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)

Protein tyrosine phosphorylation is a common mechanism of signaling in pathways that regulate T cell receptor-mediated cell activation, cell proliferation, and the cell cycle. Because human immunodeficiency virus (HIV) is though to affect normal cell signaling, tyrosine phosphorylation may be associated with HIV cytopathicity. In both HIV-infected cells and transfected cells that stably express HIV envelope glycoproteins undergoing HIVgp41-induced cell fusion, a 30-kilodalton protein was phosphorylated on tyrosine with kinetics similar to those of syncytium formation and cell death. When tyrosine phosphorylation was inhibited by the protein tyrosine kinase inhibitor herbimycin A, envelope-mediated syncytium formation was coordinately reduced. These studies show that specific intracellular signals, which apparently participate in cytopathicity, are generated by HIV and suggest strategies by which the fusion process might be interrupted.
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PMID:Participation of tyrosine phosphorylation in the cytopathic effect of human immunodeficiency virus-1. 157 May 14

A human CD4+ T cell line, Jurkat, was transfected with a constructed plasmid, which has the envelope gene of the human immunodeficiency virus (HIV) under the transcriptional control of the human metallothionein IIA promoter, and these transfected cells were then cloned. JME2, one of the cloned cell lines, expressing the envelope glycoprotein after induction with metal ions, showed the ability to form syncytia involving other CD4+ cells not expressing the HIV envelope protein. When several CD4+ cell lines were examined for their susceptibility to syncytium formation by JME2 cells, the p56lck-expressing cell lines were found to be more susceptible to syncytium formation than the p56lck-non-expressing cell lines. To substantiate the role of p56lck in the syncytium formation, a CD4+, p56lck-non-expressing monocytoid cell line, U937 clone 2, was transfected with an lck-expressing construct. Using such transfectant cell clones, it was demonstrated that p56lck-positive cells are markedly more susceptible to the syncytium formation than p56lck-negative cells, implying a regulatory role for p56lck in syncytium formation mediated by the HIV envelope and CD4 molecule. Moreover, it was suggested, in the experiments using CD45 cross-linking or a protein tyrosine kinase inhibitor, genistein, that p56lck affects syncytium formation through its protein tyrosine kinase activity. A putative mechanism by which p56lck affects the syncytium formation is also discussed.
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PMID:The effect of p56lck, a lymphocyte specific protein tyrosine kinase, on the syncytium formation induced by human immunodeficiency virus envelope glycoprotein. 162 97

The penetration of CD4+ cells by human immunodeficiency virus (HIV) involves a high affinity interaction between the viral attachment protein, gp120, and the cellular receptor, CD4. The mechanism by which the virus penetrates the host cell subsequent to viral binding is unknown. We have investigated the possibility that HIV penetration induces changes in the metabolic state of the infected cell similar to those seen with the perturbation of CD4 cells by monoclonal antibodies (MAb) directed against the CD4 molecule, or with specific antigen-mediated activation. The activation of cellular protein kinases was examined. The basal level of activity was not altered in the presence of HIV. Kinase activity was markedly increased in cells stimulated with phytohemagglutinin (PHA), and was qualitatively and quantitatively changed by a brief exposure to the phorbol ester TPA (12-o-tetradecanoyl phorbol-13-acetate). The phosphorylation state of the CD4 molecule was examined by radioimmunoprecipitation and found to be unaltered by the binding of HIV under conditions in which TPA induced rapid CD4 phosphorylation. The activity of the CD4-associated protein tyrosine kinase p56lck was measured by in vitro assays of 32PO4 incorporation in CD4 immunoprecipitates from HIV-incubated cells. TPA incubation resulted in a rapid loss of CD4-associated p56lck activity, presumably due to dissociation of the enzyme from CD4. Concanavalin A stimulation resulted in a similar change but with a slower time course. However, no change in CD4-associated activity was detected in HIV-incubated cells. We found that Ca2+ influx was not induced by the binding of HIV to CD4+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:HIV-1 binding to CD4 T cells does not induce a Ca2+ influx or lead to activation of protein kinases. 168 89

Single-cell clones, designated E11S, C11R, and A1S, were obtained from the HuT-78 T cell line persistently infected with an isolate of Simian immunodeficiency virus (SIV), SIV/Mne. The infected clones, unlike uncloned uninfected HuT-78 cells, no longer expressed the CD4 marker and, after their CD3 receptors were cross-linked, had dramatically reduced intracellular free calcium ([Ca2+]i) responses. In one clone, E11S, the unresponsiveness was not limited to the inositol phospholipid pathway of signaling since a reduction in CD3-mediated activation of protein tyrosine kinase-dependent phosphorylation also was evident in this SIV-infected clone. These results led us to test whether T lymphocytes from animals infected with SIV had defective [Ca2+]i responses prior to detectable changes in CD4 levels or lymphadenopathy. The [Ca2+]i responses to both CD3 mAb and CD2 mAb were 10-50% less in T cells from Walter Reed stage 2 animals than in healthy controls. This anergy was more pronounced in chronically infected animals progressing to Walter Reed stage 3/4. The responses of these animals could not be augmented even when combinations of CD3 and CD4 mAb were used. Both CD4+CD44lo T cells, which are not infected with SIV, and the CD4+CD44hi T cell subset, previously shown to be the reservoir of SIV infection in blood, had pronounced defective responses to CD3 mAb. Similarly, both CD4+ and CD8+ T cells were consistently unresponsive in chronically infected animals, again implying that an indirect mechanism, rather than SIV infection per se, may be responsible for this immune dysfunction.
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PMID:CD4 and CD8 T cells from SIV-infected macaques have defective signaling responses after perturbation of either CD3 or CD2 receptors. 198 Jun 19

The expression of lck gene (lymphocyte specific protein tyrosine kinase) in the human system was examined by Northern blot analysis in human T cell leukemia virus type I (HTLV-I)-positive T cell lines, HTLV-I-T cell lines, normal T cell population, and a T cell line infected with human immunodeficiency virus. In the cells of HTLV-I-integrated T cell lines, messages of lck were not detected in IL-2-independent lines, although found profusely in IL-2-dependent ones. The results of nuclear transcription assay indicated that lck expression is shut off at the stage of transcription in those cell lines. RNA products of the viral PX region were not detectable in two out of five HTLV-I+, IL-2-independent lines, suggesting that PX gene products themselves exert no direct effect on the block of lck transcription in the HTLV-I-infected T cells. Other T cell populations and a T cell line infected with human immunodeficiency virus, on the other hand, showed significant levels of lck message. These data presented the possibility that lck gene product may be one of the intervening molecules which transduce the signal from the IL-2R into the cell interior, and play an important role in the pathophysiology of adult T cell leukemia, especially in the transition of these leukemias from the IL-2-dependent stage to IL-2-independent one for their growth.
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PMID:Absence of transcription of lck (lymphocyte specific protein tyrosine kinase) message in IL-2-independent, HTLV-I-transformed T cell lines. 278 34

The CBA/N mouse carries the X-linked immunodeficiency xid, resulting in defective B cell development. B cells from these animals cannot mount antibody responses to type 2 T-independent antigens, and do not synthesize DNA when stimulated with anti-immunoglobulin (Ig) antibodies which are mitogenic for normal B cells. The primary antibody responses of CBA/N mice to T-dependent antigens have also been reported to be abnormal. Here we describe the results of experiments which demonstrate that the B cells from these animals respond abnormally to ligation of CD40, a B cell surface molecule now known to play a key role during T cell-B cell interactions, via its interaction with the counterligand (CD40L) expressed by activated T cells. Hence, xid B cells fail to proliferate when cultured with preactivated T helper type 2 (Th2)T cells (known to express CD40L), with a soluble CD40L-CD8 fusion protein, or in response to monoclonal antibodies to CD40, even in the presence of IL-4 and/or anti-Ig reagents. However, xid B cells do receive abortive activation signals following ligation of CD40, as manifested by up-regulation of class II major histocompatibility complex and CD23 antigens. Since the xid defect has now been identified as a point mutation in the protein tyrosine kinase Btk, our results point to an important role for this kinase in the downstream signaling cascade elicited in response to ligation of either surface Ig or CD40.
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PMID:B cells from CBA/N mice do not proliferate following ligation of CD40. 751 60

Mutations in the gene encoding the protein tyrosine kinase Btk are associated with the human B cell immunodeficiency X-linked agammaglobulinemia (XLA). In the mouse, a point mutation in the Btk pleckstrin homology domain segregates with a milder X-linked immunodeficiency (xid). To assess the importance of Btk function in murine lymphopoiesis, we generated multiple embryonic stem cell clones bearing a targeted disruption of the btk gene and examined their potential to produce lymphocytes in both C57BL/6 and RAG2-/- host chimeric animals. These mice provide a complementary set of in vivo competition assays that formally establish the genetic basis for the xid phenotype. Although the null mutation yields a phenotype quite similar to that of xid, it also compromises expansion of B cell precursors. Our results suggest that the murine and human consequences of Btk deficiency differ only quantitatively, and represent the same disease process.
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PMID:Impaired expansion of mouse B cell progenitors lacking Btk. 755 95

The nonreceptor protein tyrosine kinases (PTKs) have been grouped into 10 different enzyme families based on predicted amino acid sequences. As the number of enzymes belonging to the nonreceptor class of PTK is increasing, one challenge is to determine how these various classes of PTKs interact within the cell to promote signal transduction. Herein, the activation of four classes of nonreceptor PTKs is discussed in relation to their interactions with each other as well as with other signaling molecules during the process of lymphocyte surface antigen receptor-mediated activation. Recent findings of nonreceptor PTK loss-of-function mutations in different immunodeficiency diseases has revealed the important contribution of this group of enzymes to lymphocyte development.
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PMID:Nonreceptor protein tyrosine kinase involvement in signal transduction and immunodeficiency disease. 755 58

Antigen receptor-mediated activation of T and B lymphocytes results in activation of phospholipase C-gamma isozymes with subsequent hydrolysis of membrane inositol phospholipids. As a method of screening autoimmune or immunodeficient patients for early receptor signaling defects, we have developed a rapid technique for studying phosphatidylinositol (PI) hydrolysis in cultured cells and fresh clinical specimens resulting from surface receptor crosslinking. Using staphylococcal alpha-toxin, we permeabilized freshly isolated, purified human T lymphocytes to facilitate incorporation of [3H]myoinositol into membrane phospholipids. Aggregation of surface antigen receptors (TCR-CD3 complex and CD28 on T cells) with specific antibodies produced extensive ATP and Mg(2+)-dependent hydrolysis of the membrane inositol phospholipids as measured by release of water soluble inositol phosphates. Anti-human CD3 antibody produced 18.5 +/- 1.6 net % PI hydrolysis and anti-human CD28 antibody produced 4.6 +/- 0.2 net % PI hydrolysis. Simultaneous anti CD3/CD28 crosslinking produced 30.8 +/- 1.2 net % PI hydrolysis, an increase over either stimulus alone (p = 0.0013 two tailed t test). Isotype matched control antibodies produced 11.6 +/- 0.4% PI hydrolysis. The tyrosine phosphatase inhibitor orthovanadate (Na3VO4) was used as a positive control because it induces maximal protein tyrosine kinase-dependent PI hydrolysis in permeabilized cells. Na3VO4 consistently induced hydrolysis of > 50% of the membrane inositol phospholipid pool. These data indicate that costimulation of T cells with antibodies to CD3 and CD28 is synergistic and reinforces the importance of CD28 as an accessory T cell stimulus. This easy technique allows quick evaluation of the integrity of the early signaling cascade in lymphocytes as a screen for autoimmune and immunodeficiency diseases.
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PMID:Phosphatidylinositol hydrolysis in freshly isolated human T lymphocytes. 756 Nov 50

Pentosan polysulfate, a polyanionic mucopolysaccharide, which has been shown to exert inhibitory effects on human immunodeficiency virus (HIV-I) replication, inhibited the activities of protein tyrosine kinases from lymphocytes (Jurkat cells) and rat lung in a concentration dependent manner. In addition, the autophosphorylation of p56lck, a lymphocyte associated protein tyrosine kinase from Jurkat cells was also inhibited by pentosan polysulfate (100 micrograms/ml). Furthermore, the activities of protein serine/threonine kinases such as Ca2+, phospholipid-dependent protein kinase (protein kinase C) from human platelets and the catalytic subunit of cAMP-dependent protein kinase from skeletal muscle were also inhibited by this mucopolysaccharide. However, the activity of phosphorylase kinase was not altered. The inhibition of rat lung protein tyrosine kinase was rapid and competitive with respect to ATP with an apparent Ki value of 5-20 micrograms/ml. These results suggest that the ability of pentosan polysulfate to inhibit various protein serine/threonine and tyrosine kinases may be one of the mechanisms by which this compound exerts its inhibitory effect of HIV-I replication.
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PMID:Pentosan polysulfate, a potent anti HIV and anti tumor agent, inhibits protein serine/threonine and tyrosine kinases. 768 45


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