PROJECT SUMMARY There is a fundamental gap in our understanding of the pathogenic mechanisms of Bullous pemphigoid (BP), an autoimmune blistering disease of the elderly. Thus, standard treatment consists of high dose immunosuppression, which is associated with significant morbidity and mortality. Our long-term goal is to identify the pathogenic mechanisms of BP so that targeted therapies can be developed, resulting in improved efficacy, decreased off-target effects, and a reduced healthcare burden. The objective of this proposal is to define the role of bacterial colonization with Staphylococcus aureus in the pathogenesis of BP. S. aureus is a leading cause of skin and soft tissue infection and systemic disease. An estimated 30% of the general population is colonized with S. aureus, leading to an increased risk of pathologic infection. Further, S. aureus has been implicated in a host of inflammatory and autoimmune skin diseases resulting from the local or systemic effects of secreted virulence factors, known as superantigens (SAg). Our central hypothesis is that S. aureus colonization plays an important role in pathogenesis BP. The rationale for the proposed research is that establishing a role for S. aureus in the pathogenesis of BP will immediately impact patient care through the addition of antibiotic therapy to the first line of treatment for BP in order to reduce immunosuppressive burden and improve patient outcomes. Guided by our robust preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Establish the prevalence of S. aureus colonization and define SAg profiles in geographically and demographically diverse BP patients. The studies in Aim 1 will determine the impact of race or geographic location on the rate of S. aureus colonization in BP patients, and controls matched by age, sex and race, through two enrollment sites in Iowa and Georgia. The rate of S. aureus colonization, SAg expression, and protective antibody titers will be assessed in relation to measures of BP disease activity. The studies in Aim 2 will determine if S. aureus colonization promotes cutaneous autoimmunity by inducing skin- specific changes in cytokine profiles and Vβ-TCR repertoire. These studies are relevant to the NIH's mission aimed at enhancing health, lengthening life and reducing illness, and relevant to Funding Opportunity PA-18- 739 aimed at evaluating changes in microbiota and its influence in health and disease in the elderly, including those of racial/ethnic minorities, and understanding the underlying mechanisms of microbiota in aged subjects as related to health and disease. This approach innovative because it represents a substantial departure from the current paradigms of BP pathogenesis. The proposed studies are significant because they will advance and expand our understanding of the basic mechanisms of cutaneous autoimmunity in the elderly and will lay the groundwork for mechanistic studies geared toward understanding th...