| The systemic autoimmune diseases are a heterogeneous group of genetically complex diseases in which the immune system generates a specific adaptive immune response directed against a diverse group of ubiquitously expressed self antigens. These autoantigens are targeted in a phenotype-specific manner, whereby the specificity of the immune response is associated with the tissues targeted. The mechanisms which select certain molecules as autoantigens remain unclear, but recent data suggests that the antigens which are targeted in rheumatic disease are specifically overexpressed in the target tissue, and may drive this response. This implies that antigen expression within the relevant disease microenvironment plays a role in propagating systemic autoimmunity. In Part I, we examine the possibility that type I interferons (IFN), which have been implicated in the pathogenesis of systemic autoimmune disease, can induce autoantigen expression, thus providing the context necessary (suprathreshold concentration within a proimmune environment) to select a molecule for an antigen-driven immune response. We demonstrate that type I IFNs induce the expression of Ro52, and define Ro52 as an interferon-inducible ubiquitin E3 ligase, with potential anti-viral activity. Ro52 is targeted across the spectrum of rheumatic disease, but it is the only autoantigen that is upregulated by IFN. We conclude that type I IFNs are not driving autoantigen expression within the relevant disease microenvironment.; We independently identified that Ro52 expression is modulated during muscle differentiation and sought to understand the interferon/regeneration interface in the inflammatory myopathies in part II. We demonstrate an unusual confluence of inflammatory and regeneration pathways in an in vitro model of muscle regeneration using expression profiling. We confirm that the molecules which are shared between these pathways are specifically expressed in vivo in myositis muscle, and are strikingly upregulated in regions with features of ongoing regeneration. Collectively these results suggest that the expression of autoantigens and IFN-inducible molecules in myositis muscle is being driven by muscle regeneration. Defining the pathways upstream of this shared group of molecules will likely identify pathways of therapeutic relevance for the treatment of the inflammatory myopathies. |
