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 cell surface molecule CD40 is a member of the tumor necrosis factor receptor (TNFR) family and plays a pivotal role in the immune system due in part to its wide tissue distribution. Early studies focused on CD40 in B cell biology, but recent work demonstrates a broader role for CD40 in the immune system contributing to cell-mediated as well as humoral immune responses. Disruption of CD40 and its ligand, CD154 leads to immunodeficiency as in the case of hyper IgM syndrome. Likewise, blockade of CD40-CD154 interactions can be exploited to control misguided autoimmune responses. This article provides a brief overview of CD40 with a focus on its involvement in disease and its usefulness as a therapeutic target.
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PMID:CD40 and its crucial role as a member of the TNFR family. 982 76

CD40-deficient mice, when inoculated with the LP-BM5def murine retorvirus, become infected and show virus expression similar to wild-type mice. However, unlike the wild-type mice, CD40-deficient mice do not develop symptoms of immunodeficiency, lymphoproliferative disease and the typical histological changes in the lymphoid tissue. These results show that the CD40-CD40 ligand (CD40L) interaction in vivo is essential for anergy induction and the subsequent development of immunodeficiency and pathologic expansion of lymphocytes. Infected CD40-deficient mice and their littermates express a similar pattern of cytokine mRNA, which is not biased towards a Th2 phenotype. Nevertheless, hypergammaglobulinemia is induced in infected wild-type and CD40-deficient mice. Surprisingly, murine AIDS infection even induces IgE production in CD40-deficient mice in vivo. Our data demonstrate that antibody class switch to IgE and IgG1 can be induced by a retroviral infection in vivo even in the absence of CD40-CD40L interaction and an apparent switch to a Th2 cytokine production.
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PMID:CD40-deficient mice infected with the defective murine leukemia virus LP-BM5def do not develop murine AIDS but produce IgE and IgG1 in vivo. 1006 78

Cell-to-cell signals between T lymphocytes and antigen-presenting cells strictly regulate the development of the immune response. It has clearly emerged that among these signals few cell surface receptor-ligand pairs, such as CD40 and its ligand, CD154, are mandatory for the induction of lymphocyte activation. The early observation that mutations of CD154 gene are responsible for a human severe immunodeficiency primed an impressive number of studies aimed to functionally characterize this receptorial system in view of therapeutically exploiting its properties. Indeed, various approaches aimed to disrupt natural CD40-CD154 interaction were highly effective in the prevention and treatment of several experimental models of autoimmune disease and transplant rejection. In parallel, abnormalities of this pathway were constantly found in several immunologically-mediated human diseases. Furthermore, a number of studies have dissected the role of CD40 and its ligand in the immune response against various microbial and viral pathogens. Since these molecules are often expressed by tumor cells, it is not surprising that great efforts have been made to address their function also in the development of cancer. Most recent data strongly suggest an involvement of endothelial CD40 in the vascular processes that lead to atherogenesis. This review focuses on the most significant advances in the understanding of the molecular regulatory events involving CD40 and its ligand in experimental and human disease.
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PMID:CD40-CD154 interaction in experimental and human disease (review). 1008 5

Human immunodeficiency virus-associated Hodgkin's disease (HIV-HD) displays several peculiarities when compared with HD of the general population. These include overrepresentation of clinically aggressive histologic types and frequent infection of Reed-Sternberg (RS) cells by Epstein-Barr virus (EBV). Recently, we have reported that the histogenesis of HD of the general population may be assessed by monitoring the expression pattern of BCL-6, a transcription factor expressed in germinal center (GC) B cells, and of CD138/syndecan-1 (syn-1), a proteoglycan associated with post-GC, terminal B-cell differentiation. In this study, we have applied these two markers to the study of HIV-HD histogenesis and correlated their expression status to the virologic features of this disease. We have found that RS cells of all histologic categories of HIV-HD consistently display the BCL-6(-)/syn-1(+) phenotype and thus reflect post-GC B cells. Although BCL-6(-)/syn-1(+) RS cells of HIV-HD express CD40, they are not surrounded by CD40 ligand-positive (CD40L+) reactive T lymphocytes, which, in HD of the general population, are thought to regulate the disease phenotype through CD40/CD40L interactions. Conversely, RS cells of virtually all HIV-HD express the EBV-encoded latent membrane protein 1 (LMP1), which, being functionally homologous to CD40, may contribute, at least in part, to the modulation of the HIV-HD phenotype.
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PMID:Human immunodeficiency virus-associated Hodgkin's disease derives from post-germinal center B cells. 1009 Sep 42

Human immunodeficiency virus (HIV) infection causes dysregulation of surface phenotype, of accessory function and of cytokine production from peripheral blood mononuclear cells (PBMCs). As CD40 ligation induces several functional activities in these cells, this stimulation may partially mimic the situation occurring in vivo during an antigen-driven immune response. The aim of this study was to measure cytokine production and immunophenotypic changes induced by CD40 stimulation of PBMCs from HIV-positive patients. Under these experimental conditions, total and heterodimeric interleukin (IL)-12 production from PBMCs was similar, while IL-10 production was increased in HIV-positive patients compared with controls. On the contrary, CD40 ligation did not induce IL-15 production by PBMCs. Surface CD14 was down-modulated, as a consequence of CD40 stimulation, on monocytes from healthy controls but not on monocytes from HIV-positive patients. These data demonstrate that some of the CD40-mediated signals are disturbed in HIV-positive patients. These disturbances may contribute to the immune dysfunction seen in HIV infection.
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PMID:The effects of CD40 ligation on peripheral blood mononuclear cell interleukin-12 and interleukin-15 production and on monocyte CD14 surface antigen expression in human immunodeficiency virus-positive patients. 1010 46

CD40 ligand (CD40L) is a 33-kDa type II membrane glycoprotein mainly expressed on activated CD4(+) T cells in trimeric form. When it is mutated, the clinical consequences are X-linked hyper-IgM syndrome (XHIM), a primary immunodeficiency disorder characterized by low levels of IgG, IgA, and elevated or normal levels of IgM. Mutated CD40L can no longer bind CD40 nor provide signals for B cells to proliferate and to switch from IgM to other immunoglobulin isotypes. When considering gene therapy for XHIM, it is important to address the possibility that the mutated CD40L associates with transduced wild type CD40L, and as a consequence, immune reconstitution is not attained. In this study, we demonstrate that the various mutated CD40L species we have identified in patients with XHIM, including both full-length and truncated mutants, associate with wild type CD40L on the cell surface of co-transfected COS cells. The association between wild type and mutated CD40L was also observed in CD4(+) T cell lines established from XHIM patients with leaky splice site mutations. The clinical phenotype of these patients suggests that this association between wild type and mutated CD40L species may result in less efficient cross-linking of CD40.
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PMID:CD40 ligand mutants responsible for X-linked hyper-IgM syndrome associate with wild type CD40 ligand. 1019 21

Hyper-IgM syndrome (HIM) is a rare immunodeficiency disorder that has been associated with the development of symptoms and clinical features characteristic of rheumatoid arthritis (RA). We describe a patient with HIM and severe erosive arthritis with prominent nodules in the absence of detectable serum rheumatoid factor. Because HIM results from defects in either T cell CD154 (CD40 ligand) expression or abnormal CD40 signaling, the molecular basis of the patient's disease was analyzed. Activated CD4+ T cells failed to express surface CD154 protein, and molecular analysis of CD154 complementary DNA revealed a nucleotide transversion resulting in the nonconservative amino acid substitution G-D at amino acid 257. This case indicates that defective CD154-dependent CD40 signaling can be associated with susceptibility to a severe inflammatory arthritis that has both similarities to and differences from idiopathic RA.
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PMID:An aggressive form of polyarticular arthritis in a man with CD154 mutation (X-linked hyper-IgM syndrome). 1036 25

Mycobacterium avium is a common opportunistic pathogen in immunocompromised patients such as those infected with human immunodeficiency virus. Although M. avium is an intracellular organism replicating predominantly in macrophages, disseminated M. avium infection is seen in AIDS patients with CD4(+) cell counts of <50 cells/microliters, suggesting a possible involvement of a T cell-macrophage interaction for the elimination of M. avium. To determine whether CD40-CD40 ligand (CD40L) interactions play a role in M. avium infection, we studied the ability of CD40L to restrict M. avium replication in human monocyte-derived macrophages (MDM) in vitro. MDM were infected with M. avium and cocultured with CD40L-transfected 293 cells for 7 days. Intracellular growth of M. avium in these MDM was assessed by colony counting. CD40L-expressing cells inhibited growth of M. avium in MDM by 86.5% +/- 4.2% compared to MDM cultured with control cells. These findings were verified by assays using purified, soluble recombinant human CD40L (CD40LT). CD40LT (5 micrograms/ml) inhibited intracellular growth of M. avium by 76.9% +/- 18.0% compared to cells treated with medium alone. Inhibition by CD40LT was reduced by monoclonal antibodies (MAbs) against CD40 and CD40L. The inhibitory effect of CD40LT was not accompanied by enhancement of interleukin-12 (IL-12) production by M. avium-infected MDM, while CD40L-expressing cells stimulated IL-12 production by these cells. Treatment of M. avium-infected mice with MAb against murine CD40L resulted in recovery of larger numbers of organisms (0.8 to 1.0 log) from the spleens, livers, and lungs of these animals compared to infected mice which received normal immunoglobulin G. These results indicate that CD40-CD40L signaling may be an important step in host immune response against M. avium infection.
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PMID:Role of CD40 ligand in Mycobacterium avium infection. 1037 39

The recognition of antigens by specific T- and B-lymphocytic receptors underlies an immune response. However, the formation of a potential signal for the activation of lymphocytes requires an additional their stimulation (costimulation). The main source of costimulation signals is the interaction of the surface molecules of lymphocytes and accessory cells. The interaction between the T-cell surface molecules CD28 and costimulatory molecules of antigen-presenting cells (CD80 or CD86) is the most important point of the T-helper cell activation. The interaction between B-cell molecule CD40 and T-helper surface molecule CD154 is the key event of B-cell (and other antigen-presenting cell) activation. When costimulation is absent, antigen recognition induces specific lymphocytic anergy or apoptosis. Defects of costimulatory molecular expression or function can cause immunodeficiency. For example, hereditary defect of CD154 expression causes the hyper-IgM syndrome. The soluble forms of some costimulatory molecules are considered to be potential immunomodulators.
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PMID:[Cell interaction in immune response]. 1037 80

Mouse retrovirus-induced lymphoma/leukemia and immunodeficiency are useful models for analogous human diseases. Both ecotropic (mouse tropic) and recombinant retroviruses, including the polytropic mink cytopathic focus-inducing type, have been studied for disease pathogenesis and as targets for humoral and cellular immunity, particularly cytotoxic T-lymphocyte (CTL) responses. For AKR/Gross murine leukemia viruses (MuLV) we have defined an immunodominant CTL epitope in the p 15E transmembrane anchor envelope protein and three minor/subdominant epitopes. Evidence is presented for retroviral escape from CTL by selection following genetic recombination and point mutation both within and outside CTL epitope sequences, and via endogenous retrovirus-infected cell downregulation of the generation of anti-AKR/Gross MuLV CTL. As demonstrated in vivo in naturally occurring non-responder strains by adoptive transfer, and in vitro by cell-mixing experiments, a central non-responsiveness mechanism appears to be peripheral inhibition mediated by infected cells expressing MHC-presented viral peptides. Such inhibition requires Fas expression by antiviral T cells; occurs upon TCR-mediated recognition of virus-infected, Fas ligand-expressing "veto" cells; and apparently leads to an antigen-specific form of activation-induced cell death of T cells. In the LP-BM5 MuLV isolate that causes murine AIDS (MAIDS) retroviral variation also leads to CTL escape--the BM5-helper virus has altered forms of the immunodominant and two minor/subdominant epitopes. In contrast, a novel immunodominant CTL epitope is recognized by MAIDS resistant, but not MAIDS-susceptible, strains. This epitope is uniquely encoded in an alternative translational reading frame of the viral gag gene. It also appears that the LP-BM5 MuLV have co-opted the cells of the immune system for retroviral pathogenesis--CD40/CD40L (CD154) interactions are required both for the initiation and progression of MAIDS.
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PMID:Cytotoxic T lymphocytes to endogenous mouse retroviruses and mechanisms of retroviral escape. 1039 80


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