Defective germinal center selection results in persistence of self-reactive B cells from the primary to the secondary repertoire in Primary Antiphospholipid Syndrome
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.
Authors
- Raquel Lorenzetti (ORCID: https://orcid.org/0009-0008-0184-1609)
- Reinhard Voll (ORCID: https://orcid.org/0000-0002-5542-9133)
- Benoît Nespola (ORCID: https://orcid.org/0000-0003-0618-6646)
- Léa Jacquel (ORCID: https://orcid.org/0000-0002-5255-369X)
- Mickaël Ménager
- Marta Rizzi (ORCID: https://orcid.org/0000-0002-5153-6089)
- Stéphane Giorgiutti (ORCID: https://orcid.org/0000-0002-4791-9618)
- Iga Janowska (ORCID: https://orcid.org/0009-0004-7526-2803)
- Aurélien Guffroy (ORCID: https://orcid.org/0000-0003-0615-5305)
- Yannick Dieudonné (ORCID: https://orcid.org/0000-0001-5132-664X)
- Nadège Wadier (ORCID: https://orcid.org/0000-0001-8427-8736)
- Pauline Soulas‐Sprauel (ORCID: https://orcid.org/0000-0002-2058-4811)
- Vincent Gies (ORCID: https://orcid.org/0000-0002-8658-8604)
- Anne‐Sophie Korganow (ORCID: https://orcid.org/0000-0002-1664-6311)
- Julien Rottura
- Quentin Frenger (ORCID: https://orcid.org/0000-0002-2057-3813)
- Agathe Herb (ORCID: https://orcid.org/0000-0003-1040-0086)
- Sabine Depauw (ORCID: https://orcid.org/0000-0002-8148-7900)
- Olivier Vollmer
- Thierry Martin (ORCID: https://orcid.org/0000-0002-2776-2641)
- Chengsong Zhu
- Francesco Carbone (ORCID: https://orcid.org/0009-0002-0819-4471)
- Vincent Poindron (ORCID: https://orcid.org/0000-0002-3453-6976)
- Marine Luka
Institutions
- Inserm (FR)
- University of Freiburg (DE)
- Medical University of Graz (AT)
- Université Paris Cité (FR)
- University Medical Center Freiburg (DE)
- Fédération Hospitalo-Universitaire, Paris Center for Microbiome Medicine (FR)
- Université de Strasbourg (FR)
- Medical University of Vienna (AT)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-15
- DOI
- https://doi.org/10.1038/s41467-024-54228-8
- Citations
- 7
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 1.68
Funders
- University of Texas Southwestern Medical Center
- CSL Behring
- Deutsche Forschungsgemeinschaft
- Albert-Ludwigs-Universität Freiburg
- Fondation pour la Recherche Médicale
- Université de Strasbourg
- European Regional Development Fund