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)

We have recently shown that, in unfractioned peripheral blood mononuclear cells (PBMCs), the cross-linking of CD4 molecules (CD4XL) is sufficient to induce T-cell apoptosis. However, the underlying mechanism for the CD4XL-mediated T-cell apoptosis is largely unknown. Several recent studies have shown that Fas antigen (Ag), a cell-surface molecule, mediates apoptosis-triggering signals. We show here that cross-linking of CD4 molecules, induced either by anti-CD4 monoclonal antibody (MoAb) Leu3a or by human immunodeficiency virus-1 (HIV-1) envelope protein gp160, upregulates Fas Ag expression as well as Fas mRNA in normal lymphocytes. Addition of the tyrosine protein kinase inhibitor genistein or of the immunosuppressive agent cyclosporin A abrogated these effects. The upregulation of Fas Ag closely correlated with apoptotic cell death, as determined by flow cytometry. In addition, CD4XL resulted in the induction of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the absence of interleukin-2 (IL-2) and IL-4 secretion in PBMCs. Both INF-gamma and TNF-alpha were found to contribute to Fas Ag upregulation and both anti-IFN-gamma and anti-TNF-alpha antibodies blocked CD4XL-induced Fas Ag upregulation and lymphocyte apoptosis. These findings strongly suggest that aberrant cytokine secretion induced by CD4XL and consequent upregulation of Fas Ag expression might play a critical role in triggering peripheral T-cell apoptosis and thereby contribute to HIV disease pathogenesis.
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PMID:Cross-linking of CD4 molecules upregulates Fas antigen expression in lymphocytes by inducing interferon-gamma and tumor necrosis factor-alpha secretion. 752 37

Mononuclear phagocytes (monocytes, macrophages, and dendritic cells) play major roles in human immunodeficiency virus (HIV) persistence and disease pathogenesis. Macrophage antigen presentation and effector cell functions are impaired by HIV-1 infection. Abnormalities of macrophage effector cell function in bone marrow, lung, and brain likely result as a direct consequence of cellular activation and HIV replication. To further elucidate the extent of macrophage dysfunction in HIV-1 disease, a critical activation-specific regulatory molecule, nitric oxide (NO.), which may contribute to diverse pathology, was studied. Little, if any, NO. is produced by uninfected human monocytes. In contrast, infection with HIV-1 increases NO. production to modest, but significant levels (2-5 microM). Monocyte activation (with lipopolysaccharide, tumor necrosis factor alpha, or through interactions with astroglial cells) further enhances NO. production in HIV-infected cells, whereas its levels are diminished by interleukin 4. These results suggest a possible role for NO. in HIV-associated pathology where virus-infected macrophages are found. In support of this hypothesis, RNA encoding the inducible NO synthase (iNOS) was detected in postmortem brain tissue from one pediatric AIDS patient with advanced HIV encephalitis. Corresponding iNOS mRNA was not detected in brain tissue from five AIDS patients who died with less significant brain disease. These results demonstrate that HIV-1 can influence the expression of NOS in both cultured human monocytes and brain tissue. This newly described feature of HIV-macrophage interactions suggests previously unappreciated mechanisms of tissue pathology that result from productive viral replication.
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PMID:Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease. 753 Jul 62

A few protein targets were found to display a specific high-affinity interaction with the immunosuppressant cyclosporin A (CsA): cytosolic cyclophilins (CyP)A, B, C, D, E containing from 122 to 174 amino acid residues in a polypeptide chain, and secreted forms of CyP; CyP-40, 40-kDa CsA-binding polypeptide complexed with steroid receptor (SR); CyP-related 150-kDa receptor of natural killer (NK) cells; interleukin 8 (IL-8); actin; a family of molecular chaperones hsp70 and P-glycoprotein (P-GP). All CyPs possess peptidyl-prolyl cis-trans isomerase activity (PPIase) and may serve as ATP-independent molecular chaperone proteins. The CsA-CyP complexes are specific inhibitors of Ca(2+)-and calmodulin-dependent protein phosphatase calcineurin (CaN). The inhibition of CaN blocks the activation of genes of IL-2, IL-2R, IL-4, etc. in T cells. In addition, immunosuppressive and/or antiinflammatory activity of CsA can be executed via CyP-40 and hsp 70 complexed with SR, and following the interaction with CyP-related receptor of NK and with IL-8. CsA binding to CyPC, P-GP and actin may throw light on the biochemical events leading to nephrotoxicity and graft vessel disease, two major side effects produced by CsA. The discovery of the interaction of human immunodeficiency virus type 1 (HIV-1) Gag protein with CyP and effective disruption of this interaction by CsA may be important for our understanding of the pathology caused by this immunosuppressive virus and will inspire therapeutic strategies to nip HIV in the bud. Bacterial immunophilins (ImPs) contribute to the virulence of pathogenic microorganisms. Elucidation of molecular mechanisms of microbial ImPs' action in the pathogenesis of bacterial infections may lead to new strategies for designing antibacterial drugs.
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PMID:Some new aspects of molecular mechanisms of cyclosporin A effect on immune response. 754 42

Long-Evans Cinnamon (LEC) rats bear a congenital deficiency in CD4+8- thymocytes and consequently a deficiency in helper T cell function. This mutation is caused by a single recessive gene referred to as thid (T helper immunodeficiency). It has been reported that rat immunoglobulin(Ig) G2a subclass is a counterpart of the mouse IgG1. Serum IgG2a levels in LEC rats were ten-fold lower than those of normal rats. To identify a cause of low IgG2a levels in LEC rats, we made backcross rats, (F344 x LEC)F1 x LEC, and examined linkage to the thid mutation. The serum IgG2a levels of rats showing thid/thid phenotype were much lower than those of rats showing +/thid phenotype. This indicates that the thid mutation correlates with low level of IgG2a subclass. Furthermore, LEC rat B cells were shown to secret IgG2a normally when these were stimulated with LPS and IL-4, suggesting that a cause of low level of IgG2a was due to defect of T cell function but not due to B cell disfunction in LEC rats. These results confirm the idea that T-helper (Th) function is necessary for the class switch to IgG2a subclass in rats.
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PMID:Low level of immunoglobulin G2a subclass correlates with a deficiency in T helper cell function in LEC mutant rats. 754 12

Patterns of cytokine expression were analyzed in polyclonal and antigenic responses in children with perinatal HIV infection. Responses of PBL to PMA and A23187 calcium ionophore studied in patients in different stages of HIV infection revealed reduced levels of IL-2 in HIV-infected children beginning before 6 mo of age, and age-dependent increases in expression of IL-4, IL-10, and IFN-gamma. The levels of IL-4, IL-10, and IFN-gamma expression did not differ significantly between HIV-infected and age-matched uninfected children of HIV-seropositive mothers, except for a small reduction in HIV-infected children in late stages of infection. Responses to PHA, HLA alloantigens, HIV envelope peptides T1 and P18, and tetanus toxoid were studied in PBMC derived from asymptomatic and mildly symptomatic HIV-infected children. IL-2, IFN-gamma, IL-4, and IL-5 expression was detected in PHA-stimulated PBMC from all analyzed patients. HIV-infected children who failed to respond to HLA alloantigens, tetanus toxoid, or the envelope peptides had lower numbers of CD4+ cells and expressed, on PHA stimulation, higher levels of IL-4 and IL-5 and lower levels of IL-2 and IFN-gamma than patients who responded to the antigenic stimulation. Results of these analyses suggest that cytokine expression in HIV-infected children depends on the character of the stimuli as well as the phenotype of PBMC, and indicate possible prevalence of Th2 Ag-specific responses during the progression of HIV-induced immunodeficiency.
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PMID:Cytokine patterns during progression to AIDS in children with perinatal HIV infection. 756 Nov 17

Cytokines have been shown to be powerful regulators of the immune response. In this study, we analyze the effect that the newly recognized cytokine interleukin (IL)-15 has on proliferation and cytokine induction using peripheral blood mononuclear cells (PBMCs) and purified CD4+ T cells from patients infected with human immunodeficiency virus (HIV) who are at various stages in their disease. We observed that IL-15 enhances the proliferative response in a dose-dependent manner from PBMCs of HIV-infected individuals when stimulated by polyclonal mitogen, tetanus toxoid, or HIV-specific antigen. The effects of exogenous IL-15 are substantially diminished by adding a neutralizing antibody to the beta chain of the IL-2 receptor. Moreover, the ability of IL-15 to increase proliferation is enhanced by the presence of endogenous IL-2 produced in the cultures. The effect that exogenous IL-15 had on IL-2, IL-4, and interferon (IFN)-gamma induction from PBMC's or CD4+ T cells in response to mitogen or tetanus toxoid was also examined. This was compared to the effect that exogenous IL-2 and IL-12 had under the same conditions. Addition of IL-2 or IL-15 to short-term in vitro cultures of either PBMCs or CD4+ T cells had little effect on IL-2, IL-4, or IFN-gamma production. By contrast, IL-12 caused substantial enhancement of both IL-2 and IFN-gamma production from these cultures. The role that endogenous cytokines have on IFN-gamma induction was also studied. Addition of a neutralizing antibody to the alpha chain of the IL-2 receptor or IL-12 to antigen stimulated cultures caused a striking decrease in IFN-gamma production. Neutralization of endogenous IL-15 also resulted in diminished IFN-gamma production from cultures stimulated with mitogen. IL-4 and IFN-gamma protein production by PBMCs and CD4+ T cells stimulated with mitogen was assessed to see if we could detect a specific bias of cytokine production. Small amounts of IL-4 were detected from CD4+ T cells but not PBMCs from most individuals tested. IFN-gamma and IL-2, however, were also produced from these same cultures. These results further elucidate the mechanism of cytokine regulation in HIV-infected individuals, and they provide evidence that IL-15 may be a useful immune modulator.
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PMID:Cytokine interactions in human immunodeficiency virus-infected individuals: roles of interleukin (IL)-2, IL-12, and IL-15. 756 80

Children or adults with the primary immunodeficiency disease, common variable immunodeficiency (CVI), have abnormally low levels of at least two of the three serum Ig isotypes. Although there appear to be intrinsic B cell defects, many have poor T cell proliferation and deficient secretion of IL-2, IL-4, IL-5 interferon-gamma, and B cell differentiation factor. Because the addition of various T cell factors can enhance Ig secretion in vitro in CVI, we have hypothesized that the B cells in this disease may be defective because they lack appropriate investigating the in vivo effects of recombinant IL-2 using a new biologic, polyethylene glycol-conjugated recombinant IL-2 (PEG-IL-2). In these studies, CVI patients were treated with weekly subcutaneous injections of PEG-IL-2. After 12 weeks, each patient had enhanced T cell proliferation, normal IL-2 production, boosted BCDF secretion, and B cells responsive to differentiation signals. During PEG-IL-2 treatment, four of five patients produced detectable serum antibody to keyhole limpet hemocyanin. These data suggest that CVI, which has the phenotype of B cell deficiency, may be caused by a lack of appropriate T cell signals for B cell maturation.
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PMID:Immunologic effects of low-dose polyethylene glycol-conjugated recombinant human interleukin-2 in common variable immunodeficiency. 758 74

Certain infections, like that with the human immunodeficiency virus-1, deplete vitamin A, and when vitamin A levels are low, immune dysfunctions establish susceptibility to further infection. Our research has focused on the immune dysfunctions that are a consequence of vitamin A deficiency and that predispose to further infection. We previously studied a helminth infection in mice, and showed that when vitamin A levels are low, the immune response develops a strong regulatory T cell imbalance with excessive T helper type-1 cell interferon (IFN)-gamma synthesis and insufficient T helper type-2 cell development and function. Here, we studied the T cell priming environment in vitamin A-deficient mice to learn how that priming environment might produce a regulatory T cell imbalance and consequently distort the ability of the immune system to respond to an infection. Our results show that during vitamin A deficiency, the priming environment included constitutive interleukin (IL)-12 and IFN-gamma transcripts, but it was devoid of constitutive IL-4 and IL-10 transcripts. Dietary all-trans-retinoic acid supplementation down-regulated the level of constitutive IL-12 and IFN-gamma transcripts. Furthermore, when T cells from naive vitamin A-deficient animals were stimulated through the T cell receptor, they produced excess IFN-gamma protein compared to T cells from control animals. In contrast, T cell stimulation failed to induce IL-4 or IL-10 secretion. The inducible IFN-gamma was largely from CD8+ T cells and all-trans-retinoic acid addition in vitro inhibited IFN-gamma production at the transcript level. Retinoic acid addition in vitro also decreased natural killer cell IFN-gamma synthesis at the transcript level. Taken together, the distorted constitutive and inducible cytokine gene expression patterns that occurred when vitamin A levels were low would be expected strongly to favor T helper type-1 development and limit T helper type-2 cell growth and differentiation, thereby limiting the animal's humoral immune response capability.
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PMID:Vitamin A deficiency results in a priming environment conducive for Th1 cell development. 761 95

To investigate the role of B cells in the development of experimental Staphylococcus aureus-induced arthritis, we used X-linked immunodeficiency (xid) mice that carry a Bruton's tyrosine kinase mutation affecting the function of B cells. NFR/N.xid and congenic NFR/N mice were inoculated i.v. with a toxic syndrome toxin-1 producing S. aureus LS-1 strain. B cell-deficient NFR/N.xid mice developed less frequent (p < 0.01) and less severe (p < 0.01) arthritis than NFR/N mice did. These clinical findings were corroborated by histopathologic evaluation, indicating that NFR/N.xid mice had significantly lower (p < 0.01) erosivity of the disease. Interestingly, infected NFR/N.xid mice showed decreased bacterial burden in blood, joints, and other organs compared with the control mice. Serologic studies displayed poor B cell responses to staphylococcal cell walls, toxic shock syndrome toxin-1, and ssDNA, accompanied by a low level of Igs in infected NFR/N.xid mice. More importantly, xid defect affected cytokine profile. The in vitro experiments showed that the lymphocytes from NFR/N.xid mice had low IL-6, but high IFN-gamma production upon stimulation with staphylococcal cell walls compared with NFR/N mice. Furthermore, the in situ hybridization technique revealed the relative increase of IFN-gamma, but marked decrease of IL-1 beta mRNA expression in spleens of infected NFR/N.xid mice. No significant difference in IL-4, IL-10, and TNF-alpha mRNA expression was found between both strains. Our findings demonstrate that B cells may, directly or indirectly, contribute to the pathogenesis of septic arthritis. The results indicate that increased IFN-gamma production along with low IL-6 and IL-1 beta synthesis found in xid mice may provide a more favorable outcome of S. aureus arthritis.
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PMID:Mice with the xid B cell defect are less susceptible to developing Staphylococcus aureus-induced arthritis. 763 57

The intravenous injection of mice with lymphocytic choriomeningitis virus (LCMV) induces a rapid and long-lasting immunodeficiency. T lymphocytes from 7-day-infected mice do not proliferate in vitro in response to ConA stimulation, do not produce IL-2 but display high affinity IL-2 receptors on their membrane. The non-coordinated regulation of these genes suggested that other cytokine-encoding genes may also be affected in their regulation. We have thus analyzed the expression of the genes encoding different cytokines transcribed during spleen cell activation by ConA. The genes encoding T lymphocyte-derived cytokines can be classified in three groups: the genes expressed similarly by normal and LCMV-cells (the p55 and the p75 chains of the IL-2 receptor [1]), the genes under expressed in LCMV-cells (IL-2, IL-3, IL-4 and IL-5) and the genes over expressed by these cells (GM-CSF and IFN-gamma). These results show that the viral infection has provoked a profound alteration of the overall regulation of the genetic program that follows T lymphocyte activation. Since T cell activation depends strictly on accessory cell-derived cytokines, we measured the level of transcription of IL-1, IL-6 and TNF-alpha; and our data show that the expression of these genes is equivalent in normal cells and in cells from LCMV-infected mice.
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PMID:Altered cytokine genes expression by conA-activated spleen cells from mice infected by lymphocytic choriomeningitis virus. 768 35


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