Lung Inflammation, NETosis, and the Pulmonary Initiation of Anti-Citrullinated Protein Antibody Response: What Came First, the Chicken or the Egg?

Multiple recent lines of evidence suggest that, at least in some patients, RA-associated autoimmunity and inflammation may originate in the lung (1, 2). However, what exactly is/are the initiating event(s), and the sequence of subsequent events, is not fully defined. In this issue of A&R, Okumoto et al (insert new reference), make the intriguing finding that individuals at risk of developing RA have an increased spontaneous neutrophil extracellular trap (NET) formation in sputum, in particular NETs containing citH3, and that these levels associate with presence of IgA ACPA. Such evidence has previously been reported, but the new data presented begins to paint a somewhat revised and enhanced storyline by investigating the pathway of mediation underlying these associations.