SUMMARY This is a request for an Administrative Supplement for the Immune Drivers of Autoimmune Disease (IDAD) project U01 AI176320 “T cells promoting transitions toward autoimmunity”. The proposed studies for the Administrative Supplement are within the scope of the active parent grant, focused on understanding the immune mechanisms underlying the transition from sub-clinical autoimmunity to autoimmune disease. Our objective in this administrative supplement is to test the hypothesis that the transition from high-risk autoantibody positivity to clinical disease will have shared features across these diseases. The proposed studies will leverage existing longitudinal serum samples from three clinical trials evaluating the ability of hydroxychloroquine (HCQ) to prevent progression from sub-clinical autoimmunity with the presence of autoantibodies to clinical diagnosis of autoimmune disease. The three clinical trials are: the TN22 trial focused on prevention of type 1 diabetes (T1D); the SMILE trial focused on prevention of systemic lupus erythematosus (SLE); and the StopRA trial focused on prevention of rheumatoid arthritis (RA). The proposed studies will profile the serum proteome in individuals from these trials using the Olink Explore HT platform to measure 5400 serum proteins. We will select samples from baseline, 6 months, and samples drawn near disease transitions when available. The samples will be run at OMRF leveraging their expertise with Olink and ensuring that the same platform is used for all samples. For data analysis, we will compare placebo versus HCQ within each trial but also compare across trials to identify both disease-specific biomarkers and biomarkers present in all three diseases. We will use approaches that support integration of these datasets with other datasets that have already been generated for each of these trials. Specific Aim 1 will assess the change in serum protein expression from baseline to 6 months on HCQ using samples from the treatment arm of each trial. Specific Aim 2 will assess the change in serum protein expression at baseline, prior to disease transition and after transition selecting samples from individuals in the placebo group who progress to clinical disease. Specific Aim 3 will compare serum protein expression between patient types at baseline and upon disease transition. The proposed project brings together IDAD researchers at BRI, UT Southwestern and OMRF and will include additional research groups in the field including UC Denver. It also expands the IDAD disease focus to include individuals at risk for rheumatoid arthritis.