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)

The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.
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PMID:Mutation in the class II trans-activator leading to a mild immunodeficiency. 1146 4

Four transacting genes, CIITA, RFXANK, RFX5, and RFXAP, control coordinate MHC II expression. In humans, defects in these genes result in the absence of MHC II expression and thus a combined immunodeficiency. CIITA is considered to be a master MHC II regulator and is responsible for the defect in complementation group A. Eight such affected families have been reported. We investigated the molecular basis of the defect in three patients in these families, all presenting a severe immunodeficiency. CIITA transcripts were detected in all three patients but in one at an abnormally low level. Three novel heterozygous mutations of CIITA were found in patients SP and RC. One SP CIITA allele contained a nonsense mutation, G2178A, leading to a premature stop codon and the other allele in SP was found not to be expressed. In patient RC, two in-frame deletions were detected: one of the nucleotides 3003-3084 corresponding to the exon coding from Leu(964)to Asp(991), in the paternal allele, and a CATdel3193-5 of the isoleucine codon at position 1027, in the maternal allele. Transfection of a CIITA-deficient cell line with the recombinant CATdel3193-5-CIITA cDNA revealed a loss of function for this mutant and retention of the protein in the cytoplasm. No mutations were detected in the 4.5-kb cDNA from patient OK but the level of CIITA transcript was found to be profoundly decreased. However, promoters III and IV were not affected. This last case represents the first described CIITA dysfunction due to putative mutation(s) in cis regulatory sequences of CIITA.
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PMID:Three novel mutations of the CIITA gene in MHC class II-deficient patients with a severe immunodeficiency. 1186 82

Major histocompatibility complex class II (MHCII) deficiency is a primary immunodeficiency resulting from defects in one of four different MHCII-specific transcription factors-CIITA, RFX5, RFXAP, and RFXANK. Despite this genetic heterogeneity, the phenotypical manifestations are homogeneous. It is frequently difficult to establish a definitive diagnosis of the disease on the basis of clinical and immunological criteria. Moreover, the phenotypical homogeneity precludes unambiguous identification of the regulatory gene that is affected. Identification of the four genes mutated in the disease has now allowed us to develop a rapid and straightforward diagnostic test for new MHCII-deficiency patients. This test is based on direct correction of the genetic defect by transduction of cells from patients with lentiviral vectors encoding CIITA, RFXANK, RFX5, or RFXAP. We have validated this approach by defining the molecular defects in two new patients. The RFXANK vector restored MHCII expression in a T cell line from one patient. The RFXAP vector corrected primary cells (PBL) from a second patient. Molecular analysis confirmed the presence of homozygous mutations in the RFXANK and RFXAP genes, respectively. Direct genetic correction represents a valuable tool for the diagnosis and classification of new MHCII-deficiency patients.
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PMID:Direct genetic correction as a new method for diagnosis and molecular characterization of MHC class II deficiency. 1249 78

MHC class II deficiency is a combined immunodeficiency caused by defects in the four regulatory factors, CIITA, RFXANK, RFX5 and RFXAP, that control MHC II expression at the transcriptional level. The RFXANK gene encodes one subunit of the heterotrimeric RFX complex that is involved in the assembly of several transcription factors on MHC II promoters. Seven different RFXANK mutations have previously been reported in 26 unrelated patients. The most frequent mutation, a 26-bp deletion (752delG-25), has been identified in 21 patients. The other mutations are all nonsense or splice-site mutations, leading to proteins lacking all or part of the RFXANK ankyrin repeat region. We report two novel missense mutations, D121V and R212X, resulting in loss of function of the gene. We investigated the in vivo effects of these mutations and of three other point mutations on the expression of the RFXANK RNA and protein. The number of RFXANK transcripts was severely reduced in all patients except one. The RFXANK protein was barely detected in two cases. In addition, guided by a structural model of RFXANK, we investigated experimental mutants of the C-terminal tyrosine 224. Substitution Y224A, but not Y224F, led to the loss of function of RFXANK. Two null mutants, D121V and Y224A, were tested in protein interaction and DNA binding assays. The D121V mutant was unable to form the RFX complex, indicating that D121 is required for RFXAP binding. The Y224A mutant formed an RFX complex that bound normally to the MHC II promoter, but did not lead to MHC class II expression, whereas Y224F RFXANK retained the wild-type function. This indicates that an aromatic ring, but not the phenyl chain of tyrosine, is necessary at position 224 for normal RFXANK function. Studies on the Y224A mutant suggest that, in addition to the RFX subunits and CIITA, another protein is essential for MHC class II expression. This protein appears to interact with the fourth ankyrin repeat of RFXANK.
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PMID:Novel mutations in the RFXANK gene: RFX complex containing in-vitro-generated RFXANK mutant binds the promoter without transactivating MHC II. 1261 6

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

Class II MHC antigens play a critical role in the induction of immune responses through presentation of processed antigen to CD4+ T lymphocytes. The absence of MHC II normal expression results in severe primary immunodeficiency diseases, such as the bare lymphocyte syndrome (BLS). Four different MHC II regulatory genes have been identified. These genes encode RFXANK, RFX5, RFXAP and CIITA. The first three are subunits of RFX, a ubiquitously expressed factor that binds to the promoters of all MHC II genes. CIITA is the master control factor for MHC II expression. The highly regulated expression pattern of CIITA ultimately dictates the cell type specificity, induction and level of MHC II expression. This review focuses on research progress on regulation of class II MHC expression in recent years.
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PMID:[Research progress on regulation of class II MHC expression]. 1512 93

The extraordinary homology between major histocompatibility complex class II (MHC II) proteins across species from human to bony fish suggests that transcription factors that regulate these proteins might be conserved as well. Deficiencies in four proteins that regulate MHC II genes in humans (RFX-B, RFX5, RFXAP, and CIITA) cause an inherited immunodeficiency disorder known as the bare lymphocyte syndrome (BLS). To understand the structure and mechanism of function of the BLS transcription factors, we analyzed the evolutionary history of RFX-B, the factor deficient in the majority of patients with BLS. Sequence comparison and analysis of the RFX-B proteins showed that RFX-B and a closely related protein, ANKRA2, are present in humans to bony fish and that specific domains are highly conserved. In addition to sequence conservation, functional conservation exists, as mouse and Xenopus RFX-B orthologues, but not the paralogous protein ANKRA2, were able to complement the MHC II deficiency in a BLS-patient-derived cell line deficient in RFX-B. The remarkable conservation of the RFX-B lineage attests to the conservation of the regulation mechanism for this gene system and its importance to precisely regulate MHC class II molecules in both the developing and active immune response.
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PMID:Evolutionary conservation and characterization of the bare lymphocyte syndrome transcription factor RFX-B and its paralogue ANKRA2. 1565 68

MHC class II (MHCII) deficiency or bare lymphocyte syndrome (BLS) is a severe immunodeficiency characterized by deficient T helper (Th)-cell-dependent immunity. The disease is caused by defects of the MHCII promoter complex resulting in low or absent MHCII expression. We demonstrate in a murine model of MHCII deficiency (RFX5- or CIITA-deficient mice) that residual MHCII expression by professional antigen-presenting cells (APCs) is sufficient to support activation of adoptively transferred Th cells. Furthermore, upon transplantation of WT thymic epithelium, we observed development of endogenous Th cells with restoration of Th-cell-dependent antibody responses and immunity to cytomegalovirus infection, thus opening the possibility of an alternative treatment regimen for BLS. Residual MHCII expression was further induced by the presence of Th cells and also other stimuli. Analysis of CIITA/RFX5 double-deficient animals revealed that this inducible MHCII expression is genetically independent of the known promoter complex and thus constitutes an alternative MHCII expression pathway. In these experiments, we also detected a novel repressive function of the RFX complex in the absence of CIITA.
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PMID:MHC class II expression through a hitherto unknown pathway supports T helper cell-dependent immune responses: implications for MHC class II deficiency. 1625 46

Major histocompatibility complex class II deficiency, a rare autosomal recessive primary immunodeficiency, is caused by the defective expression of human leucocyte antigen (HLA) class II molecules due to mutated trans-acting elements of any one of four regulatory genes (CIITA, RFXANK, RFX5, RFXAP). The impaired CD4 T-cell differentiation and antigen presentation in the periphery results in a severe defect of cellular and humoral response consistent with severe recurrent infections, leading to a poor prognosis. Currently, allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative approach, but the overall cure rate is lower than in other immunodeficiencies. We report a single centre experience of 17 HSCTs with 15 HLA-identical donors between 1981 and 2004. Eight patients survived, while the occurrence of acute graft-versus-host disease (GVHD) was 50%. This study aimed to identify potential risk factors for GVHD and outcome within pre-HSCT complications related to the immunodeficiency. Five of seven patients with pre-existing viral infections developed acute GVHD > or = grade II, of whom four died. Two of seven patients without detectable pre-existing viral infection developed GVHD > or = grade II, and one died. The difference was significant (P < 0.05). A plausible link with other factors potentially associated with the development of GVHD could not be found. We suggest that the reduced survival after HLA-identical HSCT may be caused by the high incidence of pre-existing viral infections and associated with the onset of severe acute GVHD.
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PMID:Human leucocyte antigen-identical haematopoietic stem cell transplantation in major histocompatiblity complex class II immunodeficiency: reduced survival correlates with an increased incidence of acute graft-versus-host disease and pre-existing viral infections. 1684 95

Major histocompatibility complex class II plays a key role in the immune response, by presenting processed antigens to CD4+ lymphocytes. Major histocompatibility complex class II expression is controlled at the transcriptional level by at least four trans-acting genes: CIITA, RFXANK, RFX5 and RFXAP. Defects in these regulatory genes cause MHC class II immunodeficiency, which is frequent in North Africa. The aim of this study was to describe the immunological and molecular characteristics of ten unrelated Moroccan patients with MHC class II deficiency. Immunological examinations revealed a lack of expression of MHC class II molecules at the surface of peripheral blood mononuclear cells, low CD4+ T lymphocyte counts and variable serum immunoglobulin (IgG, IgM and IgA) levels. In addition, no MHC class II (HLA DR) expression was observed on lymphoblasts. The molecular analysis identified the same homozygous 752delG26 mutation in the RFXANK genes of all patients. This finding confirms the association between the high frequency of the combined immunodeficiency and the defect in MHC class II expression and provides strong evidence for a founder effect of the 752delG26 mutation in the North African population. These findings should facilitate the establishment of molecular diagnosis and improve genetic counselling for affected Moroccan families.
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PMID:The 752delG26 mutation in the RFXANK gene associated with major histocompatibility complex class II deficiency: evidence for a founder effect in the Moroccan population. 2041 76


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