NETosis as Source of Autoantigens in Rheumatoid Arthritis

Abstract

In neutrophils (but also in eosinophils and in mast cells), different inflammatory stimuli induce histone deimination, chromatin decondensation, and NET formation. These web-like structures that trap and kill microbes contain DNA, cationic granule proteins, and antimicrobial peptides, but the most abundant proteins are core histones. Histones contained in NETs have been deiminated, and arginines are converted in citrullines. While deimination is a physiological process amplified in inflammatory conditions, only individuals carrying genetic predisposition to develop rheumatoid arthritis (RA) make antibodies to deiminated proteins. These antibodies, collectively identified as anti-citrullinated proteins/peptides antibodies (ACPA), react with different deiminated proteins and display partially overlapping specificities. In this paper, we will summarize current evidence supporting the role of NETosis as critical mechanism in the breach of tolerance to self-antigens and in supporting expansion and differentiation of autoreactive cells. In fact, several lines of evidence connect NETosis with RA: RA unstimulated synovial fluid neutrophils display enhanced NETosis; sera from RA patients with Felty’s syndrome bind deiminated H3 and NETs; a high number of RA sera bind deiminated H4 contained in NETs; human monoclonal antibodies generated from RA synovial B cells decorate NETs and bind deiminated histones. In RA, NETs represent on one side an important source of autoantigens bearing posttranslational modifications and fueling the production of ACPA. On the other side, NETs deliver signals that maintain an inflammatory milieu and contribute to the expansion and differentiation of ACPA-producing B cells.

Meta‐analysis of neutrophil‐to‐lymphocyte and platelet‐to‐lymphocyte ratio in rheumatoid arthritis

“…Neutrophils are thought to be key players in the pathogenesis of RA, given their involvement in the activation of antigen‐presenting cells and production of pro‐oxidative mediators and lytic enzymes in the joint micro‐environment. Of interest, very recently a crucial role in the dysregulation of the adaptive response of the immune system has been attributed to the release by RA neutrophils of neutrophil extracellular traps (NETs) containing high amounts of citrullinated proteins …”

Genetic and environmental risk factors for rheumatoid arthritis

“…antibodies to carbamylated proteins and heat-shock proteins (157–159)), these aspects need to be included in models of disease development. Other processes that need to be explored include the role of neutrophil extracelluar traps (NETs) and inflammasomes in mucosal and systemic autoimmunity (160, 161), and emerging technologies that can elucidate single cell phenotypes (including IgA production) mucosally or systemically (134). Finally, it will be critically important to integrate all of these factors to understand how mucosal processes relate to other factors associated with RA such as genetics, familial factors, and sex, as well as environmental factors such as exposure to tobacco smoke, or dietary factors.…”

Anti‐β2GPI/β2GPI induces human neutrophils to generate NETs by relying on ROS

“…10 The pro-fluorophore DHR123, which is sensitive to redox, displayed similar fluorescence subsequent to supplementation with anti-β2GPI/β2GPI and PMA, despite its weakness compared with the strongest activation by H 2 O 2 ( Figure 6A). 10 The pro-fluorophore DHR123, which is sensitive to redox, displayed similar fluorescence subsequent to supplementation with anti-β2GPI/β2GPI and PMA, despite its weakness compared with the strongest activation by H 2 O 2 ( Figure 6A).…”

“…7 As a stimulator of protein kinase C (PKC), PMA stimulates several downstream pathways triggering NADPH oxidase, which generates the reactive oxygen species (ROS) necessary for NETosis. 10 If NETs are produced during viral infections, they are particularly effective in influencing tolerance and inducing autoimmunity, because viruses trigger the delivery of inflammatory cytokines including Type I interferon, which participates in SLE. 9 Consequently, the release of chromatin during the generation of NETs is a source of autoantigens.…”