A bacterial artificial chromosome transgene with polymorphic Cd72 inhibits the development of glomerulonephritis and vasculitis in MRL-Faslpr lupus mice.
Systemic lupus erythematosus is considered to be under the control of polygenic inheritance, developing according to the cumulative effects of susceptibility genes with polymorphic alleles; however, the mechanisms underlying the roles of polygenes based on functional and pathological genomics remain uncharacterized. In this study, we substantiate that a CD72 polymorphism in the membrane-distal extracellular domain impacts on both the development of glomerulonephritis and vasculitis in a lupus model strain of mice, MRL/MpJ-Fas(lpr), and the reactivity of BCR signal stimulation. We generated mice carrying a bacterial artificial chromosome transgene originating from C57BL/6 (B6) mice that contains the Cd72(b) locus (Cd72(B6) transgenic [tg]) or the modified Cd72(b) locus with an MRL-derived Cd72(c) allele at the polymorphic region corresponding to the membrane-distal extracellular domain (Cd72(B6/MRL) tg). Cd72(B6) tg mice, but not Cd72(B6/MRL) tg mice, showed a significant reduction in mortality following a marked improvement of disease associated with decreased serum levels of IgG3 and anti-dsDNA Abs. The number of splenic CD4(-)CD8(-) T cells in Cd72(B6) tg mice was decreased significantly in association with a reduced response to B cell receptor signaling. These results indicate that the Cd72 polymorphism affects susceptibility to lupus phenotypes and that novel functional rescue by a bacterial artificial chromosome transgenesis is an efficient approach with wide applications for conducting a genomic analysis of polygene diseases.
Department of Anatomy and Embryology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba 305-8575, Japan.
Hisashi
H
Oishi
Takahito
T
Tsubaki
Tatsuhiko
T
Miyazaki
Masao
M
Ono
Masato
M
Nose
Satoru
S
Takahashi
D000483:Alleles; D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015703:Antigens, CD / Q000235:genetics* / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics; D001483:Base Sequence; D022202:Chromosomes, Artificial, Bacterial; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007074:Immunoglobulin G / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D020412:Multifactorial Inheritance / Q000276:immunology; D011110:Polymorphism, Genetic; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019076:Transgenes; D014657:Vasculitis / Q000235:genetics* / Q000276:immunology / Q000473:pathology
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D001323:Autoantibodies; C513972:CD72 antigen, mouse; D007074:Immunoglobulin G