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)

In an attempt to understand the mechanisms of immunodeficiency induced by human T lymphotropic virus type I (HTLV-I), HSV-specific CD4+ human multifunctional T cell clones were infected with HTLV-I in vitro. Early after HTLV-I infection, when their growth was still IL-2-dependent, clones were found to have almost completely lost their cytotoxic activity. At that time, their HSV-Ag-induced proliferative response and helper function for anti-HSV antibody production by B cells were only partially impaired. After this initial phase, the HTLV-I-infected clone became IL-2-independent, and the helper function was also completely lost. IL-2-dependent HTLV-I-infected clones showed degrees of proliferative response and elevation of intracellular free Ca2+ concentration induced by anti-CD3 mAb equivalent to those of HTLV-I-uninfected clones. On the other hand, during the IL-2-independent stage, expression of CD3-TCR complex on the cell surface was markedly decreased, and no significant elevation of intracellular free Ca2+ concentration was detected in response to anti-CD3 mAb. These data indicated that the loss of cytotoxic activity of HSV-specific T cell clones observed early after HTLV-I infection was not the result of impaired antigen recognition via the CD3-TCR complex, but might be due to dysfunction in the effector phase. On the other hand, the dysfunction of helper activity found late after HTLV-I infection might have mainly occurred in the recognition phase due to the decreased expression of CD3-TCR complex. The present data appear to suggest certain aspects of the pathogenesis of the immunodeficiency occurring in HTLV-I infection.
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PMID:Functional alterations of herpes simplex virus-specific CD4+ multifunctional T cell clones following infection with human T lymphotropic virus type I. 247 28

Ataxia-telangiectasia (A-T) is a multisystem hereditary disease featuring neurodegeneration, immunodeficiency, extreme cancer proneness, chromosomal instability, and radiosensitivity. A-T is found in many ethnic groups, and is genetically heterogeneous: four complementation groups have been identified in A-T so far. Attempts to isolate the A-T gene are based in part on gene transfer experiments, using permanent A-T fibroblast lines, obtained by transformation with SV40. "Immortalization" of A-T primary diploid fibroblasts using SV40 is difficult, possibly because of the chromosomal instability of these cells. The number of currently available permanent A-T fibroblast lines is small, and not all of them have been assigned to specific complementation groups. Using the assay of X-ray induced inhibition of DNA synthesis, we have assigned the A-T strain AT22IJE to complementation group AB. Origin-defective SV40 was used to transfect these cells, and one transformant (AT22IJE-T), which survived crisis, was found to have the typical characteristics of permanent cell lines obtained in this way. "In-gel renaturation" analysis did not show any DNA amplification of high degree in AT22IJE-T. Cytogenetic analysis showed considerable chromosomal instability in the new cell line, and medium conditioned by these cells contained the clastogenic activity which is characteristic of the parental strain as well. Other parameters of the "cellular A-T phenotype" have also been retained in the immortalized cells: hypersensitivity to the lethal effects of X-rays and neocarzinostatin, as well as "radioresistant" DNA synthesis. However, the sensitivity of AT22IJE-T to both DNA-damaging agents is less pronounced than that of the parental cells. The capacity of the cells for uptake of foreign DNA was tested by introducing into them the plasmid pRSVneo, using three different transfection methods. Satisfactory frequency of G418-resistant transfectants (0.66%) was achieved using a protocol recently published by Chen and Okayama (Mol. Cell Biol., 7: 2745-2752, 1987), which was found to be superior to the traditional calcium phosphate transfection method and to the polybrene-based method.
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PMID:Cellular and molecular characteristics of an immortalized ataxia-telangiectasia (group AB) cell line. 253 4

CBA/N mice, which carry the xid immunodeficiency, lack a mature subpopulation of B cells. The residual B cells in these mice do not make antibodies to type-2 T-independent antigens, nor do they synthesize DNA in response to mitogenic forms of anti-Ig antibodies. It is therefore an attractive hypothesis that the surface immunoglobulin receptors (sIgR) on xid B cells signal abnormally following cross-linking. We show here that anti-Ig antibodies do cause inositol phospholipid hydrolysis and Ca2+ mobilization in xid B cells. However, the response of these cells are only 40%-50% of those of normal B cells. Studies with permeabilized cells demonstrated that the hyporesponsiveness is not due to ineffective coupling of sIgR to their associated G-protein. Rather it is apparently due to a quantitative and/or qualitative deficiency in the polyphosphoinositide-specific phosphodiesterase which mediates sIgR-induced inositol phospholipid hydrolysis. These observations may provide a biochemical explanation for the immunological abnormalities resulting from the xid mutation.
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PMID:Analysis of signaling via surface immunoglobulin receptors on B cells from CBA/N mice. 255 21

The pathogenesis of cellular immune deficiency following human immunodeficiency virus (HIV) infection could result from quantitative and/or qualitative dysfunction of the CD4+ lymphocyte population. To better characterize the T-cell response to soluble antigen with HIV infection, we have isolated peripheral blood lymphocytes and purified populations of CD4+ lymphocytes from healthy HIV antibody-positive subjects, patients with acquired immunodeficiency syndrome (AIDS)-related complex (ARC), and healthy HIV antibody-negative controls. T-lymphocyte function was determined by proliferative response to lectin (phytohemagglutinin), phorbol 12-myristate 13-acetate (PMA), calcium ionophore, purified recombinant HIV envelope gp120, tetanus toxoid antigen, and tetanus toxoid antigen in the presence of recombinant gp120 or purified recombinant soluble CD4. PBLs and CD4+ lymphocytes from asymptomatic HIV-infected subjects responded equally well to lectin, PMA, and/or calcium ionophore and to tetanus toxoid as cells from uninfected control subjects. The cells that proliferated in response to a soluble antigenic stimulus did not respond to gp120. Cells from subjects with ARC had a selective antigen recognition defect independent of the number of CD4+ lymphocytes. Recombinant gp120 inhibited CD4+ lymphocyte proliferation to antigenic stimulus by 30-40%. Recombinant soluble CD4, a proposed therapeutic for HIV, had no effect on T-cell response to antigen. A selective antigen recognition response was not compromised early in HIV infection but was compromised in subjects with ARC. Inhibition of proliferation to tetanus toxoid by gp120 suggests that HIV may affect major histocompatibility complex II restricted antigen recognition independent of CD4+ cell loss.
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PMID:CD4+ lymphocyte function with early human immunodeficiency virus infection. 256 77

The human immunodeficiency virus (HIV) binds to CD4-positive cells through interaction of its envelope glycoprotein (gp120) with the CD4 molecule. CD4 is a prominent immunoregulatory molecule, and chronic exposure to antibody against CD4 (anti-CD4) has been shown to cause immunodeficiency in mice. T cell-dependent in vitro immune responses can also be inhibited by anti-CD4. Experimental findings reported here indicate that CD4-bound gp120 attracts gp120-specific antibodies derived from the blood of HIV-seropositive individuals to form a trimolecular complex with itself and CD4. Thus targeted to CD4, the gp120-specific antibody functions as an antibody to CD4; it cross-links and modulates the CD4 molecules and suppresses the activation of T cells as measured by mobilization of intracellular calcium (Ca2i+). The synergism between gp120 and anti-gp120 in blocking T cell activation occurs at low concentrations of both components. Neither gp120 nor anti-gp120 inhibits T cell activation by itself in the concentrations tested.
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PMID:Synergism between HIV gp120 and gp120-specific antibody in blocking human T cell activation. 257 Nov 87

Following injury or activation in some immune cell lines, elevation of intracellular Ca2+ concentration (Cai2+) is an early and major event that precedes cell death. Agents shown to elevate Cai2+ and to result subsequently in the death of some cells include human immunodeficiency virus (HIV) (in T4+ cells), 25-hydroxy cholesterol, tumor necrosis factor (TNF), cyclosporine, dexamethasone, alpha-interferon, and Ca2+ ionophores. The effects of these agents, both on Cai2+ and on cytotoxicity, are additive. This type of Ca2+-related cytotoxicity may be associated with either accelerated synthesis of triglycerides (TNF), accelerated synthesis of cholesterol ester (25-hydroxy cholesterol), or cholesterol (HIV) and terminally with declining synthesis of structural phospholipid. Agents that can lower Cai2+ (e.g., phorbol esters, diglycerides, lipoproteins [LDL], oleic acid, or serum) under appropriate conditions ameliorate the Ca2+-induced cytotoxicity. Metabolism of other divalent metals, i.e., Zn2+ and Cd2+, also become altered with cell injury, e.g., glucocorticoids elevate Cai2+, but block uptake of Zn2+. These observations support the idea that chronic elevation of Cai2+ by many chemically unrelated agents leads to cell death by creating imbalance both in cell biosynthetic mechanisms--especially in those controlling lipid metabolism--as well as creating imbalances in metabolism of other trace metals, especially Zn2+.
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PMID:Intracellular Ca2+ and cytotoxicity. 257 16

Details of the molecular interactions between human immunodeficiency virus (HIV-1) and its host cell during the infection process are not entirely clear. Building on recent reports by Lehr and Zimmer (1986, DMW 111, 1001-1002) that the membrane-reactive, anti-epileptic drug diphenylhydantoin (dilantin or phenytoin) (PHT) inhibited binding of HIV to lymphocytes, we hypothesized that understanding the relevant effects of this drug on cells may shed light on aspects of HIV-1 infection. We found that PHT inhibited, in a dose-dependent manner, de novo infection of various T-cell lines as well as a monocytic cell line. Moderate inhibition of HIV-1 infection was observed with drug concentrations that are therapeutic in vivo for epilepsy (approximately 20 micrograms/ml), and no concentrations used induced deleterious effects on cell growth or viability. Surprisingly, treatment of chronically infected H9 cells reduced HIV p24 expression within 1-6 weeks according to dose. This apparent induction into latency was not inhibited by cotreatment of the chronically infected cells with 5-azacytidine, which indicated that PHT was not inducing latency by induction of methylation of the viral DNA. Flow cytometric analysis demonstrated that PHT did not significantly reduce cell-surface expression of CD4. The possibility remained that the drug inhibited HIV infection due to its known effects on calcium-dependent cellular processes. Subsequent measurements of intracellular calcium demonstrated that an increase of [Ca2+]i occurred at least 24 hr postinfection, prior to synthesis of detectable viral structural protein p24, and that this virus-induced increase in [Ca2+]i was not due to binding of HIV to the cell. This HIV-induced rise in [Ca2+]i was significantly inhibited by PHT. PHT demonstrated variable inhibitory effects on infection of normal PHA-stimulated PBLs cultured in vitro, but it was synergistic to low-dose AZT (0.01 microgram/ml) in inhibiting infection of cell lines. Because of the known inhibitory effects of PHT on calcium-dependent biochemical processes in the cell, inhibition of HIV-1 infection by PHT suggests that calcium may play a role in HIV infection and maintenance. The drug may also be a candidate therapy for individuals infected with HIV.
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PMID:Inhibition of human immunodeficiency virus (HIV-1) infection by diphenylhydantoin (dilantin) implicates role of cellular calcium in virus life cycle. 257 18

A study of peripheral and central mechanisms of secondary immunodeficiency in atherosclerotic patients demonstrated altered structural layout of lymphocyte membranes due to cholesterol accumulation in the cells. This was associated with increased membrane viscosity, suppressed mitotic activity and lower cap formation rate as well as changed intracellular calcium redistribution. Thymic ischemia due to occlusion or stenosis of thymus-supplying vessels was shown to promote age-related transformation of thymic tissue. Experimental simulation of thymic ischemia resulted in an abrupt drop of serum thymic factor in the blood of animals and the development of an immunodeficient condition.
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PMID:[Secondary atherosclerotic immunodeficiency]. 272 80

We studied a nine-year-old boy with severe, recurrent infections. The patient was exposed in utero to azathioprine and prednisone. He had autoimmune hemolytic anemia, bronchiectasis, and Hodgkin's disease. The patient's circulating lymphocytes were normal in number and phenotype, but stimulation of the T-cell receptor by antigens, mitogens, and monoclonal antibodies failed to induce interleukin-2-receptor expression, interleukin-2 synthesis, or lymphocyte proliferation. The early biochemical events necessary to initiate lymphocyte activation--accumulation of the second messenger diacylglycerol, activation of the enzyme protein kinase C, and elevation of the free intracellular calcium concentration--failed to occur in this patient's lymphocytes. The defect in the lymphocyte could be corrected in vitro by two agents that bypass the receptor-mediated signal mechanism (the diacylglycerol analogue phorbol and the calcium ionophore ionomycin). Further studies localized the defect in signal transduction to the interaction between cell-surface receptors and the guanine nucleotide-binding protein. We conclude that this patient's immunodeficiency was caused by a defective coupling of surface receptors to signal-transducing proteins in his T lymphocytes, resulting in failure of lymphocyte activation.
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PMID:An immunodeficiency characterized by defective signal transduction in T lymphocytes. 278 45

To investigate the mechanism by which immune activation augments replication of the human immunodeficiency virus type 1 (HIV-1) in infected T cells, four different classes of T cell mitogens were evaluated for their effects on the HIV-1 long terminal repeat (LTR). Phytohemagglutinin (PHA), a mitogenic lectin; phorbol 12-myristic 13-acetate, a tumor promoter; ionomycin, a calcium ionophore; and tat-1, the trans-activator protein from the human T cell leukemia/lymphoma virus type I (HTLV-I) each stimulated the HIV-1 LTR. Studies of deleted forms of the LTR supported a central role in these responses for the HIV-1 enhancer, which alone was sufficient for mitogen inducibility, but also suggested that other 5' positive and negative regulatory elements contribute to the overall magnitude of the response. Synergistic activation of the HIV-1 LTR (up to several thousandfold) was observed with combinations of these mitogens and the HIV-1--derived tat-III protein. Cyclosporin A, an immunosuppressive agent, inhibited PHA-mediated activation of the HIV-1 LTR but was without effect in the presence of other mitogens. Thus, HIV-1 gene expression and replication appear to be regulated, via the HIV-1 LTR, by the same mitogenic signals that induce T cell activation.
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PMID:Activation of the HIV-1 LTR by T cell mitogens and the trans-activator protein of HTLV-I. 282 51


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