Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Major histocompatibility complex (MHC) class II deficiency is an inherited autosomal recessive combined immunodeficiency, characterized by a lack of constitutive expression of the human leukocyte antigen (HLA) class II genes. The patients investigated in this study are histoidentical twin brothers with a new phenotype in MHC class II deficiency. Examination of HLA-D locus genes in their fractionated peripheral mononuclear cells (MNCs) revealed an unusual and uncoordinated mRNA pattern. Here we analyzed the distribution of pro- and anti-inflammatory cytokines expressed in these patients' adherent and nonadherent MNCs. We show that gene expression of IL-1 alpha, IL-1 beta, IL-6, granulocyte-colony-stimulating factor, and IL-10 was induced in both cell fractions, whereas increased mRNA levels of interferon-gamma and the inducible nitric oxide synthase were exclusively detected in the patients' nonadherent MNCs. As IL-10 is known to be able to downregulate transcription of MHC class II and expression of IL-10 in the patients' MNCs was increased, we investigated the regulatory function of this cytokine. Interestingly, inhibition of IL-10 protein synthesis with IL-10-specific antisense oligonucleotide DNA (IL-10-AS-ODN) induced HLA-D locus genes in these MHC class II-deficient patients. Exposure of the nonadherent cell fraction to IL-10-AS-ODN resulted in a profound induction of a previously absent DR beta 1 and DP alpha gene expression. HLA-DQ beta mRNA levels, however, were increased in both the adherent and the nonadherent MNC population. Albeit expression of HLA-D locus genes was inducible via inhibition of IL-10 translation, surface expression of HLA class II antigens on the patients' MNCs was essentially negative. The data presented support the concept of a coordinated network of pro- and anti-inflammatory cytokine regulation and this network obviously has a significant role in the cell-type-specific regulation of MHC class II expression.
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PMID:Inhibition of IL-10 protein synthesis induces major histocompatibility complex class II gene expression in class II-deficient patients. 934 39

MHC class II deficiency provokes a severe immunodeficiency characterized by a lack of antigen-specific immune response. In the absence of bone marrow transplantation (the only curative treatment), patients affected by this genetic recessive disease die in early childhood. However, others and we have recently described cases of mild or asymptomatic immunodeficiencies with defects in either CIITA (class II transactivator) or RFX5, both proteins required for the transcription of HLA-D genes. We describe in this report the first case of moderate immunodeficiency resulting from a defect in RFXANK, another transcription factor essential for HLA-D expression. The patient did not display any detectable expression of MHC class II molecules on B lymphocytes, monocytes or activated T lymphocytes. Accordingly HLA-D transcription was altered in the corresponding B-lymphoblastoid cell line. The defect in RFXANK was observed both at the transcript and protein level. Indeed a homozygous IVS4+5G>A mutation was evidenced in RFXANK, and shown to hamper the splicing of intron 4. However, we had shown previously that a defect in intron 4 can lead to the skipping of exon 4, and that the resulting truncated protein retains the capacity to activate HLA-DR expression. Therefore, like the two cases of moderate immunodeficiencies described previously, we demonstrate that the RFXANK defect presented here is coherent with a residual activity of the mutant protein. We thus propose that the common feature displayed by mildly immunodeficient patients is the leakiness of the mutations, which might allow a local or temporal expression of MHC class II molecules.
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PMID:Splicing defect in RFXANK results in a moderate combined immunodeficiency and long-duration clinical course. 1457 20


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