Although the pathophysiology of Graves's Disease is well defined, the factors that contribute to susceptibility and trigger autoimmunity to TSHR are not fully understood. Studies in the investigator s laboratory have shown that there is molecular mimicry between a chromosomally encoded low molecular weight protein (LP) of Yersinia enterocolitica and the thyrotropin receptor. LP is a B cell mitogen, and activation of B cells by this LP, but not LP from other gram-negative bacteria, results in production of immunoglobulin which is cross-reactive with TSHR. Importantly, immunization of mice with LP induces antibodies that are cross-reactive with TSHR. Previously, it has not been possible to test whether immunization of mice with LP could induce Grave's Disease because there was not an appropriate animal model for GD. The investigators have recently developed a highly reproducible animal model for GD using Balb/c mice. Availability of LP and an animal model for GD will now allow systematic studies to address the long-held belief concerning the role of Y.enterocolitica in GD.
In Aim 1, the investigators will clone, express, purify, and characterize the LP molecule from Y.enterocolitica.
In Aim 2, they will induce immune responses to TSHR in strains of mice that are either susceptible or resistant to experimental TSHR-mediated autoimmune disease. They will use either Y.enterocolitica LP or TSHR alone, or in combinations to immunize mice to induce GD. After optimal conditions for induction of disease in Balb/c mice are established, they will test differential susceptibility of male and female, young and old, and susceptible and resistant strains of mice. These studies should allow identification of various risk factors for development of GD and pave the way for future studies on molecular pathogenesis of GD.
