Deciphering Genetic Susceptibility of Pemphigus through Immunomics - ABSTRACT Pemphigus is a broad term denoting a subset of potentially life-threatening autoimmune blistering skin diseases with a prevalence of 5.2 cases per 100,000 adults in the United States. Pemphigus foliaceus (PF) is a unique disease intimately related to environmental factors that trigger the disease in genetically susceptible individuals residing in endemic areas, including hematophagous insect bites. Among the genetic variants strongly associated with PF risk are those located within the major histocompatibility complex (MHC), such as the human leukocyte antigen (HLA) class I and II genes. The PI has over a decade of experience in studying this disease and deciphering the unusually complex variation of the extended MHC in multiple populations. The overall goal is to apply a multi-omics approach to perform the most precise mapping of the extended MHC variation and its genetic associations in pemphigus. We will apply long-read high-fidelity large scale to sequencing the entire 5 Mbp extended MHC in pemphigus and use long-read single-cell RNA sequencing (scRNA-seq) to analyze the expression profiles in patients and controls, as well as to perform the first eQTL (expression quantitative traits loci) mapping of the extended MHC using long-read scRNA-seq. We will reveal MHC genetic variants that affect gene expression at the single-cell level and functionally demonstrate disease mechanisms. We will also use scRNA-seq to access the T-cell repertories of patients and controls from endemic areas, which, in the context of MHC variation, is a powerful tool for searching for disease mechanisms and therapeutic targets. Finally, we will apply multiple massively parallel phage sequencing assays in sera samples to measure antibody response and discover reactive antigens associated with pemphigus. We are particularly interested in identifying novel human autoantigens that might affect the disease and viral antigens that could trigger this disease in the endemic areas. This unprecedented immunomics approach will significantly advance the understanding of genetic associations of PF, in addition to discovering new disease mechanisms and possibly new treatment options. As autoimmune diseases often share genetic associations, our findings can possibly be extended to other diseases. Similarly, mapping the functional variation of the MHC will allow a broader understanding of the immune system. If viral antigens are identified as PF triggers, we may pinpoint a direct mechanism for disease prevention, marking a significant step forward in addressing the health disparities associated with this neglected disease.
