LAUSR

TNF has a multifaceted and pivotal function in orchestrating inflammatory and autoimmune responses. Indeed, TNF inhibitors are highly efficacious in various autoimmune diseases, including rheumatoid arthritis (RA). “Despite its success, anti-TNF therapy works for less than a half of patients with RA and other autoimmune diseases,” explains Andrey Kruglov, co-corresponding author on a new study published in Annals of the Rheumatic Diseases. “Considering the multiple pathogenic and non-pathogenic functions of TNF in vivo, we hypothesized that pathogenic TNF may be coming from limited cellular sources,” continues Kruglov. TNF can be soluble or membranebound; hence, the researchers began by investigating the contribution of either molecular form of TNF to collagen-induced arthritis in mice. By comparing mice lacking all TNF to mice lacking only the transmembrane form of TNF, they found that the soluble form of TNF is important for disease induction and autoantibody production, whereas the membrane-bound form is protective and suppresses the development of autoreactive T cells. Kruglov and colleagues then used conditional gene targeting to investigate the contribution of TNF from various cellular sources to experimental arthritis. Whereas T cell-derived TNF protected against arthritis development by limiting autoreactive T helper 1 cell responses, myeloid-derived TNF promoted disease initiation and I M M U N O LO GY