Toll-like receptor 9-independent aggravation of glomerulonephritis in a novel model of SLE.
The generation of anti-DNA auto-antibodies is characteristic for the human autoimmune condition systemic lupus erythematosus (SLE) and its animal models. However, the contribution of the toll-like receptor (TLR) system of innate immunity receptors and, in particular, TLR9 to this B cell-mediated autoimmune process remains controversial. Here we report that in a novel murine model of SLE, based on hyper-reactive B cell activation mediated by mutant phospholipase Cg2, the genetic deficiency of TLR9 does not protect from spontaneous anti-DNA auto-antibody formation and glomerulonephritis. On the contrary, disease induction is aggravated and additional nucleolar antibody specificity develops in autoimmune TLR9-deficient mice. In vitro studies demonstrate that, in autoimmune-prone mice, dual signaling via the B cell receptor and non-CpG DNA results in synergistic B cell activation in a TLR9-independent manner. These results suggest that engagement of a TLR9-independent DNA activation pathway may promote autoimmunity, while TLR9 signaling can ameliorate SLE-like immune pathology in vivo.
Yu
Philipp
P
Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 4a, 81675 Munich, Germany. philipp.yu@staff.uni-marburg.de
Wellmann
Ute
U
Kunder
Sandra
S
Quintanilla-Martinez
Leticia
L
Jennen
Luise
L
Dear
Neil
N
Amann
Kerstin
K
Bauer
Stefan
S
Winkler
Thomas H
TH
Wagner
Hermann
H
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D051966:Phospholipase C gamma / Q000235:genetics / Q000276:immunology; D013163:Splenomegaly / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D051217:Toll-Like Receptor 9; D004247:DNA; D051966:Phospholipase C gamma