Regulation of B cell tolerance by 129-derived chromosome 1 loci in C57BL/6 mice.
OBJECTIVE
Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129-derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.


METHODS
Anti-single-stranded DNA (anti-ssDNA)-knockin transgenic mice (V(H)3H9R/Vkappa8R and V(H)3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene-targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.


RESULTS
The combination of V(H)3H9R/Vkappa8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti-ssDNA antibodies were found in the circulation. The presence of IgG2a(a) anti-ssDNA and IgM(a) anti-Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene-targeted animals showed a similar phenotype.


CONCLUSIONS
The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti-DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.
Fossati-Jimack
Liliane
L
Molecular Genetics and Rheumatology Section, Faculty of Medicine, Imperial College, London, UK. l.fossati@imperial.ac.uk
Cortes-Hernandez
Josefina
J
Norsworthy
Peter J
PJ
Cook
H Terence
HT
Walport
Mark J
MJ
Botto
Marina
M
D000818:Animals; D001323:Autoantibodies; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002878:Chromosomes, Human, Pair 1 / Q000276:immunology*; D004277:DNA, Single-Stranded; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010641:Phenotype
D001323:Autoantibodies; D004277:DNA, Single-Stranded; D007074:Immunoglobulin G; D007075:Immunoglobulin M