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Results for “Genes, MHC Class II”

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PubMed1994

Characterization of a cis-acting regulatory element which silences expression of the class II-A beta gene in epithelium.

Class II major histocompatibility complex (MHC) genes encode for alpha/beta chain pairs that are constitutively expressed principally on mature B cells and dendritic cells in mice. These gene products are easily induced on macrophages with cytokines, and may also aberrantly appear on the surface of epithelium during immune injury. The appearance of class II determinants in parenchymal tissue potentially renders these somatic cells capable of antigen presentation to circulating CD4+ T lymphocytes, and their absence may be protective for normal tissues expressing self-antigens. The low surface class II expression observed on parenchymal cells generally correlates with low levels of mRNA, suggesting that transcription rate is a major element in class II regulation. To understand the transcriptional mechanism maintaining low basal surface expression of class II in somatic cells, we transiently transfected mini-gene reporter constructs to study the regulation of the murine A beta promoter in a cultured renal epithelial cell line. We describe here a negative cis-acting regulatory region located between -552 and -489 bp upstream of the A beta cap site that silences the transcriptional activity of the A beta promoter in epithelial cells in an orientation-dependent manner, and is also able to silence a heterologous promoter. This region is not active in class II-expressing B cells (BAL-17) in culture, but is functional in two other murine class II-negative cell lines, fibroblasts and thymoma T cells. Using competition electrophoretic mobility shift assays, we have localized the core protein binding site within this region to an 8-10-bp response element, designated A beta NRE, at -543 to -534 bp. A nuclear extract from BAL-17 cells does not bind to this element. Mutation of this site abrogates the transcriptional silencing activity of the region. We conclude that the transcription of class II-A beta in parenchymal cells, and some lymphocytes, can be actively repressed by an upstream silencing element.

Animals↗

PubMed1999

A novel role for the major histocompatibility complex class II transactivator CIITA in the repression of IL-4 production.

Class II transactivator (CIITA) is known as a coactivator for MHC class II gene expression in antigen-presenting cells. Surprisingly, when CIITA-/- CD4 T cells were stimulated in the presence of IL-12, they produced not only IFNgamma but also high levels of IL-4. The IL-4 production is due to the accumulation of IL-4 gene transcripts in Th1 cells. This transcriptional control is observed in T cells differentiating to the Th1 but not Th2 lineage, consistent with induction of expression of the CIITA gene in T cells by IFNgamma. Thus, in addition to its role in transactivation of genes involved in antigen presentation, CIITA plays a critical role during the T cell differentiation by negatively regulating the IL-4 gene transcription.

Animals↗

PubMed1995

Genetic analysis of human DNA recovered from minute amounts of serum or plasma.

A rapid and inexpensive method is described where a small amount of serum or plasma was used as the source of DNA for genetic analysis. Using a silica gel matrix DNA was isolated from 50 microliters of archived serum or plasma. The specimens were collected from 13 individuals at two separate time points 3-6 years apart. The polymorphic region of second exon of the MHC class II gene HLA DQA1 was amplified using the polymerase chain reaction (PCR) to sufficient quantities to permit genetic analysis using allele-specific oligonucleotides (ASO). Allelic typing of each specimen was performed and the reproducibility of the method was demonstrated in that in all 13 cases the two independently isolated specimens produced the identical ASO binding patterns. No qualitative difference was noted in the amplified product generated from plasma or serum. This study demonstrates (a) that minute amounts of serum or plasma are able to provide sufficient quantity and quality of DNA to permit genetic analyses (b) and that the source of serum can be archived for many years.

Alleles↗

PubMed1993

HLA-DPB1 glutamate 69: a genetic marker of beryllium disease.

Chronic beryllium disease (CBD) is a lung disorder related to beryllium exposure and is characterized by the accumulation in the lung of beryllium-specific CD4+ major histocompatibility complex (MHC) class II-restricted T lymphocytes. Evaluation of MHC class II genes in 33 CBD cases and 44 controls has shown a negative association with HLA-DPB1*0401 (P < 0.001) and a positive association with HLA-DPB1*0201 (P < 0.05) alleles, which differ at residues 36, 55 to 56, and 69 of the beta 1 chain. Among CBD cases, 97 percent expressed the HLA-DPB1*0201-associated glutamic acid (unaffected population, 30 percent; P < 0.001) at residue 69, a position involved in susceptibility to autoimmune disorders. This suggests that HLA-DP has a role in conferring susceptibility and that residue 69 of HLA-DPB1 could be used in risk assessment for CBD.

Adult↗

PubMed1989

Restricted assembly of MHC class II molecules in transgenic mice.

Studies on cell lines transfected with MHC class II genes have revealed important limitations on the assembly of haplotype-mismatched A alpha:A beta complexes. These findings led to the speculation that pairing restrictions, if applied in a cell type-specific fashion, might be involved in various autoimmune phenomena. We have investigated pairing restrictions in vivo by analyzing transgenic mice that carry an Ak alpha chain, an Ak beta chain, or the Ak alpha:Ak beta complex on an H-2b or H-2s background. Our conclusion is that the assembly of haplotype-mismatched A alpha:A beta complexes is limited in vivo, and that this is equally true for all cell types examined, regardless of their role in the immune response.

Alleles↗

PubMed1992

Unusual DNA binding characteristics of an in vitro translation product of the CCAAT binding protein mYB-1.

We have isolated a cDNA that encodes the murine CCAAT-binding protein mYB-1. The deduced amino acid sequence shows 95% identity with its presumed human homologue (hYB-1A) which was originally isolated as a protein that binds to the Y box of MHC class II genes. In vitro translated mYB-1 binds to CCAAT boxes of the MHCIIE alpha, HSVTK and mouse PCNA promoters but not to alpha-globin or human thymidine kinase CCAAT boxes. Interestingly, complexes formed between the in vitro translated protein and the various CCAAT boxes display the property of being competed more efficiently with self competitor DNA, regardless of the CCAAT box initially used as a probe. A similar phenomenon was observed in a cell extract of Con-A stimulated murine splenocytes when the same competition assays were performed. These results may reflect the generation of multiple forms of a particular CCAAT-binding protein, such as mYB-1, that display distinct, yet overlapping, DNA binding specificities.

Animals↗

PubMedDate not supplied

Expression of I-A alpha k and allelic restriction on A alpha/A beta pairing in transgenic mice.

Cell surface expression of class 11 major histocompatibility complex encoded (1a) molecules depends on association of the component alpha and beta chain into a stable heterodimer. Studies on cell lines transfected with MHC class II genes have revealed important limitations on the assembly of haplotype-mismatched A alpha:A beta complex. In order to study alpha:beta chain pairing restrictions in vivo a number of lines of transgenic mice carrying the A alpha k gene were generated. The transgene was studied in the context of H-2b, H-2s, H-2q, H-2u, H-2f and H-2v haplotypes. Initial FACS analysis of spleen and peripheral blood cells showed no A alpha kappa expression. Spleen cells stimulated with LPS and analysed by FACS showed A alpha k expression in three different H-2b strains as well as H-2u, but not in others. These data indicate that A alpha k can associate with A beta b and A alpha k, but not with A beta s, A beta q, A beta f, A beta v.

Alleles↗

PubMed1997

[High- and low-risk molecular sequences in autoimmune diseases. An analysis of type I diabetes in Latin America].

Type I diabetes is an autoimmune and a polygenic disease, in which MHC-class II genes contribute to 48% of the disease. The aim of the present study, is to provide a guideline to understanding the molecular association of these genes, through the immunogenetic analysis of 3 Latin american mestizo populations. We included 606 individuals, 349 patients with DMDI and 257 healthy controls coming from 3 geographical areas: Mexico City, Mexico; Caracas, Venezuela and Medellin, Colombia. The results clearly indicate that in mestizo groups, the diabetogenic haplotypes are from mediterranean ancestry, while protection is due to Amerindian genes. It was demonstrated that the relevant sequences for IDDM expression are located to DRB1 and DQB1 loci with a minimal contribution of DQA1 residues. The sequences determining peptide recognition and the induction of TH1 cells mediating the cellular autoimmune response are in positions DRB1-57 and 74 (an aspartic acid and a glutamic acid respectively, confer protection), modulated by D-57 in the DQ, 8 chain. These data show that DRB1-DQB1 haplotypes are central for IDDM expression and open new pathways for the disease management.

Adolescent↗

PubMed1998

Advances and controversies in etiopathogenesis of type 1 (insulin-dependent) diabetes mellitus.

The present state of knowledge and controversies about the etiopathogenesis of tyep 1 diabetes can be summarized as follows: GENETICS: MHC class II genes (IDDM1) confer the strongest susceptibility with a hierachy DQ > DR; more than ten other chromosome regions (IDDM2 to IDDM13) have been identified as candidates for linkage with type 1 diabetes: currently, there is consensus for insulin (IDDM2) and a few other loci, while the remainder await confirmation. ENVIRONMENT: The role of milk as a trigger is debated. In fact, the protective effect of breast feeding is marginal, while the immune response to milk proteins in type 1 diabetics is very heterogeneous; moreover, the putative autoantigens showing sequence homology with milk proteins have been questioned. With regard to viruses, seasonal variations of incidence have been confirmed, although not uniform across countries; serological studies are controversial, while isolation of viruses from diabetic pancreases remains anecdotal; very interesting is the demonstration of enteroviral infection in pregnant mothers of future diabetic children, although this does not prove a causal role; a new frontier of investigation could be that of endogenous retroviruses acting either as autoimmune genes or infectious agents. AUTOIMMUNITY: GAD65, IA2 and insulin are at present the only established autoantigens; autoantibodies to these molecules, used in combination with ICA, can accurately predict type 1 diabetes; B-lymphocytes and autoantibodies might play a pathogenetic role; autoantigen targets of T-lymphocytes are yet to be characterized; assays for measuring autoreactive T-lymphocytes require standardization; antigen-specific Th1/Th2 relationship in type 1 diabetes remains controversial.

Animals↗

PubMedDate not supplied

DNA elements target of transcriptional factors are not restricted to long terminal repeat of human immunodeficiency virus.

In this report we show that signals for transcriptional factors are not restricted to the HIV-1 LTR, but are present throughout the HIV-1 genome. Furthermore, we identified a sequence, AGAACAGATG, highly homologous to the X-box of class II MHC genes and located within the tat-IVS/env region of HIV-1. Double stranded oligonucleotides mimicking the HIV-1 region containing AGAACAGATG were synthesized and band shift experiments were performed demonstrating that this HIV-1 genomic region binds nuclear proteins. We further demonstrate that the binding of nuclear factors to this tat-IVS/env HIV-1 sequence is competed for, in the band-shift assay, by the highly homologous X-box of the promoter of the human HLA-DR alpha gene. The presence in the HIV-1 genome of DNA sequences homologous or identical to regulatory sequences of cellular genes represents a potential mechanism of predation of DNA elements recognized by DNA binding proteins.

Base Sequence↗

PubMed1993

The major histocompatibility complex class II promoter-binding protein RFX (NF-X) is a methylated DNA-binding protein.

A mammalian protein called RFX or NF-X binds to the X box (or X1 box) in the promoters of a number of major histocompatibility (MHC) class II genes. In this study, RFX was shown to have the same DNA-binding specificity as methylated DNA-binding protein (MDBP), and its own cDNA was found to contain a binding site for MDBP in the leader region. MDBP is a ubiquitous mammalian protein that binds to certain DNA sequences preferentially when they are CpG methylated and to other related sequences, like the X box, irrespective of DNA methylation. MDBP from HeLa and Raji cells formed DNA-protein complexes with X-box oligonucleotides that coelectrophoresed with those containing standard MDBP sites. Furthermore, MDBP and X-box oligonucleotides cross-competed for the formation of these DNA-protein complexes. DNA-protein complexes obtained with MDBP sites displayed the same partial supershifting with an antiserum directed to the N terminus of RFX seen for complexes containing an X-box oligonucleotide. Also, the in vitro-transcribed-translated product of a recombinant RFX cDNA bound specifically to MDBP ligands and displayed the DNA methylation-dependent binding of MDBP. RFX therefore contains MDBP activity and thereby also EF-C, EP, and MIF activities that are indistinguishable from MDBP and that bind to methylation-independent sites in the transcriptional enhancers of polyomavirus and hepatitis B virus and to an intron of c-myc.

Base Sequence↗

PubMed2001

Impaired class II transactivator expression in mice lacking interferon regulatory factor-2.

Class II transactivator (CIITA) is required for both constitutive and inducible expression of MHC class II genes. IFN-gamma induced expression of CIITA in various cell types is directed by CIITA type IV promoter. The two transactivators, STAT1 and IRF-1, mediate the IFN-gamma activation of the type IV promoter by binding to the GAS and IRF-E of the promoter, respectively. In addition to IRF-1, IRF-2, another member of the IRF family, also activates the human CIITA type IV promoter, and IRF-2 cooperates with IRF-1 to activate the promoter in transient transfection assays. IRF-1 and IRF-2 can co-occupy the IRF-E of the human CIITA type IV promoter. To understand the effect of loss of IRF-2 on the endogenous CIITA expression, we assayed for CIITA expression in IRF-2 knock-out mice. Both basal and IFN-gamma induced CIITA expression were reduced in IRF-2 knock-out mice. At least half of the amount of inducible CIITA mRNA depends on IRF-2. The reduction of IFN-gamma induced CIITA mRNA in IRF-2 knock-out mice was due to the reduction of the type IV CIITA mRNA induction. The reduction of basal CIITA mRNA was apparently due to the reduction of CIITA mRNA originating from other promoters. These data indicate that IRF-2, like IRF-1, plays a critical role in the regulation of the endogenous CIITA gene. The implications in understanding the previously described phenotypes of IRF-2 defective mice are discussed.

Animals↗

PubMedDate not supplied

Polymorphism of human Ia antigens generated by reciprocal intergenic exchange between two DR beta loci.

Class II molecules encoded by the human major histocompatibility complex (MHC) are involved in regulating T-cell response to antigens. The mechanisms for generating polymorphism in products of the MHC have been studied extensively for both the murine H-2 and the human HLA complex. Such studies indicate that point mutations plus selection have a major role in the generation of polymorphisms of class I and class II MHC genes. However, a non-reciprocal gene conversion mechanism has been proposed to explain several examples of clustered sequence variation in MHC genes. In all these examples, the proposed gene conversion event is unidirectional; that is, one of the two interacting genes acts as sequence donor and the other as sequence recipient. No examples of potential reciprocal genetic exchange (as occurs in the fungal system), in which the two interacting genes act as both donor and recipient of gene fragments, have been found in the MHC system or in other multigene families of higher organisms. We sequenced two different HLA-DR beta complementary DNAs from each of two different cells all expressing the same serologically defined determinant (DR2) but different T-cell-recognized (Dw) specificities (Dw12 and MN2). Sequence comparisons of these four cDNA clones (and two DR beta amino-acid sequences from the DR2-Dw2 subtype) suggest that new coding sequences for DR beta molecules in the DR2 haplotypes are potentially generated by reciprocal intergenic exchange.

Amino Acid Sequence↗

PubMed2002

Transcriptional regulation of the MHC class II trans-activator (CIITA) promoter III: identification of a novel regulatory region in the 5'-untranslated region and an important role for cAMP-responsive element binding protein 1 and activating transcription factor-1 in CIITA-promoter III transcriptional activation in B lymphocytes.

The class II trans-activator (CIITA), which acts as a master regulator for expression of MHC class II genes, is expressed constitutively in mature B cells. This constitutive expression of CIITA is driven by CIITA promoter III (CIITA-PIII). However, little is known about the factors that control the B cell-mediated trans-activation of CIITA-PIII. In this study using B cells we have identified several cAMP-responsive elements (CREs) in the proximal promoter and in the 5'-untranslated region (5'-UTR) that are involved in the activation of CIITA-PIII. We show that activating transcription factor (ATF)/CRE binding protein (CREB) factors bind to the CREs in vitro and in vivo. Notably, our results also reveal that the 5'-UTR of CIITA-PIII functions as an important regulatory region in B lymphocytes. Furthermore, transient cotransfections of a CIITA-PIII luciferase reporter construct with either CREB-1 or ATF-1 boost CIITA-PIII trans-activation in a dose-dependent manner, which was further enhanced by addition of general coactivator CREB-binding protein. Transient transfections using mutant CIITA-PIII luciferase reporter constructs that either lack the (5'-UTR) or abolish binding of CREB-1 and ATF-1 to the CRE located in activation response element-2, displayed severely reduced promoter activity in B cells. A similar successive deletion of the CREs resulted in a subsequent reduction of CREB-1-induced activity of CIITA-PIII in B cells. Together our results argue for an important role of ATF/CREB factors and the 5'-UTR of CIITA-PIII in the trans-activation of CIITA-PIII in B cells.

5' Untranslated Regions↗

PubMed2002

Gene expression profile of Vitamin D3 treated HL60 cells shows an incomplete molecular phenotypic conversion to monocytes.

By high density oligonucleotide microarrays we have studied the expression profile of proliferating and VD treated HL60 cells and the molecular phenotype of VD monocytes and that of CD14+ peripheral monocytes has been compared. The results indicate that important changes in functional categories of the differentially expressed genes underlie the differentiation transition from myeloblasts to monocytes. This differential gene expression pattern leads to an increased expression of mRNAs involved in surface and external activities since many of the VD induced genes belong to ligand binding, receptors, cell surface antigens, defense/immunity and adhesion molecules functional categories. The results also indicate that the molecular phenotypes of monocytes and VD induced cells diverge for a small but significant set of defense related genes. Particularly, class II MHC genes are not expressed in these cells. Furthermore, the high levels of expression of these genes induced by serum treatment of monocytes are decreased by VD.

Cell Differentiation↗

PubMed1997

Animal models of cutaneous lupus erythematosus and lupus erythematosus photosensitivity.

Over the past decade, the most exciting and important finding in SLE-prone mice is the discovery of Fas/Fas ligand systems in the pathogenesis of autoimmune phenomena. A human model for murine lpr/gld disease has also been reported recently. Furthermore, as shown in Table 2, studies on Ig variable region genes, TCR genes and MHC class II genes have given us much information concerning human and murine SLE. With respect to cytokines, IL-2 deficiency and the key role of IL-6 have been found in SLE-prone mouse strains, and Th2 cytokine production has been demonstrated to play a more pathogenic role than Th1 cytokine production in human and murine SLE except for MRL/pr mice. TGF is also very intriguing because TGF-beta knockout mice show SLE-like autoantibodies and Sjögren syndrome-like lymphoproliferation. Apart from these basic scientific investigations, there are also many promising and practical therapeutic approaches. In particular, treatments with anti-CD4 antibody and murine CTLA4Ig which bound B7 and blocked binding of CD28 to B7 are outstanding. However, it remains obscure whether such new approaches are effective for the skin lesions of SLE-prone mice, although some immunosuppressive agents such as FK506, cyclosporin and Chinese herbal medicines have been evaluated to determine their selective effects on the skin lesions of MRL/lpr mice. Needless to say, mouse models are not identical, but similar, to human diseases. However, they are important in the search for the underlying pathogenesis of autoimmune diseases on the basis of careful evaluation of the similarities and differences between human diseases and these models. If such studies are steadily performed, then inbred or experimental models will become more promising tools for the investigation of cutaneous lupus erythematosus.

Animals↗

PubMed1996

Retrovirus-mediated gene transfer of B7-1 and MHC class II converts a poorly immunogenic neuroblastoma into a highly immunogenic one.

The T cell co-stimulatory molecule B7-1 was transduced into a poorly immunogenic murine neuroblastoma cell line (Neuro-2a, N-2a) alone or in combination with MHC class II genes to test the ability of these genes to stimulate antitumor immunity. N-2a cells transduced with B7-1 exhibited reduced tumorigenicity, whereas N-2a cells overexpressing both MHC class II (syngeneic, I-Ak) and B7-1 totally abrogated tumorigenicity. Rejection of I-Ak/B7-1 cells was dependent on both CD4+ and CD8+ T cells. The ability of both vaccines to induce protection against parental N-2a was temporally dependent on the time of secondary N-2a challenge. To investigate the immunity generated by N-2a/B7-1 and N-2a/I-Ak/B7-1 vaccines, we tested the ability of these modified cells to stimulate in vitro the proliferation of syngeneic splenocytes from naive mice. A significant increase in splenocyte proliferation was observed with N-2a/I-Ak/B7-1 cells compared to N-2a cells. We also determined that vaccination with N-2a/I-Ak/B7-1 cells was able to generate cytotoxic T cell responses to unmodified N-2a cells. The introduction of B7-1 and I-Ak into N-2a was able to convert a poorly immunogenic tumor to a highly immunogenic one; however, mice bearing large established unmodified tumors had little response to vaccination with N-2a/I-Ak/B7-1 cells. Our results emphasize the importance of tumor immunogenicity in the treatment of established tumors with MHC class II/B7-1 tumor cell vaccines.

Animals↗

PubMed1988

Major histocompatibility complex gene product expression on pancreatic beta cells in acutely diabetic BB rats.

Type I diabetes mellitus was induced in young, diabetes-prone BB rats by the passive transfer of concanavalin A-activated T lymphocytes from the spleens of acutely diabetic BB rats. The pancreas of the recipients was examined 1-2 days after the onset of glycosuria by immunocytochemistry by means of monoclonal antibodies for determining whether 1) Class I and/or II major histocompatibility gene complex (MHC) products were expressed on beta cells and 2) the mononuclear cell infiltrates were represented by T cells. Marked expression of Class I MHC gene products was evident on beta cells. In contrast, Class II MHC gene products were not identified on normal-appearing beta cells. Dendritic cells dispersed throughout the acinar and interstitial pancreas were markedly increased in number. The mononuclear cell infiltrate contained few cells (1-15%) recognized by a pan-T cell marker. Although it is possible that this passive transfer model might differ considerably from the spontaneously occurring diabetic state in the rat, this study suggests that 1) Class I, rather than Class II, MHC gene expression may be pivotal to beta-cell injury in diabetic rats, and 2) non-T cells may constitute an effector cell population central to beta-cell necrosis in Type I diabetes mellitus.

Animals↗