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)

B cell chronic lymphocytic leukemia (B-CLL) is the most frequent hematological neoplasm in the human adult life. This tumor is often associated with hypogammaglobulinemia and infections. This review focuses on recently reported mechanisms underlying the humoral immunodeficiency occurring in B-CLL. Tumoral cells provoke several alterations to normal regulatory T cells, which, in turn, can impair the correct maturation of B cells. In addition, the direct inhibitory effect of B-CLL cells on immunoglobulin (Ig)-secreting plasma cells (PC) may account for the humoral immunodeficiency. This phenomenon is mediated by the interaction of CD95L molecules expressed by B-CLL cells with the death receptor CD95 that is up-regulated on patients' PC, leading to PC apoptosis and subsequently to hypogammaglobulinemia. Furthermore, the presence of CD95L on B-CLL cells could play an additional role in tumoral immune-escape, as reported in other neoplasms.
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PMID:Humoral immunodeficiency in chronic lymphocytic leukemia: role of CD95/CD95L in tumoral damage and escape. 1215 79

The 2 lymphotoxin subunits LTalpha (also called tumor necrosis factor beta [TNF-beta]) and LTbeta belong to the family of TNF-related cytokines. They form either a soluble homotrimeric ligand (LTalpha(3)) that binds to and signals through CD120a/b (TNFRp55 and TNFRp75), or a membrane-associated heterotrimeric ligand (LTalpha(1)beta(2)) that binds to and signals through the LTbeta receptor (LTbetaR). In mice, LTbetaR signaling is critical for the maintenance of peripheral lymphoid tissues and optimal immune responses, and its down-regulation results in immunodeficiency. To determine the possible relationship between LT-mediated immunodeficiency and the immunosuppressive effects of cyclosporin A (CsA), we tested the effects of CsA on the expression of LTalpha and LTbeta in human peripheral blood mononuclear cells (PBMCs). When PBMCs were stimulated with phorbol myristate acetate/ionomycin or with anti-CD3/anti-CD28, the accumulation of LTalpha both at mRNA and protein levels was markedly inhibited by CsA. This inhibition is likely due to CsA's effect on the nuclear factor of activated T cell (NFAT) proteins binding to a novel NFAT-binding element at position -490 relative to LTalpha transcription start. LTbeta showed a distinct expression pattern and was insensitive to CsA. Thus, in addition to its effects on the expression of other TNF family members, such as TNFalpha, CD40-L, and CD95-L, CsA can block expression of surface LT complex by selectively inhibiting the expression of the LTalpha subunit. We propose that LT dysfunction and its downstream effects may contribute to immunosuppressive effects of CsA.
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PMID:Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta, in human peripheral blood mononuclear cells. 1217 93

Apoptosis is a form of programmed cell death that is controlled by aspartate-specific cysteine proteases called caspases. In the immune system, apoptosis counters the proliferation of lymphocytes to achieve a homeostatic balance, which allows potent responses to pathogens but avoids autoimmunity. The CD95 (Fas, Apo-1) receptor triggers lymphocyte apoptosis by recruiting Fas-associated death domain (FADD), caspase-8 and caspase-10 proteins into a death-inducing signalling complex. Heterozygous mutations in CD95, CD95 ligand or caspase-10 underlie most cases of autoimmune lymphoproliferative syndrome (ALPS), a human disorder that is characterized by defective lymphocyte apoptosis, lymphadenopathy, splenomegaly and autoimmunity. Mutations in caspase-8 have not been described in ALPS, and homozygous caspase-8 deficiency causes embryonic lethality in mice. Here we describe a human kindred with an inherited genetic deficiency of caspase-8. Homozygous individuals manifest defective lymphocyte apoptosis and homeostasis but, unlike individuals affected with ALPS, also have defects in their activation of T lymphocytes, B lymphocytes and natural killer cells, which leads to immunodeficiency. Thus, caspase-8 deficiency in humans is compatible with normal development and shows that caspase-8 has a postnatal role in immune activation of naive lymphocytes.
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PMID:Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. 1235 64

Invariant human natural killer T cells (NKT) express a restricted T-cell receptor (TCR) Valpha24Vbeta11 repertoire. These cells share both phenotypic and functional similarities between NK and T cells. Given the emerging role of NKT cells as critical cells in bridging the gap between innate and adaptive immunity, we examined their susceptibility to productive human immunodeficiency virus (HIV) infection by T-tropic, M-tropic, and primary isolates of HIV. We generated three human NKT cell clones (CA5, CA29, and CA31). Phenotypic characterization of these Valpha24+ Vbeta11+ clones indicated that they were predominately positive for CD4, CD161, HLA-DR, CD38, CD45RO, and CD95 expression. The NKT cell clones expressed significantly more surface CCR5 molecules/cell and lower CXCR4 molecules/cell than phytohaemagglutinin-stimulated peripheral blood mononuclear cells (PBMC). Consistent with the surface expression of CCR5 and CXCR4, the NKT clones were also selectively susceptible to HIV M-tropic, T-tropic, and primary isolate infection, as evaluated by both HIV p24 enzyme-linked immunosorbent assay and intracellular staining of HIV proteins. The amount of p24 production was dependent on the NKT clone studied and the HIV strain used. Clones CA29 and CA31 were also susceptible to HIV IIIB infection. The virions produced by these clones were able to productively infect PHA-stimulated PBMCs with the same kinetics as for primary infection of CD4+ blast. Collectively, this data demonstrates that NKT cells can be a target for productive HIV infection but with a lag in the time to peak p24 production.
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PMID:CD1d-restricted natural killer T cells are potent targets for human immunodeficiency virus infection. 1251 95

Infection by human immunodeficiency virus (HIV) causes persistent chronic inflammation. Viral Tat protein plays a role in the intracellular increase of reactive oxygen species (ROS) thus increasing apoptotic index, mostly the one mediated by FAS/CD95, and depleting CD4+ T lymphocytes. The aim of this study was to investigate whether there is a relationship between an extensive array of redox status indices (glutathione (GSH), malondialdehyde (MDA), peroxidation potential, total antioxidant status, glutathione peroxidase (GPx), superoxide dismutase (SOD), total hydroperoxide (TH), DNA fragmentation) and relative CD4, CD95, CD38/CD8 T lymphocyte counts in HIV/AIDS patients compared to healthy subjects. Blood samples from 85 HIV/AIDS patients and 40 healthy subjects were tested by spectrophotometric techniques in order to measure oxidative stress indices, and by flow cytometry to quantify T cell subsets. Patients were divided in two groups according to CDC 1993 guidelines. CD95 and CD38 increase paralleled the severity of HIV infection. Both a reduction of GSH levels and an increase in MDA and TH levels were detected in the plasma of HIV+ patients. These patients also showed an increase of DNA fragmentation in lymphocytes as well as a significant (P<0.05) reduction of GPx and an increase in SOD activity in erythrocytes. Relatively to the control group, HIV-infected patients had significantly differences in global indices of total antioxidant status. These results corroborate that substantial oxidative stress occurs during HIV infection. To our knowledge this study is the first relating oxidative stress indices with both CD38/CD8 and CD95 lymphocytes subsets.
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PMID:Contribution to characterization of oxidative stress in HIV/AIDS patients. 1259 Oct 17

As well as the proliferation of antigen-specific T and B cells the programmed cell death (apoptosis) of lymphocytes is one of the key mechanisms of the immune homeostasis regulation. The apoptosis of immunocytes is associated with the expression of Fas/Apo-1 (CD95) glycoprotein. The expression of Fas/Apo-1 (CD95) on the peripheral blood lymphocytes from 45 healthy donors and 45 patients with pulmonary tuberculosis was studied. The percentage of CD95(+) lymphocytes of the healthy donors was 40.1 +/- 10.9, significant correlation of this parameter with the percentage of CD3(+) and CD4(+) lymphocytes was observed. In patients with pulmonary tuberculosis the percentage of CD95(+) lymphocytes was 47.0 +/- 15.9. In this case the correlations between the percentage of CD95(+) lymphocytes, CD72(+) B cells, CD25(+) lymphocytes and HLA DR(+) cells and serum IgA level were observed. Using the procedure of cluster analysis it was shown that extremal number of the CD95(+) lymphocytes is typical for the patients with the prognostically unfavorable immune abnormalities and clinic picture, high levels of serum TNFalpha and hypercortisolemia. It is tempting to speculate that apoptosis of T cells (possibly Th1 cells) is of great importance in the pathogenesis of the immunodeficiency associated with the micobacteriosis.
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PMID:Fas/Apo-1 (CD95) Antigen Expression on the Peripheral Blood Lymphocytes in Healthy Donors and Pulmonary Tuberculosis Patients. 1268 14

The immune status and the PBL apoptosis were studied in the healthy donors and the opioid addicts. Leukocytosis and the increased percentage of the CD3(+) T cells, CD8(+) T cells, CD19(+) B cells, activated CD25(+) and HLA DR(+) lymphocytes were observed in the addicted patients. The number of the CD95 and CD95L bearing cells also was increased however the percentage of the bcl-2(+) lymphocytes was the same as for the donors. The activated PBL subset "pattern" was accompanied by increased IgM level, decreased IgG and IgA levels and elevated serum IL-1beta and TNFalpha. PBL mitogenic response and LPS-induced IL-1beta, TNFalpha and IFNalpha production were suppressed in the opioid addicts. These changes were associated with the increased level of the spontaneous PBL apoptosis, which was documented by morphological method and caspase 3 activity evaluation. The anti-CD3mAbs-induced T-cell apoptosis in the 72-h cultures also was increased however the activated T cells from the addicted patients were resistant to the dexamethasone-induced apoptosis. The immune abnormalities were more prominent in patients with the clinically manifested infectious immunopathological syndrome. Thus, the activation-induced lymphocyte apoptosis may be the factor of importance in the mechanisms of the immunodeficiency in the opioid addicts.
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PMID:The Immune Status and Lymphocyte Apoptosis in the Opioid Addicts. 1268 28

In the immune system, lymphocyte activation by antigen is followed by cell proliferation and induction of effector functions. Subsequently, physiologic cell-death signals are induced, resulting in removal of expanded effector-cell populations, to maintain homeostasis. Caspases are intracellular participants in both activation responses and cell death by apoptosis. Targets of caspases include inflammatory activators and also other members of the caspase family that mediate apoptosis. Caspase-8 and caspase-10 participate in the protease cascade following cell surface CD95 engagement by its ligand. Humans with defects in these caspases were initially evaluated for the autoimmune lymphoproliferative syndrome because of their spleen and lymph node enlargement. Although both caspase-8- and caspase-10-deficient individuals had impaired apoptosis, those with caspase-8 deficiency, who also had immunodeficiency, had additional defects in activation of lymphocytes and natural killer cells. These disorders help to define the importance and specificity of the caspase proteases in intracellular signaling pathways.
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PMID:Immune disorders caused by defects in the caspase cascade. 1290 72

Studies of human immunodeficiency virus (HIV) and nonhuman primate models of pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections have suggested that enhanced ex vivo CD4 T-cell death is a feature of pathogenic infection in vivo. However, the relative contributions of the extrinsic and intrinsic pathways to programmed T-cell death in SIV infection have not been studied. We report here that the spontaneous death rate of CD4+ T cells from pathogenic SIVmac251-infected rhesus macaques ex vivo is correlated with CD4 T-cell depletion and plasma viral load in vivo. CD4+ T cells from SIVmac251-infected macaques showed upregulation of the death ligand (CD95L) and of the proapoptotic proteins Bim and Bak, but not of Bax. Both CD4+ and CD8+ T cells from SIVmac251-infected macaques underwent caspase-dependent death following CD95 ligation. The spontaneous death of CD4+ and CD8+ T cells was not prevented by a decoy CD95 receptor or by a broad-spectrum caspase inhibitor (zVAD-fmk), suggesting that this form of cell death is independent of CD95/CD95L interaction and caspase activation. IL-2 and IL-15 prevented the spontaneous death of CD4+ and CD8+ T cells, whereas IL-10 prevented only CD8 T-cell death and IL-7 had no effect on T-cell death. Our results indicate that caspase-dependent and caspase-independent pathways are involved in the death of T cells in pathogenic SIVmac251-infected primates.
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PMID:Caspase-dependent and -independent T-cell death pathways in pathogenic simian immunodeficiency virus infection: relationship to disease progression. 1457 76

Apoptotic death of CD4+ T lymphocytes is a major cause of the immunodeficiency caused by human immunodeficiency virus (HIV), but it is still unclear how this process precisely occurs. To characterize a potentially useful cellular model, we have analyzed the tendency of chronically HIV-infected CD4+ human cell lines of different origin to undergo apoptosis. We studied ACH-2 and U1 lines, derived from the CD4+ T-cell A301 and the promonocytic U937 cell lines, respectively, and induced apoptosis via several stimuli that trigger different pathways. Their capacity to regulate plasma membrane CD95 expression and to produce soluble CD95 was also analyzed. Using staurosporine, TNF-alpha plus cycloheximide, and gamma-radiations, we observed that ACH-2 were more sensitive to programmed cell death than A301, while U1 were less sensitive than U937. Both infected cell types had a lower sensitivity to CD95-induced apoptosis; the analysis of changes in mitochondrial membrane potential corroborated these observations. Plasma membrane CD95 was similarly regulated in all cell types, which, however, presented a different capacity to produce soluble CD95 molecules. Our in vitro results may offer a new perspective for developing further studies on the pathogenesis of HIV infection. A chronically infected cell line of lymphocytic origin is more susceptible to apoptosis than its parental cell type, while infected monocytic cells are less sensitive than their uninfected counterpart. Thus, it is possible to hypothesize that one of the reasons by which circulating monocytes survive and represent a viral reservoir is the capacity of HIV to decrease the sensitivity to apoptosis of this cell type. However, further studies on ex-vivo collected fresh cells, as well as on other cell lines, are urgently needed to confirm such hypothesis.
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PMID:Different sensitivity to apoptosis in cells of monocytic or lymphocytic origin chronically infected with human immunodeficiency virus type-1. 1468 50


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