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PubMed1987

Expression of class II major histocompatibility complex antigens on pancreatic B cells in the NOD mouse.

To elucidate the role of class II major histocompatibility complex antigen expression on pancreatic B cells in the development of diabetes in the non-obese diabetic (NOD) mouse, indirect immunofluorescence was employed for I-A staining on Bouin-fixed pancreas sections of NOD mice (I-A of which was reported as d), B10.GD (I-A, d), BALB/c (I-A, d) and C3H/He (I-A, k). I-A positive islets were observed in all NOD mice examined. Positive reaction was detected in islets both with and without lymphocytic infiltrations. Double staining with anti-insulin, glucagon, somatostatin or pancreatic polypeptide antibodies revealed that I-A positive cells corresponded with insulin cells, while other types of pancreatic islet cells were virtually negative for I-A. Weaker staining was seen in islets of B10.GD and, to a lesser extent, in those of BALB/c mice. C3H/He mouse islet cells showed no I-A expression. These results demonstrated the expression of I-A antigens on pancreatic B cells in the NOD mouse.

Animals↗
PubMed2001

How selection shapes variation of the human major histocompatibility complex: a review.

The nature of polymorphism and molecular sequence variation in the genes of the human major histocompatibility complex (MHC) provides strong support for the idea that these genes are under selection. With the understanding that selection shapes MHC variation new questions have become the focus of study. What is the mode of selection that accounts for MHC polymorphism? Is variation maintained by pathogen pressure or by reproductive mechanisms? Discerning between these requires drawing on information from studies on association between HLA genes and infectious diseases, reproductive success and mating preferences relative to HLA genotypes, and theoretical studies that compare the outcomes of different selection regimes. The pattern that has emerged suggests that several types of selection are plausible for the maintenance of HLA polymorphism.

Alleles↗
PubMed1984

Interaction between major histocompatibility complex antigens and epidermal growth factor receptors on human cells.

It has been suggested that products of the major histocompatibility complex, the MHC, of vertebrates function in many processes of recognition and ligand binding at the cell surface. Here we show that binding of polyclonal and monoclonal antibodies against human MHC antigens, HLA, reduced the binding of epidermal growth factor (EGF) to its membrane receptors on A-431 tumor cells and on normal human fibroblasts. Binding of EGF at 37 degrees C similarly inhibited the binding of Fab fragments and intact Ig anti-HLA to human cells. The inhibitory effect of anti-HLA antibodies was rapid and dependent upon temperature and antibody concentration and valence. Fluorescence microscopy qualitatively confirmed the binding data and showed that MHC antigens and EGF-receptors do not co-cluster in the membrane.

Animals↗
PubMed1999

Mechanisms of action of major-histocompatibility-complex-linked genes affecting reproduction.

PROBLEM: To provide insight into the mechanisms of action of the major-histocompatibility-complex (MHC)-linked genes affecting reproduction. METHOD OF STUDY: The data were obtained using a variety of cellular and molecular techniques in experimental animals and from population genetic studies in humans. RESULTS: In the mouse, the preimplantation embryonic development (Ped) locus, whose functional gene is Q9, regulates fast and slow cleavage of the early embryo. There is also evidence for a growth and reproduction complex (Grc)-like region from serologic, molecular, and cytogenetic studies. In the human, the human leukocyte antigen (HLA)-G gene has been associated with an increased rate of embryonic cleavage in those embryos that express the HLA-G antigen. Sharing of HLA antigens in couples has been associated with recurrent spontaneous abortions, gestational trophoblastic tumors, and unexplained infertility. Detailed mapping studies showed that the genes responsible are not the HLA genes themselves, but genes closely linked to the HLA-DR-DQ-B genes. The HLA region genes can interact epistatically with the C3 allele of transferrin to increase the incidence of fetal loss. In the rat, the Grc region, which is closely linked to the MHC, has been associated with embryonic loss, growth defects, and susceptibility to chemical carcinogens. The Grc can interact epistatically with the tail anomaly lethal (Tal) gene or the hood restriction (Hre) gene to enhance these effects. CONCLUSIONS: There are two basic mechanisms for the effects of MHC-linked genes on reproduction and development: individual gene effects (Ped [Q9], HLA-G) and extended genetic effects (MHC-linked genes in the rat [Grc] and in the human). The nature of these genetic effects, particularly the MHC-linked effects, can also provide some insight into the different theories of human origins: These effects are most consistent with the monogenic theory.

Animals↗
PubMed2004

Killing of human immunodeficiency virus-infected primary T-cell blasts by autologous natural killer cells is dependent on the ability of the virus to alter the expression of major histocompatibility complex class I molecules.

In the current study, we evaluated whether the capacity of HIV to modulate major histocompatibility complex (MHC) class I molecules has an impact on the ability of autologous natural killer (NK) cells to kill the HIV-infected cells. Analysis of HIV-infected T-cell blasts revealed that the decrease in MHC class I molecules on the infected cell surface was selective. HLA-A and -B were decreased on cells infected with HIV strains that could decrease MHC class I molecules, whereas HLA-C and -E remained on the surface. Blocking the interaction between HLA-C and -E and their corresponding inhibitory receptors increased NK cell killing of T-cell blasts infected with HIV strains that reduced MHC class I molecules. Moreover, we demonstrate that NK cells lacking HLA-C and -E inhibitory receptors kill T-cell blasts infected with HIV strains that decrease MHC class I molecules. In contrast, NK cells are incapable of destroying T-cell blasts infected with HIV strains that were unable to reduce MHC class I molecules. These findings suggest that NK cells lacking inhibitory receptors to HLA-C and -E kill HIV-infected CD4+ T cells, and they indicate that the capacity of NK cells to destroy HIV-infected cells depends on the ability of the virus to modulate MHC class I molecules.

CD4-Positive T-Lymphocytes↗
PubMed1996

The locus-specific enhancer activity of the class I major histocompatibility complex interferon-responsive element is associated with a gamma-interferon (IFN)-inducible factor distinct from STAT1alpha, p48, and IFN regulatory factor-1.

Recent analyses of the upstream regulatory regions of the class I major histocompatibility complex genes in higher primates provided a generalized structural basis for the differential expression of A- and B-locus gene products in response to specific physiological stimulus. Among the regulatory sequences that differ between the loci is the interferon-responsive element (IRE). While the B-IRE is conserved, the A-IREs have species-specific sequence variation. We previously demonstrated that the B-IRE was an interferon (IFN)-inducible enhancer, whereas none of the A-IREs were functional. In the present study, we examined the biochemical basis for the enhancer activity of the conserved B-IRE and found that this may be attributed to a novel gamma-IFN-inducible factor. This factor accumulated in nuclei of cells within minutes of exposure to gamma-IFN. Its appearance was independent of de novo protein synthesis. However, it was not detected in nuclei of cells treated with herbimycin A, suggesting that its appearance depends on a protein kinase activation pathway. Supershift assays indicated that it was distinct from STAT1alpha, IFN regulatory factor-1, and p48, transcription factors known to bind IRE-like sequences found in regulatory regions of many non-major histocompatibility complex gamma-IFN-responsive genes. Competition assays show that this novel factor bound B-IRE with relatively high affinity, about 100-fold more than that for the A-IRE sequence. This factor was also present in STAT1alpha and p48 somatic mutants that also exhibited B-IRE enhancer activity in reporter gene bioassays in a manner similar to those seen with wild type cells. These observations indicate the existence of a novel gamma-IFN-dependent transcriptional activation pathway that correlates with the differential enhancer activity of the HLA-B IRE.

Benzoquinones↗
PubMed1992

Major histocompatibility complex associations with clozapine-induced agranulocytosis. The USA experience.

In order to determine associations between the major histocompatibility complex (MHC) and the development of clozapine-induced agranulocytosis, HLA typing was performed in a group of 42 clozapine-treated patients, of whom 11 had developed this adverse reaction. Among the patients with agranulocytosis, 7 (63%) were of Ashkenazi Jewish background and 4 (37%) were non-Jewish. An association between the HLA-B38, -DR4, -DQw3 haplotype and clozapine-induced agranulocytosis was found in all Jewish cases (7/7; 100%); in contrast only 4 of 21 (19%) Jewish control (nonagranulocytic) patients carried this haplotype. Among non-Jewish patients the HLA-DR2, -DQw1 haplotype was present in 4 of 4 (100%) patients with clozapine-induced agranulocytosis and in only 3 of 10 (30%) ethnically matched control patients. Our results indicate that gene products within the MHC could be involved in clozapine-mediated haematological toxicity.

Agranulocytosis↗
PubMed1989

A new cluster of genes within the human major histocompatibility complex.

A 435-kilobase (kb) DNA segment, which is centromeric to HLA-B in the human major histocompatibility complex, was isolated by chromosome walking with overlapping cosmids. Within the cloned region, the genes for the tumor necrosis factors (TNFs) alpha and beta and HLA-B were 210 kb apart. The human homolog of a mouse gene, B144, was located next to TNF alpha. Moreover, the presence of additional genes was suggested by a large cluster of CpG islands. With cosmid probes, several distinct transcripts were detected in RNA samples from a variety of cell lines. Altogether, five novel genes were identified by isolation of corresponding complementary DNA clones. These "HLA-B-associated transcripts" (BATs) were mapped to different locations within a 160-kb region that includes the genes for TNF alpha and TNF beta. The presence of the genes for BAT1 and BAT5 in the vicinity of HLA-B again raises the question of which gene in this region determines susceptibility to ankylosing spondylitis.

Animals↗
PubMed1994

Ancient, highly polymorphic human major histocompatibility complex DQA1 intron sequences.

A 438 basepair intron 1 sequence adjacent to exon 2 in the human major histocompatibility complex DQA1 gene defined 16 allelic variants in 69 individuals from wide ethnic backgrounds. In contrast, the most variable coding region spanned by the 247 basepair exon 2 defined 11 allelic variants. Our phylogenetic human intron 1 tree derived by the Bootstrap algorithm reflects the same relative allelic relationships as the reported DQA1 exon 2 tree [Gyllensten and Erlich, Hum Immunol 36:1-10, 1989]. Thus 3' DQA1 intron 1 and exon 2 have cosegregated since divergence of the human races. Comparison of human alleles to a Rhesus monkey DQA1 first intron sequence found only 10 nucleotide substitutions unique to Rhesus, with the other 428 positions (98%) found in at least one human allele. This high degree of homology reflects the evolutionary stability of intron sequences since these two species diverged over 20 million years ago. Because more intron 1 alleles exist than exon 2 alleles, these polymorphic introns can be used to improve tissue typing for transplantation, paternity testing, and forensics and to derive more complete phylogenetic trees. These results suggest that introns represent a previously underutilized polymorphic resource.

Algorithms↗
PubMed1982

Identification of the 45-base-long primordial building block of the entire class I major histocompatibility complex antigen gene.

Within the 885-base-long incomplete coding sequence for the mouse class I major histocompatibility complex (MHC) antigen H-2Kb heavy chain, we have identified 32 recurring base oligomers (1 decamer, 4 octamers, 9 heptamers, and 18 hexamers), the decamer being T-C-A-C-C-C-T-G-A-G. The compilation of these recurring base oligomers led to the identification of the 45-base-long primordial building block for this class of genes which is: C-C-T-G-C-G-G-A-C-A-A-T-G-T-C-A-C-C-C-T-G-A-G-C-T-G-C-T-G-G-G-C-T-C-T-G-G-G-C-G - T-T-G-A-C. Inasmuch as these base oligomers that recurred within the mouse H-2Kb coding sequence proper also recurred within the adjacent, transcribed noncoding sequence, we conclude that the entire approximately equal to 4,000-base-long germ-line DNA segment containing eight or nine separate exons of the coding sequence for class I MHC antigen heavy chains can be construed as having evolved from tandem repeats of this one 45-base-long primordial building block.

Amino Acid Sequence↗
PubMed2001

Transplantation of metanephroi across the major histocompatibility complex in rats.

To determine whether transplanted metanephroi grow, differentiate, and function in hosts that differ in major histocompatibility complex loci (RT1 loci in rats) from donors in a defined way, we implanted metanephroi from embryonic day (E) 15 PVG (RT1(c)) rat embryos into the omentum of nonimmunosupressed uninephrectomized PVG-RT1(avl) (host) rats. By 4 wk posttransplantation, metanephroi had grown and differentiated such that glomeruli, proximal and distal tubules, and collecting ducts had normal structure and ultrastructure. At 12 wk posttransplantation, weights of metanephroi were 54 +/- 8 mg. Inulin clearances were 0.9 +/- 0.3 microl. min(-1). 100 g rat wt(-1). In vitro, splenocytes from PVG rats stimulated the proliferation of cells originating from both PVG-RT1(avl) rats in which a transplant had been performed and PVG-RT1(avl) rats with no transplant. Full-thickness PVG-RT1(avl) skin engrafted normally on PVG-RT1(avl) rats in which PVG metanephroi had been previously implanted and metanephroi retained a normal appearance. In contrast, skin from PVG rats sloughed, and the tubular architecture of metanephroi was obliterated by a mononuclear cell infiltrate consistent with acute rejection. Here we show for the first time that functional chimeric kidneys develop from metanephroi transplanted across the MHC into nonimmunosupressed hosts and provide evidence that a state of peripheral immune tolerance secondary to T cell "ignorance" permits their survival.

Animals↗
PubMed1991

Association of major histocompatibility complex class III complement components C2, BF, and C4 with Brazilian paracoccidioidomycosis.

A genetic influence of the major histocompatibility complex (MHC) on the susceptibility and the development of the different clinical forms of paracoccidioidomycosis (PCM) has been postulated. In the present investigation allotypes of MHC-coded class III gene products (complement components C2, BF, C4A, and B) were determined in 69 Brazilian PCM patients and 225 healthy control individuals matched for ethnic and geographic origin. The frequency of the non-expressed C4B allele (C4B*Q0) was significantly elevated in comparison to the controls (p less than 0.01; Fisher's exact test). Three out of 69 patients had a complete C4B deficiency as against 2 among 223 control individuals. The C4A*Q0 allele was also more frequent in the patients. Other C4 alleles were not seen to differ between the two groups. The analysis of BF allotypes showed a non-significant predominance of the rarer allele BF*S07 in the patients, whereas no difference in the distribution of C2 alleles was seen. The data on MHC class III association may support the hypothesis of immune response modulation in PCM and suggest a functional genetic role of complement action against the fungus and in the outcome of PCM infection. We conclude that MHC class III products, especially C4B*Q0, are associated with chronic uni- or multifocal PCM and may influence the course of the infection.

Adolescent↗
PubMed1993

The G9a gene in the human major histocompatibility complex encodes a novel protein containing ankyrin-like repeats.

The class III region of the human major histocompatibility complex spans approx. 1.1 Mbp on the short arm of chromosome 6 and is known to contain at least 36 genes. The complete nucleotide sequence of a 3.4 kb mRNA from one of these genes, G9a (or BAT8), has been determined from cDNA and genomic DNA clones. The single-copy G9a gene encodes a protein product of 1001 amino acids with a predicted molecular mass of 111,518 Da. The C-terminal region (residues 730-999) of the G9a protein has been expressed in Escherichia coli as a fusion protein with the 26 kDa glutathione S-transferase of Schistosoma japonicum (Sj26). The fusion protein has been used to raise antisera which, in Western-blot analysis, cross-react specifically with an intracellular protein of approx. 98 kDa. The function of the G9a protein is unknown. However, comparison of the derived amino acid sequence of G9a with the protein databases has revealed interesting similarities with a number of other proteins. The C-terminal region of G9a is 35% identical with a 149 amino acid segment of the Drosophila trithorax protein. In addition the G9a protein has been shown to contain six contiguous copies of a 33-amino acid repeat. This repeat, originally identified in the Notch protein of Drosophila and known as the cdc10/SW16 or ANK repeat, is also found in a number of other human proteins and may be involved in intracellular protein-protein interactions.

Amino Acid Sequence↗
PubMed1996

Major histocompatibility complex in the rat and blood pressure regulation.

The objective of this study was to evaluate whether the major histocompatibility complex of the rat can be related to blood pressure (BP) level and BP response to stress. Blood pressure was determined under light ether anesthesia or during moderate restraint stress in normotensive Lewis rats, in rat strains congenic with respect to their RT1 haplotype [LEW.1A (RT1a) and LEW.1W (RT1u)], and in their recombinant lines LEW.1AR1 (RT1ar1), LEW.1AR2 (RT1ar2), LEW.1WR1 (RT1wr1), and LEW.1WR2 (RT1wr2). Under light ether anesthesia, systolic blood pressure was similar in Lewis, LEW.1A, and LEW.1W rats. There were also no significant differences in blood pressure in LEW.1AR1 and LEW.1AR2 animals when compared with Lewis or LEW.1A rats. In contrast, BP was significantly increased in LEW.1WR2 rats. On the other hand, moderate restraint stress induced a BP increase in animals of all recombinant lines compared to the respective congenic strains. These results confirmed our previous finding in recombinant inbred strains about the significant role of RT1 complex in BP regulation. Moreover, our data indicated that BP can be influenced by interaction of individual regions of the RT1 complex on the genetic background of Lewis strain.

Anesthesia, Inhalation↗
PubMed1984

Mep-1 gene controlling a kidney metalloendopeptidase is linked to the major histocompatibility complex in mice.

Meprin, a glycoprotein with potent metalloendopeptidase activity, is an integral component of the brush border membrane of mouse kidney. Previously we reported that genealogically related inbred mouse strains (C3H and CBA) are markedly deficient in the activity of this enzyme. We report here that meprin deficiency is inherited as an autosomal recessive trait and that several other inbred strains also express low levels of meprin activity. All of the inbred strains deficient in meprin activity are of the H-2k haplotype; however, two strains of this haplotype (C58 and C57BR/cd) expressed normal levels of the proteinase. Congeneic and recombinant mouse strains were examined to determine whether the deficiency was linked to the H-2 complex. The gene controlling the activity of meprin (Mep-1) maps on chromosome 17 to the right of the D end of the major histocompatibility complex. The Mep-1 gene is closely linked to a gene that controls isoenzyme patterns of phosphoglycerate kinase (Pgk-2). This work represents the localization of a gene that determines the activity of an integral cellular endopeptidase in mammalian tissues. In addition, the Mep-1 gene is the only identified gene linked to the major histocompatibility complex that regulates a proteinase activity.

Alleles↗
PubMed2000

Founder effect for a 26-bp deletion in the RFXANK gene in North African major histocompatibility complex class II-deficient patients belonging to complementation group B.

Expression of major histocompatibility complex (MHC) class II genes is controlled at the transcriptional level by at least four trans-acting genes, CIITA, RFXANK, RFX5, and RFXAP. Defects in these regulatory genes result in the absence of MHC class II molecule expression and, thereby, cause a combined immunodeficiency. MHC class II deficiency is inherited as an autosomal recessive trait. Since the first description of the disease, about 70 patients from 50 families have been reported. Forty-three of these families have been classified into four complementation groups: A, B, C, and D. In the largest group, B, the majority of patients are of North African origin. In two of these patients, the same mutation in the RFXANK gene (752delG-25) was identified. We performed a mutation analysis in 20 additional patients belonging to complementation group B and detected the 752delG-25 mutation in 17. All of these patients are of North African origin. A founder effect for this mutation was documented, since all tested patients, except one, display a common haplotype spanning the RFXANK locus.

Africa, Northern↗
PubMed1999

Complete sequence and gene map of a human major histocompatibility complex. The MHC sequencing consortium.

Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system. When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, clearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.

Chromosome Mapping↗
PubMed1996

The proteolytic fragments generated by vertebrate proteasomes: structural relationships to major histocompatibility complex class I binding peptides.

Proteasomes are involved in the proteolytic generation of major histocompatibility complex (MHC) class I epitopes but their exact role has not been elucidated. We used highly purified murine 20S proteasomes for digestion of synthetic 22-mer and 41/44-mer ovalbumin partial sequences encompassing either an immunodominant or a marginally immunogenic epitope. At various times, digests were analyzed by pool sequencing and by semiquantitative electrospray ionization mass spectrometry. Most dual cleavage fragments derived from 22-mer peptides were 7-10 amino acids long, with octa- and nonamers predominating. Digestion of 41/44-mer peptides initially revealed major cleavage sites spaced by two size ranges, 8 or 9 amino acids and 14 or 15 amino acids, followed by further degradation of the latter as well as of larger single cleavage fragments. The final size distribution was slightly broader than that of fragments derived from 22-mer peptides. The majority of peptide bonds were cleaved, albeit with vastly different efficiencies. This resulted in multiple overlapping proteolytic fragments including a limited number of abundant peptides. The immunodominant epitope was generated abundantly whereas only small amounts of the marginally immunogenic epitope were detected. The frequency distributions of amino acids flanking proteasomal cleavage sites are correlated to that reported for corresponding positions of MHC class I binding peptides. The results suggest that proteasomal degradation products may include fragments with structural properties similar to MHC class I binding peptides. Proteasomes may thus be involved in the final stages of proteolytic epitope generation, often without the need for downstream proteolytic events.

Amino Acid Sequence↗