Flag in the crossroads: flagellin modulates innate and adaptive immunity.
OBJECTIVE
To consider observations suggesting that the bacterial protein flagellin, the primary structural component of flagella, plays a major role in mediating gut inflammation associated with infection by enteric pathogens and in inflammatory bowel disease.


RESULTS
Biochemical dissection of an in-vitro model of bacterial-epithelial interactions revealed flagellin, via ligation of Toll-like receptor 5, to be a major means of activating the innate immune responses defining active intestinal inflammation. Application of the novel technique of serologic expression cloning to murine models of colitis discovered that flagellin is also a dominant target of the adaptive immune responses that drive colitis in such models. Human studies observed that flagellin was also a major antigenic target of immune responses associated with Crohn's disease. Carriers of dominant-negative Toll-like receptor 5 gene exhibit reduced natural acquisition of immunity to flagellin, indicating that the adaptive immune response to flagellin is likely driven, in part, by Toll-like receptor 5. In some genetic backgrounds dominant-negative Toll-like receptor 5 associated negatively with Crohn's disease, suggesting that immune responses to flagellin are not only associated with Crohn's disease, but can promote the pathogenic response.


CONCLUSIONS
Flagellin is a major activator of innate immunity thus driving pathogen-induced acute inflammation and, perhaps, the active flares of inflammatory bowel disease. Flagellin is also a dominant antigen of the Crohn's disease-associated adaptive immune response, thus placing this molecule at the crossroads of the innate and adaptive immune responses that are the hallmark of intestinal inflammation.
Gewirtz
Andrew T
AT
Department of Pathology and Laboratory Medicine, Epithelial Pathobiology Unit, Emory University School of Medicine, Atlanta, Georgia 30322, USA. agewirt@emory.edu
D000222:Adaptation, Physiological / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D003424:Crohn Disease / Q000276:immunology* / Q000503:physiopathology; D005260:Female; D005408:Flagellin / Q000276:immunology* / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology / Q000502:physiology*; D015212:Inflammatory Bowel Diseases / Q000276:immunology / Q000503:physiopathology; D007413:Intestinal Mucosa / Q000276:immunology / Q000503:physiopathology; D008297:Male; D011379:Prognosis; D011956:Receptors, Cell Surface / Q000276:immunology; D012016:Reference Values; D012680:Sensitivity and Specificity; D051198:Toll-Like Receptor 5 / Q000276:immunology / Q000378:metabolism
D015415:Biomarkers; D011956:Receptors, Cell Surface; D051198:Toll-Like Receptor 5; D005408:Flagellin