Pathways contributing to disease mechanisms in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The 'classic neutrophil pathway' has been studied and confirmed by several groups. This pathway causes necrotizing vasculitis . We propose an additional 'T-cell pathway' that mainly causes granulomatous inflammation and promotes necrotizing vasculitis. Infections are the starting point of both pathways; infections trigger priming of neutrophils, upregulation of adhesion molecules on endothelial cells, and expansion of circulating effector T cells (Teff s). Primed neutrophils show increased surface expression of ANCA antigens and adhesion molecules. ANCA binding activates the neutrophil in the following ways: 1) enhancing vessel wall adherence and transmigration capacity, 2) production and release of oxygen radicals, and 3) degranulation and release of enzymes, including myeloperoxidase (MPO) and proteinase-3 (PR3). Transient immune complexes are formed locally by binding of ANCA to PR3/MPO sticking to endothelial cells. Subsequently, complement is activated. This all adds to the development of necrotizing vasculitis. The expanded effector memory T cells (Tems) are not sufficiently regulated by regulatory T cells (Tregs), leading to dysbalance in the homeostasis of Tregs and Tems and resulting in further release of pro-inflammatory cytokines promoting neutrophil priming; moreover, ANCA production is enhanced by further T cell/B cell interaction. Expanded circulating Tems migrate into target organs such as the lungs or the kidney. Within tissues, Tems drive formation of granuloma, which is considered an 'executioner' of tissue destruction. Granulomas are composed of numerous cell types such as T cells, B cells, giant cells, and dendritic cells. Moreover, ANCA production occurs in granulomas. Possibly, tertiary lymphoid organs (TLOs) are 'local controllers' of tissue inflammation since induction of Tregs is thought to take place in TLOs. ICX, immune complex.