Project Summary/Abstract This proposal focuses on the study of IgG4-related disease in part to obtain insights about the underlying mechanisms that specifically initiate and help maintain this disease. However, the broader goal is to leverage unusual and “advantageous” aspects of this disease to gain broader insights about the underlying principles and mechanisms that potentially lead to the initiation and maintenance of many human autoimmune disorders, in a more general sense. The indolent nature of IgG4-related disease is a factor behind why patients are typically initially seen in an untreated state. The dramatic response to B cell depletion therapy allows easy follow-up up to and at the time of remission and the regular systematic follow up of patients allows us to investigate these patients as they relapse many months later. Sequential analyses will be performed sequentially on peripheral blood mononuclear cells, serum and on the stool (for microbiome). We will use Protein arrays, ELISAs and Luciferase Immunoprecipitation Systems assays to help categorize patients according to their auto-antibody profiles, identify antigen specific B cells and use overlapping peptides to identify memory T cells against self-antigens that induce T-B collaboration and potentially drive the initial disease and the relapse. Potential cross-reactivity of microbial peptide specific CD4+ T cell for self-antigens will also be assessed. Tissue interrogation approaches that incorporate systems biology tools will be used to examine disease end organs to better understand immune mechanisms that drive fibrosis, and when possible draining lymph nodes, to attempt to understand immune dysregulation events that may help initiate the disease.