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Citrullination: A Target for Disease Intervention in Multiple Sclerosis and other Inflammatory Diseases?

Renato GS Chirivi, Jos WG van Rosmalen, Guido J Jenniskens, Ger J Pruijn and Jos MH Raats

Citrullinated histone epitopes are involved in the very early stages of inflammatory responses. An important early event is the activation of neutrophils. It has been shown that Peptidyl Arginine Deiminase (PAD) expression levels increase upon pro-inflammatory signalling followed by activation of neutrophils. Subsequently, PAD enzymes cause histone citrullination in the activated neutrophils. Histone citrullination is involved in various processes. One of the most important is NETosis, which results in the release of citrullinated histones to the extracellular space. There, they are involved in Neutrophil Extracellular Trap (NET) formation, which intensifies the inflammatory response. The central role of citrullinated histones in early inflammation makes NETs an attractive target for inflammatory disease intervention. Moreover, the safety profile is expected to be superior to immune-suppressing biologicals, like anti- Tumour Necrosis Factor (TNF) drugs. It is anticipated that shielding citrullinated histone epitopes from the immune system, as well as interfering with their putative roles in the inflammatory response, will have a broad applicability in preventing and treating various inflammatory diseases, including multiple sclerosis.