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Systemic Lupus Erythematosus Signaling

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple genes contributing to disease susceptibility. In addition, environmental factors, such as chemicals and drugs, UV light, dietary factors or viruses contribute to the disease. SLE is primarily characterized by the presence of autoantibodies targeting nuclear as well as cytoplasmic antigens. Antibody and immune-complex (IC)-mediated inflammatory processes in SLE can lead to glomerulonephritis, dermatitis, serositis and vasculitis. SLE is characterized by excess T cell activation, defective B cell suppression and the shifting from Th1 to Th2 immune responses, leading to B cell hyperactivity and the production of pathogenic autoantibodies...

Systemic Lupus Erythematosus Signaling

Pathway Summary

Systemic lupus erythematosus (SLE) is an autoimmune disease with multiple genes contributing to disease susceptibility. In addition, environmental factors, such as chemicals and drugs, UV light, dietary factors or viruses contribute to the disease. SLE is primarily characterized by the presence of autoantibodies targeting nuclear as well as cytoplasmic antigens. Antibody and immune-complex (IC)-mediated inflammatory processes in SLE can lead to glomerulonephritis, dermatitis, serositis and vasculitis. SLE is characterized by excess T cell activation, defective B cell suppression and the shifting from Th1 to Th2 immune responses, leading to B cell hyperactivity and the production of pathogenic autoantibodies. Defective immune regulatory mechanisms such as the clearance of ICs contribute to the pathogenesis of the disease.The threshold for T cell activation is lowered in patients with SLE. For instance, presentation of dsDNA and phospholipids results in aberrant activation of T cells, subsequent activation of B cells, and production of autoantibodies (PMID: 12835292). Signaling defects in T cells include: 1) increased LCK activity (PMIDs: 12746907,8428589,15085197), 2) altered coupling of GRB2 to SOS leading to altered Ras/Raf/MEK/ERK signaling (PMID: 12584050), 3) increased intracellular Ca+2 levels leading to increased CD40L and decreased IL-2 levels (PMIDs: 17237447, 15303567), and 4) altered PI3K/AKT signaling resulting in increased IL-6 and IL-10 secretion (PMID: 19080430). Furthermore, the protein composition of lipid rafts is altered in T cells of SLE patients, such as levels of ganglioside GM1 and CD45 (PMID: 15085197). Increased lipid raft clustering in SLE patients results in enhanced signaling responses. Lupus T cells also exhibit mitochondrial dysfunction. They show mitochondrial hyperpolarization (MHP) caused by ROS, increased Ca+2 and NO levels, and decreased levels of GSH (PMIDs: 12097418,14607919). The resultant ATP depletion decreases activation-induced apoptosis predisposing T cells for necrosis, thus stimulating inflammation in SLE (PMID: 12097418).B cell receptor (BCR) activation leads to activation of tyrosine kinases such as Lyn, which phosphorylate the activation motif ITAM on signaling molecules. This initiates several signaling pathways. As a counter-balance, BCR also initiates negative regulation mediated by FcγRIIB, CD22 and other coreceptors containing the inhibitory motif ITIM. In SLE patients, there is altered signaling in activating and inhibitory pathways of B cells. A deficiency in Lyn leads to altered CD22 signaling (PMIDs: 11683380,9480991,11288756) in SLE B cells. There are decreased levels of FCγRIIB in SLE B cells (PMID:15592473), which can result in decreased SHIP phosphatase activity (PMIDs: 12419280,12408047,9052858,9763612). Furthermore, a mutation in CD72 in SLE B cells reduces cell surface expression of CD72, resulting in reduced SHP-1 phosphatase activity. Excessive levels of the TNF-related cytokine BAFF produced by dendritic cells has also been implicated in promoting B cell hyperactivation and autoantibody secretion (PMID: 17276080). Additionally, constitutive expression of IL-6 receptor in conjunction with high levels of IL-6 secretion from SLE B cells contributes to B cell hyperactivation. ICs (autoantibody-antigen) bind to TLRs on plasmacytoid DCs and produce IFNs that also influence B cells to increase Ab production. Thus B cells in SLE are characterized by hyperactivity and Ab production.Defective clearance of ICs in SLE leads to their deposition in various tissues including renal glomeruli where they activate neutrophils and macrophages via FcγR, resulting in inflammation. Macrophages secrete cytokines such as TNF-α, IL-6 and IL-1 which trigger pro-inflammatory pathways. ICs also activate the complement cascade. Increased inflammation and complement activation eventually leads to lupus nephritis. In a similar manner, other tissues such as skin are damaged in SLE.

Systemic Lupus Erythematosus Signaling Genes list

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