A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome).

Steimle, Viktor; Durand, Bénédicte; Barras, Emmanuèle; Zufferey, Madeleine; Hadam, M.; Mach, Bernard; Reith, Walter

doi:10.1101/gad.9.9.1021

Cited by 323 publications

(283 citation statements)

References 56 publications

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“…Certain patients exhibit a normal MHC class II promoter binding pro®le but are de®cient in mRNA expression of transacting factors (CIITA in the group A). Patients of the B and C groups show a defect in MHC class II promoter occupancy Glimcher, 1991, 1993;Steimle et al, 1995). This latter group (C) is also characterised by a defect in RFX5 gene expression (Steimle et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

“…Patients of the B and C groups show a defect in MHC class II promoter occupancy Glimcher, 1991, 1993;Steimle et al, 1995). This latter group (C) is also characterised by a defect in RFX5 gene expression (Steimle et al, 1995). Steimle et al (1993Steimle et al ( , 1994 have described and cloned the transactivator CIITA and thereby established that this molecule is essential for both the constitutive and the IFN-g induced HLA-DR positive transcription.…”

Section: Discussionmentioning

confidence: 99%

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Inhibitor (IK) of IFN-γ induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line

et al. 1997

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The expression of major histocompatibility complex (MHC) class II antigens is constitutive in professional antigen presenting cells (APCs) but can also be induced by interferon-gamma (IFN-g) on the majority of the non professional APCs (e.g. ®broblasts). We have recently characterised a new factor called IK which is an e cient inhibitor of IFN-g induction of MHC class II antigens expression. Here, we demonstrate a novel role for IK in MHC class II expression since over-expression of this protein by stable transfection into human B cells led to a total disappearance of constitutive MHC class II mRNA expression. The class II transactivator (CIITA) is necessary for both constitutive and IFN-g induced MHC class II expressions. Examination of CIITA mRNA in IK stably transfected clones revealed a marked reduction of CIITA mRNA transcription. Taken together these results demonstrate that the IK protein plays a key role in the constitutive expression of MHC class II antigens and that inhibition induced by IK is upstream of CIITA in this regulatory pathway.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibitor (IK) of IFN-γ induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line

et al. 1997

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“…The MHC class II (MHC-II) molecules are cell surface glycoproteins that are pivotal for inducing and regulating immune responses through their ability to present peptides derived from extracellular pathogens to CD4 + promoter, and the downstream X2 box is bound by the cyclic AMP response element-binding protein CREB [6][7][8][9]. The Y box binds the heterotrimeric transcription factor, NF-Y, which consists of A, B and C subunits [10,11].…”

Section: Introductionmentioning

confidence: 99%

Direct role of NF‐κB activation in Toll‐like receptor‐triggered HLA‐DRA expression

Lee

Kim

et al. 2006

Eur J Immunol

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Microbial components, such as DNA containing immunostimulatory CpG motifs (CpG-DNA) and lipopolysaccharides (LPS), elicit the cell surface expression of MHC class II (MHC-II) through Toll-like receptor (TLR)/IL-1R. Here, we show that CpG-DNA and LPS induce expression of the HLA-DRA in the human B cell line, RPMI 8226. Ectopic expression of the dominant negative mutant of CIITA and RNA interference targeting the CIITA gene indicate that CIITA activation is not enough for the maximal MHC-II expression induced by CpG-DNA and LPS. Additionally, nuclear factor (NF)-jB activation is required for the CpG-DNA-activated and LPS-activated HLA-DRA expression, whereas IFN-c-induced MHC-II expression depends on CIITA rather than on NF-jB. Comprehensive mutant analyses, electrophoretic mobility shift assays and chromatin immunoprecipitation assays, reveal that the functional interaction of NF-jB with the promoter element is necessary for the TLR-mediated HLA-DRA induction by CpG-DNA and LPS. This novel mechanism provides the regulation of MHC-II gene expression with complexity and functional diversity.

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“…31,34 BLS is a severe hereditary immunodeficiency disease in which there is defective synthesis of class II molecules. Mutations were found in particular groups of BLS patients involving specific genes encoding the proteins binding the SXY module sequences; these included regulatory factor X (RFX)5, 35 RFX-associated protein 36 and RFX-associated ankyrin-containing protein (also known as RFXB). 37 Most significant, however, was the discovery of the remarkable class II transactivator (CIITA), found to be defective in a specific group of BLS patients and cloned using a cell line showing defective class II expression.…”

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confidence: 99%

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

et al. 2009

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Major histocompatibility complex (MHC) class II molecules are central to adaptive immune responses and maintenance of selftolerance. Since the early 1970s, the MHC class II region at chromosome 6p21 has been shown to be associated with a remarkable number of autoimmune, inflammatory and infectious diseases. Given that a full explanation for most MHC class II disease associations has not been reached through analysis of structural variation alone, in this review we examine the role of genetic variation in modulating gene expression. We describe the intricate architecture of the MHC class II regulatory system, indicating how its unique characteristics may relate to observed associations with disease. There is evidence that haplotypespecific variation involving proximal promoter sequences can alter the level of gene expression, potentially modifying the emergence and expression of key phenotypic traits. Although much emphasis has been placed on cis-regulatory elements, we also examine the role of more distant enhancer elements together with the evidence of dynamic inter-and intra-chromosomal interactions and epigenetic processes. The role of genetic variation in such mechanisms may hold profound implications for susceptibility to common disease.

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A novel DNA-binding regulatory factor is mutated in primary MHC class II deficiency (bare lymphocyte syndrome).

Cited by 323 publications

References 56 publications

Inhibitor (IK) of IFN-γ induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line

Inhibitor (IK) of IFN-γ induced HLA class II antigens expression also inhibits HLA class II constitutive expression in the human Raji B cell line

Direct role of NF‐κB activation in Toll‐like receptor‐triggered HLA‐DRA expression

Regulation of major histocompatibility complex class II gene expression, genetic variation and disease

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