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B cells in ANCA-associated vasculitides

From pathogenic players to biomarkers
PhD ceremony:Ms A. (Anouk) von Borstel
When:September 11, 2019
Supervisors:prof. dr. P. (Peter) Heeringa, prof. dr. C.A. Stegeman
Co-supervisors:dr. J.S.F. (Jan-Stephan) Sanders, W.H. (Wayel) Abdulahad
Where:Academy building RUG
Faculty:Medical Sciences / UMCG
B cells in ANCA-associated vasculitides

Granulomatosis with polyangiitis (GPA) is a systemic autoimmune disease characterized by inflammation of small- to medium-sized blood vessels. Although the disease etiology is largely unknown, activated T- and B-cells are thought to play important roles in the disease pathogenesis. In this thesis we studied the role of B-cells in the GPA pathogenesis and whether monitoring of these cells in peripheral blood of GPA patients can predict disease relapses.We studied whether B-cells are intrinsically different in their capacity to respond to B-cell receptor stimulation. This study showed that B-cells of GPA patients are more sensitive to B-cell receptor stimulation as shown by increased levels of the intracellular protein Bruton’s tyrosine kinase (BTK). Additionally, B-cell activation could be inhibited by blocking BTK activity. This finding is of importance, as it indicates that BTK could be used as a novel therapeutic target to inhibit B-cell activation in GPA patients.Another important finding described in this thesis is that an increased frequency of plasmablasts (i.e. a B-cell subset) in the circulation of GPA patients was associated with increased occurrence of disease relapses. These plasmablasts were also found in kidney biopsies and urine of GPA patients with active renal disease, indicating that these cells are directly involved in the autoinflammatory process of GPA.Collectively, the work presented in this thesis enhances our knowledge on the role of B-cells in the GPA pathogenesis and describes several new targets for treatment and prediction of disease relapses in GPA.