Myasthenia in SCID mice grafted with myasthenic patient lymphocytes role of CD4⁺ and CD8⁺ cells

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 chimetic 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.