Project Summary Hidradenitis suppurativa (HS) is a chronic inflammatory dermatosis that causes recurrent scarring abscesses and tunnels in the groin, axillae, and perineum. It affects approximately 325,000 Americans, predominantly women and African Americans. Outside the US, 1% of people from high-income countries suffer from it. HS causes recurrent scarring abscesses and reduced quality of life. Most patients live with constant pain, and this leads to chronic opioid use, impaired relationships, and higher suicide risk. Patients with HS are 2-3 times more likely to commit suicide than the general population, and this association is even stronger among women. There is one FDA-approved cure, but it is effective only in 50% of those with moderate to severe disease. A better understanding of HS pathogenesis is needed to develop novel treatment strategies to improve the quality of life in those living with this devastating disease. Epstein Barr Virus (EBV), a ubiquitous gamma herpesvirus is associated with several autoimmune diseases including Rheumatoid arthritis, Multiple Sclerosis (MS), and Systemic Lupus Erythematosus. A recent longitudinal study with a large cohort provided strong evidence that EBV is a trigger for autoimmunity by observing that EBV infection increased the risk of future MS onset by 32-fold. While the mechanisms by which EBV may trigger autoimmunity are unclear, there is compelling evidence that chronic EBV reactivation and molecular mimicry between EBV and human proteins are factors. Our preliminary data, suggests a link between EBV and HS. In preliminary studies, we compared sera from HS patients with controls. We found that HS patients make antibodies that are reactive to (a) select epitopes in EBV and (b) human self-antigens. Non-HS control individuals make antibodies against EBV but they do not make antibodies against the expanded set of EBV epitopes that the HS patients do. These preliminary results suggest a linkage between immune reactivity to novel EBV epitopes and self-antigens in HS. Interestingly, preliminary studies show that HS skin lesions contain pauciclonal, class-switched, somatically mutated B cells and plasma cells. The specificity of the antibodies encoded are unknown, and whether these play a crucial role in HS pathogenesis remains unclear as well. Here we propose to (i) determine the clonal dynamics of B cells and plasma cells in HS skin lesions (Aim 1), (ii) recreate human monoclonal antibodies encoded by these cells, and test their ability to bind EBV and self-antigens. We will also map the unique epitopes in EBV targeted by these HS skin lesion-derived monoclonal antibodies. We will then test if these EBV epitopes can be used as an ELISA screening tool to assess disease severity in HS patients (Aim 2). The proposed work is significant because the knowledge gained from these studies will help better understand the link between EBV and HS pathogenesis and may help identify novel therapeutic strategies to...