I-03 Dysregulation of T helper-type cytokines and interferons appear during early systemic lupus erythematosus pathogenesis and contribute to clinical disease development

BackgroundSystemic lupus erythematosus (SLE) is a complex autoimmune disease stemming from a poorly understood preclinical stage of autoantibody and symptom accrual. Antinuclear autoantibodies (ANAs) accumulate during this preclinical period. As many healthy individuals are also ANA-positive, this study aimed to identify further immune dysregulation that may contribute to disease pathogenesis.Materials and methodsSLE-associated autoantibodies, serum IFN-alpha activity and soluble mediators from multiple immune pathways were measured in serial serum samples from the Department of Defense Serum Repository by bead-based assays and cell-based reporter assays. Eighty-four patients with samples available pre- and post-SLE classification (average timespan = 5.98 years) were compared to 86 matched healthy controls. Temporal and predictive connexions between autoantibodies, soluble mediators, and SLE classification were determined by mixed linear regression, growth curve modelling, path analysis, analysis of covariance and random forest analyses.ResultsIn cases, but not matched controls, autoantibody specificities and IFN-associated mediators accumulated over a period of years, plateauing near the time of disease classification (p < 0.001). Nine soluble mediators, including IL-5 (q = 4.35 × 10−6) and IL-6 (q = 8.26 × 10−6), were significantly elevated in cases vs. controls >3.5 years pre-classification. Th1-type, Th17-type, and TNF superfamily soluble mediators increased longitudinally in cases approaching SLE classification, but not in controls (q < 0.05). In particular, levels of BLyS and APRIL were comparable in cases and controls until 4 years pre-classification; 97% within 2 years of SLE classification).ConclusionsYears before SLE classification, enhancement of the type II IFN pathway allows for accumulation of autoantibodies