Immunogenic cell death as driver of autoimmunity in granulomatosis with polyangiitis

Abstract

Cell death and dysregulated clearance of dead cells play essential roles in the induction of chronic inflammatory processes and autoimmune diseases. Granulomatosis with polyangiitis (GPA), a neutrophil-driven autoimmune disorder, is characterized by necrotizing inflammation predominantly of the respiratory tract and an anti-neutrophil cytoplasmic autoantibody (ANCA)-associated systemic necrotizing vasculitis. Defective regulation of neutrophil homeostasis and cell death mechanisms have been demonstrated in GPA. Disturbed efferocytosis (i.e., phagocytosis of apoptotic neutrophils by macrophages) as well as cell death-related release of damage-associated molecular patterns (DAMP) such as high mobility group box 1 (HMGB1) contribute to chronic non-resolving inflammation in GPA. DAMP have been shown to induce innate as well as adaptive cellular responses thereby creating a prerequisite for the development of pathogenic autoimmunity. In this review, we discuss factors contributing to as well as the impact of regulated cell death (RCD) accompanied by DAMP-release as early drivers of the granulomatous tissue inflammation and autoimmune responses in GPA.

Efferocytosis: Current status and future prospects in the treatment of autoimmune diseases

“…Anti-neutrophil cytoplasmic antibodies can be detected in the serum of patients. Proteinase 3 (PR3), a serine protease in neutrophil azurophil granules, is expressed on the cell membrane of apoptotic neutrophils and functions as a primary target antigen of anti-neutrophil cytoplasmic antibodies [ 120 ]. Increased expression of membrane PR3 on neutrophils in patients with GPA can impede macrophage efferocytosis [ 121 , 122 ].…”

Classification and clinical significance of immunogenic cell death-related genes in Plasmodium falciparum infection determined by integrated bioinformatics analysis and machine learning

“…Immunogenic cell death (ICD), a distinct form of regulated cell death, is characterized by the release of specific danger signals from dying cells to the immune system [ 2 ]. Immunogenic cell death has important implications for cancer research, infectious diseases, and autoimmunity, as it can be harnessed to enhance antitumour immune responses, develop strategies against pathogens, and understand autoimmune diseases [ 3 , 4 ]. However, there is limited research on the involvement of ICD in the human immune response against malaria.…”