Genetic Dissection of Spontaneous Autoimmunity Driven by 129-Derived Chromosome 1 Loci When Expressed on C57BL/6 Mice

Abstract

Extensive evidence indicates that genetic predisposition is a central element in susceptibility to systemic lupus erythematosus both in humans and animals. We have previously shown that a congenic line carrying a 129-derived chromosome 1 interval on the C57BL/6 background developed humoral autoimmunity. To further dissect the contribution to autoimmunity of this 129 interval, we have created six subcongenic strains carrying fractions of the original 129 region and analyzed their serological and cellular phenotypes. At 1 year of age the congenic strain carrying a 129 interval between the microsatellites D1Mit15 (87.9 cM) and D1Mit115 (99.7 cM) (B6.129chr1b) had high levels of autoantibodies, while all the other congenic lines were not significantly different from the C57BL/6 controls. The B6.129chr1b strain displayed only mild proliferative glomerulonephritis despite high levels of IgG and C3 deposited in the kidneys. FACS analysis of the spleens revealed that the B6.129chr1b mice had a marked increase in the percentage of activated T cells associated with a significant reduction in the proportion of CD4+CD25high regulatory T cells. Moreover, this analysis showed a significantly reduced percentage of marginal zone B cells that preceded autoantibody production. Interestingly the 129chr1b-expressing bone marrow-derived macrophages displayed an impaired uptake of apoptotic cells in vitro. Collectively, our data indicate that the 129chr1b segment when recombined on the C57BL/6 genomic background is sufficient to induce loss of tolerance to nuclear Ags. These findings have important implication for the interpretation of the autoimmune phenotype associated with gene-targeted models.

The MHC Haplotype H2b Converts Two Pure Nonlupus Mouse Strains to Producers of Antinuclear Antibodies

“…Because the vast majority of strains that carry the Sle1b susceptibility alleles are not autoimmune (7), it seems likely that these alleles must interact with polymorphic genes of the normal B6 genome to break tolerance to chromatin. This notion is supported by the finding that, unlike nonautoimmune 129 mice, B6 mice congenic for a 129-derived interval on distal chromosome 1 (denoted 129chr1b) encompassing the Sle1b locus also produce ANA (43). Hence, the genetic backgrounds of BALB.B and C3.SW mice may not be compatible with a role for Sle1 alleles in the ANA responses of these mice.…”

“…The image was taken at ϫ400 total magnification. genome mediates autoimmunity to chromatin in B6 mice despite carrying a normal Fc␥r2 gene (43,46) (45).…”

Activation of Human Peripheral IgM+ B Cells Is Transiently Inhibited by BCR-Independent Aggregation of FcγRIIB

“…In accordance with this hypothesis, the increase of primary IgM responses to T-dependent and T-independent Ags, observed in Fc␥RIIB-deficient mice, suggests that Fc␥RIIB can control the activation of naive B cells (24,43,44). Interestingly, Fc␥RIIB-deficient mice develop an autoimmune syndrome (45), although it was later shown that mice from a congenic line carrying a 129-derived chromosome 1 interval on a C57BL/6 background also develop humoral autoimmunity, suggesting that the lack of Fc␥RIIB expression is not the only parameter responsible for the autoimmune phenotype (46). However, overexpression of Fc␥RIIB, independent from this 129 region, suppresses the autoimmune syndrome, an observation that excludes a relationship between the autoimmune syndrome and the adjacent area of 129 DNA (47).…”

Genetic Segregation of Inflammatory Lung Disease and Autoimmune Disease Severity in SHIP-1−/− Mice

“…IL-6 is elevated in serum and BAL of C57.SHIP-1 2/2 mice (6,8,10,31). It is well known to influence hematopoietic progenitor number and myelopoiesis: injection of IL-6 into mice can induce myelopoiesis and myeloproliferative disease (32), and IL-6 can synergize with other cytokines to drive production of immature hematopoietic progenitors (33,34 (20,(37)(38)(39)(40)(41)(42), and there is evidence that the 129 strain is autoimmune prone (43,44). SHIP-1 2/2 mice share many phenotypes with FcgRIIB 2/2 mice, in keeping with a major role for SHIP-1 immediately downstream of this receptor (45).…”