Mutation of RFXAP, a Regulator of MHC Class II Genes, in Primary MHC Class II Deficiency

Villard, Jean; Lisowska-Grospierre, B; Elsen, Peter van den; Fischer, Alain; Reith, Walter; Mach, Bernard

doi:10.1056/nejm199709113371104

Cited by 65 publications

(33 citation statements)

References 29 publications

(54 reference statements)

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“…Patients with this syndrome carry a defect in the genes encoding the components of the RFX complex and CIITA (Steimle et al, 1993;Villard et al, 1997;Masternak et al, 1998;Nagarajan et al, 1999). To determine the role of RFX and CIITA genes in the suppression of HLA-DR expression, we carried out RT -PCR with a group of haematopoietic tumour cell lines that either did or did not express HLA-DR ( Figure 3A and B).…”

Section: Expression Of the Transactivator Of Mhc Class II In Haematopmentioning

confidence: 99%

Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells

et al. 2004

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By presenting immunogenic peptides at the cell surface, major histocompatibility complex (MHC) class II molecules play a key role in the control of adaptive immune responses. Whether expressed constitutively or induced by interferon-g, expression of MHC class II molecules is regulated via coactivator class II transactivator (CIITA); moreover, suppression of their expression is one mechanism by which cancer cells escape host immunity. In this study, we surveyed the relationship between the expression of one MHC class II antigen, HLA -DR, and its coactivators in a group of haematopoietic cell lines, and explored the role of the aberrant DNA methylation in silencing HLA-DR expression. Among 26 cell lines studied, HLA-DR expression was lost from eight T-cell and two myeloid leukaemia cell lines, and this loss was closely associated with suppression of CIITA-PIV expression. Notably, nine of the 10 cell lines that lost CIITA-PIV expression showed methylation of the gene's 5 0 CpG island. Thus, DNA methylation is believed to inhibit the expression of MHC class II molecules in haematopoietic tumour cells by silencing its coactivator, CIITA-PIV. Furthermore, methylation of CIITA-PIV was detected in seven of 32 primary acute myeloid leukaemia specimens, indicating that epigenetic alteration is not a cell line-specific phenomenon. Collectively, these data suggest that, by suppressing expression of MHC class II molecules, epigenetic inactivation of CIITA provides a survival advantage to a subset of haematopoietic tumours.

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Section: Expression Of the Transactivator Of Mhc Class II In Haematopmentioning

confidence: 99%

Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells

et al. 2004

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“…The genes affected in groups B, C, and D all encode subunits of the heterotrimeric phosphoprotein RFX (35). BLS groups B, C, and D are defective in RFX-B (also referred to as RFXANK) (36,37), RFX5 (38,39), and RFXAP (40,41), respectively. RFX-B is the smallest (33 kDa) of the three subunits that constitute the RFX complex (36,37).…”

Section: Novel Mutations Within the Rfx-b Gene And Partial Rescue Of mentioning

confidence: 99%

Novel Mutations Within the RFX-B Gene and Partial Rescue of MHC and Related Genes Through Exogenous Class II Transactivator in RFX-B-Deficient Cells

Nagarajan

Peijnenburg

Gobin

et al. 2000

The Journal of Immunology

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MHC class II deficiency or bare lymphocyte syndrome is a severe combined immunodeficiency caused by defects in MHC-specific regulatory factors. Fibroblasts derived from two recently identified bare lymphocyte syndrome patients, EBA and FZA, were found to contain novel mutations in the RFX-B gene. RFX-B encodes a component of the RFX transcription factor that functions in the assembly of multiple transcription factors on MHC class II promoters. Unlike RFX5- and RFXAP-deficient cells, transfection of exogenous class II transactivator (CIITA) into these RFX-B-deficient fibroblasts resulted in the induction of HLA-DR and HLA-DP and, to a lesser extent, HLA-DQ. Similarly, CIITA-mediated induction of MHC class I, β2-microglobulin, and invariant chain genes was also found in these RFX-B-deficient fibroblasts. Expression of wild-type RFX-B completely reverted the noted deficiencies in these cells. Transfection of CIITA into Ramia cells, a B cell line that does not produce a stable RFX-B mRNA, resulted in induction of an MHC class II reporter, suggesting that CIITA overexpression may partially override the RFX-B defect.

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“…In the case of the analogous process, peptide Ag presentation by MHC, it was shown that both Ag processing and MHC expression are under a tight transcriptional regulation (41)(42)(43)(44). Therefore, it is reasonable to assume that multiple aspects of the lipid Ag processing and presentation pathway are also transcriptionally regulated.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor γ-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells

Nakken

Varga

Szatmári

et al. 2011

The Journal of Immunology

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It is well established that dendritic cells (DCs) take up, process, and present lipid Ags in complex with CD1d molecules to invariant NKT cells. The lipid-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), has previously been shown to regulate CD1d expression in human monocyte-derived DCs, providing a link between lipid metabolism and lipid Ag presentation. We report that PPARγ regulates the expression of a lysosomal protease, cathepsin D (CatD), in human monocyte-derived DCs. Inhibition of CatD specifically reduced the expansion of invariant NKT cells and furthermore resulted in decreased maturation of saposins, a group of lipid transfer proteins required for lysosomal lipid Ag processing and loading. These results reveal a novel mechanism of lipid Ag presentation and identify CatD as a key component of this machinery and firmly place PPARγ as the transcriptional regulator linking lipid metabolism and lipid Ag processing.

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Mutation of RFXAP, a Regulator of MHC Class II Genes, in Primary MHC Class II Deficiency

Cited by 65 publications

References 29 publications

Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells

Inactivation of class II transactivator by DNA methylation and histone deacetylation associated with absence of HLA-DR induction by interferon-γ in haematopoietic tumour cells

Novel Mutations Within the RFX-B Gene and Partial Rescue of MHC and Related Genes Through Exogenous Class II Transactivator in RFX-B-Deficient Cells

Peroxisome Proliferator-Activated Receptor γ-Regulated Cathepsin D Is Required for Lipid Antigen Presentation by Dendritic Cells

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