Functional dissection of lupus susceptibility loci on the New Zealand black mouse chromosome 1: evidence for independent genetic loci affecting T and B cell activation.
In previous work, we demonstrated linkage between a broad region on New Zealand Black (NZB) chromosome 1 and increased costimulatory molecule expression on B cells and autoantibody production. In this study, we produced C57BL/6 congenic mice with homozygous NZB chromosome 1 intervals of differing lengths. We show that both B6.NZBc1(35-106) (numbers denote chromosomal interval length) and B6.NZBc1(85-106) mice produce IgG anti-nuclear autoantibodies, but B6.NZBc1(35-106) mice develop significantly higher titers of autoantibodies and more severe renal disease than B6.NZBc1(85-106) mice. Cellular analysis of B6.NZBc1(85-106) mice revealed splenomegaly and increased numbers of memory T cells. In addition to these features, B6.NZBc1(35-106) mice had altered B and T cell activation with increased expression of CD69, and for B cells, costimulatory molecules and MHC. Introduction of an anti-hen egg white lysozyme Ig transgene, as a representative nonself-reactive Ig receptor, onto the B6.NZBc1(35-106) background corrected the B cell activation phenotype and led to dramatic normalization of splenomegaly and T cell activation, but had little impact on the increased proportion of memory T cells. These findings indicate that there are multiple lupus susceptibility genes on NZB chromosome 1, and that although B cell defects play an important role in lupus pathogenesis in these mice, they act in concert with T cell activation defects.
Wither
Joan E
JE
Arthritis Center of Excellence, Toronto Western Research Institute, Toronto, Ontario, Canada. jwither@uhnres.utoronto.ca
Lajoie
Ginette
G
Heinrichs
Svinda
S
Cai
Yong-Chun
YC
Chang
Nan
N
Ciofani
Amelia
A
Cheung
Yui-Ho
YH
MacLeod
Ralph
R
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000473:pathology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002874:Chromosome Mapping / Q000379:methods; D003433:Crosses, Genetic; D005260:Female; D005819:Genetic Markers / Q000276:immunology*; D020022:Genetic Predisposition to Disease; D016130:Immunophenotyping; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics*; D008297:Male; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D017634:Self Tolerance / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019076:Transgenes / Q000276:immunology
D001323:Autoantibodies; D005819:Genetic Markers