Suppression of Experimental Autoimmune Myasthenia Gravis by Epitope-Specific Neonatal Tolerance

Abstract

An autoimmune response to muscle nicotinic acetylcholine receptor (AChR) culminates in myasthenia gravis (MG) (1,2). MG has been associated with certain HLA antigens (3), and linked to a polymorphism in the HLA-DQs subunit (4). Immunization of C57BL6(B6) mice with Torpedo californica AChR (T-AChR) produces an autoimmune disease mimicking MG called experimental autoimmune myasthenia gravis (EAMG). EAMG susceptibility has been mapped to the I-A subregion of the mouse major histocompatibility complex (MHC) (5,6). Both the I-Aα and the I-As genes contribute to EAMG pathogenesis (5–8). Further, expression of the I-E molecule on the cell surface of C57BL10.IEαk transgenic mice could partially prevent the development of EAMG (9). Thus, the development of EAMG is primarily influenced by the Class II genes. Class II restricted AChR epitope reactive T helper (Th) cells are activated in MG patients and appear to contribute to the postsynaptic pathology (10–11). Th cells are also involved in EAMG pathogenesis (5,6, 12–17), and EAMG can either be prevented, or clinical remission of established disease induced, by in vivo administration of antibodies (Abs) to CD4 molecule (14). The in vitro lymphocyte proliferation to AChR generally correlates with EAMG susceptibility in congenic strains of mice, and is controlled by a Mendelian dominant gene at the I-A locus (12,13). Further, the lymphocyte proliferation is dependent on CD4+ Th cells and I-A molecule (18,19).