Lupus-associated innate receptors drive extrafollicular evolution of autoreactive B cells.

Autor:	Zhu DY; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Harvard Graduate Program in Virology, Boston, MA 02115, USA.; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA., Maurer DP; Harvard Graduate Program in Virology, Boston, MA 02115, USA.; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA., Castrillon C; Department of Medicine, Emory University School of Medicine, Atlanta, GA 30307, USA., Deng Y; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA., Mohamed FAN; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA., Ma M; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA., Schmidt AG; Department of Microbiology, Harvard Medical School, Boston, MA 02115, USA.; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA., Lingwood D; Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA 02139, USA., Carroll MC; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 09. Date of Electronic Publication: 2024 Jan 09.
DOI:	10.1101/2024.01.09.574739
Abstrakt:	In systemic lupus erythematosus, recent findings highlight the extrafollicular (EF) pathway as prominent origin of autoantibody-secreting cells (ASCs). CD21 lo CD11c + B cells, associated with aging, infection, and autoimmunity, are contributors to autoreactive EF ASCs but have an obscure developmental trajectory. To study EF kinetics of autoreactive B cell in tissue, we adoptively transferred WT and gene knockout B cell populations into the 564Igi mice - an autoreactive host enriched with autoantigens and T cell help. Time-stamped analyses revealed TLR7 dependence in early escape of peripheral B cell tolerance and establishment of a pre-ASC division program. We propose CD21 lo cells as precursors to EF ASCs due to their elevated TLR7 sensitivity and proliferative nature. Blocking receptor function reversed CD21 loss and reduced effector cell generation, portraying CD21 as a differentiation initiator and a possible target for autoreactive B cell suppression. Repertoire analysis further delineated proto-autoreactive B cell selection and receptor evolution toward self-reactivity. This work elucidates receptor and clonal dynamics in EF development of autoreactive B cells, and establishes modular, native systems to probe mechanisms of autoreactivity.
Databáze:	MEDLINE
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