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PubMed1978

Major histocompatibility complex and non-major histocompatibility complex antigens on mouse ectoplacental cone and placental trophoblastic cells.

The expression of major histocompatibility complex and non-major histocompatibility complex antigens on mouse trophoblast cultured from two defined stages of development was investigated by the sensitive in vitro mixed haemadsorption assay. Outgrowths obtained 3 to 5 days after explanation of 7 1/2-day ectoplacental cones contained a mixed population of cells. Those with a giant cell morphology showed no haemadsorption with congenic H-2 antisera and were reactive with non H-2 antiserum only in the CBA strain. Other, smaller cells were reactive for both H-2 and non-H-2 in all strains examined except for C57BL, where the cells were nonreactive for H-2. Monolayer cultures of 13 to 14-day placental suspensions tested 24 hr after preparation were strongly reactive for both H-2 and non-H-2. The identity and alloantigenic status of the cells are discussed in relation to their function in maternal-foetal immunological interactions.

Animals↗

PubMedDate not supplied

Complexity in the major histocompatibility complex.

The human major histocompatibility complex (MHC) is one of the most intensively studied regions of the human genome, containing over 70 known genes and spanning about 4 million base pairs (4 Mbp) of DNA on chromosome 6p21.3 (Klein, 1986). It can be divided up into three regions: the class I region (telomeric), the class II region (centromeric), and the class III region (between class I and II), which includes the complement component genes C2, C4, and Bf (Trowsdale & Campbell, 1988). The MHC has been mapped in detail using pulse field gel electrophoresis (PFGE) and by cloning in yeast artificial chromosome (YAC) and cosmid vectors, revealing long stretches of DNA between the regions as well as between individual class I and class II genes. Novel genes, that have no sequence relationships with class I, class II or complement components, have recently been found in these areas, and we will present an update on these after reviewing the more established loci.

Chromosome Mapping↗

PubMed1978

The unity of genes in the major histocompatibility complex.

The major histocompatibility complex (MHC) of the mouse can be genetically divided into several regions specialized to performing specific functions. Thus the class I regions (K and D) code for antigens that activate effector (killer) T cells, class II region (I) for antigens causing T-cell proliferation, and class III regions (s) for complement components. A strong case is made for the theory that the division of labor within the MHC is not absolute. Evidence is presented that class I antigens can sometimes cause as strong T-cell proliferation as class II antigens; that class II antigens can generate effector T cells; and that class I antigens may be involved in the immune response to some antigens. The fact that different regions can perform similar functions argues for the unity of the MHC genes.

Animals↗

PubMed1992

Genes, genes and more genes in the human major histocompatibility complex.

The human major histocompatibility complex (MHC), on the short arm of chromosome 6, represents one of the most extensively characterised regions of the human genome. This approximately 4 Mb segment of DNA contains genes encoding the polymorphic MHC class I and class II molecules which are involved in antigen presentation during an immune response. Recently the whole of the MHC has been cloned in cosmids and/or yeast artificial chromosomes (YACs) and large portions have been characterised for the presence of novel genes. Many unrelated genes, both housekeeping and tissue specific, have been identified and the gene density in some regions is now approaching one gene every few kilobases. Some of the novel genes encode proteins involved in the intracellular processing and transport of antigens that are presented by MHC class I molecules. Others, however, have no obvious role in the immune response. The MHC is located in the chromosome band 6p21.3 which is a Giemsa (G)-light band. The detection of such a large number of functional genes (at least 70) in this region is compatible with the idea that both housekeeping and tissue-specific genes are localised predominantly in G-light bands.

Chromosome Mapping↗

PubMed1992

The alpha chain gene of H-2O has an unexpected location in the major histocompatibility complex.

A previously unknown major histocompatibility complex class II molecule consisting of the beta chain encoded by the H-2Ob gene and an unknown alpha chain was recently described. We now report that the alpha chain occurs in two allelic forms distinguished by charge difference. Using inbred recombinant mouse strains we were able to map the H-2Oa gene to a location between the A.TL and B10.MBR recombination points. Cosmids covering this region were used to isolate the gene. Sequence analysis revealed that the H-2Oa gene is the murine equivalent of the human HLA-DNA gene. These results indicate that the human HLA-DNA gene, the existence of which has long been known, is indeed coding for DO alpha, the alpha chain pairing with DO beta.

Amino Acid Sequence↗

PubMed1979

Suppressor T-cell mechanisms in contact sensitivity. III. Apparent non-major histocompatibility complex restriction is a result of multiple sets of major histocompatibility complex-specific suppressor T cells induced by syngeneic 2,4-dinitrophenyl-modified lymphoid cells.

This report has examined the mechanisms by which major histocompatibility complex (MHC) non-restricted suppressor T cells (Ts), induced by the i.v. injection of 2,4-dinitropheny (DNP)-modified, syngeneic lymphoid cells (DNP-LC), suppress the passive transfer of contact sensitivity mediated by syngeneic and allogeneic immune delayed hypersensitivity T cells (TDH). In terms of suppression of syngeneic TDH, it was found that the suppressive action of the Ts was only blocked by pretreatment with soluble syngeneic DNP-LC membrane preparations. Monomeric DNP-lysine, polymeric DNP-protein conjugates, and syngeneic TNP-LC membranes did not inhibit Ts function. Further experiments showed that inhibition of syngeneic suppression could be achieved by DNP-modified-membrane preparations that were only H-2D-region compatible with the Ts donor. Thus, Ts antigen receptors in this system specifically recognize DNP-modified H-2D-region determinants. In contrast, it was found that pretreatment os syninduced Ts with syngeneic DNP-LC membranes did not inhibit the ability to suppress allogeneic TDH. However, pretreatment of Ts with DNP-allogeneic membranes which were H-2D-end compatible to the allogeneic target TDH eliminated their ability to suppress the specific allogeneic TDH, leaving intact suppression of syngeneic or third party TDH. It is proposed that perturbation of the immune system by i.v. injection of syngeneic NDP-LC leads to the induction of a polyclonal wave of DNP-specific Ts activity. Some members of this set of Ts recognize DNP-self MHC determinants with moderate affinity and are thus specifically inhibited after pretreatment with those DNP-self determinants. Other members of this set display receptors which cross-react with high affinity with DNP-allogeneic determinants and thus suppress allogeneic TDH cells. These allosuppressive clones can thus be specifically inhibited only by pretreatment with DNP-LC membranes, MHC-compatible with the target TDH. The data are discussed in terms of current models of T-cell cross-reactivity and T-cell-receptor recognition.

Animals↗

PubMed1976

The evolution of genes in the major histocompatibility complex.

The mammalian major histocompatibility system (MHS) includes genes determining the structure of the classical major transplantation antigens (H-2K and H-2D), the I region-associated (Ia) antigens, and genes determining the structure level or both of the first four components of complement. In addition, the I region incudes a series of genes determining specific immune responsiveness to a wide variety of antigens - the Ir genes. The available evidence indicates that the K, D, and I gene products are cell surface glycoproteins that are structurally and perhaps functionally related. The multiple genes in this complex region apparently arose by a process of tandem gene duplication. There is some reason to believe that the murine MHS may have originated from genes in the T/t complex - a "supergene" near the centromere of the 17th mouse chromosome determining a series of steps in early embryonic development. Other evidence has led to the postulate that genes in the MHS have given rise to immunoglobulin structural genes by a process of translocation and further gene duplication. While these evolutionary relationships are speculative, it seems clear that the MHS determines a series of cell surface proteins that are intimately involved in cellular recognition and interaction, and in regulation of immune responsiveness by a new, nonimmunoglobulin recognition system.

Alleles↗

PubMed2026

Functional Annotation of the Major Histocompatibility Complex Locus.

The human major histocompatibility complex (MHC) locus has the greatest density of disease-associations in the human genome, including links to over 100 polygenic disorders. Its complex haplotype structure, rich gene density, and high degree of linkage disequilibrium combine to make deciphering the gene regulatory logic of the MHC locus extremely challenging. Employing complementary high-throughput CRISPR interference (CRISPRi) and activation (CRISPRa) epigenetic screens coupled with single-cell transcriptome profiling across three distinct human cell types, we identified hundreds of new connections between cis -regulatory elements (CREs) and their target genes in this locus. These CRE-gene links are largely cell type-specific and act as enhancers. Additionally, some CREs have complex features, including harboring both active and repressive histone marks, lacking chromatin accessibility, targeting multiple genes, or acting as silencers. Computational methods fail to predict a majority of these CRE-gene connections. These findings emphasize the potential for functional perturbation experiments to dissect complex loci and reveal shared and cell type-specific regulatory mechanisms relevant to genomics of complex diseases. Collectively, this study provides a unique resource for understanding the complex regulatory landscape within the MHC locus and supports the need for creating new models that encompass CRE-gene interactions, cell type-specific gene expression, and disease genetics in the noncoding genome.

Journal Article↗

PubMed1992

In vivo function of regulatory DNA sequence elements of a major histocompatibility complex class I gene.

Major histocompatibility complex class I genes are expressed in nearly all somatic tissues, although their level of expression varies. By analysis of a set of promoter deletion mutants introduced into transgenic mice, a complex regulatory element, consisting of overlapping enhancer and silencer activities, is demonstrated to function as a tissue-specific regulator of class I expression. The enhancer activity predominates in lymphoid tissues but not in nonlymphoid tissues. In contrast to the tissue-specific functions of the complex regulatory element, a second novel silencer element is shown to function in both lymphoid and nonlymphoid tissues. The complement of DNA-binding factors in different cell lines is shown to correlate with the levels of class I expression.

Animals↗

PubMed1992

Major histocompatibility complex class I restriction fragment length polymorphism analysis in highly inbred chicken lines and lines selected for major histocompatibility complex and immunoglobulin production.

Selected chicken populations were analyzed by restriction fragment length polymorphism (RFLP) with a chicken MHC Class I (B-F) cDNA probe. The 13 highly inbred chicken lines differed in genetic origin and in MHC (B) haplotype, as distinguished by using hemagglutination with antisera against B-G and B-F antigens. The S1 sublines differed for B haplotype and antibody response to a synthetic polypeptide, GAT. In the highly inbred lines, band-sharing between lines from different origins was less than that between lines from same origin, showing the influence of the genetic background on chicken MHC Class I gene RFLP. In the S1 line, use of three restriction endonucleases (BglII, PvuII, and TaqI) produced MHC Class I RFLP patterns that were associated with B haplotype, but not with immune response to GAT (IrGAT). A previous study in the authors' laboratory also demonstrated an association of MHC Class II beta RFLP patterns with B haplotype, but not IrGAT, in the same line, suggesting that IrGAT is not controlled by MHC Class I or Class II beta genes.

Animals↗

PubMed2024

Local Ancestry at the Major Histocompatibility Complex Region is Not a Major Contributor to Disease Heterogeneity in a Multiethnic Lupus Cohort.

OBJECTIVE: Systemic lupus erythematosus (SLE) is an autoimmune disease resulting in debilitating clinical manifestations that vary in severity by race and ethnicity with a disproportionate burden in African American, Mestizo, and Asian populations compared with populations of European descent. Differences in global and local genetic ancestry may shed light on the underlying mechanisms contributing to these disparities, including increased prevalence of lupus nephritis, younger age of symptom onset, and presence of autoantibodies. METHODS: A total of 1,139 European, African American, and Mestizos patients with SLE were genotyped using the Affymetrix LAT1 World array. Global ancestry proportions were estimated using ADMIXTURE, and local ancestry was estimated using RFMIXv2.0. We investigated associations between lupus nephritis, age at onset, and autoantibody status with both global and local ancestry proportions within the Major Histocompatibility Complex region. RESULTS: Our results showed small effect sizes that did not meet the threshold for statistical significance for global or local ancestry proportions in either African American or Mestizo patients with SLE who presented with the clinical manifestations of interest compared with those who did not. CONCLUSION: These findings suggest that local genetic ancestry within the Major Histocompatibility Complex region is not a major contributor to these SLE manifestations among patients with SLE from admixed populations.

Humans↗

PubMed2025

Major histocompatibility complex class IIB disassortative mate choice in a genetically monogamous seabird.

Among species reproducing sexually, mating strategies represent a major component of individual fitness. The major histocompatibility complex (MHC) is an extremely diverse set of genes responsible for immunological recognition and defence against pathogens. Although dissimilarity between mates at the major histocompatibility complex has been proposed to drive mate choice through increased offspring pathogen resistance, evidence is mixed. In addition, explorations of the role of the major histocompatibility complex in other mating strategies, such as divorce, are rare. We investigated whether dissimilarity at the major histocompatibility complex class IIB is associated with mate choice and divorce probability in the genetically monogamous black-legged kittiwake (Rissa tridactyla). We found that first-time male breeders, as well as divorced males, were paired with females more dissimilar at the major histocompatibility complex class IIB than expected under random mating. We did not find evidence for mate choice based on major histocompatibility complex class IIB dissimilarity when considering females. In addition, in the studied population, divorce probability was very low compared with other populations and did not significantly vary with the dissimilarity of the pair at the major histocompatibility complex class IIB. Our results pave the way to a better understanding of the complex role of major histocompatibility complex dissimilarity in mating decisions of species displaying mutual choice and biparental care.

Animals↗

PubMed1979

Gene complex controlling growth and fertility linked to the major histocompatibility complex in the rat.

The B1 strain of rats carries a unique mutation which causes defects in growth and reproduction: the males and females are small, the testes are hypoplastic and aspermatic, and the females have a reduced reproductive capacity. The loci controlling these defects are linked to the major histocompatibility complex (MHC) as determined by segregation studies in backcross and F2 hybrid populations. The levels of pituitary hormones and somatomedin C in the B1 strain are elevated or normal, and the testosterone level is elevated relative to the size of the testes. These findings suggest that hormone deficiencies are not the cause of these defects. The genes governing these defects have been designated the growth and reproduction complex (Grc). The recessive gene regulating small body size has been designated dw-3 (dwarf-3), and the recessive gene influencing reproductive capacity has been designated f. The Grc and MHC are separable by recombination, and the dw-3 and f genes are also separable by recombination. Studies in the (B1 X DA)F2 hybrid indicate that the map distance between the Grc and the MHC is 0.6 cM. Segregation distortion due to a deficiency of RT11 homozygotes is seen in some F2 hybrid populations derived from the B1 strain. Litter size data suggest that the loss of the RT11 homozygotes is due to intrauterine death. There is no apparent sex influence on the inheritance of the Grc, at least as it is presently understood, since it can be transmitted by either females or males. The growth and reproduction complex in the rat may be the analog of the T/t complex in the mouse, and the importance of the region of the chromosome adjacent to the major histocompatibility complex in the control of developmental processes may be a general phenomenon in mammals.

Animals↗

PubMed1992

A recombinant, soluble, single-chain class I major histocompatibility complex molecule with biological activity.

Heterodimeric class I major histocompatibility complex molecules, which consist of a 45-kDa heavy-chain and a 12-kDa beta 2-microglobulin (beta 2m) light chain, bind endogenously synthesized peptides for presentation to antigen-specific T cells. We have synthesized a gene encoding a single-chain, soluble class I molecule derived from mouse H-2Dd, in which the carboxyl terminus of beta 2m is linked via a peptide spacer to the amino terminus of the heavy chain. The chimeric protein is secreted efficiently from transfected L cells, is thermostable, and when loaded with an appropriate antigenic peptide, stimulates an H-2Dd-restricted antigen-specific T-cell hybridoma. Thus, functional binding of peptide does not require the complete dissociation of beta 2m, implying that a heavy chain/peptide complex is not an obligate intermediate in the assembly of the heavy-chain/beta 2m/peptide heterotrimer. Single-chain major histocompatibility complex molecules uniformly loaded with peptide have potential uses for structural studies, toxin or fluor conjugates, and vaccines.

Animals↗

PubMed1992

Invariant chain can function as a chaperone protein for class II major histocompatibility complex molecules.

During biosynthesis, class II major histocompatibility complex molecules are intimately associated with invariant chain (Ii). The Ii-class II association has been shown to block peptide-class II binding and to affect the ultimate conformation of class II expressed on the cell surface. To assess the biochemical basis for the effects of Ii on class II, we have analyzed the biosynthesis of class II in EL4 cells transfected with I-Ad with and without Ii. In these studies, we found that Ii had a profound effect on the biosynthesis of I-Ad. In the absence of Ii, class II could form dimers efficiently, but these dimers appeared to be misfolded and this altered conformation resulted in the loss of some monoclonal antibody epitopes and inefficient transport from the endoplasmic reticulum to the Golgi. In addition, class II that was transported through the Golgi accumulated an abnormally increased molecular mass associated with N-linked glycosylation. Subsequent transfection of Ii into these cells resulted in recovery of normal class II conformation, causing a restoration of monoclonal antibody epitopes, efficient intracellular transport, and normal glycosylation. Together, these data indicate that Ii can have a profound effect on the folding, transport, and modification of class II molecules and suggest that one function of Ii may be to act as a class II-specific chaperone.

Animals↗

PubMed1976

Genetics of transplantation: the major histocompatibility complex.

A genetic region called the major histocompatibility complex of MHC (which plays an important role in the control of graft survival) has been defined in a large number of different species. Several different loci of the MHC have been described, including loci coding for transplantation antigens. These antigens can be divided into two categories: first, the SD antigens that were originally defined serologically and that appear to function as targets for the killer lymphocytes involved in the rejection of a graft and second, the LD antigens that were originally defined by lymphocyte response in the mixed leukocyte culture test and that stimulate helper T lymphocytes. In addition, there are genes for other antigens (referred to as immune response-associated or Ia antigens) and genes that control the ability of an animal to respond immunologically to antigenic stimuli, the immune response or Ir genes. There is evidence for epistatic interaction between these genes in that immune recognition of LD and SD antigens lead to a more pronounced development of cytotoxic (killer) cells than does stimulation by either antigen alone. In addition, the genetic control of immune responsiveness appears, at least in some systems, to reside in two very closely linked genes that may function better in the cis than in the transposition. This latter finding suggests a possible explanation for the strong linkage disequilibrium found between genes of the MHC. A number of new tests have been described to define the antigens of the MHC. Results of these tests have been used for studies of transplantation immunology but in addition to study the very strong associations that exist between some of the MHC antigens in man and various diseases.

Antibody Formation↗

PubMed1992

In the presence of dexamethasone, gamma interferon induces rat oligodendrocytes to express major histocompatibility complex class II molecules.

Cells that express major histocompatibility complex (MHC) class II molecules can interact directly with CD4 T lymphocytes and either activate immune reactions or become the targets of T-cell-mediated cytotoxic attack. Using rat optic nerve cultures combined with immunocytochemistry and in situ hybridization, we have shown that oligodendrocytes, the major myelin-forming cells of the central nervous system and the main casualty of the immune attacks associated with multiple sclerosis and experimental allergic encephalomyelitis, can be readily induced to express MHC class II mRNA and surface antigens in vitro by exposure to gamma interferon, provided the glucocorticoid dexamethasone is included in the culture medium. Oligodendrocytes exposed to gamma interferon without dexamethasone fail to express MHC class II molecules, which may account for the failure of previous attempts to induce expression in these cells. In the experiments reported here MHC class II expression can be demonstrated both on galactocerebroside-positive cells and on mature oligodendrocytes that express proteolipid protein. These findings expand possibilities for understanding immune-related oligodendrocyte killing and demyelination in human and experimental demyelinating diseases.

Animals↗

PubMed1992

Diversity of T-cell receptors in virus-specific cytotoxic T lymphocytes recognizing three distinct viral epitopes restricted by a single major histocompatibility complex molecule.

Cytotoxic T lymphocytes (CTL) recognize virus peptide fragments complexed with class I major histocompatibility complex (MHC) molecules on the surface of virus-infected cells. Recognition is mediated by a membrane-bound T-cell receptor (TCR) composed of alpha and beta chains. Studies of the CTL response to lymphocytic choriomeningitis virus (LCMV) in H-2b mice have revealed that three distinct viral epitopes are recognized by CTL of the H-2b haplotype and that all of the three epitopes are restricted by the Db MHC molecule. The immunodominant Db-restricted CTL epitope, located at LCMV glycoprotein amino acids 278 to 286, was earlier noted to be recognized by TCRs that consistently contained V alpha 4 segments but had heterogeneous V beta segments. Here we show that CTL clones recognizing the other two H-2Db-restricted epitopes, LCMV glycoprotein amino acids 34 to 40 and nucleoprotein amino acids 397 to 407 (defined in this study), utilize TCR alpha chains which do not belong to the V alpha 4 subfamily. Hence, usage of V alpha and V beta in the TCRs recognizing peptide fragments from one virus restricted by a single MHC molecule is not sufficiently homogeneous to allow manipulation of the anti-viral CTL response at the level of TCRs. The diversity of anti-viral CTL likely provides the host with a wider option for attacking virus-infected cells and prevents the emergence of virus escape mutants that might arise if TCRs specific for the virus were homogeneous.

Amino Acid Sequence↗