Epistatic Modifiers of Autoimmunity in a Murine Model of Lupus Nephritis (original) (raw)

and Laboratory Medicine F1 hybrid is much greater than predicted by the additive † Center for Mammalian Genetics expression of the parental phenotypes, suggesting a College of Medicine role for genetic interactions, commonly termed epista-University of Florida sis, in the generation of disease susceptibility. Gainesville, Florida 32610 Our studies have focused on the genetic dissection of the lupus-prone NZM2410 mouse model of SLE. This severely lupus-prone strain is 1 of 27 congenic recombinant strains (termed NZM for New Zealand Mixed) Summary produced by Rudofsky and coworkers by inbreeding (NZB ϫ NZW)F1 ϫ NZW backcross progeny (Rudofsky Sle1 and Sle3 are NZW-derived loci that mediate lupus nephritis on a C57BL/6 background. The absence of et al., 1993). We previously defined the genomic posisevere autoimmunity in NZW suggests that the NZW tions of three recessive loci (designated Sle1, Sle2, and genome suppresses these genes. (B6.NZMc1[Sle1] ϫ Sle3) that are strongly associated with lupus susceptibil-NZW)F1 hybrids develop severe humoral autoimmuity in NZM2410 (Morel et al. , 1994). In subsequent studnity and fatal lupus nephritis, indicating that suppresies, we produced a collection of congenic strains carsion of Sle1 from NZW is recessive. Linkage analysis rying these NZM2410-derived chromosomal segments identified four epistatic modifiers, Sles1-4, whose cuon a B6 background (Morel et al., 1996) and used them mulative effect accounted for the benign autoimmuto characterize the component phenotypes associated nity in NZW. The specific suppression of Sle1 but not with each SLE susceptibility gene (Morel et al., 1997). Sle2 or Sle3 by Sles1 was directly demonstrated via These studies determined (1) that Sle1, carried by the the production and analysis of bicongenic strains. congenic strain B6.NZMc1, mediates a spontaneous Moreover, Sles1 was sufficient to completely suppress loss of immunologic tolerance to nuclear antigens (Moautoimmunity initiated by Sle1 in B6.NZMc1 ϫ NZW han et al., 1998); (2) that Sle2, carried by B6.NZMc4, hybrids. These results demonstrate the complex epilowers the activation threshold of the B cell compartstatic interactions of loci augmenting and suppressing ment and mediates polyclonal/polyreactive antibody systemic autoimmunity. production (Mohan et al., 1997); and (3) that Sle3, carried by B6.NZMc7, mediates a dysregulation of the T cell compartment that potentiates polyclonal IgG antibody Introduction production and decreases activation-induced cell death in CD4 T cells (Morel et al., 1997; Mohan et al., 1999b). Systemic lupus erythematosus (SLE) is a chronic auto-More recently, we have produced a collection of biimmune disease characterized by the development of congenic strains carrying these susceptibility alleles in systemic autoimmunity and the production of autoantivarious combinations to assess the role of genetic interbodies to a spectrum of nuclear antigens. The most actions in the development of severe disease. An analysevere clinical consequences of SLE are associated with sis of B6.NZMc1|c7, which carries Sle1 and Sle3 in comimmune complex deposition in the kidney, resulting in bination, revealed that these two susceptibility genes lupus nephritis and culminating in kidney failure. Alare sufficient to mediate the development of severe huthough the factors responsible for the development of moral autoimmunity and fatal lupus nephritis on the B6 SLE in human patients are poorly understood, a wealth background (Mohan et al., 1999a). B6.NZMc1|c7 aniof data strongly support the hypothesis that SLE susmals spontaneously develop high titers of autoantibody ceptibility is inherited as a multifactorial genetic disease directed against a broad spectrum of nuclear chromatin (Winchester, 1992; Gaffney et al., 1998; Harley et al., autoantigens and die of kidney failure (penetrance Ͼ55%) 1998; Moser et al., 1998). due to autoimmune glomerulonephritis (GN) within 12 Over the past 30 years, murine models of SLE have months of age. contributed significantly to our understanding of the The lethal phenotype produced by the combination disease (reviewed in Theofilopoulos and Dixon, 1985; of Sle1 and Sle3 on the B6 background was somewhat Theofilopoulos, 1993; Wakeland et al., 1997). An intrigusurprising, in that both of these genes are derived from ing aspect of the genetics of the classic (NZB ϫ NZW)F1 the relatively unaffected NZW strain (Morel et al., 1996), hybrid murine model of SLE has been the requirement suggesting that their severe autoimmune phenotypes of an F1 hybrid genome for the development of severe must be suppressed in some manner by the NZW genome. Here, we present our genetic analysis of this ‡ To whom correspondence should be addressed (email: morel. epistatic suppression in NZW and present the locations pathology@mail.health.ufl.edu [L. M.], edward.wakeland@email.swmed. of four SLE suppressor loci (designated Sles1 through edu [E. K. W.]). Sles4) that account for the absence of fatal disease in § Present address. B6.H2 z . Both intervals are NZW derived, as determined with all available SSLP markers that are polymorphic between NZB and NZW References (46 for B6.NZMc1 and 21 for B6.H2 z ). A total of 280 (NZW ϫ B6.NZMc1)F 1 ϫ NZW were produced and maintained along with Botto, M., Dell'Agnola, C., Bygrave, A.E., Thompson, E.M., Cook, parental controls for 1 year of age with daily checks for health status H.T., Petry, F., Loos, M., Pandolfi, P.P., and Walport, M.J. (1998). and monthly to bimonthly monitoring for proteinuria and blood urea Homozygous C1q deficiency causes glomerulonephritis associated nitrogen (BUN) for the F1 and BC1 progeny. Moribund animals and with multiple apoptotic bodies. Nat. Genet. 19, 56-59. animals with proteinuria Ͼ 300 mg/dL and BUN Ͼ 50 mg/dL were Cohen, P.L., and Eisenberg, R.A. (1991). Lpr and gld: single gene sacrificed. An equal number of males and females were used, except models of systemic autoimmunity and lymphoproliferative disease. for NZW, where only females were used for phenotype assessment, Annu. Rev. Immunol. 9, 243-269. and in the BC1 progeny, which had a male-biased sex-ratio (110 Dietrich, W.F., Miller, J., Steen, R., Merchant, M.A., Damron Boles, females and 170 males). The number of BC1 animals scored for D., Husain, Z., Dredge, R., Daly, M.J., Ingalls, K.A., O'Connor, T.J., each phenotype varied due to loss of tissues associated with early et al. (1996). A comprehensive genetic map of the mouse genome. death (lupus or nonlupus related). Nature 380, 149-152.