Early-Stage Autoimmunity in Sjögren's Disease and Systemic Lupus Erythematosus - With over eighty autoimmune diseases and millions of Americans being diagnosed each year, a critical need exists to understand disease progression from serologic changes to early symptoms, to disease classification and to late-stage disease with irreversible, target organ destruction. Great strides have been made in understanding pathogenesis of Sjögren’s disease (SjD) and systemic lupus erythematosus (SLE), which are two of these systemic, autoimmune, rheumatic diseases that share select autoantibodies, genetic associations, increased interferon, limited therapeutic options and some clinical symptoms. However, these diseases also have marked differences in primary target organs, age of onset and serious sequelae. In both diseases, knowledge gaps exist in identifying biomarkers for early diagnosis, targets for directed therapeutics and time- bound risk prediction models to enable prevention trials. This proposal addresses these gaps through study of patients who have positive serology and symptoms of these diseases, but who do not fulfill disease classification criteria, termed in this proposal as non-Sjögren’s sicca (n-SjD-sicca) and incomplete lupus erythematosus (ILE). Studying the beginning stages of autoimmune disorders offers insights into the molecular mechanisms of autoimmune disease without the interference of immunosuppressive medications used to treat autoimmune diseases or the damage of long-standing disease or medication toxicities. This proposal seeks to understand the second stage of autoimmune disease progression, where individuals exhibit autoantibody positivity along with symptoms. Samples and clinical data are available from established cohorts of n-SjD-sicca and SjD from the Oklahoma Sjogren’s Cohort and of ILE and SLE patients from the Lupus Family Registry and Repository of the Oklahoma Rheumatic Disease Research Cores Center. Preliminary experiments have already identified novel autoantibodies for ILE patients compared to SLE patients. The overarching objective is to identify common and disease-specific early-stage molecular mechanisms of autoimmune disease, achieved through two primary aims. The first aim involves identifying shared and disease-specific autoantibody specificities in nSjD sicca and ILE patient sera using complementary screening immunofluorescence, bead- based assays, and array-based technologies. The second aim evaluates shared molecular pathways of early- stage disease pathogenesis in nSjD-sicca and ILE, with a focus on interferon, inflammation, and B cell activation and regulatory pathways. Newer proteomic approaches are also applied. The impact of these studies will significantly advance our understanding of the events in progression from sicca to Sjögren’s disease and from incomplete lupus to systemic lupus erythematosus, potentially identifying and validating novel autoantibodies and specific molecular markers. This research has the potential to influence how we perceive autoimmune disease progression and open doors for earlier diagnosis and improved, directed treatment strategies.
