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Michael Karin, PhD


University of California, San Diego



New targets for treatment of glucocorticoid-resistant lupus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, the pathogenesis of which depends on autoreactive B cells, among others. B cell activating factor of TNF family (BAFF) promotes production of autoantibodies and its overexpression causes development of lupus-like disease in mice. Although a new therapy based on inhibition of BAFF has been introduced, glucocorticoids (GCs) and other immunosuppressive drugs are often needed to treat SLE (especially lupus flares). Another key feature of SLE is elevated production of type I interferons (IFNs), mainly produced by plasmacytoid dendritic cells (pDCs), which in SLE respond to nucleic acid-containing immune complexes (ICs). These ICs, detected in more than 95% of SLE patients, accumulate in various organs including the kidneys, where they cause glomerulonephritis. GCs interfere with activation of transcription factors required for production of type I IFNs and induce apoptotic death of pDCs and other immune cells, including B lymphocytes. The problems with GC therapy of SLE are the use of very high doses that cause severe metabolic side-effects and development of GC-resistance. Nucleic acid-containing ICs are ligands for TLR7 and 9, and recent studies suggest that their activation interferes with GC-mediated inhibition of IFN-alpha production and apoptosis of pDCs. This led to the suggestion that inhibitors of TLR7/9 can be used to increase the efficacy of low dose GC treatment. We propose to investigate two signaling molecules through which engagement of TLR7/9 leads to induction of type I IFNs, both in pDCs and conventional DCs (cDCs), another possible source of IFN in SLE, and protects these cells from GC-induced death. We will investigate the epistatic relationships of IRAK1, TRAF3, TRAF6 and IKKalpha in TLR7/9-mediated GC-resistance and activation of interferon regulatory factor (IRF) family members IRF3 and IRF7. We will focus our investigation especially on IKKalpha and TRAF3, which we and others have already found to play key roles in TLR7/9-mediated induction of type I IFNs. Most importantly, we will examine whether inhibition of either IKKalpha and/or TRAF3 can interfere with type I IFN production in TLR7/9-activated mouse and human DCs, and the development of lupus-like disease in BAFF transgenic (Tg) mice, a model we have used in the past. Specifically, we will determine whether inhibition of the kinase activity of IKKalpha interferes with IFN production by activated pDCs and renders them more sensitive to GCs, as well as identify the cell type(s) in which IKKalpha activation contributes to development of lupus-like disease. We will also examine the role of TRAF3 ubiquitin ligase activity in protection of activated pDCs from GCs and in the pathogenesis of lupus-like disease. The successful conclusion of these studies will provide us with novel targets for the development of drugs to treat SLE with increased efficacy and reduced side-effects.

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