Neutrophils in ANCA-associated vasculitis: Mechanisms and implications for management

Abstract

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of systemic autoimmune diseases, which is typified by inflammatory necrosis predominantly affecting the small vessels and often accompanied by positive ANCA. Clinically, AAV primarily includes microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). It has been found that in AAV pathogenesis, both innate and adaptive immunity are related to neutrophil function mutually. Many proteins, such as myeloperoxidase (MPO) and proteinase 3 (PR3), in neutrophil cytoplasm lead to the production of proteins such as MPO-ANCA and PR3-ANCA by activating adaptive immunity. In addition, through the process of neutrophil extracellular trap (NET) formation, activation of an alternative complement pathway and the respiratory burst can stimulate the neutrophils close to vascular endothelial cells and will participate the vessel inflammation. This review aims to reveal the potential mechanisms regulating the association between the neutrophils and various types of AAVs and to emphasize the results of recent findings on these interactions. Moreover, multiple underlying signaling pathways involved in the regulation of neutrophils during AAV processes have also been discussed. The ultimate goal of this review is to identify novel biomarkers and therapeutic targets for AAV management in the future.

Systemic lupus erythematosus and antineutrocytic cytoplasmic antibody-associated vasculitis overlap syndrome presenting mainly with alveolar hemorrhage: A case report and literature review

“…After neutrophil activation, the target antigens of ANCA are transported from the cell cytoplasm to the membrane surface, and the Fab2 segment of ANCA can bind to the corresponding target antigens, triggering local inflammation. [ 23 ] At the same time, the activation of neutrophils will form NETs. Excessive production of NETs or reduced clearance of NETs will lead to excessive exposure of target antigens such as MPO and PR3, thus forming a vicious circle.…”

Renal involvement in eosinophilic granulomatosis with polyangiitis

“…In this setting also B cells have a pathogenic role, mediated by ANCA. In fact, neutrophils are further activated by ANCA, which can combine with their specific antigens (MPO and PR3) ( 27 ). This concept is supported by the good results obtained with rituximab (RTX), a B-cell depleting agent ( 28 , 29 ).…”

“…Ultimately, activated neutrophils adhere to vascular endothelial cells and subsequently migrate to the vascular wall, where they accumulate, generate reactive oxygen species free radicals, and trigger cell apoptosis and tissue damage. This cascade of events culminates in the inflammatory destruction of vascular endothelial cells and significant tissue injury ( 27 , 30 , 31 ).…”

Serum proteinase-3 levels as a predictor of progression-free survival of first-line chemotherapy in metastatic colorectal cancer

“…Proteinase-3 (PRTN3) belongs to the neutrophil-derived protease family and is stored within azurophil granules [18]. It is involved in neutrophil differentiation and proliferation, in ammation, and vasculitis [19,20], as well as in the invasion of tumor and endothelial cells through the activation of matrix metalloproteinases (MMP)-2 [21,22]. In cancer, PRTN3 expression in tumor tissue is associated with poor prognosis in some carcinomas [23][24][25].…”