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Anti-CTLA-4 Antibody Treatment Triggers Determinant Spreading and Enhances Murine Myasthenia Gravis¹

Hua-Bing Wang^2,*, Fu-Dong Shi^2,3,, Hulun Li^*, Benedict J. Chambers, Hans Link^* and Hans-Gustaf Ljunggren^4,,

^* Experimental Neurology Unit, Division of Neurology, and Department of Medicine, Center for Infectious Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden; and Microbiology and Tumor Biology Center, Karolinska Institute, Stockholm, Sweden

CTLA-4 appears to be a negative regulator of T cell activation and is implicated in T cell-mediated autoimmune diseases. Experimental autoimmune myasthenia gravis (EAMG), induced by immunization of C57BL/6 mice with acetylcholine receptor (AChR) in adjuvant, is an autoantibody-mediated disease model for human myasthenia gravis (MG). The production of anti-AChR Abs in MG and EAMG is T cell dependent. In the present study, we demonstrate that anti-CTLA-4 Ab treatment enhances T cell responses to AChR, increases anti-AChR Ab production, and provokes a rapid onset and severe EAMG. To address possible mechanisms underlying the enhanced autoreactive T cell responses after anti-CTLA-4 Ab treatment, mice were immunized with the immunodominant peptide _146–162 representing an extracellular sequence of the AChR. Anti-CTLA-4 Ab, but not control Ab, treatment subsequent to peptide immunization results in clinical EAMG with diversification of the autoantibody repertoire as well as enhanced T cell proliferation against not only the immunizing _146–162 peptide, but also against other subdominant epitopes. Thus, treatment with anti-CTLA-4 Ab appears to induce determinant spreading, diversify the autoantibody repertoire, and enhance B cell-mediated autoimmune disease in this murine model of MG.

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