Correlations of autoimmunity with H-2 and T cell receptor beta chain genotypes in (NZB X NZW) F2 mice.
Accelerated autoimmunity as expressed by the classical autoimmune strain mouse (NZB x NZW)F1 is thought to be the result of major histocompatibility complex (MHC)-associated NZW genes acting on a genetic predisposition for autoimmunity as expressed by the NZB mouse. To evaluate more accurately both H-2 and T cell receptor (TcR) beta chain involvement in F1 disease, we studied the segregation of NZB (H-2d, TcRB) and NZW (H-2z, TcRW) haplotypes of these genetic elements and the development of autoimmunity in (NZB x NZW)F2 generation mice. F2 mice with the H-2d/z genotype lived shorter average life-spans and expressed elevated levels of antibodies to gp70, ssDNA and dsDNA, while those with the TcRW/W genotype (homozgous for the NZW TcR deletion) expressed elevated levels of autoantibodies but had relatively long life-spans. On the other hand, mice with the TcRB/B genotype (homozygous for the NZB TcR) produced consistently low levels of autoantibodies but died at an early age. The most severely affected F2 population were the mice carrying both the TcRB/B and H-2d/z alleles. These mice died on an average within the first 5 months of life, but produced the lowest levels of antibodies to gp70, single-stranded DNA and double-stranded DNA. These data confirm the contribution of NZW H-2-linked genes to accelerated autoimmunity in the F1 hybrid and, furthermore, define NZB TcR-linked components as primary developers of this phenomenon. They also suggest a limited, if any, contribution of both the NZW TcR deletion and traditional autoantibodies to F1 accelerated autoimmunity.
Noonan
D J
DJ
Ligand Pharmaceuticals, San Diego, CA 92121.
McConahey
P J
PJ
Cardenas
G J
GJ
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D000914:Antibodies, Viral / Q000032:analysis; D015551:Autoimmunity / Q000235:genetics*; D002872:Chromosome Deletion; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D005260:Female; D005838:Genotype; D006183:H-2 Antigens / Q000235:genetics*; D006239:Haplotypes; D006720:Homozygote; D008297:Male; D051379:Mice; D012150:Polymorphism, Restriction Fragment Length; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015682:Retroviridae Proteins, Oncogenic / Q000276:immunology; D014759:Viral Envelope Proteins / Q000276:immunology
D000974:Antibodies, Antinuclear; D000914:Antibodies, Viral; D004277:DNA, Single-Stranded; D006183:H-2 Antigens; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015682:Retroviridae Proteins, Oncogenic; D014759:Viral Envelope Proteins; D004247:DNA