Defective germinal center selection results in persistence of self-reactive B cells from the primary to the secondary repertoire in Primary Antiphospholipid Syndrome

Yannick Dieudonné (), Raquel Lorenzetti, Julien Rottura, Iga Janowska, Quentin Frenger, Léa Jacquel, Olivier Vollmer, Francesco Carbone, Zhu Chengsong, Marine Luka, Sabine Depauw, Nadège Wadier, Stéphane Giorgiutti, Benoît Nespola, Agathe Herb, Reinhard Edmund Voll, Aurélien Guffroy, Vincent Poindron, Mickaël Ménager, Thierry Martin, Pauline Soulas-Sprauel, Marta Rizzi, Anne-Sophie Korganow and Vincent Gies ()
Additional contact information
Yannick Dieudonné: Strasbourg University Hospital
Raquel Lorenzetti: University of Freiburg
Julien Rottura: Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Iga Janowska: University of Freiburg
Quentin Frenger: Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Léa Jacquel: Strasbourg University Hospital
Olivier Vollmer: Strasbourg University Hospital
Francesco Carbone: INSERM UMR 1163
Zhu Chengsong: University of Texas Southwestern Medical Center
Marine Luka: INSERM UMR 1163
Sabine Depauw: Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Nadège Wadier: Fédération de Médecine Translationnelle de Strasbourg (FMTS)
Stéphane Giorgiutti: Strasbourg University Hospital
Benoît Nespola: Strasbourg University Hospital
Agathe Herb: Strasbourg University Hospital
Reinhard Edmund Voll: University of Freiburg
Aurélien Guffroy: Strasbourg University Hospital
Vincent Poindron: Strasbourg University Hospital
Mickaël Ménager: INSERM UMR 1163
Thierry Martin: Strasbourg University Hospital
Pauline Soulas-Sprauel: Strasbourg University Hospital
Marta Rizzi: University of Freiburg
Anne-Sophie Korganow: Strasbourg University Hospital
Vincent Gies: Strasbourg University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-18

Abstract: Abstract Primary antiphospholipid syndrome (PAPS) is a life-threatening clotting disorder mediated by pathogenic autoantibodies. Here we dissect the origin of self-reactive B cells in human PAPS using peripheral blood and bone marrow of patients with triple-positive PAPS via combined single-cell RNA sequencing, B cell receptors (BCR) repertoire profiling, CITEseq analysis and single cell immortalization. We find that antiphospholipid (aPL)-specific B cells are present in the naive compartment, polyreactive, and derived from the natural repertoire. Furthermore, B cells with aPL specificities are not eliminated in patients with PAPS, persist until the memory and long-lived plasma cell stages, likely after defective germinal center selection, while becoming less polyreactive. Lastly, compared with the non-PAPS cells, PAPS B cells exhibit distinct IFN and APRIL signature as well as dysregulated mTORC1 and MYC pathways. Our findings may thus elucidate the survival mechanisms of these autoreactive B cells and suggest potential therapeutic targets for the treatment of PAPS.

Date: 2024
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DOI: 10.1038/s41467-024-54228-8

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