Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple genetic risk factors, high levels of interferon alpha (IFN-α), and the production of autoantibodies against components of the cell nucleus. Interferon regulatory factor 5 (IRF5) is a transcription factor which induces the transcription of IFN-α and other cytokines, and genetic variants of IRF5 have been strongly linked to SLE pathogenesis. IRF5 functions downstream of Toll-like receptors and other microbial pattern-recognition receptors, and immune complexes made up of SLE-associated autoantibodies seem to function as a chronic endogenous stimulus to this pathway. In this paper, we discuss the physiologic role of IRF5 in immune defense and the ways in which IRF5 variants may contribute to the pathogenesis of human SLE. Recent data regarding the role of IRF5 in both serologic autoimmunity and the overproduction of IFN-α in human SLE are summarized. These data support a model in which SLE-risk variants of IRF5 participate in a “feed-forward” mechanism, predisposing to SLE-associated autoantibody formation, and subsequently facilitating IFN-α production downstream of Toll-like receptors stimulated by immune complexes composed of these autoantibodies. 1. Introduction Systemic lupus erythematosus (SLE) is a complex and heterogeneous disease characterized by a strong genetic contribution and activation of a number of immune system pathways [1–3]. Recent advances in human genetics and gene expression studies have increased our understanding of the immunopathogenesis of the disorder [4]. Interferon (IFN)-α is a pleiotropic type I IFN with the potential to break self-tolerance by inducing dendritic cell differentiation, which can lead to the activation of autoreactive T and B cells [5, 6]. Serum IFN-α levels are often elevated in lupus patients [7–9] and the “IFN-α signature” of gene expression in peripheral blood mononuclear cells is present in more than 50% of SLE patients [10–14]. High IFN-α levels are associated with more severe disease and presence of particular autoantibodies [9, 14, 15]. Additionally, high levels of IFN-α are common in unaffected SLE family members, suggesting that IFN-α is a heritable risk factor [8, 16]. Moreover, some patients given recombinant human IFN-α for viral hepatitis C or malignancy have developed de novo SLE and recovered after the IFN-α was discontinued [17–19]. This body of evidence suggests that IFN-α plays a key role in etiology and pathogenesis of SLE. Interferon regulatory factor (IRF) 5 is a transcription factor that can induce
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