Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq

Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq

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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 bookers 2022-04 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 seal cookie cutter repertoires in human autoimmunity and the importance of antigen discovery for improved understanding of disease mechanisms.