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

• Published in: Nature communications Vol. 15; no. 1; pp. 9921 - 18
• Main Authors: Dieudonné, Yannick, Lorenzetti, Raquel, Rottura, Julien, Janowska, Iga, Frenger, Quentin, Jacquel, Léa, Vollmer, Olivier, Carbone, Francesco, Chengsong, Zhu, Luka, Marine, Depauw, Sabine, Wadier, Nadège, Giorgiutti, Stéphane, Nespola, Benoît, Herb, Agathe, Voll, Reinhard Edmund, Guffroy, Aurélien, Poindron, Vincent, Ménager, Mickaël, Martin, Thierry, Soulas-Sprauel, Pauline, Rizzi, Marta, Korganow, Anne-Sophie, Gies, Vincent
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 15.11.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 38/77; 38/91; 49/1; 49/31; 631/250/2152/2153/1291; 631/250/249/1313; 631/250/2502; 692/420/2780/2152/569/2495; Adult; Aged; Antibodies, Antiphospholipid - immunology; Antiphospholipid antibodies; Antiphospholipid syndrome; Antiphospholipid Syndrome - immunology; APRIL protein; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; B-cell receptor; B-Lymphocytes - immunology; Bone marrow; Cell immortalization; Cell survival; Clotting; Female; Gene sequencing; Germinal Center - immunology; Germinal centers; Humanities and Social Sciences; Humans; Immortalization; Immunological memory; Lymphocytes B; Male; Memory cells; Middle Aged; multidisciplinary; Myc protein; Peripheral blood; Receptors, Antigen, B-Cell - immunology; Receptors, Antigen, B-Cell - metabolism; Science; Science (multidisciplinary); Single-Cell Analysis; Therapeutic targets
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-54228-8

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. Primary antiphospholipid syndrome (PAPS) is a clotting disorder attributed to autoreactive antibodies produced by B cells. Here the authors show, using single cell omics and B cell repertoire data, that autoreactive B cells originate from the natural B cell repertoire and escape germinal center selection to persist in PAPS patient via potential dysregulation of mTORC1 and MYC pathways.