Mechanisms by which the I‐ABM12 Mutation Influences Susceptibility to Experimental Myasthenia Gravis: a Study in Homozygous and Heterozygous Mice

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Abstract
The I-Abm12 mutation in C57B1/6 (B6) mice yields the B6. C-H-2bm12 (bm12) strain, which is resistant to Experimental Myasthenia Gravis (EMG) induced by immunization with Torpedo acetylcholine receptor (TAChR), while the parental B6 strain is highly susceptible to EMG. CD4+ cells from bm12 mice immunized with TAChR do not recognize three sequence regions of the TAChR Q subunit which dominate the CD4+ cell sensitization in B6 mice. We immunized with TAChR bm12, B6 and (bm12B6)Fl mice. B6 and F1 mice developed EMG with comparable frequency. Their CD4+ cells recognized the same TAChR α subunit peptide sequences (Tα150–169, Tα181–200 and Tα360–378). CD4+ cells from TAChR-sensitized Fl mice were challenged with TAChR and α subunit epitope peptides, using F1, B6 or bml 2 APC. B6 and F1 APC presented all these Ag efficiently, while bm 12 APC presented TAChR and peptide Tα150–169 poorly and erratically. Anti-TAChR and anti-α subunit epitope CD4+ lines propagated from Fl and B6 mice had similar TcR Vβ usage. All lines but those specific for the sequence Tα150–169 had unrestricted Vβ usage. Anti-Tα150–169 lines from both B6 and Fl mice had a strong preferential usage of Vβ6. Anti-Tα150–169 lines from Fl mice had also a slightly higher Vβ14 usage. B6, bm12 and Fl mice developed similar anti-TAChR Ab titres, and had Ab bound to muscle AChR in comparable amounts. Therefore EMG resistance of bm12 mice must be due to a subtle shift in the anti-AChR Ab repertoire, and absence of special Ab able to cause destruction and/or dysfunction of muscle AChR. This is probably related to the absence of CD4+ cells sensitized to epitopes within the sequence Tα 150–160, consequent to the inability of the I-Abm12 molecule to present this sequence.