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PubMed2002

The class II transactivator requires brahma-related gene 1 to activate transcription of major histocompatibility complex class II genes.

The class II transactivator (CIITA) is the key regulator of major histocompatibility complex (MHC) class II gene transcription. We demonstrate here that CIITA requires the ATPase subunit of an hSWI/SNF complex, brahma-related gene 1 (BRG-1), to activate transcription. When introduced into a cell line lacking BRG-1, CIITA was unable to activate cellular MHC class II genes. Reexpression of the wild-type but not an ATP-binding-deficient BRG-1 protein in this cell line restored the ability of CIITA to transactivate transcription of MHC class II genes. Interestingly, when the activity of CIITA was assayed in the BRG-1-deficient cell line by using a plasmid-based reporter assay, BRG-1 was not required for transcriptional activation, suggesting that the chromatin structure on the plasmid is such that BRG-1 is not necessary. Coimmunoprecipitation experiments were performed to determine if BRG-1 and CIITA proteins associate with each other in cells. We found that the two proteins coimmunoprecipitate and that amino acids 1 to 140 of CIITA are sufficient for binding. Taken together, these data suggest that BRG-1 and, very likely, an hSWI/SNF complex are required for transcription of MHC class II genes. The complex is likely recruited to MHC class II promoters, at least in part, by interaction with CIITA.

Adenosine Triphosphatases↗

PubMed1990

Expression of class II major histocompatibility complex antigens on adult T cells in Xenopus is metamorphosis-dependent.

Class II major histocompatibility complex (MHC) antigens are expressed predominantly on B lymphocytes and macrophages of tadpoles of the South African clawed frog, Xenopus laevis, as is the pattern in lymphocyte populations of most mammals. However, unlike most mammals, young postmetamorphic frogs show expression of class II MHC antigens on a high proportion of thymocytes and most peripheral T and B lymphocytes. Using the J-strain of Xenopus and the anticlass II monoclonal antibody, 14A2, we have studied, by indirect immunofluorescence, whether inhibition of metamorphosis would alter the pattern of expression of class II antigens during ontogeny. In control animals, class II antigens were virtually absent from thymic lymphocytes and peripheral T cells of normal untreated larvae, but could be found in increasing numbers in both populations after metamorphosis (10-12 weeks of age). In contrast, larvae, whose metamorphosis was inhibited by treatment with sodium perchlorate, had relatively few class II+ thymic lymphocytes throughout the 6-month period of study, and the proportion of class II+ splenic lymphocytes was approximately equal to that of IgM+ B lymphocytes. Thus, perchlorate-treated animals retained the larval pattern of class II expression, suggesting that emergence of class II+ T cells is dependent on metamorphosis.

Animals↗

PubMed2006

Clinicopathological significance of major histocompatibility complex class I-related chain a and B expression in thyroid cancer.

CONTEXT: Major histocompatibility complex class I-related chains A and B (MICA/B) are two stress-inducible ligands for the immunoreceptor NKG2D that is expressed on cytotoxic T cells and natural killer (NK) cells. It is not known whether MICA/B expression is up-regulated in thyroid cancer as a result of oncogene activation. OBJECTIVE: The objective of the investigation was to study MICA/B expression and regulation in thyroid cancer and its role in mediating the cytotoxicity of NK cells. METHODS: MICA/B expression in thyroid cancer was analyzed by immunohistochemical staining. Cell surface MICA/B levels in thyroid tumor cell lines and fresh tumor cells were analyzed by flow cytometric analysis. The susceptibility of thyroid tumor cells to NK cell killing was tested by using (51)Cr release assay. RESULTS: MICA/B was expressed at moderate or high levels in 18 of 39 papillary thyroid carcinomas and four of eight anaplastic thyroid carcinomas. MICA/B expression was confirmed by flow cytometric analysis in three fresh thyroid neoplasms. MICA/B expression was detected in eight of 10 thyroid tumor cell lines and correlated with their sensitivity to killing by the NKG2/D-positive NK-92 cells. Blocking of NKG2D and MICA/B interaction by specific antibodies partially led to the inhibition of NK-92 cell-mediated cytotoxicity. The MAPK inhibitors were able to block MICA/B expression in MRO87 and HeLa cells. Transient transfection of mutant BRAF and RAS oncogenes led to increased MICA/B expression in 293 cells and WRO82 cells. CONCLUSION: MICA/B expression is up-regulated in thyroid cancer, probably due to the activation of the MAPK pathway. MICA/B in thyroid cancer plays an important role in NK-92 cell-mediated cytotoxicity.

Antibodies, Monoclonal↗

PubMed1986

Class II major histocompatibility complex antigen expression and cellular interactions in thyroid glands of Graves' disease.

Class II major histocompatibility complex (MHC) antigens have been demonstrated on the surface of thyroid epithelial cells (thyrocytes) from patients with autoimmune thyroid disease. The present study was designed to investigate how the expression of class II MHC antigens is involved in autoimmune processes in Graves' disease by studying cellular interactions among thyrocytes, lymphocytes within thyroid glands (TG), and peripheral blood (PB) lymphocytes. Thyrocytes were prepared by collagenase digestion, and T or non-T cells were separated by E-rosette formation. Thyrocytes were cocultured in the presence or absence of interferon-gamma, and the expression of HLA-DR antigens on cultured thyrocytes was examined by an indirect immunofluorescence method using monoclonal anti-HLA-DR antibody and monoclonal anti-HLA-DQ antibody. The cellular interactions were assessed as the proliferative response of T cells to autologous stimulators, such as thyrocytes or lymphocytes. Expression of HLA-DR antigens on thyrocytes after culture for 18 h in the absence of interferon-gamma was found in two thirds of the patients with Graves' disease studied (n = 18). Interferon-gamma induced and maintained the expression of HLA-DR antigens on thyrocytes. The percentages of HLA-DR+T cells were significantly higher among TG-T cells than among PB-T cells [32.6 +/- 12.4% (+/- SD) vs. 12.2 +/-5.0%; n = 18; P less than 0.01]. Thyrocytes from Graves' patients induced proliferation of both autologous PB-T cells and TG-T cells, and TG-T cells stimulated proliferation of autologous PB-T cells. In conclusion, interferon-gamma induces HLA-DR antigen expression on thyrocytes from patients with Graves' disease, and these cells induce proliferation of autologous T cells, which may, in turn, act on thyrocytes to perpetuate the process.

Adolescent↗

PubMed1996

In vivo and in vitro evidence for iodide regulation of major histocompatibility complex class I and class II expression in Graves' disease.

Increases in thyroid cell major histocompatibility complex (MHC) class I and class II expression have been suggested to be an important factor in the development or perpetuation of Graves' disease. It is hypothesized that elevations result in abnormal presentation of thyroid antigens to immune cells, and that iodide and/or methimazole (MMI) are effective therapeutic agents because, at least in part, of their suppression of MHC expression. In this report, we show that Graves' patients pretreated with iodide only 4 days before surgery have lower levels of MHC class I and class II RNA levels in their thyroid tissue than do patients with no iodide pretreatment (P < 0.001 and 0.03, respectively). Because patients in both groups are treated with MMI and because the change is independent of the amounts of MMI used to treat patients, the class I and class II changes cannot be ascribed to MMI. The iodide action to decrease MHC class I and class II RNA levels was duplicated using cultured human thyroid cells in vitro; the iodide effect was dependent on the iodide concentration, was not duplicated by chloride, was not associated with an alteration in cAMP levels or with a change in thyrotropin receptor RNA levels, and was evident in gamma-interferon-treated cells. The data suggest, therefore, that the therapeutic action of iodide in Graves' patients is associated with decreased MHC gene expression, that this action is a direct effect of high concentrations of iodide on the thyroid cells, and that altered MHC gene expression in the target tissue may well be associated with the development or perpetuation of Graves' disease.

Adolescent↗

PubMed1990

Expression of major histocompatibility complex antigens on the bovine placenta.

Immunohistochemistry was utilized to determine expression of the major histocompatibility complex (MHC) antigens on Day 8-9 hatched blastocysts and fetal membranes of mid- to late gestation cows and to examine the pattern of leucocytic infiltration into the gravid uterus. Hatched blastocysts were weakly positive for MHC class I antigens. In the mature placenta, chorioallantoic membranes in the interplacentomal area showed positive immunostaining for class I antigens on the chorionic epithelium but had no staining for class II antigens. There was an accumulation of lymphoid cells expressing class II antigens directly beneath the luminal epithelium of the endometrium. In addition, cells staining for leucocyte common antigen were present both within and beneath the luminal epithelium. Some cells positive for class II and leucocyte common antigen (CD45) were also associated with uterine glands. In the placentomes, class I antigens were expressed only on maternal caruncular septa. Fetal cotyledonary villi had no detectable immunostaining for class I and II antigens. No distinct pattern of leucocyte infiltration in the maternal caruncular tissue was observed; the caruncular septa contained some cells that were labelled for CD45 and a few class II-positive cells around blood vessels. The results indicate that the fetal placenta of the cow expresses MHC class I antigens in a regionally defined manner and there is a differential accumulation of lymphoid cells in the uterus.

Animals↗

PubMed1991

Cells of chemically induced tumors differentially express major histocompatibility complex class I antigens.

Several recent studies have indicated that alterations in expression of major histocompatibility complex (MHC) antigens by tumor cells affects the ability of the host to mount an effective antitumor immune response. To investigate whether newly induced tumors frequently exhibit altered MHC antigen expression, we used methylcholanthrene to induce a series of tumors and elevated MHC antigen expression by these cells. The tumors exhibited a variety of MHC phenotypes in vitro. The nature of their phenotypes suggested that these cells were, in fact, capable of independent and abnormal regulation of MHC class 1 genes. However, when maintained in vivo, these same tumor cells expressed measurable levels of all of the appropriate MHC class I antigens. Thus, newly induced tumor cells are capable of abnormal MHC class I antigen expression. However, there was no obvious correlation between the phenotypes exhibited by these tumor cells in vitro and either their phenotype or their tumorigenic potential in vivo.

Animals↗

PubMed1992

[Interactions between peptides and major histocompatibility complex molecules].

T-cell receptors recognize foreign proteins as peptide fragments associated with major histocompatibility complex (MHC) molecules. Properties of antigenic peptides, methods for detecting peptide-MHC molecule combinations, and the characteristics of the interaction are reviewed. Possible explanations for graft rejection and autoimmune disease are suggested in the light of these data.

Arthritis, Rheumatoid↗

PubMed2005

Parasite burden and constitution of major histocompatibility complex in the Malagasy mouse lemur, Microcebus murinus.

We investigated the importance of the major histocompatibility complex (MHC) constitution on the parasite burden of free-ranging mouse lemurs (Microcebus murinus) in four littoral forest fragments in southeastern Madagascar. Fourteen different MHC class II DRB-exon 2 alleles were found in 228 individuals with high levels of sequence divergence between alleles. More nonsynonymous than synonymous substitutions in the functional important antigen recognition and binding sites indicated selection processes maintaining MHC polymorphism. Animals from the four forest fragments differed in their infection status (being infected or not), in the number of different nematode morphotypes per individual (NNI) as well as in the fecal egg counts (FEC) values. Heterozygosity in general was uncorrelated with any of these measures of infection. However, a positive relationship was found between specific alleles and parasite load. Whereas the common allele Mimu-DRB*1 was more frequently found in infected individuals and in individuals with high NNI and FEC values (high parasite load), the rare alleles Mimu-DRB*6 and 10 were more prevalent in uninfected individuals and in individuals with low NNI and FEC values (low parasite load). These three alleles associated with parasite load had unique amino acid motifs in the antigen binding sites. This distinguished them from the remaining 11 Mimu-DRB alleles. Our results support the hypothesis that MHC polymorphism in M. murinus is maintained through pathogen-driven selection acting by frequency-dependent selection. This is the first study of the association of MHC variation and parasite burden in a free-ranging primate.

Analysis of Variance↗

PubMed1991

Expression of major histocompatibility complex and leukocyte common antigens in amoeboid microglia in postnatal rats.

The expression of major histocompatibility complex (MHC) antigen and leukocyte common antigen (LCA) was observed in the amoeboid microglial cells in postnatal rat brain. Considerable MHC class I surface antigen was detected at the plasma membrane and its tubular invaginations in the amoeboid microglia in the corpus callosum using the monoclonal antibody OX-18. In early postnatal (2 and 5 day) rats, the OX-18 positive cells were mostly round but a few possessed stout processes. With increasing age (9 and 15 days) the OX-18 positive amoeboid microglia assumed an oval or elongated form. By the time of weaning (21 days) and in older animals, the immunoreactivity was extremely weak and was detectable only on some branched microglia bearing fine processes. The presence of MHC class Ia antigens with OX-3 and OX-6 was hardly detectable except for a few weakly stained cells in the corpus callosum and cavum septum pellucidum in early postnatal rats. The expression of LCA was observed in amoeboid microglial using the monoclonal antibody OX-1 and this followed a similar temporal pattern to that with OX-18. The additional phenotypic features of amoeboid microglial cells in the present study support their monocytic origin. These cells are endowed with MHC class I antigens which may serve as the restriction elements for T lymphocytes, at least in the early postnatal brain.

Animals↗

PubMed1988

The relationship of modulation of major histocompatibility complex class I antigens to retrovirus transformation in rat cell lines.

The expression of major histocompatibility complex (MHC) Class I antigens has been studied, by means of monoclonal antibodies directed against nonpolymorphic determinants of MHC Class I molecules, in two epithelial differentiated cell lines (FRTL-5 clone 2 and PC clone 3) and in one fibroblast cell line (FRT Fibro) of Fischer rat thyroid origin, before and after infection with various acute retroviruses carrying the v-ras-Ha, v-mos, v-src, polyoma middle T, and c-myc oncogenes. The results obtained indicate that a single virus does not produce identical changes in MHC Class I molecule expression in all tested lines, but a general increase occurs in lines derived from FRTL-5 clone 2 and a decrease occurs in lines derived from PC clone 3 and from FRT Fibro. Thus the modulation of expression seems to proceed always in the same direction in each cell line regardless of the infecting retrovirus and appears to involve posttranscriptional mechanisms, since no modification of expression of mRNA levels has been observed between normal and transformed cells. Only one line of PC clone 3 origin, transformed by the cooperation of two oncogenes (human c-myc and middle T), almost completely lost MHC Class I antigens on the cell surface and presented a significantly reduced synthesis of Class I mRNA.

Animals↗

PubMed1976

Evidence for more than one Ia antigenic specificity on molecules determined by the I-A subregion of the mouse major histocompatibility complex.

Ia antigenic specificities determined by the I-A subregion of the mouse major histocompatibility complex have been examined in strain B10.D2 (H-2d), C57BL/10 (H-2b), and in a (C57BL/6xDBA/2) hybrid (BDF1; H-2b/d). Detergent solubilized, 3H-leucine-labeled antigen preparations were mixed with appropriate alloantisera and precipitation was induced either by addition of goat anti-mouse gamma-globulin or by addition of protein A-bearing Staphylococci. Sequential precipitation analysis showed that in strain B10.D2, Ia specificities 8 and 11 were co-precipitable, and that in strain C57BL/10, Ia specificities 8 and 9 were co-precipitable. In contrast, precipitation of specificities 9 and 11 from a BDF1 antigen preparation showed that these two Ia specificities were on separate molecules. The genetic implications of these data are discussed.

Animals↗

PubMed1994

Mutually exclusive binding of peptide and invariant chain to major histocompatibility complex class II antigens.

The invariant chain is a membrane protein associated with the major histocompatibility complex class II antigens both intra- and extracellularly. The extracellular portion of the human invariant chain (Ii) was expressed in Escherichia coli as a fusion protein with a polyhistidine tail and purified by metal affinity chromatography. The recombinant Ii was used as a ligand to probe binding to the cell surface of Chinese hamster ovary cells stably transfected with human class II alpha and beta genes of the DR4 isotype. We show that recombinant Ii inhibits peptide loading on class II polypeptides and also the converse; the presence of peptide in the antigen groove prevents binding of fluorescein-conjugated Ii. Moreover, blocking of Ii binding by peptide did not require a transition of the class II dimers to an SDS-stable state. A monoclonal antibody, L243, known to bind to (or close to) the peptide pocket of the class II molecule likewise blocked Ii-fluorescein binding. Further, we investigated whether or not the Ii, a variety of bacterial superantigens or the CD4 molecule, have overlapping binding sites on the class II heterodimer. Of the class II ligands tested, reduced binding was detected for the Staphylococcus superantigen type SEB on cells precincubated with soluble Ii while the binding of the other ligands was either unchanged or marginally changed. These data clarify by a direct biochemical approach the binding characteristics of Ii in comparison with other class II ligands.

Amino Acid Sequence↗

PubMed1996

Induction of tolerance to an experimental cardiac allograft through intrathymic inoculation of class II major histocompatibility complex disparate antigens.

Indefinite donor-specific tolerance to a cardiac allograft can be induced through pretransplantation intrathymic injection of donor spleen cells and a single intraperitoneal injection of antilymphocyte serum. This study was designed to determine whether this phenomenon was reproducible with grafts differing in either class I major histocompatibility complex only or class II MHC only. Donors of cells and hearts in all experiments were RP rats. Class I MHC disparate grafts were performed by placing an RP heart into a Lewis recipient, and class II disparate grafts were performed with RP donors and Wistar Furth recipients. Lewis (n = 10) and Wistar Furth (n = 10) recipients underwent intraperitoneal injection of 1 ml antilympocyte serum and intrathymic injection of 5 x 10(7) RP spleen cells. Three weeks later, heterotopic cardiac transplantation was done with a heart from an RP rat. Control rats had no pretreatment or received antilympocyte serum alone. Without pretreatment, RP hearts survived 7 to 9 days (mean 8 days) in Lewis recipients (n = 5) and 9 to 14 days (mean 12 days) in Wistar Furth recipients (n = 5). Antilymphocyte serum alone produced slight prolongation of graft survival. Lewis rats pretreated with class I disparate RP splenocytes and antilympocyte serum had graft survivals of 8 to 27 days (mean 14 days), not significantly different from the results with antilympocyte serum alone. Class II disparate RP grafts placed in pretreated Wistar Furth rats had significant prolongation of graft survival, with four of five grafts surviving longer than 60 days (p < 0.01 vs antilympocyte serum alone). These results suggest that a disparity at the class II locus of the major histocompatibility complex is critical for the induction of cardiac allograft tolerance after intrathymic inoculation of allogeneic cells.

Animals↗

PubMed1989

Expression of major histocompatibility complex on human medulloblastoma cells with neuronal differentiation.

Medulloblastomas are among the most common malignant brain tumors in children. These tumors consist of immature bipotential cells that may differentiate into neuronal and glial cells. We have established two cell lines for human medulloblastoma. One was derived from a 2-year-old girl with a cerebellar tumor (designated as ONS-76) and another from a 9-year-old girl with a metastatic tumor in the right frontal lobe (ONS-81). The in vitro population-doubling times were 18.6 and 19.2 h, respectively. Immunohistochemical studies showed that both cells possessed neurofilament protein (Mr 145,000 and 200,000) and neuron-specific enolase, without glial fibrillary acidic protein or S-100 protein. Human gamma-interferon enhanced class I major histocompatibility complex antigens on these medulloblastoma cells. Class II major histocompatibility complex antigens were also induced by human interferon-gamma. We here report for the first time the expression of class II major histocompatibility antigens, which play an important role in immune response, on human medulloblastoma cells with neuronal differentiation.

Cell Differentiation↗

PubMed2002

Identification of specific glycoforms of major histocompatibility complex class I heavy chains suggests that class I peptide loading is an adaptation of the quality control pathway involving calreticulin and ERp57.

Glycosylation analysis was used to probe the sequence of events accompanying the binding of antigenic peptides to the major histocompatibility complex class I heavy chains. Free heavy chains were isolated from the beta(2)-microglobulin-negative cell line Daudi and from the B-lymphoblastoid cell line Raji. Heavy chains were also isolated from Raji cells in multimolecular complexes (peptide loading complexes) containing the transporter associated with antigen processing, tapasin and ERp57 with and without the lectin-like folding chaperone, calreticulin. Calreticulin is a soluble protein that recognizes primarily the terminal glucose of Glc(1)Man(7-9)GlcNAc(2) glycans. This paper shows that monoglucosylated glycoforms of heavy chain, which exist transiently in the endoplasmic reticulum in the initial stages of the glycosylation processing pathway, are present in the peptide loading complex. The data are consistent with a model in which the release of peptide-loaded major histocompatibility complex class I molecules from calreticulin, induced by deglucosylation of the heavy chain N-linked glycan, signals the dissociation of the complex. This is consistent with the hypothesis that the class I loading process is an adaptation of the quality control mechanism involving calreticulin and ERp57.

Calreticulin↗

PubMed1981

Immunochemical characterization of Syrian hamster major histocompatibility complex homologues.

Based primarily on studies in mice and man, the organization and gene-product structures of the mammalian major histocompatibility complex (MHC) are thought to be extensively conserved. However, attempts to generalize from the specific observations of other species to Syrian hamsters have not been completely successful. Previous studies in hamsters have suggested abnormal structure, expression, and/or function of the putative hamster MHC and its products. Characterization of hamster MHC gene-products is therefore of interest. This study concerns the identification and characterization of hamster cell-surface glycoproteins homologous to MHC products of man and mouse. Utilizing radioimmunoprecipitation and serologic techniques, these molecules have been characterized with regard to molecular weight, tissue distribution and immunochemical homology to human and murine class I and II MHC products. In addition, alloantisera raised between histoincompatible hamster strains have been similarly used to identify cell-surface alloantigens of this species. The alloantisera detect cell-surface hamster molecules with immunochemical properties and tissue distribution resembling MHC class II rather than class I products. Thus, in contrast to other species, hamsters appear not to express extensively polymorphic major transplantation antigens of the class I type. Some hamster alloantigens are apparently homologous of Ia determinants since their genes are linked to Hm-1. However, other alloantigens with similar molecular weights are seemingly encoded by genes unlinked to the hamster MHC. These data support the hypothesis that the hamster MHC contains genes which encode for molecular products similar to those described in man and mouse, but that the organization and/or expression of these genes may be atypical.

Absorption↗

PubMed1982

Is the major histocompatibility complex linked to genes that increase susceptibility to affective disorder? A critical appraisal.

The evidence implicating genes linked to the major histocompatibility complex in the pathogenesis of affective disorder is reviewed, and 10 new multiplex families containing 26 affected siblings are presented. It is shown that when the data are properly analyzed by not dismantling multiplex sibships into all possible sib pairs, no individual data set presents compelling evidence of linkage. The present study is also negative. However, pooling all published families results in moderate evidence for nonrandom assortment.

Adolescent↗