Department of Clinical Immunology and Internal Medicine, National Reference Center for Systemic Autoimmune Diseases (CNR RESO), Tertiary Center for Primary Immunodeficiency, Strasbourg University Hospital, Strasbourg, France.
INSERM UMR - S1109, Institut thématique interdisciplinaire (ITI) de Médecine de Précision de Strasbourg, Transplantex NG, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France.
Nat Commun. 2024 Nov 15;15(1):9921. 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.
原发性抗磷脂综合征 (PAPS) 是一种由致病性自身抗体介导的危及生命的凝血障碍。在这里，我们通过结合单细胞 RNA 测序、B 细胞受体 (BCR) 库分析、CITEseq 分析和单细胞永生化，从三联阳性 PAPS 患者的外周血和骨髓中剖析人类 PAPS 中自身反应性 B 细胞的起源。我们发现抗磷脂 (aPL)-特异性 B 细胞存在于幼稚细胞区室中，具有多反应性，并且来源于天然库。此外，PAPS 患者体内的 aPL 特异性 B 细胞不会被清除，它们持续存在于记忆和长寿浆细胞阶段，可能是在生发中心选择缺陷后，而变得不那么多反应性。最后，与非 PAPS 细胞相比，PAPS B 细胞表现出独特的 IFN 和 APRIL 特征以及失调的 mTORC1 和 MYC 途径。因此，我们的研究结果可能阐明了这些自身反应性 B 细胞的存活机制，并为 PAPS 的治疗提供了潜在的治疗靶点。
