MHC genes modify systemic autoimmune disease. The role of the I-E locus.
The MHC exerts an important influence on systemic autoimmune disease. In C57BL/6-lpr/lpr (B6/lpr) mice, substitution of the H-2d instead of the H-2b MHC haplotype results in a global reduction in autoantibody levels. Since H-2d expresses both I-A and I-E, while H-2b expresses only I-A, general down-regulation of autoimmunity in the d haplotype might be due to I-E expression. This was tested with I-E alpha d transgenic B6/lpr mice, which expressed a functional surface I-E molecule. Five-month-old transgene-positive B6/lpr mice had much lower total IgG, IgG anti-chromatin, anti-DNA, and IgM rheumatoid factor directed against IgG1 and against IgG2b than transgene-negative littermates (p < or = 0.002), as well as significantly lower spleen and lymph node weights (p < or = 0.002). Decreases in autoantibody levels in the transgenic lpr mice were not due to a nonspecific effect of the I-E alpha d transgene, since transgene-positive B6/lpr.H-2d mice had levels of autoantibodies comparable with transgene-negative B6/lpr.H-2d mice. To determine whether autoantibody was preferentially made by I-E-negative B cells, irradiated (B6/lpr.Igha x B6/lpr.I-E alpha d)F1 mice were reconstituted with equal amounts of B6/lpr.Igha and B6/lpr.I-E alpha d bone marrow. Allotype-specific ELISA showed that most autoantibody was produced by the I-E negative B cells (range 97% to 84%). The results show that a functional I-E molecule in lpr mice leads to generalized reduction in autoantibody levels through a direct effect on the B cell. The molecular mechanism of this effect remains to be determined.
Creech
E A
EA
Department of Medicine, University of North Carolina School of Medicine, Chapel Hill 27599, USA.
Nakul-Aquaronne
D
D
Reap
E A
EA
Cheek
R L
RL
Wolthusen
P A
PA
Cohen
P L
PL
Eisenberg
R A
RA
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology*; D005260:Female; D006183:H-2 Antigens / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D008221:Lymphoid Tissue / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D011828:Radiation Chimera; D011994:Recombinant Proteins / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics
D001323:Autoantibodies; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D011994:Recombinant Proteins; D019014:fas Receptor