Dysregulation of B cell function in ANCA-associated vasculitis
BENASSINI B. 1,2, STANIEK J. 1, SCHMIDT F. 1,3, LORENZETTI R. 1, SMULSKI C. 4, SCHNEIDER P. 5, THIEL J. 1,6, VENHOFF N. 1, RIZZI M. 1,3
1 Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg Im Breisgau, Germany; 2 Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg Im Breisgau, Germany; 3 Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria; 4 Medical Physics Department, Bariloche Atomic Centre (CNEA), San Carlos De Bariloche, Argentina; 5 Department of Biochemistry, University of Lausanne, Lausanne, Switzerland; 6 Medical University of Graz, Graz, Austria
ANCA associated vasculitis (AAV) are autoimmune diseases characterized by the presence of autoantibodies against neutrophilic proteins Myeloperoxidase (MPO) and Proteinase 3 (PR3). The presence of autoantibodies and the clinical response to Rituximab (RTX) B cell depletion point to a role for B cells in disease pathogenesis and perpetuation. However, the origins of the disease in the break of tolerance in the B cell compartment that results in autoantibody formation and maintenance remains incompletely characterized.
The effectiveness of RTX suggests a minor role for long lived plasma cells in disease. Post RTX treatment, AAV patients have a substantially prolonged depletion time or no reconstitution at all, even in cases where RTX treatment is not used as maintenance treatment (Thiel et al. 2017). However, repopulating B cells post RTX treatment are enriched in switched memory cells and plasmablasts (Elmer et al. 2020). Furthermore, B cells of AAV patients post RTX treatment show elevated activation markers, such as CD86 (Rizzi preliminary data), CD95 (Fas) (Elmer et al. 2006), and decreased BAFF Receptor (Rizzi preliminary data). Additionally BAFF is elevated in patient serum (Sanders et al. 2006). Hence B cell maturation and phenotype are disturbed in AAV patients. Further, the plausible role of the different maturation pathways in the secondary lymphoid organ - the Germinal Center or Extrafollicular Response - remain elusive in AAV disease origin and maintenance.
Our study aims at understanding the origin and development of autoreactive B cells in AAV, We use high-dimensional flow cytometry of peripheral B cells combined with quantitative B cell phenotyping, activation markers, chemokine receptors, and prominent transcriptional regulator Tbet in B cells in untreated and treated AAV patients in different phase of disease. Our study will dissect the role of B cells in different phase of disease.