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.
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.