Citrullination modulates antigen processing and presentation by revealing cryptic epitopes in rheumatoid arthritis

Ashley M. Curran, Alexander A. Girgis, Yura Jang, Jonathan D. Crawford, Mekha A. Thomas, Ryan Kawalerski, Jeff Coller, Clifton O. Bingham, Chan Hyun Na and Erika Darrah ()
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Ashley M. Curran: Johns Hopkins University School of Medicine
Alexander A. Girgis: Johns Hopkins University School of Medicine
Yura Jang: Johns Hopkins University School of Medicine
Jonathan D. Crawford: Johns Hopkins University School of Medicine
Mekha A. Thomas: Johns Hopkins University School of Medicine
Ryan Kawalerski: Johns Hopkins University
Jeff Coller: Johns Hopkins University School of Medicine
Clifton O. Bingham: Johns Hopkins University School of Medicine
Chan Hyun Na: Johns Hopkins University School of Medicine
Erika Darrah: Johns Hopkins University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Cryptic peptides, hidden from the immune system under physiologic conditions, are revealed by changes to MHC class II processing and hypothesized to drive the loss of immune tolerance to self-antigens in autoimmunity. Rheumatoid arthritis (RA) is an autoimmune disease characterized by immune responses to citrullinated self-antigens, in which arginine residues are converted to citrullines. Here, we investigate the hypothesis that citrullination exposes cryptic peptides by modifying protein structure and proteolytic cleavage. We show that citrullination alters processing and presentation of autoantigens, resulting in the generation of a unique citrullination-dependent repertoire composed primarily of native sequences. This repertoire stimulates T cells from RA patients with anti-citrullinated protein antibodies more robustly than controls. The generation of this unique repertoire is achieved through altered protease cleavage and protein destabilization, rather than direct presentation of citrulline-containing epitopes, suggesting a novel paradigm for the role of protein citrullination in the breach of immune tolerance in RA.

Date: 2023
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DOI: 10.1038/s41467-023-36620-y

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