In further support of constitutive activation, Fluo-8 staining indicated increased cytoplasmic calcium levels in RA naive CD4+ T cells (Supplementary Fig. 1b), which was subsequently confirmed by ratiometric fluorescence studies with Fura Red (p = 0.01, Fig. 1c, unpaired two-tailed Student’s t test). This evidence concerns the gene CD4 and rheumatoid arthritis.