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Control of separate pathogenic autoantibody responses marks MHC gene contributions to murine lupus

Vyse, T. J.
Halterman, R. K.
Rozzo, S. J.
Kotzin, B. L.
Published in Proceedings of the National Academy of Sciences. 1999, vol. 96, no. 14, p. 8098-8103
Abstract Previous studies have suggested that MHC and non-MHC genes contribute to the development of autoimmune disease in F1 hybrids of New Zealand black (NZB) and white (NZW) mice. We conducted a genome-wide screen of 148 female (NZB x NZW)F1 x NZB backcross mice to map dominant NZW genetic loci linked with lupus disease traits. In this backcross analysis, inheritance of the NZW MHC (H2(d/z) vs. H2(d/d)) was strongly linked with the development of lupus nephritis (P approximately 1 x 10(-16)), increasing the risk of disease by over 30-fold. H2(d/z) was also linked with elevated serum levels of IgG autoantibodies to single-stranded DNA, double-stranded DNA, histones, and chromatin but not with anti-gp70 autoantibodies, measured as circulating gp70-anti-gp70 immune complexes. Non-MHC contributions from NZW seemed weak in comparison to MHC, although NZW loci on chromosomes 7 and 16 were noted to be suggestively linked with autoantibody production. Strikingly, H2(d/z) (compared with H2(d/d)) enhanced antinuclear antibodies in a coordinate fashion but did not affect anti-gp70 production in the current backcross. However, the opposite influence was noted for H2(d/z) (compared with H2(z/z)) when (NZB x NZW)F1 x NZW backcross mice were analyzed. These results suggest that H2(z) and H2(d) haplotypes differentially regulate two different sets of nephritogenic autoantibody responses. This study confirms a critical role for H2(z) compared with other dominant NZW loci in (NZB x NZW)F1 mice and provides an explanation as to why H2(d/z) heterozygosity is required for full expression of disease in this model.
Keywords AnimalsAntibody FormationAutoantibodies/ bloodChromosome MappingCrosses, GeneticFemaleGenes, DominantGenomeH-2 Antigens/geneticsHaplotypesLupus Erythematosus, Systemic/ genetics/ immunologyLupus Nephritis/ genetics/immunologyMajor Histocompatibility ComplexMaleMiceMice, Inbred StrainsPolymorphism, Restriction Fragment LengthRisk Factors
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PMID: 10393954
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