Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains

Citation
L. Morel et al., Genetic reconstitution of systemic lupus erythematosus immunopathology with polycongenic murine strains, P NAS US, 97(12), 2000, pp. 6670-6675
Citations number
37
Categorie Soggetti
Multidisciplinary
Journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
ISSN journal
00278424 → ACNP
Volume
97
Issue
12
Year of publication
2000
Pages
6670 - 6675
Database
ISI
SICI code
0027-8424(20000606)97:12<6670:GROSLE>2.0.ZU;2-H
Abstract
We previously produced three congenic strains carrying lupus susceptibility genes (Sle1-Sle3) from the lupus-prone NZM2410 mouse on the C57BL/6 backgr ound and characterized their component phenotypes, Sle1 mediates the loss o f tolerance to nuclear antigens; Sle2 lowers the activation threshold of B cells; and Sle3 mediates a dysregulation of CD4(+) T cells. We have now cre ated a collection of bi- and tricongenic strains with these intervals and a ssessed the autoimmune phenotypes they elicit in various combinations. Our results indicate that Sle1 is key for the development of fatal lupus, The c ombination of Sle1 with Sle2, Sle3, or the BXSB-derived autoimmune accelera ting gene yaa results in the development of systemic autoimmunity with vari ably penetrant severe glomerulonephritis culminating in kidney failure. In contrast, two locus combinations of Sle2, Sle3, and yaa failed to mediate f atal disease. These results indicate that the loss of tolerance to chromati n mediated by Sle1 is essential for disease pathogenesis and identify the p athway occupied by Sle1 as a strategic target for therapeutic intervention in systemic lupus erythematosus. The coexpression of Sle1, Sle2, and Sle3 a s a B6-triple congenic results in severe systemic autoimmunity and fully pe netrant, fatal glomerulonephritis. These results demonstrate the fulfillmen t of the genetic equivalent of Koch's postulate, where susceptibility loci in a lupus-prone strain have been identified by a genome scan, isolated and functionally characterized by congenic dissection, and finally shown to me diate full disease expression when recombined in a normal genome.