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)

Binding of peptide hormones to surface membrane receptors leads to the transcription of specific genes within relevant target cells. How these signals are transduced to alter gene expression is largely unknown, but this mechanism probably involves a sequence of enzymatic steps that activate factors in the nucleus that modulate transcription. We now demonstrate that two different peptide hormones, or cytokines, stimulate the human immunodeficiency virus enhancer, and this effect is mediated by nuclear factor (NF) kappa B (nuclear factor that binds the kappa immunoglobulin light chain gene enhancer). These cytokines, tumor necrosis factor alpha and interleukin 1, act on multiple cell types and represent the only naturally occurring activators of this transcription factor among eight cytokines examined. Although NF-kappa B binding can be stimulated by phorbol 12-myristate 13-acetate, tumor necrosis factor alpha acts through an independent mechanism, inducing NF-kappa B binding in HT-2 cells, which did not show increased binding in response to phorbol 12-myristate 13-acetate, and causing superinduction in Jurkat T-lymphoma cells. Tumor necrosis factor alpha is also a more selective activator of T cells than phorbol 12-myristate 13-acetate, having no effect on lymphokine production in EL-4 cells at the same time it induces NF-kappa B. These findings suggest that human immunodeficiency virus gene expression can be induced in T cells without activating lymphokine secretion and that the role of these cytokines in the activation of latent human immunodeficiency virus infection deserves further clinical evaluation. Finally, this link between binding at the surface membrane and stimulation of a specific transcription factor should help define intermediates for these cytokine activation pathways.
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PMID:Tumor necrosis factor alpha and interleukin 1 stimulate the human immunodeficiency virus enhancer by activation of the nuclear factor kappa B. 249 64

Mice with chronic Trypanosoma cruzi infections are unable to mount primary responses to T-dependent Ag, such as SRBC. Responses to SRBC were restored in vitro and in vivo with rIL-1. The cellular basis of the immunodeficiency and the mechanism of IL-1 action were investigated. B cells from infected mice were capable of normal levels of PFC production when provided with the appropriate signals, IL-2 plus IL-1. T cells from infected mice were unable to provide Th function to normal B cells. However, Th activity was provided by these cells if IL-1 was added to the cultures. Furthermore, T-depleted spleen cells from infected mice did not make antibody in the presence of normal T cells unless IL-1 was added to the cultures. Neutralizing antibody against IL-2 greatly reduced the augmentation by IL-1 of the antibody response of cells from infected mice. Together these results indicate that splenic B cells from infected mice are capable of antibody production, but that Th function is lacking in the spleens of infected mice. These results suggest that the inability of mice with T. cruzi infection to mount primary antibody responses to T-dependent Ag may be due to a macrophage defect lending to impairment of Th function. These results document the potential of IL-1 in restoring immune competence in an infectious disease model.
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PMID:Immune deficiency in chronic Trypanosoma cruzi infection. Recombinant IL-1 restores Th function for antibody production. 252 32

This study reports on the direct effect of the envelope glycoprotein (gp120) of the human immunodeficiency virus type 1 (HIV-1) on human monocyte function. Addition of preparations of purified gp120 from the HIV-1 to human monocytes resulted in the production of interleukin 1 (IL-1) and arachidonic acid metabolites from the cyclooxygenase and lipoxygenase pathways. Quantification of prostaglandin E2 (PGE2) and IL-1 revealed an increase in both mediators with 50 ng of gp120 per ml and an increase of 12- and 30- to 40-fold with 200-400 ng of gp120 per ml, respectively. Unlike native gp120, the recombinant nonglycosylated gp120 fragments PB1-RF and PB1-IIIB, as well as one of the core structural proteins of HIV-1, p24, did not increase arachidonic acid metabolism or IL-1 activity. Cytofluorometric analysis revealed that gp120 blocked the binding of OKT4A to the CD4 on monocytes, whereas OKT4 binding was unaffected. Involvement of the CD4 in signal transduction was further demonstrated by the ability of OKT4 and OKT4A monoclonal antibodies to increase monocyte PGE2, IL-1 activity, and nanogram amounts of IL-1 beta.
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PMID:Human immunodeficiency virus glycoprotein (gp120) induction of monocyte arachidonic acid metabolites and interleukin 1. 253 71

Figure 1 depicts some of the potential interactions of the interleukins. Among the substances discussed here, only IL-2 has been used to any large degree in a clinical series. Other cytokines not discussed including some of the colony stimulating factors, tumor necrosis factor and the interferons have also been used in clinical trials. Undoubtedly as we learn more about interleukins IL-1 through IL-7, clinical applications will become apparent. For the allergist/immunologist there are two areas of greatest potential interest. The first of these is in treating immunodeficiency states. Preliminary studies of the use of IL-2 in patients with T cell dysfunction suggest that this substance may be useful in treating selective T cell disorders. IL-4, 5, and 6 all have some influence on B cell function. It is likely that in the near future one or more of these agents will be used clinically. It is also clear that the interleukins have the potential to influence basic mechanisms known to be important in allergic disease. IL-3 is the major factor influencing mast cell growth. IL-4 among other things, promotes B cells to switch to IgE synthesis as well as to induce Fc epsilon RII receptors on B cells. IL-5 is important in the differentiation and growth of eosinophils. Finally, IL-6 is the terminal differentiation factor that causes B cells to become plasma cells. The next few years should result in an even better understanding of the role of each of these interleukins. It is likely that such information will greatly expand the horizons for understanding the pathogenesis of many immunologically mediated diseases and will provide the basis for new modalities of treatment.
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PMID:Interleukins in immunologic and allergic diseases. 267 43

The etiology of immunodeficiency following trauma was investigated. Plasma collected from Fischer rats 1-8 hr following a 40% surface area thermal injury (TI) displays immunosuppressive activity (ISA). Peak ISA (4 hr) exceeded 90% inhibition of Con A3-induced proliferation of normal spleen cells. Splenic macrophage IL-1 secretion and NK activity are also inhibited by 4-hr TI plasma. Most importantly, these same cellular immune functions decline in rats by 4 hr following TI. After a further decline by 16 hr (IL-1 = 19.8% and NK activity = 40% of normal), these cellular immune functions rebound toward normal values by 2 days following TI. Thus, ISA in plasma is both temporally and functionally linked to the cellular immune defects observed. Sham-treatment rats display a similar, although less marked, pattern of plasma-linked transient cellular immune defects indicating a role for stress in these responses. ISA is abolished by mild heat (56 degrees C for 30 min) and wholly contained in the greater than 10-kD fraction of plasma. Together, these results provide evidence that previously unrecognized molecules in plasma induce a "window" of immunodeficiency early following trauma.
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PMID:Evidence of a plasma-mediated "window" of immunodeficiency in rats following trauma. 278 30

Uncertainty has existed as to whether a T-cell deficiency exists in human immunodeficiency virus (HIV) infection different from that inherent in the reduced T-cell numbers characteristic of the disease. Heretofore, methods for measuring T-cell responses in patients have been carried out with systems requiring monocytes as accessory cells. In the presence of high concentrations of interleukin-2, however, highly purified T cells respond in a monocyte-independent fashion to antibody reactive with the CD3 component of the antigen receptor complex Ti/CD3. Highly purified T cells of HIV-infected patients responded subnormally in this anti-CD3/IL-2 system, even in the case of patients who were asymptomatic or had only lymphadenopathy. The defective T-cell responses occurred over a wide range of concentrations of the anti-CD3. Neither poor IL-2 receptor function as reflected by responses to limiting dilutions of IL-2 nor IL-1 receptor function as defined by incremental proliferation when IL-1 is added accounted for this defect, which also correlated poorly with T4 and T8 numbers. These results suggested that the T-cell abnormality was closely related to Ti/CD3 function, was not specifically or restrictively associated with T4 cells, and was not due to defective IL-2- or IL-1-receptor functions. The amount of HIV RNA in 10(5) T lymphocytes from the patients amounted to less than that found in one cell of a standard HIV infected laboratory cell line (CEM), using slot-blot hybridization. Thus the T-cell deficiency we have observed was not likely to be due directly to cell killing by HIV resident in the T4 cells. Other factors may be important in inducing the immunodeficiency, some of which are discussed.
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PMID:Impairment in T-lymphocyte responses during early infection with the human immunodeficiency virus. 278 31

Retroviral infections are accompanied by immunosuppression in a variety of species. For feline leukemia virus, the immunosuppression has been ascribed to the transmembrane envelope protein, p15E, which suppresses the proliferative responses of cat, mouse, and human lymphocytes. A similar suppressive effect has been shown for a lysate of human immunodeficiency virus (HIV), strain HTLV-IIIB. Here we determined that detergent-disrupted HTLV-IIIB lystate exerted a strong suppressive effect on PHA-stimulated lymphocytes. Preparations of whole virions, a lysate of a local HIV isolate grown on MP-6 cells, and a commercially obtained UV and psoralene-inactivated lysate were examined and demonstrated to have a similar suppressive effect. The HIV lysate was not directly cytotoxic to lymphocytes and did not contain tumor necrosis factor or lymphotoxin. The HIV lysate specifically suppressed the proliferation of a range of hemopoietic cell lines from man and mouse including three EBV transformed CD4- and IL-2 receptor-negative B-cell lines. The lysate also suppressed the formation of human bone marrow colonies, whereas the lysate had only a slight or no effect on fibroblasts. The suppression of lymphocyte proliferation was not abrogated by addition of IL-2 or IL-1 and the HIV lysate inhibited the expression of IL-2 receptors on suboptimal PHA-stimulated mononuclear cells. The suppressive factor(s) has not been characterized in molecular terms, but suppressive activity was recovered in fractions with a molecular weight of about 67,000 and in both the glycoprotein fraction and in the glycoprotein-depleted fraction of the HIV lysate. Sera from one-third of a small series (N = 13) of individuals with antibodies to HIV seem to be able to neutralize the suppressive properties of HIV lysate in cultures.
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PMID:Investigation of immunosuppressive properties of inactivated human immunodeficiency virus and possible neutralization of this effect by some patient sera. 278 62

The IL-2R alpha enhancer contains an 11 bp sequence that resembles kappa B, a regulatory element associated with several genes, including Ig kappa-L chain and human immunodeficiency virus. Although nuclear factor of the kappa-enhancer in B cells (NF-kappa B) binding is activated by PMA, TNF-alpha, and IL-1, activation of the IL-2R alpha enhancer does not consistently correlate with NF-kappa B induction. In this report, we show that TNF-alpha activates NF-kappa B and the human immunodeficiency virus enhancer in the Jurkat T leukemia but does not stimulate the IL-2R alpha enhancer. In contrast, this cytokine, and IL-1, increased IL-2R alpha gene expression in YT-1 cells. Comparing YT-1 and Jurkat T leukemias, we find that the IL-2R kappa B site is required for TNF-alpha and IL-1 stimulation in YT-1 cells, but that plasmids containing this site linked to a heterologous promoter do not respond to these cytokines. These data suggest that upstream regulatory elements in addition to IL-2R kappa B are needed to mediate this cytokine effect. TNF-alpha also synergized with PMA and other cytokines in the stimulation of the IL-2R alpha enhancer in YT-1. Because these effects are not observed in Jurkat cells, the function of the IL-2R kappa B site is cell-specific and likely mediated by different associated transcription factors present in each cell type.
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PMID:Regulation of the IL-2 receptor alpha-gene. Interaction of a kappa B binding protein with cell-specific transcription factors. 280 16

The mechanism of immunodeficiency in adult T-cell leukemia (ATL) patients was studied in vitro. Peripheral blood lymphocytes from ATL patients and ATL cell lines such as Hut 102, MT 1, and MT 2 were not activated to proliferate by the stimulation with concanavalin A and suppressed normal lymphocyte proliferative responses induced with concanavalin A when cultured together. The sera from ATL patients and the culture supernatants from ATL cells and ATL cell lines also suppressed normal lymphocyte proliferative responses induced with concanavalin A. By Sephacryl S-200 column chromatography, the suppressive factors were fractionated as a single peak with the molecular weights of 50,000 to 70,000. The suppressive factors were unstable to acid treatment but stable to the treatment with base, heat, freezing-thawing, and trypsin. The factors suppressed the production of interleukin 2 by T-cells and the responsiveness of T-cells to interleukin 2, but not the expression of interleukin 2 receptors on T-cells and the production of interleukin 1 by monocytes. These results suggest that the immunosuppressive factors produced by ATL cells have some roles in the induction of immunodeficient states in ATL patients.
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PMID:Immunosuppressive factors from adult T-cell leukemia cells. 287 86

Splenocytes from the motheaten mouse, after stimulation with alloantigen, lack the ability to utilize exogenous interleukin 1 (IL 1) or interleukin 2 (IL 2), express receptors for IL 2, or produce (IL 2). However, in contrast to other models of autoimmunity and immunodeficiency, after mitogen stimulation, motheaten splenocytes produced as much IL 1 or IL 2 as their normal littermates. In addition, these splenocytes expressed functional IL 2 receptors in the same quantity as normal littermate or wild-type splenocytes. Furthermore, motheaten thymocytes and splenocytes, like their normal littermates, respond synergistically to IL 1 on co-stimulation with mitogen, suggesting expression of an IL 1 receptor. Thus, motheaten mouse splenocytes are unable to utilize an antigen-delivered signal and convert it into cytokine production or IL 2 receptor expression. If the antigen signal is bypassed with mitogen, cytokine production and receptor expression appear normal.
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PMID:Cytokine production and utilization by the motheaten mouse. 293 56


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