Dissection of BXSB Lupus Phenotype Using Mice Congenic for Chromosome 1 Demonstrates That Separate Intervals Direct Different Aspects of Disease

Abstract

To dissect the individual effects of the four non-MHC, autosomal loci (Bxs1 to Bxs4) that contribute to SLE susceptibility in BXSB mice, we generated congenic lines from chromosome 1 on a C57BL/10.YBXSB (B10.Yaa) background for the intervals (values in megabases (Mb)) Bxs1 (46.3-89.2 Mb), Bxs1/4 (20.0-65.9 Mb), Bxs1/2 (64.4-159.0 Mb), and Bxs2/3 (105.4-189.0 Mb). Glomerulonephritis, qualitatively similar to that seen in the parental BXSB strain, developed in three of these congenic strains. Early onset, severe disease was observed in B10.Yaa.BXSB-Bxs2/3 congenic mice and caused 50% mortality by 12 mo. In B10.Yaa.BXSB-Bxs1/4 mice disease progressed more slowly, resulting in 13% mortality at 12 mo. The progression of renal disease in both of these strains was correlated with the level of anti-dsDNA Abs. B10.Yaa.BXSB-Bxs1 mice, despite their genetic similarity to B10.Yaa.BXSB-Bxs1/4 mice, developed a low-grade glomerulonephritis in the absence of anti-dsDNA Abs. Thus, Bxs4 directed an increase in titer and spectrum of autoantibodies, whereas Bxs1 promoted the development of nephritis. The Bxs2 interval was linked to the production of anti-dsDNA Abs without concomitant glomerulonephritis. In contrast, the Bxs3 interval was sufficient to generate classic lupus nephritis in a nonautoimmune–prone strain. Immune phenotype differed between controls and congenics with a significant increase in B220+ cells in BXSB and B10.Yaa.BXSB-Bxs2/3, and an increase in CD4 to CD8 ratio in both BXSB and B10.Yaa.BXSB-Bxs1/4. Disease in the Bxs3 mice was delayed in comparison to the BXSB parental strain, emphasizing the necessity for multiple interactions in the production of the full BXSB phenotype.

Monocytosis in BXSB mice is due to epistasis between Yaa and the telomeric region of Chromosome 1 but does not drive the disease process

“…The 8% increase in the population of B lymphocytes in B10.Yaa.Bxs3 compared to B10.Yaa control mice, was comparable with the published data for B10.Yaa.Bxs2/3. 4 The fact that the monocytes were negative for expression of CD62L (data not shown) is suggestive of the fact that they derive from the previously reported resident population of monocytes rather than the inflammatory subset. 11 The increased numbers of MHC class II expressing cells reflects the increased population of B lymphocytes.…”

“…Both strains demonstrated similar monocytic profiles until 8 months of age at which time point BXSB were no longer observed due to high mortality. By 12 months of age, B10.Yaa.Bxs2/3, which demonstrate prolonged survival times compared to parental BXSB, 4 revealed a 17-fold higher population of monocytes than B10 (Pp0.001) and an eightfold higher population than B10.Yaa (Pp0.001). B10.Yaa.Bxs1/4 and B10.Yaa.Bxs1/2 showed similar profiles to B10.Yaa.…”

“…A panel of 11 microsatellite markers was used to select offspring from a (B10 Â B10.Yaa.Bxs2/3)F 2 . The congenic mice generated were named after the BXSB susceptibility locus they contained 4 Figure 2a.…”

“…3 Furthermore, it has recently been demonstrated that while Yaa is not sufficient to cause manifestation of full autoimmune pathology in non-autoimmune prone mice, for example C57BL/6, it is sufficient to break tolerance and can drive low-level anti-chromatin autoantibody production and antinuclear antibodies (ANA) in C57BL/10. 4 That monocytosis in BXSB is a combined effect between Yaa and other BXSB loci is further illustrated by the BXSB/longlived (BXSB/ll) strain, which demonstrates a significant delay in the expression of autoimmune pathology, including delayed onset of monocytosis, 5 even though this strain has recently been shown to carry the Yaa locus. 6 BXSB-related monocytosis was first reported by Wofsy et al 7 when a dramatic progressive increase in monocytes was detected from as early as 2 months in the peripheral blood.…”

“…We have previously reported the generation of congenic mice for BXSB chromosome 1, and demonstrated that separate intervals direct different aspects of disease. 4 In an attempt to further define the BXSB and Yaa-related monocytosis, an extensive analysis of peripheral, tissuespecific and bone marrow-derived monocytes in our different congenic lines and a novel sub-congenic line, B10.Yaa.Bxs3, was performed. Mice were studied over a period of 12 months to establish the onset and progression of monocytosis and the associated autoimmune pathology.…”