Pathophysiology of ANCA-associated small vessel vasculitis

Abstract

Antineutrophil cytoplasmic autoantibodies (ANCAs) directed to proteinase 3 (PR3-ANCA) or myeloperoxidase (MPO-ANCA) are strongly associated with the ANCA-associated vasculitides--Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome. Clinical observations, including the efficacy of B-cell depletion via rituximab treatment, support--but do not prove--a pathogenic role for ANCA in the ANCA-associated vasculitides. In vitro experimental studies show that the interplay of ANCA, neutrophils, the alternative pathway of the complement system, and endothelial cells could result in lysis of the endothelium. A pathogenic role for MPO-ANCA is strongly supported by in vivo experimental studies in mice and rats, which also elucidate the pathogenic mechanisms involved in lesion development. Unfortunately, an animal model for PR3-ANCA-associated Wegener's granulomatosis is not yet available. Here, cellular immunity appears to play a major role as well, particularly via interleukin-17-producing T cells, in line with granulomatous inflammation in the lesions. Finally, microbial factors, in particular Staphylococcus aureus and gram-negative bacteria, seem to be involved in disease induction and expression, but further studies are needed to define their precise role in disease development.

Fig 1

A proposed model representing innate and adaptive immune mechanisms supposedly involved in the pathogenesis of antineutrophil cytoplasmic autoantibody (ANCA)-associated systemic vasculitis. Superantigens and peptidoglycans from Staphylococcus aureus stimulate antigen-presenting cells (APCs) in the respiratory tract to produce interleukin (IL)-23, which then induces proliferation of T-helper (Th) type 17 cells and release of IL-17. IL-17 acts further on respiratory epithelium and tissue macrophages. In response to IL-17, bronchial epithelial cells secrete CXC chemokines that attract neutrophils to the infected tissue, whereas macrophages release proinflammatory cytokines such as IL-1β and tumor necrosis factor (TNF)-α. These inflammatory cytokines cause priming of neutrophils (membrane expression of proteinase 3 [PR3]) and upregulation of adhesion molecules on their surface as well as on the vascular endothelium. Subsequently, primed neutrophils adhere to the endothelial cells. Released PR3 can be processed and presented by APCs to Th cells. As T-regulatory cells (Tregs) fail to inhibit this autoimmune response in Wegener’s granulomatosis, autoreactive T cells might undergo repeated stimulation by PR3-pulsed APCs, resulting in a pool of effector memory T cells (TEMs). Furthermore, PR3-stimulated Th cells act on B cells and enhance the production of ANCAs. Subsequently, ANCAs activate neutrophils that adhere to endothelial cells, resulting in local production of reactive oxygen species (ROS) and release of proteolytic enzymes that damage vascular endothelial cells. Moreover, the expanded population of CD4⁺ TEMs resulting from persistent activation of Th cells by PR3 upregulate their NKG2D protein and migrate to the peripheral blood and remain in the circulation during remission. When the disease becomes active, MICA protein will be upregulated on several vascular endothelial cells (especially in the kidney), which attract TEMs to the inflammatory areas. The MICA protein on the target cells can bind to NKG2D on the TEMs, which in turn enhances their cytotoxic function to kill the target cell in a perforin- and granzyme-dependent way, ending up in vasculitis. (From Abdulahad et al. [48]; with permission.)