Mechanisms by which the I-ABM12 mutation influences susceptibility to experimental myasthenia gravis: a study in homozygous and heterozygous mice.
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 alpha subunit which dominate the CD4+ cell sensitization in B6 mice. We immunized with TAChR bm12, B6 and (bm12 x B6)F1 mice. B6 and F1 mice developed EMG with comparable frequency. Their CD4+ cells recognized the same TAChR alpha subunit peptide sequences (T alpha 150-169, T alpha 181-200 and T alpha 360-378). CD4+ cells from TAChR-sensitized F1 mice were challenged with TAChR and alpha subunit epitope peptides, using F1, B6 or bm12 APC. B6 and F1 APC presented all these Ag efficiently, while bm12 APC presented TAChR and peptide T alpha 150-169 poorly and erratically. Anti-TAChR and anti-alpha subunit epitope CD4+ lines propagated from F1 and B6 mice had similar TcR V beta usage. All lines but those specific for the sequence T alpha 150-169 had unrestricted V beta usage. Anti-T alpha 150-169 lines from both B6 and F1 mice had a strong preferential usage of V beta 6. Anti-T alpha 150-169 lines from F1 mice had also a slightly higher V beta 14 usage. B6, bm12 and F1 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 T alpha 150-160, consequent to the inability of the I-Abm12 molecule to present this sequence.
Karachunski
P I
PI
Department of Biochemistry, College of Biological Sciences, University of Minnesota, St. Paul 55108, USA.
Ostlie
N
N
Bellone
M
M
Infante
A J
AJ
Conti-Fine
B M
BM
D000818:Animals; D017951:Antigen Presentation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D006239:Haplotypes; D006579:Heterozygote; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000276:immunology; D006720:Homozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology*; D011950:Receptors, Cholinergic / Q000276:immunology*; D014101:Torpedo
D000949:Histocompatibility Antigens Class II; D011950:Receptors, Cholinergic