Effects of transgenic mixed-haplotype MHC class II molecules A alpha d A beta z on autoimmune disease in New Zealand mice.
The MHC haplotype heterozygosity (H-2d/H-2z) acts as one major predisposing genetic element for autoimmune disease resembling systemic lupus erythematosus (SLE) in the F1 hybrid of NZB (H-2d) and NZW (H-2z) mice. To determine a possible role of mixed-haplotype A molecules, we introduced a transgene A beta z into H-2d/H-2d homozygous (NZB x NZW.H-2d)F1 mice, in which, compared with the original H-2d/H-2z heterozygotes, the incidence and titer of IgG anti-DNA antibodies, serum levels of nephritogenic retroviral gp70/anti-gp70 immune complexes (ICs) and the associated incidence of IC-type lupus nephritis were reduced. Evidence for the formation of mixed-haplotype A alpha d A beta z molecules in the transgenic mice was obtained by A beta z molecule expression on the cell surface of splenic B cells and macrophages, thymic epithelial cells and mature B cells in the bone marrow. A alpha d A beta z-restricted T cell clones showed good proliferative responses to spleen cells from the transgenic mice, to an extent much larger than seen in cells from the original (NZB x NZW)F1 mice, suggesting that the expression of functional A alpha d A beta z molecules on cells in transgenic mice is considerably high. Compared with findings in transgene-negative littermates and the original (NZB x NZW)F1 mice, the A beta z transgene to a greater extent promoted serum levels of IgM anti-double-stranded (ds) DNA antibodies and IgM anti-gp70/gp70 ICs in the transgenic mice. None the less, the production of IgG anti-dsDNA antibodies and IgG anti-gp70/gp70 ICs as well as the development of renal disease was markedly suppressed. Possible mechanisms of such effects of the transgene are discussed.
Nishimura
H
H
Department of Pathology, Juntendo University School of Medicine, 2-1-1, Hongo Bunkyo-ku, Tokyo 113, Japan.
Ishikawa
S
S
Nozawa
S
S
Awaji
M
M
Saito
J
J
Abe
M
M
Tokushima
M
M
Kimoto
M
M
Akakura
S
S
Tsurui
H
H
Hirose
S
S
Shirai
T
T
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000936:Antigen-Antibody Complex / Q000276:immunology; D004247:DNA / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology; D006239:Haplotypes / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000235:genetics* / Q000502:physiology*; D007075:Immunoglobulin M / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000209:etiology / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic
D000974:Antibodies, Antinuclear; D000936:Antigen-Antibody Complex; D006023:Glycoproteins; D000949:Histocompatibility Antigens Class II; D007075:Immunoglobulin M; C033589:glycoprotein gp70, murine serum; D004247:DNA