Clonal landscape of autoantibody-secreting plasmablasts in COVID-19 patients
Whereas severe COVID-19 is often associated with elevated autoantibody titers, the underlying mechanism behind their generation has remained unclear. Here we report clonal composition and diversity of autoantibodies in humoral response to SARS-CoV-2. Immunoglobulin repertoire analysis and characterization of plasmablast-derived monoclonal antibodies uncovered clonal expansion of plasmablasts producing cardiolipin (CL)-reactive autoantibodies. Half of the expanded CL-reactive clones exhibited strong binding to SARS-CoV-2 antigens. One such clone, CoV1804, was reactive to both CL and viral nucleocapsid (N), and further showed anti-nucleolar activity in human cells. Notably, antibodies sharing genetic features with CoV1804 were identified in COVID-19 patient-derived immunoglobulins, thereby constituting a novel public antibody. These public autoantibodies had numerous mutations that unambiguously enhanced anti-N reactivity, when causing fluctuations in anti-CL reactivity along with the acquisition of additional self-reactivities, such as anti-nucleolar activity, in the progeny. Thus, potentially CL-reactive precursors may have developed multiple self-reactivities through clonal selection, expansion, and somatic hypermutation driven by viral antigens. Our results revealed the nature of autoantibody production during COVID-19 and provided novel insights into the origin of virus-induced autoantibodies.
Authors
- Daisuke Motooka (ORCID: https://orcid.org/0000-0002-4616-9608)
- Daisuke Okuzaki (ORCID: https://orcid.org/0000-0002-4552-783X)
- Daron M. Standley (ORCID: https://orcid.org/0000-0003-4078-0817)
- Soichiro Haruna
- Teruaki Murakami
- Zichang Xu (ORCID: https://orcid.org/0000-0003-1940-6898)
- Fuminori Sugihara (ORCID: https://orcid.org/0000-0002-6228-4593)
- Atsushi Kumanogoh (ORCID: https://orcid.org/0000-0003-4749-7117)
- Hiroshi Ogura (ORCID: https://orcid.org/0000-0002-5013-2445)
- Shuhei Sakakibara (ORCID: https://orcid.org/0000-0003-3157-5870)
- Ryuya Edahiro (ORCID: https://orcid.org/0000-0001-5009-6408)
- Yukinari Okada
- Hitoshi Kikutani (ORCID: https://orcid.org/0000-0002-2348-3012)
- James B. Wing (ORCID: https://orcid.org/0000-0002-3462-1003)
- Yoshito Takeda (ORCID: https://orcid.org/0000-0003-2905-6537)
- Chikako Ono (ORCID: https://orcid.org/0000-0002-3965-6715)
- Takayoshi Morita (ORCID: https://orcid.org/0000-0002-7111-9506)
- Yuta Yamaguchi (ORCID: https://orcid.org/0000-0002-8314-9294)
- Hisatake Matsumoto (ORCID: https://orcid.org/0000-0001-5771-570X)
- Yuya Shirai (ORCID: https://orcid.org/0000-0002-0518-9020)
- Haruhiko Hirata (ORCID: https://orcid.org/0000-0002-1134-7283)
- Yoshiharu Matsuura (ORCID: https://orcid.org/0000-0001-9091-8285)
- Songling Li (ORCID: https://orcid.org/0000-0001-9554-2248)
- Yasuhiro Kato (ORCID: https://orcid.org/0000-0002-4050-2350)
- Yu‐Chen Liu (ORCID: https://orcid.org/0000-0002-2750-0182)
- Chao‐Yuan Tsai (ORCID: https://orcid.org/0000-0002-6186-2814)
- Yoko Naito (ORCID: https://orcid.org/0000-0003-1512-3313)
- Masakazu Ishikawa (ORCID: https://orcid.org/0000-0003-3349-6738)
- Masato Okada
- Marwa Ali El Hussien
Institutions
- Japan Agency for Medical Research and Development (JP)
- Immune Regulation (United Kingdom) (GB)
- Statistical Research (United States) (US)
- The University of Osaka (JP)
Publication Details
- Journal
- Life Science Alliance
- Published
- 2024-09-17
- DOI
- https://doi.org/10.26508/lsa.202402774
- Citations
- 2
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.78
Funders
- Takeda Science Foundation
- Japan Agency for Medical Research and Development
- Kishimoto Foundation
- Nippon Foundation
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency
- Center for Medical Research and Education, Osaka University
- Research Institute for Microbial Diseases, Osaka University
- Core Research for Evolutional Science and Technology
- Moonshot Research and Development Program