Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By reverse transcriptase polymerase chain reaction on messenger RNA from human polymorphonuclear cells, we have isolated a sequence identical to the cDNA coding for intracellular interleukin 1 receptor antagonist (icIL-1ra), but containing an additional in-frame 63-bp sequence located three codons downstream of the translation start of icIL-1ra. This additional sequence is inserted between the first and second exon of the intracellular form, the latter of which is colinear with part of the first exon of the secreted form of IL-1ra. The additional sequence is coded by an extra exon located 2 kb downstream the first icIL-1ra-specific exon. The complementary DNA sequence of the alternatively spliced form of icIL-1ra shows that the predicted protein differs from classical icIL-1ra in the NH2 terminus by insertion of a leaderless sequence of 21 amino acids rich in glycine and glutamic acid residues. Transcripts coding for this new form of icIL-1ra were detected in activated fibroblasts, keratinocytes, and at low levels in myelomonocytic cells. The recombinant protein expressed in COS cells had an apparent molecular mass in sodium dodecyl sulfate polyacrylamide gel electrophoresis of 25 kD compared to 22 kD of classical icIL-1ra, and was mostly intracellular. The ability of this new form of icIL-1ra to inhibit IL-1 activity, in terms of induction of E-selectin and human immunodeficiency virus replication, was comparable to that of classical icIL-1ra. We propose to refer to this new form of icIL-1ra as icIL-1ra type II.
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PMID:Cloning and characterization of a new isoform of the interleukin 1 receptor antagonist. 762 20

Human patients with an immunodeficiency disease caused by mutations of the protein tyrosine kinase ZAP-70 show that this enzyme plays multiple important roles in T-cell differentiation and function.
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PMID:Immunodeficiency diseases. Multiple roles for ZAP-70. 795 63

A homozygous mutation in the kinase domain of ZAP-70, a T cell receptor-associated protein tyrosine kinase, produced a distinctive form of human severe combined immunodeficiency. Manifestations of this disorder included profound immunodeficiency, absence of peripheral CD8+ T cells, and abundant peripheral CD4+ T cells that were refractory to T cell receptor-mediated activation. These findings demonstrate that ZAP-70 is essential for human T cell function and suggest that CD4+ and CD8+ T cells depend on different intracellular signaling pathways to support their development or survival.
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PMID:Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. 820 12

The recognition that defects of ZAP-70 and, more recently, of JAK3 kinase in humans result in severe combined immunodeficiency, and the demonstration that targeting of these and other protein-kinase genes in mice also leads to immunodeficiency, have highlighted the crucial role that these proteins play in T-cell differentiation and activation.
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PMID:Immunodeficiencies caused by genetic defects in protein kinases. 879 5

The effect of early human immunodeficiency virus-1 infection in vitro on proximal signal transduction events in primary peripheral blood lymphocytes was investigated with respect to CD4-mediated costimulation of CD3/T cell-receptor signalling. Tyrosine phosphorylation profiles induced by CD4 and CD3 + CD4 ligation were profoundly abrogated in virally infected cells, although CD4 receptor expression remained intact during early infection. Furthermore, the association of the tyrosine kinase p56lck with the CD4 receptor was reduced in virally infected cells. The downmodulation of CD4-mediated CD3 signalling coincided with the subsequent inhibition of the activity and tyrosine phosphorylation of the downstream kinase ZAP-70 in virally infected cells. The observed virally mediated cosignalling defects during early infection may account for the inhibition of distal signal events and thus contribute to HIV pathogenesis, such as reduced immune response to antigenic exposure, anergy, and apoptosis.
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PMID:Human immunodeficiency virus infection abolishes CD4-dependent activation of ZAP-70 by inhibition of p56lck. 911 51

Patients with common variable immunodeficiency (CVID) are heterogeneous in the clinical manifestations of the disease and the underlying mechanisms leading to the immunodeficiency. Although the overt defect is an impairment in B-cell function, there is increasing evidence of primary T-cell dysfunctions in a proportion of patients with CVID. We have analyzed T-cells from six CVID patients for activation of both early and late events in response to TCR triggering. The data showed that T-cells from three of six CVID patients were defective in the capacity to initiate the TCR/CD3 signaling pathway by activating intracellular tyrosine kinases, associated with impaired proliferative responses to TCR/CD3 triggering. Since both surface expression of the TCR/CD3 complex and intracellular expression of key tyrosine kinases such as p56lek and ZAP-70 were normal in these patients, our data suggest a defect in the earliest step of TCR signal transduction.
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PMID:Uncoupling of T-cell antigen receptor and downstream protein tyrosine kinases in common variable immunodeficiency. 919 89

We investigated the effects of early human immunodeficiency virus-1 infection (HIV-1) on CD4- and CD28-mediated co-signaling of the T cell receptor (TCR)/CD3 complex in peripheral blood lymphocytes (PBL). CD4 ligation either alone or in conjunction with TCR occupancy resulted in abrogated signaling shown by impaired co-association of the tyrosine kinase ZAP-70 with the CD3-zeta chains in virally infected PBL. In addition, down-regulation of CD4-associated TCR signaling resulted in diminished tyrosine phosphorylation of mitogen-activated protein kinase (MAPK), a serine threonine kinase which is critically involved in the regulation of transcription factors. Furthermore, these aberrant CD4-driven signals rendered HIV-1-infected PBL susceptible to activation-induced cell death. By contrast, cross-linking of the TCR/CD3 complex with the CD28 receptor improved tyrosine phosphorylation of MAPK and salvaged infected PBL from activation-induced cell death. Our data demonstrate the importance of appropriate CD3, CD4 and CD28 co-stimulatory function to prevent apoptosis. The CD4-mediated signaling defects of the TCR could contribute to the loss of immunocompetent cells during HIV-1 infection via activation-induced cell death, whereas stimulation through the CD28 pathway could reverse these detrimental effects.
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PMID:The effects of CD3, CD4 and CD28 signaling on lymphocytes during human immunodeficiency virus-1 infection. 929 33

The Nef from a highly virulent strain of simian immunodeficiency virus (SIV), SIVpbj14, and a Nef from the traditional strain SIVmac239 bearing the mutation from RQ to YE (YE-Nef) both induce an acute lethal disease in monkeys. The YE mutation and its surrounding sequence resemble the immunoreceptor tyrosine-based activation motif (ITAM), which is present in the cytoplasmic tail of T- and B-cell antigen receptors and mediates signaling during lymphocyte activation. We show here that the ITAM from YE-Nef performs the same function. First, not only does YE-Nef increase the activity of the transcription factor NFAT, which is one of the downstream targets of T-cell activation, but the ITAM from the YE-Nef by itself also activates NFAT. Second, the ITAM from YE-Nef is phosphorylated on tyrosine residues by Lck and associates with ZAP-70, a T-cell-specific tyrosine kinase. The phosphorylation of both conserved tyrosine residues on the ITAM is required for the recruitment of ZAP-70. Finally, Lck is required for the activation of NFAT by YE-Nef. These results demonstrate that YE-Nef contains a functional ITAM and elucidate the molecular mechanisms underlying the pathogenesis of SIVpbj14.
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PMID:Activation of the T-cell receptor signaling pathway by Nef from an aggressive strain of simian immunodeficiency virus. 937 16

The simian immunodeficiency virus SIV-PBj14 is the most virulent primate lentivirus identified to date. Other SIV strains, including the parental SIVsmm9, require mitogen-activated peripheral blood mononuclear cells (PBMC) for replication in vitro; however, SIV-PBj14 replicates in quiescent pig-tailed macaque PBMC and induces cellular proliferation, consistent with its in vivo pathogenesis. To identify mechanisms involved in SIV-PBj14-induced T-cell proliferation, kinases important in early T-cell receptor-mediated activation pathways were studied. Immunoblot analyses showed that ZAP-70 protein, a tyrosine kinase, was downregulated, primarily in CD8+ T cells, as early as 30 minutes after in vitro infection of quiescent macaque PBMC with SIV-PBj 14. Furthermore, this downregulation required the presence of either CD4+ T cells or adherent cells or both cell populations. In agreement with the in vitro results, ZAP-70 expression was downregulated in macaque PBMC, spleen, and rectal lymph node cells as early as 2 days after rectal inoculation of pig-tailed macaques with SIV-PBj14. This phenomenon, however, was not observed in cells obtained from distal lymph nodes to which the virus had not disseminated, implying that the presence of SIV-PBj14 is necessary to induce downregulation of ZAP-70.
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PMID:Down-modulation of the ZAP-70 protein tyrosine kinase in macaque T lymphocytes infected with SIVsmmPBj14. 974 55

Murine AIDS (MAIDS), caused by a defective murine leukemia virus, is a severe lymphoproliferative disease associated with profound immunodeficiency and increased susceptibility to opportunistic infections. Most subsets of lymphocytes, including CD4+ and CD8+ T cells, are refractory to mitogen stimulation. As a first step to examine proximal signal transduction in the infected mice, Western and Northern blot analyses were performed, and showed that p56lck is dramatically decreased at the protein as well as the mRNA level in the lymph nodes (LN). In contrast, p59(fyn) and its mRNA were slightly increased in the LN of the same mice. Similar results were obtained with purified T cells. Interestingly, the thymus of the infected animals did not show any abnormality regarding p56(lck) or p59(fyn). Tyrosine phosphorylation was constitutively increased in the infected mice and was barely amplified by anti-CD3 mAb stimulation. A similar pattern was observed when tyrosine phosphorylation was selectively examined at the level of ZAP-70. Our results suggest that a reciprocal regulation of p56(lck) and p59(fyn) protein tyrosine kinases, previously described in various models of anergy, could also be involved in the pathogenesis of MAIDS.
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PMID:Reciprocal regulation of protein tyrosine kinases p56lck and p59fyn, and altered tyrosine phosphorylation in murine AIDS. 979 14


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