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)

Results of therapeutic trials of transfer factor in a number of laboratories suggest clinical benefit and enhancement of immunological reactivity in patients with primary or secondary immunodeficiency diseases. Long term follow-up of 32 patients with the Wiskott-Aldrich syndrome suggested that transfer factor caused conversion of immunologic reactivity, apparent clinical benefit, and prolonged survival in some, but not in all patients. In 18 patients with disseminated (Stage III) malignant melanoma treated with surgery and transfer factor, survival was better than would ordinarily be expected for disseminated disease (78% with mean follow-up of 2 years). A randomized trial has been initiated which will answer the question of the efficacy of transfer factor as surgical adjuvant therapy in malignant melanoma. Studies in human subjects suggested that transfer factor does not cause enhancement of reactivity in normal subjects, when evaluated in a controlled, double-blind fashion. Similar controlled studies in immunodeficient patients are necessary to ascertain whether transfer factor does cause enhancement of immune responses in these patients. Based on these observations, a guinea pig model was developed in which transfer factor caused abrogation of tolerance to ABA-Tyrosine.
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PMID:Transfer factor in immunodeficiency diseases. 11 60

Defective T cell activation has been recognized in a number of patients with primary immunodeficiencies (ID). A distal defect resulting in abnormal production of IL2, IL3, IL4 and IFN gamma was found to be associated with reduced binding of the NF-AT transcription factor to the promoters of the genes coding for these lymphokines. Defect in early steps of T cell activation have been described in primary IDs, consisting in defective calcium flux and phosphoinositides turnover following TCR/CD3 ligation. We herein report a primary ID found in a 13 year old girl. It consists in a partially defective T cell proliferation which could be related to a defective Tyrosine phosphorylation.
Immunodeficiency 1993
PMID:Functional T cell immunodeficiency characterized by defective TCR/CD3 induced tyrosylphosphorylation. 816 86

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

Tyrosine kinases of the Src family are regulated via their Src homology 2 (SH2) and SH3 domains. The Nef protein of human immunodeficiency virus-1 (HIV-1) has previously been shown to bind with high affinity and specificity in vitro to the SH3 domain of Hck, a Src family member expressed primarily in myeloid cells. However, the effect of Nef on Hck activity in living cells is unknown. Here we show that Rat-2 fibroblasts co-expressing Hck and Nef rapidly developed transformed foci, whereas control cells expressing either protein alone did not. Nef formed a stable complex with Hck and stimulated its tyrosine kinase activity in vivo. Mutagenesis of the Nef proline-rich motif essential for SH3 binding completely blocked complex formation, kinase activation, and transformation, indicating that the Nef SH3-binding function is required for its effects on Hck. These results provide direct evidence that SH3 engagement is sufficient to activate a Src family kinase in vivo and suggest that Hck may be activated by Nef in HIV-infected macrophages.
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PMID:SH3-mediated Hck tyrosine kinase activation and fibroblast transformation by the Nef protein of HIV-1. 921 12

Tyrosine phosphorylation of cellular proteins is a critical early event in the T-cell activation process induced by the antigenic peptide or monoclonal antibodies specific for the CD3 T-cell receptor (TCR) complex. Phosphoproteins are currently detected by Western blotting experiments or, recently, by labelling intracellular proteins with an antiphosphotyrosine monoclonal antibody and flow cytometric analysis (Farahi Far et al.: Cytometry 15:327-334, 1994; Vuillier et al.: J Immunol Methods 185:43-56, 1995). Here, we describe improvements of these latter methods in order to study selectively the CD3-TCR signaling pathway of patients with immunodeficiency diseases or lymphopenia. This new technique quantifies tyrosine-phosphorylated proteins in in vitro-activated T-cell subsets directly on whole blood samples. The stimulation of the CD3-TCR complex induces a specific and significant increase in the phosphotyrosine fluorescence intensity in both CD4 and CD8 subpopulations. The simplicity and the good reproducibility of this method make it particularly convenient for laboratory routine evaluation, and the use of very small volumes of blood is well adapted to the study of immunodepressed patients. Moreover, this technique allows the detection of early molecular defects of the CD3-TCR signal-transduction pathway.
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PMID:Analysis by flow cytometry of tyrosine-phosphorylated proteins in activated T-cell subsets on whole blood samples. 929 15

Multiple extracellular domains of the CC-chemokine receptor CCR5 are important for its function as a human immunodeficiency virus type 1 (HIV-1) coreceptor. We have recently demonstrated by alanine scanning mutagenesis that the negatively charged residues in the CCR5 amino-terminal domain are essential for gp120 binding and coreceptor function. We have now extended our analysis of this domain to include most polar and nonpolar amino acids. Replacement of alanine with all four tyrosine residues and with serine-17 and cysteine-20 decrease or abolish gp120 binding and CCR5 coreceptor activity. Tyrosine-15 is essential for viral entry irrespective of the test isolate. Substitutions at some of the other positions impair the entry of dualtropic HIV-1 isolates more than that of macrophagetropic ones.
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PMID:Alanine substitutions of polar and nonpolar residues in the amino-terminal domain of CCR5 differently impair entry of macrophage- and dualtropic isolates of human immunodeficiency virus type 1. 952 83

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

Chemokine receptors and related seven-transmembrane-segment (7TMS) receptors serve as coreceptors for entry of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) into target cells. Each of these otherwise diverse coreceptors contains an N-terminal region that is acidic and tyrosine rich. Here, we show that the chemokine receptor CCR5, a principal HIV-1 coreceptor, is posttranslationally modified by O-linked glycosylation and by sulfation of its N-terminal tyrosines. Sulfated tyrosines contribute to the binding of CCR5 to MIP-1 alpha, MIP-1 beta, and HIV-1 gp120/CD4 complexes and to the ability of HIV-1 to enter cells expressing CCR5 and CD4. CXCR4, another important HIV-1 coreceptor, is also sulfated. Tyrosine sulfation may contribute to the natural function of many 7TMS receptors and may be a modification common to primate immunodeficiency virus coreceptors.
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PMID:Tyrosine sulfation of the amino terminus of CCR5 facilitates HIV-1 entry. 1008 82

Wiskott Aldrich syndrome (WAS) is an X-linked recessive disorder associated with abnormalities in platelets and lymphocytes giving rise to thrombocytopenia and immunodeficiency. WAS is caused by a mutation in the gene encoding the cytoskeletal protein (WASp). Despite its importance, the role of WASp in platelet function is not established. WASp was recently shown to undergo tyrosine phosphorylation in platelets after activation by collagen, suggesting that it may play a selective role in activation by the adhesion molecule. In the present study, we show that WASp is heavily tyrosine phosphorylated by a collagen-related peptide (CRP) that binds to the collagen receptor glycoprotein (GP) VI, but not to the integrin alpha2beta1. Tyrosine phosphorylation of WASp was blocked by Src family kinase inhibitors and reduced by treatment with wortmannin and in patients with X-linked agammaglobulinemia (XLA), a condition caused by a lack of functional expression of Btk. This indicates that Src kinases, phosphatidylinositol 3-kinase (PI 3-kinase), and Btk all contribute to the regulation of tyrosine phosphorylation of WASp. The functional importance of WASp was investigated in 2 WAS brothers who show no detectable expression of WASp. Platelet aggregation and secretion from dense granules induced by CRP and thrombin was slightly enhanced in the WAS platelets relative to controls. Furthermore, there was no apparent difference in morphology in WAS platelets after stimulation by these agonists. These observations suggest that WASp does not play a critical role in intracellular signaling downstream of tyrosine kinase-linked and G protein-coupled receptors in platelets.
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PMID:Regulation and function of WASp in platelets by the collagen receptor, glycoprotein VI. 1059 61

The role of phosphatidylinositol 3,4,5-trisphosphate (PI3,4,5P(3)) and Btk in signalling by the collagen receptor glycoprotein VI was investigated. PI3,4,5P(3) was increased in platelets from mice deficient in the SH2 domain-containing inositol 5-phosphatase (SHIP), in response to collagen related peptide (CRP). Tyrosine phosphorylation and activation of phospholipase Cgamma2 (PLCgamma2) were unaltered in SHIP(-/-) platelets, whereas Btk was heavily tyrosine phosphorylated under basal conditions and maximally phosphorylated by low concentrations of CRP. There was an increase in basal Ca(2+), maximal expression of P-selectin, and potentiation of Ca(2+) and aminophospholipid exposure to CRP in SHIP(-/-) platelets in the presence of Ca(2+) (1 mM). Microinjection of PI3,4, 5P(3) into megakaryocytes caused a 3-fold increase in Ca(2+) in response to CRP, which was absent in X-linked immunodeficiency (Xid) mice, which have a mutation in the PH domain of Btk. There was a corresponding partial reduction in the sustained level of intracellular Ca(2+) in response to CRP in Xid mice but no change in PLC activity. These results demonstrate a novel pathway of Ca(2+) entry that involves PI3,4,5P(3) and Btk, and which is independent of increased PLC activity.
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PMID:Phosphatidylinositol 3,4,5-trisphosphate regulates Ca(2+) entry via btk in platelets and megakaryocytes without increasing phospholipase C activity. 1085 25


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