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PubMed1989

Marek's disease and major histocompatibility complex haplotypes in chickens selected for high or low antibody response.

Sublines of chickens differing in genotypes at the major histocompatibility complex (MHC) were developed from lines selected for high (HA) and low (LA) antibody response to sheep erythrocytes. To evaluate the influence of MHC genotypes in diverse background genomes on resistance to Marek's disease, chicks with MHC genotypes B13B13, B13B21 and B21B21 from both background genomes were exposed naturally commencing at 1 day of age. Individuals which died up to 120 days of age were autopsied to determine cause of death. Mortality due to Marek's disease was greater for HA than LA chickens and greater for males than females. Interactions of MHC genotypes with background genome and with sex suggest a complex picture of the influence of MHC genotypes. A heterozygous advantage for resistance to Marek's disease was noted, as would be predicted by genetic theory concerning maintenance of polymorphism at the MHC.

Animals↗
PubMed1996

Major histocompatibility complex expression and lung ischemia-reperfusion in rats.

BACKGROUND: Clinical studies in kidney and liver transplantation have suggested that poor early function is associated with increased graft loss due to rejection. Ischemia-reperfusion injury may contribute to rejection by enhancing graft immunogenicity. METHODS: A rat model of unilateral in situ pulmonary ischemia-reperfusion was used to examine class II major histocompatibility complex (MHC) antigen expression. The effects of deflation during ischemia (which augments subsequent injury) as well as concurrent allostimulation were also examined. Major histocompatibility complex expression was examined 9 days after ischemia using the binding of radiolabeled anti-class II antibody and immunohistochemistry. RESULTS: Four hours of ischemia in full inflation or 2 hours of atelectatic ischemia both led to severe lung injury. Ischemia-reperfusion injury led to greater MHC expression in the ischemic lung compared with the nonischemic side. Allostimulation with mononuclear cells did not increase MHC expression in the nonischemic lung but did enhance the increase found in the ischemic lung. This was not due to a graft-versus-host response because allostimulation with F1 cells also led to a significant increase. CONCLUSIONS: Severe ischemic lung injury leads to significant increases in MHC expression, detectable after 9 days of reperfusion. Deflation during ischemia, which augments lung injury, also augments increased MHC expression. Concurrent allostimulation with foreign mononuclear cells appears to potentiate increased MHC expression after ischemia. Increases in graft MHC expression may enhance immunogenicity and increase the rejection response.

Animals↗
PubMedDate not supplied

Corneal allograft rejection. The role of the major histocompatibility complex.

The greater success of corneal transplantation compared to other organ transplants has led to the concept that the cornea is a site of "immunological privilege." Corneal cells possess the antigens of the major histocompatibility complex responsible for allograft rejection in other tissues (i.e., HLA antigens). The avascularity of the cornea accounts for the relative protection of the donor cornea from the immunological surveillance of the recipient. As the roles and functions of the major histocompatibility complex are unravelled, the mechanisms responsible for host sensitization, lymphocyte activation and allograft rejection are becoming better understood. In particular, the HLA-DR antigen in humans is believed to play an integral part in allograft rejection. Langerhans cells in human corneal epithelium have been shown to bear this antigen. Evidence suggests that these cells or similar HLA-DR-bearing cells in the cornea play a major role in corneal allograft rejection. In light of these advances in transplantation immunobiology, new methods of suppressing and possibly preventing allograft rejection in corneal transplantation are presented.

Animals↗
PubMed1986

A deletion in a rat major histocompatibility complex class I gene is linked to the absence of beta 2-microglobulin-containing serum molecules.

Class I major histocompatibility antigens are composed of a heavy chain that is noncovalently associated with beta 2-microglobulin (beta 2m). Most class I molecules are membrane bound, but mouse and rat cDNA clones and genes without a functional code for the transmembrane amino acids have been identified. The membrane-associated class I molecules are important in the control of cell-mediated cytotoxicity, while the function of the soluble molecules remains unclear. Previous studies have shown that beta 2m circulates in rat serum in three different molecular weight classes. The first is free beta 2m (Mr, 12,000), the second is about Mr 70,000, and the third is roughly Mr 200,000. In an inbred subline of immunodeficient, diabetes-prone BioBreeding rats (BioBreeding/Hagedorn), previous work detected two restriction fragment polymorphisms in class I major histocompatibility complex genes, one of them a gene deletion on a 7-kilobase BamHI fragment and the other on a 2-kilobase BamHI fragment. In these rats we have found that the third serum beta 2m-binding size class is absent. Analysis of F1 and F2 individuals following cross-breeding between BioBreeding/Hagedorn rats and genetically related (nondiabetic) control BioBreeding w-subline rats demonstrated that the large-size serum peak of beta 2m was associated with the presence of the class I restriction fragments.

Animals↗
PubMed1991

Characterization of naturally processed antigen bound to major histocompatibility complex class II molecules.

Helper T lymphocytes recognize peptide fragments of antigen bound to major histocompatibility complex (MHC) class II molecules presented on the surface of antigen-presenting cells (APCs). Previous studies showed that the MHC class II, I-Ek molecules purified from APCs that had processed Drosophila melanogaster cytochrome c (DMc) contained functional, processed antigen-I-Ek complexes. This was demonstrated by the ability of purified I-Ek, incorporated into liposomes, to stimulate DMc-specific T cells in the absence of any additional antigen. Here we describe the isolation and characterization of the processed antigen bound to I-Ek. This was accomplished using DMc radiolabeled across its entire length by reductive methylation of its lysine residues, allowing an analysis of the totality of processed antigen bound to MHC class II molecules. After processing, only about 0.2% of the APC I-Ek molecules contained processed DMc (approximately 800 per cell), yet these were sufficient to stimulate specific T cells. The DMc peptides isolated from the I-Ek molecules showed only two predominant radioactive peaks as analyzed by reverse-phase chromatography. Less processed antigen was bound to purified I-Ak molecules, and these peptides were distinct from those bound to I-Ek. The association of processed DMc with the I-Ek and I-Ak molecules appears highly specific in that no radiolabeled peptides were isolated from purified MHC class I molecules, Kk and Dk, or from the B-cell differentiation antigen B220. The majority of processed antigen-I-Ek complexes migrated more slowly than the majority of the I-Ek protein as analyzed by SDS/PAGE under nonreducing conditions without heating of the sample. This form of I-Ek may be analogous to the earlier described "floppy" form of MHC class II molecules [Dormair, K., Rothenhausler, B. & McConnell, H. M. (1990) Cold Spring Harbor Symp. Quant. Biol. 54, 409-416]. Since newly processed antigen binds nearly exclusively to this slow-migrating form, it may be of functional significance.

Amino Acid Sequence↗
PubMed2001

IMGT/HLA Database--a sequence database for the human major histocompatibility complex.

The IMGT/HLA Database (www.ebi.ac.uk/imgt/hla/) specialises in sequences of polymorphic genes of the HLA system, the human major histocompatibility complex (MHC). The HLA complex is located within the 6p21.3 region on the short arm of human chromosome 6 and contains more than 220 genes of diverse function. Many of the genes encode proteins of the immune system and these include the 21 highly polymorphic HLA genes, which influence the outcome of clinical transplantation and confer susceptibility to a wide range of non-infectious diseases. The database contains sequences for all HLA alleles officially recognised by the WHO Nomenclature Committee for Factors of the HLA System and provides users with online tools and facilities for their retrieval and analysis. These include allele reports, alignment tools and detailed descriptions of the source cells. The online IMGT/HLA submission tool allows both new and confirmatory sequences to be submitted directly to the WHO Nomenclature Committee. The latest version (release 1.7.0 July 2000) contains 1220 HLA alleles derived from over 2700 component sequences from the EMBL/GenBank/DDBJ databases. The HLA database provides a model which will be extended to provide specialist databases for polymorphic MHC genes of other species.

Alleles↗
PubMed2002

Structure of a complex of the human alpha/beta T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity.

The alpha/beta T cell receptor (TCR) HA1.7 specific for the hemagglutinin (HA) antigen peptide from influenza A virus is HLA-DR1 restricted but cross-reactive for the HA peptide presented by the allo-major histocompatibility complex (MHC) class II molecule HLA-DR4. We report here the structure of the HA1.7/DR4/HA complex, determined by X-ray crystallography at a resolution of 2.4 A. The overall structure of this complex is very similar to the previously reported structure of the HA1.7/DR1/HA complex. Amino acid sequence differences between DR1 and DR4, which are located deep in the peptide binding groove and out of reach for direct contact by the TCR, are able to indirectly influence the antigenicity of the pMHC surface by changing the conformation of HA peptide residues at position P5 and P6. Although TCR HA1.7 is cross-reactive for HA presented by DR1 and DR4 and tolerates these conformational differences, other HA-specific TCRs are sensitive to these changes. We also find a dependence of the width of the MHC class II peptide-binding groove on the sequence of the bound peptide by comparing the HA1.7/DR4/HA complex with the structure of DR4 presenting a collagen peptide. This structural study of TCR cross-reactivity emphasizes how MHC sequence differences can affect TCR binding indirectly by moving peptide atoms.

Alleles↗
PubMed2004

Parasites and individual major histocompatibility complex diversity--an optimal choice?

Overdominant selection or heterozygote advantage can partly explain the extraordinary polymorphism found at classical major histocompatibility complex (MHC) loci. However, several studies employing only single infectious agents often failed to detect it. Here, we review recent studies suggesting that due to the dominant nature of MHC-mediated resistance, a heterozygote advantage is most likely to be detected in multiple pathogen challenges.

Animals↗
PubMed1997

Expression of major histocompatibility complex molecules in rodent retina. Immunohistochemical study.

PURPOSE: In Lewis rats, S-antigen-induced intraocular inflammation, which occurs initially in the retina, is mediated by T cells requiring major histocompatibility complex (MHC)-restricted antigen presentation. In such organ-specific inflammation, antigen presentation may take place at the site of the initial inflammatory response. In the present study an attempt was made to determine the presence of the putative antigen-presenting cells in the retina of rats. METHODS: Six bone marrow chimeras were constructed by transferring 50 x 10(6) donor [Lewis x Brown Norway, (LBN) F1] bone marrow cells into lethally irradiated Brown Norway rats. Three chimeras, 3 Lewis, and 2 Brown Norway rats each received intravenous injections of gamma interferon (IFN-gamma) at a dose of 2 x 10(5) U/rat, 48 and 24 hours before enucleation of the globes. Enucleated globes from the 3 remaining untreated chimeras, 21 additional Lewis rats, and 6 Brown Norway rats served as controls. Retinas from all globes were prepared for either wholemount or cryosectioning and were stained using various primary antibodies, including anti-Lewis MHC class II (OX3), anti-rat MHC class II (OX6), anti-Lewis MHC class I (II-69), anti-rat MHC class I (OX18), anti-macrophage complement receptor 3 (OX42), anti-monocytes/macrophages (ED1, ED2, and ED3), and anti-glial fibrillary acidic protein (GFAP). Fluorescein-conjugated goat anti-mouse and rhodamine-conjugated anti-rabbit immunoglobulins were used to detect the monoclonal or polyclonal antibodies, respectively. All the specimens were examined under Zeiss confocal laser scanning microscopy. The positively stained cells were counted for quantitative analysis. RESULTS: Major histocompatibility complex class II (OX6)-positive cells were demonstrated in the wholemount retinas of IFN-gamma-untreated chimeras, Lewis, and Brown Norway rats. These cells showed a dendritic morphology and increased significantly in number in IFN-gamma-treated Lewis and Brown Norway rats. Expression of Lewis-specific class I (II-69) and class II (OX3) molecules was detected in a few perivascular cells in the retina of chimeric rats treated with IFN-gamma. Most dendritic cells in the retina expressed the macrophage markers, ED1 and OX42, without IFN-gamma treatment. However, vascular endothelia, retinal pigment epithelia, Müller cells, and astrocytes stained neither by Class II molecules nor by macrophage markers. The vascular endothelium and retinal pigment epithelium was found to express constitutively class I molecules (OX18). CONCLUSIONS: A subpopulation of retinal microglia can express MHC class II molecules. Only a few of these are derived from bone marrow. Retinal microglial cells, particularly those derived from bone marrow, may participate in antigen presentation and the subsequent development of retinitis, as seen in S-antigen-induced experimental autoimmune uveoretinitis.

Animals↗
PubMed1981

The major histocompatibility complex of primates: evolutionary aspects and comparative histogenetics.

All mammalian species investigated have a chromosomal region designated as the major histocompatibility complex or m.h.c. The biological significance of the m.h.c. goes far beyond controlling the most important histocompatibility or transplantation antigens; the capacity to respond immunologically, the susceptibility to disease (including cancer), the serum level of several complement factors and numerous other biological traits are regulated by genetic systems closely linked within that chromosomal region. While the basic structure of the m.h.c. seems to be rather similar for all mammalian species, the similarities among the m.h.c. of human and non-human primates are particularly impressive. In this communication, m.h.c. gene products of rhesus monkey, chimpanzee and man are compared and reviewed. Evolutionary aspects of the persistence of the m.h.c. region or 'supergene' throughout the animal kingdom are discussed.

Animals↗
PubMed1997

The recognition of the nonclassical major histocompatibility complex (MHC) class I molecule, T10, by the gammadelta T cell, G8.

Recent studies have shown that many nonclassical major histocompatibility complex (MHC) (class 1b) molecules have distinct antigen-binding capabilities, including the binding of nonpeptide moieties and the binding of peptides that are different from those bound to classical MHC molecules. Here, we show that one of the H-2T region-encoded molecules, T10, when produced in Escherichia coli, can be folded in vitro with beta2-microglobulin (beta2m) to form a stable heterodimer in the absence of peptide or nonpeptide moieties. This heterodimer can be recognized by specific antibodies and is stimulatory to the gammadelta T cell clone, G8. Circular dichroism analysis indicates that T10/beta2m has structural features distinct from those of classical MHC class I molecules. These results suggest a new way for MHC-like molecules to adopt a peptide-free structure and to function in the immune system.

Clone Cells↗
PubMed1991

Inhibitory effect of interferon-gamma-dependent induction of major histocompatibility complex class II antigen by expressing exogenous poly(ADP-ribose) synthetase gene.

Ia antigen, one of class II major histocompatibility complexes, was induced by treatment of mouse macrophage P388D1 cells with interferon-gamma. During the process, expression of poly(ADP-ribose) synthetase gene was depressed. We examined whether or not down-regulation of the synthetase was required for the interferon-gamma-dependent induction of Ia antigen. We constructed expression plasmid harboring metallothionein promoter-regulated synthetase gene. The enzyme activity and mRNA level of the synthetase were increased in exogenous synthetase gene-transfected clones. Induction of Ia antigen gene was strongly inhibited by expressing the exogenous synthetase gene upon treatment of the transfected clones with interferon-gamma. The result suggests that interferon-gamma-dependent down-regulation of the synthetase may be involved in a step of the signal transduction to induce Ia antigen.

Animals↗
PubMed1983

Influence of culturing on the functioning of major-histocompatibility-complex-compatible and incompatible islet grafts in diabetic mice.

Culturing B10.BR (H-2k) islets promotes their survival in major histocompatibility complex (MHC)-incompatible BALB/c (H-2d) mice, but not in MHC-compatible CBA (H-2k) animals. These results provide further evidence that MHC restriction is involved in transplantation immunity--i.e., that allografts are only recognized as foreign if they possess donor macrophages (or cells of this family), or if antigen-presenting cells MHC-compatible with the graft can be provided by the host.

Animals↗
PubMed1982

A molecular map of the immune response region from the major histocompatibility complex of the mouse.

A stretch of 200 kilobases (kb) of DNA from the I region of the mouse major histocompatibility complex has been cloned and characterized. It contains the genes for the biochemically defined class II proteins E alpha, E beta and A beta. DNA blot analyses suggest that the I region may contain only 6-8 class II genes. Correlation of our molecular map with the genetic map of the I region confines two of the five I subregions, I-J and I-B, to less than 3.4 kb of DNA at the 3' end of the E beta gene where a hotspot for recombination has been observed. Indeed, the I-A and I-E subregions may be contiguous. If so, the I-B and I-J subregions are not encoded in the I region between the I-A and I-E subregions.

Animals↗
PubMed1982

Orientation of loci in the major histocompatibility complex of the rat and its comparison to man and the mouse.

Among 290 F2 progeny of an r10 X ACP cross were two recombinants which allowed the loci for glyoxalase-1 and neuraminidase-1 to be mapped relative to the RT1.A and dw-3 loci in the major histocompatibility complex (MHC) of the rat. In 673 progeny of the same cross there was a recombinant between ft and dw-3, and in 403 progeny of the backcross BY1 X (BY1 X BDIX)F1 there was another recombinant between ft and dw-3. These data, combined with those from previous studies, provide the information for constructing a detailed map of the rat major histocompatibility complex: the gene order and size in the rat are very similar to those in the mouse and different from those in man and in the other species that have been studied. Comparison of the structures of the MHC in the various species leads to a hypothesis about the evolution of the MHC which involves sequential duplications of the genes coding for class I and class II loci and an inversion in the prototypic muridae which placed the class II loci between the class I loci.

Animals↗
PubMed1997

Neuronal expression of class II major histocompatibility complex (HLA-DR) in 2 cases of Pick disease.

BACKGROUND: Pick disease is a progressive form of dementia characterized by personality changes, speech disturbances, inattentiveness, and occasionally extrapyramidal phenomena. Although several variants have been recognized, the pathological profile of Pick disease includes focal frontotemporal atrophy, neuronal loss, astrocytosis, Pick bodies, and Pick cells. To date, little is known about the etiology of Pick disease. OBJECTIVE: To evaluate the possibility of inflammatory processes occurring in Pick disease pathophysiology. DESIGN: Immunohistochemistry for HLA-DR and related molecules was performed in brain tissue from individuals with Pick disease, Alzheimer disease, and diffuse Lewy body disease, as well as from neurologically normal controls. RESULTS: We report the unusual expression of the class II major histocompatibility complex protein Ia (HLA-DR) on neurons in 2 cases of Pick disease. In addition, both cases exhibited a dramatic microglial response. Neuronal HLA-DR immunostaining was not observed in 12 other cases of Pick disease or cases of Alzheimer disease, cases of diffuse Lewy body disease, or in control cases run con-currently. In addition, the pattern of HLA-DR staining observed in Pick disease was confirmed with another monoclonal antibody to HLA-DR. Frequent in vitro inducers of HLA-DR expression and enhanced class I major histocompatibility expression, interferon gamma, and tumor necrosis factor alpha were not detected. CD4-positive T lymphocytes were also not present and class I major histocompatibility complex expression was not detected on neurons or glia from brain tissue with Pick disease. CONCLUSIONS: These results are the first to demonstrate class II major histocompatibility complex expression on neurons. Based on these preliminary results, we suggest that some cases of Pick disease may be complicated by or involve in inflammatory process.

Aged↗
PubMed2001

Sequence of the swine major histocompatibility complex region containing all non-classical class I genes.

A segment of 158,063 nucleotides of the pig major histocompatibility complex (SLA) and corresponding to the junction of the class I and class III regions was sequenced entirely. The centromeric part of the segment contained six class III genes including the three tumor necrosis factor genes, while the telomeric part contained three genes belonging to the class I region. The order and the molecular organization of these genes were exactly conserved in the SLA and HLA complexes, except for the SC1 gene which displayed a shift of the reading frame in swine. The cluster of the three SLA class I-related genes (Ib) and the MIC1 and MIC2 genes were located in the middle of the segment, in the following order from the centromeric side onwards, SLA-6, SLA-7, SLA-8, MIC-1 and MIC-2. All three SLA Ib genes displayed an overall molecular structure compatible with the expression of membrane-anchored glycoproteins. The SLA-7 and SLA-8 genes bear greater resemblance than to the SLA-6 gene. Six SLA-6 alleles have been previously defined differing each from the other by unique point mutations. One of them, appeared to have arisen through the occurrence of a gene conversion event in which the SLA-7 gene served as template. Only MIC-2 gene might be functional, the second MIC-1 gene being truncated. In all, the 14 genes characterized spans 37% of the total sequence. The remaining 63% nucleotides comprised a number of repeat DNA motives, including LINE fragments, SINEs, microsatellites, and also numerous nucleotide stretches not yet defined in swine.

Alleles↗