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PubMed1977

Analysis of the major histocompatibility complex in Syrian hamsters. III. Cellular and humoral immunity to alloantigens.

Among the genetic loci incorporated into the major histocompatibility complex in every species studied to date have been prominent genes encoding for strong histocompatibility determinants that elicit detectable alloantibody responses and which are the chief antigenic targets of cell-mediated cytotoxicity reactions. The K and D regions of the H-2 complex in the mouse and the A, B, and C regions of the HLA complex in man are representative examples. Syrian hamsters, as described in this report, do not make alloantibodies to antigens of this type and only very poorly do they carry out in vitro cell-mediated cytotoxicity to target cells putatively bearing these antigens. Since hamsters are quite capable of discriminating analogous antigenic differences in xenogeneic species, and xenogeneic sources cannot distinguish immunologically between the antigens encoded by the two hamster major histocompatibility alleles. Hm-1a and Hm-1b, we conclude that the hamster strains we work with are serologically indistinguishable by the methods used here. However, they obviously differ for determinants which elicit T cell-mediated responses, as evidenced by their ability to express acute skin graft rejection, mixed lymphocyte reactivity, graft-vs-host reactions, and cell-mediated cytotoxicity reactions. Such alloreactivity may reflect a mutation at an SD locus, affecting antigenic sites recognized only by T cells, or that the available hamster strains are SD identical, but differ at loci similar to the I region loci in mice. Alternatively, we cannot exclude the possibility that Syrian hamsters somehow fail to express properly the genes coding for SD determinants.

Animals↗
PubMed1987

Linkage of the preimplantation-embryo-development (Ped) gene to the mouse major histocompatibility complex (MHC).

The preimplantation-embryo-development (Ped) gene influences the rate of cleavage division of preimplantation mouse embryos. The location of the Ped gene in the mouse major histocompatibility complex (MHC), the H-2 complex, has been inferred from the analysis of cleavage rates of embryos from mouse strains congenic at the H-2 complex. In this paper, formal genetic linkage studies were undertaken to evaluate linkage of the Ped gene to the H-2 complex. Co-segregation of Ped gene phenotype and H-2 haplotype was found in back-cross embryos. These data support the hypothesis that the Ped gene is linked to the H-2 complex.

Animals↗
PubMed1994

Constitutive CD8 expression allows inefficient maturation of CD4+ helper T cells in class II major histocompatibility complex mutant mice.

Although mature CD4+ T cells bear T cell receptors (TCRs) that recognize class II major histocompatibility complex (MHC) and mature CD8+ T cells bear TCRs that recognize class I MHC, it is possible that the initial commitment of an immature thymocyte to a CD4 or CD8 lineage is made without regard to the specificity of the TCR. According to this model, CD4+ cells with class I TCR do not mature because the CD8 coreceptor is required for class I MHC recognition and positive selection. If this model is correct, constitutive expression of CD8 should allow CD4+ T cells with class I-specific TCRs to develop. In this report, we show that mature peripheral CD4+ cells are present in class II MHC-deficient mice that express a constitutive CD8.1 transgene. These cells share a number of properties with the major class II MHC-selected CD4 population, including the ability to express CD40 ligand upon activation. Although mature CD4 cells are also detectable in the thymus of class II MHC mutant/CD8.1 transgenic mice, they represent a small fraction of the mature CD4 cells found in mice that express class II MHC. These results indicate that some T cells choose the CD4 helper lineage independent of their antigen receptor specificity; however, the inefficiency of generating class I-specific CD4 cells leaves open the possibility that an instructive signal generated upon MHC recognition may bias lineage commitment.

Animals↗
PubMed1989

Structure of the human RD gene: a highly conserved gene in the class III region of the major histocompatibility complex.

We cloned and determined the DNA sequence of a novel gene (termed RD or D6S45) situated in the class III region of the human major histocompatibility complex (HLA) between the Bf and C4A complement genes. The coding region of the gene is contained in 10 exons spread over approximately 6 kb of DNA. The encoded protein is predicted to contain 371 amino acid residues with a molecular weight of 41,000. The predicted amino acid sequence is notable for a central region containing 24 consecutive pairs of alternating basic (Arg) and acidic (Asp or Glu) residues similar to, but more strictly alternating than, those seen in the 70K protein of the U1 small nuclear ribonucleoprotein (snRNP). There is a high degree of homology both at the amino acid and DNA level between the human RD gene and its murine homology. Although the central region is highly repetitious and contains a high proportion (13%) of CpG dinucleotides-both features that might predispose to frequent mutations-sequence analysis of this region in genes amplified from six individuals revealed no polymorphism.

Amino Acid Sequence↗
PubMed1984

Distribution of the major histocompatibility complex antigens on different cellular components of human liver.

Monoclonal mouse antibodies to the "framework" determinants of the class I and II molecules of the major histocompatibility complex (MHC) were used to demonstrate the presence of the MHC antigens in human liver. First, the localization of these antigens was demonstrated from frozen section histology with indirect FITC immunofluorescence and the cell component(s) binding the mouse antibody were identified by rabbit marker antisera and indirect TRITC immunofluorescence. Second, the antigen expression on the cell surface was analyzed by the Staphylococcus aureus rosette method from cytological cell smears. All antibodies reacted with cells in the liver sinusoids, both with the Kupffer cells and at least partially with the sinusoidal endothelial cells. The same antisera reacted also with the bile duct cells, though weaker, and with some stromal cells in close proximity of the blood vessels. The vascular endothelial cells of hepatic artery, hepatic vein, and portal vein displayed no reaction. Thus human liver differs strikingly from, e.g., human kidney, where the vascular endothelial cells contain large amounts of MHC antigens on the cell surface. This difference may be one explanation to why liver allografts are less promptly rejected than renal allografts in man.

Animals↗
PubMed1978

Acquisition of murine major histocompatibility complex gene products by schistosomula of Schistosoma mansoni.

Schistosoma mansoni schistosomula recovered from the lungs of inbred mice were shown to possess serologically detectable alloantigens on their tegumental surfaces. Using appropriate antisera and infected congenic and recombinant mice as worm donors, gene products of the K and I subregions of the major histocompatibility complex were demonstrated among these alloantigens acquired by the parasites. In contrast, other cell surface alloantigens, such as Thy 1, Ly 1, and H-Y and the serum proteins albumin, C3 and Ig, could not be detected on the surface of lung schistosomula by means of comparable techniques. In another series of experiments, schistosomula recovered from the lungs of mice and reinjected into allogeneic recipients were shown to exchange their alloantigens during an 87-h period of examination. Similarly, lung schistosomula cocultured with allogeneic lymphocytes were shown to acquire major histocompatibility complex (MHC) coded antigens from the cells. It is possible that as acquired host molecules, MHC gene products may disguise the surface of schistosome parasites thereby rendering them insusceptible to immune attack.

Animals↗
PubMed1990

DNA polymorphism of major histocompatibility complex class II and class III genes in systemic lupus erythematosus.

We investigated the Taq I digested DNA restriction fragment length polymorphism (RFLP) of the Major Histocompatibility Complex (MHC) class II genes: HLA-DRB, -DQA, and the class III genes: C4 and 21-hydroxylase(CYP21) in 56 caucasoid patients with systemic lupus erythematosus (SLE) and 62 control subjects in order to define the molecular variation of these genes and their association with SLE. The results showed that the gene frequencies of both HLA-DR2 and -DR3 were significantly increased in the SLE population compared to normal subjects (DR2: 21.4% vs 10.7% chi 2 = 4.5. DR3: 29.6% vs 13.3%; chi 2 = 8.3). A high frequency of C4A and CYP21A gene deletions was also found in SLE patients (SLE 52%, normals 24%). All of 22 SLE patients, and 12 of 15 normal subjects who had C4A and CYP21A gene deletions had a 10.0kb Taq 1 DRB RFLP attributable to the presence of HLA-DR3. Family studies showed linkage of C4A/CYP21A deletions with HLA-B8 and -DR3, and confirmed the previously demonstrated association of the HLA-B8, DR3, C4A*Q0, C4*B1, Bf*S, C2*C haplotype with SLE. Deletions affecting the C4A and CYP21A genes were the commonest cause of C4A null alleles in SLE. No strong association between C4 null phenotype or C4 gene deletion, as determined by RFLP, was observed in patients who possessed DR2.

Complement C4↗
PubMed1996

The chicken beta 2-microglobulin gene is located on a non-major histocompatibility complex microchromosome: a small, G+C-rich gene with X and Y boxes in the promoter.

beta 2-Microglobulin is an essential subunit of major histocompatibility complex (Mhc) class I molecules, which present antigenic peptides to T lymphocytes. We sequenced a number of cDNAs and two genomic clones corresponding to chicken beta 2-microglobulin. The chicken beta 2-microglobulin gene has a similar genomic organization but smaller introns and higher G+C content than mammalian beta 2-microglobulin genes. The promoter region is particularly G+C-rich and contains, in addition to interferon regulatory elements, potential S/W, X, and Y boxes that were originally described for mammalian class II but not class I alpha or beta 2-microglobulin genes. There is a single chicken beta 2-microglobulin gene that has little polymorphism in the coding region. Restriction fragment length polymorphisms from Mhc homozygous lines, Mhc congenic lines, and backcross families, as well as in situ hybridization, show that the beta 2-microglobulin gene is located on a microchromosome different from the one that contains the chicken Mhc. We propose that the structural similarities between the beta 2-microglobulin and Mhc genes in the chicken are due to their presence on microchromosomes and suggest that these features and the microchromosomes appeared by deletion of DNA in the lineage leading to the birds.

Amino Acid Sequence↗
PubMed1987

Genetic resistance to fowl cholera is linked to the major histocompatibility complex.

Chickens of the Iowa State S1 line have been selected for ability to regress Rous sarcoma virus-induced (RSV) tumors, humoral immune response to GAT (Ir-GAT), and erythrocyte antigen B. Sublines homozygous at the major histocompatibility complex (MHC), as well as F1 heterozygotes and F2 segregants, were tested for resistance to fowl cholera by challenge with Pasteurella multocida strain X73. Control of the response at high doses was associated in a preliminary study with Ir-GAT and response to RSV tumors. Genetic control of resistance to low doses of P. multocida was demonstrated via sublines and F2 segregants to be linked with genes of the B-G region. Thus, genetic control of resistance to fowl cholera in chickens after exposure to Pasteurella multocida was shown to be linked to the major histocompatibility B complex, in this first demonstration of MHC-linked resistance to bacterial disease challenge.

Alleles↗
PubMed1995

The major histocompatibility complex region marked by HSP70-1 and HSP70-2 variants is associated with clozapine-induced agranulocytosis in two different ethnic groups.

Genes of the major histocompatibility complex (MHC) have been associated with susceptibility to drug-induced adverse reactions. We previously found that clozapine-induced agranulocytosis (CA) is associated with the HLA-DRB1*0402, DRB4*0101, DQB1*0302, DQA1*0301 haplotype in Ashkenazi Jewish patients and with the HLA-DRB1*1601, DRB5*02, DQB1*0502, DQA1*0102 haplotype in non-Jewish patients. In the present study, we tested the hypothesis that the variants of the heat-shock protein 70 (HSP-70) encoded by the HSP-70 loci located within the MHC region and known to be involved in apoptosis and regulation of cell proliferation could play an important role in molecular mechanisms of CA. First, we analyzed HSP70-2 polymorphism in risk-associated haplotypes from HLA homozygous cells and normal individuals and confirmed that the HSP70-2 9-kb variant was associated invariably with DR4 (HLA-DRB1*0402, DQB1*0302) and DR2 (HLA-DRB1*01601, DQB1*0502, DQA1*0102 and HLA-DRB1*1501, DQB1*0602) haplotypes, which were the haplotypes found increased in Jewish and non-Jewish patients with CA, respectively. The 9.0-kb variant was also found to be associated with HLA-B44, DRB1*0401 and HLA-B44, DRB1*07 haplotypes. Second, in patients with CA (12 Ashkenazi Jewish and 20 non-Jewish patients), HSP70-1 A and HSP70-2 9.0-kb variants were associated with the MHC haplotypes found by us to be markers of susceptibility to CA. The clozapine-treated control group had an excess number of HSP70-1 C and HSP70-2 8.5-kb variants, consistent with genetic resistance to CA associated with those variants. This finding supports our hypothesis that a dominant gene within the MHC region (marked by HSP70-1 and HSP70-2), but not necessarily HLA, is associated with CA in two different ethnic groups.

Agranulocytosis↗
PubMed1991

Novel detection of restriction fragment length polymorphisms in the human major histocompatibility complex.

Cosmid genomic DNA clones have been used as hybridization probes in genomic Southern blot analysis to define restriction fragment length polymorphisms (RFLPs) in the major histocompatibility complex (MHC). Using 14 different enzymes and three overlapping cosmid clones we have detected six RFLPs in a 100 kilobase (kb) segment of DNA in the class III region extending centromeric of the TNFA gene toward HLA-DR. Four of the five RFLPs, defined using the enzymes Taq I, Rsa I, Hinc II, and Hind III, and detected by the cosmid clone cosM7B, map to a 29 kb segment of DNA that includes all of the recently described G2 (BAT2) gene and a large portion of the 3' end of the G3 (BAT3) gene. The different RFLP variants were established by analyzing the DNA from three informative families and a panel of 51 HLA-homozygous typing cell lines. CosM7B detects Taq I variants of 4.3 kb, and 2.9 kb or 2.8 kb, Rsa I variants of 2.9 kb or 2.4 kb, Hinc II variants of 5.8 kb or 3.8 kb and 1.4 kb, and a Hind III variant of 4.8 kb, while cosOT2 detects Taq I variants of 4.5 kb or 4 kb. The distribution of the Rsa I, Hinc II and Taq I RFLPs detected by cosM7B, and the Taq I RFLP detected with cosOT2, within the panel of cell line DNAs was assessed by Southern blotting. The 4.3 kb Taq I variant was observed in only one cell line with the extended haplotype HLA-A29, C-, B44, SC30, DR4. The other RFLPs, however, occurred much more frequently. The 2.8 kb Taq I variant was observed in 20% of haplotypes, the 2.9 kb Rsa I variant was observed in 42% of haplotypes, and the 5.8 kb Hinc II variant was observed in 12% of haplotypes analyzed. The 4.5 kb Taq I variant detected by the overlapping cosmid cosOT2 was present in 21% of haplotypes. Analysis of the RFLP variants with each other revealed seven different haplotypic combinations. Three of the haplotypic combinations were each subdivided into two subsets on the basis of the Nco I RFLP variant they carried at the TNF-B locus. These haplotypic combinations potentially allow differentiation among different extended haplotypes such as HLA-B8, SC01, DR3, HLA-B18, F1C30, DR3, and HLA-B44, FC31, DR7. The RFLPs detected by the cosmid clones thus provide new tools which will be useful in the further genetic analysis of the MHC class III region.

Alleles↗
PubMed1994

Processing and major histocompatibility complex binding of the MTV7 superantigen.

Mouse mammary tumor viruses produce superantigens (vSAGs) which interact with class II major histocompatibility complex (MHC) proteins and stimulate T cells. vSAGs are synthesized as Type II membrane proteins, but at least one of these proteins (vSAG7) is found on the cell surface in a proteolytically processed form. Monoclonal antibodies (MAbs) were used to characterize vSAG7 and its binding to class II molecules. vSAG7 is synthesized in the endoplasmic reticulum (ER) as a 45 kd glycoprotein containing N-asparagine-linked oligomannosyl carbohydrates. vSAG7 transits the golgi complex, where it is modified by the addition of complex-type glycans and proteolysed at three positions. After proteolysis, the amino and carboxyl termini remain noncovalently associated. The ER, golgi, and surface forms of vSAG7 are stably bound to class II, but one of the proteolysed forms comprises the majority of the class II-bound material.

Amino Acid Sequence↗
PubMed2003

The major histocompatibility complex gene region and sarcoidosis susceptibility in African Americans.

Investigators have intensively evaluated the major histocompatibility (MHC) complex for sarcoidosis susceptibility genes with the majority of reports implicating the human leukocyte antigen (HLA)-DRB1 gene. Because most studies have been performed in white and Asian populations, we sought to determine which MHC genes might be risk factors for sarcoidosis in African Americans. We genotyped six microsatellite markers spanning 11.6 megabases that overlapped the MHC region on chromosome 6p21-22 in 225 nuclear families ascertained by African American probands with a history of sarcoidosis. Using a family-based association methods approach, we performed multiallelic tests of association between each marker and sarcoidosis. A statistically significant association was detected between sarcoidosis and the DQCAR marker (p = 0.002) less than two kilobases telomeric from the HLA-DQB1 gene. Typing two additional markers in this region revealed that DQCAR-G51152 haplotypes, spanning a 38-kilobase region across the HLA-DQB1 gene, were associated with sarcoidosis on a global level (p = 0.022). Analysis of individual DQCAR and G51152 alleles showed that the DQCAR 178 (expected = 21.0; observed = 10; p = 0.0005) and G51152 217 (expected = 25.6; observed = 14; p = 0.0009) alleles were transmitted to affected offspring less often than expected; whereas the DQCAR 182 allele was transmitted more often than expected (expected = 52.6; observed = 66; p = 0.002). Our results indicate that HLA-DQB1 and not HLA-DRB1 plays an important role in sarcoidosis susceptibility in African Americans. Identification of the specific HLA-DQB1 alleles that influence sarcoidosis susceptibility in African Americans and the study of their antigenic-binding properties may reveal why African Americans suffer disproportionately from this disease.

Black People↗
PubMed1989

Testing for cell surface forms of class II major histocompatibility complex antigens and Ii by radioiodination, biotinylation, and membrane immunofluorescence.

Antibodies to either Ii or class II major histocompatibility complex (MHC) antigens did not recognize cell surface forms of Ii in immunoprecipitates of cells that had been radioiodinated by the lactoperoxidase method, whereas they bound [35S]methionine metabolically labeled molecules. N-hydroxysuccinimidobiotin (NHS-B) and biotin hydrazide (B-H) were used to react more generally with cell surface proteins via amino groups and nitrene coupling, respectively. Each of these latter compounds labeled alpha and beta chains of class II MHC antigens as seen in Western-blotted, electrophoresed immunoprecipitates probed with 125I-labeled streptavidin but not Ii or its associated forms. Although tyrosine residues might have been inaccessible to radioiodination in carbohydrate-derivatized forms of Ii, the lack of Ii biotinylation in these controlled, sensitive studies was consistent with the view that Ii forms were not surface expressed, with the possible exception of the chondroitin sulfate-derivatized forms of Ii (Ii-CS).

Antigens, Surface↗
PubMed1989

Different staphylococcal enterotoxins bind preferentially to distinct major histocompatibility complex class II isotypes.

The stimulation of T cells by staphylococcal enterotoxins (SE) is strictly dependent on major histocompatibility complex (MHC) class II-bearing cells. The interaction between SE and MHC class II molecules was studied on the human B cell lymphoma Raji and its MHC class II-negative variant RJ 2.2.5. Affinity purification with SEA and SEB matrix allowed the isolation of HLA-DR-like molecules from detergent lysates of 125I surface-labeled Raji cells, but not from RJ 2.2.5 cells. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis also revealed preferences in the binding of other SE such as SED, SEE and toxic shock syndrome toxin 1 to DR-like molecules, SEC2 to HLA-DQ-like molecules and SEC3 to DR- and DQ-like molecules. Preadsorption of the different MHC class II MHC isotypes confirmed the preferential binding of SEA to DR and of SEC2 to DQ. The implications of these findings for the understanding of SE-induced T cell activation and the potency of SE as a tool in the study of MHC class II antigens are discussed.

Chromatography, Affinity↗
PubMed1996

'Empty' Ld molecules capture peptides from endocytosed hepatitis B surface antigen particles for major histocompatibility complex class I-restricted presentation.

Peptides recognized by CD8+ cytotoxic T lymphocytes in the context of major histocompatibility complex (MHC) class I molecules are usually derived from endogenous proteins synthesized within the cell. Exogenous 22-nm hepatitis B surface antigen (HBsAg) particles are taken up by many cells, and are processed in a novel peptide-transporter-independent, endosomal or lysosomal pathway for class I (Ld)-restricted epitope presentation. Here, we present evidence that 'empty' Ld molecules derived from the cell surface are involved in presenting antigenic peptides from endocytosed HBsAg particles. Intracellular assembly of presentation-competent, trimeric Ld molecules required endocytosis of the exogenous antigen and 'empty' Ld molecules. These data assign a functional role to surface-associated, 'empty' MHC class I molecules.

Animals↗
PubMed1997

Engagement of a T cell receptor by major histocompatibility complex irrespective of peptide.

T cell receptors (TCR) identify target cells presenting a ligand consisting of a major histocompatibility complex molecule (MHC) and an antigenic peptide. A considerable amount of evidence indicates that the TCR contacts both the peptide and the MHC components of the ligand. In fully differentiated T cells the interaction between the peptide and the TCR makes the critical contribution to eliciting a cellular response. However, during the positive selection of thymocytes the contribution of peptide relative to MHC is less well established. Indeed it has been suggested that the critical interaction for positive selection is between the TCR and the MHC molecule and that peptides can be viewed as either allowing or obstructing this contact. This predicts that a given TCR is capable of engaging multiple MHC/peptide complexes. In this study a system is described which detects simply engagement of the TCR by MHC/peptide complexes rather than the functional outcome of such interactions. Using this approach the extent to which peptides can influence contacts between the TCR and the MHC molecule has been examined. The results show that the TCR does in fact engage a wide range of ligands in an MHC-restricted but largely peptide-independent manner, suggesting that only a few peptides are able to prevent the TCR from contacting the MHC molecule.

Animals↗
PubMed1997

Location-specific regulation of transgenic Ly49A receptors by major histocompatibility complex class I molecules.

Inhibitory receptors expressed on natural killer (NK) cells and T cells specific for major histocompatibility complex (MHC) class I are believed to prevent these cells from responding to normal self tissues. To understand the regulation and function of Ly49 receptor molecules in vivo, we used the CD2 promoter to target Ly49A expression to all thymocytes, T cells, and NK cells. In animals expressing its MHC class I ligand, H-2Dd or H-2Dk, there was a large decrease in the expression of Ly49A on thymocytes, peripheral T cells, and NK1.1+ cells. The extent of the down-regulation of Ly49A was dependent on the expression of the MHC ligand for Ly49A and on the site where the cells were located. The level of expression of endogenous Ly49A was similarly found to be dependent upon the organ where the cells resided. Data from bone marrow chimeras indicated that most cell types may regulate Ly49A expression, but the efficacy to regulate receptor expression may vary depending on the cell type.

Animals↗