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PubMed2002

HLA-G transactivation by cAMP-response element-binding protein (CREB). An alternative transactivation pathway to the conserved major histocompatibility complex (MHC) class I regulatory routes.

The expression of HLA-G in extravillous cytotrophoblast cells coincides with a general lack of classical major histocompatibility complex (MHC) class I expression in this tissue. This differential expression of HLA-G and classical HLA class I molecules in trophoblasts suggests a tight transcriptional control of MHC class I genes. Transactivation of the classical MHC class I genes is mediated by two groups of juxtaposed cis-acting elements that can be viewed as regulatory modules. Both modules are divergent in HLA-G, rendering this gene unresponsive to NF-kappaB, IRF1, and class II transactivator (CIITA)-mediated induction pathways. In this study, we searched for alternative regulatory elements in the 1438-bp HLA-G promoter region. HLA-G was not responsive to interferon-alpha (IFNalpha), IFNbeta, or IFNgamma, despite the presence of an upstream ISRE binding IRF1 in vitro. However, the HLA-G promoter contains three CRE/TRE elements with binding affinity for CREB/ATF and Fos/Jun proteins both in vitro and in vivo. In transient transfection assays, it was shown that HLA-G transactivation is regulated by CREB, CREB-binding protein (CBP), and p300. Moreover, immunohistochemical analysis demonstrated that HLA-G is co-expressed with CREB and CBP in extravillous cytotrophoblasts, revealing the in vivo relevance of this transactivation pathway. This implies a unique regulation of HLA-G transcription among the MHC class I genes.

Chromatin↗
PubMed1983

Complete primary structures of the E beta chain and gene of the mouse major histocompatibility complex.

Using the cross-hybridization with plasmid pDC beta-1, containing the cDNA coding for the DC beta chain of the human major histocompatibility complex class II molecules, we have cloned and subjected to sequence analysis both the cDNA and genomic gene for the E beta chain of the BALB/c (d haplotype) mouse. The nucleotide sequences of the cDNA and genomic DNA clones permitted us to deduce the entire primary structure of the E beta chain and the complete exon-intron structure of the E beta gene. Unlike alpha chain genes that contain five exons, the E beta gene consists of six exons corresponding to the six functional domains--the leader, beta 1 and beta 2 domains, transmembrane peptide, intracytoplasmic peptide, and 3' untranslated region. In addition, two short blocks of sequences common to alpha and beta chain genes were identified in the 5' flanking regions. We propose that these sequences are involved in the coordinate expression of alpha and beta chains.

Amino Acid Sequence↗
PubMed2001

Differing processing requirements of four recombinant antigens containing a single defined T-cell epitope for presentation by major histocompatibility complex class II.

A set of predictive rules governing the likelihood of generating a particular peptide-major histocompatibility complex (MHC) class II complex from an intact antigen has not been fully elucidated. We investigated the influence of positional and structural constraints in the region of the epitope by designing a set of recombinant antigens that each contained the well-characterized T-cell epitope moth cytochrome c (MCC) (88-103), which is specifically recognized by the monoclonal antibody (mAb) D4 when complexed with H-2Ek. Our model antigens contained MCC(88-103) either peripherally, at or towards the C-terminus, or internally. Their abilities to bind directly to soluble H-2Ek, and the extent of D4 epitope formation from them by antigen processing-competent and -incompetent cell lines, were determined. Here we report that three of these four antigens yielded MCC(88-103)/H-2Ek complexes independently of the conventional MHC class II antigen-processing and presentation pathway, and in each case the epitope was carried peripherally; two bound directly as intact proteins, probably as a result of spatial separation of the epitope from the major globular domain, and one was processed to peptide by a cell-surface protease. One protein, which carried the epitope inserted into an internal loop, acted as a conventional processing-dependent MCC(88-103) delivery vehicle. Thus, this epitope has different presentation requirements depending on its context. These antigens constitute a panel whose framework could be modified to further define predictive rules for antigen processing for presentation through the different MHC class II complex-generating pathways.

Animals↗
PubMed1994

Novel genes in the human major histocompatibility complex class-II region.

Recent studies have identified a number of new genes mapping to the class-II region of the human major histocompatibility complex. Functionally these can be grouped into three broad categories: those encoding the new class-II-related genes DMA and DMB; those involved in aspects of class-I antigen-processing and presentation, and those with no apparent association with the immune system. There is evidence that further factors involved in class-II antigen presentation are located in the DMB to DQB1 interval.

Antigen Presentation↗
PubMed1999

The mouse major histocompatibility complex: some assembly required.

We have assembled a contig of 81 yeast artificial chromosome clones that spans 8 Mb and contains the entire major histocompatibility complex (Mhc) from mouse strain C57BL/6 (H2b), and we are in the process of assembling an Mhc contig of bacterial artificial chromosome (BAC) clones from strain 129 (H2bc), which differs from C57BL/6 in the H2-Q and H2-T regions. The current BAC contig extends from Tapasin to D17Leh89 with gaps in the class II, H2-Q, and distal H2-M regions. Only four BAC clones were required to link the class I genes of the H2-Q and H2-T regions, and no new class I gene was found in the previous gap. The proximal 1 Mb of the H2-M region has been analyzed in detail and is ready for sequencing; it includes 21 class I genes or fragments, at least 14 olfactory receptor-like genes, and a number of non-class I genes that clearly establish a conserved synteny with the class I regions of the human and rat Mhc.

Animals↗
PubMed1991

Overexpression of class I major histocompatibility complex accompanies insulitis in the non-obese diabetic mouse and is prevented by anti-interferon-gamma antibody.

Overexpression of class I major histocompatibility complex (MHC) proteins on pancreatic islet cells is a characteristic of autoimmune Type 1 (insulin-dependent) diabetes mellitus in humans and in animal models. Studies of post-mortem pancreases from humans with Type 1 diabetes suggest that overexpression of class I MHC proteins may precede mononuclear cell infiltration of the islets (insulitis). Pancreatic histology from the earliest stages of human Type 1 diabetes is rarely available. We have used the non-obese diabetic mouse, given cyclophosphamide to accelerate Beta-cell destruction, to investigate the temporal relationship between the overexpression of class I MHC protein and mRNA and other pathological changes associated with Beta-cell destruction. Prior to cyclophosphamide, immunoperoxidase staining showed that expression of class I MHC proteins was greater on islet cells and infiltrating inflammatory cells of the non-obese diabetic mouse than on islet cells of other mouse strains, whereas staining on exocrine cells was similar. On day three after cyclophosphamide administration, when insulitis had regressed, islet class I MHC protein expression had diminished. A dramatic increase in class I MHC protein expression occurred between days seven and nine, concomitant with reinfiltration of the islets by mononuclear cells; overexpression was seen both on islet cells and on surrounding exocrine cells, but only in the presence of mononuclear cell infiltration. By day 21, class I MHC protein overexpression was again confined to the islets, the exocrine pancreas being free of infiltration. Class I mRNA also increased dramatically by day eight but had virtually returned to normal by day 12.2+ effected by cytokines secreted by activated immuno-inflammatory cells. Class I MHC overexpression should enhance targeting of cytotoxic T cells to Beta cells bearing autoantigen.

Animals↗
PubMed2001

Effects of genotype matching of feline major histocompatibility complex (FLA) class II DRB on skin-allograft transplantation in cats.

In order to confirm the effects of matching of expressed feline major histocompatibility complex (FLA) class II DRB genotype on transplantation immunity in cats, skin-allogeneic transplantation was carried out between cats, in which DRB genes expressed were genotyped by the RT-PCR-RFLP method using group-specific primers. Duration until grafts were rejected was 14.63 +/- 1.69 days (mean +/- standard deviation) in the pairs that had the same type of subgroups, 7.25 +/- 0.71 days in the pairs that had one different type of subgroup and 6.88 +/- 0.35 days in the pairs that had two different types of subgroups. The duration of graft survival in the pairs with the same type of subgroups was significantly longer (P<0.01) than those in the pairs with different types. Although FLA components involved in transplantation immunity should not only be DRB genes, it was suggested that the expressed FLA-DRB genotype might associate with feline transplantation immunity, and that typing and matching of expressed FLA-DRB genes might be one of the important factors in the control of feline transplantation immunity.

Animals↗
PubMed2000

BTL-II: a polymorphic locus with homology to the butyrophilin gene family, located at the border of the major histocompatibility complex class II and class III regions in human and mouse.

Comparison of human and mouse genomic sequence at the border of the major histocompatibility complex (MHC) class II and class III regions revealed a locus encoding six exons with homology to the butyrophilin gene family and the location of a previously described gene, testis-specific basic protein (TSBP). We named the new locus BTL-II, for butyrophilin-like MHC class II associated. The six discernable exons of the BTL-II locus encode a small hydrophobic amino acid sequence (which may be a signal peptide), two immunoglobulin domains, a small 7-amino acid, heptad repeat-like exon, and a further two immunoglobulin domains. In mouse, an additional butyrophilin-like gene (NG10) is situated adjacent to BTL-II. Expression studies of the BTL-II locus in mouse showed that it is expressed in a range of gut tissues. We demonstrate that like many other genes from the MHC, BTL-II is polymorphic in a selection of diverse HLA haplotypes. In the light of the newly discovered locus, we revisit and discuss the possible origin of the butyrophilin gene family.

Amino Acid Sequence↗
PubMed2006

An ancient balanced polymorphism in a regulatory region of human major histocompatibility complex is retained in Chinese minorities but lost worldwide.

The coding regions of many of the major histocompatibility complex (MHC) (human leukocyte antigen [HLA] in humans) molecules are believed to be subject to balancing selection. But it is less certain whether the regulatory regions of such coding sequences are also subject to the same type of selection. Here, we studied the polymorphism of the regulatory regions of the HLA-DPA1 and HLA-DPB1 genes among ethnic minorities in southwestern China. Phylogenetic analysis revealed two deep clades >10 million years old. There is almost complete linkage disequilibrium between the regulatory and coding regions of HLA-DPA1, which hints at coadaptive balancing selection on the entire region. Thus, the molecular mechanism of balancing selection in MHC may involve expression modulation in addition to coding-region polymorphisms. Although the frequency of clade II is >30% in some ethnic minorities, it decreases to <5% among southern Han Chinese and vanishes among Europeans. As suspected, some ancient balanced polymorphisms, lost in major populations, still exist in isolated ethnicities. These isolated populations may thus contribute disproportionately to the total diversity of modern humans.

Amino Acid Sequence↗
PubMed1994

Cytokine-induced major histocompatibility complex class II antigens on cultured bovine mammary gland epithelial cells.

The aim of this work was to establish a simple but reliable method of collecting epithelial cells from tissue lining the gland cistern of the bovine mammary gland and to investigate the ability of cultured epithelial cells to express major histocompatibility complex class II antigens. Bovine mammary gland epithelial cells were isolated and grown as monolayers on five substrates in vitro. The cells were identified as epithelial in origin by immunofluorescent staining with anticytokeratin monoclonal antibodies. Major histocompatibility complex class II antigens were induced on epithelial monolayers by incubation with supernatants from bovine peripheral blood mononuclear cells stimulated with concanavalin A or incubation with recombinant bovine interferon-gamma. These results suggest that, in bovine mammary gland epithelium, recombinant bovine interferon-gamma, acting alone, can induce class II expression. This observation permits future investigation of the putative role of bovine mammary gland epithelial cells as accessory cells in the initiation of local immune responses and their involvement in peptide transport.

Animals↗
PubMed1983

[Effect of major histocompatibility complex disparity on reproductive performance].

From the viewpoint of transplantation immunology, the fetus is a allograft which bears antigens incompatible with the mother. So immunological rejection reaction has been considered as one possible mechanism of abortion. To investigate this possibility, we applied some immunological procedures to rat and mouse. The results were as follows: 1) Prior active immunization with allogeneic placental cells or spleen cells emulsified with Freund's complete adjuvant increased the rate of abortion in the rat. But this effect was not manifested in the cases to which these cells were administered without the adjuvant. 2) Prior active immunization with major histocompatibility complexes had no deleterious effect on gestation in either the rat or the mouse. 3) Compared with inbred mating, decrease in the incidence of abortion, increase in fetal weight and increase in litter size were noticed in outbred mating in the rat. The latter two were statistically significant but the former was not significant. These results suggest that the major histocompatibility complex disparity between the fetus and mother does not have a deleterious but a beneficial effect on reproductive performance. Some possible immunological mechanisms of abortion are discussed.

Abortion, Spontaneous↗
PubMed1994

Class II transactivator (CIITA) is sufficient for the inducible expression of major histocompatibility complex class II genes.

The class II transactivator (CIITA) has been shown to be required for major histocompatibility complex (MHC) class II gene expression in B cells and its deficiency is responsible for a hereditary MHC class II deficiency. Here we show that CIITA is also involved in the inducible expression of class II genes upon interferon gamma (IFN-gamma) treatment. The expression of CIITA is also inducible with IFN-gamma before the induction of MHC class II mRNA. In addition, CIITA mRNA expression does not require new protein synthesis, although new protein synthesis is necessary for the transcription of class II. This suggests that synthesis of new CIITA protein may be essential to induce class II gene expression. We also showed that the JAK1 protein tyrosine kinase activity is required to induce the expression of CIITA upon IFN-gamma stimulation. This finding indicates that CIITA is part of the signaling cascade from the IFN-gamma receptor to the activation of class II genes. In addition, the expression of CIITA is sufficient to activate class II genes in the absence of IFN-gamma stimulation suggesting that CIITA is the major regulatory factor for the inducible expression of class II genes. Together, these data suggest that CIITA is the IFN-inducible cycloheximide sensitive factor previously shown to be required for the induction of MHC class II gene expression.

Base Sequence↗
PubMed1995

Presentation of a self-peptide for in vivo tolerance induction of CD4+ T cells is governed by a processing factor that maps to the class II region of the major histocompatibility complex locus.

Self-proteins are regularly processed for presentation to autoreactive T cells in association with both class I and class II major histocompatibility complex (MHC) molecules. The presentation of self-peptides plays a crucial role in the acquisition of T cell repertoire during thymic selection. We previously reported that the self-MHC class I peptide Ld 61-80 was immunogenic in syngeneic B10.A mice (H-2a). We showed that despite its high affinity for self-MHC class II molecules, Ld 61-80 peptide failed to induce elimination of autoreactive CD4+ T cells, presumably due to incomplete processing and presentation in the B10.A's developing thymus (cryptic-self peptide). In this report, we showed that the cryptic phenotype was not an intrinsic property of the self-peptide Ld 61-80 since it was found to be naturally presented and subsequently tolerogenic in BALB/c mice (H-2d) (dominant self-peptide). In addition, the self-peptide Ld 61-80 was found to be immunogenic in different H-2a mice while it was invariably tolerogenic in H-2d mice regardless of their background genes. We observed that Ld 61-80 bound equally well to H-2d and H-2k MHC class II molecules. Also, no correlation was found between the quantity of self-Ld protein and the tolerogenicity of Ld 61-80. Surprisingly, Ld 61-80 was not naturally presented in (H-2d x H-2a) F1 mice, indicating that the H-2a MHC locus contained a gene that impaired the presentation of the self-peptide. Analyses of T cell responses to the self-peptide in several H-2 recombinant mice revealed that the presentation of Ld 61-80 was controlled by genes that mapped to a 170-kb portion of the MHC class II region. This study shows that (a) endogenously processed self-peptides presented by MHC class II molecules are involved in shaping the CD4+ T cell repertoire in the thymus; (b) The selection of self-peptides for presentation by MHC class II molecules to nascent autoreactive T cells is influenced by nonstructural MHC genes that map to a 170-kb portion of the MHC class II region; and (c) the MHC locus of H-2a mice encodes factors that prevent or abrogate the presentation by MHC class II molecules of the self-peptide Ld 61-80. These findings may have important implications for understanding the molecular mechanisms involved in T cell repertoire acquisition and self-tolerance induction.

Amino Acid Sequence↗
PubMed1976

The major histocompatibility complex and its relationship to allergic disease.

Two tests, the mixed leukocyte culture (MLC) and cell-mediated lympholysis (CML) tests, have been used as in vitro models of the in vivo allograft reaction. These tests have been applied to histocompatibility testing for transplantation as well as to assay of immune function. They involve the use of peripheral blood lymphocytes as "responding" cells in mixed leukocyte culture or as "stimulating" cells in the generation of a proliferative or a cytotoxic response. The proliferative events in MLC are primarily in response to LD antigens of the major histocompatibility complex; the cytotoxic cells use as their targets the SD antigens of that complex. A new method for defining the LD antigens, the primed LD typing (PLT) test, is based on in vitro sensitization of lymphocytes to certain LD antigens of the major histocompatibility complex and their subsequent restimulation with test cells.

ABO Blood-Group System↗
PubMed1984

Identification of class I major histocompatibility complex encoded molecules in the amphibian Xenopus.

Class I-like molecules have been immunoprecipitated from Xenopus leukocytes and erythrocytes with alloantisera directed against major histocompatibility complex (MHC)-linked antigens. The heavy chains, depending on the allele examined, have molecular weights of 40 000-44 000 of which 3000 daltons are asparagine-linked carbohydrates, probably present as one N-linked glycan. The presumed analogue of beta 2-microglobulin has a molecular weight of 13 000 and bears no asparagine-linked glycans. Family studies show that the heavy chains are encoded by genes residing in or closely linked to the MHC.

Alleles↗
PubMed1989

Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B.

A 600-kilobase (kb) DNA segment from the human major histocompatibility complex (MHC) class III region was isolated by extension of a previous 435-kb chromosome walk. The contiguous series of cloned overlapping cosmids contains the entire 555-kb interval between C2 in the complement gene cluster and HLA-B. This region is known to encode the tumor necrosis factors (TNFs) alpha and beta, B144, and the major heat shock protein HSP70. Moreover, a cluster of genes, BAT1-BAT5 (HLA-B-associated transcripts) has been localized in the vicinity of the genes for TNF alpha and TNF beta. An additional four genes were identified by isolation of corresponding cDNA clones with cosmid DNA probes. These genes for BAT6-BAT9 were mapped near the gene for C2 within a 120-kb region that includes a HSP70 gene pair. These results, together with complementary data from a similar recent study, indicated the presence of a minimum of 19 genes within the C2-HLA-B interval of the MHC class III region. Although the functional properties of most of these genes are yet unknown, they may be involved in some aspects of immunity. This idea is supported by the genetic mapping of the hemopoietic histocompatibility locus-1 (Hh-1) in recombinant mice between TNF alpha and H-2S, which is homologous to the complement gene cluster in humans.

Cell Line↗
PubMed1978

Analysis of the major histocompatibility complex in Syrian hamsters. I. Skin graft rejection, graft-versus-host reactions, mixed lymphocyte reactions, and immune response genes in inbred strains.

Five inbred strains of Syrian hamsters (Mesocricetus auratus) were examined for the presence of disparity at a genetic region similar to the major histocompatibility complex in other species. Vigorous reciprocal alloreactions developed in several strain combinations, which resulted in acute skin graft rejection, strong mixed lymphocyte reactions, and potent graft-versus-host reactions. In addition, we found evidence for an immune response gene which controls the antibody response to bovine serum albumin. Patterns of alloreactivity observed for skin graft rejection, graft-versus-host reactivity, and mixed lymphocyte reactivity are compatible with the hypothesis that hamsters possess a major histocompatibility complex, but the absence of discernable disparity at a serologically defined locus makes a definitive statement premature.

Animals↗
PubMed1997

An isotype-specific activator of major histocompatibility complex (MHC) class II genes that is independent of class II transactivator.

Patients with one type of major histocompatibility complex class II combined immunodeficiency have mutations in a gene termed class II transactivator (CIITA), which coordinately controls the transcription of the three major human class II genes, HLA-DR, -DQ, and -DP. However, the experimentally derived B-lymphoblastoid cell line, clone 13, expresses high levels of HLADQ in the absence of HLA-DR and HLA-DP, despite its mapping by complementation analysis to this group. It was possible that one of the clone 13 CIITA alleles bore a mutation that allowed HLA-DQ, but not HLA-DR or -DP transcription. Alternatively, another factor, distinct from CIITA, might control HLA-DQ expression. We report here that ectopic expression of CIITA cDNAs derived by reverse transcriptase polymerase chain reaction from clone 13 do not restore expression of HLA-DQ in another CIITA-deficient cell line, RJ2.2.5. In addition, no CIITA protein is detectable in clone 13 nuclear extracts. In contrast, somatic cell fusion between clone 13 and RJ2.2.5 restored expression of the HLA-DQ haplotype encoded by the RJ2.2.5 DQB gene. Taken together, these data demonstrate the existence of an HLA-DQ isotype-specific trans-acting factor, which functions independently of CIITA.

Blotting, Western↗