Defects in B-lymphopoiesis and B-cell maturation underlie prolonged B-cell depletion in ANCA-associated vasculitis.

Autor:	Thiel J; Division of Rheumatology and Clinical Immunology, Medical University of Graz, Graz, Austria marta.rizzi@uniklinik-freiburg.de jens.thiel@medunigraz.at.; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Schmidt FM; Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria., Lorenzetti R; Division of Rheumatology and Clinical Immunology, Medical University of Graz, Graz, Austria.; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Troilo A; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Janowska I; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Nießen L; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Pfeiffer S; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Staniek J; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Benassini B; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Bott MT; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Korzhenevich J; Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria., Konstantinidis L; Department of Orthopedics and Trauma Surgery, University of Freiburg, Freiburg im Breisgau, Germany., Burgbacher F; Department of Orthopedics and Trauma Surgery, University of Freiburg, Freiburg im Breisgau, Germany., Dufner AK; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Frede N; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Voll RE; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany.; Centre of Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany., Stuchly J; Department of Paediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic., Bakardjieva M; Department of Paediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic., Kalina T; Department of Paediatric Haematology and Oncology, University Hospital Motol, Prague, Czech Republic., Smulski CR; Medical Physics Department, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Bariloche, Argentina., Venhoff N; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany., Rizzi M; Department of Rheumatology and Clinical Immunology, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany marta.rizzi@uniklinik-freiburg.de jens.thiel@medunigraz.at.; Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria.; Centre of Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
Jazyk:	angličtina
Zdroj:	Annals of the rheumatic diseases [Ann Rheum Dis] 2024 Oct 21; Vol. 83 (11), pp. 1536-1548. Date of Electronic Publication: 2024 Oct 21.
DOI:	10.1136/ard-2024-225587
Abstrakt:	Objectives: B-cell depletion time after rituximab (RTX) treatment is prolonged in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with other autoimmune diseases. We investigated central and peripheral B-cell development to identify the causes for the defect in B-cell reconstitution after RTX therapy. Methods: We recruited 91 patients with AAV and performed deep phenotyping of the peripheral and bone marrow B-cell compartment by spectral flow and mass cytometry. B-cell development was studied by in vitro modelling and the role of BAFF receptor by quantitative PCR, western blot analysis and in vitro assays. Results: Treatment-naïve patients with AAV showed low transitional B-cell numbers, suggesting impaired B-lymphopoiesis. We analysed bone marrow of treatment-naïve and RTX-treated patients with AAV and found reduced B-lymphoid precursors. In vitro modelling of B-lymphopoiesis from AAV haematopoietic stem cells showed intact, but slower and reduced immature B-cell development. In a subgroup of patients, after RTX treatment, the presence of transitional B cells did not translate in replenishment of naïve B cells, suggesting an impairment in peripheral B-cell maturation. We found low BAFF-receptor expression on B cells of RTX-treated patients with AAV, resulting in reduced survival in response to BAFF in vitro . Conclusions: Prolonged depletion of B cells in patients with AAV after RTX therapy indicates a B-cell defect that is unmasked by RTX treatment. Our data indicate that impaired bone marrow B-lymphopoiesis results in a delayed recovery of peripheral B cells that may be further aggravated by a survival defect of B cells. Our findings contribute to the understanding of AAV pathogenesis and may have clinical implications regarding RTX retreatment schedules and immunomonitoring after RTX therapy. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)
Databáze:	MEDLINE
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