Granulomatosis with Polyangiitis (GPA) is an ANCA-associated vasculitis that primarily affects the respiratory tract and lungs, leading to a severe, relapsing-remitting condition involving small blood vessels in vital organs like the lungs and kidneys. The disease is closely linked to autoantibodies known as ANCA, particularly those targeting the neutrophil serine protease proteinase 3 (PR3). Despite extensive research, the role of ANCA in GPA's onset and progression remains unclear. This thesis investigates how ANCA contribute to GPA development and influence its severity. A novel humanized mouse model was created to study small-vessel vasculitis induced by ANCA. Monoclonal antibodies (mAbs) against human PR3 were transferred into a hPR3 knock-in mouse to gain insights into ANCA pathogenicity. The study confirmed that active hPR3 was present on neutrophil surfaces, making it accessible to antibodies. Notably, one mAb, MCPR3-7, inhibited PR3 and disrupted its interaction with its natural inhibitor, a1-proteinase inhibitor, but could not be used for transfer experiments due to binding issues. Analysis of a large GPA patient cohort revealed inhibitory ANCA, but these were not linked to disease relapses or severity. Instead, non-inhibitory antibodies were evaluated, with one mAb inducing a significant inflammatory response in mice, leading to vasculitis-like and pulmonary lesions. The findings suggest that the IgG subclass influe
