VIENNA — A polymorphism in the gene coding for toll-like receptor 2 seems to constitute a powerful susceptibility gene for acute rheumatic fever, H. Hakan Aydin, M.D., Ph.D., said at the annual European Congress of Rheumatology.
Indeed, 56 of 61 unselected Turkish children who met diagnostic criteria for acute rheumatic fever were heterozygous for the simple polymorphism, in which arginine is replaced by glutamine at position 753 in the toll-like receptor 2 (TLR-2) gene, according to Dr. Aydin of Ege University, Izmir, Turkey.
In contrast, just 9 of 91 ethnically matched healthy pediatric controls and 12 of 116 healthy adult controls were heterozygous for TLR-2 Arg753Gln. Not a single patient or control was homozygous for Arg753Gln.
Genetic differences in host susceptibility to acute rheumatic fever as reflected in the TLR-2 polymorphism go a long way toward explaining why only 0.3–3.0% of patients with acute group A streptococcal pharyngitis go on to develop acute rheumatic fever. Some investigators have also argued that certain strains of group A strep may be more selectively rheumatogenic than others, although to date the evidence supporting this proposition is sketchy, he added at the meeting sponsored by the European League Against Rheumatism.
TLRs play a key role in host immunity, initiating the full range of both adaptive and innate immune responses against all manner of foreign microbes. Stimulation of the TLRs results in production of proinflammatory cytokines, adhesion molecules, chemokines, antibodies, costimulatory molecules, and the major histocompatibility complex, as well as the nuclear transcription factor-kappa-B.
Thus, a polymorphism in TLR-2 rendering affected individuals hyporesponsive to bacteria that contain TLR-2 agonists—as do gram-positive group A strep—could have important clinical consequences. Dr. Aydin and his coinvestigators have also studied polymorphisms in TLR-4 but saw no association with acute rheumatic fever.
The finding that a TLR-2 polymorphism is strongly associated with increased susceptibility to rheumatic fever should eventually lead to a simple genetic test to risk-stratify patients for a disorder the World Health Organization says is still a major health problem, particularly in developing countries. It also opens the door to pharmacologic manipulation of TLR-2 for therapeutic purposes, Dr. Aydin predicted.