RESEARCH HIGHLIGHTS Nature Reviews Rheumatology 9, 3 (2013); published online 11 December 2012; doi:10.1038/nrrheum.2012.221 AUTOIMMUNITY New insights into functional effects of the shared epitope Does the shared epitope—a common enhancing the differentiation of TH17 cells early onset of arthritis and a transient but five-amino-acid sequence in the β1 expressing receptor activator of nuclear nonetheless significant increase in joint subunit of the HLA-DR molecule—act factor κB ligand (RANKL). Notably, the swelling. Articular bone erosion was also as a ligand to trigger innate immune shared epitope effect on differentiation more severe in shared epitope-treated mice signalling? This hypothesis, put forth of mouse osteoclasts was augmented by than in controls; consistent with this effect, by Joseph Holoshitz and colleagues, the presence of IL-17, suggesting that the osteoclasts were more abundant in synovial could help explain the mechanism shared epitope and IL-17 act synergystically tissue of mice that received the peptide. that underlies the well-established yet to promote bone destruction. “The shared epitope ligand, devoid of poorly understood relationship between any antigen presentation capabilities, was HLADRB1 alleles that encode the shared …a synthetic shared epitope able to specifically and potently activate epitope and susceptibility to, and severity T 17-cell and osteoclast differentiation peptide induced the differentiation H of, rheumatoid arthritis (RA). Recent work ‘‘ in vitro and accelerated erosive arthritis in by this group, published in The Journal of osteoclasts… mice in vivo,” says Holoshitz. “This is the of Immunology, suggests that the shared first direct mechanistic insight into the epitope has direct arthritogenic effects in Osteoclast differentiation’’ and function role of the shared epitope in inflammatory RA via activation of osteoclastogenesis. was also enhanced in bone marrow cells arthritis, and the first evidence linking Holoshitz et al. demonstrated in vitro isolated from transgenic mice expressing TH17-cell and osteoclast differentiation to that treatment of mouse and human cells genes encoding the human shared epitope, the shared epitope.” with a synthetic shared epitope peptide in comparison with cells from mice Sarah Onuora induced the differentiation of osteoclasts, expressing a different HLADRB1 allele. and augmented the production of the pro- The researchers also examined the effects Original article Holoshitz, J. et al. An HLA-DRB1–coded osteoclastogenic cytokines IL-6 and TNF. of the shared epitope in vivo, in mice with signal transduction ligand facilitates inflammatory Furthermore, the peptide facilitated T-cell- collagen-induced arthritis. Intraperitoneal arthritis: a new mechanism of autoimmunity. J. Immunol. doi:10.4049/jimmunol.1202150 mediated effects on osteoclastogenesis, by injection of a shared epitope peptide led to NATURE REVIEWS | RHEUMATOLOGY VOLUME 9 | JANUARY 2013 © 2013 Macmillan Publishers Limited. All rights reserved.