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In This Issue

S pecific HLA alleles may contribute to autoimmune disease susceptibility through presentation of self Ags or other, as yet elusive, mechanisms. The 5-aa shared epitope (SE) motif in HLADRB1 increases both the risk of rheumatoid arthritis development and the severity of disease. The SE has been found to act as a signal transduction ligand that activates pro-oxidative signaling and Th17 polarization. In this issue, to better understand the SE’s role in arthritis development, Holoshitz et al. (p. 48) addressed its ability to affect osteoclastogenesis. A peptide containing the SE directly stimulated NO and reactive oxygen species signaling and osteoclast differentiation in an osteoclast precursor cell line and promoted osteoclastogenesis in murine bone marrow and human PBMCs. Transgenic HLA-DRB1 expression also augmented osteoclast differentiation from bone marrow precursors and subsequent bone-degrading activity. Compared with control peptide, a peptide containing the SE upregulated production of IL-6 and TNF-a, which were important for the SE’s osteoclastogenic activity. The SE could also induce upregulation of receptor activator for NFkB (RANK) on osteoclast precursors and, together with IL-17, synergistically promote osteoclastogenesis. Treatment of collagen-induced arthritis with the SE-containing peptide resulted in the selective expansion of collagen II-specific Th17 cells, increased numbers of osteoclasts, and significantly increased disease, relative to control treatments. Taken together, these data reveal a pathogenic mechanism that may be responsible for the strong association of the SE with rheumatoid arthritis and may advance understanding of HLA linkage to autoimmune disease in general.