Mechanisms of natural tolerance in the intestine: implications for inflammatory bowel disease

Tolerance, the regulated inability to respond to a specific immunologic stimulant, is a physiological event important to normal immune function. Just as loss of tolerance to self-proteins results in autoimmune diseases, we assert that loss of tolerance to commensal flora in the intestinal lumen leads to inflammatory bowel disease (IBD). Mechanisms through which the mucosal immune system establishes and remains hyporesponsive toward the presence of food proteins and commensal flora, which we define as natural tolerance, are discussed. In addition to the contributions by commensal flora, the innate host defense and the adaptive immune systems promote natural tolerance to sustain normal mucosal homeostasis. Understanding the molecular and cellular events that mediate natural tolerance will lead to more advanced insights into IBD pathogenesis and improved therapeutic options.