Citrullination of autoantigens implicates NETosis in the induction of autoimmunity

Abstract

Tolerance blocks the expression of autoantibodies, whereas autoimmunity promotes it. How tolerance breaks and autoantibody production begins thus are crucial questions for understanding and treatment of autoimmune diseases. Evidence implicates cell death and autoantigen modifications in the initiation of autoimmune reactions. One form of neutrophil cell death called NETosis deserves attention because it requires the post-translational modification of histones and results in the extracellular release of chromatin. NETosis received its name from NET, the acronym given to Neutrophil Extracellular Trap. The extracellular chromatin incorporates histones in which arginines have been converted to citrullines by peptidylarginine deiminase IV (PAD4). The deiminated chromatin may function to capture or 'trap' bacterial pathogens, thus generating an extracellular complex of deiminated histones and bacterial cell adjuvants. The complex of bacterial antigens and deiminated chromatin may be internalised by host phagocytes during acute inflammatory conditions, as arise during bacterial infections or chronic autoinflammatory disorders. The uptake and processing of deiminated chromatin together with bacterial adjuvants by phagocytes may induce the presentation of modified histone epitopes and co-stimulation, thus yielding a powerful stimulus to break tolerance. Autoantibodies to deiminated histones are prevalent in Felty's syndrome patients and are present in systemic lupus erythematosus (SLE) and patients with rheumatoid arthritis (RA). These observations clearly implicate histone deimination as an epigenetic mark that can act as an autoantibody stimulant.

Increased Neutrophil Elastase and Proteinase 3 and Augmented NETosis Are Closely Associated With β-Cell Autoimmunity in Patients With Type 1 Diabetes

“…Furthermore, NETs is associated with altered patterns of epigenetic and posttranslational modifications, such as methylation, acetylation, and citrullination, which may represent an important source of autoantigens promoting the generation of autoantibodies (32). In particular, a growing body of evidence supports a pathogenic role for citrullinated autoantigens in triggering autoimmune responses in SLE, rheumatoid arthritis, and multiple sclerosis (33). However, the pathophysiological roles of NETosis and its associated changes in T1D remain elusive.…”

Signal Inhibitory Receptor on Leukocytes-1 Limits the Formation of Neutrophil Extracellular Traps, but Preserves Intracellular Bacterial Killing

“…The release of NETs within the circulation, as well as their interaction with platelets and RBCs, has devastating procoagulant and prothrombotic consequences (18,19,(22)(23)(24). Histones directly cause epithelial and endothelial cell death (25,26), whereas release of NETs exposes self-antigens (27)(28)(29), possibly leading to induction and perpetuation of autoimmunity (16,30). This is most evident in systemic lupus erythematosus (SLE), as immune complexes detected in SLE were found to trigger NET release (25,31,32).…”

Mouse Models of Rheumatoid Arthritis

“…While some of this material may represent chromatin of lysed neutrophils, some of it may correspond to the formation of neutrophilic extracellular traps, which have been implicated in the pathogenesis of rheumatoid arthritis. 11,61 The boxed area in Figure 10 denotes the region shown in Figure 11. Hematoxylin and eosin.…”

“…In addition, neutrophils may promote autoimmunity by formation of neutrophil extracellular chromatin traps (NETs) and the associated promotion of ACPA. 11,70 m Cartilage and bone injury is driven by the formation of an inflammatory pannus that classically invades the joint from the capsular angle. In mouse models, however, substantial amounts of pannus also extend from the bone marrow cavity subjacent to the articular cartilage (Figs.…”