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The Loss of Bcl-6 Expressing T Follicular Helper Cells and the Absence of Germinal Centers in COVID-19

51 Pages Posted: 16 Jul 2020 Publication Status: Published

See all articles by Naoki Kaneko

Naoki Kaneko

Ragon Institute of MGH, MIT and Harvard

Hsiao-Hsuan Kuo

Ragon Institute of MGH, MIT and Harvard

Julie Boucau

Ragon Institute of MGH, MIT and Harvard

Jocelyn R. Farmer

Ragon Institute of MGH, MIT and Harvard

Hugues Allard-Chamard

Ragon Institute of MGH, MIT and Harvard

Vinay S. Mahajan

Ragon Institute of MGH, MIT and Harvard

Alicja Piechocka-Trocha

Ragon Institute of MGH, MIT and Harvard

Kristina Lefteri

Ragon Institute of MGH, MIT and Harvard

Matt Osborn

Ragon Institute of MGH, MIT and Harvard

Julia Bals

Ragon Institute of MGH, MIT and Harvard

Yannic C. Bartsch

Ragon Institute of MGH, MIT and Harvard

Nathalie Bonheur

Ragon Institute of MGH, MIT and Harvard

Timothy M. Caradonna

Ragon Institute of MGH, MIT and Harvard

Josh Chevalier

Ragon Institute of MGH, MIT and Harvard

Fatema Chowdhury

Ragon Institute of MGH, MIT and Harvard

Thomas J. Diefenbach

Ragon Institute of MGH, MIT and Harvard

Kevin Einkauf

Ragon Institute of MGH, MIT and Harvard

Jon Fallon

Ragon Institute of MGH, MIT and Harvard

Jared Feldman

Ragon Institute of MGH, MIT and Harvard

Kelsey K. Finn

Ragon Institute of MGH, MIT and Harvard

Pilar Garcia-Broncano

Ragon Institute of MGH, MIT and Harvard

Ciputra Adijaya Hartana

Ragon Institute of MGH, MIT and Harvard

Blake M. Hauser

Ragon Institute of MGH, MIT and Harvard

Chenyang Jiang

Ragon Institute of MGH, MIT and Harvard

Paulina Kaplonek

Ragon Institute of MGH, MIT and Harvard

Marshall Karpell

Ragon Institute of MGH, MIT and Harvard

Eric C. Koscher

Ragon Institute of MGH, MIT and Harvard

Xiaodong Lian

Ragon Institute of MGH, MIT and Harvard

Hang Liu

Ragon Institute of MGH, MIT and Harvard

Jinqing Liu

Ragon Institute of MGH, MIT and Harvard

Ngoc L. Ly

Ragon Institute of MGH, MIT and Harvard

Ashlin R. Michell

Ragon Institute of MGH, MIT and Harvard

Yelizaveta Rassadkina

Ragon Institute of MGH, MIT and Harvard

Kyra Seiger

Ragon Institute of MGH, MIT and Harvard

Libera Sessa

Ragon Institute of MGH, MIT and Harvard

Sally Shin

Ragon Institute of MGH, MIT and Harvard

Nishant Singh

Ragon Institute of MGH, MIT and Harvard

Weiwei Sun

Ragon Institute of MGH, MIT and Harvard

Xiaoming Sun

Ragon Institute of MGH, MIT and Harvard

Hannah J. Ticheli

Ragon Institute of MGH, MIT and Harvard

Michael T. Waring

Ragon Institute of MGH, MIT and Harvard

Alex L. Zhu

Ragon Institute of MGH, MIT and Harvard

Jonathan Li

Brigham and Women's Hospital - Department of Medicine

Daniel Lingwood

Ragon Institute of MGH, MIT and Harvard

Aaron G. Schmidt

Ragon Institute of MGH, MIT and Harvard

Matthias Lichterfeld

Ragon Institute of MGH, MIT and Harvard

Bruce D. Walker

Ragon Institute of MGH, MIT and Harvard; Howard Hughes Medical Institute (HHMI) - Chevy Chase; Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science

Xu Yu

Ragon Institute of MGH, MIT and Harvard

Robert F. Padera

Brigham and Women's Hospital - Department of Pathology

Shiv Pillai

Ragon Institute of MGH, MIT and Harvard

Massachusetts Consortium on Pathogen Readiness Specimen Working Group

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Abstract

Humoral responses in COVID-19 disease are often of limited durability, as seen with other human coronavirus epidemics. To address the underlying etiology, we examined postmortem thoracic lymph nodes and spleens in acute SARS-CoV-2 infection and observed the absence of germinal centers, a striking reduction in Bcl-6+ germinal center B cells but preservation of AID+ B cells. Absence of germinal centers correlated with an early specific block in Bcl-6+TFH cell differentiation together with an increase in T-bet+TH1 cells and aberrant extra-follicular TNF-a accumulation.  Parallel peripheral blood studies revealed loss of transitional and follicular B cells in severe disease and accumulation of SARS-CoV-2-specific “disease-related” B cell populations. These data identify defective Bcl-6+TFH cell generation and dysregulated humoral immune induction early in COVID-19 disease, providing a mechanistic explanation for the limited durability of antibody responses in coronavirus infections and suggest that achieving herd immunity through natural infection may be difficult.

Funding: This work was supported by NIH U19 AI110495 to SP, NIH R01 AI146779 to AGS, NIH R01AI137057 and DP2DA042422 to DL, BMH was supported by NIGMS T32 GM007753, TMC was supported by T32 AI007245. Funding for these studies from the Massachusetts Consortium of Pathogen Readiness, the Mark and Lisa Schwartz Foundation and Enid Schwartz is also acknowledged.

Conflict of Interest: None.

Ethical Approval: This study was performed with the approval of the Institutional Review Boards at the Massachusetts General Hospital and the Brigham and Women’s Hospital.

Suggested Citation

Kaneko, Naoki and Kuo, Hsiao-Hsuan and Boucau, Julie and Farmer, Jocelyn R. and Allard-Chamard, Hugues and Mahajan, Vinay S. and Piechocka-Trocha, Alicja and Lefteri, Kristina and Osborn, Matt and Bals, Julia and Bartsch, Yannic C. and Bonheur, Nathalie and Caradonna, Timothy M. and Chevalier, Josh and Chowdhury, Fatema and Diefenbach, Thomas J. and Einkauf, Kevin and Fallon, Jon and Feldman, Jared and Finn, Kelsey K. and Garcia-Broncano, Pilar and Hartana, Ciputra Adijaya and Hauser, Blake M. and Jiang, Chenyang and Kaplonek, Paulina and Karpell, Marshall and Koscher, Eric C. and Lian, Xiaodong and Liu, Hang and Liu, Jinqing and Ly, Ngoc L. and Michell, Ashlin R. and Rassadkina, Yelizaveta and Seiger, Kyra and Sessa, Libera and Shin, Sally and Singh, Nishant and Sun, Weiwei and Sun, Xiaoming and Ticheli, Hannah J. and Waring, Michael T. and Zhu, Alex L. and Li, Jonathan and Lingwood, Daniel and Schmidt, Aaron G. and Lichterfeld, Matthias and Walker, Bruce D. and Yu, Xu and Padera, Robert F. and Pillai, Shiv and Group, Massachusetts Consortium on Pathogen Readiness Specimen Working, The Loss of Bcl-6 Expressing T Follicular Helper Cells and the Absence of Germinal Centers in COVID-19. Available at SSRN: https://ssrn.com/abstract=3652322 or http://dx.doi.org/10.2139/ssrn.3652322
This version of the paper has not been formally peer reviewed.

Naoki Kaneko

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Hsiao-Hsuan Kuo

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Julie Boucau

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Jocelyn R. Farmer

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Hugues Allard-Chamard

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Vinay S. Mahajan

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Alicja Piechocka-Trocha

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Kristina Lefteri

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Matt Osborn

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Julia Bals

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Yannic C. Bartsch

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Nathalie Bonheur

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Timothy M. Caradonna

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Josh Chevalier

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Fatema Chowdhury

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Thomas J. Diefenbach

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Kevin Einkauf

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Jon Fallon

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Jared Feldman

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Kelsey K. Finn

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Pilar Garcia-Broncano

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Ciputra Adijaya Hartana

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Blake M. Hauser

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Chenyang Jiang

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Paulina Kaplonek

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Marshall Karpell

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Eric C. Koscher

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Xiaodong Lian

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Hang Liu

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Jinqing Liu

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Ngoc L. Ly

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Ashlin R. Michell

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Yelizaveta Rassadkina

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Kyra Seiger

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Libera Sessa

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Sally Shin

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Nishant Singh

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Weiwei Sun

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Xiaoming Sun

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Hannah J. Ticheli

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Michael T. Waring

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Alex L. Zhu

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Jonathan Li

Brigham and Women's Hospital - Department of Medicine ( email )

Boston, MA 02115
United States

Daniel Lingwood

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Aaron G. Schmidt

Ragon Institute of MGH, MIT and Harvard

Boston, MA
United States

Matthias Lichterfeld

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Bruce D. Walker

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Howard Hughes Medical Institute (HHMI) - Chevy Chase ( email )

4000 Jones Bridge Road
Chevy Chase, MD 20815-6789
United States

Massachusetts Institute of Technology (MIT) - Institute for Medical Engineering and Science ( email )

Cambridge, MA
United States

Xu Yu

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

Robert F. Padera

Brigham and Women's Hospital - Department of Pathology

75 Francis St.
Boston, MA 02115
United States

Shiv Pillai (Contact Author)

Ragon Institute of MGH, MIT and Harvard ( email )

Boston, MA
United States

No contact information is available for Massachusetts Consortium on Pathogen Readiness Specimen Working Group

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