Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Production of pathogenic autoantibodies in systemic lupus erythematosus (SLE) requires T cell help, along with ligation of the B cell surface immunoglobulin receptor by antigen. It is likely that macrophages, dendritic cells, and endothelial cells are also activated by interactions with T cells and contribute to lupus pathology. CD40 ligand (CD40L, CD154), a member of the tumor necrosis factor family of cell surface molecules, mediates these contact dependent signals delivered by CD4 + T helper cells to CD40 + target cells. Recent data from SLE patients and murine lupus models have demonstrated prolonged expression of CD40L on lupus T cells and its capacity to mediate excessive B cell activation. This review summarizes the current information regarding transcriptional and post-transcriptional regulation of CD40L expression in normal and SLE T cells. More complete characterization of the mechanisms that regulate the magnitude and duration of CD40L expression should suggest new approaches to modulate this promising therapeutic target.
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PMID:Regulation of CD40 ligand expression in systemic lupus erythematosus. 1160 89

Regulation of B cell receptor signaling is essential for the development of specific immunity while retaining tolerance to self. Systemic lupus erythematosus (SLE) is characterized by a loss of B cell tolerance and the production of anti-self antibodies. Accompanying this break down in tolerance are alterations in B cell receptor signal transduction including elevated induced calcium responses and increased protein phosphorylation. Specific pathways that negatively regulate B cell signaling have been shown to be impaired in some SLE patients. These patients have reduced levels of the kinase Lyn in lipid raft microdomains and this reduction is inversely correlated with increased CD45 in lipid rafts. Function and expression of the inhibitory immunoglobulin receptor FcgammaRIIB is also reduced in Lupus IgM- CD27+ memory cells. Because the relative contribution of different memory and transitional B cell subsets can be abnormal in SLE patients, we believe studies targeted to well defined B cell subsets will be necessary to further our understanding of signaling abnormalities in SLE. Intracellular flow cytometric analysis of signaling is a useful approach to accomplish this goal.
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PMID:Altered B cell receptor signaling in human systemic lupus erythematosus. 1872 29

The non-receptor tyrosine kinase Syk has a diverse range of biological functions, including a critical role in the intracellular signalling cascade for the surface immunoglobulin receptor on B lymphocytes, and the Fc receptor expressed on numerous immune effector cells. It is therefore seen as a potential therapeutic target in a variety of conditions, including autoimmune, allergic and malignant diseases. Fostamatinib disodium is the orally bioavailable prodrug of R406, a relatively selective small molecule inhibitor of Syk, that has accordingly shown activity in numerous cell types in vitro, and efficacy in a remarkable range of animal models in vivo, including rodent models of asthma, inflammatory arthritis, lupus, glomerulonephritis, diabetes and lymphoma. Success in these models has translated to phase II clinical trials in autoimmune thrombocytopenia, lymphoma and, most notably, rheumatoid arthritis, in which larger phase III trials are currently in progress. Whilst the diverse biological functions of Syk, coupled to the potential off-target effects of this kinase inhibitor are a source of possible toxicity, the available data thus far augurs well for future clinical use of Fostamatinib in a wide range of human diseases.
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PMID:Fostamatinib Disodium. 2328 23