New Zealand Black (NZB) mice develop a lupus-like autoimmune disease that is characterized by production of autoantibodies and mild glomerulonephritis that develops late in life [8
]. Offspring (NZB × NZW)F1 of the cross between NZB and New Zealand White (NZW) mice develop a progressive immune complex-mediated glomerulonephritis and high titer anti-dsDNA antibodies. These mice are considered to be excellent models of SLE [8
]. Importantly, characterization of immune defects in (NZB × NZW)F1 mice has contributed to our understanding of the human lupus disease.
Mapping studies [9
] have revealed that susceptibility to lupus disease in NZB and (NZB × NZW)F1 mice is polygenic, with multiple genes contributing to the generation of autoantibodies, kidney disease, and mortality. In particular, genetic loci on NZB chromosome 1 have been shown in multiple crosses to play a prominent role in disease susceptibility [10
]. In particular, an interval extending from ~79 to 109 cM, which is termed Nba2
(NZB autoimmunity 2
) has emerged as a major genetic contribution for the development of lupus-like disease [10
Our studies [36
] involving generation of congenic mice (designated as B6.Nba2) on C57BL/6 background, which contains the Nba2
interval, revealed that the congenic female mice develop splenomegaly and produce high titer IgG anti-nuclear antibodies. Interestingly, the NZB-derived Nba2
interval contains the Ifi200
-gene cluster [44
]. Furthermore, in an independent study, Wither et al.
] that mice that are congenic for the NZB derived interval extending from 85
cM (this interval includes the Ifi200
-gene cluster) on C57BL/6 background also develop splenomegaly, anti-nuclear antibodies, and increased memory T cells. These observations are consistent with an important role for Ifi200
-family genes in lupus susceptibility in NZB and (NZB × NZW)F1 mice.
In our study [44
], a comparison of gene expression analysis in splenic cells between C57BL/6 and B6.Nba2 congenic female mice revealed that: (i) Ifi202
(probably both Ifi202a
genes; see below) expression is up-regulated in B6.Nba2 mice; (ii) Ifi203
expression is down-regulated in B6.Nba2 mice; and (iii) Ifi204
expression remains unchanged between C57BL/6 and B6.Nba2 mice. Interestingly, a SNP in the promoter region of the Ifi202
gene correlated well with levels of expression: high in NZB and Balb/C mice that share the 95 C-allele, low in NZW, C57BL/6, and B10 mice that are characterized by a 95 T-allele. Although, these observations provided evidence that a particular SNP (the 95-C allele) in the promoter region of the Ifi202
gene is associated with increased steady-state levels of Ifi202
mRNA in congenic mice and the development of lupus-like disease, these observations did not provide a molecular basis for allelic variation contributing to alterations in the expression of Ifi202
gene. Our further analysis (see below) of the promoter region of the Ifi202
gene in C57BL/6 and NZB mice has identified additional polymorphisms in the promoter region that could account for differential expression of Ifi202
gene between the C57BL/6 and NZB mice. Additionally, we have identified polymorphisms in the coding region of the Ifi202
gene in the NZB mice (see below), which could account for increased levels of p202 protein in the B6.Nba2 mice through post-translational mechanisms.
Notably, steady-state levels of Ifi202
mRNA are not detectable in splenic cells from C57BL/6 mice and cells derived from these mice [6
]. However, the steady-state levels of Ifi203
mRNA are readily detectable in C57BL/6 mice [44
]. Interestingly, a recent study [47
] has revealed that the Ifi203
mRNA is multiply spliced and encodes for at least two p203 proteins. Intriguingly, the study also revealed that p203 proteins are exclusively detected in the liver of adult C129/SvJ and C57BL/6 mice. Because p200-family proteins are predicted to homo- and heterodimerize [35
], and levels of p200-family proteins are also regulated by post-transcriptional mechanisms [36
], further studies are needed to examine potential role for other p200-family proteins, such as p203 and p204 proteins, in lupus susceptibility.