Basic science for the clinician 27: Toll-like receptors and nucleotide oligomerization domains

Ancient protective mechanisms are in place, deep within our defenses against infection and malignancy, often unappreciated until homologous proteins found within less phylogenetically advanced organisms are identified. Such is the case with 2 major recent finds, the Toll-like receptors (TLRs) and nucleotide oligomerization domain (NOD) families of innate immunity molecules. These families of receptors have high specificity, limited heterogeneity, and no plasticity; nonetheless, they play a pivotal role in rapid initial defenses against pathogens. Moreover, studies of the mechanisms of TLRs and NODs show how they and IL-1 and IL-18 stand at the threshold of the adaptive immune response and help to accelerate specific immune responsivity. Nonspecific reactivity of these preprogrammed receptors may be how relatively nonpathogenic organisms like yersinia and chlamydia may drive the inflammation of reactive arthritis and atherosclerosis. The inflammation of rheumatoid arthritis may be magnified, if not initiated, by these innate mechanisms as well.