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Polymorphism at the HLA-DQ Locus Determines Susceptibility to Experimental Autoimmune Myasthenia Gravis¹

Raghavan Raju^*, Wen-Zhi Zhan, Peter Karachunski, Bianca Conti-Fine, Gary C. Sieck and Chella David^2,*

Departments of ^* Immunology and Anesthesiology Research, Mayo Clinic, Rochester, MN 55905; and Department of Biochemistry and Pharmacology, University of Minnesota, St. Paul, MN 55108

Studies in myasthenia gravis (MG) patients demonstrate that polymorphism at the HLA-DQ locus influences the development of MG. Several studies using the mouse models also demonstrate the influence of class II molecules, especially the H2-A, which is the mouse homologue of HLA-DQ, in experimental autoimmune myasthenia gravis (EAMG). We used transgenic mice expressing two different DQ molecules, DQ8 (DQA1*0301/B1*0302) and DQ6 (DQA1*0103/B1*0601), to evaluate the role of HLA-DQ genes in MG. These mice do not express endogenous mouse class II molecules since they contain the mutant H2-Aß⁰ gene. The mice were immunized with Torpedo acetylcholine receptor, and EAMG was assessed by clinical evaluation and was confirmed by electrophysiology. Clinical scores for EAMG were highest in HLA-DQ8 transgenic mice, whereas the scores of HLA-DQ6 mice rarely exceeded grade 1. There was no incidence of EAMG in class II-deficient (H2-Aß⁰) mice. These results demonstrate that polymorphism at the HLA-DQ locus affects the incidence and the severity of EAMG. The manifestation of susceptibility to EAMG in the context of human class II molecules underscores the important roles of these molecules in the initiation and perpetuation of EAMG.

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