Disease relevance of Sle2

• The coexpression of Sle1, Sle2, and Sle3 as a B6-triple congenic results in severe systemic autoimmunity and fully penetrant, fatal glomerulonephritis [1].
• To determine the contribution of these three Sle2 loci to lupus pathogenesis, we used a mapping by genetic interaction strategy, in which we bred them to B6.Sle1.Sle3 mice [2].
• However, Sle2 by itself on the normal B6 background is insufficient to generate IgG antinuclear Abs (ANA) or nephritis [3].
• Genetic dissection of systemic lupus erythematosus pathogenesis: Sle2 on murine chromosome 4 leads to B cell hyperactivity [3].

High impact information on Sle2

• Sle1 mediates the loss of tolerance to nuclear antigens; Sle2 lowers the activation threshold of B cells; and Sle3 mediates a dysregulation of CD4(+) T cells [1].
• The combination of Sle1 with Sle2, Sle3, or the BXSB-derived autoimmune accelerating gene yaa results in the development of systemic autoimmunity with variably penetrant severe glomerulonephritis culminating in kidney failure [1].
• These results show that the Sle2 locus contains several loci affecting B cell development, with only the two NZW-derived loci having the least effect of B-1a cell accumulation significantly contributing to lupus pathogenesis [2].
• Given that the locus for IFN-I is positioned within the Sle2 murine lupus susceptibility interval on chromosome 4, we undertook this study to investigate whether differences in IFN-I levels might potentially contribute to the phenotypes ascribed to this locus [4].
• CONCLUSION: Unexpectedly, reduction of IFN-I levels reproduced the serologic and cellular phenotypes previously associated with the Sle2 lupus susceptibility interval [4].

Biological context of Sle2

• In this paper, we examined the mechanisms responsible for this phenotype by comparing congenic C57BL/6 mice with or without Sle2 [5].
• Sle2 on chromosome 4 was significantly linked to glomerulonephritis in a linkage analysis of a NZM2410 x B6 cross [2].
• Increased proliferation and decreased apoptosis did not affect Sle2 peritoneal B-2 cells [5].

Anatomical context of Sle2

• Yet, Sle2 expression alone on a C57BL/6 background did not result in any clinical manifestation, but in an abnormal B cell development, including the accumulation of B-1a cells in the peritoneal cavity and spleen [2].
• In addition, a significant number of peritoneal cavity B-1a cells were recovered in lethally irradiated B6.Sle2 mice reconstituted with B6.Igh(a) bone marrow, showing radiation resistance in Sle2 B-1a cells or its precursors [5].
• The focus of this study was to understand how Sle2 on murine chromosome 4 impacts the immune system [3].

Other interactions of Sle2

• In contrast, two locus combinations of Sle2, Sle3, and yaa failed to mediate fatal disease [1].

Analytical, diagnostic and therapeutic context of Sle2

• Sle2-expressing B1-a cells proliferated significantly more in vivo than their B6 counterparts, and reciprocal adoptive transfers showed that this phenotype is intrinsic to Sle2 peritoneal B cells [5].

References