The regulatory and effector functions of B cells in ANCA-associated vasculitis

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are systemic autoimmune diseases characterized by necrotizing inflammation of small- to medium-sized blood vessels. In patients with AAV, B cells are considered pathogenic as they produce autoantibodies (ANCA) that mediate neutrophil activation which leads to vascular injury. Although ANCA play a pathogenic role in AAV, it is unclear what drives ANCA production. The first aim of this thesis was to study the mechanisms and factors that stimulate autoantibody production in patients with AAV. We demonstrated that interleukin (IL)-21 in combination with B cell activating factor (BAFF) stimulates ANCA production in vitro. In agreement, we demonstrated an increased frequency of IL-21-producing T helper cells in ANCA-positive patients when compared with ANCA-negative patients and healthy controls, suggesting that IL-21 might contribute to ANCA production in patients. Besides antibody production, B cells are known to affect immune responses by providing co-stimulatory signals and secretion of cytokines and growth factors. Recently a novel B cell subset, termed regulatory B cells, was described and reported to exert a suppressive effect on other immune cells. Therefore, the second aim was to characterize the circulating B cell subsets and evaluate the suppressive function of B cells in AAV patients. We found disturbed homeostasis of circulating B cells in AAV patients but the capacity of B cells in these patients to produce the anti-inflammatory cytokine IL-10 and suppress monocyte activation was not impaired.
Overall, the data presented in this thesis contribute to the knowledge on the humoral and cellular functions of B cells in AAV.