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PubMed2003

Steroid receptor coactivator 1 links the steroid and interferon gamma response pathways.

We show here that steroid receptor coactivator 1 (SRC-1) is a coactivator of MHC class II genes that stimulates their interferon gamma (IFNgamma) and class II transactivator (CIITA)-mediated expression. SRC-1 interacts physically with the N-terminal activation domain of CIITA through two regions: one central [extending from amino acids (aa) 360-839] that contains the nuclear receptors binding region and one C-terminal (aa 1138-1441) that contains the activation domain 2. Using chromatin immunoprecipitation assays we show that SRC-1 recruitment on the class II promoter is enhanced upon IFNgamma stimulation. Most importantly, SRC-1 relieves the inhibitory action of estrogens on the IFNgamma-mediated induction of class II genes in transient transfection assays. We provide evidence that inhibition by estradiol is due to multiple events such as slightly reduced recruitment of CIITA and SRC-1 and severely inhibited assembly of the preinitiation complex.

Animals↗

PubMed1987

Immunogenetics of collagen-induced arthritis.

CIA is a unique experimental model of disease, which may be particularly relevant to the study of RA, since it represents a true autoimmune reaction against a major joint component. Since it represents a model of the association of MHC genes and disease, it has a broad relevance to the study of disease, particularly the contribution of class II MHC genes to autoimmunity. This disease model has been demonstrated in three species, and a marked influence of immunogenetic control is apparent. Native type II collagen is a large protein with a genetically conserved structure, giving rise to a number of cross-reactive antigen epitopes between species. Susceptibility to CIA correlates with an Ir directed against certain epitopes, and this autoimmune response appears to be controlled by MHC-linked genes. In the mouse, susceptibility has been specifically associated with variations in the I-A beta chain. The immunogenetic control may be effected through the T-cell recognition of the collagen molecule, resulting in antibodies and reactive cells with a specificity for native autologous type II collagen. Although the specificity of the anti-type II collagen response is the critical element in the generation of the autoimmune reaction, production of a high level of antibody is important, as well as a complement-fixing isotype. Cell-mediated immunity to type II collagen contributes to the disease chronicity, either through the generation of inappropriate T help, or a suppressor defect, and the production of factors. However, the precise sequence of events, from antigen recognition to joint damage, has yet to be elucidated fully. Some aspects of this experimental model bear a striking resemblence to RA. Hopefully, this experimental model will provide valuable insights into the significance of collagen autoimmunity and the contribution of class II genes to the pathology of arthritic disease.

Animals↗

PubMed2004

Analysis of genomic and expressed major histocompatibility class Ia and class II genes in a hexaploid Lake Tana African 'large' barb individual (Barbus intermedius).

Expression of too many co-dominant major histocompatibility complex (MHC) alleles is thought to be detrimental to proper functioning of the immune system. Polyploidy of the genome will increase the number of expressed MHC genes unless they are prone to a silencing mechanism. In polyploid Xenopus species, the number of MHC class I and II genes has been physically reduced, as it does not increase with higher ploidy genomes. In the zebrafish some class II B loci have been silenced, as only two genomically bona fide loci, DAA/DAB and DEA/DEB, have been described. Earlier studies indicated a reduction in the number of genomic and expressed class II MHC genes in a hexaploid African 'large' barb. This prompted us to study the number of MHC genes present in the genome of an African 'large' barb individual (Barbus intermedius) in relation to those expressed, adopting the following strategy. Full-length cDNA sequences were generated from mRNA and compared with partial genomic class Ia and II sequences generated by PCR using the same primer set. In addition, we performed Southern hybridizations to obtain a verification of the number of class I and II B genes. Our study revealed three beta2-microglobulin, five class Ia, four class II A, and four class II B genes at the genomic level, which were shown to be expressed in the hexaploid barb individual. The class Ia and class II data indicate that the ploidy status does not correlate with the presence and expression of these MHC genes.

Amino Acid Sequence↗

PubMed1992

Single base pair substitutions within the HLA-DRA gene promoter separate the functions of the X1 and X2 boxes.

The class II MHC genes are expressed on the surfaces of B cells, activated T cells, and macrophages and may be induced in other cell types by IFN-gamma. The control of class II gene expression has been shown to be mediated by a series of conserved cis-acting sequences (W, X1, X2, and Y boxes) located immediately 5' to the genes. Although these sequences are conserved, the bp that are important for transcriptional regulation have yet to be identified. To address this issue with regard to the MHC gene HLA-DRA, a series of single bp substitutions spanning the conserved upstream sequences was created and analyzed for their effects on transcription in both B cells and IFN-gamma-treated fibroblasts. In addition, the effects of X1 and X2 box mutations on DNA/protein interactions were examined and compared to the transcriptional data. The results of these studies show that each of the conserved elements participate in maximal expression in B cells and that W, X1, and X2 boxes are important for IFN-gamma induction and expression in fibroblasts. Interestingly, some of the bp changes that altered B cell expression did not alter expression and IFN-gamma induction in fibroblasts, suggesting that different or altered factors control the expression of these genes in the different cell types. Mutant templates designed to eliminate the binding of X1- and X2-specific DNA binding proteins in vivo suggest that these elements and their factors may interact to promote transcription.

B-Lymphocytes↗

PubMed1999

Two distinct gamma interferon-inducible promoters of the major histocompatibility complex class II transactivator gene are differentially regulated by STAT1, interferon regulatory factor 1, and transforming growth factor beta.

The major histocompatibility complex (MHC) class II transactivator (CIITA) is the master regulatory factor required for appropriate expression of class II MHC genes. Understanding the expression of CIITA is key to understanding the regulation of class II MHC genes. This report describes the independent regulation of two distinct CIITA promoters by cytokines with opposing functions, gamma interferon (IFN-gamma) and transforming growth factor beta (TGF-beta). A functional analysis of deletion mutations of the upstream promoter (promoter III) identified an IFN-gamma-responsive region located approximately 5 kb from the transcriptional start site. An in vivo DNase I hypersensitivity analysis detected a hypersensitive site in this area which supports the relevance of this region. When the downstream promoter (promoter IV) was studied by in vivo genomic footprinting, IFN-gamma-induced changes at putative binding sites for STAT1, interferon regulatory factor 1 (IRF-1), and E-box proteins were seen. Gel shift and supershift analyses for IRF-1 confirmed the in vivo footprint results. The role of the IFN-gamma-inducible transcription factor STAT1 was examined functionally. Although both promoters were controlled by STAT1, promoter-specific regulation was exhibited. The IFN-gamma response of promoter III was completely dependent on STAT1 and not IRF-1, while promoter IV was partially activated by IRF-1 in the total absence of STAT1 expression. While both promoters were affected by TGF-beta, activation of promoter III by IFN-gamma was more severely diminished by TGF-beta treatment. The differential control of CIITA promoters by TGF-beta, IRF-1, and STAT1 may be important in refining regulation of class II MHC genes in different cell types and under different stimulatory conditions.

Base Sequence↗

PubMed2003

Structural and functional characteristics of a dominant-negative isoform of porcine MHC class II transactivator.

The MHC class II transactivator, CIITA, is critical for MHC class II gene expression in all species studied to date. We isolated an interferon (IFN)-gamma-inducible isoform of porcine CIITA (pCIITA') encoding a protein of 566 amino acids (aa) with significant homology to human CIITA (hCIITA). Analysis indicated that pCIITA' lacks the entire GTP-binding domain that is important for nuclear translocation and activation of target genes by hCIITA. In pCIITA' this region is replaced by a 14-aa motif with homology to several signalling peptide sequences. Expression of pCIITA' in porcine (ST-IOWA) and human (HeLa) cell lines resulted in suppression of IFN-gamma-stimulated MHC class II gene expression, at the protein and mRNA levels. We also identified two IFN-gamma-inducible variants of hCIITA, hCIITAlo and hCIITA' from Hela cells, both exhibiting dominant-negative suppression of MHC class II gene expression. Interestingly, hCIITA' encodes a predicted protein of 546 aa with a strikingly similar organization to pCIITA' including the 14-aa GTP-binding domain-replacement motif in which 10 out of 14 amino acids are identical to the pig sequence. Expression of hCIITA' and hCIITAlo sequences in Hela cells suppressed IFN-gamma-induced MHC class II gene expression. hCIITAlo, a predicted 303-aa protein with deleted GTP-binding and carboxy-terminal domain, displayed a more subtle suppression of IFN-gamma-induced MHC class II expression. These in vitro data indicate that there may be a role in vivo for isoforms of CIITA that can suppress full-length CIITA-mediated MHC class II gene expression. Both humans and now, potentially, pigs are candidate donors for organ and tissue allografts and xenografts, respectively. Regulation of MHC class II gene expression by manipulation of CIITA isoform expression in humans and pigs may provide a useful strategy for attenuation of T-cell-mediated cellular rejection.

Amino Acid Sequence↗

PubMed2001

Evolution of Mhc class II B genes in Darwin's finches and their closest relatives: birth of a new gene.

The 15 extant species of Darwin's finches on the Galápagos and Cocos Islands are the products of an unfinished adaptive radiation from a founder flock of birds related to the South American species Tiaris obscura. Molecular characterization of their major histocompatibility complex ( Mhc) class II B genes has revealed the existence of several related groups of sequences (presumably encoded in distinct loci) from which one (group 5) stands out because of its low divergence over extended time periods. Analysis of group 5 exon 2 and intron 2 sequences has revealed that the encoding locus apparently arose 2-3 million years ago in the Tiaris group of South and Central American Thraupini. The locus shows no evidence of inactivation, but displays a very low degree of polymorphism, both in terms of number of alleles and genetic distances between alleles. Some of the polymorphism, however, appears to be trans-specific. All the observed intergenic differences can be explained by point mutations and most of the exon 2 changes represent non-synonymous substitutions, although the rate of non-synonymous and synonymous substitutions appears to be the same. The origin of the new locus is explained by the birth-and-death model of Mhc evolution with two important extensions. First, the ancestor of the group 5 genes may have arisen without new gene duplication and second, the birth of the new group may have been brought about by a switch from balancing to directional selection. The ancestor of the group 5 genes may have been a classical class II B allele (one of many) which directional selection fixed in the ancestral population and drove into the category of nonclassical genes.

Animals↗

PubMed2003

Class II transactivator (CIITA) promoter methylation does not correlate with silencing of CIITA transcription in trophoblasts.

Trophoblast cells are unique because they do not express major histocompatibility complex (MHC) class II antigens, either constitutively or after exposure to interferon-gamma (IFN-gamma). The absence of MHC class II antigens on trophoblasts is thought to play a critical role in preventing rejection of the fetus by the maternal immune system. The inability of trophoblasts to express MHC class II genes is primarily due to lack of the class II transactivator (CIITA), a transacting factor that is required for constitutive and IFN-gamma-inducible MHC class II transcription. We, therefore, investigated the silencing of CIITA expression in trophoblasts. In transient transfection assays, transcription from the IFN-gamma-responsive CIITA type IV promoter was upregulated by IFN-gamma in trophoblasts, which suggests that CIITA is silenced by an epigenetic mechanism in these cells. Polymerase chain reaction analysis demonstrated that the CIITA type IV promoter is methylated in both the human choriocarcinoma cell lines JEG-3 and Jar and in 2fTGH fibrosarcoma cells, which are IFN-gamma inducible for CIITA. Conversely, methylation of the CIITA type IV promoter was not observed in human primary cytotrophoblasts isolated from term placentae or in mouse or rat trophoblast cell lines. Simultaneous treatment with IFN-gamma and the histone deacetylase inhibitor trichostatin A weakly activated CIITA transcription in mouse trophoblasts. Stable hybrids between human choriocarcinoma and fibrosarcoma cells and between mouse trophoblasts and fibroblasts expressed CIITA following treatment with IFN-gamma. These results suggest that silencing of CIITA transcription is recessive in trophoblasts and involves an epigenetic mechanism other than promoter methylation. The fact that CIITA is expressed in the stable hybrids implies that trophoblasts may be missing a factor that regulates chromatin structure at the CIITA promoter.

Animals↗

PubMed1997

The DMB promoter: delineation, in vivo footprint, trans-activation, and trans-dominant suppression.

The HLA-DM loci encode the heterodimeric unconventional class II MHC molecules that are coexpressed with conventional class II MHC molecules. DM molecules are essential for the proper formation and function of conventional class II MHC molecules. This report characterizes the DMB promoter both by in vivo footprint and by in vitro functional analysis and reveals a promoter structure similar to that of conventional class II MHC genes. DR-negative mutant cell lines selectively defective in the transcription factor or class II trans-activator (CIITA) were used to reveal a requirement for both these factors in DMB promoter activation. Complementation of defective cell lines with the appropriate transcription factor reconstituted DMB promoter activation. Further analysis with CIITA identified several mutant forms of CIITA that are trans-dominant-negative mutants, i.e., they suppressed DMB promoter activation by transfected and endogenous CIITA. These mutants may be used in abiological setting to down-regulate the function of DM in Ag processing.

Base Sequence↗

PubMed2002

Modulation of gamma interferon-induced major histocompatibility complex class II gene expression by Porphyromonas gingivalis membrane vesicles.

Gamma interferon (IFN-gamma)-induced endothelial cells actively participate in initiating immune responses by interacting with CD4(+) T cells via class II major histocompatibility complex (MHC) surface glycoproteins. Previously, Porphyromonas gingivalis membrane vesicles were shown to selectively inhibit IFN-gamma-induced surface expression of HLA-DR molecules by human umbilical cord vascular endothelial cells. In this study, we demonstrated an absence of HLA-DR alpha mRNA from IFN-gamma-induced cells in the presence of P. gingivalis membrane vesicles by using reverse transcriptase-PCR and Southern blotting. Vesicles also prevented transcription of the gene encoding class II transactivator, a transactivator protein required for IFN-gamma-induced expression of MHC class II genes. In addition, the effects of vesicles on IFN-gamma signal transduction involving Jak and Stat proteins were characterized by using immunoprecipitation and Western blot analyses. Jak1 and Jak2 proteins could not be detected in endothelial cells treated with membrane vesicles. Consequently, IFN-gamma-induced phosphorylation of Jak1, Jak2, and Stat1 alpha proteins was prevented. The class II-inhibitory effect of the membrane vesicles could be eliminated by heating vesicles at 100 degrees C for 30 min or by treating them with a cysteine proteinase inhibitor. This indicates that the cysteine proteinases were most likely responsible for the absence of Jak proteins observed in vesicle-treated cells. The observed increased binding of radiolabeled IFN-gamma to vesicle-treated cells suggests that vesicles may also modulate the IFN-gamma interactions with the cell surface. However, no evidence was obtained demonstrating that vesicles affected the expression of IFN-gamma receptors. Thus, P. gingivalis membrane vesicles apparently inhibited IFN-gamma-induced MHC class II by disrupting the IFN-gamma signaling transduction pathway. Vesicle-inhibited class II expression also occurred in other IFN-gamma-inducible cells. This suggested that the ability of P. gingivalis membrane vesicles to modulate antigen presentation by key cells may be an important mechanism used by this particular bacterium to escape immunosurveillance, thereby favoring its colonization and invasion of host tissues.

Cells, Cultured↗

PubMed1986

Further studies on psoriasis-associated HLA-Dw/DR7 using PLT cells primed against a familial psoriasis-linked HLA haplotype.

The products of the HLA-D region and their correlation to psoriasis vulgaris was studied using the primed lymphocyte typing (PLT) assay. In families with one healthy and one psoriatic parent and one psoriatic child primary MLC (mixed lymphocyte culture) stimulation was carried out between responder cells from the healthy parent and stimulator cells from the psoriatic child. In this way 21 PLT reagents directed against putative psoriasis-associated lymphocyte activating determinants were produced. Three reagents that gave clear bimodal stimulation patterns against lymphocytes of 51 psoriasis patients were further tested against 78 controls. Specificity of these reagents was studied using homozygous typing cells (HTC's) as stimulators. Compiled data show that cells from DR7 positive psoriatic patients give higher restimulation of these PLT reagents than do cells from healthy DR7 positive controls. In addition, a higher frequency of psoriasis patients compared to controls gave significant restimulation. Therefore we concluded that these PLT reagents recognized at least partly different DR7 associated determinants in the psoriasis patients and in controls. The reason is either that psoriasis patients carry a different lymphocyte activating DR associated specificity or, alternatively, that restimulation was caused by products of a distinct psoriasis associated locus in linkage disequilibrium with D/DR7 or of a determinant recognized together with D/DR7 as a restriction element. These data further support the notion that psoriasis is a disease with primary HLA associations to both class I and class II MHC genes.

Alleles↗

PubMed1993

Class II MHC transcriptional mutants are defective in higher order complex formation.

Human class II MHC genes are regulated in part by a series of conserved upstream sequence elements termed the X1, X2, and Y boxes. Class II MHC transcriptional mutant B cell lines have been defined that differ with regard to the presence of RFX, an X1 box DNA-binding activity. To further characterize these mutant cell lines, we tested the ability of these conserved upstream elements to respond to the presence of known transcriptional activation domains. A series of HLA-DRA promoter reporter constructions carrying Gal4 binding sites and GAL4 fusion protein expression vectors were cotransfected into both wild type B cells and mutant B cells representing the two RFX phenotypes. Regardless of RFX or class II phenotype, the activation domains of GAL4-VP16 and GAL4-E1a could synergistically stimulate expression of constructions containing both the X2 and Y boxes. GAL4-VP16- and GAL4-E1a-mediated expression was inhibited by the presence of the X1 box in cells that contained RFX. In mutant cells that lacked RFX, GAL4-VP16 activation was not inhibited. In the RFX-positive class II mutant cell line RJ2.2.5, the X1 box inhibitory activity could be overcome by separating the Gal4 site from the X1 box by two additional helical turns, suggesting that the RFX factor is bound at the X1 site and sterically interferes with activation. This was not the case in wild type B cells, suggesting that a stable higher order complex forms in wild type cells and not in the mutant cells.

B-Lymphocytes↗

PubMed1994

A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor.

The class II major histocompatibility complex (MHC) molecules function in the presentation of processed peptides to helper T cells. As most mammalian cells can endocytose and process foreign antigen, the critical determinant of an antigen-presenting cell is its ability to express class II MHC molecules. Expression of these molecules is usually restricted to cells of the immune system and dysregulated expression is hypothesized to contribute to the pathogenesis of a severe combined immunodeficiency syndrome and certain autoimmune diseases. Human complementary DNA clones encoding a newly identified, cysteine-rich transcription factor, NF-X1, which binds to the conserved X-box motif of class II MHC genes, were obtained, and the primary amino acid sequence deduced. The major open reading frame encodes a polypeptide of 1,104 amino acids with a symmetrical organization. A central cysteine-rich portion encodes the DNA-binding domain, and is subdivided into seven repeated motifs. This motif is similar to but distinct from the LIM domain and the RING finger family, and is reminiscent of known metal-binding regions. The unique arrangement of cysteines indicates that the consensus sequence CX3CXL-XCGX1-5HXCX3CHXGXC represents a novel cysteine-rich motif. Two lines of evidence indicate that the polypeptide encodes a potent and biologically relevant repressor of HLA-DRA transcription: (a) overexpression of NF-X1 from a retroviral construct strongly decreases transcription from the HLA-DRA promoter; and (b) the NF-X1 transcript is markedly induced late after induction with interferon gamma (IFN-gamma), coinciding with postinduction attenuation of HLA-DRA transcription. The NF-X1 protein may therefore play an important role in regulating the duration of an inflammatory response by limiting the period in which class II MHC molecules are induced by IFN-gamma.

Amino Acid Sequence↗

PubMed1993

Identification of class II major histocompatibility complex polymorphisms predicted to be important in peptide antigen presentation.

Chickens of the B2, B5, B15, B19, and B21 B-congenic haplotypes differ in disease resistance. Complementary DNA from B-congenic chicken strains have been analyzed for allelic diversity of expressed Class II MHC genes. The predicted amino acid sequences of eight genes from five haplotypes were subjected to Wu-Kabat variability analysis. The B-L gene polymorphic regions and conserved regions are highly similar to the human leukocyte antigen Class II genes. Therefore, the present analysis reveals candidate polymorphisms important in determining the spectrum of antigenic peptides presented to T helper cells, and allelic differences possibly important in resistance to avian disease.

Animals↗

PubMed1993

Composite origin of major histocompatibility complex genes.

Major histocompatibility complex (MHC) genes have now been cloned from representatives of all vertebrate classes except Agnatha. The recent accumulation of sequence data has given great insight into the course of evolution of these genes. Although the primary structure of the MHC genes varies greatly from class to class and also within the individual classes, the general features of the tertiary and quaternary structure have been conserved remarkably well during more than 400 million years of evolution. The ancestral MHC genes may have been assembled from at least three structural elements derived from different gene families. Class II MHC genes appear to have been assembled first, and then to have given rise to class I genes.

Amino Acid Sequence↗

PubMed2006

Molecular study of Mhc-DRB in wild chacma baboons reveals high variability and evidence for trans-species inheritance.

The MHC class II genes of many primate species were investigated extensively in recent years. However, while Mhc-DRB genes were studied in Old World monkeys such as rhesus macaques, the Mhc-DRB of baboons was only studied in a limited way. Because of their close anatomical and physiological relationship to humans, baboons are often used as models for reproduction and transplantation research. Baboons are also studied as a model species in behavioural ecology. Thus, identification of MHC genes would provide a foundation for studies of Mhc, biology and behaviour. Here, we describe the use of PCR, cloning, denaturing gradient gel electrophoresis (DGGE) and sequencing to identify Mhc-DRB sequences in wild chacma baboons (Papio ursinus). We amplified the highly variable second exon of baboon Mhc-DRB sequences using generic DRB primers. To validate and optimize the DGGE protocol, four DNA samples were initially studied using cloning and sequencing. Clones were screened using a novel RFLP approach to increase the number of clones identified for each individual. Results from cloning and sequencing were used to optimise DGGE conditions for Mhc-DRB genotyping of the remaining study subjects. Using these techniques, we identified 16 Paur-DRB sequences from 30 chacma baboons. On the basis of phylogenetic tree analyses, representatives of the Mhc-DRB1 and Mhc-DRB5 loci, and 13 different DRB lineages were identified. Evidence for trans-species inheritance of some Mhc-DRB sequences comes from high identity between the new Paur-DRB sequences and sequences from Papio cynocephalus, Macaca mulatta and possibly Galago moholi.

Amino Acid Sequence↗

PubMed2004

Cutting edge: induction of the antigen-processing enzyme IFN-gamma-inducible lysosomal thiol reductase in melanoma cells Is STAT1-dependent but CIITA-independent.

Presentation and CD4(+) T cell responses to Ag in the context of MHC class II molecules require processing of native proteins into short peptide fragments. Within this pathway, IFN-gamma-inducible lysosomal thiol reductase (GILT) functions to catalyze thiol bond reduction, thus unfolding native protein Ag and facilitating further processing via cellular proteases. In contrast with professional APCs such as B cells, class II-positive human melanomas expressed relatively little to no GILT protein or mRNA. Tumor cell GILT expression was partially restored with IFN-gamma treatment but unlike other genes required for class II Ag presentation, GILT was not regulated by CIITA. Rather, studies revealed STAT1 plays a direct role in IFN-gamma-inducible GILT expression. These results define a molecular mechanism for the uncoupled regulation of MHC class II genes and the processing enzyme GILT in human melanomas.

Antigen Presentation↗

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↗