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
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.