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PubMed1995

Human MHC class II gene transcription directed by the carboxyl terminus of CIITA, one of the defective genes in type II MHC combined immune deficiency.

Type II major histocompatibility complex combined immune deficiency (type II MHC CID or bare lymphocyte syndrome) is a congenital immunodeficiency disease characterized by absent MHC class II expression. Four distinct complementation groups have been identified. Recently, the defective gene in group II type II MHC CID has been isolated and termed CIITA. Here, we demonstrate that CIITA is an MHC class II gene-specific transcription activator. The transcription activation function is provided by the N-terminal acidic domain (amino acids 26-137), which is experimentally exchangeable with a heterologous viral transcription-activating domain. The specificity of CIITA for three major MHC class II genes, DR, DQ and DP, is mediated by its remaining C-terminal residues (amino acids 317-1130). The transactivation of multiple cis elements, especially S and X2, of the DR alpha proximal promoter in group II CID cells is CIITA dependent. Since CIITA overexpression in normal cells did not increase class II expression, we propose that initiation of CIITA expression serves as the on-off switch, while availability of downstream interactor(s) limits transcription.

B-Lymphocytes↗
PubMed2002

MHC class I genes of the tree shrew Tupaia belangeri.

Two MHC class I cDNA sequences from the tree shrew (Tupaia belangeri), Tube-W01 and Tube-W02, have been isolated which are probably derived from classical class I genes. Expression of the tupaia class I genes was investigated in several organs, in particular the brain, in which slightly different amounts of class I transcripts are detectable in different areas. Gene tree analysis performed with Tube-W01 and Tube-W02, and including class I sequences derived from other orders, indicated that the tupaia sequences cluster differently from Primates, Carnivora, Artiodactyla, Perissodactyla, and Rodentia, but might be related to Lagomorpha class I genes.

Amino Acid Sequence↗
PubMed2003

Expression of nonclassical MHC class Ib genes: comparison of regulatory elements.

Peptide binding proteins of the major histocompatibility complex consist of the "classical" class Ia and "nonclassical" class Ib genes. The gene organization and structure/function relationship of the various exons comprising class I proteins are very similar among the class Ia and class Ib genes. Although the tissue-specific patterns of expression of these two gene families are overlapping, many class Ib genes are distinguished by relative low abundance and/or limited tissue distribution. Further, many of the class Ib genes serve specialized roles in immune responses. Given that the coding sequences of the class Ia and class Ib genes are highly homologous we sought to examine the promoter regions of the various class Ib genes by comparison to the well characterized promoter elements regulating expression of the class Ia genes. This analysis revealed a surprising complexity of promoter structures among all class I genes and few instances of conservation of class Ia promoter regulatory elements among the class Ib genes.

Animals↗
PubMed1985

In vivo priming of mouse CTL precursors directed to product of a newly defined minor H-42 locus is under a novel control of class II MHC gene.

In a previous study, we discovered a new mouse minor histocompatibility antigen encoded by a locus at 8.5 cM apart from the H-2 complex, and we have since named the locus H-42. One allele of H-42, which is named H-42a, had been elucidated, but the other alleles, which we tentatively named H-42b, have not been elucidated. In the present study, we explored MHC control on the anti-H-42a cytotoxic T lymphocyte (CTL) responsiveness in H-42b mice. In vivo immunization (i.v. injection) of H-42b mice with 5 to 30 X 10(6) spleen cells (SC) bearing allogeneic H-42a antigen but carrying H-2 complex (mouse MHC) matched with the H-42b mice failed to prime anti-H-42a CTL but induced stable and specific anti-H-42a CTL unresponsiveness, i.e., tolerance, in the H-42b recipient mice. In contrast, H-2 heterozygous H-42b F1 mice injected with SC bearing H-42a alloantigen on either of the parental H-2 haplotypes were effectively primed to generate anti-H-42a CTL. Exploration of the region or subregion in the H-2 complex of H-42a donor SC that should be compatible with H-42b recipient mice for the induction of their anti-H-42a CTL tolerance demonstrated that the compatibility at I region, most probably I-A subregion, but not at K, S, or D region, determined the induction of the tolerance. MHC class II compatible H-42a skin graft (SG) to H-42b mice, however, consistently primed the anti-H-42a CTL in the H-42b recipients. These results were discussed in several aspects, including uniqueness of MHC class II control on the CTL response to minor H-42a antigen, possibility of inactivation of responding anti-H-42a precursor CTL or helper T cells in H-42b mice by encountering the veto cells present in MHC class II-matched H-42a SC population, and significance of the present observations as a mechanism of CTL tolerance to self-components.

Animals↗
PubMed1997

Susceptibility to anti-glomerular basement membrane disease and Goodpasture syndrome is linked to MHC class II genes and the emergence of T cell-mediated immunity in mice.

We developed a new mouse model of human anti-glomerular basement membrane (GBM) disease to better characterize the genetic determinants of cell-mediated injury. While all major histocompatibility complex (MHC) haplotypes (H-2a, k, s, b, and d) immunized with alpha3 NC1 domains of type IV collagen produce anti-alpha3(IV) NC1 antibodies that cross-react with human Goodpasture [anti-GBM/anti-alpha3(IV) NC1] autoantibodies, only a few strains developed nephritis and lung hemorrhage associated with Goodpasture syndrome. Crescentic glomerulonephritis and lung hemorrhage were MHC-restricted in haplotypes H-2s, b, and d (A beta/A alpha region in H-2s) and associated with the emergence of an IL-12/Th1-like T cell phenotype. Lymphocytes or anti-alpha3(IV) NC1 antibodies from nephritogenic strains transfer disease to syngeneic recipients. However, passive transfer of isogenic alpha3(IV) NC1 antibodies into -/- T cell receptor-deficient mice failed to produce nephritis. Finally, nephritis and its associated IL-12/Th1-like T cell response attenuate in disease-susceptible mice tolerized orally to alpha3(IV) collagen before immunization. Our findings suggest collectively, as a hypothesis, that anti-GBM antibodies in mice only facilitate disease in MHC haplotypes capable of generating nephritogenic lymphocytes with special T cell repertoires.

Adoptive Transfer↗
PubMed1997

Class I mhc genes of cichlid fishes: identification, expression, and polymorphism.

Cichlid fishes of the East African Rift Valley lakes constitute an important model of adaptive radiation. Explosive speciation in the Great Lakes, in some cases as recently as 12 400 years ago, generated large species flocks that have been the focus of evolutionary studies for some time. The studies have, however, been hampered by the paucity of biochemical markers for phylogenetic reconstruction. Here, we describe a set of markers which should help to alleviate this problem. They are the class I genes of the major histocompatibility complex. We provide evidence for the existence of at least 17 class I loci in cichlid fishes, and for extensive polymorphism of three of these loci. Since the polymorphism has a trans-species character, it will be possible to use it in investigating the founding events of the individual species. The sequences of the cichlid class I fishes support the monophyly of actinopterygian fish on the one hand, and of tetrapods on the other.

Animals↗
PubMed1993

Control of MHC class II gene expression in autoimmune, infectious, and neoplastic diseases.

The major histocompatibility complex (MHC) class II genes encode surface molecules that are required for presentation of antigenic peptides to helper T-cells. The concentration of these proteins on the surface of effector cells (antigen-presenting cells such as B-cells and macrophage) is one of the parameters affecting the intensity of the immune response. Many studies have thus focused their attention on the mechanisms that control the expression of class II genes, particularly in B-cells. The anatomy of MHC class II promoters has been dissected in detail, and many trans-acting factors and their cognate DNA regulatory elements have been identified and characterized, thus helping to elucidate the molecular circuitry which determines tissue-specific, coordinate expression of these genes. In most cases, regulation has been investigated at the level of mRNA transcription. MHC class II gene expression has been observed as well, under physiological conditions, in many other tissues and organs such as brain, thyroid, thymus, and intestine, thus implying that class II molecules may be involved, whether directly or indirectly, in the modulation of other important biological responses in addition to the control of the immune reaction against soluble antigens. Spurious MHC class II activity is also detected in tumor cells and in other pathological conditions such as those found in autoimmune, inflammatory, and infectious diseases. In autoimmunity, cells that express class II molecules may present tissue-specific antigens, thus triggering a mechanism of self-destruction. In tumors, instead, unscheduled MHC class II expression may be part of a mechanism that prevents tumor progression. Comprehension of the regulatory functions operating in pathological conditions as compared to those active in B-cells and in macrophages is still rudimentary. Because of the possible pathogenetic importance of aberrant class II expression, knowledge of the cis- and trans-acting elements controlling gene expression at either the transcriptional or posttranscriptional level may allow the development of strategies for immunointervention against these diseases.

Autoimmune Diseases↗
PubMed1998

MHC class II gene silencing in trophoblast cells is caused by inhibition of CIITA expression.

PROBLEM: Major histocompatibility complex (MHC) class II molecule expression is specifically suppressed on fetal trophoblasts, even in response to interferon (IFN)-gamma, a potent inducer of MHC class II genes. The suppression of class II induction has been suggested to play a role in preventing rejection of the fetal allograft. The mechanism of this suppression is unknown. METHOD OF STUDY: Human trophoblast cell lines were examined for expression of MHC class II transcription factors and for activity of the IFN-gamma signaling pathway. Additionally, trophoblast cells were transfected with a vector expressing the class II transactivator, CIITA, and assayed for class II expression. RESULTS: The MHC class II transcription factors RFX and X2BP and the IFN-gamma signaling pathway components are expressed constitutively and are functional in trophoblasts. However, CIITA expression was absent in trophoblasts and could not be induced by IFN-gamma. Transfection of CIITA into trophoblast cells resulted in derepression of class II gene expression. CONCLUSIONS: The lack of induction of MHC class II genes in response to IFN-gamma in trophoblast cells is caused neither by the absence of factors that bind class II promoters, nor by a lesion in the IFN-gamma signaling pathway, but results from a specific inhibition of the CIITA gene.

Cell Line↗
PubMed2002

Ectopic expression of MHC class II genes (RT1.B(I) beta/alpha) in rat hepatocytes in vivo and in culture can be elicited by treatment with the pregnane X receptor agonists pregnenolone 16 alpha-carbonitrile and dexamethasone.

The synthetic steroid, pregnenolone-16-alpha-carbonitrile (PCN), has served for decades as a probe for a postulated series of hepatic defenses activated under situations of environmental "stress". PCN, an antiglucocorticoid, and also such glucocorticoids as dexamethasone (Dex) appear to stimulate hepatic metabolism and elimination of xenobiotics by binding to the nuclear pregnane X receptor (PXR) which then interacts with a distinct DNA response element associated with induction of cytochrome P450 3A genes. To explore the full domain of genes controlled by PCN/PXR, we used differential display to detect rat liver mRNA species selectively induced by PCN or by Dex. Sequence analysis identified one of many PCN induced cDNA fragments as RT1.B(I)beta, a member of the major histocompatability class II (MHC) gene family usually found only in antigen presenting cells. Northern blot analysis of RNA from rat liver or from cultured hepatocytes confirmed that amounts of RT1.B(I)beta mRNA and also of its companion gene, RT1.B(I)alpha mRNA, became readily detectable within 3-6 hours following treatment with PCN or Dex, whereas no induction was observed in spleen RNA. Induction by PCN of RT1.B(I)beta immunoreactive protein was localized to the hepatocytes as judged by immunofluorescence. We conclude that ectopic expression of MHC II genes, an unprecedented effect of steroids or drugs, is rapidly evoked by PCN acting on the liver, directly. The concept of a set of genes coordinately controlled to maintain homeostasis in parenchymal tissues during toxic stress must now be extended to include the immune system.

Animals↗
PubMed1990

Natural anti-self reactivity which maps to MHC class I genes.

Responder spleen cells of [B10.A(5R) x B10.A(2R)]F1 hybrid mice cultured in vitro with irradiated parental spleen cells, generate a cytotoxic T cell response which maps to the H-2Dd and H-2(K-I)b genes of the B10.A(5R) parent. Specific reactivity of (5R x 2R) cells to B10.A(5R) parental (P) stimulators and not to F1 hybrid or B10.A(2R) stimulators was also demonstrated as an F1 anti-P proliferative response. Generation of a (5R x 2R) anti-5R response has also been noted during 2 degrees in vitro anti-viral cytotoxic responses where (5R x 2R) cells from either ectromelia or Sendai virus primed mice have been stimulated in vitro with infected 5R cells, but not when stimulated with infected 2R or (5R x 2R) cells. The generation of these responses is dependent on the use of parental stimulators for F1 hybrid cells during in vitro culture. All data is consistent with the hypothesis that (5R x 2R) F1 cells are not tolerant of 5R cells, and of the 4-fold higher level of Class I H-2Kb/Dd antigens which they express.

Animals↗