The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Peter J Van Den Elsen - One of the best experts on this subject based on the ideXlab platform.
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type iii Bare Lymphocyte Syndrome associated with a novel rfxap mutation a case report
International Journal of Immunogenetics, 2012Co-Authors: Bahar Gokturk, Marja C J A Van Eggermond, Peter J Van Den Elsen, Hasibe Artac, Ismail ReisliAbstract:Type III Bare Lymphocyte Syndrome (BLS) is a severe combined immunodeficiency disease caused by the absence of MHC Class II expression associated with low expression of class I molecules. Here, we report a case with type III BLS who lacked RFXAP (Regulatory factor X-associated protein) expression as a result from a novel mutation introducing a premature stopcodon in DE-region at amino acid 73.
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t cell immune reconstitution after allogeneic bone marrow transplantation in Bare Lymphocyte Syndrome
Human Immunology, 2000Co-Authors: Barbara C Godthelp, Marja C J A Van Eggermond, Maarten J D Van Tol, Jaak M Vossen, Peter J Van Den ElsenAbstract:Abstract To study the impact of an MHC class II-negative environment on T cell immune reconstitution, we have analyzed the phenotypical and functional characteristics of FACS-sorted cultured CD4 + and CD8 + T cells in two Bare Lymphocyte Syndrome (BLS) patients before and after allo-BMT. A similar analysis was performed in two MHC class II expressing pediatric leukemia patients after treatment with an allo-BMT who were included in our study as control. It was observed that CD4 + T cells displayed cytolytic alloreactivity in both BLS patients prior to and within the first year after allo-BMT, whereas such cells were absent at a later time-point, in the donors and pediatric leukemia controls. In addition, reduced MHC class II expression was observed in CD8 + T cells of both recipients early after allo-BMT, irrespective of the T cell chimerism pattern. Lack of endogenous MHC class II expression in BLS patients, therefore, results in aberrant T cell selection within the first year after allo-BMT, analogous to T cell selection before transplantation. These T cell selection processes seem to be normalized at a later time point after allo-BMT probably due to migration and integration of graft-derived MHC class II-positive antigen presenting cells to sites of T cell selection.
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incomplete t cell immune reconstitution in two major histocompatibility complex class ii deficiency Bare Lymphocyte Syndrome patients after hla identical sibling bone marrow transplantation
Blood, 1999Co-Authors: Barbara C Godthelp, Ad Peijnenburg, Marja C J A Van Eggermond, Ilhan Tezcan, Maarten J D Van Tol, Jaak M Vossen, Stefaan Van Lierde, Peter J Van Den ElsenAbstract:To study the effects of major histocompatibility complex (MHC) class II expression on T-cell development, we have investigated T-cell immune reconstitution in two MHC class II–deficiency patients after allogeneic bone marrow transplantation (allo-BMT). Our study showed that the induction of MHC class II antigen expression on BM graft-derived T cells in these allo-BMT recipients was hampered upon T-cell activation. This reduction was most striking in the CD8+ T-cell subset. Furthermore, the peripheral T-cell receptor (TCR) repertoire in these graft-derived MHC class II–expressing CD4+ and in the CD8+ T-cell fractions was found to be restricted on the basis of TCR complementarity determining region 3 (CDR3) size profiles. Interestingly, the T-cell immune response to tetanus toxoid (TT) was found to be comparable to that of the donor. However, when comparing recipient-derived TT-specific T cells with donor-derived T cells, differences were observed in TCR gene segment usage and in the hydropathicity index of the CDR3 regions. Together, these results reveal the impact of an environment lacking endogenous MHC class II on the development of the T-cell immune repertoire after allo-BMT.
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the rfx complex is crucial for the constitutive and ciita mediated transactivation of mhc class i and β2 microglobulin genes
Immunity, 1998Co-Authors: Sam J. P. Gobin, Ad Peijnenburg, Marja C J A Van Eggermond, Marlijn Van Zutphen, Rian Van Den Berg, Peter J Van Den ElsenAbstract:In type III Bare Lymphocyte Syndrome (BLS) patients, defects in the RFX protein complex result in a lack of MHC class II and reduced MHC class I cell surface expression. Using type III BLS cell lines, we demonstrate that the RFX subunits RFX5 and RFXAP are crucial for constitutive and CIITA-induced MHC class I and beta2m transactivation. Similar to MHC class II, the promoters of MHC class I and beta2m contain an S-X-Y region of which the X1 box is crucial for constitutive and CIITA-induced MHC class I and beta2m transactivation. Thus, the RFX complex is part of a regulatory pathway linking the transactivation of MHC class I and II and their accessory genes.
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lymphokine gene transcription in cd4 cd8 t cells of a type iii Bare Lymphocyte Syndrome patient
Human Immunology, 1993Co-Authors: M Lambert, Marja C J A Van Eggermond, Peter J Van Den ElsenAbstract:In this study we analyzed the impact of a MHC class-II-deficient environment on the differentiation of CD4+CD8- T Lymphocytes into functional defined subsets of lymphokine-producing T-helper cells. To this end a CD4+CD8- T-cell line and CD4+CD8- T-cell clones, isolated from PBMCs of a type III BLS patient, were stimulated in vitro with anti-CD3 and PMA and assessed for lymphokine transcription patterns. The results of these analyses show that CD4+CD8- T cells that have matured in a MHC class-II-deficient environment display lymphokine transcription patterns that resemble those of MHC class-II-expressing family control-derived CD4+CD8- T cells.
Jeremy M. Boss - One of the best experts on this subject based on the ideXlab platform.
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conserved residues of the Bare Lymphocyte Syndrome transcription factor rfxap determine coordinate mhc class ii expression
Molecular Immunology, 2006Co-Authors: Alyssa B Long, Uma M Nagarajan, Angela M Ferguson, Parimal Majumder, Jeremy M. BossAbstract:RFXAP is required for the transcriptional regulation of MHC-II genes. Mutations in RFXAP are the genetic basis for complementation group D cases of the Bare Lymphocyte Syndrome (BLS) immunodeficiency. Comparative genomic sequence analysis was conducted and found that only the C-terminal half of the protein is conserved among vertebrates. The C-terminal third of RFXAP, which contained an extensive glutamine-rich tract, could rescue HLA-DR, but not HLA-DQ or HLA-DP expression in a BLS cell line. To understand this phenomenon, a detailed analysis of the role of specific sequences in the C-terminal third of RFXAP with respect to MHC-II regulation was undertaken. Surprisingly, mutation of the conserved glutamine residues had no effect on activity, whereas mutation of hydrophobic and other conserved residues resulted in discoordinate MHC-II isotype expression. Moreover, mutation of potential phosphorylation sites abolished RFXAP activity. The ability of RFXAP mutants to rescue one isotype, but not another was investigated by their ability to form RFX complexes, bind DNA in vivo, recruit CIITA to promoters and to activate a series of chimeric reporter genes. The results suggest that certain RFXAP mutants exaggerate isotype promoter-specific differences and form transcriptionally inefficient activation complexes with factors at the neighboring cis-acting elements. These results show a distinction in factor recognition that is associated with specific MHC-II isotypes and may explain the basis of allele-specific expression differences.
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Evolutionary conservation and characterization of the Bare Lymphocyte Syndrome transcription factor RFX-B and its paralogue ANKRA2
Immunogenetics, 2005Co-Authors: Alyssa Bushey Long, Jeremy M. BossAbstract: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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Associations and Interactions between Bare Lymphocyte Syndrome Factors
Molecular and cellular biology, 2000Co-Authors: Angela Desandro, Uma M Nagarajan, Jeremy M. BossAbstract:The Bare Lymphocyte Syndrome, a severe combined immunodeficiency due to loss of major histocompatibility complex (MHC) class II gene expression, is caused by inherited mutations in the genes encoding the heterotrimeric transcription factor RFX (RFX-B, RFX5, and RFXAP) and the class II transactivator CIITA. Mutagenesis of the RFX genes was performed, and the properties of the proteins were analyzed with regard to transactivation, DNA binding, and protein-protein interactions. The results identified specific domains within each of the three RFX subunits that were necessary for RFX complex formation, including the ankyrin repeats of RFX-B. DNA binding was dependent on RFX complex formation, and transactivation was dependent on a region of RFX5. RFX5 was found to interact with CIITA, and this interaction was dependent on a proline-rich domain within RFX5. Thus, these studies have defined the protein domains required for the functional regulation of MHC class II genes. Type II Bare Lymphocyte Syndrome (BLS), an inherited severe combined immunodeficiency in humans, is caused by the inability to transcribe major histocompatibility complex (MHC) class II genes (9, 15, 32). MHC class II genes encode heterodimeric glycoproteins that present antigens to CD4 1 T cells to initiate the acquired arm of the immune response. They are also crucial for determining the repertoire of CD4 1 T cells during positive and negative selection in the thymus. Patients with BLS typically present in the first year of life with recurrent infections and have reduced levels of CD4 1 T cells (9, 11). Their humoral immune response is severely impaired as well, and most patients die before reaching puberty. Patient and experimentally derived cell lines were used to separate the BLS phenotype into four complementation groups: BLS groups A, B, C, and D (3, 46, 54). The genes responsible for each of these groups have been identified and found to encode proteins required for MHC class II gene transcription. MHC class II genes are expressed on the surface of B cells, dendritic cells, macrophages, thymic epithelia, and activated T cells. Additionally, non-antigen-presenting cells can be induced to express MHC class II by exposure to the cytokine gamma interferon (IFN-g) (8). Aberrant expression of MHC class II genes is associated with autoimmunity, tumor growth, and failure to mount an immune response. The three MHC class II isotypes, HLA-DR, HLA-DP, and HLA-DQ, contain conserved cis-acting elements in their promoters (the W, X1, X2, and Y boxes) that allow their coordinate regulation (reviewed in references 4 and 31). Homologous sequence elements are also found in the HLA-DM, invariant chain, and MHC class I genes. These elements allow the coordinate expression of the different isotypes in antigen-presenting cells and the induction of these genes by IFN-g. Regulatory factor X (RFX) and the X2 box-binding protein (X2BP), which was identified as the cyclic AMP response element-binding protein (CREB) (34), bind to the X1 and X2 boxes, respectively. The Y box, an inverted CAAT box, is bound by the heterotrimeric nuclear factor Y (NF-Y) (4). The W box has not been extensively studied, but it was suggested to bind the X1 box factor, RFX (22). While all of these promoter-bound factors are required for MHC class II expression, they are not sufficient. The class II transactivator, CIITA, is also required. CIITA does not bind DNA and is believed to interact with factors on the MHC class II promoter, as well as the general transcriptional machinery, to activate transcription through its acidic activation domain (44, 49, 55). CIITA expression correlates directly with MHC class II expression and is regulated by IFN-g (6, 7, 50). Thus, the presence of CIITA functions as a molecular switch for MHC class II gene regulation.
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the Bare Lymphocyte Syndrome molecular clues to the transcriptional regulation of major histocompatibility complex class ii genes
American Journal of Human Genetics, 1999Co-Authors: Angela Desandro, Uma M Nagarajan, Jeremy M. BossAbstract:We thank the members of the laboratory for their comments on the manuscript. This work was supported by National Institutes of Health grants AI34000, GM47310, and HD34440.
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rfx b is the gene responsible for the most common cause of the Bare Lymphocyte Syndrome an mhc class ii immunodeficiency
Immunity, 1999Co-Authors: Uma M Nagarajan, Angela Desandro, Pascale Louisplence, Roger Nilsen, Alyssa Bushey, Jeremy M. BossAbstract:The Bare Lymphocyte Syndrome (BLS) is characterized by the absence of MHC class II transcription and humoral- and cellular-mediated immune responses to foreign antigens. Three of the four BLS genetic complementation groups have defects in the activity of the MHC class II transcription factor RFX. We have purified the RFX complex and sequenced its three subunits. The sequence of the smallest subunit describes a novel gene, termed RFX-B. RFX-B complements the predominant BLS complementation group (group B) and was found to be mutant in cell lines from this BLS group. The protein has no known DNA-binding domain but does contain three ankyrin repeats that are likely to be important in protein-protein interactions.
Walter Reith - One of the best experts on this subject based on the ideXlab platform.
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major histocompatibility complex class ii deficiency
Reference Module in Biomedical Sciences#R##N#Encyclopedia of Immunobiology, 2016Co-Authors: Walter Reith, Capucine PicardAbstract:Major histocompatibility complex (MHC) class II deficiency, also called the Bare Lymphocyte Syndrome, is a rare primary immunodeficiency disease characterized by a virtual absence of MHC class II expression associated with a variable reduction in MHC class I expression. The disease is genetically heterogeneous. It can result from loss-of-function mutations in any one of four genes – CIITA , RFX5 , RFXAP , and RFXANK – encoding regulatory factors required for transcription of class I and/or class II MHC genes. RFX5 , RFXAP , and RFXANK encode subunits of regulatory factor X, a DNA-binding transcription factor required for transcription of both class I and class II MHC genes. Class II transactivator (CIITA) encodes a transcriptional coactivator showing high specificity for MHC class II genes. CIITA is referred to as the ‘master regulator’ of MHC class II genes because its highly regulated pattern of expression dictates most qualitative and quantitative aspects of MHC class II expression. At MHC class I promoters, CIITA is replaced by a related coactivator, NLRC5. Deficient MHC expression leads to the inability to mount antigen-specific adaptive immune responses against infectious agents. Patients consequently suffer from a broad range of severe and recurrent infections, generally resulting in death at a young age, unless they are treated by hematopoietic stem cell transplantation.
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In vivo, RFX5 binds differently to the human leucocyte antigen-E, -F, and -G gene promoters and participates in HLA class I protein expression in a cell type-dependent manner.
Immunology, 2004Co-Authors: Philippe Rousseau, Walter Reith, Michal Krawczyk, Jean Dausset, Edgardo D. Carosella, Philippe MoreauAbstract:We analysed the regulation of human leucocyte antigen (HLA)-E, -F and -G genes, focusing on the SXY module, a promoter region that controls major histocompatibility complex (MHC) class II expression and participates in the expression of classical HLA class I molecules. It comprises the X1, X2 and Y boxes, bound by RFX, X2-BP/ATF/CREB and NFY factors, respectively. The complex recruits the master control factor CIITA. The SXY module is conserved in HLA-E and HLA-F gene promoters, whereas in the HLA-G promoter, the only conserved boxes are S and X1. Chromatin immunoprecipitation assays, performed on HLA-G positive and negative cell lines, demonstrated the in situ binding of RFX5 and CIITA to HLA-E and HLA-F, but not to HLA-G, promoters. In B cells from Bare Lymphocyte Syndrome patients lacking RFX5 or CIITA, we observed lower steady-state levels of HLA-E and HLA-F transcripts but did not find any significant decrease in the cell-surface expression of HLA-E/classical HLA class I. In RFX5-deficient fibroblasts, the cell-surface expression of HLA molecules was decreased. RFX5 and CIITA are thus not involved in HLA-G expression and their importance for the surface expression of HLA-E/classical HLA class I molecules may vary depending on the cell type.
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The Bare Lymphocyte Syndrome and the regulation of MHC expression.
Annual review of immunology, 2001Co-Authors: Walter ReithAbstract:The Bare Lymphocyte Syndrome (BLS) is a hereditary immunodeficiency resulting from the absence of major histocompatibility complex class II (MHCII) expression. Considering the central role of MHCII molecules in the development and activation of CD4(+) T cells, it is not surprising that the immune system of the patients is severely impaired. BLS is the prototype of a "disease of gene regulation." The affected genes encode RFXANK, RFX5, RFXAP, and CIITA, four regulatory factors that are highly specific and essential for MHCII genes. The first three are subunits of RFX, a trimeric complex that binds to all MHCII promoters. CIITA is a non-DNA-binding coactivator that functions as the master control factor for MHCII expression. The study of RFX and CIITA has made major contributions to our comprehension of the molecular mechanisms controlling MHCII genes and has made this system into a textbook model for the regulation of gene expression.
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Maturation of Dendritic Cells Is Accompanied by Rapid Transcriptional Silencing of Class II Transactivator (CIITA) Expression
2001Co-Authors: Salomé L, Jean-marc Waldburger, Annick Mühlethaler-mottet, Luca Bernasconi, Tobias Suter, Krzysztof Masternak, Jean-françois Arrighi, Conrad Hauser, Adriano Fontana, Walter ReithAbstract:Cell surface expression of major histocompatibility complex class II (MHCII) molecules is increased during the maturation of dendritic cells (DCs). This enhances their ability to present antigen and activate naive CD4 � T cells. In contrast to increased cell surface MHCII expression, de novo biosynthesis of MHCII mRNA is turned off during DC maturation. We show here that this is due to a remarkably rapid reduction in the synthesis of class II transactivator (CIITA) mRNA and protein. This reduction in CIITA expression occurs in human monocyte-derived DCs and mouse bone marrow–derived DCs, and is triggered by a variety of different maturation stimuli, including lipopolysaccharide, tumor necrosis factor �, CD40 ligand, interferon �, and infection with Salmonella typhimurium or Sendai virus. It is also observed in vivo in splenic DCs in acute myelin oligodendrocyte glycoprotein induced experimental autoimmune encephalitis. The arrest in CIITA expression is the result of a transcriptional inactivation of the MHC2TA gene. This is mediated by a global repression mechanism implicating histone deacetylation over a large domain spanning the entire MHC2TA regulatory region. Key words: MHC class II • class II transactivator • experimental autoimmune encephalitis • Bare Lymphocyte Syndrome • histone deacetylatio
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structure of the winged helix protein hrfx1 reveals a new mode of dna binding
Nature, 2000Co-Authors: Ketan Gajiwala, Walter Reith, H Chen, Fabrice Cornille, Bernard P Roques, S K BurleyAbstract:Regulatory factor X (RFX) proteins are transcriptional activators that recognize X-boxes (DNA of the sequence 5'-GTNRCC(0-3N)RGYAAC-3', where N is any nucleotide, R is a purine and Y is a pyrimidine) using a highly conserved 76-residue DNA-binding domain (DBD). DNA-binding defects in the protein RFX5 cause Bare Lymphocyte Syndrome or major histocompatibility antigen class II deficiency. RFX1, -2 and -3 regulate expression of other medically important gene products (for example, interleukin-5 receptor alpha chain, IL-5R alpha). Fusions of the ligand-binding domain of the oestrogen receptor with the DBD of RFX4 occur in some human breast tumours. Here we present a 1.5 A-resolution structure of two copies of the DBD of human RFX1 (hRFX1) binding cooperatively to a symmetrical X-box. hRFX1 is an unusual member of the winged-helix subfamily of helix-turn-helix proteins because it uses a beta-hairpin (or wing) to recognize DNA instead of the recognition helix typical of helix-turn-helix proteins. A new model for interactions between linker histones and DNA is proposed.
Bernard Mach - One of the best experts on this subject based on the ideXlab platform.
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correction of defective expression in mhc class ii deficiency Bare Lymphocyte Syndrome cells by retroviral transduction of ciita
Journal of Immunology, 1997Co-Authors: M B Bradley, Viktor Steimle, Bernard Mach, Richard J Oreilly, J M Fernandez, G Ungers, T Diazbarrientos, J S LeeAbstract:Retrovirus-mediated gene transfer was used to restore expression to MHC class II-negative patient cells from complementation group A(II) of MHC class II immunodeficiency or Bare Lymphocyte Syndrome (BLS). The cells of these patients do not transcribe MHC class II genes due to a defect in the trans-acting factor, CIITA. We constructed a vector, pGAG/Ii-CIITA, with the MHC class II-associated invariant chain promoter driving CIITA expression. Cocultivation with the virus producer line was consistently shown to be the optimal method for infection of all cell types. The induction of MHC class II expression after virus infection was rapid, and high levels of expression were achieved in cell lines within 1 wk of infection. In addition, expression was easily detectable even in peripheral blood cells of a BLS patient within a few days. Cell lines maintained in vitro for several months remained positive, and the proportion of cells with surface expression of DR was correlated with the number of integrated proviruses. Moreover, transduced B lymphoblastoid cell lines readily established tumors in CB17-scid/scid mice, and the MHC class II-positive cells demonstrated a clear competitive advantage in vivo. Ultimately, we hope to use this transduction system to restore normal immune function to a BLS patient for which no other therapeutic option currently exists.
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molecular defects in the Bare Lymphocyte Syndrome and regulation of mhc class ii genes
Immunology Today, 1995Co-Authors: Walter Reith, Viktor Steimle, Bernard MachAbstract:The complex pattern of expression of major histocompatibility complex (MHC) class II molecules plays an essential role in the control of the immune response. Our understanding of the molecular mechanisms controlling this expression has benefited greatly from the identification of the regulatory factors defective in two forms of a hereditary disease of MHC class II regulation: Bare Lymphocyte Syndrome. This has also provided new tools for the experimental modulation of MHC class II expression.
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purified x2 binding protein x2bp cooperatively binds the class ii mhc x box region in the presence of purified rfx the x box factor deficient in the Bare Lymphocyte Syndrome
Journal of Immunology, 1995Co-Authors: Carlos S. Moreno, Walter Reith, Bénédicte Durand, Bernard Mach, P Emery, J E West, Jeremy M. BossAbstract:The conserved X2 box sequence of MHC class II promoters is homologous to TRE/CRE elements, and is required for B cell expression and IFN-gamma induction of MHC class II genes. The X2 binding protein (X2BP) was initially identified as a DNA-binding activity that specifically interacts with the conserved X2 box sequence in both the MHC HLA-DRA and HLA-DRB promoters. To begin to demonstrate that X2BP is the X2 box factor responsible for class II expression in B cells, we have purified X2BP to homogeneity from B cell nuclear extracts using DNA-affinity chromatography. X-box DNA-affinity purification indicates that X2BP is most likely composed of two polypeptides of 120 kDa and 46 kDa. The 120-kDa protein was specifically cross-linked to an X-box probe by exposure to UV irradiation. The 46-kDa subunit of X2BP cross-reacted with anti-rat CREB polyclonal Abs but not to anti-human CREB Abs in Western analysis and supershift assays, indicating that it may be a novel member of the ATF/CREB family. Purified X2BP interacted with purified RFX, a factor that binds to the adjacent X1 box and is absent in some cell lines that are mutant for MHC class II transcription. This interaction increases the DNA-binding half-life of RFX from 5 to at least 60 min, suggesting that X2BP functions in class II MHC gene expression by forming a stable complex with RFX.
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complementation cloning of an mhc class ii transactivator mutated in hereditary mhc class ii deficiency or Bare Lymphocyte Syndrome
Cell, 1993Co-Authors: Viktor Steimle, Madeleine Zufferey, Luc A. Otten, Bernard MachAbstract:Hereditary major histocompatibility complex (MHC) class II deficiency (or Bare Lymphocyte Syndrome) is a form of severe primary immunodeficiency with a total lack of MHC class II expression. It is due to a defect in the regulation of MHC class II genes. A novel gene was isolated by complementation cloning, using an MHC class II-negative mutant cell line. This gene (CIITA) functions as a transactivator of MHC class II gene expression and restores expression of all MHC class II isotypes in mutant cells. In addition, CIITA fully corrects the MHC class II regulatory defect of cells from patients with Bare Lymphocyte Syndrome. In this disease we have identified a splicing mutation that results in a 24 amino acid deletion in CIITA, resulting in loss of function of the transactivator. Hence, the CIITA gene is essential for MHC class II gene expression and has been shown to be responsible for hereditary MHC class II deficiency.
Marja C J A Van Eggermond - One of the best experts on this subject based on the ideXlab platform.
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type iii Bare Lymphocyte Syndrome associated with a novel rfxap mutation a case report
International Journal of Immunogenetics, 2012Co-Authors: Bahar Gokturk, Marja C J A Van Eggermond, Peter J Van Den Elsen, Hasibe Artac, Ismail ReisliAbstract:Type III Bare Lymphocyte Syndrome (BLS) is a severe combined immunodeficiency disease caused by the absence of MHC Class II expression associated with low expression of class I molecules. Here, we report a case with type III BLS who lacked RFXAP (Regulatory factor X-associated protein) expression as a result from a novel mutation introducing a premature stopcodon in DE-region at amino acid 73.
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t cell immune reconstitution after allogeneic bone marrow transplantation in Bare Lymphocyte Syndrome
Human Immunology, 2000Co-Authors: Barbara C Godthelp, Marja C J A Van Eggermond, Maarten J D Van Tol, Jaak M Vossen, Peter J Van Den ElsenAbstract:Abstract To study the impact of an MHC class II-negative environment on T cell immune reconstitution, we have analyzed the phenotypical and functional characteristics of FACS-sorted cultured CD4 + and CD8 + T cells in two Bare Lymphocyte Syndrome (BLS) patients before and after allo-BMT. A similar analysis was performed in two MHC class II expressing pediatric leukemia patients after treatment with an allo-BMT who were included in our study as control. It was observed that CD4 + T cells displayed cytolytic alloreactivity in both BLS patients prior to and within the first year after allo-BMT, whereas such cells were absent at a later time-point, in the donors and pediatric leukemia controls. In addition, reduced MHC class II expression was observed in CD8 + T cells of both recipients early after allo-BMT, irrespective of the T cell chimerism pattern. Lack of endogenous MHC class II expression in BLS patients, therefore, results in aberrant T cell selection within the first year after allo-BMT, analogous to T cell selection before transplantation. These T cell selection processes seem to be normalized at a later time point after allo-BMT probably due to migration and integration of graft-derived MHC class II-positive antigen presenting cells to sites of T cell selection.
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incomplete t cell immune reconstitution in two major histocompatibility complex class ii deficiency Bare Lymphocyte Syndrome patients after hla identical sibling bone marrow transplantation
Blood, 1999Co-Authors: Barbara C Godthelp, Ad Peijnenburg, Marja C J A Van Eggermond, Ilhan Tezcan, Maarten J D Van Tol, Jaak M Vossen, Stefaan Van Lierde, Peter J Van Den ElsenAbstract:To study the effects of major histocompatibility complex (MHC) class II expression on T-cell development, we have investigated T-cell immune reconstitution in two MHC class II–deficiency patients after allogeneic bone marrow transplantation (allo-BMT). Our study showed that the induction of MHC class II antigen expression on BM graft-derived T cells in these allo-BMT recipients was hampered upon T-cell activation. This reduction was most striking in the CD8+ T-cell subset. Furthermore, the peripheral T-cell receptor (TCR) repertoire in these graft-derived MHC class II–expressing CD4+ and in the CD8+ T-cell fractions was found to be restricted on the basis of TCR complementarity determining region 3 (CDR3) size profiles. Interestingly, the T-cell immune response to tetanus toxoid (TT) was found to be comparable to that of the donor. However, when comparing recipient-derived TT-specific T cells with donor-derived T cells, differences were observed in TCR gene segment usage and in the hydropathicity index of the CDR3 regions. Together, these results reveal the impact of an environment lacking endogenous MHC class II on the development of the T-cell immune repertoire after allo-BMT.
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the rfx complex is crucial for the constitutive and ciita mediated transactivation of mhc class i and β2 microglobulin genes
Immunity, 1998Co-Authors: Sam J. P. Gobin, Ad Peijnenburg, Marja C J A Van Eggermond, Marlijn Van Zutphen, Rian Van Den Berg, Peter J Van Den ElsenAbstract:In type III Bare Lymphocyte Syndrome (BLS) patients, defects in the RFX protein complex result in a lack of MHC class II and reduced MHC class I cell surface expression. Using type III BLS cell lines, we demonstrate that the RFX subunits RFX5 and RFXAP are crucial for constitutive and CIITA-induced MHC class I and beta2m transactivation. Similar to MHC class II, the promoters of MHC class I and beta2m contain an S-X-Y region of which the X1 box is crucial for constitutive and CIITA-induced MHC class I and beta2m transactivation. Thus, the RFX complex is part of a regulatory pathway linking the transactivation of MHC class I and II and their accessory genes.
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lymphokine gene transcription in cd4 cd8 t cells of a type iii Bare Lymphocyte Syndrome patient
Human Immunology, 1993Co-Authors: M Lambert, Marja C J A Van Eggermond, Peter J Van Den ElsenAbstract:In this study we analyzed the impact of a MHC class-II-deficient environment on the differentiation of CD4+CD8- T Lymphocytes into functional defined subsets of lymphokine-producing T-helper cells. To this end a CD4+CD8- T-cell line and CD4+CD8- T-cell clones, isolated from PBMCs of a type III BLS patient, were stimulated in vitro with anti-CD3 and PMA and assessed for lymphokine transcription patterns. The results of these analyses show that CD4+CD8- T cells that have matured in a MHC class-II-deficient environment display lymphokine transcription patterns that resemble those of MHC class-II-expressing family control-derived CD4+CD8- T cells.