Furthermore, since sPD-1 aggravates progression of symptoms in a murine model of collagen-induced arthritis [24], and increased serum sPD-1 has been reported in RA patient [21, 22, 24], we examined the possibility that increased sPD-1 may interfere with cell surface PD-L1 and T cell-bound PD-1 resulting in defective PD-1 pathway signaling. This evidence concerns the gene HOXD13 and rheumatoid arthritis.