Under normal conditions, the body is protected against immune system-mediated self-destruction by marker proteins that indicate that host cells are ‘off limits’ and should be ignored. In patients with rheumatoid arthritis (RA), however, such safeguards fail to prevent immune cells from damaging joint tissues.
Although an estimated 1% of the world’s population is affected by RA, the roots of this disorder are poorly understood. Now, a multi-institutional team of Japanese researchers led by Yuta Kochi and Kazuhiko Yamamoto of the RIKEN Center for Genomic Medicine in Yokohama has characterized potential genetic risk factors1.
The researchers performed a large-scale ‘genome-wide association study’, screening thousands of Japanese individuals to identify small genomic sequence variations—so-called ‘single-nucleotide polymorphisms’ (SNPs)—that are linked with RA susceptibility to a statistically meaningful degree. The strongest association they identified was for a SNP in the vicinity of the gene encoding chemokine (C-C motif) receptor 6 (CCR6). Subsequent analysis of two large, independent cohorts of Japanese subjects provided further confirmation of the connection between this CCR6 SNP and RA.
The CCR6 receptor recognizes signals that stimulate immune cell development, and triggers immune system effects that could be directly relevant to RA. “This receptor has been shown to be important for the migration and recruitment of immune cells such as dendritic cells, T cells, and B-cells during inflammatory and immunological responses” says Kochi, “and it may also regulate the differentiation and maturation of these cells.” Closer examination by the researchers subsequently revealed a second potentially important genetic variation affecting CCR6 expression. They also determined that the elevated CCR6 activity resulting from this variation was strongly associated with RA.
CCR6 appears to exert its pathological effects by promoting the inflammatory response triggered by a recently identified class of helper T cells known as Th17 cells. “We believe the primary role of CCR6 in RA pathogenesis is facilitating the entry of Th17 cells into the joints,” says Kochi. “And as CCR6 is also involved in the migration and differentiation of B-cells, it could also influence the activity of auto-reactive B-cells.” Strikingly, these CCR6 variants also appear to contribute to two other inflammatory conditions, Graves’ disease and Crohn’s disease.
Following on from this discovery, Kochi and Yamamoto are hopeful that their data will yield additional candidate genes that enable further insights into how RA patients’ immune systems end up going off-course. “Many other genetic factors other than CCR6 remain to be discovered,” says Kochi.
The corresponding author for this highlight is based at the Laboratory for Autoimmune Diseases, RIKEN Center for Genomic Medicine
1. Kochi, Y., Okada, Y., Suzuki, A., Ikari, K., Terao, C., Takahashi, A., Yamazaki, K., Hosono, N., Myouzen, K., Tsunoda, T. et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nature Genetics 42, 515–519 (2010)
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