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Results for “Major Histocompatibility Complex”

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PubMed1993

Nonimmune thyroid destruction results from transgenic overexpression of an allogeneic major histocompatibility complex class I protein.

The overexpression of major histocompatibility complex (MHC) class I molecules in endocrine epithelial cells is an early feature of autoimmune thyroid disease and insulin-dependent diabetes mellitus, which may reflect a cellular response, e.g., to viruses or toxins. Evidence from a transgenic model in pancreatic beta cells suggests that MHC class I overexpression could play an independent role in endocrine cell destruction. We demonstrate in this study that the transgenic overexpression of an allogeneic MHC class I protein (H-2Kb) linked to the rat thyroglobulin promoter, in H-2Kk mice homozygous for the transgene, leads to thyrocyte atrophy, hypothyroidism, growth retardation, and death. Thyrocyte atrophy occurred in the absence of lymphocytic infiltration. Tolerance to allogeneic class I was revealed by the reduced ability of primed lymphocytes from transgenic mice to lyse H-2Kb target cells in vitro. This nonimmune form of thyrocyte destruction and hypothyroidism recapitulates the beta-cell destruction and diabetes that results from transgenic overexpression of MHC class I molecules in pancreatic beta cells. Thus, we conclude that overexpression of MHC class I molecules may be a general mechanism that directly impairs endocrine epithelial cell viability.

Animals↗
PubMed1989

[Genetic analysis of the class II region of rat major histocompatibility complex (RT1)].

Class II subregions of rat major histocompatibility complex (RT1) consist of RT1. B (HLA-DQ equivalent), D (HLA-DR equivalent), and a newly defined H (HLA-DP equivalent) subregions, arranged in the order of RT1.A (class I-H-B beta (beta 1, beta 2)-D (alpha, beta) RFLP analyses of RT1. B and D subregions confirmed that RFLP patterns were correlated well with the allelic specificities which have been determined by serology or MLR. RT1.B locus of BDIX was shown to have RT1.Bd. RFLF analyses of intra-RT1 recombinant rats revealed that recombinations occurred at the sites between RT1.H and B in NIG III, WIN, KGH, between RT1.A and H in DA. BI, BDIX, and between RT1. H alpha and H beta in LEJ. Taken together, the order of genes around H subregion was determined as follows: RT1.A (class I)-H beta-H alpha-B-. Expressions of H subregion genes has not been known. However, Northern hybridization analysis with DP alpha probe detected mRNA of approximately 1.7 kb, suggesting the transcription of RT1. H alpha gene.

Animals↗
PubMed1989

Time course of intracellular associations, processing, and cleavages of Ii forms and class II major histocompatibility complex molecules.

To determine how changing forms of class II major histocompatibility complex proteins and associated Ii molecules in intracellular compartments of human B lymphocytes might regulate or catalyze antigen processing or presentation, we analyzed immunoprecipitates of such molecules from subcellular fractions of [35S]methionine pulse-chase-labeled, 3-day-activated B lymphocytes after homogenization and distribution in Percoll density gradients. Two-dimensional gel electrophoresis of immunoprecipitates of subcellular fractions demonstrated: 1) progressive sialic acid addition to class II major histocompatibility complex beta chains and Ii but not to gamma 2, gamma 2', gamma 3, gamma 3' (p35), or p41 and its satellites; 2) association of p35 and p41 with class II complexes at 30-60 min after pulse labeling; 3) cleavage of an immature form of Ii without sialic acid at 15-30 min after pulse labeling to a COOH-terminal, 25,000-dalton fragment, p25, with a 60-90-min half-life; 4) the presence of Ii-related p29 at only 30-min chase times; 5) an effect of chloroquine or monensin, at maximal nontoxic doses, to increase (a) the time for associations of p35 and p41 with class II complexes and (b) the half-life of p25, which was then formed from Ii at reduced levels. In addition, while the half-lives of class II alpha and beta chains and Ii were comparable within intracellular fractions of any one density, in intracellular fractions of intermediate densities the complexes appeared to be longer lived (much greater than 6 h) than in lighter fractions (2-3-h half-lives).

B-Lymphocytes↗
PubMed1998

Peptide dependence of major histocompatibility complex class II specific alloreactive responses.

Splenic cells from transgenic mice, in which a single peptide is complexed to all major histocompatibility complex (MHC) class II molecules, are found to be incapable of triggering primary allogeneic mixed lymphocyte/leucocyte reactions (MLR) when co-cultured with lymphocytes from MHC class II congenic mouse strains. In addition, a single HLA-DR-blocking peptide can completely abrogate the capacity of splenocytes from chimeric HLA-DR/H2-E transgenic mice to stimulate primary MLR of T cells from wild-type mice. These results indicate that the primary alloreactive response is directed against a multitude of peptides presented by allogeneic MHC molecules.

Amino Acid Sequence↗
PubMed1991

A complex regulatory DNA element associated with a major histocompatibility complex class I gene consists of both a silencer and an enhancer.

A novel regulatory element which contributes to the regulation of quantitative, tissue-specific differences in gene expression has been found between -771 and -676 bp upstream of the major histocompatibility complex (MHC) class I gene, PD1. Molecular dissection of this element reveals the presence of two overlapping functional activities: an enhancer and a silencer. Distinct nuclear factors bind to the overlapping enhancer and silencer DNA sequence elements within the regulatory domain. The levels of factors binding the silencer DNA sequence in different cell types are inversely related to levels of class I expression; in contrast, factors binding the enhancer DNA sequence can be detected in all cells. In cultured cell lines, inhibition of protein synthesis leads to the rapid loss of silencer complexes, with a concomitant increase in both enhancer complexes and MHC class I RNA. From these data, we conclude that a labile silencer factor competes with a constitutively expressed, stable enhancer factor for overlapping DNA-binding sites; the relative abundance of the silencer factor contributes to establishing steady-state levels of MHC class I gene expression.

Animals↗
PubMed1996

Structural comparison of major histocompatibility complex class I molecules and homology modelling of five distinct human leukocyte antigen-A alleles.

The peptide complexes of 19 major histocompatibility complex class I alpha 1 and alpha 2 domains have been compared to identify similarities that can be interpreted as constraints necessary for the function or stability of the molecule. It was found that nearly half of the residues maintained their side-chain conformations (or had no side chain), with the remaining residues being highly solvent exposed and/or polymorphic. Seven hydrogen bonds between the molecule and peptide are conserved in all the structures and serve to orientate the ends of the peptide in the binding groove. Furthermore, the general orientations of most residue side chains in the peptide are similar. Based on these constraints, homology models for the distinct human leukocyte antigen-A alleles A*0302, A*2403, A*2603, A*3101 and A*8001 have been constructed and the implications for peptide binding discussed. The models provide a useful framework from which to engineer allele-specific peptides with a high binding affinity.

Alleles↗
PubMed1979

The influence of the major histocompatibility complex (H-2) on experimental diabetes in mice.

Mice with different histocompatibility loci on an identical background genome (congenic resistant lines of mice) were used to study the possible influence of the histocompatibility complex on experimental diabetes. The major histocompatibility complex (H-2) was not found to influence the diabetogenic effect of encephalomyocarditis (EMC) virus. In contrast the glucose intolerance following heterologous and homologous immunization with pancreatic antigens appeared H-2 influenced. Antibodies against cell surface components on viable B-cells were present in serum from mice with glucose intolerance induced by homologous immunization. The results suggest that the susceptibility to experimental autoimmune diabetes in mice is influenced by the H-2 complex.

Animals↗
PubMed1993

Major histocompatibility complex class I deficiency prolongs islet allograft survival.

Because of islet allograft rejection, nonimmunosuppressed pancreatic islet allotransplantation has been unsuccessful for the treatment of type I diabetes. The role of major histocompatibility complex class I antigen expression on islet allograft survival was evaluated with the use of mice homozygous for a beta 2-microglobulin gene disruption. These mice express little if any functional major histocompatibility complex class I antigen. When these major histocompatibility complex class I-deficient islets were used as donors in an allogenic murine transplantation model, islet allograft survival was markedly prolonged. These results demonstrate a major importance for the alloresponse directed against major histocompatibility complex class I antigen.

Animals↗
PubMed1994

Upregulation and induction of major histocompatibility complex class I and II antigens on microglial cells in early postnatal rat brain following intraperitoneal injections of recombinant interferon-gamma.

Interferon-gamma when given intraperitoneally by single daily injection into one-day-old rats upregulated the expression of major histocompatibility complex class I antigen on ramified microglial cells in cerebral cortex and induced the expression of major histocompatibility complex class II antigen both on amoeboid and ramified microglial cells present in corpus callosum and cerebral cortex, respectively. In rats receiving single daily injections of interferon-gamma over a period of three consecutive days and killed at the age of seven days, the endothelium exhibited a moderate to weak immunoreaction for major histocompatibility complex class I antigen as detected with the monoclonal antibody OX-18. The immunoreactivity of major histocompatibility complex class I antigen on amoeboid microglial cells was comparable to that of control rats. On the other hand, it was remarkably enhanced on ramified microglial cells and was further intensified with four or six injections of interferon-gamma. In the latter, the endothelial cells also showed a stronger immunoreactivity with OX-18. In rats given three successive injections of interferon-gamma and killed at the age of seven days, 7.5% of amoeboid microglial cells in corpus callosum were induced to exhibit major histocompatibility complex class II antigen as detected with OX-6. An upsurge of the amoeboid microglial cells with major histocompatibility complex class II antigen amounting to about 40% was observed following four and six injections of interferon-gamma. A minimum of four successive injections of interferon-gamma were needed to elicit the expression of major histocompatibility complex class II antigen on ramified microglial cells in cerebral cortex.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Decreased endosomal delivery of major histocompatibility complex class II-invariant chain complexes in dynamin-deficient cells.

Major histocompatibility complex class II molecules are heterodimeric cell surface molecules which acquire antigenic peptides in the endosomal/lysosomal system. Invariant chain (Ii), a third chain which is associated with class II molecules intracellularly mediates the endosomal targeting, but it is debated whether class II molecules reach the endosomal system mainly from the trans-Golgi network or via the cell surface. Dynamin is a cytosolic GTPase which is necessary for the formation of clathrin-coated vesicles from the plasma membrane, but which is not required for vesicle formation from the trans-Golgi network. Here we have used HeLa cells expressing a dominant negative form of dynamin to show that inhibition of clathrin-mediated uptake from the plasma membrane leads to accumulation of transfected Ii-class II complexes at the cell surface, while delivery of such complexes to endosomes/lysosomes is decreased. Our data therefore suggest that in this experimental system the majority of Ii-class II complexes traverse the cell surface before they reach the endosomal system.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1989

Inhibition of insulin receptor phosphorylation by peptides derived from major histocompatibility complex class I antigens.

Peptides from the alpha 1 region (residues 61-85) of the D and K molecules of the major histocompatibility complex class I antigens inhibit insulin-induced tyrosine kinase activity of the purified human insulin receptors (IRs) as measured both by autophosphorylation and IR-mediated substrate [poly(Glu,Tyr)] phosphorylation. Half-maximal effect of the Dk-(61-85) peptide on IR autophosphorylation is obtained at 1.2 microM, and almost complete inhibition of IR kinase activity is obtained at 10 microM peptide. The corresponding K kappa-(61-85) peptide has a significantly weaker effect on autophosphorylation. No such effects are observed with nine peptides of similar length, but unrelated to major histocompatibility complex class I antigens. Neither of the major histocompatibility complex class I-derived peptides has any effect on the constitutively active kinase of a genetically engineered cytoplasmic IR domain. Further, insulin binding to IR is unaltered in the presence of the major histocompatibility complex class I-derived peptides. The inhibitory activity of the peptides on insulin-induced IR phosphorylation facilitated the observation that IRs require insulin to become substrate for an independent tyrosine kinase. In the presence of an inhibitory peptide, the constitutively active cytoplasmic IR kinase domain only phosphorylates the intact IR in the presence of insulin. We conclude that the tyrosine kinase activity of IRs may be altered by peptide interaction at an allosteric site and, moreover, IRs require insulin to assume a conformation permitting phosphorylation by an independent kinase.

Allosteric Site↗
PubMed1992

Impaired expression of chimaeric major histocompatibility complex transgenes associated with plasmid sequences.

Plasmid vector sequences were retained (vector+), or removed (vector-) from hybrid major histocompatibility complex gene constructs prior to microinjection of fertilized ova for the production of transgenic mice. In transgenic mice containing integrated vector+ gene constructs, low levels of class II cell surface determinants were detected on splenocytes from only two out of six independent lines. Class II membrane determinants were not detectable on splenocytes from the remaining four vector+ transgenic lines. Expression of transgene products did not correlate with transgene copy number which ranged from 1-10 copies. Low levels of mRNA transcripts were detected in thymic mRNA from vector+ lines. In contrast, high levels of thymic and splenic mRNA transcripts were detected in offspring from all four vector- transgenic lines. Spleen cells from the vector- transgenic animals also expressed high levels of the hybrid major histocompatibility complex transgene products. These results implicate plasmid vector sequences in the inhibition of expression of the hybrid class II-class I major histocompatibility complex genes in transgenic mice. This putative inhibition of transgene expression presumably occurs at the level of gene transcription.

Animals↗
PubMed1997

Specific T cell recognition of kinetic isomers in the binding of peptide to class II major histocompatibility complex.

Helper T cells are triggered by molecular complexes of antigenic peptides and class II proteins of the major histocompatibility complex. The formation of stable complexes between class II major histocompatibility complex proteins and antigenic peptides is often accompanied by the formation of a short-lived complex. In this report, we describe T cell recognition of two distinct complexes, one short-lived and the other long-lived, formed during the binding of an altered myelin basic protein peptide to I-Ak. One myelin basic protein-specific T cell clone is triggered by only the short-lived complex, and another is triggered by only the stable complex. Thus, a single peptide bound to a particular class II molecule can activate different T cells depending on the conditions of the binding reaction.

Animals↗
PubMed2005

Impaired assembly of the major histocompatibility complex class I peptide-loading complex in mice deficient in the oxidoreductase ERp57.

The thiol-oxidoreductase ERp57 is an integral component of the peptide-loading complex of the major histocompatibility complex (MHC) class I pathway, but its function is unknown. To investigate its function in antigen presentation, we generated ERp57-deficient mice. Death in utero caused by ubiquitous ERp57 deletion was prevented by specific deletion in the B cell compartment. We demonstrate that ERp57 was central for recruitment of MHC class I molecules into the loading complex. In ERp57-deficient cells, we found short-lived interaction of MHC class I molecules with the loading complex. Thus, in the steady state, very few MHC class I molecules were present in the loading complex. Surface H-2K(b)-peptide expression and stability were reduced, and presentation of a model antigen was decreased. Our results indicate that ERp57 does not influence the redox state of MHC class I molecules but is an essential structural component required for stable assembly of the peptide-loading complex.

Animals↗
PubMed1983

Genes of the major histocompatibility complex in mouse and man.

The genes of the major histocompatibility complex code for cell-surface molecules that play an important role in the generation of the immune response. These genes and molecules have been studied intensively over the last five decades by geneticists, biochemists, and immunologists, but only recently has the isolation of the genes by molecular biologists facilitated their precise characterization. Many surprising findings have been made concerning their structure, multiplicity, organization, function, and evolution.

Animals↗
PubMed1990

The major histocompatibility complex and human evolution.

Many alleles at the human major histocompatibility complex (HLA) loci diverged before the divergence of humans and great apes from a common ancestor. This fact puts a lower limit on the size of the bottleneck in human evolution: the genus Homo must have been founded by no less than ten and probably by more than 10,000 individuals.

Alleles↗
PubMed1999

Major histocompatibility complex variation in the endangered Przewalski's horse.

The major histocompatibility complex (MHC) is a fundamental part of the vertebrate immune system, and the high variability in many MHC genes is thought to play an essential role in recognition of parasites. The Przewalski's horse is extinct in the wild and all the living individuals descend from 13 founders, most of whom were captured around the turn of the century. One of the primary genetic concerns in endangered species is whether they have ample adaptive variation to respond to novel selective factors. In examining 14 Przewalski's horses that are broadly representative of the living animals, we found six different class II DRB major histocompatibility sequences. The sequences showed extensive nonsynonymous variation, concentrated in the putative antigen-binding sites, and little synonymous variation. Individuals had from two to four sequences as determined by single-stranded conformation polymorphism (SSCP) analysis. On the basis of the SSCP data, phylogenetic analysis of the nucleotide sequences, and segregation in a family group, we conclude that four of these sequences are from one gene (although one sequence codes for a nonfunctional allele because it contains a stop codon) and two other sequences are from another gene. The position of the stop codon is at the same amino-acid position as in a closely related sequence from the domestic horse. Because other organisms have extensive variation at homologous loci, the Przewalski's horse may have quite low variation in this important adaptive region.

Animals↗