Proposed pathophysiological mechanisms of anti-neutrophil cytoplasmic autoantibody-associated vasculitides. Inflammatory cytokines (IL-1β, IL-6, transforming growth factor beta (TGFβ)) released due to bacterial or viral infections can promote skewing of a subset of functional regulatory T cells (TRegs) towards IL-17-producing nonfunctional TRegs. These IL-17-producing cells play a key role in disease onset through their cytokine IL-17. This cytokine induces CXC chemokine release from the target tissue that will attract neutrophils to the site of inflammation. In addition, IL-17 stimulates the release of IL-1β and TNFα from macrophages, which causes upregulation of the expression of endothelial adhesion molecules and induces translocation of proteinase-3 (PR3) and myeloperoxidase (MPO) to the neutrophil membrane (priming). Released PR3 and MPO can be processed and presented by antigen-presenting cells (APC) to T-helper cells. Since TRegs are converted into nonfunctional IL-17-producing cells that fail to inhibit this autoimmune response, autoreactive T cells may undergo repeated stimulation by PR3-pulsed or MPO-pulsed APC, resulting in a pool of effector memory T cells (TEM). In addition, PR3-stimulated T-helper cells act on B cells. The presence of IL-17 can enhance the production of anti-neutrophil cytoplasmic autoantibody (ANCA) by autoreactive B cells. Subsequently, ANCA binds to PR3 or MPO on primed neutrophils that adhere to endothelial cells, which enhances neutrophil activation resulting in degranulation and release of reactive oxygen species (ROS) and proteolytic enzymes that can damage vascular endothelial cells. Moreover, persistent activation of T-helper cells by PR3 or MPO, together with the breakdown of TReg-mediated self-tolerance mechanisms, will induce autoreactive CD4+ TEM expansion. Expanded CD4+ TEM upregulate their killer immunoglobulin-like receptor (NKG2D) and interact with their ligand (major histocompatibility complex class-I chain-related molecule A (MICA)) on vascular endothelial cells, which in turn enhances their cytotoxic function and kills target cells in a perforin-dependent and granzyme-dependent way, ending up in vasculitis.
Abdulahad et al. Arthritis Research & Therapy 2011 13:236 doi:10.1186/ar3362