Myasthenia in SCID mice grafted with myasthenic patient lymphocytes - Roleof 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 req uires intervention of CD4(+) cells. The role of CD4(+) cells in MG pathogen esis has been postulated but never proven. MG patients do not have anti-ACh R cytotoxic phenomena, and it has been assumed that CD8(+) cells do not hav e a pathogenic role in MG. However, CD8(+) cells may facilitate rodent expe rimental MG, raising the possibility that CD8(+) cells might be necessary a lso 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) dri ve the synthesis of pathogenic antibodies. Methods: First we characterized a chimeric human-mouse model of MG in severe combined immunodeficiency (SCI D) mice engrafted with blood lymphocytes (BL) from MG patients. We used tha t model to determine whether CD4(+) and CD8(+) cells are necessary for tran sfer 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(+) dep leted BL reconstituted with CD4(+) T cells from the same patient, specific for "universal" AChR epitopes or for two unrelated antigens, tetanus and di phtheria toxoids. We tested the mice for myasthenic symptoms for 7 to 18 we eks. Results: Mice transplanted with BL, or CD8(+) depleted BL, or CD4(+)-d epleted BL reconstituted with anti-AChR CD4(+) cells from MG patients frequ ently developed myasthenic weakness. The mice had human anti-AChR Ab in the serum and bound to muscle AChR. Mice transplanted with BL from controls, o r CD4(+)-depleted BL from MG patients, or CD4(+)-depleted BL from an MG pat ient reconstituted with CD4(+) cells specific for tetanus or diphtheria tox oids 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 pathogen ic Ab.