Submitted on November 29, 2005
Accepted on January 24, 2006
Dominant-Negative TLR5 Polymorphism Reduces Adaptive Immune Response to Flagellin and negatively associates with Crohn's Disease
Andrew T. Gewirtz1*, Matam Vijay-Kumar1, Steven R. Brant2, Richard H. Duerr3, Dan L. Nicolae4, and Judy H. Cho5
1 Department of Pathology and Laboratory Medicine, Epithelial Pathobiology Unit, Emory University School of Medicine, Atlanta, GA, USA
2 Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA
3 Department of Medicine, Uinversity of Pittsburgh, Pittsburgh, PA, USA
4 Department of Statistics, The University of Chicago, Chicago, IL, USA
5 Department of Medicine, The University of Chicago, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: agewirt{at}emory.edu.
Background & Aims: Crohn's disease (CD) is associated with elevated adaptive immunity to commensal microbes, with flagellin being a dominant antigen. In light of heightened awareness of the importance of innate immunity in regulating adaptive immunity and ambiguity as to the role of CD-associated immune responses in CD pathophysiology, we sought to determine whether natural acquisition of immune responses to flagellin were regulated by the innate immune flagellin receptor toll-like receptor 5 (TLR5) and determine whether persons carrying a recently-defined common dominant-negative TLR5 polymorphism (TLR5-stop) might be protected from developing CD. Methods: Carriage rates of a recently-defined dominant-negative TLR5 polymorphism (TLR5-stop) and levels of serum immunoreactivity to bacterial products were measured in IBD patients, first-degree relatives, and unrelated controls. Results: In healthy subjects, persons carrying TLR5-stop had significantly lower levels of flagellin-specific IgG and IgA but had similar levels of total and LPS-specific Ig. Moreover, we observed that among Jewish subjects, the carriage rate of TLR5-stop (in heterozygous state) was significantly less in CD patients, but not ulcerative colitis (UC) patients, compared to unaffected relatives and unrelated controls (5.4%, 0.9%, 6.0%, and 6.5% for unaffected relatives, CD, UC, and unrelated Jewish controls respectively, n= 296, 215, 185, and 416; p=0.037 by likelihood calculation for CD vs. controls) indicating that TLR5-stop can protect persons of Jewish ethnicity against CD. We did not observe a significant association of TLR5-stop with CD in a non-Jewish cohort (11.1%, 10.4%, and 11.7% for unaffected relatives, CD, and UC; n=841, 543, and 300 for unaffected relatives). Conclusions: These results demonstrate that natural acquisition of immune responses to flagellin are regulated by TLR5 and suggest that immune responses to flagellin are not merely associated with CD but rather increase one's potential for developing CD.
