NETosis: At the crossroads of rheumatoid arthritis, lupus, and vasculitis.

Suicidal NETosis differs from other mechanisms of cell death by the release of a lattice, composed of DNA associated with proteins citrullinated by protein-arginine deiminase 4, from neutrophils. These 'NETs' are composed of granule-derived proteins with microbicidal activity. A similar type of release occurs during vital NETosis, in which anuclear neutrophils maintain their chemotactic ability and imprison live bacteria, even after NET extrusion. Mitochondrial NETosis is limited to the expulsion of oxidised mitochondrial DNA and cytoplasmic enzymes. NETs include the targets of most autoantibodies found in rheumatoid arthritis, lupus, and vasculitis. The clinical and biological overlaps sometimes observed between bronchectiasis and RA, RA and SLE, or SLE and vasculitis, implicate NETosis as a major triggering event common to these disorders. NETosis increases the possibility of association between autoantigens and infectious antigens in mucosal biofilms, impairing the clearance of pathogens and possibly triggering autoimmune reactions. NETosis aggravates these three conditions and increases endothelial damage and the risk of thrombosis. However, the pathogenesis of RA, SLE, and vasculitis is not confined to autoantibodies against NET components, and other mechanisms have been suggested to explain the breakdown of tolerance to NET autoantigens, such as hypercitrullination. The question of whether continuous presentation of autoantigens mixed with antigens from dormant intracellular pathogens (released following suicidal, vital, or mitochondrial NETosis) is required to induce and sustain autoimmunity must be addressed. Inhibiting NETois may not be sufficient to improve autoimmune disorders whereas such latent infections remain uncontrolled.