UC San Diego

Rheumatoid arthritis (RA) is a chronic autoimmune disorder of the joints. In K/BxN arthritis, disease is mediated by autoantibodies directed towards glucose 6-phosphate isomerase (G6PI). It is currently believed that G6PI is deposited on the joint cartilage where it facilitates autoantibody-mediated attack. Here, we show that intracellular G6PI is expunged by neutrophils undergoing 'ETosis' in an area encompassed by DNA-based extracellular traps (ETs). K/BxN arthritic synovial tissue staining revealed the presence of ETs. We investigated the capacity of K/BxN serum to stimulate the release of ETs by neutrophils (NETs) and observed the formation of NETs. Co- staining for G6PI showed that the autoantigen is externalized during NET release and that it is colocalized in NETs. We also found a novel role for cathelin-related antimicrobial peptides (CRAMP) in the pathogenesis of K/ BxN arthritis, as cathelicidin-deficient (Cnlp-/-) mice have an attenuated course of K/BxN arthritis. Two key mediators of K/BxN arthritis are mast cells and neutrophils, both of which are capable of releasing ETs. Mast cells from Cnlp-/- mice are capable of releasing extracellular traps (MCETs), and reconstitution of mast- cell deficient (Pretty2) mice with Cnlp-/- mast cells recapitulates arthritis. Furthermore, reconstitution of Cnlp-/- mice with wild-type neutrophils recapitulated arthritis to levels comparable to that of a wild-type arthritic mouse. We hypothesize that activated mast cells release MCETs, externalizing G6PI in the process. This is further exacerbated by the recruitment of neutrophils and their subsequent production of NETs. This causes more release of cognate antigen into the joint, perpetuating inflammation