Dysregulated naive B cells and de novo autoreactivity in severe COVID-19

Matthew C. Woodruff, Richard P. Ramonell, Natalie S. Haddad, Fabliha A. Anam, Mark E. Rudolph, Tiffany A. Walker, Alexander D. Truong, Adviteeya N. Dixit, Jenny E. Han, Monica Cabrera-Mora, Martin C. Runnstrom, Regina Bugrovsky, Jennifer Hom, Erin C. Connolly, Igor Albizua, Vidhi Javia, Kevin S. Cashman, Doan C. Nguyen, Shuya Kyu, Ankur Singh Saini, Michael Piazza, Christopher M. Tipton, Arezou Khosroshahi, Greg Gibson, Greg S. Martin, Cheryl L. Maier, Annette Esper, Scott A. Jenks, F. Eun-Hyung Lee () and Ignacio Sanz ()
Additional contact information
Matthew C. Woodruff: Emory University
Richard P. Ramonell: University of Pittsburgh
Natalie S. Haddad: MicroB-plex
Fabliha A. Anam: Emory University
Mark E. Rudolph: Exagen Inc.
Tiffany A. Walker: Emory University
Alexander D. Truong: Emory University
Adviteeya N. Dixit: Emory University
Jenny E. Han: Emory University
Monica Cabrera-Mora: Emory University
Martin C. Runnstrom: Emory University
Regina Bugrovsky: Emory University
Jennifer Hom: Emory University
Erin C. Connolly: Georgia Institute of Technology
Igor Albizua: Emory University School of Medicine, Emory University
Vidhi Javia: Emory University
Kevin S. Cashman: Emory University
Doan C. Nguyen: Emory University
Shuya Kyu: Emory University
Ankur Singh Saini: Emory University
Michael Piazza: Nicoya
Christopher M. Tipton: Emory University
Arezou Khosroshahi: Emory University
Greg Gibson: Georgia Institute of Technology
Greg S. Martin: Emory University
Cheryl L. Maier: Emory University School of Medicine, Emory University
Annette Esper: Emory University
Scott A. Jenks: Emory University
F. Eun-Hyung Lee: Emory University
Ignacio Sanz: Emory University

Nature, 2022, vol. 611, issue 7934, 139-147

Abstract: Abstract Severe SARS-CoV-2 infection1 has been associated with highly inflammatory immune activation since the earliest days of the COVID-19 pandemic2–5. More recently, these responses have been associated with the emergence of self-reactive antibodies with pathologic potential6–10, although their origins and resolution have remained unclear11. Previously, we and others have identified extrafollicular B cell activation, a pathway associated with the formation of new autoreactive antibodies in chronic autoimmunity12,13, as a dominant feature of severe and critical COVID-19 (refs. 14–18). Here, using single-cell B cell repertoire analysis of patients with mild and severe disease, we identify the expansion of a naive-derived, low-mutation IgG1 population of antibody-secreting cells (ASCs) reflecting features of low selective pressure. These features correlate with progressive, broad, clinically relevant autoreactivity, particularly directed against nuclear antigens and carbamylated proteins, emerging 10–15 days after the onset of symptoms. Detailed analysis of the low-selection compartment shows a high frequency of clonotypes specific for both SARS-CoV-2 and autoantigens, including pathogenic autoantibodies against the glomerular basement membrane. We further identify the contraction of this pathway on recovery, re-establishment of tolerance standards and concomitant loss of acute-derived ASCs irrespective of antigen specificity. However, serological autoreactivity persists in a subset of patients with postacute sequelae, raising important questions as to the contribution of emerging autoreactivity to continuing symptomology on recovery. In summary, this study demonstrates the origins, breadth and resolution of autoreactivity in severe COVID-19, with implications for early intervention and the treatment of patients with post-COVID sequelae.

Date: 2022
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DOI: 10.1038/s41586-022-05273-0

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