Extrafollicular B cell responses correlate with neutralizing antibodies and morbidity in COVID-19

A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell response...

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Published in:	Nature immunology Vol. 21; no. 12; pp. 1506 - 1516
Main Authors:	Woodruff, Matthew C., Ramonell, Richard P., Nguyen, Doan C., Cashman, Kevin S., Saini, Ankur Singh, Haddad, Natalie S., Ley, Ariel M., Kyu, Shuya, Howell, J. Christina, Ozturk, Tugba, Lee, Saeyun, Suryadevara, Naveenchandra, Case, James Brett, Bugrovsky, Regina, Chen, Weirong, Estrada, Jacob, Morrison-Porter, Andrea, Derrico, Andrew, Anam, Fabliha A., Sharma, Monika, Wu, Henry M., Le, Sang N., Jenks, Scott A., Tipton, Christopher M., Staitieh, Bashar, Daiss, John L., Ghosn, Eliver, Diamond, Michael S., Carnahan, Robert H., Crowe, James E., Hu, William T., Lee, F. Eun-Hyung, Sanz, Ignacio
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-12-2020 Nature Publishing Group
Subjects:	631/250 631/250/2152 631/250/254 Antibodies Antibodies, Neutralizing - immunology Antibodies, Viral - immunology B cells B-Lymphocytes - immunology Biomedical and Life Sciences Biomedicine Cell activation Coronaviruses COVID-19 COVID-19 - immunology Flow cytometry Health aspects Heterogeneity Humans Immune response Immunology Immunomodulation Immunophenotyping Infectious Diseases Lymphocytes B Morbidity Observations Pandemics SARS-CoV-2 - immunology Severe acute respiratory syndrome coronavirus 2 Subpopulations Systemic lupus erythematosus United States
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Summary:	A wide spectrum of clinical manifestations has become a hallmark of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic, although the immunological underpinnings of diverse disease outcomes remain to be defined. We performed detailed characterization of B cell responses through high-dimensional flow cytometry to reveal substantial heterogeneity in both effector and immature populations. More notably, critically ill patients displayed hallmarks of extrafollicular B cell activation and shared B cell repertoire features previously described in autoimmune settings. Extrafollicular activation correlated strongly with large antibody-secreting cell expansion and early production of high concentrations of SARS-CoV-2-specific neutralizing antibodies. Yet, these patients had severe disease with elevated inflammatory biomarkers, multiorgan failure and death. Overall, these findings strongly suggest a pathogenic role for immune activation in subsets of patients with COVID-19. Our study provides further evidence that targeted immunomodulatory therapy may be beneficial in specific patient subpopulations and can be informed by careful immune profiling. Sanz and colleagues examine B cell subsets in a cohort of patients with COVID-19. Severely ill patients have higher frequencies of activated extrafollicular T-bet + B cells that form antibody-secreting cells, the majority of which express germline sequences and are reminiscent of antibody responses observed in patients with systemic lupus erythematosus during flares.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 M.C.W., R.P.R., F.E.-H.L. and I.S. conceived the experimental design, analyzed and interpreted the data, designed figures and wrote the manuscript. D.C.N., K.S.C., A.S.S., A.M.L., W.C., S.A.J., J.L.D. and E.G. provided input into experimental design and assisted with figures and manuscript writing. M.C.W. and J.E. designed and ran the FCM panel. R.P.R., S.L., H.M.W., S.N.L., B.S. and F.E.-H.L. designed the inclusion and exclusion criteria for the study, identified research subjects and obtained samples. D.C.N., K.S.C., A.S.S., S.K., A.M.-P., A.D. and F.A.A. assisted with sample preparation and processing. A.S.S. performed FACS sorting and single-cell RNA sequencing. D.C.N., M.S. and C.M.T. performed B cell isolations, bulk V(D)J repertoire library preparation and sequencing. D.C.N., J.C.H., T.O. and W.T.H. performed cytokine and chemokine measurement. R.B. performed serum 9G4-idiotype antibody measurement. D.C.N., N.S.H., S.K., A.M.-P. and A.D. performed anti-SARS-CoV-2 RBD antibody measurements. N.S.H., J.B.C., M.S.D., R.H.C. and J.E.C. performed neutralization testing and data analysis. Author contributions
ISSN:	1529-2908 1529-2916 1529-2916
DOI:	10.1038/s41590-020-00814-z