Medical Scientist Training Program, University of California, San Francisco, San Francisco, United States; Tetrad Graduate Program, University of California, San Francisco, San Francisco, United States; Diabetes Center, University of California, San Francisco, San Francisco, United States; Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Elise MN Ferré
Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, United States
David W Scheel
Diabetes Center, University of California, San Francisco, San Francisco, United States
Sara Sunshine
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, United States
Diabetes Center, University of California, San Francisco, San Francisco, United States
Caleigh Mandel-Brehm
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States
Zoe Quandt
Department of Medicine, University of California, San Francisco, San Francisco, United States
Alice Y Chan
Department of Pediatrics, University of California, San Francisco, San Francisco, United States
Mickie Cheng
Diabetes Center, University of California, San Francisco, San Francisco, United States
Michael German
Diabetes Center, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United States; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, United States
Michail Lionakis
Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy & Infectious Diseases, National Institutes of Health, Bethesda, United States
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, United States; Chan Zuckerberg Biohub, San Francisco, United States
Diabetes Center, University of California, San Francisco, San Francisco, United States; Department of Medicine, University of California, San Francisco, San Francisco, United States
The identification of autoantigens remains a critical challenge for understanding and treating autoimmune diseases. Autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic form of autoimmunity, presents as widespread autoimmunity with T and B cell responses to multiple organs. Importantly, autoantibody discovery in APS1 can illuminate fundamental disease pathogenesis, and many of the antigens found in APS1 extend to more common autoimmune diseases. Here, we performed proteome-wide programmable phage-display (PhIP-Seq) on sera from a cohort of people with APS1 and discovered multiple common antibody targets. These novel APS1 autoantigens exhibit tissue-restricted expression, including expression in enteroendocrine cells, pineal gland, and dental enamel. Using detailed clinical phenotyping, we find novel associations between autoantibodies and organ-restricted autoimmunity, including a link between anti-KHDC3L autoantibodies and premature ovarian insufficiency, and between anti-RFX6 autoantibodies and diarrheal-type intestinal dysfunction. Our study highlights the utility of PhIP-Seq for extensively interrogating antigenic repertoires in human autoimmunity and the importance of antigen discovery for improved understanding of disease mechanisms.
