Multigenic control of lupus-associated antiphospholipid syndrome in a model of (NZW x BXSB) F1 mice.
In a subset of systemic lupus erythematosus (SLE) patients, antiphospholipid syndrome, characterized by occurrence of anti-cardiolipin (CL) antibodies, thrombocytopenia, thrombosis and recurrent intrauterine fetal death occurs. Male (NZW x BXSB)F1 mice, carrying the BXSB Yaa gene, serve as a model for SLE-associated antiphospholipid syndrome. Using microsatellite markers in the NZW x (NZW x BXSB)F1 backcross male progeny, we mapped BXSB alleles contributing to the generation of anti-CL antibodies, platelet-binding antibodies, thrombocytopenia and myocardial infarction. Generation of each disease character was controlled by two major independently segregating dominant alleles, i.e. those on chromosomes (Chr.) 4 and 17 for anti-CL antibodies, Chr. 8 and 17 for both anti-platelet antibodies and thrombocytopenia and, to our surprise, Chr. 7 and 14 for myocardial infarction, and that a combination of the two alleles appeared to produce full expression of each character, as a complementary gene action. The alleles on Chr. 17 linked to the above three characters were all mapped in close proximity to the H-2 complex. Therefore, no single factor such as anti-CL antibodies can explain the pathogenesis of SLE-associated antiphospholipid syndrome. Rather, a combination of susceptibility alleles such as described here, along with additional modifying loci, i.e. BXSB Yaa and some from NZW, characterizes unique SLE features in male (NZW x BXSB) F1 mice. There are potentially important candidate genes which may be linked to the syndrome.
Ida
A
A
Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan.
Hirose
S
S
Hamano
Y
Y
Kodera
S
S
Jiang
Y
Y
Abe
M
M
Zhang
D
D
Nishimura
H
H
Shirai
T
T
D000818:Animals; D016736:Antiphospholipid Syndrome / Q000235:genetics* / Q000276:immunology; D002874:Chromosome Mapping; D004276:DNA, Satellite / Q000235:genetics; D005786:Gene Expression Regulation / Q000276:immunology*; D008040:Genetic Linkage; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice
D004276:DNA, Satellite