Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ig-isotype switching to IgE requires interleukin-4 and a contact-dependent T-cell signal delivered by the ligand for CD40. The recent discovery that defects in the gene encoding the CD40 ligand are the underlying cause of the X-linked hyper IgM syndrome highlights the role of CD40 and its ligand in Ig-isotype switching.
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PMID:Role of CD40-CD40-ligand interaction in Ig-isotype switching. 750 84

Recent studies show that most patients with X-linked hyper IgM syndrome have defects in the gene for CD40 ligand. We evaluated 17 unrelated males suspected of having X-linked hyper IgM syndrome. Activated T cells from 13 of the 17 patients failed to bind a soluble CD40 construct. In these patients, the sequence of CD40 ligand demonstrated mutations. By contrast, T cells from the remaining four patients exhibited normal binding to the CD40 construct. Sequencing of the cDNA for CD40 ligand from these patients did not show mutations. The possibility that hyper IgM syndrome in these four patients was due to abnormalities in the B cell response to CD40-mediated signals was examined. Peripheral blood lymphocytes were stimulated with anti-CD40 alone, IL4 alone or anti-CD40 plus IL4. In comparison with B cells from controls or patients with hyper IgM syndrome and mutant CD40 ligand, B cells from the patients with hyper IgM syndrome and normal CD40 ligand were defective in their ability to secrete IgE (P < 0.02) or express activation markers, CD25 and CD23 (P < 0.02) in response to stimulation with anti-CD40. The failure of these B cells to respond to CD40-mediated activation could not be attributed to a generalized deficiency in B cell activation because IL4 induced normal up-regulation of CD23 and CD25 expression. These findings indicate that hyper IgM syndrome may result from defects in expression of CD40 ligand by activated T cells or defects in CD40-mediated signal transduction in B cells.
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PMID:Hyper IgM syndrome associated with defective CD40-mediated B cell activation. 752 48

Recent progress in the definition of molecules involved in immune regulation has led to the discovery of a number of type I membrane glycoproteins with a distinctive, cysteine-rich, repetitive domain structure within their extracellular regions. Because the prototype members of this family are receptors for cytokines (tumor necrosis factor [TNF] and nerve growth factor [NGF]), it was expected that the ligands for the other receptors would possess cytokine-like activities. This prediction has been fulfilled by the cloning of cDNA encoding a series of type II membrane glycoproteins, with homology to TNF, that bind to, and signal through, their cognate receptors. While the biological role of some of these ligand-receptor pairs remains obscure, at least two members of the family, CD40 and Fas, have proven their importance. The human X-linked immunodeficiency, hyper IgM syndrome, is the result of mutations in the CD40 ligand gene, and the Fas and Fas ligand genes are mutated in two mouse strains, lpr and gld, that develop autoimmune disease. These findings, together with other evidence, point to key roles of CD40/CD40 ligand interactions in immune activation, particularly in T-dependent B cell responses, and of Fas/Fas ligand in apoptosis and peripheral tolerance. These molecules, as well as the other ligands of the family, share the property of costimulation of T cell proliferation and are all expressed by activated T cells. More detailed analysis of the expression patterns of ligands and receptors on lymphocyte subpopulations will be necessary to define their different roles in immune activation and suppression.
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PMID:A family of ligands for the TNF receptor superfamily. 752 88

CD40 ligand (CD40L) is a 33 kDa type II glycoprotein which is transiently expressed on the surface of T cells following activation. The demonstration that signals delivered by CD40L are essential for the process of affinity maturation and immunoglobulin isotype switching following antigenic challenge came from the study of X-linked hyper-IgM patients whose T cells cannot express functional CD40L. While some of the biological activities of CD40L, especially on B cells, can be mimicked by monoclonal antibodies (MAb) specific for CD40, it is becoming increasingly clear that CD40L also mediates various functional effects on other cell types. Not only are there distinctions between the activities of CD40L and CD40 MAb, but the manner in which CD40 is ligated appears to play an important part in the biological outcome of signaling through this receptor. In this review, we compare and contrast the activities which can currently be ascribed to CD40L and CD40 MAb and consider the role that ligand oligomerization plays in CD40-mediated signal transduction.
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PMID:Structural characteristics of CD40 ligand that determine biological function. 753 57

The interaction between the CD40 ligand (gp39), expressed by activated T cells, and CD40, constitutively expressed by B cells, is critical for an effective antibody response to T cell dependent antigens. Patients with X-linked hyper IgM (HIM) syndrome fail to express a functional CD40 ligand due to a mutation within the gene for gp39. As a direct consequence, HIM patients, when immunized with T dependent antigens, produce only small amounts of IgM antibody without the development of immunologic memory, amplification and switch from IgM to IgG. Mutations affecting the gene for the HIM syndrome are localized throughout the coding region of gp39 and consist predominantly of point mutations. The resulting amino acid substitutions interfere directly with the receptor binding site or lead to stop codons or deletions secondary to splice site mutations. Expression of gp39 by activated T cells from patients with common variable immunodeficiency (CVI) is low in approximately half of the patients and is associated with depressed expression of IL-2. These findings suggest that inefficient signaling via CD40 may be responsible in part for failure of B cell differentiation in CVI.
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PMID:The role of CD40L (gp39)/CD40 in T/B cell interaction and primary immunodeficiency. 753 62

Somatic mutation of Ig variable regions occurs prominently in germinal centers, but it has been debated whether the mutation process initiates in germinal centers or is activated before germinal center entry of B cells. We have analyzed for the presence of somatic mutation in Ig gene rearrangements of the nonpolymorphic human VH6 gene in the X-linked HyperIgM syndrome, which is associated with defective CD40 ligand expression and absence of germinal centers and generation of memory B lymphocytes. IgM and rare IgG VH6 productive rearrangements were isolated from PBL of patients with X-linked HyperIgM syndrome. Although the majority of both the IgM and IgG VH6 rearrangements had a germline VH6 sequence, 7 of 102 VH6 IgM and 1 of 6 IgG rearrangements had a mutated VH6 gene. The mutation frequency (mutations/bp) was 1.4% with a range of 2-9 mutations per clone, a mutation frequency lower, however, than that observed in IgM (3.2%) and IgG (5.4%) VH6 rearrangements of normal individuals. These results suggest that somatic mutation may be initiated in a CD40 ligand-independent pathway before entry of B cells into germinal centers, but fails to achieve the high mutation frequency observed in the presence of germinal centers.
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PMID:Somatic mutation of human immunoglobulin V genes in the X-linked HyperIgM syndrome. 753 92

The immunologic defect in X-linked immunodeficiency and hyperimmunoglobulinemia M (HIM) are related to defective expression of the CD40 ligand (CD40L). We have studied two female patients with HIM to evaluate the role of CD40/CD40L in the pathogenesis of impaired immunoglobulin switching. In addition to recurrent infections characteristic of humoral immunodeficiencies, the two patients had chronic hepatitis caused by type C virus. Phenotypic characterization of peripheral blood mononuclear cells showed a similar picture in both patients, with a reduction in the absolute numbers of CD4 cells and increased numbers of CD8 and CD3/DR cells. B cells (CD19+) were reduced in one patient, but CD40 was expressed on all CD19+ cells in both patients. The expression of CD40L was normal on peripheral blood mononuclear cells from the two patients with HIM on both resting and stimulated cells. The combination of anti-CD40 and cytokines (interleukin-2, interleukin-4, and interleukin-10) was able to restore proliferative capacity to anti-IgM. Peripheral blood mononuclear cells from the two patients with HIM showed a high spontaneous production of IgM in vitro and no production of IgG or IgE. Our data suggest that the defect of isotype switching in female patients with HIM is not related to defective expression of the CD40/CD40L receptor system. A possible role for chronic hepatitis C virus infection in the pathogenesis of the disease is suggested by the detection of specific production of anti-hepatitis C virus IgM.
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PMID:Immunodeficiency with hyperimmunoglobulinemia M in two female patients is not associated with abnormalities of CD40 or CD40 ligand expression. 756 Jun 43

We challenge the theory that the CD40-CD40 ligand is the only explanation for X-linked immunodeficiency in patients with hyper-immunoglobulin M (IgM) syndrome (HIGM1), and we demonstrate an intrinsic defect in the patients' B cells. Patients with HIGM1 have a defective CD40 ligand on their activated T-helper cells; therefore, they cannot receive signals for isotype switching when the cells are activated by T cell-dependent antigens. We activated mononuclear cells from three patients with HIGM1 and from three healthy blood donors with T cell-independent mitogens and studied their proliferative responses and Ig secretion. Normal murine plasma membrane fragments were implanted into peripheral blood mononuclear cells, and the cells were activated with Staphylococcus aureus Cowan I, pokeweed mitogen, and lipopolysaccharide. This implantation significantly augmented the proliferative responses to the mitogens in two patients. However, it augmented IGM secretion in response to B-cell mitogens in only one patient. No IgG or IgA response could be detected in the implanted mononuclear cells that originated from patients with HIGM1, unlike implanted mononuclear cells from healthy donors, which responded by IgM, IgG, and IgA antibody secretion following their stimulation with B-cell mitogens. The data suggest that the B cells of patients with HIGM1 possess an additional defect which prevents Ig isotype switching in response to T cell-independent mitogens. This defect is not located in the membrane receptors or within the membrane enzymes.
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PMID:Intrinsic defect in B cells of patients with hyper-immunoglobulin M syndrome. 758 16

We studied the ability of B lymphocytes from patients with X-linked hyper IgM syndrome (HIGM1) to be activated via the CD40 membrane receptor. HIGM1 is caused by a CD40 ligand gene mutation, leading to defective expression on the membrane of activated T lymphocytes. We found that triggering of B cells by an anti-CD40 monoclonal antibody or the soluble CD40 ligand plus interleukin (IL)-4 or IL-10 led to B cell proliferation and/or differentiation towards IgG, IgA and IgE secretion. This was reflected by transcription of C gamma, alpha and epsilon membrane isotype expression and IgG, IgA and IgE production. These results confirm the integrity of B cells in patients with the HIGM1 immunodeficiency and open up new therapeutic possibilities.
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PMID:Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome. 769 Mar 28

Gene defects causing three X-linked human immunodeficiencies, agammaglobulinemia (XLA), hyper-IgM syndrome (HIGM), and X-linked severe combined immunodeficiency (SCID), have been identified. These represent the first human disease phenotypes associated with three gene families already recognized to be important in lymphocyte development and signaling: XLA is caused by mutations of a B-cell specific intracellular tyrosine kinase; HIGM by mutations in the tumor necrosis factor-related CD40 ligand, through which T cells deliver helper signals by direct contact with B-cell CD40; and SCID by mutations in the gamma chain of the lymphocyte receptor for interleukin-2. The great variety of patient mutations in all three genes represent both a challenge for genetic diagnosis and a resource for dissecting molecular domains and physiologic functions of the gene products.
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PMID:Molecular basis for three X-linked immune disorders. 784 38


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