Interstitial lung disease (ILD) is a complex and heterogeneous disorder that is often associated with autoimmune syndromes; however, despite the connection between ILD and autoimmunity, studies have yet to identify a pathogenic mechanism whereby an autoimmune response specifically targets the lung within ILD patients. With our discovery of novel mouse and human lung antigens (BPIFB1) targeted in autoimmune- mediated ILD, we have linked an autoimmune response to the lung-specific protein BPIFB1 and clinical ILD. Our studies in the Aire translational model have demonstrated a critical role for lun autoantigens in ILD pathogenesis. Patients with defects in the AIRE gene develop the human Autoimmune Polyglandular Syndrome Type 1 (APS1), which includes lung autoimmunity, due to a well-defined breakdown in immune tolerance. Importantly, lung autoimmunity in this model shows relevance to more common forms of autoimmune-associated ILD, as patients and mice with defects in Aire develop autoimmune ILD that is pathologically identical to the ILD of autoimmune connective tissue disorders such as in RA. Strikingly, a subset of non-APS1 patients with autoimmune ILD harbor autoantibodies to BPIFB1, the major human antigen we identified in our model. These results strongly suggest that the Aire model represents a novel ideal system for studying the role of lung-specific autoimmunity in ILD pathogenesis. We hypothesize that autoreactive T cell responses targeting self-antigens in the lung are an important mechanism for inciting interstitial lung inflammation and fibrosis in autoimmune disease. We aim to develop improved insights into disease mechanisms to allow targeted cytokine or cellular interventions in preventing lung autoimmunity and lung fibrosis. To this end we will: (1) define the role of BPIFB1 as a major lung autoantigen in lung autoimmunity; (2) define the role of TH17 cells in autoimmune lung fibrosis; and (3) develop tools for improved diagnosis and disease monitoring in ILD patients. With completion of the proposed studies, we will be poised to gain significant insight into the relevant antigenic targets and effector mechanisms of autoimmune-mediated ILD. By demonstrating that loss of self-tolerance to lung-specific antigens contributes to ILD in a subset of patients with known or unrecognized autoimmunity, we will establish the role of these mechanisms in autoimmune lung injury and progression to lung fibrosis. With development of sensitive and antigen-specific assays, we hope to more accurately diagnosis autoimmune-associated ILD at earlier stages, allowing at risk patients to be monitored or undergo more specific immune-targeted interventions to alter the devastating course of ILD and resultant lung fibrosis.