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Myasthenia in SCID mice grafted with myasthenic patient lymphocytes

Role of CD4 and CD8 cells

From the Department of Biochemistry, College of Biological Sciences, University of Minnesota, St. Paul, and the Department of Pharmacology (Drs. Wang, Karachunski, and Conti-Fine), School of Medicine, University of Minnesota, Minneapolis, MN; and the Department of Neurology (Dr. Howard), University of North Carolina at Chapel Hill, NC.

Address correspondence and reprint requests to Dr. Bianca M. Conti-Fine, Department of Biochemistry, University of Minnesota, 1479 Gortner Avenue, St. Paul, MN 55108.

OBJECTIVES: Acetylcholine receptor (AChR)-specific CD4⁺ cells are present in MG patients, and synthesis of the high-affinity immunoglobulin G (IgG) autoantibodies (autoAb) against the muscle AChR that causes MG symptoms requires intervention of CD4⁺ cells. The role of CD4⁺ cells in MG pathogenesis has been postulated but never proven. MG patients do not have anti-AChR cytotoxic phenomena, and it has been assumed that CD8⁺ cells do not have a pathogenic role in MG. However, CD8⁺ cells may facilitate rodent experimental MG, raising the possibility that CD8⁺ cells might be necessary also in MG. In this study we examined whether CD4⁺ and CD8⁺ cells play a role in the pathogenesis of MG and whether CD4⁺ cells specific for AChR epitope sequences recognized by most MG patients ("universal" epitopes) drive the synthesis of pathogenic antibodies.

METHODS: First we characterized a chimeric human-mouse model of MG in severe combined immunodeficiency (SCID) mice engrafted with blood lymphocytes (BL) from MG patients. We used that model to determine whether CD4⁺ and CD8⁺ cells are necessary for transfer of MG symptoms. We engrafted SCID mice intraperitoneum with BL from 19 MG patients and 5 healthy controls. We engrafted some mice with either BL, BL depleted in CD4⁺ or CD8⁺ cells from the same patient, or CD4⁺ depleted BL reconstituted with CD4⁺ T cells from the same patient, specific for "universal" AChR epitopes or for two unrelated antigens, tetanus and diphtheria toxoids. We tested the mice for myasthenic symptoms for 7 to 18 weeks.

RESULTS: Mice transplanted with BL, or CD8⁺ depleted BL, or CD4⁺-depleted BL reconstituted with anti-AChR CD4⁺ cells from MG patients frequently developed myasthenic weakness. The mice had human anti-AChR Ab in the serum and bound to muscle AChR. Mice transplanted with BL from controls, or CD4⁺-depleted BL from MG patients, or CD4⁺-depleted BL from an MG patient reconstituted with CD4⁺ cells specific for tetanus or diphtheria toxoids did not develop myasthenic weakness or anti-AChR Ab.

CONCLUSIONS: CD4⁺ cells are necessary for MG pathogenesis; CD8⁺ cells may not be. CD4⁺ cells specific for "universal" AChR epitopes help the synthesis of pathogenic Ab.

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