In RA synovial tissue, the interaction between activated M1 macrophages and Th1 cells fosters the production of several pro-inflammatory mediators, including IL-1β, IL-6, TNFα, IL-23, CXCLs, and CCLs; this crosstalk is mediated first by MHC class II and secondarily by costimulatory molecules CD80/CD86, which are overexpressed in RA M1 macrophages (Figure 2) (77, 80, 81). This evidence concerns the gene TNF and rheumatoid arthritis.