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)

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

Malignant mesothelioma is a rare neoplasm which could be favored by an hereditary predisposing factor. So far, malignant mesothelioma have never been described in patients with hereditary diseases of the connective tissue. Here, we report some cases of mesothelioma affecting subjects who were not exposed to inhalation of asbestos. One of these subjects was affected by Ehlers-Danlos syndrome, whereas in two brothers, mesothelioma was associated with Marfan's syndrome. The observation of the same histologic subtype of mesothelioma in two brothers and the coexistence of two pathologic conditions of mesodermal origin indicate the presence of hereditary factors predisposing to the cancerogenic action of even small amounts of asbestos. Structural alterations of collagen and primary immunodeficiency may represent the host factor inducing development of the neoplasm. We conclude that the association between these rare disorders of the connective tissue and mesothelioma may not be coincidental, but could be the result of the exposition to small amounts of asbestos in predisposed individuals.
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PMID:Malignant mesothelioma in subjects with Marfan's syndrome and Ehlers-Danlos syndrome: only an apparent association? 1077

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

Serum mannose-binding protein (MBP) or mannose-binding lectin initiates the lectin branch of the innate immune response by binding to the surface of potentially pathogenic microorganisms and initiating complement fixation through an N-terminal collagen-like domain. Mutations in this region of human MBP are associated with immunodeficiency resulting from a reduction in the ability of the mutant MBPs to fix complement as well as from reduced serum concentrations. Inefficient secretion of the mutant proteins, which is one possible cause of the reduced serum levels, has been investigated using a mammalian expression system in which each of the naturally occurring human mutations has been recreated in rat serum MBP. The mutations Gly25-->Asp and Gly28-->Glu disrupt the disulfide-bonding arrangement of the protein and cause at least a 5-fold increase in the half-time of secretion of MBP compared with wild-type rat serum MBP. A similar phenotype, including a 3-fold increase in the half-time of secretion, disruption of the disulfide bonding arrangement, and inefficient complement fixation, is observed when nearby glucosylgalactosyl hydroxylysine residues at positions 27 and 30 are replaced with arginine residues. The results suggest that defective secretion resulting from structural changes in the collagen-like domain is likely to be a contributory factor for MBP immunodeficiency.
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PMID:Impaired secretion of rat mannose-binding protein resulting from mutations in the collagen-like domain. 1090 44

Activation of the collagen receptor glycoprotein VI (GPVI) by a collagen-related peptide (CRP) induces stimulation of platelets and megakaryocytes through the phosphatidylinositol (PI) 3-kinase-dependent pathway leading to activation of Bruton tyrosine kinase (Btk) and phospholipase Cgamma2 (PLCgamma2). Here, we present evidence that both proteins undergo PI 3-kinase-dependent translocation to the plasma membrane on CRP stimulation that is markedly inhibited by wortmannin and LY294002. Translocation of PLCgamma2 but not Btk is also seen in megakaryocytes from X-linked immunodeficiency mice, which have a mutation that reduces the affinity of the pleckstrin homology (PH) domain of Btk for PI 3,4,5-trisphosphate (PI 3,4,5-P3). Activation of PC12 cells by epidermal growth factor (EGF) results in increased PI 3-kinase activity and high PI 3,4,5-P3 levels that trigger translocation of the green fluorescent protein (GFP)-labeled PH of Btk, but not the GFP-labeled PH and tandem Src homology 2 (SH2) domains of PLCgamma2. In contrast to the results with CRP, the G protein-coupled receptor agonist thrombin stimulates PI 3-kinase-independent translocation of Btk but not PLCgamma2. In conclusion, these results demonstrate that in mouse megakaryocytes, CRP leads to PI 3-kinase-dependent translocation of PLCgamma2 and Btk that are independent of one another, whereas thrombin only induces translocation of Btk through a pathway that is independent of PI 3-kinase activity.
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PMID:Phosphatidylinositol 3-kinase-dependent translocation of phospholipase Cgamma2 in mouse megakaryocytes is independent of Bruton tyrosine kinase translocation. 1115 84

Women with acquired immune deficiency syndrome wasting are at an increased risk of osteopenia because of low weight, changes in body composition, and hormonal alterations. Although women comprise an increasing proportion of human immunodeficiency virus-infected patients, prior studies have not investigated bone loss in this expanding population of patients. In this study we investigated bone density, bone turnover, and hormonal parameters in 28 women with acquired immune deficiency syndrome wasting and relative androgen deficiency (defined as free testosterone < or =3.0 pg/ml, weight < or =90% ideal body weight, weight loss > or =10% from preillness maximum weight, or weight <100% ideal body weight with weight loss > or =5% from preillness maximum weight). Total body (1.04 +/- 0.08 vs. 1.10 +/- 0.07 g/cm2, human immunodeficiency virus-infected vs. control respectively; P < 0.01), anteroposterior lumbar spine (0.94 +/- 0.12 vs. 1.03 +/- 0.09 g/cm2; P = 0.005), lateral lumbar spine (0.71 +/- 0.14 vs. 0.79 +/- 0.09 g/cm2; P = 0.02), and hip (Ward's triangle; 0.68 +/- 0.14 vs. 0.76 +/- 0.12 g/cm2; P = 0.05) bone density were reduced in the human immunodeficiency virus-infected compared with control subjects. Serum N-telopeptide, a measure of bone resorption, was increased in human immunodeficiency virus-infected patients, compared with control subjects (14.6 +/- 5.8 vs. 11.3 +/- 3.8 nmol/liter bone collagen equivalents, human immunodeficiency virus-infected vs. control respectively; P = 0.03). Although body mass index was similar between the groups, muscle mass was significantly reduced in the human immunodeficiency virus-infected vs. control subjects (16 +/- 4 vs. 21 +/- 4 kg, human immunodeficiency virus-infected vs. control, respectively; P < 0.0001). In univariate regression analysis, muscle mass (r = 0.53; P = 0.004) and estrogen (r = 0.51; P = 0.008), but not free testosterone (r = -0.05, P = 0.81), were strongly associated with lumbar spine bone density in the human immunodeficiency virus-infected patients. The association between muscle mass and bone density remained significant, controlling for body mass index, hormonal status, and age (P = 0.048) in multivariate regression analysis. These data indicate that both hormonal and body composition factors contribute to reduced bone density in women with acquired immune deficiency syndrome wasting. Anabolic strategies to increase muscle mass may be useful to increase bone density among osteopenic women with acquired immune deficiency syndrome wasting.
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PMID:Reduced bone density in androgen-deficient women with acquired immune deficiency syndrome wasting. 1150 75

Migration of endothelial cells induced by vascular endothelial growth factor (VEGF) is a critical step in angiogenesis. Stimulation of motility by growth factors such as VEGF requires interaction with the signal transduction pathways activated by the extracellular matrix (ECM). Here we demonstrate that the Rac GTPase is the critical intersection activated by type 1 collagen ECM and VEGF during stimulation of endothelial cell motility. To analyze the role of the Rho family GTPases in VEGF-stimulated endothelial cell chemotaxis and ECM-stimulated haptotaxis, we transduced the respective fusion proteins in human foreskin dermal endothelial cells using a Tat peptide from the human immunodeficiency virus Tat protein. VEGF signaling required Rac activation during chemotaxis, and Rac and Cdc42 were activated during haptotaxis on type I collagen. Similar to VEGF, Rac activation induced an increase in endothelial cell stress fiber and focal adhesion. Surprisingly, Rho activation was not present in collagen-induced haptotaxis or stimulation of chemotaxis by VEGF, although Rho induced stress fibers and focal adhesions similar to Rac activation. The result of constitutive Rho activation was an inhibition of haptotaxis. Thus, Rac is required and sufficient for the activation of endothelial cell haptotaxis and VEGF-stimulated chemotaxis.
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PMID:Rho family GTPases regulate VEGF-stimulated endothelial cell motility. 1152 41

It has been postulated that the inflammatory response that occurs after cutaneous wounding is a prerequisite for healing and that inflammatory cytokines, such as interleukin-6 (IL-6) are involved in this process. We showed previously that IL-6-deficient mice display delayed wound healing, which could be reversed by administration of a murine IL-6 expression plasmid or recombinant murine IL-6 (rMuIL-6). In the present study, we observed that delayed cutaneous wound healing, which occurs as a result of glucocorticoid-induced immunosuppression, can also be reversed by rMuIL-6, as evidenced by epithelialization, granulation tissue formation, and wound closure. In vehicle control mice, rMuIL-6 did not augment healing but rather delayed the process. Immunochemical studies indicated that the expression of matrix metalloproteinase-10 (MMP-10) was increased in dexamethasone-treated mice and that rMuIL-6 treatment reduced its expression, indicating that IL-6 may influence dermal matrix formation and, specifically, collagen synthesis. These results demonstrate that IL-6 can restore abnormal wound repair that occurs in immunodeficiency and suggest its use as a potential therapy.
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PMID:Interleukin-6 treatment augments cutaneous wound healing in immunosuppressed mice. 1155 38

It has been previously shown that the sequence similarity between a portion of the envelope glycoprotein 120 (gp120) from the human immunodeficiency virus type-1 (HIV-1) and several types of human collagen and collagen-like molecules exists. That observation led to the suggestion that the antibodies against the third hypervariable region (V3) of HIV-1 gp120 (V3-specific antibodies) might have a role in the autoimmune phenomena observed in HIV-infected persons. In this study we have examined the cross-reactivity of the V3-specific antibodies purified from sera of HIV-infected individuals, sera obtained from the rheumatoid arthritis and systemic lupus crythematosus patients, as well as from the sera of healthy volunteers with the separate chains of a subcomponent of the first component of the human complement system, Clq. Our results show that the V3-specific antibodies are present in the sera of the HIV-infected individuals, patients suffering of the systemic autoimmune diseases as well as in the sera of healthy volunteers. Whereas these antibodies appeared in the HIV+-sera after antigen challenge, those present in the HIV- -sera probably represent the antibodies that are cross-reactive with the antigen. V3-reactive antibodies can be purified by affinity chromatography and they were highly specific for the V3-peptide. Additionally, they showed cross-reactivity with the separate chains of the human Clq as well as with the chicken collagen type VI. Possible physiological implications are discussed.
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PMID:Cross--reactivity of the V3-speciflc antibodies with the human C1q. 1183 69

Bruton's XLA and DiGeorge syndrome patients show that two basic immune systems are distinct from each other in humans - thymus-dependent cell-mediated immunodeficiencies vs. antibody-based immunodeficiencies. The appendix-sacculus lymphoid organ of rabbits, like the bursa of Fabricius, represents a central lymphoid organ. Chronic granulomatous disease of childhood (CGD) revealed that phagocytosis killing of catalase-positive microorganisms employ oxidative burst. Bone marrow transplantation (BMT) proved life saving in severe combined immunodeficiency (SCID). The first BMT cured XSCID and the second BMT cured a complicating aplastic anemia launching BMT as a treatment of many diseases. Now 75 fatal diseases have been cured by myeloablative BMT. BMT also cured experimental autoimmune diseases. BMT alone did not cure lupus with polyarthritis in MRL/lpr mice or polyarthritis in NZB/KN mice, but BMT plus bone (stromal cell) transplants cured these diseases. Autoimmune diseases and lethal glomerulonephritis were prevented or cured in BXSB mice by mixed allogeneic plus syngeneic BMT. X-linked Hyper IgM syndrome (XHIM) was also cured by BMT from a 2-year-old MHC-matched sibling donor. Nonmyeloablative BMT plus mesenchymal stem cells (stromal cells) was effective treatment for a form of collagen-vascular disease and also a lethal form of hypophosphatasia. Mannan-binding lectin, an opsonin that activates the complement system when mutated and at low levels in blood, opens a door to frequent infections throughout childhood and adult life. This new immunodeficiency is based on genetic mutations that involve a native defense system.
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PMID:Cellular immunology in a historical perspective. 1219 Sep 28


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