Nine neutrophil enzyme pathways can initiate hyperinflammatory or autoimmune diseases.

There is substantial experimental evidence suggesting several autoimmune or hyperinflammatory diseases, including multisystem inflammatory syndrome and Kawasaki disease, can be initiated by at least nine neutrophil enzyme pathways. One pathway can also be facilitated by lymphocyte suppression or exhaustion by a virulent pathogen, but eight pathways involving subtypes of neutrophil extracellular traps, are independent from lymphocyte suppression or exhaustion by a pathogen. All nine pathways involve activated neutrophils. In the first pathway, abnormally high releases of proteases from neutrophils and other immune cells respond to certain pathogen infections, and can expose auto-antigens to initiate auto-reactive T cells or antibodies. In eight pathways, immune cells including neutrophils can respond to pathogens by undergoing one of eight different subtypes of NETosis, which will release enzymes causing a posttranslational removal of amine groups (citrullination) from nuclear histones which include positively charged arginine amino acid residues. The enzyme peptidyl arginine deaminase 4 is a major catalytic enzyme released from neutrophils and its catalytic reaction produces ammonium ions and neutral citrulline amino acid residues in histones and other proteins. The citrullinated host proteins can act as auto-antigens to the immune system, causing auto-reactive T cells or antibodies. The trigger for any of these nine neutrophil enzyme pathways can be a novel virulent infection, or possibly a reactivated latent pathogen.

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