As with many autoimmune diseases, T1D is initiated by some unknown inciting event (or events) that results in the appearance of disease-relevant biomarkers. Serum autoantibodies to islet antigens or changes in whole blood gene expression that appear before the onset of glucose intolerance can serve as biomarkers to identify pre-diabetic individuals. As we enter the era of intervention trials to block progression of T1D before beta cell destruction, it is important and beneficial to identify relevant biomarkers that can be used to stage early disease progression in T1D. Recent studies from my lab have demonstrated that changes in gene expression of pancreatic lymph node (PLN) tissue samples from AA+ individuals provided by nPOD, can be seen before the onset of abnormal glucose tolerance. These data also demonstrated that gene expression in the PLN is similar between T1D patients who have had hyperglycemia for two or more years and normal subjects, suggesting that the inflammation accompanying progression to hyperglycemia in AA+ subjects can be identified by changes in gene expression in AA+ subjects, and may be used to identify biomarkers, and/or suggest targets of, or response to therapy. Because PLN tissues cannot be readily biopsied from AA+ individuals, our rationale is to examine gene expression in PBC samples provided by the TrialNet Natural History tissue repository to ask if there are distinct changes in gene expression seen in the PBCs (similar to those seen in the PLN) that occur with the progression of disease. As a second project arising from these data, we will ask if there are changes in gene expression that accompany intervention therapy with CTLA4-Ig in a TrialNet intervention trial being run by Dr. Bill Russell at Vanderbilt. These approaches may help identify early biomarkers of disease that will allow sub-setting of AA+ patients based on stage of disease or rate of progression, and could identify prediction of, or response to, therapy.