The BM12 mutation and autoantibodies to dsDNA in NZB.H-2bm12 mice.
Molecular and genetic tools have been used to shed light on the genes that contribute to susceptibility to murine lupus and the mechanisms that lead to immunopathology. The MHC genes and their products have been consistently shown to contribute toward the development of disease. To understand the contribution of MHC-class II genes, our laboratory had derived two inbred strains of mice, NZB.H-2bm12 and NZB.H-2b. These new colonies of mice were studied and compared in the 10th generation backcross; inbreeding was serially followed by H-2 typing, responses to beef/porcine insulin, and the presence of the B6 Ig allotype, IgG2ab. Of great interest is the finding that NZB.H-2bm12, in contrast to NZB.H-2b or NZB (H-2d), mice develop high titer autoantibodies to dsDNA. This result is unique because NZB (H-2d) mice, unliked NZB x NZW (NZB/W F1) or NZB x SWR (SNF1) hybrids do not develop autoantibodies to dsDNA, even after immunization. NZB mice, in contrast, are characterized only by autoantibodies to ssDNA. Our observation is also striking because the gene conversion that resulted in the I-A beta bm12 mutation occurred at amino acid residues 68, 71, and 72 of I-E beta b. Recently the contribution of NZW to accelerated autoimmunity in the NZB x NZW F1 hybrid has also been linked to H-2 and a single amino acid change at amino acid 72 of I-E beta. Thus, amino acid residue 72 may be a hot spot for disorders of immune regulation when superimposed on the appropriate genetic background. NZB mice expressing the I-Abm12 mutation will allow specific dissection of the requirements for autoantibody production to dsDNA uncomplicated by heterozygosity.
Chiang
B L
BL
Division of Rheumatology/Allergy, University of California, Davis 95616.
Bearer
E
E
Ansari
A
A
Dorshkind
K
K
Gershwin
M E
ME
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics*; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells; D004247:DNA / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D005434:Flow Cytometry; D005838:Genotype; D006183:H-2 Antigens / Q000032:analysis; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology*; D007074:Immunoglobulin G / Q000032:analysis; D051379:Mice; D008817:Mice, Mutant Strains; D011507:Proteinuria / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology
D000974:Antibodies, Antinuclear; D004277:DNA, Single-Stranded; D006183:H-2 Antigens; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G; D004247:DNA