Unveiling the proteome-wide autoreactome enables enhanced evaluation of emerging CAR T cell therapies in autoimmunity.

2024
https://researcherprofiles.org/profile/510210286
38753445
Bodansky A, Yu DJ, Rallistan A, Kalaycioglu M, Boonyaratanakornkit J, Green DJ, Gauthier J, Turtle CJ, Zorn K, O'Donovan B, Mandel-Brehm C, Asaki J, Kortbawi H, Kung AF, Rackaityte E, Wang CY, Saxena A, de Dios K, Masi G, Nowak RJ, O'Connor KC, Li H, Diaz VE, Saloner R, Casaletto KB, Gontrum EQ, Chan B, Kramer JH, Wilson MR, Utz PJ, Hill JA, Jackson SW, Anderson MS, DeRisi JL
Abstract

Given the global surge in autoimmune diseases, it is critical to evaluate emerging therapeutic interventions. Despite numerous new targeted immunomodulatory therapies, comprehensive approaches to apply and evaluate the effects of these treatments longitudinally are lacking. Here, we leveraged advances in programmable-phage immunoprecipitation methodology to explore the modulation, or lack thereof, of autoantibody profiles, proteome-wide, in both health and disease. Using a custom set of over 730,000 human-derived peptides, we demonstrated that each individual, regardless of disease state, possesses a distinct and complex constellation of autoreactive antibodies. For each individual, the set of resulting autoreactivites constituted a unique immunological fingerprint, or "autoreactome," that was remarkably stable over years. Using the autoreactome as a primary output, we evaluated the relative effectiveness of various immunomodulatory therapies in altering autoantibody repertoires. We found that therapies targeting B cell maturation antigen (BCMA) profoundly altered an individual's autoreactome, while anti-CD19 and anti-CD20 therapies had minimal effects. These data both confirm that the autoreactome comprises autoantibodies secreted by plasma cells and strongly suggest that BCMA or other plasma cell-targeting therapies may be highly effective in treating currently refractory autoantibody-mediated diseases.

Journal Issue
Volume 134 of Issue 13