Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The importance of protein kinases as a major class of drug targets across multiple diseases has generated a critical need for technologies that enable the identification of potent and selective kinase inhibitors. Bruton's tyrosine kinase (Btk) is a compelling drug target in multiple therapeutic areas, including systemic lupus erythematosus, asthma, rheumatoid arthritis, and B cell malignancies. We have combined potent, selective kinase inhibition through chemical genetics with gene expression profiling to identify a "fingerprint" of transcriptional changes associated with selective Btk kinase inhibition. The Btk transcriptional fingerprint shows remarkable relevance for Btk's biological roles and was used for functional selectivity profiling of two kinase inhibitor compounds. The fingerprint was able to rank the compounds by relative selectivity for Btk, and revealed broader off-target effects than observed in a broad panel of biochemical kinase cross screens. In addition to being useful for functional selectivity profiling, the fingerprint genes are themselves potential preclinical and clinical biomarkers for developing Btk-directed therapies.
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PMID:Chemical genetic transcriptional fingerprinting for selectivity profiling of kinase inhibitors. 1735 99

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

In this study, we compared the association of several newly discovered susceptibility genes for systemic lupus erythematosus (SLE) between populations of European origin and two Asian populations. Using 910 SLE patients and 1440 healthy controls from Chinese living in Hong Kong, and 278 SLE patients and 383 controls in Thailand, we studied association of STAT4, BLK and PXK with the disease. Our data confirmed association of STAT4 (rs7574865, odds ratio (OR) =1.71, P=3.55 x 10(-23)) and BLK (rs13277113, OR=0.77, P=1.34 x 10(-5)) with SLE. It was showed that rs7574865 of STAT4 is also linked to hematologic disorders and potentially some other subphenotypes of the disease. More than one genetic variant in STAT4 were found to be associated with the disease independently in our populations (rs7601754, OR=0.59, P=1.39 x 10(-9), and P=0.00034 when controlling the effect of rs7574865). With the same set of samples, however, our study did not detect any significant disease association for PXK, a risk factor for populations of European origin (rs6445975, joint P=0.36, OR=1.06, 95% confidence interval: 0.93-1.21). Our study indicates that some of the susceptibility genes for this disease may be population specific.
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PMID:Population differences in SLE susceptibility genes: STAT4 and BLK, but not PXK, are associated with systemic lupus erythematosus in Hong Kong Chinese. 1922 26

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.
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PMID:Genetic associations of LYN with systemic lupus erythematosus. 1936 46

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

The JAK2 [V617F] mutation has recently been recognised as critical to the pathogenesis of the myeloproliferative disorders (MPDs). Thus, a common mutation affecting a haematopoietic precursor stem cell is capable of giving rise to diverse clinical phenotypes. In this hypothesis paper, we propose that a similar mutation affecting a stem cell precursor, most likely of the B cell lineage, could underlie the development of the connective tissue disorders which could be regarded as "lymphoproliferative" disorders. Consistent with this hypothesis is the observation that there are similarities between the myeloproliferative disorders and the connective tissue disorders in terms of their biological behaviour. Diseases within each family can transform into each other and sometimes into haematological malignancies (most often B cell origin non-Hodgkins lymphoma for the connective tissue disorders and acute myeloid leukemia for the myeloproliferative disorders). The timecourse for development of the connective tissue disorders involves a long latent period when autoantibodies are present (anti-CCP and ANA) possibly reflecting production by a B cell clone. A similar time-dependent increase in clonal dominance has been described in erythroblastic clones taken from the bone marrow of polycythemia vera patients, long before the onset of clinical disease. Evidence of B cell clonality has been described in bone marrow samples from rheumatoid arthritis patients and from glandular biopsies from those with Sjogren's syndrome. Moreover, pseudofollicles containing activated B cells are features of rheumatoid synovial membrane and have also recently been described in subchondral bone where they are associated with macrophages, T cells and osteoclasts. The success of B cell depletion therapy in rheumatoid arthritis and systemic lupus erythematosus is also strong circumstantial evidence for this hypothesis.
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PMID:Will Jill come tumbling after? The case for a JAK2-type mutation as a prequel to the connective tissue disorders. 1948 42

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


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