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At least 109 records · Page 6Linked to original sources
PubMed1989

Specific inhibition of class II MHC gene expression by anti-sense RNA.

We have established an anti-sense RNA system which is capable of regulating expression of the class II (Ia) molecule coded for by the major histocompatibility complex in cultured mouse cells. Various areas of the I-A beta chain gene were subcloned in an anti-sense orientation to the 3' of the dihydrofolate reductase (DHFR) cDNA under the control of the human metallothionein IIa gene promoter. These anti-sense DNA constructs were transfected into M12.4 cells, a BALB/c B lymphoma cell line which expresses both I-A and I-E molecules on the cell surface. I-A expression of selected clones transfected with anti-sense DNA encompassing the 5' untranslated region (UT) (100 or 310 bp) including the translation start site or the poly(A) addition signalling sequence in the 3' UT (250 bp) of the I-A beta chain gene were specifically reduced to less than 5% of the control M12.4 cell surface I-A expression. These clones had normal levels of I-E expression. However, transfection of the anti-sense DNA to the beta 1 domain (510 bp) including the splicing donor and acceptor sequences did not affect the expression of I-A molecules. The same antisense DNA constructs (100 bp of the 5' UT or 250 bp of the 3' UT) without the DHFR cDNA (710 bp) did not down-regulate the expression of I-A molecules, indicating that either the physical length of the anti-sense RNA or specific DHFR cDNA sequences are also important.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1996

IFN-gamma-induced MHC class II gene expression is suppressed in endothelial cells by dextran sulfate.

IFN-gamma-activated endothelial cells actively participate in initiating immune responses by interacting with immunocompetent cells via class II MHC proteins. In this study, dextran sulfate, a synthetic heparin analogue, was shown to selectively inhibit IFN-gamma-induced surface expression of HLA-DR molecules by human umbilical cord vascular endothelial cells, but not other cytokine-induced molecules such as ELAM-1 or ICAM-1. Inhibition occurred regardless of whether dextran sulfate was added 24 h before, at the same time as, or 24 h after IFN-gamma stimulation of cells. In addition, both high (500 kDa) and low (5 kDa) molecular mass dextran sulfate molecules were able to block class II expression, whereas treating cells with naturally occurring polysulfated glycosaminoglycans such as heparin, heparan, and chondroitin sulfate did not produce any suppressive effects. Radiolabeling of cells with [35S]methionine followed by radioimmunoprecipitation using anti-HLA-DR alpha mAb demonstrated that biosynthesis of class II proteins was specifically blocked. RT-PCR and Southern blotting were utilized to examine transcription of the HLA-DR alpha gene and demonstrated an absence of HLA-DR alpha mRNA from dextran sulfate-treated and IFN-gamma-induced cells. Dextran sulfate also prevented transcription of the gene encoding CIITA, a transactivator protein required for IFN-gamma-inducible expression of class II genes. Thus, dextran sulfate apparently inhibited this step or an earlier one in the intracellular signaling pathway for IFN-gamma in human endothelial cells, subsequent to IFN-gamma binding to its cell surface receptor.

Base Sequence↗
PubMed1989

Protective modulation of class II MHC gene expression in tubular epithelium by target antigen-specific antibodies. Cell-surface directed down-regulation of transcription can influence susceptibility to murine tubulointerstitial nephritis.

We have been studying the factors which permit autoimmune injury to the kidney leading to interstitial nephritis. Nonsusceptible mice develop L3T4+ effector T cells which do not recognize their 3M-1 target Ag, nor produce interstitial lesions in the kidney unless proximal tubular class II MHC Ag expression is increased, for example, by rIFN-gamma. Anti-tubular basement membrane/alpha 3M-1-Ab, normally present in such mice after immunization with 3M-1, produce an opposite result by diminishing class II transcription and expression. This unique antibody-ligand interaction on the surface of proximal tubular epithelium secreting 3M-1 serves as a novel protective regulatory response in interstitial parenchyma. The in vitro studies conveyed in this current report suggest that alpha 3M-1-Ab mediate this protective effect by reducing the transcription of mRNA encoding class II gene products. These findings, within the overall complexity of a nephritogenic immune response, demonstrate the important role certain elements may play in maintaining functional nonsusceptibility to autoimmune injury.

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↗
PubMed1993

Developmental and cytokine-mediated regulation of MHC class II gene promoter occupancy in vivo.

The class II genes of the major histocompatibility complex are a family of genes whose expression is regulated developmentally in cells of the B lineage and by IFN-gamma in many other cell types. Using the approach of in vivo footprinting, which allows for the examination of protein-promoter interactions within intact cells, we demonstrated a transition from unoccupied to occupied to once again unoccupied class II promoters in cell lines representing the developmental pathway of B cells. IFN-gamma treatment of HeLa cells led to increased promoter occupancy of the DR alpha and DR beta promoters at the same sites that are constitutively bound in mature B cells. No IFN-gamma-specific binding site was induced. Additionally, an octamer element in the DR alpha gene displayed preferential binding in B cells. These results demonstrate that changes in the transcription of the class II genes are associated with changes in factor binding at the promoter in vivo. Moreover, given the ubiquity of class II promoter binding proteins, these results suggest that throughout B cell development and upon IFN-gamma stimulation, the accessibility of class II promoter DNA is subject to regulation.

B-Lymphocytes↗
PubMed2001

Can MHC class II genes mediate resistance to type 1 diabetes?

Numerous studies have associated carriage of HLA-DRB1*1501, DQA1*0102 and DQB1*0602 (DR15, DQ6) with dominant resistance to type 1 diabetes and have concluded that one or more of the component HLA class II molecules mediate this effect. Mechanisms for MHC class II-mediated resistance to diabetes have been proposed from studies of transgenic mice, usually using the diabetes-prone non-obese diabetic (NOD) strain. However, these studies have not reached any consensus on a plausible mechanism. In this study we question why the role of central MHC genes in resistance to diabetes has not been addressed, as the central MHC carries markers of susceptibility to diabetes in linkage disequilibrium with several genes with known or putative immunoregulatory functions. To illustrate the type of studies required to address this issue, we selected diabetes patients and control subjects for carriage of HLA-DR15 and the C allele at position +738 in the inhibitor of kappa B-like gene (IKBL). These alleles mark the 7.1 haplotype (HLA-A3, B7, IKBL738*C, DR15, DQ6). HLA-DR15 was the most effective marker of resistance, but an effect may be evident with IKBL738*C in a larger study. Moreover, carriage of the entire haplotype was particularly rare in patients. The best explanation for this is that the critical gene lies between IKBL and HLA-DRB1, and is more closely linked to HLA-DRB1. Candidate genes at the centromeric end of the central MHC are reviewed, highlighting the need for further study.

Adult↗
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↗
PubMed2004

The DY genes of the cattle MHC: expression and comparative analysis of an unusual class II MHC gene pair.

The major histocompatibility complex of cattle (BoLA) contains the class II genes DYA and DIB which are transcribed with a dendritic cell restricted distribution. As part of the process to determine whether these genes have any functional significance, we demonstrate that they form a closely linked pair characteristic of other expressed class II MHC molecules. Accepted nomenclature convention suggests that BoLA-DIB should therefore be renamed BoLA-DYB. Analysis of the first full-length DYA and DYB transcripts revealed open reading frames with potential to translate 253 and 259 amino acid proteins, respectively. Comparative sequence analysis between the DY polypeptides and classical cattle, human and mouse class II MHC alpha and beta polypeptide chains revealed 16 unique amino acid residues at positions predicted to form and line the putative peptide-binding region. Expression of tagged constructs demonstrates for the first time that the DY genes of cattle are capable of translating distinctive class II MHC alpha and beta polypeptide chains.

Amino Acid Sequence↗
PubMed1994

Characterization of astrocyte nuclear proteins involved in IFN-gamma- and TNF-alpha-mediated class II MHC gene expression.

IFN-gamma is a potent inducer of class II MHC Ags on different cell types, including the astrocyte. TNF-alpha alone has no effect on class II MHC expression, but enhances IFN-gamma-induced class II expression. IFN-gamma acts by inducing transcription of the class II gene, and TNF-alpha enhances the rate of IFN-gamma-induced transcription. We have previously described two factors, IFN-gamma-enhanced factor X (IFNEX) and TNF-alpha induced complex X (TIC-X), whose expression is induced by IFN-gamma and IFN-gamma/TNF-alpha, respectively, which interacted with the X box of the DRA promoter. In this study, we show that IFNEX and TIC-X bind to the X2 core, with contacts extending into the 3' end of X1 and into the spacer region of the DRA promoter. We also show a functional correlation between binding activity and transcriptional activity of the DRA promoter. These results strongly suggest that both IFNEX and TIC-X play important roles in the regulation of class II MHC gene expression in the astrocyte.

Animals↗
PubMed2000

The expression of MHC class II genes in macrophages is cell cycle dependent.

Using different drugs, we stopped the cell cycle of bone marrow-derived macrophages at different points. After IFN-gamma stimulation, macrophages arrested at the G(1) phase of the cell cycle did not increase cell surface expression of the MHC class II IA. This inhibition is specific, because, under the same conditions, IFN-gamma induces the expression of Fcgamma receptors and the inducible NO synthase mRNA. Treatments that inhibit macrophage proliferation by blocking the cell cycle at the G(1) phase, such as adenosine, forskolin, or LPS, blocked the IFN-gamma induction of IA. Under IFN-gamma treatment, the steady-state levels of IAalpha and IAss mRNA did not increase in cells arrested at the G(1) phase and the half-life of the MHC mRNA was not modified. These data suggest that the cell cycle modulation of IFN-gamma-induced MHC II gene expression occurs at the transcriptional level. The expression of the class II transactivator mRNA induced by IFN-gamma was also blocked when macrophages were arrested at the G(1) phase of the cell cycle, suggesting that the lack of IFN-gamma response occurs at the early steps of MHC class II expression. Finally, macrophages arrested at the G(1) phase showed increased basal levels of cell surface IA due to an increase of the translational efficiency. These data show that the expression of MHC class II genes is regulated by the cell cycle.

Animals↗