Neutrophil-endothelial interaction in ANCA associated vasculitis

Antineutrophil cytoplasmic autoantibodies (ANCA) associated vasculitides comprise three disease phenotypes: granulomatosis with polyangiitis (GPA), formerly Wegener’s Granulomatosis, microscopic polyangiitis (MPA) and Churg-Strauss syndrome (CSS). A central feature of AAV is fibrinoid necrosis affecting small- to medium-sized vessels with little or no deposition of immunoglobulins or complement, in a so-called pauci-immune pattern. It has been intriguing that ANCA-mediated vascular lesions preferentially occur in the microvasculature, the loci where neutrophil trafficking takes place. This would suggest that close interaction of neutrophils and endothelial cells is important for disease development. In this thesis, the mechanisms underlying retaining of neutrophils within the vascular wall and the ensuing vascular damage were investigated. Secondly, up-regulated expression of ANCA antigens, such as membrane-bound proteinase 3 (mPR3), is an important event for ANCA-induced neutrophil activation. The mechanisms of PR3 expression on the neutrophil membrane were, therefore, also investigated. We demonstrated that decreased expression of CXCR1 and CXCR2 on neutrophils in AAV is instrumental in neutrophil accumulation in the microvascular compartment. Effector mechanisms become operational in this process, but the role of AECA is minor. Membrane expression of ANCA-antigens, such as PR3, is induced during neutrophil recruitment. CD177 is responsible for mPR3 expression, but it is not essential for PR3-ANCAmediated neutrophil activation. The underlying mechanism of the increased percentage of CD177+/PR3high neutrophils in AAV is not clear. Differences in gene expression of granule proteins between CD177+ and CD177- subsets cannot easily be translated into functional differences, but indicate heterogeneity of neutrophil populations, which might be dysbalanced in AAV.