with beta globin cluster S (HBB(*)S). We analyzed a total of 62 patients who had SCA and had been treated with hydroxyurea; they had received a dose ranging between 15 and 25 (20.0±0.6)mg/kg/day for 6-60 (18±3.4)months; their data were compared with those for 30 normal individuals. The presence of HbS was detected and the haplotypes of the beta S gene cluster were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Our study demonstrated that SCA patients have increased inflammatory profile when compared to the healthy individuals. Further, analysis of the association between the haplotypes and inflammatory profile showed that the levels of IL-6 and TNF-α were greater in subjects with the Bantu/Bantu haplotype than in subjects with the Benin/Benin haplotype. The Bantu/Benin haplotype individuals had lower levels of cytokines than those with

Improved prediction of MHC class I and class II epitopes using a novel Gibbs sampling approach

DEFF Research Database (Denmark)

Nielsen, Morten; Lundegaard, Claus; Worning, Peder

2004-01-01

Prediction of which peptides will bind a specific major histocompatibility complex (MHC) constitutes an important step in identifying potential T-cell epitopes suitable as vaccine candidates. MHC class II binding peptides have a broad length distribution complicating such predictions. Thus......, identifying the correct alignment is a crucial part of identifying the core of an MHC class II binding motif. In this context, we wish to describe a novel Gibbs motif sampler method ideally suited for recognizing such weak sequence motifs. The method is based on the Gibbs sampling method, and it incorporates...

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

Directory of Open Access Journals (Sweden)

Ottaviani Diego

2008-05-01

Full Text Available Abstract 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.

Discovery, evaluation and distribution of haplotypes of the wheat Ppd-D1 gene.

Science.gov (United States)

Guo, Zhiai; Song, Yanxia; Zhou, Ronghua; Ren, Zhenglong; Jia, Jizeng

2010-02-01

Ppd-D1 is one of the most potent genes affecting the photoperiod response of wheat (Triticum aestivum). Only two alleles, insensitive Ppd-D1a and sensitive Ppd-D1b, were known previously, and these did not adequately explain the broad adaptation of wheat to photoperiod variation. In this study, five diagnostic molecular markers were employed to identify Ppd-D1 haplotypes in 492 wheat varieties from diverse geographic locations and 55 accessions of Aegilops tauschii, the D genome donor species of wheat. Six Ppd-D1 haplotypes, designated I-VI, were identified. Types II, V and VI were considered to be more ancient and types I, III and IV were considered to be derived from type II. The transcript abundances of the Ppd-D1 haplotypes showed continuous variation, being highest for haplotype I, lowest for haplotype III, and correlating negatively with varietal differences in heading time. These haplotypes also significantly affected other agronomic traits. The distribution frequency of Ppd-D1 haplotypes showed partial correlations with both latitudes and altitudes of wheat cultivation regions. The evolution, expression and distribution of Ppd-D1 haplotypes were consistent evidentially with each other. What was regarded as a pair of alleles in the past can now be considered a series of alleles leading to continuous variation.

Prospects for immunotherapy of MHC class I-deficient tumours

Czech Academy of Sciences Publication Activity Database

Bubeník, Jan

2003-01-01

Roč. 49, č. 3 (2003), s. 95-99 ISSN 0015-5500 Institutional research plan: CEZ:AV0Z5052915 Keywords : MHC class I * immunotherapy Subject RIV: FD - Oncology ; Hematology Impact factor: 0.527, year: 2003

Characterization of MHC-I in the blue tit (Cyanistes caeruleus) reveals low levels of genetic diversity and trans-population evolution across European populations

NARCIS (Netherlands)

Schut, Elske; Rivero-de Aguilar, Juan; Merino, Santiago; Magrath, Michael J. L.; Komdeur, Jan; Westerdahl, Helena

The major histcompatibility complex (MHC) is a vital component of the adaptive immune system in all vertebrates. This study is the first to characterize MHC class I (MHC-I) in blue tits (Cyanistes caeruleus), and we use MHC-I exon 3 sequence data from individuals originating from three locations

MHC class I loaded ligands from breast cancer cell lines: A potential HLA-I-typed antigen collection

Science.gov (United States)

Rozanov, Dmitri V.; Rozanov, Nikita D.; Chiotti, Kami; Reddy, Ashok; Wilmarth, Phillip A.; David, Larry L.; Cha, Seung W.; Woo, Sunghee; Pevzner, Pavel; Bafna, Vineet; Burrows, Gregory G.; Rantala, Juha K.; Levin, Trevor; Anur, Pavana; Johnson-Camacho, Katie; Tabatabaei, Shaadi; Munson, Daniel J.; Bruno, Tullia C.; Slansky, Jill E.; Kappler, John W.; Hirano, Naoto; Boegel, Sebastian; Fox, Bernard A.; Egelston, Colt; Simons, Diana L.; Jimenez, Grecia; Lee, Peter P.; Gray, Joe W.; Spellman, Paul T.

2018-01-01

Breast cancer therapy based on amplifying a patient’s antitumor immune response depends on the availability of appropriate MHC class I-restricted, breast cancer-specific epitopes. To build a catalog of peptides presented by breast cancer cells, we undertook systematic MHC class I immunoprecipitation followed by elution of MHC class I-loaded peptides in breast cancer cell lines. We determined the sequence of 3,196 MHC class I-bound peptides representing 1,921 proteins from a panel of 20 breast cancer cell lines including basal, luminal, and claudin-low subtypes. The data has been deposited to the ProteomeXchange with identifier PXD006406. After removing duplicate peptides, i.e., the same peptide eluted from more than one cell line, the total number of unique peptides was 2,740. Of the unique peptides eluted, more than 1,750 had been previously identified, and of these, sixteen have been shown to be immunogenic. Importantly, only 3 of these immunogenic peptides have been identified in breast cancer cells in earlier studies. MHC class I binding probability of eluted peptides was used to plot the distribution of MHC class I allele-specific peptides in accordance with the binding score for each breast cancer cell line. We also determined that the tested breast cancer cells presented 89 mutation-containing peptides and peptides derived from aberrantly translated genes, 7 of which were shared between four or two different cell lines. Overall, the high throughput identification of MHC class I-loaded peptides is an effective strategy for systematic characterization of cancer peptides, and could be employed for design of multi-peptide anticancer vaccines. PMID:29331515

Characterization of MHC-I in the blue tit (Cyanistes caeruleus) reveals low levels of genetic diversity and trans-population evolution across European populations.

Science.gov (United States)

Schut, Elske; Aguilar, Juan Rivero-de; Merino, Santiago; Magrath, Michael J L; Komdeur, Jan; Westerdahl, Helena

2011-08-01

The major histcompatibility complex (MHC) is a vital component of the adaptive immune system in all vertebrates. This study is the first to characterize MHC class I (MHC-I) in blue tits (Cyanistes caeruleus), and we use MHC-I exon 3 sequence data from individuals originating from three locations across Europe: Spain, the Netherlands to Sweden. Our phylogeny of the 17 blue tit MHC-I alleles contains one allele cluster with low nucleotide diversity compared to the remaining more diverse alleles. We found a significant evidence for balancing selection in the peptide-binding region in the diverse allele group only. No separation according to geographic location was found in the phylogeny of alleles. Although the number of MHC-I loci of the blue tit is comparable to that of other passerine species, the nucleotide diversity of MHC-I appears to be much lower than that of other passerine species, including the closely related great tit (Parus major) and the severely inbred Seychelles warbler (Acrocephalus sechellensis). We believe that this initial MHC-I characterization in blue tits provides an important step towards understanding the mechanisms shaping MHC-I diversity in natural populations.

Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells.

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Shan Wan

Full Text Available Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT, a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1 or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data

DEFF Research Database (Denmark)

Jurtz, Vanessa Isabell; Paul, Sinu; Andreatta, Massimo

2017-01-01

by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging......Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway....... Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified...

MGMT DNA repair gene promoter/enhancer haplotypes alter transcription factor binding and gene expression.

Science.gov (United States)

Xu, Meixiang; Cross, Courtney E; Speidel, Jordan T; Abdel-Rahman, Sherif Z

2016-10-01

The O 6 -methylguanine-DNA methyltransferase (MGMT) protein removes O 6 -alkyl-guanine adducts from DNA. MGMT expression can thus alter the sensitivity of cells and tissues to environmental and chemotherapeutic alkylating agents. Previously, we defined the haplotype structure encompassing single nucleotide polymorphisms (SNPs) in the MGMT promoter/enhancer (P/E) region and found that haplotypes, rather than individual SNPs, alter MGMT promoter activity. The exact mechanism(s) by which these haplotypes exert their effect on MGMT promoter activity is currently unknown, but we noted that many of the SNPs comprising the MGMT P/E haplotypes are located within or in close proximity to putative transcription factor binding sites. Thus, these haplotypes could potentially affect transcription factor binding and, subsequently, alter MGMT promoter activity. In this study, we test the hypothesis that MGMT P/E haplotypes affect MGMT promoter activity by altering transcription factor (TF) binding to the P/E region. We used a promoter binding TF profiling array and a reporter assay to evaluate the effect of different P/E haplotypes on TF binding and MGMT expression, respectively. Our data revealed a significant difference in TF binding profiles between the different haplotypes evaluated. We identified TFs that consistently showed significant haplotype-dependent binding alterations (p ≤ 0.01) and revealed their role in regulating MGMT expression using siRNAs and a dual-luciferase reporter assay system. The data generated support our hypothesis that promoter haplotypes alter the binding of TFs to the MGMT P/E and, subsequently, affect their regulatory function on MGMT promoter activity and expression level.

Haplotype reconstruction error as a classical misclassification problem: introducing sensitivity and specificity as error measures.

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Claudia Lamina

Full Text Available BACKGROUND: Statistically reconstructing haplotypes from single nucleotide polymorphism (SNP genotypes, can lead to falsely classified haplotypes. This can be an issue when interpreting haplotype association results or when selecting subjects with certain haplotypes for subsequent functional studies. It was our aim to quantify haplotype reconstruction error and to provide tools for it. METHODS AND RESULTS: By numerous simulation scenarios, we systematically investigated several error measures, including discrepancy, error rate, and R(2, and introduced the sensitivity and specificity to this context. We exemplified several measures in the KORA study, a large population-based study from Southern Germany. We find that the specificity is slightly reduced only for common haplotypes, while the sensitivity was decreased for some, but not all rare haplotypes. The overall error rate was generally increasing with increasing number of loci, increasing minor allele frequency of SNPs, decreasing correlation between the alleles and increasing ambiguity. CONCLUSIONS: We conclude that, with the analytical approach presented here, haplotype-specific error measures can be computed to gain insight into the haplotype uncertainty. This method provides the information, if a specific risk haplotype can be expected to be reconstructed with rather no or high misclassification and thus on the magnitude of expected bias in association estimates. We also illustrate that sensitivity and specificity separate two dimensions of the haplotype reconstruction error, which completely describe the misclassification matrix and thus provide the prerequisite for methods accounting for misclassification.

Y-STR haplotypes of Native American populations from the Brazilian Amazon region.

Science.gov (United States)

Palha, Teresinha Jesus Brabo Ferreira; Rodrigues, Elzemar Martins Ribeiro; dos Santos, Sidney Emanuel Batista

2010-10-01

The allele and haplotype frequencies of nine Y-STRs (DYS19, DYS389 I, DYS389 II, DYS390, DYS391, DYS392, DYS393, DYS385 I/II) were determined in a sample of six native tribes from the Brazilian Amazon (Tiriyó, Awa-Guajá, Waiãpi, Urubu-Kaapor, Zoé and Parakanã). Forty-eight different haplotypes were identified, 28 of which unique. Five haplotypes are very frequent and were shared by over 10 individuals. The estimated haplotype diversity (0.9114) was very low compared to other geographic groups, including Africans, Europeans and Asians. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Inhibition of MHC class I is a virulence factor in herpes simplex virus infection of mice.

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Mark T Orr

2005-09-01

Full Text Available Herpes simplex virus (HSV has a number of genes devoted to immune evasion. One such gene, ICP47, binds to the transporter associated with antigen presentation (TAP 1/2 thereby preventing transport of viral peptides into the endoplasmic reticulum, loading of peptides onto nascent major histocompatibility complex (MHC class I molecules, and presentation of peptides to CD8 T cells. However, ICP47 binds poorly to murine TAP1/2 and so inhibits antigen presentation by MHC class I in mice much less efficiently than in humans, limiting the utility of murine models to address the importance of MHC class I inhibition in HSV immunopathogenesis. To address this limitation, we generated recombinant HSVs that efficiently inhibit antigen presentation by murine MHC class I. These recombinant viruses prevented cytotoxic T lymphocyte killing of infected cells in vitro, replicated to higher titers in the central nervous system, and induced paralysis more frequently than control HSV. This increase in virulence was due to inhibition of antigen presentation to CD8 T cells, since these differences were not evident in MHC class I-deficient mice or in mice in which CD8 T cells were depleted. Inhibition of MHC class I by the recombinant viruses did not impair the induction of the HSV-specific CD8 T-cell response, indicating that cross-presentation is the principal mechanism by which HSV-specific CD8 T cells are induced. This inhibition in turn facilitates greater viral entry, replication, and/or survival in the central nervous system, leading to an increased incidence of paralysis.

Organelle DNA haplotypes reflect crop-use characteristics and geographic origins of Cannabis sativa.

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Gilmore, Simon; Peakall, Rod; Robertson, James

2007-10-25

Comparative sequencing of cannabis individuals across 12 chloroplast and mitochondrial DNA loci revealed 7 polymorphic sites, including 5 length variable regions and 2 single nucleotide polymorphisms. Simple PCR assays were developed to assay these polymorphisms, and organelle DNA haplotypes were obtained for 188 cannabis individuals from 76 separate populations, including drug-type, fibre-type and wild populations. The haplotype data were analysed using parsimony, UPGMA and neighbour joining methods. Three haplotype groups were recovered by each analysis method, and these groups are suggestive of the crop-use characteristics and geographical origin of the populations, although not strictly diagnostic. We discuss the relationship between our haplotype data and taxonomic opinions of cannabis, and the implications of organelle DNA haplotyping to forensic investigations of cannabis.

MHC classⅠ gene in two duck lines

Indian Academy of Sciences (India)

Navya

Weishan Ma duck (WS) is the eugenic endemic breed, one of the four famous ducks in China, as well Cherry Valley duck (CV) is the largest number of breeding variety. WS is egg strain and CV is meat type. The two duck lines mainly support the. Chinese waterfowl industry. In this study, MHC class Ⅰ genes of WS and CV ...

Expression and phylogenetic analyses reveal paralogous lineages of putatively classical and non-classical MHC-I genes in three sparrow species (Passer).

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Drews, Anna; Strandh, Maria; Råberg, Lars; Westerdahl, Helena

2017-06-26

The Major Histocompatibility Complex (MHC) plays a central role in immunity and has been given considerable attention by evolutionary ecologists due to its associations with fitness-related traits. Songbirds have unusually high numbers of MHC class I (MHC-I) genes, but it is not known whether all are expressed and equally important for immune function. Classical MHC-I genes are highly expressed, polymorphic and present peptides to T-cells whereas non-classical MHC-I genes have lower expression, are more monomorphic and do not present peptides to T-cells. To get a better understanding of the highly duplicated MHC genes in songbirds, we studied gene expression in a phylogenetic framework in three species of sparrows (house sparrow, tree sparrow and Spanish sparrow), using high-throughput sequencing. We hypothesize that sparrows could have classical and non-classical genes, as previously indicated though never tested using gene expression. The phylogenetic analyses reveal two distinct types of MHC-I alleles among the three sparrow species, one with high and one with low level of polymorphism, thus resembling classical and non-classical genes, respectively. All individuals had both types of alleles, but there was copy number variation both within and among the sparrow species. However, the number of highly polymorphic alleles that were expressed did not vary between species, suggesting that the structural genomic variation is counterbalanced by conserved gene expression. Overall, 50% of the MHC-I alleles were expressed in sparrows. Expression of the highly polymorphic alleles was very variable, whereas the alleles with low polymorphism had uniformly low expression. Interestingly, within an individual only one or two alleles from the polymorphic genes were highly expressed, indicating that only a single copy of these is highly expressed. Taken together, the phylogenetic reconstruction and the analyses of expression suggest that sparrows have both classical and non

Modeling coverage gaps in haplotype frequencies via Bayesian inference to improve stem cell donor selection.

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Louzoun, Yoram; Alter, Idan; Gragert, Loren; Albrecht, Mark; Maiers, Martin

2018-05-01

Regardless of sampling depth, accurate genotype imputation is limited in regions of high polymorphism which often have a heavy-tailed haplotype frequency distribution. Many rare haplotypes are thus unobserved. Statistical methods to improve imputation by extending reference haplotype distributions using linkage disequilibrium patterns that relate allele and haplotype frequencies have not yet been explored. In the field of unrelated stem cell transplantation, imputation of highly polymorphic human leukocyte antigen (HLA) genes has an important application in identifying the best-matched stem cell donor when searching large registries totaling over 28,000,000 donors worldwide. Despite these large registry sizes, a significant proportion of searched patients present novel HLA haplotypes. Supporting this observation, HLA population genetic models have indicated that many extant HLA haplotypes remain unobserved. The absent haplotypes are a significant cause of error in haplotype matching. We have applied a Bayesian inference methodology for extending haplotype frequency distributions, using a model where new haplotypes are created by recombination of observed alleles. Applications of this joint probability model offer significant improvement in frequency distribution estimates over the best existing alternative methods, as we illustrate using five-locus HLA frequency data from the National Marrow Donor Program registry. Transplant matching algorithms and disease association studies involving phasing and imputation of rare variants may benefit from this statistical inference framework.

Haematopoietic depletion in vaccine-induced neonatal pancytopenia depends on both the titre and specificity of alloantibody and levels of MHC I expression.

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Bell, Charlotte R; MacHugh, Niall D; Connelley, Timothy K; Degnan, Kathryn; Morrison, W Ivan

2015-07-09

Bovine Neonatal Pancytopenia (BNP) is a disease of calves characterised by haematopoietic depletion, mediated by ingestion of alloantibodies in colostrum. It has been linked epidemiologically to vaccination of the dams of affected calves with a particular vaccine (Pregsure) containing a novel adjuvant. Evidence suggests that BNP-alloantibodies are directed against MHC I molecules, induced by contaminant bovine cellular material from Madin-Darby Bovine Kidney (MDBK) cells used in the vaccine's production. We aimed to investigate the specificity of BNP-alloantibody for bovine MHC I alleles, particularly those expressed by MDBK cells, and whether depletion of particular cell types is due to differential MHC I expression levels. A complement-mediated cytotoxicity assay was used to assess functional serum alloantibody titres in BNP-dams, Pregsure-vaccinated dams with healthy calves, cows vaccinated with an alternative product and unvaccinated controls. Alloantibody specificity was investigated using transfected mouse lines expressing the individual MHC I alleles identified from MDBK cells and MHC I-defined bovine leukocyte lines. All BNP-dams and 50% of Pregsure-vaccinated cows were shown to have MDBK-MHC I specific alloantibodies, which cross-reacted to varying degrees with other MHC I genotypes. MHC I expression levels on different blood cell types, assessed by flow cytometry, were found to correlate with levels of alloantibody-mediated damage in vitro and in vivo. Alloantibody-killed bone marrow cells were shown to express higher levels of MHC I than undamaged cells. The results provide evidence that MHC I-specific alloantibodies play a dominant role in the pathogenesis of BNP. Haematopoietic depletion was shown to be dependent on the titre and specificity of alloantibody produced by individual cows and the density of surface MHC I expression by different cell types. Collectively, the results support the hypothesis that MHC I molecules originating from MDBK cells

MHC-I affects infection intensity but not infection status with a frequent avian malaria parasite in blue tits.

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Helena Westerdahl

Full Text Available Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load and infection status (infected or not. It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.

MHC-I affects infection intensity but not infection status with a frequent avian malaria parasite in blue tits.

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Westerdahl, Helena; Stjernman, Martin; Råberg, Lars; Lannefors, Mimi; Nilsson, Jan-Åke

2013-01-01

Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC) molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load) and infection status (infected or not). It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.

Expression and characterization of recombinant single-chain salmon class I MHC fused with beta2-microglobulin with biological activity

DEFF Research Database (Denmark)

Zhao, Heng; Stet, René J M; Skjødt, Karsten

2008-01-01

Heterodimeric class I major histocompatibility complex (MHC) molecules consist of a putative 45-kDa heavy chain and a 12-kDa beta2-microglobulin (beta2m) light chain. The knowledge about MHC genes in Atlantic salmon accumulated during the last decade has allowed us to generate soluble and stable ...... MHC class I molecules with biological activity. We report here the use of a bacterial expression system to produce the recombinant single-chain MHC molecules based on a specific allele Sasa-UBA*0301. This particular allele was selected because previous work has shown its association...... antibodies were successfully produced against both the MHC class I heavy chain and beta(2)m, and showed binding to the recombinant molecule. The recombinant complex Sasabeta2mUBA*0301 was expressed and isolated; the production was scaled up by adjusting to its optimal conditions. Subsequently......, the recombinant proteins were purified by affinity chromatography using mAb against beta2m and alpha3. Eluates were analyzed by Western blot and refolded by the removal of denaturant. The correct folding was confirmed by measuring its binding capacity against mAb produced to recognize the native form of MHC...

Extreme MHC class I diversity in the sedge warbler (Acrocephalus schoenobaenus); selection patterns and allelic divergence suggest that different genes have different functions.

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Biedrzycka, Aleksandra; O'Connor, Emily; Sebastian, Alvaro; Migalska, Magdalena; Radwan, Jacek; Zając, Tadeusz; Bielański, Wojciech; Solarz, Wojciech; Ćmiel, Adam; Westerdahl, Helena

2017-07-05

Recent work suggests that gene duplications may play an important role in the evolution of immunity genes. Passerine birds, and in particular Sylvioidea warblers, have highly duplicated major histocompatibility complex (MHC) genes, which are key in immunity, compared to other vertebrates. However, reasons for this high MHC gene copy number are yet unclear. High-throughput sequencing (HTS) allows MHC genotyping even in individuals with extremely duplicated genes. This HTS data can reveal evidence of selection, which may help to unravel the putative functions of different gene copies, i.e. neofunctionalization. We performed exhaustive genotyping of MHC class I in a Sylvioidea warbler, the sedge warbler, Acrocephalus schoenobaenus, using the Illumina MiSeq technique on individuals from a wild study population. The MHC diversity in 863 genotyped individuals by far exceeds that of any other bird species described to date. A single individual could carry up to 65 different alleles, a large proportion of which are expressed (transcribed). The MHC alleles were of three different lengths differing in evidence of selection, diversity and divergence within our study population. Alleles without any deletions and alleles containing a 6 bp deletion showed characteristics of classical MHC genes, with evidence of multiple sites subject to positive selection and high sequence divergence. In contrast, alleles containing a 3 bp deletion had no sites subject to positive selection and had low divergence. Our results suggest that sedge warbler MHC alleles that either have no deletion, or contain a 6 bp deletion, encode classical antigen presenting MHC molecules. In contrast, MHC alleles containing a 3 bp deletion may encode molecules with a different function. This study demonstrates that highly duplicated MHC genes can be characterised with HTS and that selection patterns can be useful for revealing neofunctionalization. Importantly, our results highlight the need to consider the

Identification of the Mislabeled Breast Cancer Samples by Mitochondrial DNA Haplotyping

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Xiaogang Chen

2015-01-01

Full Text Available The task to identify whether an archival malignant tumor specimen had been mislabeled or interchanged is a challenging one for forensic genetics. The nuclear DNA (nDNA markers were affected by the aberration of tumor cells, so they were not suitable for personal identification when the tumor tissues were tested. In this study, we focused on a new solution - mitochondrial single nucleotide polymorphism (mtSNP haplotyping by a multiplex SNaPshot assay. To validate our strategy of haplotyping with 25 mtSNPs, we analyzed 15 pairs of cancerous/healthy tissues taken from patients with ductal breast carcinoma. The haplotypes of all the fifteen breast cancer tissues were matched with their paired breast tissues. The heteroplasmy at 2 sites, 14783A/G and 16519C/T was observed in one breast tissue, which indicated a mixture of related mitochondrial haplotypes. However, only one haplotype was retained in the paired breast cancer tissue, which could be considered the result of proliferation of tumor subclone. The allele drop-out and allele drop-in were observed when 39 STRs and 20 tri-allelic SNPs of nDNA were applied. Compared to nDNA markers applied, 25 mtSNPs were more stable without interference from aberrance of breast cancer. Also, two cases were presented where the investigation of haplotype with 25 mtSNPs was used to prove the origin of biopsy specimen with breast cancer. The mislabeling of biopsy specimen with breast cancer could be certified in one case but could not be supported in the other case. We highlight the importance of stability of mtSNP haplotype in breast cancer. It was implied that our multiplex SNaPshot assay with 25 mtSNPs was a useful strategy to identify mislabeled breast cancer specimen.

Patterns of linkage disequilibrium and haplotype distribution in disease candidate genes.

Science.gov (United States)

Long, Ji-Rong; Zhao, Lan-Juan; Liu, Peng-Yuan; Lu, Yan; Dvornyk, Volodymyr; Shen, Hui; Liu, Yong-Jun; Zhang, Yuan-Yuan; Xiong, Dong-Hai; Xiao, Peng; Deng, Hong-Wen

2004-05-24

The adequacy of association studies for complex diseases depends critically on the existence of linkage disequilibrium (LD) between functional alleles and surrounding SNP markers. We examined the patterns of LD and haplotype distribution in eight candidate genes for osteoporosis and/or obesity using 31 SNPs in 1,873 subjects. These eight genes are apolipoprotein E (APOE), type I collagen alpha1 (COL1A1), estrogen receptor-alpha (ER-alpha), leptin receptor (LEPR), parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1), transforming growth factor-beta1 (TGF-beta1), uncoupling protein 3 (UCP3), and vitamin D (1,25-dihydroxyvitamin D3) receptor (VDR). Yin yang haplotypes, two high-frequency haplotypes composed of completely mismatching SNP alleles, were examined. To quantify LD patterns, two common measures of LD, D' and r2, were calculated for the SNPs within the genes. The haplotype distribution varied in the different genes. Yin yang haplotypes were observed only in PTHR1 and UCP3. D' ranged from 0.020 to 1.000 with the average of 0.475, whereas the average r2 was 0.158 (ranging from 0.000 to 0.883). A decay of LD was observed as the intermarker distance increased, however, there was a great difference in LD characteristics of different genes or even in different regions within gene. The differences in haplotype distributions and LD patterns among the genes underscore the importance of characterizing genomic regions of interest prior to association studies.

Forming a complex with MHC class I molecules interferes with mouse CD1d functional expression.

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Renukaradhya J Gourapura

Full Text Available CD1d molecules are structurally similar to MHC class I, but present lipid antigens as opposed to peptides. Here, we show that MHC class I molecules physically associate with (and regulate the functional expression of mouse CD1d on the surface of cells. Low pH (3.0 acid stripping of MHC class I molecules resulted in increased surface expression of murine CD1d on antigen presenting cells as well as augmented CD1d-mediated antigen presentation to NKT cells. Consistent with the above results, TAP1-/- mice were found to have a higher percentage of type I NKT cells as compared to wild type mice. Moreover, bone marrow-derived dendritic cells from TAP1-/- mice showed increased antigen presentation by CD1d compared to wild type mice. Together, these results suggest that MHC class I molecules can regulate NKT cell function, in part, by masking CD1d.

Haplotype analysis and linkage disequilibrium for DGAT1

OpenAIRE

Strucken, Eva M.; Rahmatalla, Siham; De Koning, Dirk-Jan; Brockmann, Gudrun A.

2010-01-01

This study focused on haplotype effects and linkage disequilibrium (LD) for the K232A locus and the promoter VNTR in the DGAT1 gene. Analyses were carried out in three German Holstein Frisian populations (including 492, 305, and 518 animals) for milk yield, milk fat and protein yield, and milk fat and protein content. We found that effects of the promoter VNTR were not significant and explain only a small amount of the variation of the QTL on BTA14. Haplotype effects were less significant tha...

The mRNA expression profile of metabolic genes relative to MHC isoform pattern in human skeletal muscles

DEFF Research Database (Denmark)

Plomgaard, Peter; Penkowa, Milena; Leick, Lotte

2006-01-01

The metabolic profile of rodent muscle is generally reflected in the myosin heavy chain (MHC) fiber-type composition. The present study was conducted to test the hypothesis that metabolic gene expression is not tightly coupled with MHC fiber-type composition for all genes in human skeletal muscle....... Triceps brachii, vastus lateralis quadriceps, and soleus muscle biopsies were obtained from normally physically active, healthy, young male volunteers, because these muscles are characterized by different fiber-type compositions. As expected, citrate synthase and 3-hydroxyacyl dehydrogenase activity...... of a broad range of metabolic genes. The triceps muscle had two- to fivefold higher MHC IIa, phosphofructokinase, and LDH A mRNA content and two- to fourfold lower MHC I, lipoprotein lipase, CD36, hormone-sensitive lipase, and LDH B and hexokinase II mRNA than vastus lateralis or soleus. Interestingly...

MHC class II tetramers made from isolated recombinant α and β chains refolded with affinity-tagged peptides

DEFF Research Database (Denmark)

Braendstrup, Peter; Justesen, Sune Frederik Lamdahl; Osterbye, Thomas

2013-01-01

Targeting CD4+ T cells through their unique antigen-specific, MHC class II-restricted T cell receptor makes MHC class II tetramers an attractive strategy to identify, validate and manipulate these cells at the single cell level. Currently, generating class II tetramers is a specialized undertaking...... effectively limiting their use and emphasizing the need for improved methods of production. Using class II chains expressed individually in E. coli as versatile recombinant reagents, we have previously generated peptide-MHC class II monomers, but failed to generate functional class II tetramers. Adding...... a monomer purification principle based upon affinity-tagged peptides, we here provide a robust method to produce class II tetramers and demonstrate staining of antigen-specific CD4+ T cells. We also provide evidence that both MHC class II and T cell receptor molecules largely accept affinity-tagged peptides...

Cluster analysis of European Y-chromosomal STR haplotypes using the discrete Laplace method

DEFF Research Database (Denmark)

Andersen, Mikkel Meyer; Eriksen, Poul Svante; Morling, Niels

2014-01-01

The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models the probabi......The European Y-chromosomal short tandem repeat (STR) haplotype distribution has previously been analysed in various ways. Here, we introduce a new way of analysing population substructure using a new method based on clustering within the discrete Laplace exponential family that models...... the probability distribution of the Y-STR haplotypes. Creating a consistent statistical model of the haplotypes enables us to perform a wide range of analyses. Previously, haplotype frequency estimation using the discrete Laplace method has been validated. In this paper we investigate how the discrete Laplace...... method can be used for cluster analysis to further validate the discrete Laplace method. A very important practical fact is that the calculations can be performed on a normal computer. We identified two sub-clusters of the Eastern and Western European Y-STR haplotypes similar to results of previous...

VNTR alleles associated with the {alpha}-globin locus are haplotype and population related

Energy Technology Data Exchange (ETDEWEB)

Martinson, J.J.; Clegg, J.B.; Boyce, A.J. [Univ. of Oxford (United Kingdom)

1994-09-01

The human {alpha}-globin complex contains several polymorphic restriction-enzyme sites (i.e., RFLPs) linked to form haplotypes and is flanked by two hypervariable VNTR loci, the 5{prime} hypervariable region (HVR) and the more highly polymorphic 3{prime}HVR. Using a combination of RFLP analysis and PCR, the authors have characterized the 5{prime}HVR and 3{prime}HVR alleles associated with the {alpha}-globin haplotypes of 133 chromosomes, and they here show that specific {alpha}-globin haplotypes are each associated with discrete subsets of the alleles observed at these two VNTR loci. This statistically highly significant association is observed over a region spanning {approximately} 100 kb. With the exception of closely related haplotypes, different haplotypes do not share identically sized 3{prime}HVR alleles. Earlier studies have shown that {alpha}-globin haplotype distributions differ between populations; the current findings also reveal extensive population substructure in the repertoire of {alpha}-globin VNTRs. If similar features are characteristic of other VNTR loci, this will have important implications for forensic and anthropological studies. 42 refs., 5 figs., 5 tabs.

Peripheral nerve injury causes transient expression of MHC class I antigens in rat motor neurons and skeletal muscles

DEFF Research Database (Denmark)

Maehlen, J; Nennesmo, I; Olsson, A B

1989-01-01

After a peripheral nerve lesion (rat facial and sciatic) an induction of major histocompatibility complex (MHC) antigens class I was detected immunohistochemically in skeletal muscle fibers and motor neurons. This MHC expression was transient after a nerve crush, when regeneration occurred......, but persisted after a nerve cut, when regeneration was prevented. Since the time course of MHC class I expression correlates to that of regeneration a role for this cell surface molecule in regeneration may be considered....

Cell surface appearance of unexpected host MHC determinants on thymocytes from radiation bone marrow chimeras

International Nuclear Information System (INIS)

Sharrow, S.O.; Mathieson, B.J.; Singer, A.

1981-01-01

The phenotypic appearance of cell surface antigens on murine thymocytes from long-term radiation bone marrow chimeras was analyzed using indirect immunofluorescence and flow microfluorometry. Cells maturing in the thymi of these mice were typed for MHC (Kk, I-Ak, H-2b, Kb, and Ib) and non-MHC (Lty 1, Ly 9, and TL) determinants. All cells were of donor origin as determined by non-MHC (Ly) phenotype in P1 leads to P2, P1 x P2 leads to P1, and P1 leads to P2 radiation chimeras. In contrast, the MHC phenotypes of these thymocytes were markedly affected by the host environment. Specifically, H-2 and I-A determinants of both parental phenotypes were detected on thymocytes from P1 leads to P1 x P2 chimeras; I-A determinants of host phenotype were present, whereas I-A determinants of donor phenotype were reduced on thymocytes from P1 x P2 leads to P1 chimeras; and thymocytes from P1 leads to P2 chimeras possessed H-2 and I-A determinants of host phenotype but showed reduction of donor I-A phenotype determinants. The appearance of host cell surface H-2 and I-A determinants on thymocytes from chimeras closely parallels the functional recognition of MHC determinants by T cells from chimeric mice and thus may be significantly related to the development of the self-recognition repertoire by maturing T cells

High-throughput discovery of T cell epitopes in type 1 diabetes using DNA barcode labelledpeptide-MHC multimers

DEFF Research Database (Denmark)

Lyngaa, Rikke Birgitte; Bentzen, Amalie Kai; Overgaard, A. Julie

2016-01-01

applying a novel technology where the selection of MHC-multimer binding T cells is followed by amplification and sequencing of MHC multimer-associated DNA barcodes revealing their recognition. This technique enables simultaneous detection of >1000 specificities. Identifying post translational modifications...

Immunohistochemical detection and correlation between MHC antigen and cell-mediated immune system in recurrent glioma by APAAP method.

Science.gov (United States)

Miyagi, K; Ingram, M; Techy, G B; Jacques, D B; Freshwater, D B; Sheldon, H

1990-09-01

As part of an on-going clinical trial of immunotherapy for recurrent malignant gliomas, using alkaline phosphatase-anti-alkaline phosphatase method with monoclonal antibodies, we investigated the correlation between expression of the major histocompatibility complex (MHC) and the subpopulation of tumor-infiltrating lymphocytes (TILs) in 38 glioma specimens (20 grade IV, 11 grade III, and 7 grade II) from 33 patients. Thirty specimens (78.9%) were positive to class I MHC antigen and 20 (52.6%) were positive to class II MHC antigen. The correlations between class I MHC antigen expression and the number of infiltrating T8 (p less than 0.01), and also between class II MHC antigen expression and the number of infiltrating T4 (p less than 0.05) were significant. We conclude that TILs are the result of immunoreaction (host-defense mechanism). 31.6% of specimens had perivascular infiltration of T cells. The main infiltrating lymphocyte subset in moderate to marked perivascular cuffing was T4. Our results may indicate that lack of MHC antigen on the glioma cell surface has a share in the poor immunogenicity in glioma-bearing patients. In addition, considering the effector/target ratio, the number of infiltrating lymphocytes against glioma cells was too small, so the immunological intervention seems to be essential in glioma therapy. Previous radiation therapy and chemotherapy, including steroid therapy, did not influence lymphocyte and macrophage infiltration.

Plasmodium falciparum isolates from Angola show the StctVMNT haplotype in the pfcrt gene

Science.gov (United States)

2010-01-01

Background Effective treatment remains a mainstay of malaria control, but it is unfortunately strongly compromised by drug resistance, particularly in Plasmodium falciparum, the most important human malaria parasite. Although P. falciparum chemoresistance is well recognized all over the world, limited data are available on the distribution and prevalence of pfcrt and pfmdr1 haplotypes that mediate resistance to commonly used drugs and that show distinct geographic differences. Methods Plasmodium falciparum-infected blood samples collected in 2007 at four municipalities of Luanda, Angola, were genotyped using PCR and direct DNA sequencing. Single nucleotide polymorphisms in the P. falciparum pfcrt and pfmdr1 genes were assessed and haplotype prevalences were determined. Results and Discussion The most prevalent pfcrt haplotype was StctVMNT (representing amino acids at codons 72-76). This result was unexpected, since the StctVMNT haplotype has previously been seen mainly in parasites from South America and India. The CVIET, CVMNT and CVINT drug-resistance haplotypes were also found, and one previously undescribed haplotype (CVMDT) was detected. Regarding pfmdr1, the most prevalent haplotype was YEYSNVD (representing amino acids at codons 86, 130, 184, 1034, 1042, 1109 and 1246). Wild haplotypes for pfcrt and pfmdr1 were uncommon; 3% of field isolates harbored wild type pfcrt (CVMNK), whereas 21% had wild type pfmdr1 (NEYSNVD). The observed predominance of the StctVMNT haplotype in Angola could be a result of frequent travel between Brazil and Angola citizens in the context of selective pressure of heavy CQ use. Conclusions The high prevalence of the pfcrt SVMNT haplotype and the pfmdr1 86Y mutation confirm high-level chloroquine resistance and might suggest reduced efficacy of amodiaquine in Angola. Further studies must be encouraged to examine the in vitro sensitivity of pfcrt SVMNT parasites to artesunate and amodiaquine for better conclusive data. PMID:20565881

Evolution of MHC class I genes in the endangered loggerhead sea turtle (Caretta caretta) revealed by 454 amplicon sequencing.

Science.gov (United States)

Stiebens, Victor A; Merino, Sonia E; Chain, Frédéric J J; Eizaguirre, Christophe

2013-04-30

In evolutionary and conservation biology, parasitism is often highlighted as a major selective pressure. To fight against parasites and pathogens, genetic diversity of the immune genes of the major histocompatibility complex (MHC) are particularly important. However, the extensive degree of polymorphism observed in these genes makes it difficult to conduct thorough population screenings. We utilized a genotyping protocol that uses 454 amplicon sequencing to characterize the MHC class I in the endangered loggerhead sea turtle (Caretta caretta) and to investigate their evolution at multiple relevant levels of organization. MHC class I genes revealed signatures of trans-species polymorphism across several reptile species. In the studied loggerhead turtle individuals, it results in the maintenance of two ancient allelic lineages. We also found that individuals carrying an intermediate number of MHC class I alleles are larger than those with either a low or high number of alleles. Multiple modes of evolution seem to maintain MHC diversity in the loggerhead turtles, with relatively high polymorphism for an endangered species.

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

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Maciej Jan Ejsmond

2015-11-01

Full Text Available 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.

MHC class II expression through a hitherto unknown pathway supports T helper cell-dependent immune responses: implications for MHC class II deficiency

NARCIS (Netherlands)

Buch, Thorsten; Polic, Bojan; Clausen, Björn E.; Weiss, Susanne; Akilli-Ozturk, Ozlem; Chang, Cheong-Hee; Flavell, Richard; Schulz, Ansgar; Jonjic, Stipan; Waisman, Ari; Förster, Irmgard

2006-01-01

MHC class II (MHCII) deficiency or bare lymphocyte syndrome (BLS) is a severe immunodeficiency characterized by deficient T helper (Th)-cell-dependent immunity. The disease is caused by defects of the MHCII promoter complex resulting in low or absent MHCII expression. We demonstrate in a murine

Peptide-MHC-based nanomedicines for autoimmunity function as T-cell receptor microclustering devices

Science.gov (United States)

Singha, Santiswarup; Shao, Kun; Yang, Yang; Clemente-Casares, Xavier; Solé, Patricia; Clemente, Antonio; Blanco, Jesús; Dai, Qin; Song, Fayi; Liu, Shang Wan; Yamanouchi, Jun; Umeshappa, Channakeshava Sokke; Nanjundappa, Roopa Hebbandi; Detampel, Pascal; Amrein, Matthias; Fandos, César; Tanguay, Robert; Newbigging, Susan; Serra, Pau; Khadra, Anmar; Chan, Warren C. W.; Santamaria, Pere

2017-07-01

We have shown that nanoparticles (NPs) can be used as ligand-multimerization platforms to activate specific cellular receptors in vivo. Nanoparticles coated with autoimmune disease-relevant peptide-major histocompatibility complexes (pMHC) blunted autoimmune responses by triggering the differentiation and expansion of antigen-specific regulatory T cells in vivo. Here, we define the engineering principles impacting biological activity, detail a synthesis process yielding safe and stable compounds, and visualize how these nanomedicines interact with cognate T cells. We find that the triggering properties of pMHC-NPs are a function of pMHC intermolecular distance and involve the sustained assembly of large antigen receptor microclusters on murine and human cognate T cells. These compounds show no off-target toxicity in zebrafish embryos, do not cause haematological, biochemical or histological abnormalities, and are rapidly captured by phagocytes or processed by the hepatobiliary system. This work lays the groundwork for the design of ligand-based NP formulations to re-program in vivo cellular responses using nanotechnology.

RSCA genotyping of MHC for high-throughput evolutionary studies in the model organism three-spined stickleback Gasterosteus aculeatus

Science.gov (United States)

Lenz, Tobias L; Eizaguirre, Christophe; Becker, Sven; Reusch, Thorsten BH

2009-01-01

Background In all jawed vertebrates, highly polymorphic genes of the major histocompatibility complex (MHC) encode antigen presenting molecules that play a key role in the adaptive immune response. Their polymorphism is composed of multiple copies of recently duplicated genes, each possessing many alleles within populations, as well as high nucleotide divergence between alleles of the same species. Experimental evidence is accumulating that MHC polymorphism is a result of balancing selection by parasites and pathogens. In order to describe MHC diversity and analyse the underlying mechanisms that maintain it, a reliable genotyping technique is required that is suitable for such highly variable genes. Results We present a genotyping protocol that uses Reference Strand-mediated Conformation Analysis (RSCA), optimised for recently duplicated MHC class IIB genes that are typical for many fish and bird species, including the three-spined stickleback, Gasterosteus aculeatus. In addition we use a comprehensive plasmid library of MHC class IIB alleles to determine the nucleotide sequence of alleles represented by RSCA allele peaks. Verification of the RSCA typing by cloning and sequencing demonstrates high congruency between both methods and provides new insight into the polymorphism of classical stickleback MHC genes. Analysis of the plasmid library additionally reveals the high resolution and reproducibility of the RSCA technique. Conclusion This new RSCA genotyping protocol offers a fast, but sensitive and reliable way to determine the MHC allele repertoire of three-spined sticklebacks. It therefore provides a valuable tool to employ this highly polymorphic and adaptive marker in future high-throughput studies of host-parasite co-evolution and ecological speciation in this emerging model organism. PMID:19291291

RSCA genotyping of MHC for high-throughput evolutionary studies in the model organism three-spined stickleback Gasterosteus aculeatus

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Becker Sven

2009-03-01

Full Text Available Abstract Background In all jawed vertebrates, highly polymorphic genes of the major histocompatibility complex (MHC encode antigen presenting molecules that play a key role in the adaptive immune response. Their polymorphism is composed of multiple copies of recently duplicated genes, each possessing many alleles within populations, as well as high nucleotide divergence between alleles of the same species. Experimental evidence is accumulating that MHC polymorphism is a result of balancing selection by parasites and pathogens. In order to describe MHC diversity and analyse the underlying mechanisms that maintain it, a reliable genotyping technique is required that is suitable for such highly variable genes. Results We present a genotyping protocol that uses Reference Strand-mediated Conformation Analysis (RSCA, optimised for recently duplicated MHC class IIB genes that are typical for many fish and bird species, including the three-spined stickleback, Gasterosteus aculeatus. In addition we use a comprehensive plasmid library of MHC class IIB alleles to determine the nucleotide sequence of alleles represented by RSCA allele peaks. Verification of the RSCA typing by cloning and sequencing demonstrates high congruency between both methods and provides new insight into the polymorphism of classical stickleback MHC genes. Analysis of the plasmid library additionally reveals the high resolution and reproducibility of the RSCA technique. Conclusion This new RSCA genotyping protocol offers a fast, but sensitive and reliable way to determine the MHC allele repertoire of three-spined sticklebacks. It therefore provides a valuable tool to employ this highly polymorphic and adaptive marker in future high-throughput studies of host-parasite co-evolution and ecological speciation in this emerging model organism.

On detecting incomplete soft or hard selective sweeps using haplotype structure

DEFF Research Database (Denmark)

Ferrer-Admetlla, Anna; Liang, Mason; Korneliussen, Thorfinn Sand

2014-01-01

We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust, particu......We present a new haplotype-based statistic (nSL) for detecting both soft and hard sweeps in population genomic data from a single population. We compare our new method with classic single-population haplotype and site frequency spectrum (SFS)-based methods and show that it is more robust......, particularly to recombination rate variation. However, all statistics show some sensitivity to the assumptions of the demographic model. Additionally, we show that nSL has at least as much power as other methods under a number of different selection scenarios, most notably in the cases of sweeps from standing...

Two families from New England with usher syndrome type IC with distinct haplotypes.

Science.gov (United States)

DeAngelis, M M; McGee, T L; Keats, B J; Slim, R; Berson, E L; Dryja, T P

2001-03-01

To search for patients with Usher syndrome type IC among those with Usher syndrome type I who reside in New England. Genotype analysis of microsatellite markers closely linked to the USH1C locus was done using the polymerase chain reaction. We compared the haplotype of our patients who were homozygous in the USH1C region with the haplotypes found in previously reported USH1C Acadian families who reside in southwestern Louisiana and from a single family residing in Lebanon. Of 46 unrelated cases of Usher syndrome type I residing in New England, two were homozygous at genetic markers in the USH1C region. Of these, one carried the Acadian USH1C haplotype and had Acadian ancestors (that is, from Nova Scotia) who did not participate in the 1755 migration of Acadians to Louisiana. The second family had a haplotype that proved to be the same as that of a family with USH1C residing in Lebanon. Each of the two families had haplotypes distinct from the other. This is the first report that some patients residing in New England have Usher syndrome type IC. Patients with Usher syndrome type IC can have the Acadian haplotype or the Lebanese haplotype compatible with the idea that at least two independently arising pathogenic mutations have occurred in the yet-to-be identified USH1C gene.

Generation of murine tumor cell lines deficient in MHC molecule surface expression using the CRISPR/Cas9 system.

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Krishna Das

Full Text Available In this study, the CRISPR/Cas9 technology was used to establish murine tumor cell lines, devoid of MHC I or MHC II surface expression, respectively. The melanoma cell line B16F10 and the murine breast cancer cell line EO-771, the latter stably expressing the tumor antigen NY-BR-1 (EO-NY, were transfected with an expression plasmid encoding a β2m-specific single guide (sgRNA and Cas9. The resulting MHC I negative cells were sorted by flow cytometry to obtain single cell clones, and loss of susceptibility of peptide pulsed MHC I negative clones to peptide-specific CTL recognition was determined by IFNγ ELISpot assay. The β2m knockout (KO clones did not give rise to tumors in syngeneic mice (C57BL/6N, unless NK cells were depleted, suggesting that outgrowth of the β2m KO cell lines was controlled by NK cells. Using sgRNAs targeting the β-chain encoding locus of the IAb molecule we also generated several B16F10 MHC II KO clones. Peptide loaded B16F10 MHC II KO cells were insusceptible to recognition by OT-II cells and tumor growth was unaltered compared to parental B16F10 cells. Thus, in our hands the CRISPR/Cas9 system has proven to be an efficient straight forward strategy for the generation of MHC knockout cell lines. Such cell lines could serve as parental cells for co-transfection of compatible HLA alleles together with human tumor antigens of interest, thereby facilitating the generation of HLA matched transplantable tumor models, e.g. in HLAtg mouse strains of the newer generation, lacking cell surface expression of endogenous H2 molecules. In addition, our tumor cell lines established might offer a useful tool to investigate tumor reactive T cell responses that function independently from MHC molecule surface expression by the tumor.

A highly tilted binding mode by a self-reactive T cell receptor results in altered engagement of peptide and MHC

Energy Technology Data Exchange (ETDEWEB)

Sethi, D.K.; Heroux, A.; Schubert, D. A.; Anders, A.-K.; Bonsor, D. A.; Thomas, C. P.; Sundberg, E. J.; Pyrdol, J.; Wucherpfennig, K. W.

2011-01-17

Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-{alpha} chain with the MHC class II {beta} chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3{beta} loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3{alpha} loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.

A Highly Tilted Binding Mode by a Self-Reactive T Cell Receptor Results in Altered Engagement of Peptide and MHC

Energy Technology Data Exchange (ETDEWEB)

D Sethi; D Schubert; A Anders; A Heroux; D Bonsor; C Thomas; E Sundberg; J Pyrdol; K Wucherpfennig

2011-12-31

Self-reactive T cells that escape elimination in the thymus can cause autoimmune pathology, and it is therefore important to understand the structural mechanisms of self-antigen recognition. We report the crystal structure of a T cell receptor (TCR) from a patient with relapsing-remitting multiple sclerosis that engages its self-peptide-major histocompatibility complex (pMHC) ligand in an unusual manner. The TCR is bound in a highly tilted orientation that prevents interaction of the TCR-{alpha} chain with the MHC class II {beta} chain helix. In this structure, only a single germline-encoded TCR loop engages the MHC protein, whereas in most other TCR-pMHC structures all four germline-encoded TCR loops bind to the MHC helices. The tilted binding mode also prevents peptide contacts by the short complementarity-determining region (CDR) 3{beta} loop, and interactions that contribute to peptide side chain specificity are focused on the CDR3{alpha} loop. This structure is the first example in which only a single germline-encoded TCR loop contacts the MHC helices. Furthermore, the reduced interaction surface with the peptide may facilitate TCR cross-reactivity. The structural alterations in the trimolecular complex are distinct from previously characterized self-reactive TCRs, indicating that there are multiple unusual ways for self-reactive TCRs to bind their pMHC ligand.

Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents.

Science.gov (United States)

Habara, Alawi H; Shaikho, Elmutaz M; Steinberg, Martin H

2017-11-01

Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF. © 2017 Wiley Periodicals, Inc.

Expressão do complexo de histocompatilidade principal de classe I (MHC I no sistema nervoso central: plasticidade sináptica e regeneração Expresión del complejo principal de histocompatibilidad de clase I (MHC I en el sistema nervioso central: plasticidad sináptica y regeneración Expression of class I major histocompatibility complex (MHC I in the central nervous system: role in synaptic plasticity and regeneration

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Renata Graciele Zanon

2010-06-01

Full Text Available Foi demonstrado recentemente que o complexo de histocompatibilidade principal de classe I (MHC I, expresso no sistema nervoso central (SNC, não funciona somente como molécula com papel imunológico, mas também como parte de um mecanismo envolvido na plasticidade sináptica. A expressão de MHC I interfere na intensidade e seletividade da retração de sinapses em contato com neurônios que sofreram lesão e também influencia a reatividade das células gliais próximas a esses neurônios. A intensidade do rearranjo sináptico e resposta glial após lesão, ligadas à expressão de MHC I no SNC, repercute em diferenças na capacidade regenerativa e recuperação funcional em linhagens de camundongos isogênicos. Dessa forma, os novos aspectos sobre a função do MHC I no SNC direcionam futuras pesquisas no sentido de buscar o envolvimento do MHC I em doenças neurológicas e também o desenvolvimento de novas estratégias terapêuticas.El complejo mayor de histocompatibilidad de clase I (MHC I, expresado en el sistema nervioso central (SNC, no sólo funciona como una molécula con función inmunológica, sino que es crucial para las respuestas del tejido nervioso en casos de lesiones. El MHC I está involucrado con los procesos de plasticidad sináptica y las células gliales en el microambiente de la médula espinal después de realizada axotomía periférica. La expresión de MHC I interfiere con la intensidad y la forma en que se producen la contracción y la eliminación de sinapsis con relación a las neuronas, cuyos axones se han comprometido, y también influye en la reactividad de las células gliales, cerca de estas neuronas. La intensidad de estos cambios, que responden a la expresión de MHC I en el SNC, implica diferencias en la capacidad de regeneración axonal de las células dañadas por axotomía, por lo que el nivel de expresión de las moléculas MHC I se relaciona con el proceso de regeneración de los axones y, en

Characteristics of MHC class I genes in house sparrows Passer domesticus as revealed by long cDNA transcripts and amplicon sequencing.

Science.gov (United States)

Karlsson, Maria; Westerdahl, Helena

2013-08-01

In birds the major histocompatibility complex (MHC) organization differs both among and within orders; chickens Gallus gallus of the order Galliformes have a simple arrangement, while many songbirds of the order Passeriformes have a more complex arrangement with larger numbers of MHC class I and II genes. Chicken MHC genes are found at two independent loci, classical MHC-B and non-classical MHC-Y, whereas non-classical MHC genes are yet to be verified in passerines. Here we characterize MHC class I transcripts (α1 to α3 domain) and perform amplicon sequencing using a next-generation sequencing technique on exon 3 from house sparrow Passer domesticus (a passerine) families. Then we use phylogenetic, selection, and segregation analyses to gain a better understanding of the MHC class I organization. Trees based on the α1 and α2 domain revealed a distinct cluster with short terminal branches for transcripts with a 6-bp deletion. Interestingly, this cluster was not seen in the tree based on the α3 domain. 21 exon 3 sequences were verified in a single individual and the average numbers within an individual were nine and five for sequences with and without a 6-bp deletion, respectively. All individuals had exon 3 sequences with and without a 6-bp deletion. The sequences with a 6-bp deletion have many characteristics in common with non-classical MHC, e.g., highly conserved amino acid positions were substituted compared with the other alleles, low nucleotide diversity and just a single site was subject to positive selection. However, these alleles also have characteristics that suggest they could be classical, e.g., complete linkage and absence of a distinct cluster in a tree based on the α3 domain. Thus, we cannot determine for certain whether or not the alleles with a 6-bp deletion are non-classical based on our present data. Further analyses on segregation patterns of these alleles in combination with dating the 6-bp deletion through MHC characterization across the

Probing natural killer cell education by Ly49 receptor expression analysis and computational modelling in single MHC class I mice.

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Sofia Johansson

Full Text Available Murine natural killer (NK cells express inhibitory Ly49 receptors for MHC class I molecules, which allows for "missing self" recognition of cells that downregulate MHC class I expression. During murine NK cell development, host MHC class I molecules impose an "educating impact" on the NK cell pool. As a result, mice with different MHC class I expression display different frequency distributions of Ly49 receptor combinations on NK cells. Two models have been put forward to explain this impact. The two-step selection model proposes a stochastic Ly49 receptor expression followed by selection for NK cells expressing appropriate receptor combinations. The sequential model, on the other hand, proposes that each NK cell sequentially expresses Ly49 receptors until an interaction of sufficient magnitude with self-class I MHC is reached for the NK cell to mature. With the aim to clarify which one of these models is most likely to reflect the actual biological process, we simulated the two educational schemes by mathematical modelling, and fitted the results to Ly49 expression patterns, which were analyzed in mice expressing single MHC class I molecules. Our results favour the two-step selection model over the sequential model. Furthermore, the MHC class I environment favoured maturation of NK cells expressing one or a few self receptors, suggesting a possible step of positive selection in NK cell education. Based on the predicted Ly49 binding preferences revealed by the model, we also propose, that Ly49 receptors are more promiscuous than previously thought in their interactions with MHC class I molecules, which was supported by functional studies of NK cell subsets expressing individual Ly49 receptors.

Expression, refolding and crystallization of murine MHC class I H-2Db in complex with human β2-microglobulin

International Nuclear Information System (INIS)

Sandalova, Tatyana; Michaëlsson, Jakob; Harris, Robert A.; Ljunggren, Hans-Gustaf; Kärre, Klas; Schneider, Gunter; Achour, Adnane

2005-01-01

Mouse MHC class I H-2Db in complex with human β2m and the LCMV-derived peptide gp33 has been produced and crystallized. Resolution of the structure of this complex combined with the structural comparison with the previously solved crystal structure of H-2Db/mβ2m/gp33 should lead to a better understanding of how the β2m subunit affects the overall conformation of MHC complexes as well as the stability of the presented peptides. β 2 -Microglobulin (β 2 m) is non-covalently linked to the major histocompatibility (MHC) class I heavy chain and interacts with CD8 and Ly49 receptors. Murine MHC class I can bind human β 2 m (hβ 2 m) and such hybrid molecules are often used in structural and functional studies. The replacement of mouse β 2 m (mβ 2 m) by hβ 2 m has important functional consequences for MHC class I complex stability and specificity, but the structural basis for this is unknown. To investigate the impact of species-specific β 2 m subunits on MHC class I conformation, murine MHC class I H-2D b in complex with hβ 2 m and the peptide gp33 derived from lymphocytic choriomeningitis virus (LCMV) has been expressed, refolded in vitro and crystallized. Crystals containing two complexes per asymmetric unit and belonging to the space group P2 1 , with unit-cell parameters a = 68.1, b = 65.2, c = 101.9 Å, β = 102.4°, were obtained

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

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Masha Fridkis-Hareli

2013-01-01

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

Haplotypes of CYP3A4 and their close linkage with CYP3A5 haplotypes in a Japanese population.

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Fukushima-Uesaka, Hiromi; Saito, Yoshiro; Watanabe, Hidemi; Shiseki, Kisho; Saeki, Mayumi; Nakamura, Takahiro; Kurose, Kouichi; Sai, Kimie; Komamura, Kazuo; Ueno, Kazuyuki; Kamakura, Shiro; Kitakaze, Masafumi; Hanai, Sotaro; Nakajima, Toshiharu; Matsumoto, Kenji; Saito, Hirohisa; Goto, Yu-ichi; Kimura, Hideo; Katoh, Masaaki; Sugai, Kenji; Minami, Narihiro; Shirao, Kuniaki; Tamura, Tomohide; Yamamoto, Noboru; Minami, Hironobu; Ohtsu, Atsushi; Yoshida, Teruhiko; Saijo, Nagahiro; Kitamura, Yutaka; Kamatani, Naoyuki; Ozawa, Shogo; Sawada, Jun-ichi

2004-01-01

In order to identify single nucleotide polymorphisms (SNPs) and haplotype frequencies of CYP3A4 in a Japanese population, the distal enhancer and proximal promoter regions, all exons, and the surrounding introns were sequenced from genomic DNA of 416 Japanese subjects. We found 24 SNPs, including 17 novel ones: two in the distal enhancer, four in the proximal promoter, one in the 5'-untranslated region (UTR), seven in the introns, and three in the 3'-UTR. The most common SNP was c.1026+12G>A (IVS10+12G>A), with a 0.249 frequency. Four non-synonymous SNPs, c.554C>G (p.T185S, CYP3A4(*)16), c.830_831insA (p.E277fsX8, (*)6), c.878T>C (p.L293P, (*)18), and c.1088 C>T (p.T363M, (*)11) were found with frequencies of 0.014, 0.001, 0.028, and 0.002, respectively. No SNP was found in the known nuclear transcriptional factor-binding sites in the enhancer and promoter regions. Using these 24 SNPs, 16 haplotypes were unambiguously identified, and nine haplotypes were inferred by aid of an expectation-maximization-based program. In addition, using data from 186 subjects enabled a close linkage to be found between CYP3A4 and CYP3A5 SNPs, especially among the SNPs at c.1026+12 in CYP3A4 and c.219-237 (IVS3-237, a key SNP site for CYP3A5(*)3), c.865+77 (IVS9+77) and c.1523 in CYP3A5. This result suggested that CYP3A4 and CYP3A5 are within the same gene block. Haplotype analysis between CYP3A4 and CYP3A5 revealed several major haplotype combinations in the CYP3A4-CYP3A5 block. Our findings provide fundamental and useful information for genotyping CYP3A4 (and CYP3A5) in the Japanese, and probably Asian populations. Copyright 2003 Wiley-Liss, Inc.

MHC-I Ligand Discovery Using Targeted Database Searches of Mass Spectrometry Data: Implications for T-Cell Immunotherapies

DEFF Research Database (Denmark)

Murphy, J. Patrick; Konda, Prathyusha; Kowalewski, Daniel J.

2017-01-01

Class I major histocompatibility complex (MHC-I)-bound peptide ligands dictate the activation and specificity of CD8+ T cells and thus are important for devising T-cell immunotherapies. In recent times, advances in mass spectrometry (MS) have enabled the precise identification of these MHC-I pept...

Association of TAP Gene Polymorphisms and Risk of Cervical Intraepithelial Neoplasia

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Camilla Natter

2013-01-01

Full Text Available Background. Transporter associated with antigen processing (TAP is responsible for peptide loading onto class I major histocompatibility complex (MHC-I molecules. TAP seems to facilitate the detection of HPV by MHC-I molecules and contributes to successful eradication of HPV. TAP polymorphisms could have an important impact on the course of HPV infection. Objective. The aim of this study is to evaluate the association between five TAP gene polymorphisms and the risk of CIN. Methods. This case-control study investigated five common TAP polymorphisms in TAP1 (1341 and 2254 and TAP2 (1135, 1693, and 1993 in 616 women with CIN and 206 controls. Associations between gene polymorphisms and risk of CIN were analysed by univariate and multivariable models. The combined effect of the five TAP gene polymorphisms on the risk for CIN was investigated by haplotype analysis. Results. No significant difference in genotype distribution of the five TAP polymorphisms was observed in women with CIN and controls. Haplotype analysis revealed that women with haplotype mut-wt-wt-wt-wt (TAP polymorphisms t1135-t1341-t1693-t1993-t2254 had a significantly lower risk for CIN, compared to women with the haplotype wt-wt-wt-wt-wt (; OR 0.5 []. Conclusion. Identification of this haplotype combination could be used to identify women, less susceptible for development of CIN following HPV infection.

NetMHCpan 4.0: Improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data

OpenAIRE

Jurtz, Vanessa; Paul, Sinu; Andreatta, Massimo; Marcatili, Paolo; Peters, Bjoern; Nielsen, Morten

2017-01-01

Cytotoxic T cells are of central importance in the immune systems response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC (major histocompatibility complex) class I molecules. Peptide binding to MHC molecules is the single most selective step in the antigen presentation pathway. On the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has therefore attracted large attention. In the past, predictors of peptide-...

Common ataxia telangiectasia mutated haplotypes and risk of breast cancer: a nested case–control study

International Nuclear Information System (INIS)

Tamimi, Rulla M; Hankinson, Susan E; Spiegelman, Donna; Kraft, Peter; Colditz, Graham A; Hunter, David J

2004-01-01

The ataxia telangiectasia mutated (ATM) gene is a tumor suppressor gene with functions in cell cycle arrest, apoptosis, and repair of DNA double-strand breaks. Based on family studies, women heterozygous for mutations in the ATM gene are reported to have a fourfold to fivefold increased risk of breast cancer compared with noncarriers of the mutations, although not all studies have confirmed this association. Haplotype analysis has been suggested as an efficient method for investigating the role of common variation in the ATM gene and breast cancer. Five biallelic haplotype tagging single nucleotide polymorphisms are estimated to capture 99% of the haplotype diversity in Caucasian populations. We conducted a nested case–control study of breast cancer within the Nurses' Health Study cohort to address the role of common ATM haplotypes and breast cancer. Cases and controls were genotyped for five haplotype tagging single nucleotide polymorphisms. Haplotypes were predicted for 1309 cases and 1761 controls for which genotype information was available. Six unique haplotypes were predicted in this study, five of which occur at a frequency of 5% or greater. The overall distribution of haplotypes was not significantly different between cases and controls (χ 2 = 3.43, five degrees of freedom, P = 0.63). There was no evidence that common haplotypes of ATM are associated with breast cancer risk. Extensive single nucleotide polymorphism detection using the entire genomic sequence of ATM will be necessary to rule out less common variation in ATM and sporadic breast cancer risk

Psychometric evaluation of the Mental Health Continuum-Short Form (MHC-SF) in Chinese adolescents - a methodological study.

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Guo, Cheng; Tomson, Göran; Guo, Jizhi; Li, Xiangyun; Keller, Christina; Söderqvist, Fredrik

2015-12-10

In epidemiological surveillance of mental health there is good reason to also include scales that measure the presence of well-being rather than merely symptoms of ill health. The Mental Health Continuum-Short Form (MHC-SF) is a self-reported scale to measure emotional, psychological and social well-being and conduct categorical diagnosis of positive mental health. This particular instrument includes the three core components of the World Health Organization's definition of mental health and had previously not been psychometrically evaluated on adolescents in China. In total 5,399 students (51.1% female) from schools in the urban areas of Weifang in China were included in the study (mean age = 15.13, SD = 1.56). Participants completed a comprehensive questionnaire with several scales, among them the MHC-SF. Statistical analyses to evaluate reliability, structural validity, measurement invariance, presence of floor and ceiling effects and to some extent external validity of the MHC-SF were carried out. The Cronbach's α coefficients for sub-scales as well as the total scale were all above 0.80 indicating good reliability. Confirmative factor analysis confirmed the three-dimensional structure of the Chinese version of MHC-SF and supported the configural and metric invariance across gender and age. Noteworthy ceiling effects were observed for single items and sub-scales although not for the total scale. More importantly, observed floor effects were negligible. The stronger correlation found between MHC-SF and Minneapolis-Manchester Quality of Life Instrument (as measure of positive mental health) than between MHC-SF and Hospital Anxiety Depression Scale (as measure of mental illness and distress) yielded support for external validity. In conclusion, the main findings of this study are in line with studies from other countries that evaluated the psychometric properties of the MHC-SF and show that this instrument, that includes the three core components of the

Cholesterol Corrects Altered Conformation of MHC-II Protein in Leishmania donovani Infected Macrophages: Implication in Therapy

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Chakrabarti, Saikat; Roy, Syamal

2016-01-01

Background Previously we reported that Kala-azar patients show progressive decrease in serum cholesterol as a function of splenic parasite burden. Splenic macrophages (MΦ) of Leishmania donovani (LD) infected mice show decrease in membrane cholesterol, while LD infected macrophages (I-MΦ) show defective T cell stimulating ability that could be corrected by liposomal delivery of cholesterol. T helper cells recognize peptide antigen in the context of class II MHC molecule. It is known that the conformation of a large number of membrane proteins is dependent on membrane cholesterol. In this investigation we tried to understand the influence of decreased membrane cholesterol in I-MΦ on the conformation of MHC-II protein and peptide-MHC-II stability, and its bearing on the antigen specific T-cell activation. Methodology/Principal Findings MΦ of CBA/j mice were infected with Leishmania donovani (I-MΦ). Two different anti-Aκ mAbs were used to monitor the status of MHC-II protein under parasitized condition. One of them (11.5–2) was conformation specific, whereas the other one (10.2.16) was not. Under parasitized condition, the binding of 11.5–2 decreased significantly with respect to the normal counterpart, whereas that of 10.2.16 remained unaltered. The binding of 11.5–2 was restored to normal upon liposomal delivery of cholesterol in I-MΦ. By molecular dynamics (MD) simulation studies we found that there was considerable conformational fluctuation in the transmembrane domain of the MHC-II protein in the presence of membrane cholesterol than in its absence, which possibly influenced the distal peptide binding groove. This was evident from the faster dissociation of the cognate peptide from peptide-MHC complex under parasitized condition, which could be corrected by liposomal delivery of cholesterol in I-MΦ. Conclusion The decrease in membrane cholesterol in I-MΦ may lead to altered conformation of MHC II, and this may contribute to a faster dissociation of

NetMHCpan-3.0; improved prediction of binding to MHC class I molecules integrating information from multiple receptor and peptide length datasets

DEFF Research Database (Denmark)

Nielsen, Morten; Andreatta, Massimo

2016-01-01

Background: Binding of peptides to MHC class I molecules (MHC-I) is essential for antigen presentation to cytotoxic T-cells.Results: Here, we demonstrate how a simple alignment step allowing insertions and deletions in a pan-specific MHC-I binding machine-learning model enables combining informat...... specificities and ligand length scales, and demonstrated how this approach significantly improves the accuracy for prediction of peptide binding and identification of MHC ligands. The method is available at www.cbs.dtu.dk/services/NetMHCpan-3.0....

The Prognostic Value of Haplotypes in the Vascular Endothelial Growth Factor

DEFF Research Database (Denmark)

Hansen, Torben Frøstrup; Spindler, Karen-Lise Garm; Andersen, Rikke Fredslund

2010-01-01

Abstract: New prognostic markers in patients with colorectal cancer (CRC) are a prerequisite for individualized treatment. Prognostic importance of single nucleotide polymorphisms (SNPs) in the vascular endothelial growth factor A (VEGF-A) gene has been proposed. The objective of the present study...... using the PHASE program. The prognostic influence was evaluated using Kaplan-Meir plots and log rank tests. Cox regression method was used to analyze the independent prognostic importance of different markers. All three SNPs were significantly related to survival. A haplotype combination, responsible...... findings in a second and independent cohort. Haplotype combinations call for further investigation. Keywords: colorectal neoplasm; single nucleotide polymorphisms; haplotypes; vascular endothelial growth factor A; survival...

Molecular characterization of classical and nonclassical MHC class I genes from the golden pheasant (Chrysolophus pictus).

Science.gov (United States)

Zeng, Q-Q; Zhong, G-H; He, K; Sun, D-D; Wan, Q-H

2016-02-01

Classical major histocompatibility complex (MHC) class I allelic polymorphism is essential for competent antigen presentation. To improve the genotyping efforts in the golden pheasant, it is necessary to differentiate more accurately between classical and nonclassical class I molecules. In our study, all MHC class I genes were isolated from one golden pheasant based on two overlapping PCR amplifications. In total, six full-length class I nucleotide sequences (A-F) were identified, and four were novel. Two (A and C) belonged to the IA1 gene, two (B and D) were alleles derived from the IA2 gene through transgene amplification, and two (E and F) comprised a third novel locus, IA3 that was excluded from the core region of the golden pheasant MHC-B. IA1 and IA2 exhibited the broad expression profiles characteristic of classical loci, while IA3 showed no expression in multiple tissues and was therefore defined as a nonclassical gene. Phylogenetic analysis indicated that the three IA genes in the golden pheasant share a much closer evolutionary relationship than the corresponding sequences in other galliform species. This observation was consistent with high sequence similarity among them, which likely arises from the homogenizing effect of recombination. Our careful distinction between the classical and nonclassical MHC class I genes in the golden pheasant lays the foundation for developing locus-specific genotyping and establishing a good molecular marker system of classical MHC I loci. © 2015 John Wiley & Sons Ltd.

Analysis of SNPs and haplotypes in vitamin D pathway genes and renal cancer risk.

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Sara Karami

2009-09-01

Full Text Available In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR, most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC etiology. RCC cases (N = 777 and controls (N = 1,035 were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02 and retinoid-X-receptor-alpha (RXRA (p-value = 0.10 were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991 across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09-1.57 haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3' of the coding sequence (rs748964, rs3118523, increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings.

Salmonella Typhimurium induces SPI-1 and SPI-2 regulated and strain dependent downregulation of MHC II expression on porcine alveolar macrophages

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Van Parys Alexander

2012-06-01

Full Text Available Abstract Foodborne salmonellosis is one of the most important bacterial zoonotic diseases worldwide. Salmonella Typhimurium is the serovar most frequently isolated from persistently infected slaughter pigs in Europe. Circumvention of the host’s immune system by Salmonella might contribute to persistent infection of pigs. In the present study, we found that Salmonella Typhimurium strain 112910a specifically downregulated MHC II, but not MHC I, expression on porcine alveolar macrophages in a Salmonella pathogenicity island (SPI-1 and SPI-2 dependent way. Salmonella induced downregulation of MHC II expression and intracellular proliferation of Salmonella in macrophages were significantly impaired after opsonization with Salmonella specific antibodies prior to inoculation. Furthermore, the capacity to downregulate MHC II expression on macrophages differed significantly among Salmonella strains, independently of strain specific differences in invasion capacity, Salmonella induced cytotoxicity and altered macrophage activation status. The fact that strain specific differences in MHC II downregulation did not correlate with the extent of in vitro SPI-1 or SPI-2 gene expression indicates that other factors are involved in MHC II downregulation as well. Since Salmonella strain dependent interference with the pig’s immune response through downregulation of MHC II expression might indicate that certain Salmonella strains are more likely to escape serological detection, our findings are of major interest for Salmonella monitoring programs primarily based on serology.

The JAK2 GGCC (46/1 Haplotype in Myeloproliferative Neoplasms: Causal or Random?

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Luisa Anelli

2018-04-01

Full Text Available The germline JAK2 haplotype known as “GGCC or 46/1 haplotype” (haplotypeGGCC_46/1 consists of a combination of single nucleotide polymorphisms (SNPs mapping in a region of about 250 kb, extending from the JAK2 intron 10 to the Insulin-like 4 (INLS4 gene. Four main SNPs (rs3780367, rs10974944, rs12343867, and rs1159782 generating a “GGCC” combination are more frequently indicated to represent the JAK2 haplotype. These SNPs are inherited together and are frequently associated with the onset of myeloproliferative neoplasms (MPN positive for both JAK2 V617 and exon 12 mutations. The association between the JAK2 haplotypeGGCC_46/1 and mutations in other genes, such as thrombopoietin receptor (MPL and calreticulin (CALR, or the association with triple negative MPN, is still controversial. This review provides an overview of the frequency and the role of the JAK2 haplotypeGGCC_46/1 in the pathogenesis of different myeloid neoplasms and describes the hypothetical mechanisms at the basis of the association with JAK2 gene mutations. Moreover, possible clinical implications are discussed, as different papers reported contrasting data about the correlation between the JAK2 haplotypeGGCC_46/1 and blood cell count, survival, or disease progression.

An MHC-I cytoplasmic domain/HIV-1 Nef fusion protein binds directly to the mu subunit of the AP-1 endosomal coat complex.

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Rajendra Kumar Singh

2009-12-01

Full Text Available The down-regulation of the major histocompatibility complex class I (MHC-I from the surface of infected cells by the Nef proteins of primate immunodeficiency viruses likely contributes to pathogenesis by providing evasion of cell-mediated immunity. HIV-1 Nef-induced down-regulation involves endosomal trafficking and a cooperative interaction between the cytoplasmic domain (CD of MHC-I, Nef, and the clathrin adaptor protein complex-1 (AP-1. The CD of MHC-I contains a key tyrosine within the sequence YSQA that is required for down-regulation by Nef, but this sequence does not conform to the canonical AP-binding tyrosine-based motif Yxxphi, which mediates binding to the medium (micro subunits of AP complexes. We previously proposed that Nef allows the MHC-I CD to bind the mu subunit of AP-1 (micro1 as if it contained a Yxxphimotif.Here, we show that a direct interaction between the MHC-I CD/Nef and micro1 plays a primary role in the down-regulation of MHC-I: GST pulldown assays using recombinant proteins indicated that most of the MHC-I CD and Nef residues that are required for the down-regulation in human cells contribute to direct interactions with a truncated version of micro1. Specifically, the tyrosine residue of the YSQA sequence in the MHC-I CD as well as Nef residues E62-65 and P78 each contributed to the interaction between MHC-I CD/Nef and micro1 in vitro, whereas Nef M20 had little to no role. Conversely, residues F172/D174 and V392/L395 of the binding pocket on micro1 for Yxxphi motifs were required for a robust interaction.These data indicate that the MHC-I cytoplasmic domain, Nef, and the C-terminal two thirds of the mu subunit of AP-1 are sufficient to constitute a biologically relevant interaction. The data also reveal an unexpected role for a hydrophobic pocket in micro1 for interaction with MHC-I CD/Nef.

Grouping preprocess for haplotype inference from SNP and CNV data

International Nuclear Information System (INIS)

Shindo, Hiroyuki; Chigira, Hiroshi; Nagaoka, Tomoyo; Inoue, Masato; Kamatani, Naoyuki

2009-01-01

The method of statistical haplotype inference is an indispensable technique in the field of medical science. The authors previously reported Hardy-Weinberg equilibrium-based haplotype inference that could manage single nucleotide polymorphism (SNP) data. We recently extended the method to cover copy number variation (CNV) data. Haplotype inference from mixed data is important because SNPs and CNVs are occasionally in linkage disequilibrium. The idea underlying the proposed method is simple, but the algorithm for it needs to be quite elaborate to reduce the calculation cost. Consequently, we have focused on the details on the algorithm in this study. Although the main advantage of the method is accuracy, in that it does not use any approximation, its main disadvantage is still the calculation cost, which is sometimes intractable for large data sets with missing values.

Grouping preprocess for haplotype inference from SNP and CNV data

Energy Technology Data Exchange (ETDEWEB)

Shindo, Hiroyuki; Chigira, Hiroshi; Nagaoka, Tomoyo; Inoue, Masato [Department of Electrical Engineering and Bioscience, School of Advanced Science and Engineering, Waseda University, 3-4-1, Okubo, Shinjuku-ku, Tokyo 169-8555 (Japan); Kamatani, Naoyuki, E-mail: masato.inoue@eb.waseda.ac.j [Institute of Rheumatology, Tokyo Women' s Medical University, 10-22, Kawada-cho, Shinjuku-ku, Tokyo 162-0054 (Japan)

2009-12-01

The method of statistical haplotype inference is an indispensable technique in the field of medical science. The authors previously reported Hardy-Weinberg equilibrium-based haplotype inference that could manage single nucleotide polymorphism (SNP) data. We recently extended the method to cover copy number variation (CNV) data. Haplotype inference from mixed data is important because SNPs and CNVs are occasionally in linkage disequilibrium. The idea underlying the proposed method is simple, but the algorithm for it needs to be quite elaborate to reduce the calculation cost. Consequently, we have focused on the details on the algorithm in this study. Although the main advantage of the method is accuracy, in that it does not use any approximation, its main disadvantage is still the calculation cost, which is sometimes intractable for large data sets with missing values.

The E5 protein of human papillomavirus type 16 perturbs MHC class II antigen maturation in human foreskin keratinocytes treated with interferon-γ

International Nuclear Information System (INIS)

Zhang Benyue; Li Ping; Wang Exing; Brahmi, Zacharie; Dunn, Kenneth W.; Blum, Janice S.; Roman, Ann

2003-01-01

Major histocompatibility complex (MHC) class II antigens are expressed on human foreskin keratinocytes (HFKs) following exposure to interferon gamma. The expression of MHC class II proteins on the cell surface may allow keratinocytes to function as antigen-presenting cells and induce a subsequent immune response to virus infection. Invariant chain (Ii) is a chaperone protein which plays an important role in the maturation of MHC class II molecules. The sequential degradation of Ii within acidic endocytic compartments is a key process required for the successful loading of antigenic peptide onto MHC class II molecules. Since human papillomavirus (HPV) 16 E5 can inhibit the acidification of late endosomes in HFKs, the E5 protein may be able to affect proper peptide loading onto the MHC class II molecule. To test this hypothesis, HFKs were infected with either control virus or a recombinant virus expressing HPV16 E5 and the infected cells were subsequently treated with interferon-γ. ELISAs revealed a decrease of MHC class II expression on the surface of E5-expressing cells compared with control virus-infected cells after interferon treatment. Western blot analysis showed that, in cells treated with interferon gamma, E5 could prevent the breakdown of Ii and block the formation of peptide-loaded, SDS-stable mature MHC class II dimers, correlating with diminished surface MHC class II expression. These data suggest that HPV16 E5 may be able to decrease immune recognition of infected keratinocytes via disruption of MHC class II protein function

MHC class I phenotype and function of human beta 2-microglobulin transgenic murine lymphocytes

DEFF Research Database (Denmark)

Bjerager, L; Pedersen, L O; Bregenholt, S

1996-01-01

. Based on data from cellular binding studies, Scatchard analyses and flow cytometry, it is concluded that exogenous h beta 2m does not bind to hybrid MHC class I (MHC-I) molecules composed of mouse heavy chain/h beta 2m molecules expressed on lymphocytes of transgenic mice. Immunoprecipitation and SDS......-PAGE analysis of metabolically labelled normal C57BL/6 lymph node cells showed binding of exogenous h beta 2m to MHC-I, in particular, to the H-2Db molecule through an exchange with endogenous mouse beta 2m. In contrast to normal H-2Db molecules, hybrid H-2Db expressed on the surface of transgenic lymphocytes...... binds radiolabelled peptide in the absence of exogenous added h beta 2m suggesting that a stable fraction of hybrid H-2Db molecules is empty or contain peptides with very low affinity. In a one-way allogenic mixed lymphocyte culture, transgenic splenocytes were found to be far less stimulatory than...

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells

Science.gov (United States)

Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

2015-01-01

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach. PMID:25949869

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells.

Science.gov (United States)

Catalán, Elena; Charni, Seyma; Jaime, Paula; Aguiló, Juan Ignacio; Enríquez, José Antonio; Naval, Javier; Pardo, Julián; Villalba, Martín; Anel, Alberto

2015-01-01

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.

HLA-G regulatory haplotypes and implantation outcome in couples who underwent assisted reproduction treatment.

Science.gov (United States)

Costa, Cynthia Hernandes; Gelmini, Georgia Fernanda; Wowk, Pryscilla Fanini; Mattar, Sibelle Botogosque; Vargas, Rafael Gustavo; Roxo, Valéria Maria Munhoz Sperandio; Schuffner, Alessandro; Bicalho, Maria da Graça

2012-09-01

The role of HLA-G in several clinical conditions related to reproduction has been investigated. Important polymorphisms have been found within the 5'URR and 3'UTR regions of the HLA-G promoter. The aim of the present study was to investigate 16 SNPs in the 5'URR and 14-bp insertion/deletion (ins/del) polymorphism located in the 3'UTR region of the HLA-G gene and its possible association with the implantation outcome in couples who underwent assisted reproduction treatments (ART). The case group was composed of 25 ART couples. Ninety-four couples with two or more term pregnancies composed the control group. Polymorphism haplotype frequencies of the HLA-G were determined for both groups. The Haplotype 5, Haplotype 8 and Haplotype 11 were absolute absence in ART couples. The HLA-G*01:01:02a, HLA-G*01:01:02b alleles and the 14-bp ins polymorphism, Haplotype 2, showed an increased frequency in case women and similar distribution between case and control men. However, this susceptibility haplotype is significantly presented in case women and in couple with failure implantation after treatment, which led us to suggest a maternal effect, associated with this haplotype, once their presence in women is related to a higher number of couples who underwent ART. Copyright © 2012. Published by Elsevier Inc.

Association between the MHC gene region and variation of serum IgE levels against specific mould allergens in the horse

Directory of Open Access Journals (Sweden)

Curik Ino

2003-06-01

Full Text Available Abstract To investigate whether the equine major histocompatibility complex (MHC gene region influences the production of mould-specific immunoglobulin E antibodies (IgE, alleles of the equine leukocyte antigen (ELA-A locus and three microsatellite markers (UM-011, HTG-05 and HMS-42 located on the same chromosome as the equine MHC were determined in 448 Lipizzan horses. Statistical analyses based on composite models, showed significant associations of the ELA-A and UM-011 loci with IgE titres against the recombinant Aspergillus fumigatus 7 antigen (rAsp f 7. UM-011 was also significantly associated with IgE titres against the recombinant Aspergillus fumigatus 8 antigen (rAsp f 8. In addition to the loci mentioned above, the MHC class II DQA and DRA loci were determined in 76 Lipizzans from one stud. For IgE levels against rAsp f 7, the composite model showed the strongest association for DQA (P rAsp f 8 specific IgE levels, similarly to the results found with all 448 horses, the strongest association was found with UM-011 (P = 0.01, which is closely linked with the MHC class II DRB locus. These results suggest that the equine MHC gene region and possibly MHC class II loci, influence the specific IgE response in the horse. However, although the strongest associations were found with DQA and UM-011, this study did not distinguish if the observed effects were due to the MHC itself or to other tightly linked genes.

A caspase-2-RFXANK interaction and its implication for MHC class II expression.

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Forsberg, Jeremy; Li, Xinge; Akpinar, Birce; Salvatori, Roger; Ott, Martin; Zhivotovsky, Boris; Olsson, Magnus

2018-01-23

Despite recent achievements implicating caspase-2 in tumor suppression, the enzyme stands out from the apoptotic caspase family as a factor whose function requires further clarification. To specify enzyme characteristics through the definition of interacting proteins in apoptotic or non-apoptotic settings, a yeast 2-hybrid (Y2H) screen was performed using the full-length protein as bait. The current report describes the analysis of a captured prey and putative novel caspase-2 interacting factor, the regulatory factor X-associated ankyrin-containing protein (RFXANK), previously associated with CIITA, the transactivator regulating cell-type specificity and inducibility of MHC class II gene expression. The interaction between caspase-2 and RFXANK was verified by co-immunoprecipitations using both exogenous and endogenous proteins, where the latter approach suggested that binding of the components occurs in the cytoplasm. Cellular co-localization was confirmed by transfection of fluorescently conjugated proteins. Enhanced caspase-2 processing in RFXANK-overexpressing HEK293T cells treated with chemotherapeutic agents further supported Y2H data. Yet, no distinct differences with respect to MHC class II expression were observed in plasma membranes of antigen-presenting cells derived from wild type and caspase-2 -/- mice. In contrast, increased levels of the total MHC class II protein was evident in protein lysates from caspase-2 RNAi-silenced leukemia cell lines and B-cells isolated from gene-targeted mice. Together, these data identify a novel caspase-2-interacting factor, RFXANK, and indicate a potential non-apoptotic role for the enzyme in the control of MHC class II gene regulation.

Geographical distribution of a specific mitochondrial haplotype of Zymoseptoria tritici

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Sameh BOUKEF

2014-01-01

Full Text Available Severity of disease caused by the fungus Zymoseptoria tritici throughout world cereal growing regions has elicited much debate on the potential evolutionary mechanism conferring high adaptability of the pathogen to diverse climate conditions and different wheat hosts (Triticum durum and T. aestivum. Specific mitochondrial DNA sequence was used to investigate geographic distribution of the type 4 haplotype (mtRFLP4 within 1363 isolates of Z. tritici originating from 21 countries. The mtRFLP4 haplotype was detected from both durum and bread wheat hosts with greater frequency on durum wheat. The distribution of mtRFLP4 was limited to populations sampled from the Mediterranean and the Red Sea region. Greater frequencies of mtRFLP4 were found in Tunisia (87% and Algeria (60%. The haplotype was absent within European, Australian, North and South American populations except Argentina. While alternative hypotheses such as climatic adaptation could not be ruled out, it is postulated that mtRFLP4 originated in North Africa (e.g. Tunisia or Algeria as an adaptation to durum wheat as the prevailing cereal crop. The specialized haplotype has subsequently spread as indicated by lower frequency of occurrence in the surrounding Mediterranean countries and on bread wheat hosts.

Inhibition of MHC-I by Brucella abortus is an early event during infection and involves EGFR pathway.

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Velásquez, Lis N; Milillo, M Ayelén; Delpino, M Victoria; Trotta, Aldana; Mercogliano, M Florencia; Pozner, Roberto G; Schillaci, Roxana; Elizalde, Patricia V; Giambartolomei, Guillermo H; Barrionuevo, Paula

2017-04-01

Brucella abortus is able to persist inside the host despite the development of potent CD8 + T-cell responses. We have recently reported the ability of B. abortus to inhibit the interferon-γ-induced major histocompatibility complex (MHC)-I cell surface expression on human monocytes. This phenomenon was due to the B. abortus-mediated retention of MHC-I molecules within the Golgi apparatus and was dependent on bacterial viability. However, the implications of bacterial virulence or replicative capacity and the signaling pathways remained unknown. Here we demonstrated that the B. abortus mutant strains RB51 and virB10 - are able to inhibit MHC-I expression in the same manner as wild-type B. abortus, even though they are unable to persist inside human monocytes for a long period of time. Consistent with this, the phenomenon was triggered early in time and could be observed at 8 h postinfection. At 24 and 48 h, it was even stronger. Regarding the signaling pathway, targeting epidermal growth factor (EGF) receptor (EGFR), ErbB2 (HER2) or inhibition of tumor necrosis factor-α-converting enzyme, one of the enzymes which generates soluble EGF-like ligands, resulted in partial recovery of MHC-I surface expression. Moreover, recombinant EGF and transforming growth factor-α as well as the combination of both were also able to reproduce the B. abortus-induced MHC-I downmodulation. Finally, when infection was performed in the presence of an extracellular signal-regulated kinase 1/2 (Erk1/2) inhibitor, MHC-I surface expression was significantly recovered. Overall, these results describe how B. abortus evades CD8 + T-cell responses early during infection and exploits the EGFR-ERK signaling pathway to escape from the immune system and favor chronicity.

A community resource benchmarking predictions of peptide binding to MHC-I molecules.

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Peters, Bjoern; Bui, Huynh-Hoa; Frankild, Sune; Nielson, Morten; Lundegaard, Claus; Kostem, Emrah; Basch, Derek; Lamberth, Kasper; Harndahl, Mikkel; Fleri, Ward; Wilson, Stephen S; Sidney, John; Lund, Ole; Buus, Soren; Sette, Alessandro

2006-06-09

Recognition of peptides bound to major histocompatibility complex (MHC) class I molecules by T lymphocytes is an essential part of immune surveillance. Each MHC allele has a characteristic peptide binding preference, which can be captured in prediction algorithms, allowing for the rapid scan of entire pathogen proteomes for peptide likely to bind MHC. Here we make public a large set of 48,828 quantitative peptide-binding affinity measurements relating to 48 different mouse, human, macaque, and chimpanzee MHC class I alleles. We use this data to establish a set of benchmark predictions with one neural network method and two matrix-based prediction methods extensively utilized in our groups. In general, the neural network outperforms the matrix-based predictions mainly due to its ability to generalize even on a small amount of data. We also retrieved predictions from tools publicly available on the internet. While differences in the data used to generate these predictions hamper direct comparisons, we do conclude that tools based on combinatorial peptide libraries perform remarkably well. The transparent prediction evaluation on this dataset provides tool developers with a benchmark for comparison of newly developed prediction methods. In addition, to generate and evaluate our own prediction methods, we have established an easily extensible web-based prediction framework that allows automated side-by-side comparisons of prediction methods implemented by experts. This is an advance over the current practice of tool developers having to generate reference predictions themselves, which can lead to underestimating the performance of prediction methods they are not as familiar with as their own. The overall goal of this effort is to provide a transparent prediction evaluation allowing bioinformaticians to identify promising features of prediction methods and providing guidance to immunologists regarding the reliability of prediction tools.

Characterization of a Nonclassical Class I MHC Gene in a Reptile, the Galápagos Marine Iguana (Amblyrhynchus cristatus)

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Glaberman, Scott; Du Pasquier, Louis; Caccone, Adalgisa

2008-01-01

Squamates are a diverse order of vertebrates, representing more than 7,000 species. Yet, descriptions of full-length major histocompatibility complex (MHC) genes in this group are nearly absent from the literature, while the number of MHC studies continues to rise in other vertebrate taxa. The lack of basic information about MHC organization in squamates inhibits investigation into the relationship between MHC polymorphism and disease, and leaves a large taxonomic gap in our understanding of amniote MHC evolution. Here, we use both cDNA and genomic sequence data to characterize a class I MHC gene (Amcr-UA) from the Galápagos marine iguana, a member of the squamate subfamily Iguaninae. Amcr-UA appears to be functional since it is expressed in the blood and contains many of the conserved peptide-binding residues that are found in classical class I genes of other vertebrates. In addition, comparison of Amcr-UA to homologous sequences from other iguanine species shows that the antigen-binding portion of this gene is under purifying selection, rather than balancing selection, and therefore may have a conserved function. A striking feature of Amcr-UA is that both the cDNA and genomic sequences lack the transmembrane and cytoplasmic domains that are necessary to anchor the class I receptor molecule into the cell membrane, suggesting that the product of this gene is secreted and consequently not involved in classical class I antigen-presentation. The truncated and conserved character of Amcr-UA lead us to define it as a nonclassical gene that is related to the few available squamate class I sequences. However, phylogenetic analysis placed Amcr-UA in a basal position relative to other published classical MHC genes from squamates, suggesting that this gene diverged near the beginning of squamate diversification. PMID:18682845

Characterization of a nonclassical class I MHC gene in a reptile, the Galápagos marine iguana (Amblyrhynchus cristatus.

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Scott Glaberman

Full Text Available Squamates are a diverse order of vertebrates, representing more than 7,000 species. Yet, descriptions of full-length major histocompatibility complex (MHC genes in this group are nearly absent from the literature, while the number of MHC studies continues to rise in other vertebrate taxa. The lack of basic information about MHC organization in squamates inhibits investigation into the relationship between MHC polymorphism and disease, and leaves a large taxonomic gap in our understanding of amniote MHC evolution. Here, we use both cDNA and genomic sequence data to characterize a class I MHC gene (Amcr-UA from the Galápagos marine iguana, a member of the squamate subfamily Iguaninae. Amcr-UA appears to be functional since it is expressed in the blood and contains many of the conserved peptide-binding residues that are found in classical class I genes of other vertebrates. In addition, comparison of Amcr-UA to homologous sequences from other iguanine species shows that the antigen-binding portion of this gene is under purifying selection, rather than balancing selection, and therefore may have a conserved function. A striking feature of Amcr-UA is that both the cDNA and genomic sequences lack the transmembrane and cytoplasmic domains that are necessary to anchor the class I receptor molecule into the cell membrane, suggesting that the product of this gene is secreted and consequently not involved in classical class I antigen-presentation. The truncated and conserved character of Amcr-UA lead us to define it as a nonclassical gene that is related to the few available squamate class I sequences. However, phylogenetic analysis placed Amcr-UA in a basal position relative to other published classical MHC genes from squamates, suggesting that this gene diverged near the beginning of squamate diversification.

Mitochondrial and Y chromosome haplotype motifs as diagnostic markers of Jewish ancestry: a reconsideration.

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Sergio eTofanelli

2014-11-01

Full Text Available Several authors have proposed haplotype motifs based on site variants at the mitochondrial genome (mtDNA and the non-recombining portion of the Y chromosome (NRY to trace the genealogies of Jewish people. Here, we analyzed their main approaches and test the feasibility of adopting motifs as ancestry markers through construction of a large database of mtDNA and NRY haplotypes from public genetic genealogical repositories. We verified the reliability of Jewish ancestry prediction based on the Cohen and Levite Modal Haplotypes in their classical 6 STR marker format or in the extended 12 STR format, as well as four founder mtDNA lineages (HVS-I segments accounting for about 40% of the current population of Ashkenazi Jews. For this purpose we compared haplotype composition in individuals of self-reported Jewish ancestry with the rest of European, African or Middle Eastern samples, to test for non-random association of ethno-geographic groups and haplotypes. Overall, NRY and mtDNA based motifs, previously reported to differentiate between groups, were found to be more represented in Jewish compared to non-Jewish groups. However, this seems to stem from common ancestors of Jewish lineages being rather recent respect to ancestors of non-Jewish lineages with the same haplotype signatures. Moreover, the polyphyly of haplotypes which contain the proposed motifs and the misuse of constant mutation rates heavily affected previous attempts to correctly dating the origin of common ancestries. Accordingly, our results stress the limitations of using the above haplotype motifs as reliable Jewish ancestry predictors and show its inadequacy for forensic or genealogical purposes.

NetMHCpan-4.0: Improved Peptide-MHC Class I Interaction Predictions Integrating Eluted Ligand and Peptide Binding Affinity Data.

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Jurtz, Vanessa; Paul, Sinu; Andreatta, Massimo; Marcatili, Paolo; Peters, Bjoern; Nielsen, Morten

2017-11-01

Cytotoxic T cells are of central importance in the immune system's response to disease. They recognize defective cells by binding to peptides presented on the cell surface by MHC class I molecules. Peptide binding to MHC molecules is the single most selective step in the Ag-presentation pathway. Therefore, in the quest for T cell epitopes, the prediction of peptide binding to MHC molecules has attracted widespread attention. In the past, predictors of peptide-MHC interactions have primarily been trained on binding affinity data. Recently, an increasing number of MHC-presented peptides identified by mass spectrometry have been reported containing information about peptide-processing steps in the presentation pathway and the length distribution of naturally presented peptides. In this article, we present NetMHCpan-4.0, a method trained on binding affinity and eluted ligand data leveraging the information from both data types. Large-scale benchmarking of the method demonstrates an increase in predictive performance compared with state-of-the-art methods when it comes to identification of naturally processed ligands, cancer neoantigens, and T cell epitopes. Copyright © 2017 by The American Association of Immunologists, Inc.

Genetic and molecular characterization of three novel S-haplotypes in sour cherry (Prunus cerasus L.).

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Tsukamoto, Tatsuya; Potter, Daniel; Tao, Ryutaro; Vieira, Cristina P; Vieira, Jorge; Iezzoni, Amy F

2008-01-01

Tetraploid sour cherry (Prunus cerasus L.) exhibits gametophytic self-incompatibility (GSI) whereby the specificity of self-pollen rejection is controlled by alleles of the stylar and pollen specificity genes, S-RNase and SFB (S haplotype-specific F-box protein gene), respectively. As sour cherry selections can be either self-compatible (SC) or self-incompatible (SI), polyploidy per se does not result in SC. Instead the genotype-dependent loss of SI in sour cherry is due to the accumulation of non-functional S-haplotypes. The presence of two or more non-functional S-haplotypes within sour cherry 2x pollen renders that pollen SC. Two new S-haplotypes from sour cherry, S(33) and S(34), that are presumed to be contributed by the P. fruticosa species parent, the complete S-RNase and SFB sequences of a third S-haplotype, S(35), plus the presence of two previously identified sweet cherry S-haplotypes, S(14) and S(16) are described here. Genetic segregation data demonstrated that the S(16)-, S(33)-, S(34)-, and S(35)-haplotypes present in sour cherry are fully functional. This result is consistent with our previous finding that 'hetero-allelic' pollen is incompatible in sour cherry. Phylogenetic analyses of the SFB and S-RNase sequences from available Prunus species reveal that the relationships among S-haplotypes show no correspondence to known organismal relationships at any taxonomic level within Prunus, indicating that polymorphisms at the S-locus have been maintained throughout the evolution of the genus. Furthermore, the phylogenetic relationships among SFB sequences are generally incongruent with those among S-RNase sequences for the same S-haplotypes. Hypotheses compatible with these results are discussed.

β-globin haplotypes in normal and hemoglobinopathic individuals from Reconcavo Baiano, State of Bahia, Brazil

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Wellington dos Santos Silva

2010-01-01

Full Text Available Five restriction site polymorphisms in the β-globin gene cluster (HincII-5'ε, HindIII-Gγ, HindIII-ªγ, HincII-'ψβ1 and HincII-3''ψβ1 were analyzed in three populations (n = 114 from Reconcavo Baiano, State of Bahia, Brazil. The groups included two urban populations from the towns of Cachoeira and Maragojipe and one rural Afro-descendant population, known as the "quilombo community", from Cachoeira municipality. The number of haplotypes found in the populations ranged from 10 to 13, which indicated higher diversity than in the parental populations. The haplotypes 2 (+----,3(----+,4(-+--+and6(-++-+onthe βA chromosomes were the most common, and two haplotypes, 9 (-++++and 14 (++--+, were found exclusively in the Maragojipe population. The other haplotypes (1, 5, 9, 11, 12, 13, 14 and 16 had lower frequencies. Restriction site analysis and the derived haplotypes indicated homogeneity among the populations. Thirty-two individuals with hemoglobinopathies (17 sickle cell disease, 12 HbSC disease and 3 HbCC disease were also analyzed. The haplotype frequencies of these patients differed significantly from those of the general population. In the sickle cell disease subgroup, the predominant haplotypes were BEN (Benin and CAR (Central African Republic, with frequencies of 52.9% and 32.4%, respectively. The high frequency of the BEN haplotype agreed with the historical origin of the afro-descendant population in the state of Bahia. However, this frequency differed from that of Salvador, the state capital, where the CAR and BEN haplotypes have similar frequencies, probably as a consequence of domestic slave trade and subsequent internal migrations to other regions of Brazil.

Endothelial Nitric Oxide Synthase Haplotypes Are Associated with Preeclampsia in Maya Mestizo Women

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Díaz-Olguín, Lizbeth; Coral-Vázquez, Ramón Mauricio; Canto-Cetina, Thelma; Canizales-Quinteros, Samuel; Ramírez Regalado, Belem; Fernández, Genny; Canto, Patricia

2011-01-01

Preeclampsia is a specific disease of pregnancy and believed to have a genetic component. The aim of this study was to investigate if three polymorphisms in eNOS or their haplotypes are associated with preeclampsia in Maya mestizo women. A case-control study was performed where 127 preeclamptic patients and 263 controls were included. Genotyped and haplotypes for the -768T→C, intron 4 variants, Glu298Asp of eNOS were determined by PCR and real-time PCR allelic discrimination. Logistic regression analysis with adjustment for age and body mass index (BMI) was used to test for associations between genotype and preeclampsia under recessive, codominant and dominant models. Pairwise linkage disequilibrium between single nucleotide polymorphisms was calculated by direct correlation r2, and haplotype analysis was conducted. Women homozygous for the Asp298 allele showed an association of preeclampsia. In addition, analysis of the haplotype frequencies revealed that the -786C-4b-Asp298 haplotype was significantly more frequent in preeclamptic patients than in controls (0.143 vs. 0.041, respectively; OR = 3.01; 95% CI = 1.74–5.23; P = 2.9 × 10−4). Despite the Asp298 genotype in a recessive model associated with the presence of preeclampsia in Maya mestizo women, we believe that in this population the -786C-4b-Asp298 haplotype is a better genetic marker. PMID:21897002

Interrelationships between Amerindian tribes of lower Amazonia as manifest by HLA haplotype disequilibria.

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Black, F L

1984-11-01

HLA B-C haplotypes exhibit common disequilibria in populations drawn from four continents, indicating that they are subject to broadly active selective forces. However, the A-B and A-C associations we have examined show no consistent disequilibrium pattern, leaving open the possibility that these disequilibria are due to descent from common progenitors. By examining HLA haplotype distributions, I have explored the implications that would follow from the hypothesis that biological selection played no role in determining A-C disequilibria in 10 diverse tribes of the lower Amazon Basin. Certain haplotypes are in strong positive disequilibria across a broad geographic area, suggesting that members of diverse tribes descend from common ancestors. On the basis of the extent of diffusion of the components of these haplotypes, one can estimate that the progenitors lived less than 6,000 years ago. One widely encountered lineage entered the area within the last 1,200 years. When haplotype frequencies are used in genetic distance measurements, they give a pattern of relationships very similar to that obtained by conventional chord measurements based on several genetic markers; but more than that, when individual haplotype disequilibria in the several tribes are compared, multiple origins of a single tribe are discernible and relationships are revealed that correlate more closely to geographic and linguistic patterns than do the genetic distance measurements.

Protein tyrosine kinases p53/56lyn and p72syk in MHC class I-mediated signal transduction in B lymphoma cells

DEFF Research Database (Denmark)

Pedersen, Anders Elm; Bregenholt, S; Skov, S

1998-01-01

syk are among the tyrosine-phosphorylated proteins. The kinetics of phosphorylation of these kinases after MHC-I crosslinking differ from the kinetics observed after crosslinking of the B cell antigen receptor (BCR). Additional experiments were performed with chicken lyn- and syk-negative DT40 B cells...... mobilization of intracellular free calcium compared with MHC-I crosslinking of wild-type DT40 cells. Thus, expression of BCR at the cell surface is likely to be important for the signal cascade initiated by MHC-I crosslinking. Our data suggest that signal transduction initiated through ligation of the MHC...

The performance of phylogenetic algorithms in estimating haplotype genealogies with migration.

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Salzburger, Walter; Ewing, Greg B; Von Haeseler, Arndt

2011-05-01

Genealogies estimated from haplotypic genetic data play a prominent role in various biological disciplines in general and in phylogenetics, population genetics and phylogeography in particular. Several software packages have specifically been developed for the purpose of reconstructing genealogies from closely related, and hence, highly similar haplotype sequence data. Here, we use simulated data sets to test the performance of traditional phylogenetic algorithms, neighbour-joining, maximum parsimony and maximum likelihood in estimating genealogies from nonrecombining haplotypic genetic data. We demonstrate that these methods are suitable for constructing genealogies from sets of closely related DNA sequences with or without migration. As genealogies based on phylogenetic reconstructions are fully resolved, but not necessarily bifurcating, and without reticulations, these approaches outperform widespread 'network' constructing methods. In our simulations of coalescent scenarios involving panmictic, symmetric and asymmetric migration, we found that phylogenetic reconstruction methods performed well, while the statistical parsimony approach as implemented in TCS performed poorly. Overall, parsimony as implemented in the PHYLIP package performed slightly better than other methods. We further point out that we are not making the case that widespread 'network' constructing methods are bad, but that traditional phylogenetic tree finding methods are applicable to haplotypic data and exhibit reasonable performance with respect to accuracy and robustness. We also discuss some of the problems of converting a tree to a haplotype genealogy, in particular that it is nonunique. © 2011 Blackwell Publishing Ltd.

Three Novel Haplotypes of Theileria bicornis in Black and White Rhinoceros in Kenya.

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Otiende, M Y; Kivata, M W; Jowers, M J; Makumi, J N; Runo, S; Obanda, V; Gakuya, F; Mutinda, M; Kariuki, L; Alasaad, S

2016-02-01

Piroplasms, especially those in the genera Babesia and Theileria, have been found to naturally infect rhinoceros. Due to natural or human-induced stress factors such as capture and translocations, animals often develop fatal clinical piroplasmosis, which causes death if not treated. This study examines the genetic diversity and occurrence of novel Theileria species infecting both black and white rhinoceros in Kenya. Samples collected opportunistically during routine translocations and clinical interventions from 15 rhinoceros were analysed by polymerase chain reaction (PCR) using a nested amplification of the small subunit ribosomal RNA (18S rRNA) gene fragments of Babesia and Theileria. Our study revealed for the first time in Kenya the presence of Theileria bicornis in white (Ceratotherium simum simum) and black (Diceros bicornis michaeli) rhinoceros and the existence of three new haplotypes: haplotypes H1 and H3 were present in white rhinoceros, while H2 was present in black rhinoceros. No specific haplotype was correlated to any specific geographical location. The Bayesian inference 50% consensus phylogram recovered the three haplotypes monophyleticly, and Theileria bicornis had very high support (BPP: 0.98). Furthermore, the genetic p-uncorrected distances and substitutions between T. bicornis and the three haplotypes were the same in all three haplotypes, indicating a very close genetic affinity. This is the first report of the occurrence of Theileria species in white and black rhinoceros from Kenya. The three new haplotypes reported here for the first time have important ecological and conservational implications, especially for population management and translocation programs and as a means of avoiding the transport of infected animals into non-affected areas. © 2014 Blackwell Verlag GmbH.

The putative oncogene Pim-1 in the mouse: its linkage and variation among t haplotypes.

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Nadeau, J H; Phillips, S J

1987-11-01

Pim-1, a putative oncogene involved in T-cell lymphomagenesis, was mapped between the pseudo-alpha globin gene Hba-4ps and the alpha-crystallin gene Crya-1 on mouse chromosome 17 and therefore within the t complex. Pim-1 restriction fragment variants were identified among t haplotypes. Analysis of restriction fragment sizes obtained with 12 endonucleases demonstrated that the Pim-1 genes in some t haplotypes were indistinguishable from the sizes for the Pim-1b allele in BALB/c inbred mice. There are now three genes, Pim-1, Crya-1 and H-2 I-E, that vary among independently derived t haplotypes and that have indistinguishable alleles in t haplotypes and inbred strains. These genes are closely linked within the distal inversion of the t complex. Because it is unlikely that these variants arose independently in t haplotypes and their wild-type homologues, we propose that an exchange of chromosomal segments, probably through double crossingover, was responsible for indistinguishable Pim-1 genes shared by certain t haplotypes and their wild-type homologues. There was, however, no apparent association between variant alleles of these three genes among t haplotypes as would be expected if a single exchange introduced these alleles into t haplotypes. If these variant alleles can be shown to be identical to the wild-type allele, then lack of association suggests that multiple exchanges have occurred during the evolution of the t complex.

Species-specific evolution of class I MHC genes in iguanas (order: Squamata; subfamily: Iguaninae).

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Glaberman, Scott; Caccone, Adalgisa

2008-07-01

Over the last few decades, the major histocompatibility complex (MHC) has emerged as a model for understanding the influence of natural selection on genetic diversity in populations as well as for investigating the genetic basis of host resistance to pathogens. However, many vertebrate taxa remain underrepresented in the field of MHC research, preventing its application to studies of disease, evolution, and conservation genetics in these groups. This is particularly true for squamates, which are by far the most diversified order of non-avian reptiles but have not been the subject of any recent MHC studies. In this paper, we present MHC class I complementary DNA data from three squamate species in the subfamily Iguaninae (iguanas): the Galápagos marine iguana (Amblyrhynchus cristatus), the Galápagos land iguana (Conolophus subcristatus), and the green iguana (Iguana iguana). All sequences obtained are related to the few published class I genes from other squamates. There is evidence for multiple loci in each species, and the conserved alpha-3 domain appears to be evolving in a species-specific manner. Conversely, there is some indication of shared polymorphism between species in the peptide-binding alpha-1 and alpha-2 domains, suggesting that these two regions have different phylogenetic histories. The great similarity between alpha-3 sequences in marine iguanas in particular suggests that concerted evolution is acting to homogenize class I loci within species. However, while less likely, the data are also compatible with a birth and death model of evolution.

Genetic relationships among native americans based on b-globin gene cluster haplotype frequencies

OpenAIRE

Mousinho-Ribeiro Rita de Cassia; Pante-de-Sousa Gabriella; Santos Eduardo José Melo dos; Guerreiro João Farias

2003-01-01

The distribution of b-globin gene haplotypes was studied in 209 Amerindians from eight tribes of the Brazilian Amazon: Asurini from Xingú, Awá-Guajá, Parakanã, Urubú-Kaapór, Zoé, Kayapó (Xikrin from the Bacajá village), Katuena, and Tiriyó. Nine different haplotypes were found, two of which (n. 11 and 13) had not been previously identified in Brazilian indigenous populations. Haplotype 2 (+ - - - -) was the most common in all groups studied, with frequencies varying from 70% to 100%, followed...

Circumsporozoite Protein-Specific Kd-Restricted CD8+ T Cells Mediate Protective Antimalaria Immunity in Sporozoite-Immunized MHC-I-Kd Transgenic Mice

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Jing Huang

2014-01-01

Full Text Available Although the roles of CD8+ T cells and a major preerythrocytic antigen, the circumsporozoite (CS protein, in contributing protective antimalaria immunity induced by radiation-attenuated sporozoites, have been shown by a number of studies, the extent to which these players contribute to antimalaria immunity is still unknown. To address this question, we have generated C57BL/6 (B6 transgenic (Tg mice, expressing Kd molecules under the MHC-I promoter, called MHC-I-Kd-Tg mice. In this study, we first determined that a single immunizing dose of IrPySpz induced a significant level of antimalaria protective immunity in MHC-I-Kd-Tg mice but not in B6 mice. Then, by depleting various T-cell subsets in vivo, we determined that CD8+ T cells are the main mediator of the protective immunity induced by IrPySpz. Furthermore, when we immunized (MHC-I-Kd-Tg × CS-Tg F1 mice with IrPySpz after crossing MHC-I-Kd-Tg mice with PyCS-transgenic mice (CS-Tg, which are unable to mount PyCS-specific immunity, we found that IrPySpz immunization failed to induce protective antimalaria immunity in (MHC-I-Kd-Tg × CS-Tg F1 mice, thus indicating the absence of PyCS antigen-dependent immunity in these mice. These results indicate that protective antimalaria immunity induced by IrPySpz in MHC-I-Kd-Tg mice is mediated by CS protein-specific, Kd-restricted CD8+ T cells.

Selection on MHC class II supertypes in the New Zealand endemic Hochstetter's frog.

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Lillie, Mette; Grueber, Catherine E; Sutton, Jolene T; Howitt, Robyn; Bishop, Phillip J; Gleeson, Dianne; Belov, Katherine

2015-04-13

The New Zealand native frogs, family Leiopelmatidae, are among the most archaic in the world. Leiopelma hochstetteri (Hochstetter's frog) is a small, semi-aquatic frog with numerous, fragmented populations scattered across New Zealand's North Island. We characterized a major histocompatibility complex (MHC) class II B gene (DAB) in L. hochstetteri from a spleen transcriptome, and then compared its diversity to neutral microsatellite markers to assess the adaptive genetic diversity of five populations ("evolutionarily significant units", ESUs). L. hochstetteri possessed very high MHC diversity, with 74 DAB alleles characterized. Extremely high differentiation was observed at the DAB locus, with only two alleles shared between populations, a pattern that was not reflected in the microsatellites. Clustering analysis on putative peptide binding residues of the DAB alleles indicated four functional supertypes, all of which were represented in 4 of 5 populations, albeit at different frequencies. Otawa was an exception to these observations, with only two DAB alleles present. This study of MHC diversity highlights extreme population differentiation at this functional locus. Supertype differentiation was high among populations, suggesting spatial and/or temporal variation in selection pressures. Low DAB diversity in Otawa may limit this population's adaptive potential to future pathogenic challenges.

A class representative model for Pure Parsimony Haplotyping under uncertain data.

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Daniele Catanzaro

Full Text Available The Pure Parsimony Haplotyping (PPH problem is a NP-hard combinatorial optimization problem that consists of finding the minimum number of haplotypes necessary to explain a given set of genotypes. PPH has attracted more and more attention in recent years due to its importance in analysis of many fine-scale genetic data. Its application fields range from mapping complex disease genes to inferring population histories, passing through designing drugs, functional genomics and pharmacogenetics. In this article we investigate, for the first time, a recent version of PPH called the Pure Parsimony Haplotype problem under Uncertain Data (PPH-UD. This version mainly arises when the input genotypes are not accurate, i.e., when some single nucleotide polymorphisms are missing or affected by errors. We propose an exact approach to solution of PPH-UD based on an extended version of Catanzaro et al.[1] class representative model for PPH, currently the state-of-the-art integer programming model for PPH. The model is efficient, accurate, compact, polynomial-sized, easy to implement, solvable with any solver for mixed integer programming, and usable in all those cases for which the parsimony criterion is well suited for haplotype estimation.

Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques.

Directory of Open Access Journals (Sweden)

Joseph L Mankowski

Full Text Available Human immunodeficiency virus (HIV infection frequently causes neurologic disease even with anti-retroviral treatment. Although associations between MHC class I alleles and acquired immunodeficiency syndrome (AIDS have been reported, the role MHC class I alleles play in restricting development of HIV-induced organ-specific diseases, including neurologic disease, has not been characterized. This study examined the relationship between expression of the MHC class I allele Mane-A*10 and development of lentiviral-induced central nervous system (CNS disease using a well-characterized simian immunodeficiency (SIV/pigtailed macaque model. The risk of developing CNS disease (SIV encephalitis was 2.5 times higher for animals that did not express the MHC class I allele Mane-A*10 (P = 0.002; RR = 2.5. Animals expressing the Mane-A*10 allele had significantly lower amounts of activated macrophages, SIV RNA, and neuronal dysfunction in the CNS than Mane-A*10 negative animals (P<0.001. Mane-A*10 positive animals with the highest CNS viral burdens contained SIV gag escape mutants at the Mane-A*10-restricted KP9 epitope in the CNS whereas wild type KP9 sequences dominated in the brain of Mane-A*10 negative animals with comparable CNS viral burdens. These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease.

Association between β2-adrenoceptor (ADRB2) haplotypes and insulin resistance in PCOS.

Science.gov (United States)

Tellechea, Mariana L; Muzzio, Damián O; Iglesias Molli, Andrea E; Belli, Susana H; Graffigna, Mabel N; Levalle, Oscar A; Frechtel, Gustavo D; Cerrone, Gloria E

2013-04-01

The aim of this study was to explore β2-adrenoceptor (ADRB2) haplotype associations with phenotypes and quantitative traits related to insulin resistance (IR) and the metabolic syndrome (MS) in a polycystic ovary syndrome (PCOS) population. A secondary purpose was to assess the association between ADRB2 haplotype and PCOS. Genetic polymorphism analysis. Cross-sectional case-control association study. Medical University Hospital and research laboratory. One hundred and sixty-five unrelated women with PCOS and 116 unrelated women without PCOS (control sample). Clinical and biochemical measurements, and ADRB2 genotyping in PCOS patients and control subjects. ADRB2 haplotypes (comprising rs1042711, rs1801704, rs1042713 and rs1042714 in that order), genotyping and statistical analysis to evaluate associations with continuous variables and traits related to IR and MS in a PCOS population. Associations between ADRB2 haplotypes and PCOS were also assessed. We observed an age-adjusted association between ADRB2 haplotype CCGG and lower insulin (P = 0·018) and HOMA (P = 0·008) in the PCOS sample. Interestingly, the expected differences in surrogate measures of IR between cases and controls were not significant in CCGG/CCGG carriers. In the case-control study, genotype CCGG/CCGG was associated with a 14% decrease in PCOS risk (P = 0·043), taking into account confounding variables. Haplotype I (CCGG) has a protective role for IR and MS in PCOS. © 2012 Blackwell Publishing Ltd.

Regulatory Lymphocytes Are Key Factors in MHC-Independent Resistance to EAE

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Marín, Nieves; Mecha, Miriam; Espejo, Carmen; Mestre, Leyre; Eixarch, Herena; Montalban, Xavier; Álvarez-Cermeño, José C.; Guaza, Carmen; Villar, Luisa M.

2014-01-01

Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35–55 peptide of myelin oligodendrocyte glycoprotein (MOG35−55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35−55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35−55. Accordingly, resistant mice experienced a rise in regulatory B cells (P = 0.001) and, to a lower extent, in regulatory T cells (P = 0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35−55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P = 0.02) and IL-17 (P = 0.009) and higher serum levels of IL-17 (P = 0.04) than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism. PMID:24868560

Regulatory Lymphocytes Are Key Factors in MHC-Independent Resistance to EAE

Directory of Open Access Journals (Sweden)

Nieves Marín

2014-01-01

Full Text Available Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE, an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain and CD1 (resistant outbred strain showing heterogeneous MHC antigens mice were immunized with the 35–55 peptide of myelin oligodendrocyte glycoprotein (MOG35−55. We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35−55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35−55. Accordingly, resistant mice experienced a rise in regulatory B cells (P=0.001 and, to a lower extent, in regulatory T cells (P=0.02 compared with C57BL/6 susceptible mice. As a consequence, MOG35−55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P=0.02 and IL-17 (P=0.009 and higher serum levels of IL-17 (P=0.04 than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism.

Specific blockade by CD54 and MHC II of CD40-mediated signaling for B cell proliferation and survival

DEFF Research Database (Denmark)

Doyle, I S; Hollmann, C A; Crispe, I N

2001-01-01

Regulation of B lymphocyte proliferation is critical to maintenance of self-tolerance, and intercellular interactions are likely to signal such regulation. Here, we show that coligation of either the adhesion molecule ICAM-1/CD54 or MHC II with CD40 inhibited cell cycle progression and promoted...... these effects. Addition of BCR or IL-4 signals did not overcome the effect of ICAM-1 or MHC II on CD40-induced proliferation. FasL expression was not detected in B cell populations. These results show that MHC II and ICAM-1 specifically modulate CD40-mediated signaling, so inhibiting proliferation...

Transcription Factor NF-IL6 (C/EBPbeta) Activates the Expression of the Mouse MHC Class I H2-Kb Gene in Response to TNF-alpha via the Intragenic Downstream Regulatory Element

Czech Academy of Sciences Publication Activity Database

Hatina, J.; Jansa, Petr; Reischig, J.

2002-01-01

Roč. 22, - (2002), s. 741-749 ISSN 1079-9907 R&D Projects: GA MŠk(CZ) LN00A079 Institutional research plan: CEZ:AV0Z5052915 Keywords : Mouse MHC Class I Gene, Intragenic Downstream Regulatory Element Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.885, year: 2002

Brucella abortus down-regulates MHC class II by the IL-6-dependent inhibition of CIITA through the downmodulation of IFN regulatory factor-1 (IRF-1).

Science.gov (United States)

Velásquez, Lis N; Milillo, M Ayelén; Delpino, M Victoria; Trotta, Aldana; Fernández, Pablo; Pozner, Roberto G; Lang, Roland; Balboa, Luciana; Giambartolomei, Guillermo H; Barrionuevo, Paula

2017-03-01

Brucella abortus is an intracellular pathogen capable of surviving inside of macrophages. The success of B. abortus as a chronic pathogen relies on its ability to orchestrate different strategies to evade the adaptive CD4 + T cell responses that it elicits. Previously, we demonstrated that B. abortus inhibits the IFN-γ-induced surface expression of MHC class II (MHC-II) molecules on human monocytes, and this phenomenon correlated with a reduction in antigen presentation. However, the molecular mechanisms, whereby B. abortus is able to down-regulate the expression of MHC-II, remained to be elucidated. In this study, we demonstrated that B. abortus infection inhibits the IFN-γ-induced transcription of MHC-II, transactivator (CIITA) and MHC-II genes. Accordingly, we observed that the synthesis of MHC-II proteins was also diminished. B. abortus was not only able to reduce the expression of mature MHC-II, but it also inhibited the expression of invariant chain (Ii)-associated immature MHC-II molecules. Outer membrane protein 19 (Omp19), a prototypical B. abortus lipoprotein, diminished the expression of MHC-II and CIITA transcripts to the same extent as B. abortus infection. IL-6 contributes to these down-regulatory phenomena. In addition, B. abortus and its lipoproteins, through IL-6 secretion, induced the transcription of the negative regulators of IFN-γ signaling, suppressor of cytokine signaling (SOCS)-1 and -3, without interfering with STAT1 activation. Yet, B. abortus lipoproteins via IL-6 inhibit the expression of IFN regulatory factor 1 (IRF-1), a critical regulatory transcription factor for CIITA induction. Overall, these results indicate that B. abortus inhibits the expression of MHC-II molecules at very early points in their synthesis and in this way, may prevent recognition by T cells establishing a chronic infection. © Society for Leukocyte Biology.

CD4+ T cell-mediated cytotoxicity is associated with MHC class II expression on malignant CD19+ B cells in diffuse large B cell lymphoma.

Science.gov (United States)

Zhou, Yong; Zha, Jie; Lin, Zhijuan; Fang, Zhihong; Zeng, Hanyan; Zhao, Jintao; Luo, Yiming; Li, Zhifeng; Xu, Bing

2018-01-15

Diffuse large B cell lymphoma (DLBCL) is a common B cell malignancy with approximately 30% of patients present relapsed or refractory disease after first-line therapy. Research of further treatment options is needed. Cytotoxic CD4 + T cells express cytolytic molecules and have potential antitumor function. Here, we showed that the CD19 + cells from DLBCL patients presented significantly reduced expression of MHC II molecules than those from healthy controls. Three years after the first-line treatment, patients that presented relapsed disease had significantly lower MHC II expression on their CD19 + cells than patients who did not show recurrence. Examining cytotoxic CD4 + T cells show that DLBCL patients presented significantly elevated frequencies of granzyme A-, granzyme B-, and/or perforin-expressing cytotoxic CD4 + T cells. Also, frequency of cytotoxic CD4 + T cells in DLBCL patients was positively correlated with the MHC II expression level. Subsequently, the cytotoxic potential of CD4 + T cells against autologous CD19 + cells was investigated. We found that the cytotoxic potential of CD4 + T cells was highest in MHC II-high, intermediate in MHC II-mid, and lowest in MHC II-low patients. The percentage of MHC II-expressing viable CD19 + cells presented a significant reduction after longer incubation with cytotoxic CD4 + T cells, suggesting that cytotoxic CD4 + T cells preferentially eliminated MHC II-expressing CD19 + cells. Blocking MHC II on CD19 + cells significantly reduced the cytolytic capacity of CD4 + T cells. Despite these discoveries, the frequency of cytotoxic CD4 + T cells did not predict the clinical outcome of DLBCL patients. Together, these results demonstrated that cytotoxic CD4 + T cells presented an MHC II-dependent cytotoxic potential against autologous CD19 + cells and could potentially represent a future treatment option for DLBCL. Copyright © 2017 Elsevier Inc. All rights reserved.

Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies.

NARCIS (Netherlands)

Pas, J. van der; Hengstman, G.J.D.; Laak, H.J. ter; Borm, G.F.; Engelen, B.G.M. van

2004-01-01

BACKGROUND: Identification of mononuclear cellular infiltrates in skeletal muscle tissue is the histological cornerstone of the diagnosis of idiopathic inflammatory myopathy (IIM). However, these infiltrates are not always present. OBJECTIVE: To determine whether MHC class I antigen expression on

Linking the Y-chromosomal haplotype from a high medieval (1160-1421) skeleton from a Podlazice excavation site with living descendants

Czech Academy of Sciences Publication Activity Database

Votrubová, J.; Sasková, L.; Frolík, Jan; Vaněk, D.

2017-01-01

Roč. 6, December (2017), „e129”-„e131” ISSN 1875-1768 R&D Projects: GA ČR GB14-36938G Institutional support: RVO:67985912 Keywords : Y chromosome haplotype * surname * inheritance * forensics * bone * bioarchaeology * genetics of cemeteries Subject RIV: AC - Archeology, Anthropology, Ethnology OBOR OECD: Archaeology http://www.fsigeneticssup.com/article/S1875-1768(17)30160-9/pdf

Structural and Functional Characterization of a Single-chain Peptide-MHC Molecule that Modulates both Naive and Activated CD8plus T Cells

Energy Technology Data Exchange (ETDEWEB)

D Samanta; G Mukherjee; U Ramagopal; R Chaparro; S Nathenson; T DiLorenzo; S Almo

2011-12-31

Peptide-MHC (pMHC) multimers, in addition to being tools for tracking and quantifying antigen-specific T cells, can mediate downstream signaling after T-cell receptor engagement. In the absence of costimulation, this can lead to anergy or apoptosis of cognate T cells, a property that could be exploited in the setting of autoimmune disease. Most studies with class I pMHC multimers used noncovalently linked peptides, which can allow unwanted CD8{sup +} T-cell activation as a result of peptide transfer to cellular MHC molecules. To circumvent this problem, and given the role of self-reactive CD8{sup +} T cells in the development of type 1 diabetes, we designed a single-chain pMHC complex (scK{sup d}.IGRP) by using the class I MHC molecule H-2K{sup d} and a covalently linked peptide derived from islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP{sub 206-214}), a well established autoantigen in NOD mice. X-ray diffraction studies revealed that the peptide is presented in the groove of the MHC molecule in canonical fashion, and it was also demonstrated that scK{sup d}.IGRP tetramers bound specifically to cognate CD8{sup +} T cells. Tetramer binding induced death of naive T cells and in vitro- and in vivo-differentiated cytotoxic T lymphocytes, and tetramer-treated cytotoxic T lymphocytes showed a diminished IFN-{gamma} response to antigen stimulation. Tetramer accessibility to disease-relevant T cells in vivo was also demonstrated. Our study suggests the potential of single-chain pMHC tetramers as possible therapeutic agents in autoimmune disease. Their ability to affect the fate of naive and activated CD8{sup +} T cells makes them a potential intervention strategy in early and late stages of disease.

Population genetic segmentation of MHC-correlated perfume preferences.

Science.gov (United States)

Hämmerli, A; Schweisgut, C; Kaegi, M

2012-04-01

It has become difficult to find a matching perfume. An overwhelming number of 300 new perfumes launch each year, and marketing campaigns target pre-defined groups based on gender, age or income rather than on individual preferences. Recent evidence for a genetic basis of perfume preferences, however, could be the starting point for a novel population genetic approach to better match perfumes with people's preferences. With a total of 116 participants genotyped for alleles of three loci of the major histocompatibility complex (MHC), the aim of this study was to test whether common MHC alleles could be used as genetic markers to segment a given population into preference types. Significant deviations from random expectations for a set of 10 common perfume ingredients indicate how such segmentation could be achieved. In addition, preference patterns of participants confronted with images that contained a sexual communication context significantly differed in their ratings for some of the scents compared with participants confronted with images of perfume bottles. This strongly supports the assumption that genetically correlated perfume preferences evolved in the context of sexual communication. The results are discussed in the light of perfume customization. © 2011 The Authors. ICS © 2011 Society of Cosmetic Scientists and the Société Française de Cosmétologie.

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide

International Nuclear Information System (INIS)

Feng, Youjun; Qi, Jianxun; Zhang, Huimin; Wang, Jinzi; Liu, Jinhua; Jiang, Fan; Gao, Feng

2005-01-01

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β 2 m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide

Energy Technology Data Exchange (ETDEWEB)

Feng, Youjun [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Graduate School, Chinese Academy of Sciences, Beijing (China); Qi, Jianxun [Graduate School, Chinese Academy of Sciences, Beijing (China); Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Zhang, Huimin; Wang, Jinzi [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); Liu, Jinhua [College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China); Jiang, Fan [Institute of Physics, Chinese Academy of Sciences, Beijing 100080 (China); Gao, Feng, E-mail: gaofeng@im.ac.cn [Laboratory of Molecular Immunology and Molecular Virology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100080 (China); College of Veterinary Medicine, China Agricultural University, Beijing 100094 (China)

2006-01-01

X-ray crystallographic characterization of rhesus macaque MHC Mamu-A*02 complexed with an immunodominant SIV-Gag nonapeptide. Simian immunodeficiency virus (SIV) in the rhesus macaque is regarded as a classic animal model, playing a crucial role in HIV vaccine strategies and therapeutics by characterizing various cytotoxic T-lymphocyte (CTL) responses in macaque monkeys. However, the availability of well documented structural reports focusing on rhesus macaque major histocompatibility complex class I (MHC I) molecules remains extremely limited. Here, a complex of the rhesus macaque MHC I molecule (Mamu-A*02) with human β{sub 2}m and an immunodominant SIV-Gag nonapeptide, GESNLKSLY (GY9), has been crystallized. The crystal diffracts X-rays to 2.7 Å resolution and belongs to space group C2, with unit-cell parameters a = 124.11, b = 110.45, c = 100.06 Å, and contains two molecules in the asymmetric unit. The availability of the structure, which is being solved by molecular replacement, will provide new insights into rhesus macaque MHC I (Mamu-A*02) presenting pathogenic SIV peptides.

Reversible epigenetic down-regulation of MHC molecules by devil facial tumour disease illustrates immune escape by a contagious cancer

DEFF Research Database (Denmark)

Siddle, Hannah V; Kreiss, Alexandre; Tovar, Cesar

2013-01-01

Contagious cancers that pass between individuals as an infectious cell line are highly unusual pathogens. Devil facial tumor disease (DFTD) is one such contagious cancer that emerged 16 y ago and is driving the Tasmanian devil to extinction. As both a pathogen and an allograft, DFTD cells should...... be rejected by the host-immune response, yet DFTD causes 100% mortality among infected devils with no apparent rejection of tumor cells. Why DFTD cells are not rejected has been a question of considerable confusion. Here, we show that DFTD cells do not express cell surface MHC molecules in vitro or in vivo......, MHC class I molecules can be restored to the surface of DFTD cells in vitro by using recombinant devil IFN-γ, which is associated with up-regulation of the MHC class II transactivator, a key transcription factor with deacetylase activity. Further, expression of MHC class I molecules by DFTD cells can...

Bacterial superantigens promote acute nasopharyngeal infection by Streptococcus pyogenes in a human MHC Class II-dependent manner.

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Katherine J Kasper

2014-05-01

Full Text Available Establishing the genetic determinants of niche adaptation by microbial pathogens to specific hosts is important for the management and control of infectious disease. Streptococcus pyogenes is a globally prominent human-specific bacterial pathogen that secretes superantigens (SAgs as 'trademark' virulence factors. SAgs function to force the activation of T lymphocytes through direct binding to lateral surfaces of T cell receptors and class II major histocompatibility complex (MHC-II molecules. S. pyogenes invariably encodes multiple SAgs, often within putative mobile genetic elements, and although SAgs are documented virulence factors for diseases such as scarlet fever and the streptococcal toxic shock syndrome (STSS, how these exotoxins contribute to the fitness and evolution of S. pyogenes is unknown. Here we show that acute infection in the nasopharynx is dependent upon both bacterial SAgs and host MHC-II molecules. S. pyogenes was rapidly cleared from the nasal cavity of wild-type C57BL/6 (B6 mice, whereas infection was enhanced up to ∼10,000-fold in B6 mice that express human MHC-II. This phenotype required the SpeA superantigen, and vaccination with an MHC -II binding mutant toxoid of SpeA dramatically inhibited infection. Our findings indicate that streptococcal SAgs are critical for the establishment of nasopharyngeal infection, thus providing an explanation as to why S. pyogenes produces these potent toxins. This work also highlights that SAg redundancy exists to avoid host anti-SAg humoral immune responses and to potentially overcome host MHC-II polymorphisms.

Fundamental problem of forensic mathematics--the evidential value of a rare haplotype.

Science.gov (United States)

Brenner, Charles H

2010-10-01

Y-chromosomal and mitochondrial haplotyping offer special advantages for criminal (and other) identification. For different reasons, each of them is sometimes detectable in a crime stain for which autosomal typing fails. But they also present special problems, including a fundamental mathematical one: When a rare haplotype is shared between suspect and crime scene, how strong is the evidence linking the two? Assume a reference population sample is available which contains n-1 haplotypes. The most interesting situation as well as the most common one is that the crime scene haplotype was never observed in the population sample. The traditional tools of product rule and sample frequency are not useful when there are no components to multiply and the sample frequency is zero. A useful statistic is the fraction κ of the population sample that consists of "singletons" - of once-observed types. A simple argument shows that the probability for a random innocent suspect to match a previously unobserved crime scene type is (1-κ)/n - distinctly less than 1/n, likely ten times less. The robust validity of this model is confirmed by testing it against a range of population models. This paper hinges above all on one key insight: probability is not frequency. The common but erroneous "frequency" approach adopts population frequency as a surrogate for matching probability and attempts the intractable problem of guessing how many instances exist of the specific haplotype at a certain crime. Probability, by contrast, depends by definition only on the available data. Hence if different haplotypes but with the same data occur in two different crimes, although the frequencies are different (and are hopelessly elusive), the matching probabilities are the same, and are not hard to find. Copyright © 2009 Elsevier Ireland Ltd. All rights reserved.

MHC-like molecules in some nonmammalian vertebrates can be detected by some cross-reactive xenoantisera

DEFF Research Database (Denmark)

Kaufman, J; Skjoedt, K; Salomonsen, J

1990-01-01

in the contact regions between the chains. These latter antibodies recognized biosynthetic intermediates and also a variety of unusual cell surface MHC-like molecules present in reptile and amphibian, but absent in the mammal and chicken cells tested. These included E homodimers whose relationship to chicken B......-G molecules is unknown. 5) MHC-like molecules were identified in a bird, three reptiles, and two amphibians, but no molecules with the expected properties were found with these reagents in any of the fish tested. Udgivelsesdato: 1990-Mar-15...

A Novel Therapeutic Vaccine for Metastatic Mammary Carcinoma: Focusing MHC/Peptide Complexes to Lipid Rafts

Science.gov (United States)

2006-11-01

reportable outcomes). Briefly, the T cell lymphoma EL4 and the immortalized fibroblast cell line DAP (both expressing ova) were used to measure...and Use Committee. Cells , transfections, and antibodies B16.BL6 8.2, A20, EL4 and EL4 /ova were cultured as described (20-22). NIH3T3 cells were...types can donate MHC class I molecules to DC. To determine if the levels of MHC class I on the donor cell affected the efficiency of transfer, EL4 /ova

Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness

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Blöcker Helmut

2009-11-01

Full Text Available Abstract Background Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. Results Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ. Conclusion This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.

Novel Harmful Recessive Haplotypes Identified for Fertility Traits in Nordic Holstein Cattle

Science.gov (United States)

Sahana, Goutam; Nielsen, Ulrik Sander; Aamand, Gert Pedersen; Lund, Mogens Sandø; Guldbrandtsen, Bernt

2013-01-01

Using genomic data, lethal recessives may be discovered from haplotypes that are common in the population but never occur in the homozygote state in live animals. This approach only requires genotype data from phenotypically normal (i.e. live) individuals and not from the affected embryos that die. A total of 7,937 Nordic Holstein animals were genotyped with BovineSNP50 BeadChip and haplotypes including 25 consecutive markers were constructed and tested for absence of homozygotes states. We have identified 17 homozygote deficient haplotypes which could be loosely clustered into eight genomic regions harboring possible recessive lethal alleles. Effects of the identified haplotypes were estimated on two fertility traits: non-return rates and calving interval. Out of the eight identified genomic regions, six regions were confirmed as having an effect on fertility. The information can be used to avoid carrier-by-carrier mattings in practical animal breeding. Further, identification of causative genes/polymorphisms responsible for lethal effects will lead to accurate testing of the individuals carrying a lethal allele. PMID:24376603

Common ADRB2 haplotypes derived from 26 polymorphic sites direct beta2-adrenergic receptor expression and regulation phenotypes.

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Alfredo Panebra

2010-07-01

Full Text Available The beta2-adrenergic receptor (beta2AR is expressed on numerous cell-types including airway smooth muscle cells and cardiomyocytes. Drugs (agonists or antagonists acting at these receptors for treatment of asthma, chronic obstructive pulmonary disease, and heart failure show substantial interindividual variability in response. The ADRB2 gene is polymorphic in noncoding and coding regions, but virtually all ADRB2 association studies have utilized the two common nonsynonymous coding SNPs, often reaching discrepant conclusions.We constructed the 8 common ADRB2 haplotypes derived from 26 polymorphisms in the promoter, 5'UTR, coding, and 3'UTR of the intronless ADRB2 gene. These were cloned into an expression construct lacking a vector-based promoter, so that beta2AR expression was driven by its promoter, and steady state expression could be modified by polymorphisms throughout ADRB2 within a haplotype. "Whole-gene" transfections were performed with COS-7 cells and revealed 4 haplotypes with increased cell surface beta2AR protein expression compared to the others. Agonist-promoted downregulation of beta2AR protein expression was also haplotype-dependent, and was found to be increased for 2 haplotypes. A phylogenetic tree of the haplotypes was derived and annotated by cellular phenotypes, revealing a pattern potentially driven by expression.Thus for obstructive lung disease, the initial bronchodilator response from intermittent administration of beta-agonist may be influenced by certain beta2AR haplotypes (expression phenotypes, while other haplotypes may influence tachyphylaxis during the response to chronic therapy (downregulation phenotypes. An ideal clinical outcome of high expression and less downregulation was found for two haplotypes. Haplotypes may also affect heart failure antagonist therapy, where beta2AR increase inotropy and are anti-apoptotic. The haplotype-specific expression and regulation phenotypes found in this transfection

Vitamin D Receptor Gene Polymorphisms and Haplotypes in Hungarian Patients with Idiopathic Inflammatory Myopathy

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Levente Bodoki

2015-01-01

Full Text Available Idiopathic inflammatory myopathies are autoimmune diseases characterized by symmetrical proximal muscle weakness. Our aim was to identify a correlation between VDR polymorphisms or haplotypes and myositis. We studied VDR-BsmI, VDR-ApaI, VDR-TaqI, and VDR-FokI polymorphisms and haplotypes in 89 Hungarian poly-/dermatomyositis patients (69 females and 93 controls (52 females. We did not obtain any significant differences for VDR-FokI, BsmI, ApaI, and TaqI genotypes and allele frequencies between patients with myositis and healthy individuals. There was no association of VDR polymorphisms with clinical manifestations and laboratory profiles in myositis patients. Men with myositis had a significantly different distribution of BB, Bb, and bb genotypes than female patients, control male individuals, and the entire control group. Distribution of TT, Tt, and tt genotypes was significantly different in males than in females in patient group. According to four-marker haplotype prevalence, frequencies of sixteen possible haplotypes showed significant differences between patient and control groups. The three most frequent haplotypes in patients were the fbAt, FBaT, and fbAT. Our findings may reveal that there is a significant association: Bb and Tt genotypes can be associated with myositis in the Hungarian population we studied. We underline the importance of our result in the estimated prevalence of four-marker haplotypes.

Ligation of major histocompatibility complex class I antigens (MHC-I) prevents apoptosis induced by Fas or SAPK/JNK activation in T-lymphoma cells

DEFF Research Database (Denmark)

Lamberth, K; Claesson, M H

2001-01-01

Early apoptosis in Jurkat T-lymphoma cells was induced by agonistic anti-Fas Ab or by anisomycin which activates the stress kinases SAPK/JNK. Apoptosis was inhibited by ligation of major histocompatibility complex class I antigens (MHC-I). MHC-I ligation induced upregulation of the anti-apoptotic......Early apoptosis in Jurkat T-lymphoma cells was induced by agonistic anti-Fas Ab or by anisomycin which activates the stress kinases SAPK/JNK. Apoptosis was inhibited by ligation of major histocompatibility complex class I antigens (MHC-I). MHC-I ligation induced upregulation of the anti......-apoptotic Bcl-2 protein and stabilized the mitochondrial membrane potential (Deltapsim). MHC-I ligation also prevented downregulation of Bcl-2 and destabilization of Deltapsim induced by anti-Fas Ab treatment or anisomycin exposure. Studies on three different Jurkat cell mutants deficient for src p56(lck), ZAP......-70 kinase, or TCR/CD3 gamma-chain showed that the cells undergo apoptosis after Fas ligation. Anisomycin exposure induced apoptosis in the src p56(lck)-deficient cell line but not in the two other mutant cell lines. Simultaneous cross-linking of MHC-I and Fas ligation inhibited apoptosis in the ZAP...

Repression of MHC class I transcription by HPV16E7 through interaction with a putative RXRβ motif and NF-κB cytoplasmic sequestration

International Nuclear Information System (INIS)

Li, Hui; Zhan, TaiLan; Li, Chang; Liu, Mugen; Wang, Qing K.

2009-01-01

Down-regulation of transcription of the MHC class I genes in HPV16 tumorigenic cells is partly due to HPV16E7 associated with the MHC class I promoter and repressed chromatin activation. In this study, we further demonstrated that HPV16E7 is physically associated with a putative RXRβ binding motif (GGTCA) of the proximal promoter of the MHC class I genes by using reporter transcriptional assays and chromatin immunoprecipitation assays. Our data also provide evidence that HPV16E7 inhibits TNF-α-induced up-regulation of MHC class I transcription by impaired nuclear translocation of NF-κB. More importantly, CaSki tumor cells treated with TSA and transfected with the constitutively active mutant form of IKK-α (which can activate NF-κB directly) showed a maximal level of up-regulation of MHC-I expression. Taken together, our results suggest that HPV16E7 may employ two independent mechanisms to ensure that either the constitutive or inducible transcription of MHC class I genes is down-regulated.

MCP1 haplotypes associated with protection from pulmonary tuberculosis

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Owusu-Dabo Ellis

2011-04-01

Full Text Available Abstract Background The monocyte chemoattractant protein 1 (MCP-1 is involved in the recruitment of lymphocytes and monocytes and their migration to sites of injury and cellular immune reactions. In a Ghanaian tuberculosis (TB case-control study group, associations of the MCP1 -362C and the MCP1 -2581G alleles with resistance to TB were recently described. The latter association was in contrast to genetic effects previously described in study groups originating from Mexico, Korea, Peru and Zambia. This inconsistency prompted us to further investigate the MCP1 gene in order to determine causal variants or haplotypes genetically and functionally. Results A 14 base-pair deletion in the first MCP1 intron, int1del554-567, was strongly associated with protection against pulmonary TB (OR = 0.84, CI 0.77-0.92, Pcorrected = 0.00098. Compared to the wildtype combination, a haplotype comprising the -2581G and -362C promoter variants and the intronic deletion conferred an even stronger protection than did the -362C variant alone (OR = 0.78, CI 0.69-0.87, Pnominal = 0.00002; adjusted Pglobal = 0.0028. In a luciferase reporter gene assay, a significant reduction of luciferase gene expression was observed in the two constructs carrying the MCP1 mutations -2581 A or G plus the combination -362C and int1del554-567 compared to the wildtype haplotype (P = 0.02 and P = 0.006. The associated variants, in particular the haplotypes composed of these latter variants, result in decreased MCP-1 expression and a decreased risk of pulmonary TB. Conclusions In addition to the results of the previous study of the Ghanaian TB case-control sample, we have now identified the haplotype combination -2581G/-362C/int1del554-567 that mediates considerably stronger protection than does the MCP1 -362C allele alone (OR = 0.78, CI 0.69-0.87 vs OR = 0.83, CI 0.76-0.91. Our findings in both the genetic analysis and the reporter gene study further indicate a largely negligible role of the

Extended HLA-D region haplotype associated with celiac disease

Energy Technology Data Exchange (ETDEWEB)

Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

1988-01-01

Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II ..beta..-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this ..beta..-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP ..beta..-chain. This celiac disease-associated HLA-DP ..beta..-chain gene was flanked by HLA-DP ..cap alpha..-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DP..cap alpha..-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP ..cap alpha..- and ..beta..-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion.

Extended HLA-D region haplotype associated with celiac disease

International Nuclear Information System (INIS)

Howell, M.D.; Smith, J.R.; Austin, R.K.; Kelleher, D.; Nepom, G.T.; Volk, B.; Kagnoff, M.F.

1988-01-01

Celiac disease has one of the strongest associations with HLA (human leukocyte antigen) class II markers of the known HLA-linked diseases. This association is primarily with the class II serologic specificities HLA-DR3 and -DQw2. The authors previously described a restriction fragment length polymorphism (RFLP) characterized by the presence of a 4.0-kilobase Rsa I fragment derived from an HLA class II β-chain gene, which distinguishes the class II HLA haplotype of celiac disease patients from those of many serologically matched controls. They now report the isolation of this β-chain gene from a bacteriophage genomic library constructed from the DNA of a celiac disease patient. Based on restriction mapping and differential hybridization with class II cDNA and oligonucleotide probes, this gene was identified as one encoding an HLA-DP β-chain. This celiac disease-associated HLA-DP β-chain gene was flanked by HLA-DP α-chain genes and, therefore, was probably in its normal chromosomal location. The HLA-DPα-chain genes of celiac disease patients also were studied by RFLP analysis. Celiac disease is associated with a subset of HLA-DR3, -DQw2 haplotypes characterized by HLA-DP α- and β-chain gene RFLPs. Within the celiac-disease patient population, the joint segregation of these HLA-DP genes with those encoding the serologic specificities HLA-DR3 and -DQw2 indicates: (i) that the class II HLA haplotype associated with celiac disease is extended throughout the entire HLA-D region, and (ii) that celiac-disease susceptibility genes may reside as far centromeric on this haplotype as the HLA-DP subregion

Mutation Analysis in Classical Phenylketonuria Patients Followed by Detecting Haplotypes Linked to Some PAH Mutations.

Science.gov (United States)

Dehghanian, Fatemeh; Silawi, Mohammad; Tabei, Seyed M B

2017-02-01

Deficiency of phenylalanine hydroxylase (PAH) enzyme and elevation of phenylalanine in body fluids cause phenylketonuria (PKU). The gold standard for confirming PKU and PAH deficiency is detecting causal mutations by direct sequencing of the coding exons and splicing involved sequences of the PAH gene. Furthermore, haplotype analysis could be considered as an auxiliary approach for detecting PKU causative mutations before direct sequencing of the PAH gene by making comparisons between prior detected mutation linked-haplotypes and new PKU case haplotypes with undetermined mutations. In this study, 13 unrelated classical PKU patients took part in the study detecting causative mutations. Mutations were identified by polymerase chain reaction (PCR) and direct sequencing in all patients. After that, haplotype analysis was performed by studying VNTR and PAHSTR markers (linked genetic markers of the PAH gene) through application of PCR and capillary electrophoresis (CE). Mutation analysis was performed successfully and the detected mutations were as follows: c.782G>A, c.754C>T, c.842C>G, c.113-115delTCT, c.688G>A, and c.696A>G. Additionally, PAHSTR/VNTR haplotypes were detected to discover haplotypes linked to each mutation. Mutation detection is the best approach for confirming PAH enzyme deficiency in PKU patients. Due to the relatively large size of the PAH gene and high cost of the direct sequencing in developing countries, haplotype analysis could be used before DNA sequencing and mutation detection for a faster and cheaper way via identifying probable mutated exons.

Divergence at the casein haplotypes in dairy and meat goat breeds.

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Küpper, Julia; Chessa, Stefania; Rignanese, Daniela; Caroli, Anna; Erhardt, Georg

2010-02-01

Casein genes have been proved to have an influence on milk properties, and are in addition appropriate for phylogeny studies. A large number of casein polymorphisms exist in goats, making their analysis quite complex. The four casein loci were analyzed by molecular techniques for genetic polymorphism detection in the two dairy goat breeds Bunte Deutsche Edelziege (BDE; n=96), Weisse Deutsche Edelziege (WDE; n=91), and the meat goat breed Buren (n=75). Of the 35 analyzed alleles, 18 were found in BDE, and 17 in Buren goats and WDE. In addition, a new allele was identified at the CSN1S1 locus in the BDE, showing a frequency of 0.05. This variant, named CSN1S1*A', is characterized by a t-->c transversion in intron 9. Linkage disequilibrium was found at the casein haplotype in all three breeds. A total of 30 haplotypes showed frequencies higher than 0.01. In the Buren breed only one haplotype showed a frequency higher than 0.1. The ancestral haplotype B-A-A-B (in the order: CSN1S1-CSN2-CSN1S2-CSN3) occurred in all three breeds, showing a very high frequency (>0.8) in the Buren.

HLA alleles and haplotypes in Burmese (Myanmarese) and Karen in Thailand.

Science.gov (United States)

Kongmaroeng, C; Romphruk, A; Puapairoj, C; Leelayuwat, C; Kulski, J K; Inoko, H; Dunn, D S; Romphruk, A V

2015-09-01

This is the first report on human leukocyte antigen (HLA) allele and haplotype frequencies at three class I loci and two class II loci in unrelated healthy individuals from two ethnic groups, 170 Burmese and 200 Karen, originally from Burma (Myanmar), but sampled while residing in Thailand. Overall, the HLA allele and haplotype frequencies detected by polymerase chain reaction sequence-specific primer (PCR-SSP) at five loci (A, B, C, DRB1 and DRQB1) at low resolution showed distinct differences between the Burmese and Karen. In Burmese, five HLA-B*15 haplotypes with different HLA-A and HLA-DR/DQ combinations were detected with three of these not previously reported in other Asian populations. The data are important in the fields of anthropology, transplantation and disease-association studies. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Mechanical Stress Downregulates MHC Class I Expression on Human Cancer Cell Membrane

DEFF Research Database (Denmark)

La Rocca, Rosanna; Tallerico, Rossana; Hassan, Almosawy Talib

2014-01-01

In our body, cells are continuously exposed to physical forces that can regulate different cell functions such as cell proliferation, differentiation and death. In this work, we employed two different strategies to mechanically stress cancer cells. The cancer and healthy cell populations were...... treated either with mechanical stress delivered by a micropump (fabricated by deep X-ray nanolithography) or by ultrasound wave stimuli. A specific down-regulation of Major Histocompatibility Complex (MHC) class I molecules expression on cancer cell membrane compared to different kinds of healthy cells...... between 700–1800 cm-1, indicated a relative concentration variation of MHC class I. PCA analysis was also performed to distinguish control and stressed cells within different cell lines. These mechanical induced phenotypic changes increase the tumor immunogenicity, as revealed by the related increased...

Mitochondrial Haplotype Diversity in Zambian Lions: Bridging a Gap in the Biogeography of an Iconic Species.

Science.gov (United States)

Curry, Caitlin J; White, Paula A; Derr, James N

2015-01-01

Analysis of DNA sequence diversity at the 12S to 16S mitochondrial genes of 165 African lions (Panthera leo) from five main areas in Zambia has uncovered haplotypes which link Southern Africa with East Africa. Phylogenetic analysis suggests Zambia may serve as a bridge connecting the lion populations in southern Africa to eastern Africa, supporting earlier hypotheses that eastern-southern Africa may represent the evolutionary cradle for the species. Overall gene diversity throughout the Zambian lion population was 0.7319 +/- 0.0174 with eight haplotypes found; three haplotypes previously described and the remaining five novel. The addition of these five novel haplotypes, so far only found within Zambia, nearly doubles the number of haplotypes previously reported for any given geographic location of wild lions. However, based on an AMOVA analysis of these haplotypes, there is little to no matrilineal gene flow (Fst = 0.47) when the eastern and western regions of Zambia are considered as two regional sub-populations. Crossover haplotypes (H9, H11, and Z1) appear in both populations as rare in one but common in the other. This pattern is a possible result of the lion mating system in which predominately males disperse, as all individuals with crossover haplotypes were male. The determination and characterization of lion sub-populations, such as done in this study for Zambia, represent a higher-resolution of knowledge regarding both the genetic health and connectivity of lion populations, which can serve to inform conservation and management of this iconic species.

Mitochondrial Haplotype Diversity in Zambian Lions: Bridging a Gap in the Biogeography of an Iconic Species.

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Caitlin J Curry

Full Text Available Analysis of DNA sequence diversity at the 12S to 16S mitochondrial genes of 165 African lions (Panthera leo from five main areas in Zambia has uncovered haplotypes which link Southern Africa with East Africa. Phylogenetic analysis suggests Zambia may serve as a bridge connecting the lion populations in southern Africa to eastern Africa, supporting earlier hypotheses that eastern-southern Africa may represent the evolutionary cradle for the species. Overall gene diversity throughout the Zambian lion population was 0.7319 +/- 0.0174 with eight haplotypes found; three haplotypes previously described and the remaining five novel. The addition of these five novel haplotypes, so far only found within Zambia, nearly doubles the number of haplotypes previously reported for any given geographic location of wild lions. However, based on an AMOVA analysis of these haplotypes, there is little to no matrilineal gene flow (Fst = 0.47 when the eastern and western regions of Zambia are considered as two regional sub-populations. Crossover haplotypes (H9, H11, and Z1 appear in both populations as rare in one but common in the other. This pattern is a possible result of the lion mating system in which predominately males disperse, as all individuals with crossover haplotypes were male. The determination and characterization of lion sub-populations, such as done in this study for Zambia, represent a higher-resolution of knowledge regarding both the genetic health and connectivity of lion populations, which can serve to inform conservation and management of this iconic species.

Deletion analysis of male sterility effects of t-haplotypes in the mouse.

Science.gov (United States)

Bennett, D; Artzt, K

1990-01-01

We present data on the effects of three chromosome 17 deletions on transmission ratio distortion (TRD) and sterility of several t-haplotypes. All three deletions have similar effects on male TRD: that is, Tdel/tcomplete genotypes all transmit their t-haplotype in very high proportion. However, each deletion has different effects on sterility of heterozygous males, with TOr/t being fertile, Thp/t less fertile, and TOrl/t still less fertile. These data suggest that wild-type genes on chromosomes homologous to t-haplotypes can be important regulators of both TRD and fertility in males, and that the wild-type genes concerned with TRD and fertility are at least to some extent different. The data also provide a rough map of the positions of these genes.

Self-compatible peach (Prunus persica) has mutant versions of the S haplotypes found in self-incompatible Prunus species.

Science.gov (United States)

Tao, Ryutaro; Watari, Akiko; Hanada, Toshio; Habu, Tsuyoshi; Yaegaki, Hideaki; Yamaguchi, Masami; Yamane, Hisayo

2007-01-01

This study demonstrates that self-compatible (SC) peach has mutant versions of S haplotypes that are present in self-incompatible (SI) Prunus species. All three peach S haplotypes, S (1), S (2), and S (2m), found in this study encode mutated pollen determinants, SFB, while only S (2m) has a mutation that affects the function of the pistil determinant S-RNase. A cysteine residue in the C5 domain of the S (2m)-RNase is substituted by a tyrosine residue, thereby reducing RNase stability. The peach SFB mutations are similar to the SFB mutations found in SC haplotypes of sweet cherry (P. avium) and Japanese apricot (P. mume). SFB (1) of the S (1) haplotype, a mutant version of almond (P. dulcis) S (k) haplotype, encodes truncated SFB due to a 155 bp insertion. SFB (2) of the S (2) and S (2m) haplotypes, both of which are mutant versions of the S (a) haplotype in Japanese plum (P. salicina), encodes a truncated SFB due to a 5 bp insertion. Thus, regardless of the functionality of the pistil determinant, all three peach S haplotypes are SC haplotypes. Our finding that peach has mutant versions of S haplotypes that function in almond and Japanese plum, which are phylogenetically close and remote species, respectively, to peach in the subfamily Prunoideae of the Roasaceae, provides insight into the SC/SI evolution in Prunus. We discuss the significance of SC pollen part mutation in peach with special reference to possible differences in the SI mechanisms between Prunus and Solanaceae.

An ancestral haplotype of the human PERIOD2 gene associates with reduced sensitivity to light-induced melatonin suppression.

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Tokiho Akiyama

Full Text Available Humans show various responses to the environmental stimulus in individual levels as "physiological variations." However, it has been unclear if these are caused by genetic variations. In this study, we examined the association between the physiological variation of response to light-stimulus and genetic polymorphisms. We collected physiological data from 43 subjects, including light-induced melatonin suppression, and performed haplotype analyses on the clock genes, PER2 and PER3, exhibiting geographical differentiation of allele frequencies. Among the haplotypes of PER3, no significant difference in light sensitivity was found. However, three common haplotypes of PER2 accounted for more than 96% of the chromosomes in subjects, and 1 of those 3 had a significantly low-sensitive response to light-stimulus (P < 0.05. The homozygote of the low-sensitive PER2 haplotype showed significantly lower percentages of melatonin suppression (P < 0.05, and the heterozygotes of the haplotypes varied their ratios, indicating that the physiological variation for light-sensitivity is evidently related to the PER2 polymorphism. Compared with global haplotype frequencies, the haplotype with a low-sensitive response was more frequent in Africans than in non-Africans, and came to the root in the phylogenetic tree, suggesting that the low light-sensitive haplotype is the ancestral type, whereas the other haplotypes with high sensitivity to light are the derived types. Hence, we speculate that the high light-sensitive haplotypes have spread throughout the world after the Out-of-Africa migration of modern humans.

Parasites and parallel divergence of the number of individual MHC alleles between sympatric three-spined stickleback Gasterosteus aculeatus morphs in Iceland.

Science.gov (United States)

Natsopoulou, M E; Pálsson, S; Ólafsdóttir, G Á

2012-10-01

Two pairs of sympatric three-spined stickleback Gasterosteus aculeatus morphs and two single morph populations inhabiting mud and lava or rocky benthic habitats in four Icelandic lakes were screened for parasites and genotyped for MHC class IIB diversity. Parasitic infection differed consistently between G. aculeatus from different benthic habitats. Gasterosteus aculeatus from the lava or rocky habitats were more heavily infected in all lakes. A parallel pattern was also found in individual MHC allelic variation with lava G. aculeatus morphs exhibiting lower levels of variation than the mud morphs. Evidence for selective divergence in MHC allele number is ambiguous but supported by two findings in addition to the parallel pattern observed. MHC allele diversity was not consistent with diversity reported at neutral markers (microsatellites) and in Þingvallavatn the most common number of alleles in each morph was associated with lower infection levels. In the Þingvallavatn lava morph, lower infection levels by the two most common parasites, Schistocephalus solidus and Diplostomum baeri, were associated with different MHC allele numbers. © 2012 The Authors. Journal of Fish Biology © 2012 The Fisheries Society of the British Isles.

MHC class II-assortative mate choice in European badgers (Meles meles)

NARCIS (Netherlands)

Sin, Yung Wa; Annavi, Geetha; Newman, Chris; Buesching, Christina D.; Burke, Terry; Macdonald, David W.; Dugdale, Hannah

The major histocompatibility complex (MHC) plays a crucial role in the immune system, and in some species, it is a target by which individuals choose mates to optimize the fitness of their offspring, potentially mediated by olfactory cues. Under the genetic compatibility hypothesis, individuals are

The MHC locus and genetic susceptibility to autoimmune and infectious diseases

NARCIS (Netherlands)

Matzaraki, Vasiliki; Kumar, Vinod; Wijmenga, Cisca; Zhernakova, Alexandra

2017-01-01

In the past 50 years, variants in the major histocompatibility complex (MHC) locus, also known as the human leukocyte antigen (HLA), have been reported as major risk factors for complex diseases. Recent advances, including large genetic screens, imputation, and analyses of non-additive and epistatic

Casein haplotypes and their association with milk production traits in Norwegian Red cattle

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Nome Torfinn

2009-02-01

Full Text Available Abstract A high resolution SNP map was constructed for the bovine casein region to identify haplotype structures and study associations with milk traits in Norwegian Red cattle. Our analyses suggest separation of the casein cluster into two haplotype blocks, one consisting of the CSN1S1, CSN2 and CSN1S2 genes and another one consisting of the CSN3 gene. Highly significant associations with both protein and milk yield were found for both single SNPs and haplotypes within the CSN1S1-CSN2-CSN1S2 haplotype block. In contrast, no significant association was found for single SNPs or haplotypes within the CSN3 block. Our results point towards CSN2 and CSN1S2 as the most likely loci harbouring the underlying causative DNA variation. In our study, the most significant results were found for the SNP CSN2_67 with the C allele consistently associated with both higher protein and milk yields. CSN2_67 calls a C to an A substitution at codon 67 in β-casein gene resulting in histidine replacing proline in the amino acid sequence. This polymorphism determines the protein variants A1/B (CSN2_67 A allele versus A2/A3 (CSN2_67 C allele. Other studies have suggested that a high consumption of A1/B milk may affect human health by increasing the risk of diabetes and heart diseases. Altogether these results argue for an increase in the frequency of the CSN2_67 C allele or haplotypes containing this allele in the Norwegian Red cattle population by selective breeding.

Mass Spectrometry Reveals Changes in MHC I Antigen Presentation After Lentivector Expression of a Gene Regulation System

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Roland Vogel

2013-01-01

Full Text Available The rapamycin-inducible gene regulation system was designed to minimize immune reactions in man and may thus be suited for gene therapy. We assessed whether this system indeed induces no immune responses. The protein components of the regulation system were produced in the human cell lines HEK 293T, D407, and HER 911 following lentiviral transfer of the corresponding genes. Stable cell lines were established, and the peptides presented by major histocompatibility complex class I (MHC I molecules on transduced and wild-type (wt cells were compared by differential mass spectrometry. In all cell lines examined, expression of the transgenes resulted in prominent changes in the repertoire of MHC I-presented self-peptides. No MHC I ligands originating from the transgenic proteins were detected. In vitro analysis of immunogenicity revealed that transduced D407 cells displayed slightly higher capacity than wt controls to promote proliferation of cytotoxic T cells. These results indicate that therapeutic manipulations within the genome of target cells may affect pathways involved in the processing of peptide antigens and their presentation by MHC I. This makes the genomic modifications visible to the immune system which may recognize these events and respond. Ultimately, the findings call attention to a possible immune risk.

B. abortus RNA is the component involved in the down-modulation of MHC-I expression on human monocytes via TLR8 and the EGFR pathway

Science.gov (United States)

Milillo, M. Ayelén; Velásquez, Lis N.; Trotta, Aldana; Delpino, M. Victoria; Balboa, Luciana; Vermeulen, Mónica; Espindola, Sonia L.; Rodriguez-Rodrigues, Nahuel; Fernández, Gabriela C.; Oliveira, Sergio Costa; Giambartolomei, Guillermo H.

2017-01-01

Despite eliciting a potent CD8+ T cell response, Brucella abortus is able to persist and establish a chronic infection inside its host. We have previously reported that the infection of human monocytes/macrophages with B. abortus inhibits the IFN-γ-induced MHC-I cell surface expression down-modulating cytotoxic CD8+ T cell responses. MHC-I down-modulation depends on bacterial viability and results from the capacity of B. abortus to retain the MHC-I molecules within the Golgi apparatus. Furthermore, we recently demonstrated that epidermal growth factor receptor (EGFR) pathway is involved in this phenomenon and that this is an early event during infection. However, the components and mechanisms whereby B. abortus is able to down-modulate MHC-I remained to be elucidated. In this study we demonstrated that the down-modulation of MHC-I expression is not mediated by well-known Brucella virulence factors but instead by B. abortus RNA, a PAMP associated to viability (vita-PAMP). Surprisingly, completely degraded RNA was also able to inhibit MHC-I expression to the same extent as intact RNA. Accordingly, B. abortus RNA and its degradation products were able to mimic the MHC-I intracellular retention within the Golgi apparatus observed upon infection. We further demonstrated that TLR8, a single-stranded RNA and RNA degradation products sensor, was involved in MHC-I inhibition. On the other hand, neutralization of the EGFR reversed the MHC-I inhibition, suggesting a connection between the TLR8 and EGFR pathways. Finally, B. abortus RNA-treated macrophages display diminished capacity of antigen presentation to CD8+ T cells. Overall, our results indicate that the vita-PAMP RNA as well as its degradation products constitute novel virulence factors whereby B. abortus, by a TLR8-dependent mechanism and through the EGFR pathway, inhibits the IFN-γ-induced MHC-I surface expression on human monocytes/macrophages. Thus, bacteria can hide within infected cells and avoid the