Control of separate pathogenic autoantibody responses marks MHC gene contributions to murine lupus.
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.
Departments of Medicine and Immunology, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
T J
TJ
Vyse
R K
RK
Halterman
S J
SJ
Rozzo
S
S
Izui
B L
BL
Kotzin
D000818:Animals; D000917:Antibody Formation; D001323:Autoantibodies / Q000097:blood*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D005799:Genes, Dominant; D016678:Genome; D006183:H-2 Antigens / Q000235:genetics; D006239:Haplotypes; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology*; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D012150:Polymorphism, Restriction Fragment Length; D012307:Risk Factors
D001323:Autoantibodies; D006183:H-2 Antigens