Autoimmune hepatitis (AIH) is traditionally viewed as rare and of unclear etiology. More than 70 years since its first description, nonspecific immunosuppression with corticosteroids remains the cornerstone of therapy. Like other autoimmune disorders, recent data suggest that AIH may be rising in incidence and prevalence. Our group has shown that AIH not only disproportionately affects women but also people of color, both among San Francisco?s underserved population and nationally in terms of hospitalizations for AIH. In order to understand these disparities, we have developed collaborations to study biologic mechanisms underlying AIH. With funding from the American Association for the Study of Liver Diseases, we performed transcriptomic analysis of whole blood samples from AIH patients and controls at Indiana University. The blood of AIH patients was notable for activation of interferon signaling and the presence of pegivirus in several samples. Molecular mimicry has been proposed as a mechanism of AIH pathogenesis, e.g. exposure to a viral antigen may result in aberrant immune recognition of structurally similar antigens in the liver. While the autoantigen for the rarer Type 2 AIH has been identified, no autoantigen has been identified in the more commonly encountered Type 1 AIH. Our collaborators have developed a system for identifying human and viral antigens called Phage Immunoprecipitation-Sequencing (PhIP-Seq). In an ongoing study Prospective Observational Study to Understand Liver Diseases (POSULD), we have been collecting clinical data and biospecimens from AIH patients and controls at UCSF. Preliminary analysis of a small number of POSULD samples by PhIP-Seq identified six potential autoantigens for AIH. These data suggest that analysis of more samples from racially and ethnically diverse patients with AIH and controls could lead to the identification of an autoantigen or autoantigens and clarify the etiopathogenesis of this enigmatic disease. Given these findings, we hypothesize that there is a heretofore unidentified hepatic autoantigen in Type 1 AIH, which may be structurally similar to a viral antigen. This hypothesis will be addressed in the following Specific Aims: (1) To determine human autoantigens in patients with Type 1 AIH; and (2) To investigate viral antigens in patients with Type 1 AIH and, if any are found, assess their similarity to any human autoantigens found in Aim 1. Should this exploratory study improve our understanding of AIH pathogenesis, the findings may provide insight into the health disparities observed by our group and others. Furthermore, therapies aimed at treating or preventing viral infection or modifying the immune response to said antigens may open new avenues of therapy for AIH.

Public Health Relevance

This project will use a novel technology (PhIP-Seq) to look for human and viral antigens involved in a poorly understood and understudied disease, autoimmune hepatitis. We will explore the hypothesis that exposure to viral proteins leads to a dysregulated immune response to structurally similar human proteins in the liver.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Hepatobiliary Pathophysiology Study Section (HBPP)
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Sherker, Averell H
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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