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REAP: A platform to identify autoantibodies that target the human exoproteome

By Eric Y. Wang, Yile Dai, Connor E. Rosen, Monica M. Schmitt, Mei X. Dong, Elise M. N. Ferre, Feimei Liu, Yi Yang, Jaime A. Gonzalez-Hernandez, Eric Meffre, Monique Hinchcliffe, Fotios Koumpouras, Michail S. Lionakis, Aaron M Ring

Posted 12 Feb 2021
bioRxiv DOI: 10.1101/2021.02.11.430703

Autoantibodies that recognize extracellular protein epitopes (the "exoproteome") exert potent functional effects that underlie numerous disease processes. Identifying these antibodies can thus provide insights into the pathophysiology of a wide spectrum of illnesses and therapeutic strategies to treat them. Here, we developed Rapid Extracellular Antigen Profiling (REAP) as a technique for comprehensive and high-throughput discovery of exoproteome-targeting autoantibodies. With REAP, patient samples are applied to a genetically-barcoded library containing 2,688 unique members of the human exoproteome displayed on the surface of yeast. Antibody-coated cells are isolated by magnetic selection and deep sequencing of their barcodes is used to identify the displayed antigens, thereby converting an antibody:antigen binding event into a digital sequencing readout. To benchmark the performance of REAP, we screened 77 patients with the rare monogenic autoimmune disease autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). REAP sensitively and specifically detected known autoantibody reactivities in APECED, including responses against type I interferons, IL-17, IL-22, and gastric intrinsic factor. REAP also identified highly prevalent reactivities that had not been previously described such as those against the glycoprotein hormone GPHB5. We additionally screened 106 patients with systemic lupus erythematosus (SLE) and identified novel autoantibody reactivities against a diverse set of antigens including growth factors, extracellular matrix components, cytokines, and immunomodulatory proteins. Several of these responses were associated with disease severity and specific clinical manifestations of SLE, including autoantibodies that target immunoreceptors, antagonize the pro-inflammatory cytokine IL-33, and recognize endosialin (CD248) and the chemokine CCL8. In summary, these findings demonstrate the utility of REAP to atlas the expansive landscape of exoproteome-targeting autoantibodies in patients.

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