Dysregulation of type II interferon associated mediators precedes autoantibody accumulation and type I interferon elevation and predicts transition to systemic lupus erythematosus classification (BA3P.109)

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Abstract Autoantibodies and interferon (IFN) are associated with clinical illness in systemic lupus erythematosus (SLE), but how these factors influence autoimmune disease development is unknown. This study evaluates the timing and changes in SLE-linked autoantibody specificities, serum IFN-α activity, and IFN-associated soluble mediator levels in the years preceding SLE classification. Serial sera from 55 SLE cases spanning pre- and post-SLE classification (average time = 4.3 years) and matched healthy controls (HC) were obtained from the Department of Defense Serum Repository. Cases with positive serum IFN-α activity had more SLE-linked autoantibody specificities (p<0.05). Growth curve modeling and path analysis corroborated that most autoantibody specificities precede IFN-α activity, and IFN-γ and IP-10 were elevated prior to or concurrent with autoantibody positivity (p<0.01). The number of autoantibody specificities and IFN-associated soluble mediators, as well as female gender, predicted increases in IFN-α activity (p<0.04; ANCOVA). IFN-γ and MCP-3 levels, as well as the presence of anti-chromatin and spliceosomal autoantibodies, best predicted transition to SLE with 93% accuracy >4 years before SLE classification (Random Forest). These data indicate that pre-clinical immune system perturbations allow for the accumulation of autoantibodies and subsequent elevation in IFN-α activity immediately preceding clinical symptoms and SLE classification.