Research Interests: Immunogenetics and infectious/autoimmune diseases
The major focus of the research effort in my laboratory is the identification and characterization of non-classical immune response genes controlling susceptibility and resistance to immunopathologically mediated diseases. These include murine models of both infectious and autoimmune disease. The overall strategy is to use forward genetics to identify genes of interest. With respect to infectious diseases, we have mapped loci that control the quantitative variation in a number of the component phenotypes seen in murine Lyme disease. Similarly, we have identified quantitative trait loci (QTL) which govern phenotypic variation in a number of traits associated with Theiler’s murine encephalomyelitis induced demyelination, an infectious disease model for multiple sclerosis (MS). The autoimmune disease models that we study are experimental allergic encephalomyelitis (EAE), experimental allergic orchitis (EAO), and day three thymectomy induced autoimmune ovarian dysgenesis (AOD). For each of these models we have identified a large number of QTL many of which co-localize with genetic regions implicated in other autoimmune and infectious diseases. This lead us to hypothesize that there may be both common and disease-specific loci that regulate susceptibility to immunopathologically mediated phenotypes, i.e., share immunopathology disease gene hypothesis. This was proven true for Bphs, an autoimmune disease susceptibility gene implicated in both EAE and EAO and susceptibility to B. pertussis toxin, when all three genes were identified as histamine H1 receptor. Similarly, we showed that a 2538 G-->A missense mutation in tyrosine-2 (Tyk2) controlling opposing differential susceptibility to Toxoplasma gondii and autoimmune arthritis is also a susceptibility gene in EAE whose effect is environmentally sensitive. Importantly, TYK2 has been identified as a susceptibility gene in GWAS studies for multiple sclerosis and systemic lupus erythematosis making Tyk2/TYK2 a shared immunopathology gene in both human autoimmune disease and their animals models. Studies are currently underway to delineate the mechanism whereby Hrh1 and Tyk2/TYK2 alleles function in disease pathogenesis.