Factors that determine the severity of experimental myasthenia gravis.
Based on our current information, the robust differences in responses of B6 and bm12 mice after immunization with AChR are as follows: (1) The AChR-specific T cell repertoires are strikingly different. The epitope specificities, as well as the rearranged TCR alpha and beta chains and their CDR3 domains, are virtually nonoverlapping in the two strains of mice. (2) The AChR antibody responses are quantitatively different, both to Torpedo AChR and to the autoantigen--mouse AChR. (3) The isotype distribution of AChR antibodies favors IgG2b in B6 mice, but not in bm12 mice. (4) The clinical manifestations of EAMG are qualitatively and quantitatively different in the two strains. These considerations have led to the following scheme, illustrated diagrammatically in FIGURE 2, to explain the differences in EAMG in B6 and bm12 mice: (1) The MHC Class II of B6 mice binds the alpha 146-162 peptide of Torpedo AChR with high affinity, while the genetically altered MHC Class II of bm12 mice does not, as previously suggested (see FIGURE 2). (2) The alpha 146-162/MHC Class II complex occurs only in B6 mice and interacts with T cells having appropriate TCRs, resulting in their stimulation and expansion. Although T cells of appropriate specificity are also available in the bm12 strain, the relevant peptide/MHC Class II complex is not present. Therefore, very few T cells with specificity for alpha 146-162 are stimulated, and those that are stimulated have different TCRs. T cells with specificity for other AChR peptides are also present and expanded in both strains of mice, but they have less influence on the outcome of the immune response. (3) The alpha 146-162-specific T cells of B6 mice, in turn, interact strongly with AChR-specific B cells of B6 mice. These B cells present the same epitope/MHC Class II complex as the APCs and therefore interact well with the alpha 146-162-specific T cells (FIGURE 2). Thus, T cells of this specificity appear to provide more efficient help for AChR antibody production than T cells with specificity for other Torpedo AChR epitopes. This results in production of greater amounts of AChR antibodies, including a critical subset that cross-reacts with autologous mouse AChR. The higher autoantibody levels contribute to the greater susceptibility to EAMG and to the greater severity of manifestations in the B6 strain compared with the bm12 strain. (4) There is a bias in B6 mice toward the production of AChR antibodies of IgG2b isotype. We suggest that T cells specific for alpha 146-162 may contribute to this isotype bias. The IgG2b antibodies appear to have particularly potent "myasthenogenic" effects in rats and mice. (5) Finally, it should be emphasized that these differences in immunological and clinical aspects of EAMG in B6 and bm12 mice are relative rather than absolute. T cells that respond to AChR epitopes other than alpha 146-162 can also provide help for AChR antibody production, albeit less potent. In a sense, this model represents a special case of molecular mimicry. In this case, the source of the foreign antigenic molecule is injection rather than the more usual route of infection. The antigen (Torpedo AChR) is one that these mice would never naturally encounter, and the critical amino acid (lysine 155) of the key epitope (alpha 146-162) is present only in the AChR of electric organs of electric fish and not in the AChR of mice, chickens, cows, or humans. The important point is that a detail of the structure of the foreign antigen--that is, a particular peptide of Torpedo AChR--can determine the severity of an antibody-mediated autoimmune disease, depending on how it interacts with a detail of the structure of the MHC Class II molecule and, in turn, on how the peptide/MHC Class II complex interacts with the available T cell repertoire. (ABSTRACT TRUNCATED)
Drachman
D B
DB
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-7519, USA.
McIntosh
K R
KR
Yang
B
B
D000595:Amino Acid Sequence; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology / Q000503:physiopathology*; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D016693:Receptors, Antigen, T-Cell, alpha-beta