Spontaneous autoimmunity in 129 and C57BL/6 mice-implications for autoimmunity described in gene-targeted mice.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 x C57BL/6) model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE.
Bygrave
Anne E
AE
Rheumatology Section, Eric Bywaters Centre, Imperial College, London, United Kingdom.
Rose
Kirsten L
KL
Cortes-Hernandez
Josefina
J
Warren
Joanna
J
Rigby
Robert J
RJ
Cook
H Terence
HT
Walport
Mark J
MJ
Vyse
Timothy J
TJ
Botto
Marina
M
D000818:Animals; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology*; D002467:Cell Nucleus / Q000378:metabolism; D002874:Chromosome Mapping; D015331:Cohort Studies; D004195:Disease Models, Animal; D004843:Epistasis, Genetic; D005260:Female; D018390:Gene Targeting; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018895:Microsatellite Repeats; D008957:Models, Genetic; D040641:Quantitative Trait Loci; D013045:Species Specificity