Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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 early HIV disease, immunodeficiency is characterized by the inability of CD4+ T cells to produce a critical cytokine, IL-2, and to express the receptor for IL-2 (IL-2R) in response to antigenic or mitogenic stimulation. The shared common gamma-chain (gamma(c)) of IL-2R and its associated Janus kinase, JAK3, are indispensable for normal T cell function. Here, we show that the inhibition of IL-2R expression and proliferation induced by ligation of CD4 by HIV envelope glycoprotein, gp120, is correlated with inhibition of expression and activation of JAK3. Stimulation through the gamma(c)-related cytokine receptors restores JAK3 expression and activation and rescues CD4-mediated T cell unresponsiveness. Collectively, these data argue that inhibition of JAK3 expression and activation may, in part, explain the T cell dysfunction seen in early HIV disease. In addition, rescue from gp120-mediated T cell unresponsiveness by activation of JAK3 suggests a novel therapeutic approach for enhancing immune function in HIV disease.
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PMID:Cutting edge: JAK3 activation and rescue of T cells from HIV gp120-induced unresponsiveness. 963 77

Replication of the human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), is under the control of both viral and host factors. Among the latter, the regulatory network of cytokines has been shown to affect virtually every step of the virus life cycle, from cell entry to budding of new progeny virions. Proinflammatory cytokines, such as tumour necrosis factor alpha, can either trigger or potentiate HIV expression via activation of the cellular transcription factor NF-kappaB. Other molecules, including interleukin 6 (IL-6) and the interferons, can up-regulate HIV expression by acting predominantly at post-transcriptional and/or post-translational levels. Anti-inflammatory cytokines, including transforming growth factor beta, IL-4 and IL-10, counteract these effects but can also potentiate viral replication under different experimental conditions. Chemotactic cytokines (chemokines) have recently entered the arena of host factors controlling viral spreading as potent inhibitors competing with the virus for cell-surface 7-transmembrane domain receptors also acting, together with CD4, as entry co-receptors for HIV. The cytokine network is constitutively activated in most HIV-infected individuals, as demonstrated by recent analysis of intracellular signalling molecules such as the Janus kinase/signal transducer and activator of transcription pathway. Finally, cytokines have already shown their potential use as pharmacological agents able to restore at least some of the compromised immune functions in infected individuals, as exemplified by the potent enhancing effect of IL-2 on the number of circulating CD4+ T lymphocytes.
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PMID:Laureate ESCI award for excellence in clinical science 1999. Cytokines and the human immunodeficiency virus: from bench to bedside. European Society for Clinical Investigation. 1045 58

Infection by the human immunodeficiency virus (HIV) either upregulates or downregulates the expression of several cytokines and interferons (IFNs) that use the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway for signal transduction. However, very little is known on the state of activation of the JAK/STAT pathway after HIV infection either in vivo or in vitro. In this regard, we report here that a constitutive activation of a C-terminal truncated STAT5 (STAT5triangle up) and of STAT1alpha occurs in the majority ( approximately 75%) of individuals with progressive HIV disease. We have further demonstrated that, among peripheral blood mononuclear cells (PBMCs), STAT5triangle up is activated preferentially in CD4(+) T cells. In contrast to a published report, expression of STATs from PBMCs of infected individuals was comparable with that of seronegative donors. In addition, in vitro infection of mitogen-activated PBMCs with a panel of laboratory-adapted and primary HIV strains characterized by differential usage of chemokine coreceptors did not affect STAT protein levels. However, enhanced activation of STAT was observed after in vitro infection of resting PBMCs and nonadherent PBMCs by different viral strains. Thus, constitutive STAT activation in CD4(+) T lymphocytes represents a novel finding of interest also as a potential new marker of immunological reconstitution of HIV-infected individuals.
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PMID:Constitutive activation of STATs upon in vivo human immunodeficiency virus infection. 1059 65

Intermittent administration of recombinant interleukin-2 (rIL-2) to individuals infected with human immunodeficiency virus (HIV) has been shown to raise and maintain the absolute number of circulating CD4(+) T cells to normal or near normal levels. One of the signaling pathways triggered by IL-2 is the Janus kinase-signal transducer and activator of transcription (JAK-STAT). In particular, IL-2 activates the tyrosine kinases JAK1 and JAK3 and the transcription factors STAT3 and STAT5. We have previously observed that most HIV(+) individuals, unlike healthy seronegative controls, show a constitutive activation of STAT1 and a C-terminal truncated isoform of STAT5 (STAT5 Delta). In the present study, we have analyzed the protein level and activation state of STAT5 isoforms expressed in peripheral blood mononuclear cells of two HIV-infected individuals who showed a good or a poor response to intermittent IL-2 administration, respectively, and of a single individual before and after initiation of Zidovudine monotherapy. We provide evidence that both therapeutic interventions enhanced the expression and activation of the C-terminal truncated isoform of STAT5 (STAT5 Delta) in vivo.
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PMID:Expression and activation of a C-terminal truncated isoform of STAT5 (STAT5 Delta) following interleukin 2 administration or AZT monotherapy in HIV-infected individuals. 1128 43

Human immunodeficiency virus (HIV) infection leads to a profound T cell dysfunction well before the clinical onset of acquired immunodeficiency syndrome (AIDS). We have been accumulating evidence that one of the mechanisms responsible for this T cell deficiency may be the dysregulation of signal transduction via the interleukin (IL)-2/IL-2 receptor (R) complex. In CD4 T cells, we have observed previously that viral envelope (env) glycoproteins induce IL-2 unresponsiveness and the down-regulation of the three chains making up the IL-2R (alpha, beta, gamma) in vitro. We have now established further that this disruption of the IL-2/IL-2R system manifests itself in defective signal propagation via the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) pathway in response to IL-2. The treatment of CD4 T cells with HIV env or surface ligation of CD4 with anti-CD4 monoclonal antibodies inhibited the IL-2-induced activation of Jak-1 and Jak-3, as well as their targets, STAT5a and STAT5b. This Jak/STAT deficiency may contribute to the crippling of CD4 T cell responses to a cytokine central to the immune response by HIV.
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PMID:Human immunodeficiency virus-1 envelope glycoproteins and anti-CD4 antibodies inhibit interleukin-2-induced Jak/STAT signalling in human CD4 T lymphocytes. 1260 94

Haemopoietic stem-cell transplantation is a life-saving treatment for severe combined immune deficiency. However, there has been little long-term follow-up of this treatment. There is evidence for the persistance of partial immunodeficiency associated with significant infections, including severe human papillomavirus (HPV) disease. We did a retrospective analysis of severe HPV disease in a group of 41 patients with severe combined immune deficiency from one centre who were alive 10 years or longer after haemopoietic stem-cell transplantation. Nine of the 41 patients had extensive chronic HPV disease limited to the skin, with a median onset at 8 years after transplantation. Four had lesions typical of epidermodysplasia verruciformis, a rare genodermatosis. Transplant characteristics, immune status, and chimerism of these nine patients did not differ significantly from those of the other patients. The nine patients with HPV disease had severe combined immune deficiency associated with either common gammac receptor cytokine subunit or Janus kinase-3 (JAK-3) deficiency. By contrast, patients with other forms of severe combined immune deficiency did not have any signs of HPV disease. That genetic causes are the only predisposing factor to be identified for severe combined immune deficiency, suggests that natural-killer cells or gammac/JAK-3-dependent signalling in keratinocytes could have a role in anti-HPV immunity.
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PMID:Severe cutaneous papillomavirus disease after haemopoietic stem-cell transplantation in patients with severe combined immune deficiency caused by common gammac cytokine receptor subunit or JAK-3 deficiency. 1520 58

The production of blood cells is regulated by a number of protein growth factors and cytokines that influence cell survival, proliferation and differentiation. Many of these molecules bind to cell surface receptors, which belong to a family of closely related cytokine receptors that lack intrinsic catalytic activity but are intimately associated with tyrosine kinases of the Janus kinase (JAK) family. Ligand binding induces the activation of JAKs, which sit at the apex of a signalling cascade in which a key role is played by members of the signal transducers and activators of transcription (STAT) group. Congenital deficiencies in JAK-STAT signalling are associated with immunodeficiency states and acquired activating mutations and translocations are involved in the pathophysiology of haematological malignancy. The latter findings have raised hopes that drugs that target aberrant JAK-STAT signalling may be useful for the treatment of human disease.
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PMID:The role of Janus kinases in haemopoiesis and haematological malignancy. 1682 89

The C77G polymorphism in exon A of the human CD45 gene occurs with low frequency in healthy individuals. An enhanced frequency of C77G individuals has been reported in cohorts of patients suffering from multiple sclerosis, systemic sclerosis, autoimmune hepatitis, hepatitis C and human immunodeficiency virus (HIV)-1. C77G individuals overexpress CD45RA isoforms on activated/memory T cells. We have shown previously that aberrant expression of CD45RA isoforms enhances the intensity of T cell receptor (TCR) signalling. Here we report that the C77G polymorphism also influences the responsiveness of T cells to cytokines and alters their adhesion properties. When stimulated by interleukin (IL)-2, C77G T cells proliferated more strongly than wild-type controls and showed accelerated phosphorylation of Janus kinase (Jak1). Furthermore, C77G T cells exhibited a higher tendency to form homotypic aggregates in culture which could be enhanced significantly by antibody-mediated triggering of the variant CD45RA molecules. These data indicate that the changes in CD45 isoform combination resulting from C77G may not only affect TCR signalling but also cytokine-driven T cell responses and cellular adhesion. Altered immune responsiveness may enhance susceptibility of C77G carriers for certain diseases.
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PMID:Altered CD45 isoform expression in C77G carriers influences cytokine responsiveness and adhesion properties of T cells. 1790 20

Despite extensive evidence of cell signaling alterations induced by human immunodeficiency virus type 1 (HIV-1) in vitro, the relevance of these changes to the clinical and/or immunologic status of HIV-1-infected individuals is often unclear. As such, mapping the details of cell type-specific degradation of immune function as a consequence of changes to signaling network responses has not been readily accessible. We used a flow cytometric-based assay of signaling to determine Janus kinase/signal transducers and activators of transcription (Jak/STAT) signaling changes at the single-cell level within distinct cell subsets from the primary immune cells of HIV-1-infected donors. We identified a specific defect in granulocyte-macrophage colony-stimulating factor (GM-CSF)-driven Stat5 phosphorylation in the monocytes of HIV-1+ donors. This inhibition was statistically significant in a cohort of treated and untreated individuals. Ex vivo Stat5 phosphorylation levels varied among HIV-1+ donors but did not correlate with CD4(+) T-cell counts or HIV-1 plasma viral load. Low Stat5 activation occurred in HIV-1-infected donors despite normal GM-CSF receptor levels. Investigation of mitogen-activated protein kinase (MAPK) pathways, also stimulated by GM-CSF, led to the observation that lipopolysaccharide-stimulated extracellular signal-regulated kinase phosphorylation is enhanced in monocytes. Thus, we have identified a specific, imbalanced monocyte signaling profile, with inhibition of STAT and enhancement of MAPK signaling, associated with HIV-1 infection. This understanding of altered monocyte signaling responses that contribute to defective antigen presentation during HIV-1 infection could lead to immunotherapeutic approaches that compensate for the deficiency.
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PMID:Single-cell, phosphoepitope-specific analysis demonstrates cell type- and pathway-specific dysregulation of Jak/STAT and MAPK signaling associated with in vivo human immunodeficiency virus type 1 infection. 1821 16

Naturally occurring CD4+CD25(high)FOXP3+ regulatory T cells (Tregs) constitute a powerful mechanism of immune regulation and therefore, have important therapeutic potential for disorders such as autoimmune diseases, allograft rejection and graft-versus-host disease. Disruption of the IL-2R signalling pathway by genetic defects of the interleukin (IL)-2 gene or components of the IL-2 receptor (R) complex results in severe T cell-mediated autoimmunity rather than immunodeficiency, indicating a crucial role for IL-2R signalling for Treg development and function. Signalling downstream of the IL-2R can act through the phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR pathway, the Janus kinase (JAK)/Signal transducers and Activators of Transcription (STAT) pathway and the mitogen-activated protein kinase (MAPK) pathway. In this report we focus on the relevance of these pathways as well as the impact of immunosuppressive drugs that may affect or enhance Treg function by targeting IL-2R signalling.
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PMID:Interleukin-2 receptor downstream events in regulatory T cells: implications for the choice of immunosuppressive drug therapy. 1823 49


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