Background/Purpose: An emerging feature of COVID-19 is the identification of autoreactivity in patients with severe disease that may contribute to disease pathology, however the origins of these responses remain unclear. Previously, we identified extrafollicular B cell activation as a shared immune feature between severe COVID-19 and active rheumatic disease. In autoimmune settings, this pathway is associated with relaxed peripheral tolerance in the antibody secreting cell compartment and the generation of de novo autoreactive responses.

Methods: To further investigate these responses in COVID-19, we performed single-cell B-cell repertoire analysis on 7 patients with severe disease to understand the nature of the antibody secreting cell compartment. We paired these data with cytometry-based and serological assays to detail the nature of these cells, and their contribution to antiviral, and autoreactive responses.

Results: In these patients, we identify a unique low-mutation IgG1 fraction of the antibody secreting cell compartment that lacks surface-expressed B cell receptor, and thus cannot be studied through traditional antigen-labeling studies. These cells are not memory derived, display very low levels of selective pressure, and are enriched for autoreactivity-prone V gene IGHV4-34. Within this compartment, we identify B cell lineages that display specificity to both SARS-CoV-2 and autoantigens, and describe progressive, broad, clinically relevant autoreactivity within these patients including emerging reactivity against the glomerular basement membrane. While progressive early in acute infection, we identify the contraction of this pathway 6 months post-recovery, and a re-establishment of tolerance standards coupled with a concomitant loss of acute-derived responders irrespective of antigen specificity.

Conclusion: In total, this study reveals the origins, breadth, and resolution of emerging autoreactivity in severe COVID-19, with significant implications in both acute-phase rheumatologic interventions and potential treatment of patients with post-COVID sequelae.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/relaxed-peripheral-tolerance-drives-broad-de-novo-autoreactivity-in-severe-covid-19/