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A Single Nucleotide Polymorphism in Tyk2 Controls Susceptibility to Experimental Allergic Encephalomyelitis¹

Karen M. Spach^*, Rajkumar Noubade^*, Ben McElvany^*, William F. Hickey, Elizabeth P. Blankenhorn and Cory Teuscher^2,*,

^* Department of Medicine and Department of Pathology, University of Vermont, Burlington, VT 05405; Department of Pathology, Dartmouth Medical School, Hanover, NH 03755; and Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129

Genes controlling immunopathologic diseases of differing etiopathology may also influence susceptibility to autoimmune disease. B10.D1-H2^q/SgJ mice with a 2538 GA missense mutation in the tyrosine kinase-2 gene (Tyk2) are susceptible to Toxoplasma gondii yet resistant to autoimmune arthritis, unlike the wild-type B10.Q/Ai substrain. To understand whether Tyk2 is also important in a second autoimmune model, experimental allergic encephalomyelitis (EAE) was induced in B10.D1-H2^q/SgJ (Tyk2^A) and B10.Q/Ai (Tyk2^G) mice with the myelin oligodendrocyte glycoprotein peptide 79–96. B10.D1-H2^q/SgJ mice were resistant to EAE whereas B10.Q/Ai mice were susceptible, and a single copy of the Tyk2^G allele conferred EAE susceptibility in F₁ hybrids. Furthermore, EAE resistance in B10.D1-H2^q/SgJ mice was overridden when pertussis toxin (PTX) was used to mimic the effects of environmental factors derived from infectious agents. Numerous cytokines and chemokines were increased when PTX was included in the immunization protocol. However, only RANTES, IL-6, and IFN- increased significantly with both genetic compensation and PTX treatment. These data indicate that Tyk2 is a shared autoimmune disease susceptibility gene whose genetic contribution to disease susceptibility can be modified by environmental factors. Single nucleotide polymorphisms like the one that distinguishes Tyk2 alleles are of considerable significance given the potential role of gene-by-environment interactions in autoimmune disease susceptibility.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants NS36526, AI41747, AI058052, NS061014, NS060901, and AI45666 and by National Multiple Sclerosis Society Grant RG3575.

² Address correspondence and reprint requests to Dr. Cory Teuscher, C317 Given Medical Building, University of Vermont, Burlington, VT 05405. E-mail address: c.teuscher{at}uvm.edu

³ Abbreviations used in this paper: EAE, experimental allergic encephalomyelitis; CIA, collagen-induced arthritis; MOG, myelin oligodendrocyte glycoprotein; PTX, pertussis toxin; Tyk, tyrosine kinase.