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At least 991 records · Page 55Linked to original sources
PubMed1998

Sequence variation at the major histocompatibility complex DRB loci in beluga (Delphinapterus leucas) and narwhal (Monodon monoceros).

The variation at loci with similarity to DRB class II major histocompatibility complex loci was assessed in 313 beluga collected from 13 sampling locations across North America, and 11 narwhal collected in the Canadian high Arctic. Variation was assessed by amplification of exon 2, which codes for the peptide binding region, via the polymerase chain reaction, followed by either cloning and DNA sequencing or single-stranded conformation polymorphism analysis. Two DRB loci were identified in beluga: DRB1, a polymorphic locus, and, DRB2, a monomorphic locus. Eight alleles representing five distinct lineages (based on sequence similarity) were found at the beluga DRB1 locus. Although the relative number of alleles is low when compared with terrestrial mammals, the amino acid variation found among the lineages is moderate. At the DRB1 locus, the average number of nonsynonymous substitutions per site is greater than the average number of synonymous substitutions per site (0.0806 : 0.0207, respectively; P<0.01). Most of the 31 amino acid substitutions do not conserve the physiochemical properties of the residue, and 21 of these are located at positions implicated as forming pockets responsible for the selective binding of foreign peptide side chains. Only DRB1 variation was examined in 11 narwhal, revealing a low amount of variation. These data are consistent with an important role for the DRB1 locus in the cellular immune response of beluga. In addition, the ratio of nonsynonymous to synonymous substitutions is similar to that among primate alleles, arguing against a reduction in the balancing selection pressure in the marine environment. Two hypotheses may explain the modest amount of Mhc variation when compared with terrestrial mammals: small population sizes at speciation or a reduced neutral substitution rate in cetaceans.

Alleles↗
PubMed2003

Early cell-mediated immune responses to Marek's disease virus in two chicken lines with defined major histocompatibility complex antigens.

N2a and P2a chickens, resistant and susceptible to Marek's disease (MD), respectively, were used to examine relationships between major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTL) and natural killer (NK)-like cell activity with resistance to infection with Marek's disease virus (MDV). Ten-day-old chickens were infected with MDV and euthanatized at selected times to evaluate for NK cell and MHC-restricted cytotoxicity. The N2a MDV-infected chickens had an early cell-mediated immune response characterized by a sustained NK-like cytotoxicity that coincided with a measurable MHC-cytotoxicity that was lower than controls. Although MHC-restricted and NK cell cytotoxicity was demonstrated in P2a MDV-infected chickens at 8 dpi, both abruptly decreased and remained low for the remainder of the 20-day experiment. The critical time point that may determine the resistance to MD appears to be within the first 2 weeks post-infection. Improvement of the chicken NK cell activity may be a good candidate for both selection and immunomodulation MD control programs.

Animals↗
PubMed1986

Regulation of a transfected human class II major histocompatibility complex gene in human fibroblasts.

To investigate the cis-acting DNA elements that are involved in regulation of class II major histocompatibility complex genes, including gamma-interferon (gamma-IFN) induction, 5' flanking DNA deletions of a DQ beta "minigene" were analyzed in stable transfected cell lines. At least four elements 5' to the gene were found to be involved in DQ beta regulation. Deletion of sequences from -2500 to -159 base pairs (bp) resulted in increased transcription, suggesting that negative regulatory elements resided in the deleted region. These clones were all capable of responding to gamma-IFN. Further deletion of sequences from -159 to -128 bp resulted in constitutive high level transcription and the inability of these constructions to respond to gamma-IFN. A deletion to -107 bp resulted in a decrease in the basal level of expression that was restored by removal of the 5' DNA sequence to -82 bp, suggesting the presence of a second negative element. Finally, deletion to -64 bp caused a marked decrease in expression, suggesting the loss of an element necessary for high levels of transcription. The gamma-IFN control and the transcription control elements contain the conserved upstream sequences found in all class II genes, suggesting a role for these sequences.

Fibroblasts↗
PubMed2005

A high-resolution linkage-disequilibrium map of the human major histocompatibility complex and first generation of tag single-nucleotide polymorphisms.

Autoimmune, inflammatory, and infectious diseases present a major burden to human health and are frequently associated with loci in the human major histocompatibility complex (MHC). Here, we report a high-resolution (1.9 kb) linkage-disequilibrium (LD) map of a 4.46-Mb fragment containing the MHC in U.S. pedigrees with northern and western European ancestry collected by the Centre d'Etude du Polymorphisme Humain (CEPH) and the first generation of haplotype tag single-nucleotide polymorphisms (tagSNPs) that provide up to a fivefold increase in genotyping efficiency for all future MHC-linked disease-association studies. The data confirm previously identified recombination hotspots in the class II region and allow the prediction of numerous novel hotspots in the class I and class III regions. The region of longest LD maps outside the classic MHC to the extended class I region spanning the MHC-linked olfactory-receptor gene cluster. The extended haplotype homozygosity analysis for recent positive selection shows that all 14 outlying haplotype variants map to a single extended haplotype, which most commonly bears HLA-DRB1*1501. The SNP data, haplotype blocks, and tagSNPs analysis reported here have been entered into a multidimensional Web-based database (GLOVAR), where they can be accessed and viewed in the context of relevant genome annotation. This LD map allowed us to give coordinates for the extremely variable LD structure underlying the MHC.

Haplotypes↗
PubMed1993

Immunosuppressive activity of macrophages in mice undergoing graft-versus-host reaction due to major histocompatibility complex class I plus II difference.

In a previous report, we showed that the injection of parental CD4+ T cells into major histocompatibility complex (MHC) class II disparate F1 hybrid mice induces autoimmune-like graft versus-host reaction (GVHR) resembling systemic lupus erythematosus (SLE) and the hepatic lesion of primary biliary cirrhosis (PBC). In the present study, we examined whether or not simultaneous or subsequent injection of CD8+ T cells changes the GVHR form. When parental CD8+ T cells together with CD4+ T cells were injected into MHC class I plus class II-disparate F1 mice, autoimmune phenomena did not develop and alternatively a profound immunosuppressive state was induced. Furthermore, ongoing autoimmune-like GVHR induced by CD4+ T cells was also suppressed by later injection of CD8+ T cells. In these mice, an increase of donor type CD8+ T cells and a marked decrease of host B and T cells in the spleen were observed. The spleen cells from these mice strongly inhibited the mitogenic response of normal spleen cells against lipopolysaccharide (LPS). In vitro studies demonstrated that this immunosuppression was not induced by CD8+ T cells themselves but by macrophages which produced suppressive factor(s) by LPS stimulation. These findings were discussed with reference to suppressive mechanisms of GVHR.

Animals↗
PubMed1989

Prevention of experimental encephalomyelitis with peptides that block interaction of T cells with major histocompatibility complex proteins.

Two synthetic immunodominant and nonencephalitogenic peptides of myelin basic protein, N1-20 and AcN9-20, effectively compete with an encephalitogenic peptide, AcN1-11, in an in vitro T-cell response restricted by class II major histocompatibility complex products (I-Au). These mutant peptide constructs, which do not occur in nature, also compete with the self-antigen for the in vivo induction of T cells primed with the encephalitogen AcN1-11. By using these nonpathogenic competitor peptides, it is possible to prevent the development of a prototypic T-cell-mediated autoimmune disease, experimental allergic encephalomyelitis. These results suggest possibilities for the utilization of competitor peptides for therapy of T-cell-mediated autoimmune diseases linked to specific major histocompatibility complex genes.

Amino Acid Sequence↗
PubMed1985

Restriction fragment length polymorphism of the major histocompatibility complex of the pig.

Human HLA cDNA probes were used to analyze the restriction fragment length polymorphism (RFLP) of the SLA major histocompatibility complex in swine. Cellular genomic DNA from 19 SLA homozygous pigs representing 13 different haplotypes was digested with restriction endonucleases Eco R1, Hind III, or Bam H1, separated by electrophoresis, and transferred onto diazobenzyloxymethyl paper by the Southern blot technique. The blots were probed with 32P-labeled class I or beta-DR class II cDNA. Depending on the haplotypes and the endonucleases used, seven to ten restriction fragments hybridized with the class I probe, and five to seven with the beta-DR probe. Their sizes ranged from 3.4 to 22 kilobase-pairs. Few bands were common to all 13 haplotypes. With all but one haplotype, identical autoradiogram patterns were obtained from unrelated, but phenotypically SLA-identical pigs, suggesting that most of the RFLP revealed were controlled by the SLA region. Further polymorphism was found in a group of seven unrelated pigs which typed serologically as SLA A15 C1 B18 homozygotes but could be divided into two subgroups, with five animals in one subgroup and two in the other, when the genomic DNA was hybridized with the class I probe. When the class II beta-DR probe was tested on the same seven pigs, another subdivision was seen, and this correlated with MLR data. These results demonstrate that HLA class I and class II probes can be used to identify certain well-established SLA haplotypes and to identify subclasses within at least one SLA haplotype.

Animals↗
PubMed1998

Characterization of a human lysophosphatidic acid acyltransferase that is encoded by a gene located in the class III region of the human major histocompatibility complex.

Sequence analysis of cDNA clones corresponding to a number of genes located in the class III region of the human major histocompatibility complex (MHC), in the chromosome band 6p21.3, has shown that the G15 gene encodes a 283-amino acid polypeptide with significant homology over the entire polypeptide with the enzyme lysophosphatidic acid acyltransferase (LPAAT) from different yeast, plant, and bacterial species. The amino acid sequence of the MHC-encoded human LPAAT (hLPAATalpha) is 48% identical to the recently described hLPAAT (Eberhardt, C., Gray, P. W., and Tjoelker, L. W. (1997) J. Biol. Chem. 272, 20299-20305), which is encoded by a gene located on chromosome 9p34.3. LPAAT is the enzyme that in lipid metabolism converts lysophosphatidic acid (LPA) into phosphatidic acid (PA). The expression of the hLPAATalpha polypeptide in the baculovirus system and in mammalian cells has shown that it is an intracellular protein that contains LPAAT activity. Cell extracts from insect cells overexpressing hLPAATalpha were analyzed in different LPAAT enzymatic assays using, as substrates, different acyl acceptors and acyl donors. These cell extracts were found to contain up to 5-fold more LPAAT activity compared with control cell extracts, indicating that the hLPAATalpha specifically converts LPA into PA, incorporating different acyl-CoAs with different affinities. The hLPAATalpha polypeptide expressed in the mammalian Chinese hamster ovary cell line was found, by confocal immunofluorescence, to be localized in the endoplasmic reticulum. Due to the known role of LPA and PA in intracellular signaling and inflammation, the hLPAATalpha gene represents a candidate gene for some MHC-associated diseases.

Acyltransferases↗
PubMed2003

An ordered BAC contig map of the equine major histocompatibility complex.

A physical map of ordered bacterial artificial chromosome (BAC) clones was constructed to determine the genetic organization of the horse major histocompatibility complex. Human, cattle, pig, mouse, and rat MHC gene sequences were compared to identify highly conserved regions which served as source templates for the design of overgo primers. Thirty-five overgo probes were designed from 24 genes and used for hybridization screening of the equine USDA CHORI 241 BAC library. Two hundred thirty-eight BAC clones were assembled into two contigs spanning the horse MHC region. The first contig contains the MHC class II region and was reduced to a minimum tiling path of nine BAC clones that span approximately 800 kb and contain at least 20 genes. A minimum tiling path of a second contig containing the class III/I region is comprised of 14 BAC clones that span approximately 1.6 Mb and contain at least 34 genes. Fluorescence in situ hybridization (FISH) using representative clones from each of the three regions of the MHC localized the contigs onto ECA20q21 and oriented the regions relative to one another and the centromere. Dual-colored FISH revealed that the class I region is proximal to the centromere, the class II region is distal, and the class III region is located between class I and II. These data indicate that the equine MHC is a single gene-dense region similar in structure and organization to the human MHC and is not disrupted as in ruminants and pigs.

Animals↗
PubMed1994

Investigating the genetic basis for ankylosing spondylitis. Linkage studies with the major histocompatibility complex region.

OBJECTIVE: To assess the hypothesis that B27 or a gene(s) in close proximity (e.g., within or near the major histocompatibility complex [MHC]) represents a disease-causing ankylosing spondylitis (AS) gene, and therefore contributes directly to the pathogenesis of this disorder. METHODS: MHC haplotypes were determined by both serologic and molecular analyses in 15 multiple-case AS families from Toronto and Newfoundland. Segregation of MHC haplotypes with AS within these families was examined by linkage and identity-by-descent analyses. Attributable risk estimates for various genetic markers and for sex were calculated. RESULTS: Linkage analyses established significant linkage between AS and the MHC, the maximal logarithm of odds (LOD) score being 3.48 at a recombination frequency (O) of 0.05. In a second analysis in which the population association of the MHC gene HLA-B27 with AS was taken into account, the maximal LOD score was 7.5 at O = 0.05. Identity-by-descent analyses showed a significant departure from random segregation among affected avuncular (P < 0.05) and cousin (P < 0.01) pairs. The presence of HLA-B40 in HLA-B27 positive individuals increased the risk for disease more than 3-fold, confirming previous reports. Disease susceptibility modeling suggested an autosomal dominant pattern of inheritance, with penetrance of approximately 20%. CONCLUSION: These data provide the first conclusive demonstration of linkage between the MHC region and AS, and confirm that genes within this region contribute directly to the genetic susceptibility for AS.

Adolescent↗
PubMed1990

Differential expression of class I major histocompatibility complex determinants by lymphoblastic leukemia-lymphoma cell lines.

Two T-cell lines (XR11-4T and XR11-5T), established from radiation-induced, murine lymphoblastic lymphomas, were examined for the expression of class I major histocompatibility complex antigen and tumor induction. These cell lines expressed class I private determinants, H-2.9 and H-2.26, but not the monomorphic determinant defined by monoclonal antibody M1/42. Both cell lines produced tumors in syngeneic and allogeneic hosts. The monomorphic determinant could be demonstrated on both cell lines following growth in allogeneic (BALB/c mice) but not in syngeneic (RFM mice) hosts. The re-expressed determinant present on cells following growth in allogeneic mice was not of host origin. Thus, tumorigenic x irradiation may differentially affect the expression of class I major histocompatibility complex determinants.

Animals↗
PubMed1988

Microrecombinations generate sequence diversity in the murine major histocompatibility complex: analysis of the Kbm3, Kbm4, Kbm10, and Kbm11 mutants.

The mechanism that generates spontaneous mutants of the Kb histocompatibility gene was analyzed. Nucleotide sequence analysis of four mutant genes (Kbm3, Kbm4, Kbm10, and Kbm11) revealed that each mutant K gene contains clustered, multiple nucleotide substitutions. Hybridization analyses of parental B6 genomic DNA and cloned class I genes with mutant-specific oligonucleotide probes, followed by sequence analyses, have identified major histocompatibility complex class I genes in the K, D, and Tla regions (K1, Db, and T5, respectively) that contain the exact sequences as substituted into mutant Kb genes. These data provide evidence for the hypothesis that the mutant Kb genes are generated by a microrecombination (gene conversion) mechanism that results in the transfer of small DNA segments from class I genes of all four regions of the major histocompatibility complex (K, D, Qa, and Tla) to Kb. Many of the nucleotides substituted into the mutant Kb genes were identical to those found in other naturally occurring K alleles such as Kd. Thus, we propose that the accumulation of microrecombination products within the K genes of a mouse population is responsible for the high sequence diversity among H-2 alleles.

Alleles↗
PubMed1979

Mast cell membrane antigens and Fc receptors in anaphylaxis. I. Products of the major histocompatibility complex involved in alloantibody-induced mast cell activation.

Mast cell membrane antigens, coded by the K, I and D regions of the major histocompatibility complex of the mouse, were investigated for their presence at the cell surface and their participation in alloantibody-induced anaphylactic degranulation (DAAD). Anti-H-2 K, as well as anti-H-2 D antibodies were found to elicit DAAD. Recognition, on the mast cell membrane, of any product of the K or the D regions, either as the whole molecule, or as public or private antigens only, or even as a single private specificity, enabled alloimmune sera to trigger mast cell degranulation. By contrast, anti-Ia antibodies failed to elicit DAAD. By the autoradiographic technique, peritoneal mast cells were found to constitute a single homogeneous population, bearing H-2 D-coded antigens, although in smaller amounts than other peritoneal cells, but no Ia antigens or, if any, in much smaller amounts than other peritoneal cell type. These findings bring new evidence that mast cell alloantigens do participate in anaphylactic alloantibody-induced mast cell degranulation, by allowing bridging of (one?) Fc receptor with H-2 molecules.

Anaphylaxis↗
PubMed2006

Major histocompatibility complex class I chain-related gene A polymorphisms and extended haplotypes are associated with familial alopecia areata.

Alopecia areata (AA) is characterized by hair loss in patches and may progress to total loss of scalp hair, or total loss of scalp and body hair. The major histocompatibility complex (HLA) is associated with susceptibility to AA, as well as other autoimmune diseases. In addition to HLA molecules, non-HLA molecules including the major histocompatibility complex class I chain-related gene A (MICA), a stress-inducible antigen, are also associated with several autoimmune diseases. To investigate associations between AA and the HLA loci, two genes and eight microsatellite markers spanning the HLA region were genotyped. MICA(*)6 was significantly associated with all phenotypes of AA (P=0.0083), whereas MICA(*)5.1 was significantly associated with patchy AA (P=0.029). Extended haplotype analysis shows the significant associations of haplotypes HLA-DQ1-DR6-MICA(*)5.1 (P=0.004) and HLA-DQB1*0201-DR3-MICA(*)5.1 (P=0.009) with AA. These results suggest that MICA is both a potential candidate gene and part of an extended HLA haplotype that may contribute to susceptibility to and severity of AA.

Alleles↗
PubMed1991

Defective assembly of class I major histocompatibility complex molecules in an embryonic cell line.

Developmentally regulated expression of the products of the major histocompatibility complex (MHC) is thought to play a key role in maternal tolerance of the fetal allograft. Here we analyze a cell line (EE2H3), derived from early post-implantation-stage mouse embryos, that is defective for MHC class I assembly. To follow expression of a single well-defined class I product, we introduced the H-2Dd gene under control of the human beta-actin promoter. We found that the transfected EE2H3 cells expressed abundant levels of H-2Dd heavy chains and beta 2-microglobulin protein, but only small amounts of H-2Dd surface protein. Surface expression was rescued by the addition of an appropriate antigenic peptide, or by culturing the cells at low temperature. The phenotype exhibited by EE2H3 is thus remarkably similar to that described for class I-negative somatic cell variants selected using antibodies and complement. However, a striking difference was that surface expression in H-2Dd-transfected EE2H3 cells was markedly enhanced in response to treatment with interferon. Thus, we have identified a novel class I assembly-defective cell line. Considering that EE2H3 was established from primary cultures of mouse embryo cells without immunoselection, and is therefore likely to represent a cell population normally present in post-implantation-stage embryos, these findings raise the possibility that expression of class I surface antigens during early development may in part be controlled post-translationally at the level of MHC class I assembly.

Animals↗
PubMed1994

Ly-49-independent inhibition of natural killer cell-mediated cytotoxicity by a soluble major histocompatibility complex class I molecule.

Natural killer (NK) cells lyse their targets in a non-major histocompatibility complex (MHC)-restricted manner, and the cytotoxicity can be inhibited by a number of MHC class I allele products, suggesting that NK cells may have a "positive receptor" that recognizes the target and a "negative receptor" that receives an inhibitory signal from class I. Since negative receptors could also exert their effect by masking a positive ligand, we have determined whether there may be a direct interaction between class I and an NK surface receptor by measuring cytotoxicity in the presence of a soluble class I molecule, Kd. Soluble Kd at micromolar concentrations could efficiently block NK cell cytotoxicity, suggesting that class I has a direct effect on cytotoxicity, rather than masking another target cell ligand. Inhibition required that Kd be at least divalent, probably because of its higher affinity or its ability to cross-link the NK surface receptor. In addition, the effect was independent of the peptide used to load Kd, and there was inhibition of cytotoxicity of NK cells derived from either H-2d or H-2b mice. Finally, depletion of NK cells expressing Ly-49 had no effect on the specific inhibition by Kd, raising the possibility that NK cells are endowed with additional negative receptors besides Ly-49. Taken together, these results suggest that there may be a family of NK receptors recognizing different class I alleles, which can receive negative signals by directly binding to class I on the target cell surface.

Animals↗
PubMed1999

Soluble, high-affinity dimers of T-cell receptors and class II major histocompatibility complexes: biochemical probes for analysis and modulation of immune responses.

T cell receptors (TCR) and major histocompatibility complex (MHC) molecules are integral membrane proteins that have central roles in cell-mediated immune recognition. Therefore, soluble analogs of these molecules would be useful for analyzing and possibly modulating antigen-specific immune responses. However, due to the intrinsic low-affinity and inherent solubility problems, it has been difficult to produce soluble high-affinity analogs of TCR and class II MHC molecules. This report describes a general approach which solves this intrinsic low-affinity by constructing soluble divalent analogs using IgG as a molecular scaffold. The divalent nature of the complexes increases the avidity of the chimeric molecules for cognate ligands. The generality of this approach was studied by making soluble divalent analogs of two different classes of proteins, a TCR (2C TCR2Ig) and a class II MHC (MCCI-Ek2Ig) molecule. Direct flow cytometry assays demonstrate that the divalent 2C TCR2Ig chimera retained the specificity of the native 2C TCR, while displaying increased avidity for cognate peptide/MHC ligands, resulting in a high-affinity probe capable of detecting interactions that heretofore have only been detected using surface plasmon resonance. TCR2IgG was also used in immunofluorescence studies to show ER localization of intracellular peptide-MHC complexes after peptide feeding. MCCI-Ek2Ig chimeras were able to both stain and activate an MCC-specific T cell hybridoma. Construction and expression of these two diverse heterodimers demonstrate the generality of this approach. Furthermore, the increased avidity of these soluble divalent proteins makes these chimeric molecules potentially useful in clinical settings for probing and modulating in vivo cellular responses.

Base Sequence↗