Hawn TR et al. (2005) A stop codon polymorphism of Toll-like receptor 5 is associated with resistance to systemic lupus erythematosus. Proc Natl Acad Sci USA 102: 10593–10597

Signals from Toll-like receptors (TLRs) are essential for regulating inflammation and for generating innate immune responses to pathogens. A study now shows that signaling downstream of TLR5 might have a role in the development of systemic lupus erythematosus (SLE).

The TLR5 gene, which encodes the receptor for bacterial flagellin, contains a common stop-codon polymorphism that blocks signaling downstream of this receptor. In this paper, Hawn et al. used transmission disequilibrium testing to investigate whether the allele containing this stop codon (allele C1174T) was associated with susceptibility to SLE.

In a cohort of 199 SLE patients and their unaffected relatives (75 siblings and 326 parents) the wild-type allele was preferentially transmitted to individuals with SLE, but the stop-codon allele was not. The allele containing the stop codon was under-represented in individuals with SLE; other TLR5 alleles were equally distributed between the two groups. These data suggest that the TLR5 stop codon is associated with resistance to SLE.

What effect does the presence of the stop codon have on the immune response to flagellin? Peripheral-blood mononuclear cells from individuals with the TLR5 stop codon produced lower levels of proinflammatory cytokines in response to flagellin stimulation than individuals carrying the wild-type allele. The authors concluded that abrogation of TLR5 signaling might therefore blunt the immune response in individuals carrying the stop-codon polymorphism, thereby protecting them from developing SLE.