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 underlying immunological defect in humoral immunodeficiency with decreased production of immunoglobulin and normal level of circulating B cells (IgA deficiency, transient hypogammaglobulinemia of infancy, common variable immunodeficiency) remains unknown. There is evidence that B cells maturation and differentiation is regulated by cytokines and hence aberrant cytokine production may be involved in the pathogenesis of these diseases. Among interleukins, IL-1, IL-4, IL-6 and IL-10 may each play a role in regulation of B cell growth. Interferons (IFNs) have been described as having both positive and negative effects on B cell growth. The precise role of tumor necrosis factors (TNF alpha and beta) remains obscure. In the present study the in vitro cytokine production by peripheral blood mononuclear cells (PBMC) from children with different forms of immunodeficiency, in particular with IgA deficiency and transient hypogammaglobulinemia of infancy, was evaluated. In the first stage of the study the release of IL-1, IL-6, IFN and TNF by PBMC was analysed in following groups of patients: transient hypogammaglobulinemia (n = 30), IgA deficiency (n = 29), Bruton's disease (n = 7), decreased proliferative response to mitogenes (n = 10), CD4+ lymphocytopenia (n = 8), CD8+ lymphocytopenia (n = 10). The concurrent control group consisted 52 sex- and age-matched children, in whom no immunological immunological abnormalities were detected. The release of bioactive IL-1, IL-6, IFNs and TNF was measured in the culture supernatants from PBMC stimulated with mitogens for 48 hours. While the release of bioactive IL-1, IL-6, and IFNs was comparable in all studied groups, the secretion of TNF was significantly increased in children with transient hypogammaglobulinemia and IgA deficiency. The next issue was determination of the type of TNF (alpha or beta) involved. The production of other cytokines important for the regulation of B cell function (IL-4, IL-10) was also assessed. Production of TNF alpha, TNF beta and IL-10 was significantly elevated in transient hypogammaglobulinemia. The data from the ELISPOT assay suggested, that in these patients also the number of cells secreting TNF alpha after PHA stimulation was increased. These results indicate, that elevated TNF alpha production was probably due to both an enhanced release and an increased number of circulating secreting cells. As the methods employed in the quantification of cytokine levels in culture supernatants do not allow identification of the cytokine producing cell, the studies on intracellular expression of cytokines were undertaken. The fluorochrome-labelled monoclonal antibodies against the cell surface markers and a given cytokine were used simultaneously to identify the cellular source of cytokine production. The intracellular IL-4 expression in CD4+ lymphocytes from patients with transient hypogammaglobulinemia was comparable to that of control while the number of CD4+ lymphocytes expressing TNF alpha, TNF beta and IFN gamma was elevated. The number of CD14+ cells (monocytes) producing of TNF alpha was comparable to the control. These results suggest that an excessive Th-1 type response may contribute to pathology of this disease. In patients with isolated IgA deficiency the significantly increased release of TNF alpha but not: IL-1, IL-4, IL-6, IL-10 and TNF beta was observed. The proportion of CD4+ lymphocytes that expressed TNF alpha was significantly increased while the number CD14+ cells staining for TNF alpha was unchanged. No changes in the expression of TNF type I and II receptors on PBMC were observed, which suggested that regulatory effects of TNF alpha and beta are associated rather with an increased production of these cytokines than an abnormal receptor expression. Some patients with transient hypogammaglobulinemia were followed-up and the serum level of IgG and production of TNF alpha, TNF beta, and IL-10 by their PBMCs was determined 6 to 12 months after first
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PMID:[Cytokines in children with immunodeficiencies]. 1090 68

Kaposi sarcoma (KS) is an angioproliferative inflammatory condition that occurs commonly in patients infected with human immunodeficiency virus (HIV). Inflammatory cytokines and growth factors promote the development of KS. Because physiologically important cytokine polymorphisms modulate host inflammatory responses, we investigated the association between KS and common regulatory polymorphisms in 5 proinflammatory cytokine genes encoding interleukin (IL) IL-1alpha, IL-1beta, tumor necrosis factor (TNF) alpha, TNF-beta, and IL-6 and in the IL-1 receptor antagonist (IL1RN). We also examined the contribution of stromal-derived factor 1 and chemokine receptor 5 (Delta32) polymorphisms to KS development. The population consisted of 115 HIV-infected men with KS and 126 deceased HIV-infected men without KS. The only strong association was observed between an IL6 promoter polymorphism (G-174C) and susceptibility to KS in HIV-infected men (P =.0035). Homozygotes for IL6 allele G, associated with increased IL6 production, were overrepresented among patients with KS (P =.0046), whereas allele C homozygotes were underrepresented (P =.0062). Substantial in vitro evidence indicates that IL-6 contributes to the pathogenesis of KS. Our results show that IL6 promoter genotypes associated with altered gene expression are risk factors for development of KS. Identification of a genetic risk factor for development of KS has important clinical implications for prevention and therapy.
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PMID:An IL6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with human immunodeficiency virus. 1100 12

This study addresses the role of interleukin (IL)-8, a CXC-chemokine, the level of which is reported to be raised in the peripheral circulation of human immunodeficiency virus-1 (HIV-1)-infected individuals, during the induction of HIV-1 expression from latency and during cytokine-mediated HIV-1 up-regulation. IL-8 at the higher concentrations tested (> or = 100 ng/ml) was unable to induce HIV-1 expression in the chronically infected promonocytic U1 cell line, as measured by p24 antigen enzyme-linked immunosorbent assay (ELISA), whereas at lower concentrations of 1 and 10 ng/ml, constitutive HIV-1 expression was only marginally reduced. HIV-1 replication in acutely infected U937 cells was also significantly reduced by IL-8. The potent up-regulation of HIV-1 expression in U1 cells by tumour necrosis factor-alpha (TNF-alpha) remained unaffected by the addition of IL-8. HIV-1 induction by IL-1beta, IL-6 and TNF-beta, cytokines grouped here as intermediate HIV-1 inducers, was suppressed by IL-8 at concentrations of 1 and 10 ng/ml. However, IL-8 at 100 ng/ml did not significantly alter the effect of IL-1beta, synergized with IL-6 in enhancing, and marginally suppressed TNF-beta-induced HIV-1 expression. IL-8 suppressed granulocyte-macrophage colony-stimulating factor (GM-CSF) and enhanced interferon-gamma (IFN-gamma)-induced HIV-1 expression in a dose-dependent manner. Pretreatment of U1 cells with IL-8 did not alter the IL-8-mediated effects on cytokine-induced HIV-1 expression, suggesting that this chemokine exerts its effect at the time of HIV-1 induction or at a postinduction stage. Furthermore, IL-8 was itself induced by cytokines that up-regulate HIV-1 expression in U1 cells and the levels produced correlated directly with the levels of p24 antigen produced, suggesting common pathways for cytokine induction of both HIV-1 and IL-8. These results show that IL-8, typically a non-inducer, can differentially modulate HIV-1 expression in U1 cells and that this is dependent on the inducing cytokine and on the concentration of IL-8.
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PMID:Interleukin-8 fails to induce human immunodeficiency virus-1 expression in chronically infected promonocytic U1 cells but differentially modulates induction by proinflammatory cytokines. 1101 65

Spontaneous secretion of interleukin 8 (IL-8) was higher in latently infected U1 cells than in acutely infected or uninfected parental U937 cells. However, the induction of IL-8 by various cytokines (IL-1 alpha, TNF-alpha, IL-6, TNF-beta, GM-CSF, IFN-gamma) was significantly reduced in U1 cells. Cytokine modulation of IL-8 production in U937 cells acutely infected with a T cell-tropic strain (IIIB) or monocytotropic strain (ADA) of human immunodeficiency virus 1 (HIV-1) (HIV-1IIIB and HIV-1ADA) was variable and showed strain-specific differences. The obtained results showed that the in vitro induction of IL-8 is impaired in promonocytic cells latently infected with HIV-1 and is differently modulated under acute conditions of infection depending on the IL-8 inducing cytokine and on the infecting virus strain.
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PMID:Cytokine-induced interleukin-8 production is depressed in chronic as opposed to acute human immunodeficiency virus 1 infection of promonocytic cells. 1115 65

Infection of the central nervous system (CNS) by several viruses can lead to upregulation of proinflammatory cytokines and chemokines. In immunocompetent adults, these molecules induce prominent inflammatory infiltrates. However, with immunosuppressive retroviruses, such as human immunodeficiency virus (HIV), little CNS inflammation is observed yet proinflammatory cytokines and chemokines are still upregulated in some patients and may mediate pathogenesis. The present study examined expression of cytokines and chemokines in brain tissue of neonatal mice infected with virulent (Fr98) and avirulent (Fr54) polytropic murine retroviruses. While both viruses infect microglia and endothelia primarily in the white matter areas of the CNS, only Fr98 induces clinical CNS disease. The pathology consists of gliosis with minimal morphological changes and no inflammation, similar to HIV. In the present experiments, mice infected with Fr98 had increased cerebellar mRNA levels of proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha), TNF-beta, and interleukin-1 alpha and chemokines macrophage inflammatory protein-1 alpha (MIP-1 alpha), MIP-1 beta, monocyte chemoattractant protein 1 (MCP-1), gamma-interferon-inducible protein 10 (IP-10), and RANTES compared to mice infected with Fr54 or mock-infected controls. The increased expression of these genes occurred prior to the development of clinical symptoms, suggesting that these cytokines and chemokines might be involved in induction of neuropathogenesis. Two separate regions of the Fr98 envelope gene are associated with neurovirulence. CNS disease associated with the N-terminal portion of the Fr98 env gene was preceded by upregulation of cytokines and chemokines. In contrast, disease associated with the central region of the Fr98 env gene showed no upregulation of cytokines or chemokines and thus did not require increased expression of these genes for disease induction.
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PMID:Differences in cytokine and chemokine responses during neurological disease induced by polytropic murine retroviruses Map to separate regions of the viral envelope gene. 1122 10

OX40 is a member of the tumor necrosis factor (TNF) receptor superfamily and known to be an important costimulatory molecule expressed on activated T cells. To investigate the role of costimulation of OX40 in human immunodeficiency virus type 1 (HIV-1) infection by its natural ligand, gp34, the OX40-transfected ACH-2 cell line, ACH-2/OX40, chronically infected with HIV-1, was cocultured with paraformaldehyde (PFA)-fixed gp34-transfected mouse cell line, SV-T2/gp34. The results showed that HIV-1 production was strongly induced. This was followed by apparent apoptosis, and both processes were specifically inhibited by the gp34-specific neutralizing monoclonal antibody 5A8. Endogenous TNF alpha (TNF-alpha) and TNF-beta production were not involved in the enhanced HIV-1 production. Furthermore, enhanced HIV-1 transcription in gp34-stimulated ACH-2/OX40 cells was dependent on the kappa B site of the HIV-1 long terminal repeat, and the OX40-gp34 interaction activated NF-kappa B consisting of p50 and p65 subunits. When primary activated CD4(+) T cells acutely infected with HIV-1(NL4-3) (CXCR4-using T-cell-line-tropic) were cocultured with PFA-fixed gp34(+) human T-cell leukemia virus type 1-bearing MT-2 cells or SV-T2/gp34 cells, HIV-1 production was also markedly enhanced. The enhancement was again significantly inhibited by 5A8. The present study first shows that OX40-gp34 interaction stimulates HIV-1 expression and suggests that OX40 triggering by gp34 may play an important role in enhancing HIV-1 production in both acutely and latently infected CD4(+) T cells in vivo.
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PMID:OX40 stimulation by gp34/OX40 ligand enhances productive human immunodeficiency virus type 1 infection. 1143 53

Intracellular expression of several cytokines was assessed in lymphocytes and monocytes of children with transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). THI was characterized by an increased frequency of CD3+/CD4+ lymphocytes expressing tumour necrosis factor alpha (TNF-alpha), TNF-beta and interleukin 10 (IL-10), while in SIgAD elevated numbers of these cells containing TNF-alpha and interferon gamma (IFN-gamma) were observed. No changes in the number of CD4+ T cells expressing IL-4 in both diseases were noted. The proportion of CD33+ monocytes containing TNF-alpha both in THI and SIgAD was unchanged. The secretion of IL-12 by peripheral blood mononuclear cells (PBMCs) of patients with THI and SIgAD was significantly elevated and associated with an increased frequency of IL-12 expressing monocytes in THI but not in SIgAD. IL-18 secretion was slightly, but not significantly, elevated in both diseases. Intracellular Th1 and Th2 type cytokines within CD3+/CD4+ lymphocytes were also determined in the normal blood donors that showed high or low production of IgG and IgA in vitro. In low producers of IgG an increased proportion of CD3+/CD4+ cells expressing TNF-alpha and IFN-gamma was found, while in low IgA responders only elevated TNF-alpha positive CD3+/CD4+ cells were observed. These results suggest that THI and SIgAD may represent diseases with an excessive Th1 type response that is associated with an up-regulation of IL-12 secretion and, at least in THI, elevated numbers of monocytes expressing intracellular IL-12. Up-regulation of IL-12 may be the essential factor in the patomechanism(s) of these diseases as already described in common variable immunodeficiency (CVID).
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PMID:Intracellular cytokine production by Th1/Th2 lymphocytes and monocytes of children with symptomatic transient hypogammaglobulinaemia of infancy (THI) and selective IgA deficiency (SIgAD). 1196 68

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

The potential of a dendritic cell (DC)-based vaccine against human immunodeficiency virus type 1 (HIV-1) infection in humans was explored with SCID mice reconstituted with human peripheral blood mononuclear cells (PBMC). HIV-1-negative normal human PBMC were transplanted directly into the spleens of SCID mice (hu-PBL-SCID-spl mice) together with autologous mature DCs pulsed with either inactivated HIV-1 (strain R5 or X4) or ovalbumin (OVA), followed by a booster injection 5 days later with autologous DCs pulsed with the same respective antigens. Five days later, these mice were challenged intraperitoneally with R5 HIV-1(JR-CSF). Analysis of infection at 7 days postinfection showed that the DC-HIV-1-immunized hu-PBL-SCID-spl mice, irrespective of the HIV-1 isolate used for immunization, were protected against HIV-1 infection. In contrast, none of the DC-OVA-immunized mice were protected. Sera from the DC-HIV-1- but not the DC-OVA-immunized mice inhibited the in vitro infection of activated PBMC and macrophages with R5, but not X4, HIV-1. Upon restimulation with HIV-1 in vitro, the human CD4(+) T cells derived from the DC-HIV-1-immunized mice produced a similar R5 HIV-1 suppressor factor. Neutralizing antibodies against human RANTES, MIP-1alpha, MIP-1beta, alpha interferon (IFN-alpha), IFN-beta, IFN-gamma, interleukin-4 (IL-4), IL-10, IL-13, IL-16, MCP-1, MCP-3, tumor necrosis factor alpha (TNF-alpha), or TNF-beta failed to reverse the HIV-1-suppressive activity. These results show that inactivated HIV-1-pulsed autologous DCs can stimulate splenic resident human CD4(+) T cells in hu-PBL-SCID-spl mice to produce a yet-to-be-defined, novel soluble factor(s) with protective properties against R5 HIV-1 infection.
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PMID:Induction of protective immune responses against R5 human immunodeficiency virus type 1 (HIV-1) infection in hu-PBL-SCID mice by intrasplenic immunization with HIV-1-pulsed dendritic cells: possible involvement of a novel factor of human CD4(+) T-cell origin. 1288 91

The progressive loss of CD4 T lymphocyte is patognomonic of Human Immunodeficiency Virus (HIV) infection and results in immunodeficiency and the appearance of acquired immunodeficiency syndrome (AIDS)-defining pathologies. Although a percentage of CD4 T lymphocytes is destroyed directly by HIV infection, a much higher proportion of lymphocytes remains uninfected and therefore must be destroyed by mechanisms not directly involving viral infection. One such mechanism is apoptotic T cell death (ATCD). ATCD in HIV infection has been shown to be: 1) secondary to cross-linking of CD4 by viral proteins; 2) mediated by both APO-1/Fas and lymphotoxin (LT); and 3) differentially modulated by type 1 and type 2 cytokines. We will briefly analyze the experimental evidences suggesting that ATCD contributes significantly to the immunopathogenesis of HIV/AIDS via depletion of CD4+ T cells.
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PMID:Apoptotic cell death and cytokine dysregulation in human immunodeficiency virus infection: pivotal factors in disease progression. 1646 82


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