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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The immune system of patients infected with human immunodeficiency virus (HIV) is in a state of chronic activation; however, the nature of HIV-related immune activation is unknown. As normal T-cell activation involves early tyrosine phosphorylation induced by the T-cell antigen receptor-associated src-family protein tyrosine kinase p59(fyn(T)) (Fyn), we examined a potential role for this kinase in HIV-related immune dysfunction. We determined the relative specific kinase activity of Fyn in lysates of peripheral blood mononuclear cells from 47 normal control individuals tested negative for HIV-1 and -2, human T-cell lymphotropic virus Type I, hepatitis B virus (HBV), hepatitis C virus (HCV), and syphilis; 14 asymptomatic HIV-infected patients having near-normal CD4+ T-cell counts (350 to 980 CD4+ cells/microL); 4 patients with symptomatic acquired immunodeficiency syndrome (AIDS) (<30 CD4+ cells/microL); 13 patients having chronic infection with HBV (6 patients) or HCV (7 patients); and 6 patients with systemic lupus erythematosis (SLE). All patients with asymptomatic HIV disease were shown to have a profound increase (mean increase of 19-fold; range threefold to 56-fold increase; p = 1.33 x 10(-9)) in the relative specific kinase activity of Fyn compared to uninfected controls or patients with hepatitis or SLE. In contrast, patients with AIDS had an Fyn-specific kinase activity that was much less affected (mean increase of threefold; range onefold to sevenfold increase; p = 1.30 x 10(-5)). It was further shown that HIV infection affects the Fyn-specific kinase activity in CD8+-enriched cells, suggesting abnormal Fyn activity in both CD8+ as well as CD4+ T lymphocytes. Initial results implicate a role for the CSK protein tyrosine kinase as responsible for the abnormal Fyn kinase activity observed in HIV-infected patients. These data indicate early and chronic activation of Fyn as a unique HIV-related effect that has the potential to be diagnostic for early HIV infection and/or may serve as a prognostic indicator for advancement to full-blown AIDS. More importantly, sustained activation of the protein tyrosine kinase associated with T-cell antigen receptor function may result in, or contribute to, the immunopathogenic effects associated with HIV infection.
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PMID:Increased enzymatic activity of the T-cell antigen receptor-associated fyn protein tyrosine kinase in asymptomatic patients infected with the human immunodeficiency virus. 934 44

Much progress has been made in understanding how mammalian cells receive a diverse array of external stimuli and convert them into intracellular biochemical signals. Such efforts have identified a large number of signalling molecules. However, our knowledge is limited as to their pathophysiological role in particular diseases. We demonstrate herein that an integrin-linked signalling molecule, focal adhesion kinase p125FAK (FAK), is overexpressed in glomeruli of lupus-prone MRL/MP-lpr/lpr (MRL-lpr) mouse as compared to its congeneic MRL-+/+ strain. Increased expression was specifically demonstrated in glomeruli but not in other tissues examined. The overexpression was observed in 16-week-old MRL-lpr mice with active nephritis, as well as in younger animals at 4 weeks of age. Thus, the upregulation of FAK clearly preceded the clinical onset of nephritis. FAK in MRL-lpr glomeruli is highly tyrosine phosphorylated and is associated with adapter protein Grb2. Previous in vitro studies have shown that the association of FAK/Grb2 links cell adhesion to the Ras pathway, which ultimately stimulates mitogen-activated protein (MAP) kinase, an important regulator of cell proliferation. In accordance, we observed constitutive MAP kinase activation in MRL-lpr glomeruli. Our findings suggest that signalling pathways involving FAK are activated in MRL-lpr glomeruli, and are likely to play a role in the development and progression of autoimmune-mediated murine nephritis.
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PMID:Glomerular overexpression and increased tyrosine phosphorylation of focal adhesion kinase p125FAK in lupus-prone MRL/MP-lpr/lpr mice. 1045 17

In the last few years it has become clear that in cells of the immune system, specialized microdomains present in the plasma membrane, called lipid rafts, have been found to play a central role in regulating signalling by immune receptors. Recent studies have looked at whether lipid rafts may be connected to the abnormalities in signalling seen in T lymphocytes isolated from patients with systemic lupus erythematosus (SLE). These early findings show that in SLE T cells, the expression and protein composition of lipid rafts is different when compared with normal T cells. These results also demonstrate changes in the function and localization of critical signalling molecules such as the LCK tyrosine kinase and the CD45 tyrosine phosphatase.
Lupus 2004
PMID:T-lymphocyte signalling in systemic lupus erythematosus: a lipid raft perspective. 1530 67

Phosphoinositide 3-kinases (PI3K) orchestrate cell responses including mitogenic signaling, cell survival and growth, metabolic control, vesicular trafficking, degranulation, cytoskeletal rearrangement and migration. Deregulation of the PI3K pathway occurs by activating mutations in growth factor receptors or the PIK3CA locus coding for PI3Kalpha, by loss of function of the lipid phosphatase and tensin homolog deleted in chromosome ten (PTEN/MMAC/TEP1), by the up-regulation of protein kinase B (PKB/Akt), or the impairment of the tuberous sclerosis complex (TSC1/2). All these events are linked to growth and proliferation, and have thus prompted a significant interest in the pharmaceutical targeting of the PI3K pathway in cancer. Genetic targeting of PI3Kgamma (p110gamma) and PI3Kdelta (p110delta) in mice has underlined a central role of these PI3K isoforms in inflammation and allergy, as they modulate chemotaxis of leukocytes and degranulation in mast cells. Proof-of-concept molecules selective for PI3Kgamma have already successfully alleviated disease progress in murine models of rheumatoid arthritis and lupus erythematosus. As targeting PI3K moves forward to therapy of chronic, non-fatal disease, safety concerns for PI3K inhibitors increase. Many of the present inhibitor series interfere with target of rapamycin (TOR), DNA-dependent protein kinase (DNA-PK(cs)) and activity of the ataxia telangiectasia mutated gene product (ATM). Here we review the current disease-relevant knowledge for isoform-specific PI3K function in the above mentioned diseases, and review the progress of >400 recent patents covering pharmaceutical targeting of PI3K. Currently, several drugs targeting the PI3K pathway have entered clinical trials (phase I) for solid tumors and suppression of tissue damage after myocardial infarction (phases I,II).
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PMID:Targeting phosphoinositide 3-kinase: moving towards therapy. 1799 86

An HIV-infected man receiving antiretroviral therapy-who also had lupus-like vasculitis and membranous glomerulonephritis (treated with prednisolone and azathioprine), beta-thalassaemia minor trait and post-radiotherapy functional asplenia (mimicking sickle cell disease-induced hyposplenism)-developed focal soft issue and bone infection caused by Salmonella enteritidis at the site of previous mycobacterial infection.
Int J STD AIDS 2008 Jul
PMID:Focal Salmonella enteritidis infection in a patient with HIV infection and other multiple causes of immunodeficiency. 1857 27

Anti-ribosomal phosphoprotein autoantibodies have been shown to be significantly associated with multiple manifestations of systemic lupus erythematosus (SLE). High levels of interleukin-10 (IL-10) have been demonstrated to contribute to lupus susceptibility and severity. In this study, we investigated the molecular mechanisms of anti-ribosomal phosphoprotein monoclonal antibody (anti-P mAb)-induced autoimmune responses. Anti-P mAb promoted IL-10 overproduction in a dose- and time-dependent manner in both lipopolysaccharide (LPS)-activated RAW 264.7 cells and primary human macrophages. Anti-P mAb enhanced phosphorylation of Akt (PKB; protein kinase B), extracellular signal regulated kinase 1/2 (ERK1/2) and c-Jun NH2-terminal kinase 1/2 (JNK1/2), while phosphorylation of p38 remained unaltered. Furthermore, anti-P mAb decreased glycogen synthase kinase 3 (GSK3) activity and reduced the phosphorylation of I kappaB alpha in LPS-activated macrophages. The Syk, phosphatidylinositol 3-kinase (PI3K), protein kinase C (PKC), JNK and ERK signalling pathways involved in anti-P mAb-triggered IL-10 secretion were also confirmed using various pharmacological inhibitors. In addition, nuclear factor (NF)-kappaB had negative regulatory effects on anti-P mAb-triggered IL-10 secretion. Using reporter plasmids containing the nuclear factor binding sites of NF-kappaB, cAMP-enhanced activation protein 1 (AP-1), serum response element (SRE) or cyclic AMP response element (CRE), treatment of anti-P mAb led to activation of the corresponding factors that bind to the AP-1 site, SRE and CRE in the LPS-activated macrophages. Furthermore, by transfection with reporter plasmids bearing various lengths of the IL-10 promoter, the AP-1 binding site, SRE and CRE were shown to be required for anti-P mAb-induced effects. Collectively, our results provide a molecular model for anti-P mAb-induced IL-10 overproduction in LPS-activated macrophages, which may play a role in the pathogenesis of SLE.
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PMID:Anti-ribosomal phosphoprotein autoantibody triggers interleukin-10 overproduction via phosphatidylinositol 3-kinase-dependent signalling pathways in lipopolysaccharide-activated macrophages. 1877 81

Susceptibility to autoimmune disorders results from the interaction of multiple genetic factors that regulate the threshold of autoreactivity. Genome-wide microsatellite screens and large-scale single nucleotide polymorphism (SNP) association studies have identified chromosomal loci that are associated with specific disorders including systemic lupus erythematosus, rheumatoid arthritis, juvenile arthritis, multiple sclerosis, and diabetes. Numerous candidate gene association studies have in turn investigated the association of specific genes within these chromosomal regions, with susceptibility to autoimmune diseases (e.g. FcgammaReceptors, TYK2 and systemic lupus). More recently, large-scale differential gene expression studies performed on selected tissues from patients with autoimmune disorders, have led to the identification of gene signatures associated with the activation of specific pathways in these diseases (e.g. interferon signature in lupus). In the future, integrated analyses of gene (and protein) expression together with SNP data will allow us to sketch an intelligible picture of the genesis of autoimmunity in humans. This review sets out to illustrate how the most recent advances in the field of systemic lupus erythematosus, rheumatoid arthritis and juvenile arthritis have led to a better understanding of these disorders.
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PMID:Genetic susceptibility to autoimmune disorders: clues from gene association and gene expression studies. 1878 62

Genetic variation was first shown to be important in systemic lupus erythematosus (SLE or lupus) in the 1970s with associations in the human leukocyte antigen region. Almost four decades later, and with the help of increasingly powerful genetic approaches, more than 25 genes are now known to contribute to the mechanisms that predispose individuals to lupus. Over half of these loci have been discovered in the past 2 years, underscoring the extraordinary success of genome-wide association approaches in SLE. Well-established risk factors include alleles in the major histocompatibility complex region (multiple genes), IRF5, ITGAM, STAT4, BLK, BANK1, PDCD1, PTPN22, TNFSF4, TNFAIP3, SPP1, some of the Fcgamma receptors, and deficiencies in several complement components, including C1q, C4 and C2. As reviewed here, many susceptibility genes fall into key pathways that are consistent with previous studies implicating immune complexes, host immune signal transduction and interferon pathways in the pathogenesis of SLE. Other loci have no known function or apparent immunological role and have the potential to reveal novel disease mechanisms. Certainly, as our understanding of the genetic etiology of SLE continues to mature, important new opportunities will emerge for developing more effective diagnostic and clinical management tools for this complex autoimmune disease.
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PMID:Recent insights into the genetic basis of systemic lupus erythematosus. 1944 Jan 99

Treatment of (NZB x NZW)F(1) (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.
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PMID:Modulation of p38 MAPK activity in regulatory T cells after tolerance with anti-DNA Ig peptide in (NZB x NZW)F1 lupus mice. 1949 64

Patients with advanced HIV disease with low CD4 count are more prone to thrombo-embolism and various predisposing factors have been identified. These include the presence of anticardiolipin antibodies and the lupus anticoagulant, deficiencies of proteins C and S, heparin co-factor II and antithrombin. Increased levels of Von Willebrand factor and d-dimers have also been linked with thrombo-embolism, as has the presence of concurrent infections and malignancies. We report a case of an AIDS patient who presented with acute hemiparesis. He was severely immunosuppressed. Computed tomography of the head confirmed cerebral infarction with haemorrhagic transformation. He had no known risk factors apart from being severely immunocompromised and had high anticardiolipin antibodies and low free protein S.
Int J STD AIDS 2009 Nov
PMID:Haemorrhagic transformation of cerebral infarction in an AIDS patient--thrombophilia screen essential! 1983 95


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