PROJECT SUMMARY/ABSTRACT PD-1 is a key immune checkpoint receptor that dampens T cell function. While extensive studies have investigated how PD-1 modulates T cell effector function in cancer settings, how PD-1 regulates systemic autoimmunity and humoral immunity remains poorly defined. Clinically, immune checkpoint inhibitors, including anti-PD-1, induces inflammatory arthritis immune related adverse events (IA-irAE), but the underlying mechanisms and the relationship between IA-irAE and classic rheumatic diseases are unexplored. Importantly, no autoimmune animal models exist that permit direct analysis of clinically-used anti-PD-1 antibodies because they do not interact with mouse PD-1. We utilize novel humanized PD-1 and PD-L1 mouse models to investigate the mechanisms by which clinically-used anti-PD-1 and anti-PD-L1 biologics modulate humoral immune response in a classic collagen induced arthritis model. Furthermore, through comparative analysis of clinical data and immunological profiles between anti-PD-1 induced IA-irAE and rheumatoid arthritis, we uncover remarkable similarity between IA-irAE and seronegative rheumatoid arthritis, a hitherto little understood form of systemic autoimmunity. Our central hypothesis is that anti-PD-1 and anti-PD-L1 biologics induces T cell-dominating and antibody-independent autoimmune toxicity, and impaired PD-1 signaling is a contributing factor to IA-irAE and seronegative rheumatoid arthritis (RA). To test this hypothesis, we will (1) To determine the immunopathology and molecular mechanisms of clinically-used PD-1 and PD-L1 blockade mediated autoimmune diseases, and (2) To investigate how dysregulation of PD-1 signaling contributes to IA-irAE and seronegative RA in human subjects. Building on our clinical and basic research expertise and innovations that integrate novel mouse models, innovative pharmacological interventions and comparative patient cohort analysis, our research will address fundamental questions in PD- 1 signaling, humoral immunity, and systemic autoimmunity, with direct relevance to the improvement of clinical practice and patients’ wellbeing. Additionally, our study will provide a valuable animal model as a research tool for the field of irAE.