This product consists of a mixture of the native histone core proteins [H2A, H2B, H3 and H4] isolated from calf thymus and treated with the peptidyl deiminase 4 (PAD4) enzyme to convert multiple arginine residues to citrulline residues. Citrullinated histone H3 is a NET-specific biomarker.
Post translational modifications of histones in neutrophils have a critical role in regulating neutrophil death and in both innate and adaptive immune responses, with one of the most important being the formation — NETosis — and release of neutrophil extracellular traps (NETs). Upon strong stimulation, the citrullination of histones in neutrophils (also in eosinophils and in mast cells), promotes a rapid calcium-dependent NADPH oxidase independent form of NET formation. NETs are composed of web-like structures, comprised of DNA and other released antibacterial proteins and lots of histone proteins that are released by activated neutrophils and that trap and kill microbes.
In addition to defense against infections, there is strong evidence that NETosis plays an important role in the pathogenesis of several pathological states, including autoimmune diseases. The persistence of citrullinated histones and other NET components in blood can stimulate the production of antibodies to citrullinated proteins. These proteins and antibodies directed against them are implicated in multiple diseases including rheumatoid arthritis, systemic lupus erythematosus, cancer-associated thrombosis, metastasis, multiple sclerosis and Alzheimer’s disease. Therefore, NETosis has become an important therapeutic target. Inhibitors of components of NETosis, including arginine deiminase 4 (PAD4) inhibitors, are key to this therapeutic approach.
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