Analysis of the New Zealand Black contribution to lupus-like renal disease. Multiple genes that operate in a threshold manner.

Abstract

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.

Contributions ofEazandEbzMHC Genes to Lupus Susceptibility in New Zealand Mice

“…A correlation between severe proteinuria and death from renal failure was demonstrated previously (6), and a strong correlation with histologic severity of glomerulonephritis has been more recently confirmed (T. J. Vyse and B. L. Kotzin, unpublished observations), supporting the validity of using high levels of proteinuria as an indicator of severe and progressive glomerulonephritis. Similar to past studies (3,6,17,18), the development of proteinuria also predicted early mortality in the current study. For example, of the 14 (B6.H2 z ϫ NZB)F 1 ϫ NZB backcross mice that developed proteinuria by 10 mo of age, 13 (93%) died by 12 mo of age.…”

“…It is important to emphasize that the stringent statistical thresholds proposed for a genome-wide screening (31) do not apply to the directed linkage analysis of one non-MHC locus in the current study. In previous genome-wide screenings of (B6.H2 z ϫ NZB)F 1 ϫ NZB and (SM/ J ϫ NZB)F 1 ϫ NZW backcrosses, Nba2 was shown to be strongly linked with the development of nephritis and increased serum levels of IgG autoantibodies (10,11,18). A locus in a similar chromosomal location has been mapped in other studies analyzing NZB and/or NZW genes (18,53,54).…”

“…Thus, New Zealand hybrid or backcross mice that are H2 d/z have increased IgG autoantibody production and increased incidence of nephritis compared with genetically similar mice homozygous for either H2 d or H2 z haplotypes. More recent studies have suggested that heterozygosity for H2 haplotypes other than H2 d or H2 z may also enhance disease (18,54,55). For example, in an analysis of (NZM ϫ B6)F 1 ϫ NZM backcross mice (NZM is an H2 z -positive recombinant inbred of NZB and NZW mice), inheritance of H2 b from the B6 strain was strongly linked with the production of autoantibodies and the development of nephritis (54).…”

“…In previous genome-wide screenings of (B6.H2 z ϫ NZB)F 1 ϫ NZB and (SM/ J ϫ NZB)F 1 ϫ NZW backcrosses, Nba2 was shown to be strongly linked with the development of nephritis and increased serum levels of IgG autoantibodies (10,11,18). A locus in a similar chromosomal location has been mapped in other studies analyzing NZB and/or NZW genes (18,53,54). In the B6.H2 z backcross, Nba2 in conjunction with H2 z provided Ͼ90% of the genetic contribution to nephritis and autoantibody production (10,11).…”