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PubMed2003

Polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A: association of five GCT repetitions with Graves' disease in children.

Graves' disease is an autoimmune disease involving a complex interplay of multiple genetic and environmental influences. An association between the disorder and the major histocompatibility complex (MHC; human leukocyte antigen [HLA]) region has long been reported. The major histocompatibility complex class I chain-related gene A (MICA) has a triplet repeat polymorphism in the transmembrane region consisting of six alleles. For this study, the polymorphism in question was analyzed for 129 unrelated children with Graves' disease (97 girls and 32 boys, 10.0 +/- 3.0 years of age) and 396 randomly selected, unrelated subjects (205 females, 191 males, 8.4 +/- 13.5 years of age). The frequencies of genotype A5/A5 and A5/A5.1 were significantly higher in patients than in controls (relative risk [RR] = 2.49, 95% confidence interval [CI] 1.52-4.10, p = 0.00024, pc = 0.0035 and RR = 2.13, 95% CI 1.31-3.47, p = 0.0020, pc = 0.030; respectively). The frequency of genotype A5.1/A5.1 was significantly lower in patients than in controls (RR = 0.09, 95% CI 0.01-0.66, p = 0.0030, pc = 0.044). Allele frequency for allele A5 was significantly higher for children with Graves' disease compared to controls (RR = 2.12; 95% CI = 1.59-2.82; p = 1.9 x 10(-7); pc = 9.5 x 10(-7)). This study demonstrates that MICA allele A5 confers the risk for Graves' disease.

Adolescent↗
PubMed1996

The human gene encoding the heavy chain of the major histocompatibility complex class I-like Fc receptor (FCGRT) maps to 19q13.3.

FcRn is an Fc receptor that structurally resembles the major histocompatibility complex class I molecule. In this study, we isolated the human gene encoding the heavy chain of FcRn (FCGRT) and mapped it by fluorescence in situ hybridization to chromosome band 19q13.3. Thus, like its mouse counterpart, the human FCGRT gene is located outside the major histocompatibility complex.

Animals↗
PubMed1990

Homologies between the major histocompatibility complex of man and cattle: consequences for disease resistance and susceptibility.

The major histocompatibility complex (MHC) of mammals contains a large number of mostly duplicated genes. In the HLA system (the MHC of man), which is by far the best-studied major histocompatibility system so far, roughly 20 genes have been defined and mapped. They code for three classes of proteins: HLA-A, -B and -C (Class I), HLA-DP, -DQ and -DR (Class II) and serum complement components C2, C4 and Bf (Class III). Furthermore, the region contains genes for 21-hydroxylase (21-OH) and tumor necrosis factor (TNF). The MHC thus forms a chromosomal segment containing several clusters of genes of only partially defined biological significance, but ondoubtedly playing a role in disease susceptibility. In view of the recently obtained structural information on BoLA, the MHC of cattle, it is hypothesized that susceptibility to diseases in cattle is associated with BoLA in the same way as human diseases. Finally, new technical and conceptual developments in the field of MHC research and their application to the BoLA system are discussed.

Animals↗
PubMed1993

Failure of a protective major histocompatibility complex class II molecule to delete autoreactive T cells in autoimmune diabetes.

The association of major histocompatibility complex genes with autoimmune diseases is firmly established, but the mechanisms by which these genes confer resistance or susceptibility remain controversial. The controversy extends to the nonobese diabetic (NOD) mouse that develops disease similar to human insulin-dependent diabetes mellitus. The transgenic incorporation of certain class II major histocompatibility complex genes protects NOD mice from diabetes, and clonal deletion or functional silencing of autoreactive T cells has been proposed as the mechanism by which these molecules provide protection. We show that neither thymic deletion nor anergy of autoreactive T cells occurs in NOD mice transgenic for I-Ak. Autoreactive T cells are present, functional, and can transfer diabetes to appropriate NOD-recipient mice.

Animals↗
PubMed1986

Identification of chicken major histocompatibility complex (B) haplotypes by an immunoblot technique.

A means of identifying the major histocompatibility complex (MHC) phenotype of chickens has been developed using solubilised extracts of cell membranes. The proteins from the solubilised membranes are separated by gel electrophoresis, applied to nitrocellulose membranes and detected using specific alloantisera followed by biotin-conjugated secondary antisera and avidin-glucose oxidase complex. This procedure allows samples to be stored frozen for at least 2 years before analysis and in conjunction with Western blotting allows characterisation of the class of MHC-encoded protein identified by the antisera.

Animals↗
PubMed2003

DNA typing revealing high HLA-Cw polymorphism completes availability of major histocompatibility complex loci in forensic medicine.

Studies of human population genetics in Hungary have revealed relevant heterogeneity in the major histocompatibility complex. In the present studies, two isolated ethnic groups were chosen: people living in the Káli Basin westward from the Danube River, and those living in Opusztaszer, a village eastward from Danube, who are known as native ancient Hungarians. Blood samples were collected from 70 people in the Káli Basin and from 45 people in Opusztaszer. The frequency of HLA-Cw alleles was determined by serology as well as by DNA typing in 46 and 32 samples of the two populations, respectively, and in 44 randomly selected subjects of Hungarian origin. Compared with a random population of cadaver donors (the deaths having resulted mostly from accidents or, in a smaller number, strokes or heart infarcts) and voluntary bone marrow donors (typed in the last 10 years) recruited from all parts of Hungary and representing the mixed Hungarian population, remarkable differences were found in haplotype and allele frequencies. HLA-A, -B, -Cw typing was performed by serology and, in the case of the HLA-Cw locus, by polymerase chain reaction (PCR)-SSP and/or PCR-SSOP techniques, as well. The PCR-SSO oligotyping procedure allowed the identification of 32 Cw alleles in contrast with the 9 serologically detectable types. Because of the combination of low antigen expression and the lack of specific serologic reagents of good quality, no HLA-Cw antigens were detectable in 41%, and only one was detected in 48%, of the investigated individuals by standard serologic typing. With PCR-SSO typing, however, 97% of the investigated individuals proved to be heterozygous for HLA-Cw alleles. The two isolated populations differed from each other, from mixed Hungarian and other Caucasian populations in HLA-Cw* allele frequencies, as well as in haplotype distribution. This newly recognized polymorphism at the HLA-Cw locus completes the availability of major histocompatibility complex typing in forensic science and practice.

Cadaver↗
PubMed1992

Long-lived complexes between peptide and class II major histocompatibility complex are formed at low pH with no requirement for pH neutralization.

The binding of peptide antigens to class II histocompatibility glycoproteins can be markedly enhanced at pH values approximating those found in acidic endosomal compartments in antigen-presenting cells (APC). It has been proposed by others that low pH may increase the conformational flexibility of class II, facilitating both the association and dissociation of peptides. Neutralization of pH, as class II is expressed on the plasma membrane of APC, could then serve to trap peptide in a stable complex. If this were the only mechanism accounting for enhanced peptide binding at low pH, one would predict that there should be a concordance between the pH conditions required for enhanced binding and those associated with increased peptide dissociation. Furthermore, long-lived complexes of class II and peptide should not be observed at low pH without neutralization. In the present communization, I provide the data that support the generality of my previous conclusion that both affinity and maximal binding are regulated by pH in experiments using purified class II and biotin-labeled peptides. The pH profile for binding and dissociation using three different class II glycoproteins was analyzed, and the results demonstrated that enhanced binding is not coupled to enhanced dissociation. Peptide complexes were observed to be quite stable at pH 4.5 and above. This result was further substantiated in experiments where biotin-peptide/class II complexes were extensively dialyzed at low pH followed by analysis on Western blots probed with avidin. Finally, a low pH assay system was devised to analyze the formation of stable peptide/class II complexes without pH neutralization. Our results indicate that stable complexes can be formed at low pH without the requirement for a shift to neutral pH.

Amino Acid Sequence↗
PubMed2001

A role for a novel luminal endoplasmic reticulum aminopeptidase in final trimming of 26 S proteasome-generated major histocompatability complex class I antigenic peptides.

Peptides presented to cytotoxic T lymphocytes by the class I major histocompatability complex are 8-11 residues long. Although proteasomal activity generates the precise C termini of antigenic epitopes, the mechanism(s) involved in generation of the precise N termini is largely unknown. To investigate the mechanism of N-terminal peptide processing, we used a cell-free system in which two recombinant ornithine decarboxylase (ODC) constructs, one expressing the native H2-K(b)-restricted ovalbumin (ova)-derived epitope SIINFEKL (ODC-ova) and the other expressing the extended epitope LESIINFEKL (ODC-LEova), were targeted to degradation by 26 S proteasomes followed by import into microsomes. We found that the cleavage specificity of the 26 S proteasome was influenced by the N-terminal flanking amino acids leading to significantly different yields of the final epitope SIINFEKL. Following incubation in the presence of purified 26 S proteasome, ODC-LEova generated largely ESIINFEKL that was efficiently converted to the final epitope SIINFEKL following translocation into microsomes. The conversion of ESIINFEKL to SIINFEKL was strictly dependent on the presence of H2-K(b) and was completely inhibited by the metalloaminopeptidase inhibitor 1,10-phenanthroline. Importantly, the converting activity was resistant to a stringent salt/EDTA wash of the microsomes and was only apparent when transport of TAP, the transporter associated with antigen processing, was facilitated. These results strongly suggest a crucial role for a luminal endoplasmic reticulum-resident metalloaminopeptidase in the N-terminal trimming of major histocompatability complex class I-associated peptides.

Amino Acids↗
PubMed1988

Major histocompatibility complex associations with systemic lupus erythematosus.

This study focused on clinical subsets within systemic lupus erythematosus (SLE) in order to identify more homogeneous patient groups in which to define disease susceptibility gene(s). Analysis of the major histocompatibility complex gene products and genes with major histocompatibility complex class II and class III locus-specific probes and oligonucleotide probes for selected human leukocyte antigen DQ-beta alleles showed significant increases of human leukocyte antigen DR2 and the rare DQ-beta allele DR2-DQw1.AZH in the lupus nephritis patients compared with lupus patients without renal disease (relative risk = 8.3). C4A null was detected in one third of all of the SLE patients. In two thirds of the C4A null patients this was due to a DR3-associated C4A gene deletion. The remaining third may have a regulatory defect and this was DR2-associated. DR4 was significantly decreased in the nephritis patients in comparison with the non-renal SLE patients (relative risk = 0.3). A novel DQ-beta gene has been sequenced from two SLE patients that has not been observed in the normal population. Potential implications of these findings are discussed.

Complement C2↗
PubMed1991

The same CCAAT box-binding factor binds to the promoter of two coordinately regulated major histocompatibility complex class II genes.

Using competition mobility shift, methylation interference, and proteolytic clipping DNA binding assays, we demonstrate that the protein binding the major histocompatibility complex A beta CCAAT box is indistinguishable from the protein previously named NF-Y, which binds the major histocompatibility complex E alpha CCAAT box. Although the two CCAAT boxes share the same 10-base core sequence, termed the Y box, their flanking sequences, known to be important for binding, are very different.

Animals↗
PubMed1989

The major histocompatibility complex and insulin dependent (type 1) diabetes.

The majority of the genetic component in insulin dependent (Type 1) diabetes mellitus can be explained by associations with genes on short arm of chromosome 6 located in the major histocompatibility complex. With the advent of cloning of the HLA Class II region genes it has been possible to refine the previous known association of HLA-DR3 and DR4 with this disease. Strong associations of IDDM have now been shown to exist with the DQB1 gene and/or linked genes, although this does not completely explain the HLA susceptibility to this disease.

DNA↗
PubMed1999

Primary cortical glial reaction versus secondary thalamic glial response in the excitotoxically injured young brain: microglial/macrophage response and major histocompatibility complex class I and II expression.

The excitatory amino acid analog, N-methyl-D-aspartate, was injected intracortically into nine-day-old rats. Resulting axon-sparing lesions in the developing sensorimotor cortex, which secondarily affect thalamic neurons that become deprived of cortical targets, provide an experimental model for the study of the glial response in distantly affected areas. The microglial/macrophage response was studied using tomato lectin histochemistry and major histocompatibility complex I and II immunocytochemistry. Blood-brain barrier integrity was evaluated. In the cortical lesion site, where blood-brain barrier breakdown occurs, the rapid microglial response was restricted to the degenerating area. Microglial changes were first seen at 4 h post-injection, peaking at days 3-5. Reactive microglia changed morphology, increased tomato lectin binding and expressed major histocompatibility complex I. Additionally, some cells expressed major histocompatibility complex II. In the secondarily affected thalamus, the microglial response was not as pronounced as in the cortex, was first seen at 10 h post-injection and peaked at days 3-5. Reactive microglia showed a bushy morphology, were intensely lectin positive and expressed major histocompatibility complex I. The exceptional response of the nine-day-old brain to cortical lesions makes this model an interesting tool for studying the implications of microglial major histocompatibility factor expression in still enigmatic processes such as wound healing and plasticity.

Animals↗
PubMed1985

The major histocompatibility complex of the cynomolgus monkey: absorption analysis of 24 CyLA antisera.

The major histocompatibility complex (MHC) of the cynomolgus monkey consists of at least 35 serologically defined specificities, 14 of which have been assigned to the CyLA-A locus, 10 to the B locus, and six to the newly identified C locus. Selected specificities and antisera were further studied by the analysis of data obtained from absorptions with single donor platelets of known CyLA type. These data confirmed the existence of four groups of cross-reactive specificities identified by serological typing and revealed that three other well-defined specificities could be divided into two or more subtypes. Seven sera were shown to contain two or more populations of distinct, probably noncross-reactive antibodies that could be readily separated by absorption. Of the 24 sera analyzed, only three could be considered likely to contain antibodies reactive with a single CyLA specificity. At least three antibody specificities, after repeated absorption attempts, could not be readily removed by platelets and may reflect poor expression of the determinants on the platelet membrane. The complexity and degree of polymorphism of the CyLA system approaches that known for the human HLA complex. This homology of genetic organization and serologic features provide additional evidence in yet another species for the important role that these systems of alloantigens play in the organism.

Animals↗
PubMed1988

Expression of immunoreactive major histocompatibility complex products in human skeletal muscles.

Immunoreactive class 1 and class 2 major histocompatibility complex gene products (MHCP) and beta 2 microglobulin (beta 2 MG) were demonstrated by microscopic immunocytochemistry in cryostat sections of skeletal muscle biopsies of 67 patients with various neuromuscular diseases. Diagnoses included normal muscle, chronic partial denervation, Duchenne dystrophy, polymyositis, dermatomyositis, inclusion body myositis, and miscellaneous neuromuscular diseases. Normal mature muscle fibers did not express MHCP, but blood vessels showed both class 1 and 2 MHCP and beta 2 MG. Regenerating muscle fibers showed consistent sarcolemmal class 1 MHCP expression irrespective of the disease. In polymyositis, the majority of extrafusal muscle fibers of most patients showed strong sarcolemmal class 1 MHCP expression. In dermatomyositis, muscle fibers situated either in perifascicular or in randomly clustered distribution revealed strong class 1 MHCP reactivity. In inclusion body myositis, scattered small clusters of muscle fibers were positive for class 1 MHCP. In polymyositis and inclusion body myositis, particularly strong class 1 MHCP expression was invariably seen in nonnecrotic muscle fibers partially invaded by lymphocytes whose cytotoxic effects are believed to be class 1 MHCP restricted. Factors or agents that trigger class 1 MHCP expression are presumed also to sensitize lymphocytes to muscle fibers in these diseases, but their identity remains obscure at this time. In dermatomyositis, the expression of MHCP in perifascicular muscle fibers and in areas of capillary loss may represent the triggering of MHCP expression by a nonspecific cellular stress reaction, in this case probably low-grade ischemia.

Adult↗
PubMed1990

Human oligodendrocytes are susceptible to cytolysis by major histocompatibility complex class I-restricted lymphocytes.

The majority of human oligodendrocytes in enriched glial cell cultures expresses class I major histocompatibility complex (MHC) antigens. We used a 51Cr release assay to study the susceptibility of oligodendrocyte-enriched glial cells to MHC-restricted and non-restricted immune-mediated cytolysis. Mitogen-activated mononuclear cells induced significant lysis in a lectin-dependent cytotoxicity assay. Mononuclear cells allo-activated in a one-way mixed lymphocyte culture with E- cells from the glial cell donor induced a significantly higher degree of oligodendrocyte cytolysis than mononuclear cells activated with E- cells bearing MHC-class I antigens discordant with the glia. Cytolysis by alloactivated unfractionated lymphocytes and by purified CD8+ lymphocytes was reduced by an anti-class I antibody (W6/32). Our findings suggest that human oligodendrocytes can be susceptible targets for MHC class I-restricted lysis.

CD4-Positive T-Lymphocytes↗
PubMed2004

Association of major histocompatibility complex II with cholesterol- and sphingolipid-rich membranes precedes peptide loading.

Major histocompatibility complex class II protein (MHC II) molecules present antigenic peptides to CD4-positive T-cells. Efficient T cell stimulation requires association of MHC II with membrane microdomains organized by cholesterol and glycosphingolipids or by tetraspanins. Using detergent extraction at 37 degrees C combined with a modified flotation assay, we investigated the sequence of events leading to the association of MHC II with cholesterol- and glycosphingolipid-rich membranes (DRMs) that are distinct from tetraspanins. We find two stages of association of MHC II with DRMs. In stage one, complexes of MHC II and invariant chain, a chaperone involved in MHC II transport, enter DRMs in the Golgi stack. In early endosomes, these complexes are almost quantitatively associated with DRMs. Upon transport to late endocytic compartments, MHC II-bound invariant chain is stepwise proteolyzed to the MHC class II-associated invariant chain peptide (CLIP) that remains MHC II-bound and retains a preference for DRMs. At the transition between the two stages, CLIP is exchanged against processed antigens, and the resulting MHC II-peptide complexes are transported to the cell surface. In the second stage, MHC II shows a lower overall association with DRMs. However, surface MHC II molecules occupied with peptides that induce resistance to denaturation by SDS are enriched in DRMs relative to SDS-sensitive MHC II-peptide complexes. Likewise, MHC II molecules loaded with long-lived processing products of hen-egg lysozyme containing the immunodominant epitope 48-61 show a very high preference for DRMs. Thus after an initial mainly intracellular stage of high DRM association, MHC II moves to a second stage in which its preference for DRMs is modulated by bound peptides.

Animals↗
PubMed1981

Major histocompatibility complex antigens in rat kidney, ureter, and bladder. Localization with monoclonal antibodies and demonstration of Ia-positive dendritic cells.

Monoclonal mouse xenoantibodies to the SD and part of the Ia antigen complex of the rat major histocompatibility complex (MHC) were raised, and used to localize MHC antigens on frozen sections of kidney, ureter, and bladder of the DA rat strain. The Ia antigens recognized by our monoclonal antibody were located almost entirely within the cells of some, probably the proximal, convoluted tubules of the kidney. The only other Ia-bearing structures were intensely Ia-positive dendritic cells found predominantly in the renal cortex and in the mucosal connective tissues of the ureter and bladder. The SD antigens were widely distributed in the kidney with a major portion again located within the tubular cells, although in the case of SD antigens all tubular cells, including those of the medulla, were positive. By far the brightest tubules were clusters in the outer medulla, probably representing the thick loops of Henle. The endothelium of arterioles, venules and glomerular and interstitial capillaries all stained very brightly for SD antigens. The glomerular mesangium and the interstitial connective tissues of the kidney, ureter, and bladder all gave diffuse positive staining for SD antigens. Transplantation studies established that the tubular Ia and SD antigens of the kidney are produced by the cells and are not in the process of excretion or reabsorption.

Animals↗
PubMed2006

A comparison of variability and population structure for major histocompatibility complex and microsatellite loci in California coastal steelhead (Oncorhynchus mykiss Walbaum).

The major histocompatibility complex (MHC) contains genes integral to immune response in vertebrates. MHC genes have been shown to be under selection in a number of vertebrate taxa, making them intriguing for population genetic studies. We have conducted a survey of genetic variation in an MHC class II gene for steelhead trout from 24 sites in coastal California and compared this variation to that observed at 16 presumably neutral microsatellite loci. A high amount of allelic variation was observed at the MHC when compared to previously published studies on other Pacific salmonids. Elevated nonsynonymous substitutions, relative to synonymous substitutions, were detected at the MHC gene, indicating the signature of historical balancing selection. The MHC data were tested for correlations to and deviations from the patterns found with the microsatellite data. Estimates of allelic richness for the MHC gene and for the microsatellites were positively correlated, as were estimates of population differentiation (F(ST)). An analysis for F(ST) outliers indicates that the MHC locus has an elevated F(ST) relative to the neutral expectation, although a significant result was found for only one particular geographical subgroup. Relatively uniform allele frequency distributions were detected in four populations, although this finding may be partially due to recent population bottlenecks. These results indicate that, at the scale studied here, drift and migration play a major role in the observed geographical variability of MHC genes in steelhead, and that contemporary selection is relatively weak and difficult to detect.

Alleles↗