Analysis of the New Zealand Black contribution to lupus-like renal disease. Multiple genes that operate in a threshold manner.
F1 progeny of New Zealand Black (NZB) and New Zealand White (NZW) mice spontaneously develop an autoimmune process remarkably similar to human systemic lupus erythematosus. Previous studies have implicated major genetic contributions from the NZW MHC and from a dominant NZB gene on chromosome 4. To identify additional NZB contributions to lupus-like disease, (NZB x SM/J)F1 x NZW backcross mice were followed for the development of severe renal disease and were comprehensively genotyped. Despite a 50% incidence of disease, significant associations between the presence of the NZB genotype and disease were noted on chromosomes 1, 4, 7, 10, 13, and 19. The data indicated that multiple NZB genes, in different combinations, contribute to severe renal disease, and that no single gene is required. To further investigate this NZB contribution, NZB x SM/J (NXSM) recombinant inbred (RI) strains were crossed with NZW mice, and F1 progeny were analyzed for the presence of lupus-like renal disease. Interestingly, nearly all of the (RI x NZW)F1 cohorts studied expressed some level of disease. Five RI strains generated a high incidence of disease, similar to (NZB x NZW)F1 mice, and nearly one-half of the cohorts developed disease at intermediate levels. Only two cohorts demonstrated very little disease, supporting the conclusion that multiple genes are capable of disease induction. Experiments correlating the genotypes of these RI strains with their ability to generate disease revealed that none of the disease-associated loci defined by the backcross analysis were present in all five RI strains that generated disease at high levels. Overall, both the backcross data and RI analysis provide additional support for the genetic complexity of lupus nephritis and uphold the conclusion that heterogeneous combinations of contributing NZB genes seem to operate in a threshold manner to generate the disease phenotype.
Drake
C G
CG
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Rozzo
S J
SJ
Hirschfeld
H F
HF
Smarnworawong
N P
NP
Palmer
E
E
Kotzin
B L
BL
D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D005796:Genes; D005838:Genotype; D006801:Humans; D006824:Hybridization, Genetic; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008181:Lupus Nephritis / Q000235:genetics*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB / Q000235:genetics*; D010641:Phenotype