POS0275 IMPAIRED BONE MARROW B CELL DEVELOPMENT AND PERIPHERAL B CELL MATURATION IN ANCA-ASSOCIATED VASCULITIS
Authors: M. Rizzi, J. Thiel, F. M. Schmidt, R. Lorenzetti, A. Troilo, I. Janowska, L. Nießen, S. Pfeiffer, J. Staniek, B. Benassini Orozco, A. K. Dufner, M. T. Bott, J. Korzhenevich, L. Konstantinidis, F. Burgbacher, N. Frede, R. Voll, J. Stuchly, M. Bakardjieva, T. Kalina, C. Smulski, N. Venhoff
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> B cells are central in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV). The efficacy of remission induction and maintenance by B cell depleting therapy strongly underlines the importance of B cells in the disease and the use of rituximab (RTX) has successfully been implemented in the treatment of AAV. However, B cell depletion after application of RTX is markedly prolonged in AAV compared to other autoimmune diseases, suggesting an impairment of the B cell compartment. <h3>Objectives:</h3> Our study aimed to understand the base of the defect in B cell reconstitution after RTX treatment in AAV, and to dissect B cell function and development in AAV. <h3>Methods:</h3> We recruited 91 AAV patients and performed deep phenotyping of the peripheral B cell compartment by spectral flow cytometry. In a subgroup of patients, we analyzed the bone marrow using flow- as well as mass cytometry. <i>In vitro</i> modeling assays of B lymphopoiesis have been applied to study dynamic of development of AAV B cell precursors. BAFFR involvement into peripheral B cell survival and maturation have been studied by investigating serum BAFF concentration by ELISA, BAFFR expression of isolated B cells was determined by qPCR and Western Blot, and by <i>in vitro</i> survival assays. <h3>Results:</h3> AAV patients show B-lymphocytopenia. Low transitional B cell numbers in treatment-naive patients indicate an impaired central B cell development. In RTX-treated AAV patients the median time of B cell depletion, defined as less than 5 cells/µL, was 17 months (IQR 9-36). We studied phenotype and development of bone marrow B cells and found a defect in early B cell development in both treatment-naive and RTX-treated AAV patients. Only in a subgroup of RTX-treated patients, transitional B cells were increased, indicative of beginning or ongoing B cell repopulation. The increased amount of transitional B cells did not lead to replenishment of the later stages of peripheral B cell maturation, suggesting a maturation stop in peripheral B cell reconstitution in these patients. We found low BAFFR expression in AAV peripheral B cells, caused by enhanced shedding of BAFFR, that resulted in a reduced B cell survival in response to BAFF. <h3>Conclusion:</h3> Our data suggest that prolonged depletion of B cells in AAV patients after RTX therapy indicate a B cell defect that is unmasked by treatment. Impaired central B lymphopoiesis associated with disturbed peripheral B cell maturation because of enhanced BAFFR processing and shedding, resulting in reduced immature B cell survival, contribute to a delayed recovery of the peripheral B cell pool after RTX treatment in AAV. Our data point to a severe defect in B cell maturation and development in patients with AAV that may influence the therapeutic use of B cell depleting agents in this disease. In addition, our results emphasize the need for close immune monitoring after B cell depletion in AAV. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>