TLR4 and Cowden disease: Hyperreactivity to flagellins was observed in sera from patients with CD.67,143,144 A recently identified dominant-negative TLR5 polymorphism (TLR5-stop), which leads to 75% loss of TLR5 function, reduces adaptive immune responses to flagellin, and, in Jewish cohorts, protects against the development of CD.145 Conversely, complete loss of TLR5 in mice may result in the development of spontaneous colitis via aberrant TLR4 signaling in response to changes in the commensal composition.44