The major murine systemic lupus erythematosus susceptibility locus, Sle1, is a cluster of functionally related genes

被引:268
作者
Morel, L [1 ]
Blenman, KR
Croker, BP
Wakeland, EK
机构
[1] Univ Florida, Dept Med, Gainesville, FL 32610 USA
[2] Univ Florida, Dept Pathol, Gainesville, FL 32610 USA
[3] N Florida S George Vet Hlth Syst, Gainesville, FL 32608 USA
[4] Univ Texas, SW Med Ctr, Ctr Immunol, Dallas, TX 75235 USA
关键词
D O I
10.1073/pnas.031336098
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The major murine systemic lupus erythematosus (SLE) susceptibility locus Sle1 is syntenic to a chromosomal region linked with SLE susceptibility in multiple human studies. Congenic analyses have shown that sie 1 breaks tolerance to chromatin, a necessary step for full disease induction that can be suppressed by specific modifier loci. In the present study, our fine mapping analysis of the location of Sle1 has determined that th ree loci within th is congenic interval, termed Sle1a, Sle1b, and Sle1c, can independently cause a loss of tolerance to chromatin, Each displays a distinctive profile of serological and cellular characteristics, with T and B cell functions being more affected by Sle1a and Sle1b, respectively. The epistatic interactions of Sle1 with other susceptibility loci to cause severe nephritis cannot be accounted, however, by these three loci alone, suggesting the existence of an additional locus, termed Sle1d. These findings indicate that the potent autoimmune phenotype caused by the Sle1 genomic interval reflects the combined impact of four, separate, susceptibility genes. This level of genetic complexity, combined with similar findings in other systems, supports the possibility that many complex trait loci reflect the impact of polymorphisms in linked clusters of genes with related functions.
引用
收藏
页码:1787 / 1792
页数:6
相关论文
共 29 条
[1]   Serum amyloid P component controls chromatin degradation and prevents antinuclear autoimmunity [J].
Bickerstaff, MCM ;
Botto, M ;
Hutchinson, WL ;
Herbert, J ;
Tennent, GA ;
Bybee, A ;
Mitchell, DA ;
Cook, HT ;
Butler, PJG ;
Walport, MJ ;
Pepys, MB .
NATURE MEDICINE, 1999, 5 (06) :694-697
[2]   Uncoupling of immune complex formation and kidney damage in autoimmune glomerulonephritis [J].
Clynes, R ;
Dumitru, C ;
Ravetch, JV .
SCIENCE, 1998, 279 (5353) :1052-1054
[3]   A comprehensive genetic map of the mouse genome [J].
Dietrich, WF ;
Miller, J ;
Steen, R ;
Merchant, MA ;
DamronBoles, D ;
Husain, Z ;
Dredge, R ;
Daly, MJ ;
Ingalls, KA ;
OConnor, TJ ;
Evans, CA ;
DeAngelis, MM ;
Levinson, DM ;
Kruglyak, L ;
Goodman, N ;
Copeland, NG ;
Jenkins, NA ;
Hawkins, TL ;
Stein, L ;
Page, DC ;
Lander, ES .
NATURE, 1996, 380 (6570) :149-152
[4]  
DRAKE CG, 1995, J IMMUNOL, V154, P2441
[5]   The genetics of human systemic lupus erythematosus [J].
Harley, JB ;
Moser, KL ;
Gaffney, PM ;
Behrens, TW .
CURRENT OPINION IN IMMUNOLOGY, 1998, 10 (06) :690-696
[6]  
Hattori M, 1999, J IMMUNOL, V163, P1721
[7]   LUPUS SUSCEPTIBILITY LOCI IN NEW-ZEALAND MICE [J].
KONO, DH ;
BURLINGAME, RW ;
OWENS, DG ;
KURAMOCHI, A ;
BALDERAS, RS ;
BALOMENOS, D ;
THEOFILOPOULOS, AN .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (21) :10168-10172
[8]  
LYONS PA, 1998, GENES GENETICS AUTOI, P208
[9]  
Mohan C, 1999, J IMMUNOL, V162, P6492
[10]  
Mohan C, 1997, J IMMUNOL, V159, P454