Identification and characterization of a lupus suppressor 129 locus on chromosome 3.
The 129-derived Sle16 is a susceptibility locus for systemic autoimmunity when present on the C57BL/6 (B6) background. Genetic analysis of a (129xB6)F2 cross identified a region from the B6 chromosome 3 (Sle18) with positive linkage to antinuclear Abs. In this study, we have generated a B6 congenic strain harboring the 129 allele of Sle18 and intercrossed this line with the lupus-prone B6.129-Sle16 strain. The presence of the 129-Sle18 allele in the B6.129-Sle16Sle18 double congenic mice suppressed the development of Sle16-mediated autoantibody production and ameliorated the renal pathology. The 129-Sle18 locus rectified the B cell abnormalities detected in the B6.129-Sle16 mice, such as the reduction in the percentage of marginal zone B and B1a cells and the increased number of germinal centers. The B6.129-Sle16Sle18 spleens still displayed an increased percentage of activated T and B cells. However, in the B6.129-Sle16Sle18 strain the percentage of naive T cells was equivalent to that in B6.129-Sle18 and B6 mice and these cells showed a reduced proliferative response to anti-CD3 stimulation compared with B6.129-Sle16 T cells. There was a significant increase in the percentage of CD4(+)FoxP3(+)regulatory T cells in all congenic strains. These cells had normal regulatory function when tested in vitro. Thus, 129-Sle18 represents a novel, non-MHC lupus-suppressor locus probably operating as a functional modifier of B cells that, in combination with other factors, leads to lupus resistance. Further characterization of this locus will help to uncover the immune mechanism(s) conferring protection against lupus.
Carlucci
Francesco
F
Rheumatology Section, Faculty of Medicine, Imperial College, London, United Kingdom.
Fossati-Jimack
Liliane
L
Dumitriu
Ingrid E
IE
Heidari
Yasin
Y
Walport
Mark J
MJ
Szajna
Marta
M
Baruah
Paramita
P
Garden
Oliver A
OA
Cook
H Terence
HT
Botto
Marina
M
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020022:Genetic Predisposition to Disease; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D051379:Mice; D020297:Mice, Congenic; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
D001323:Autoantibodies