Requirement of Toll-like receptor 7 for pristane-induced production of autoantibodies and development of murine lupus nephritis.
OBJECTIVE
The detection of high titers of antibodies against small nuclear ribonucleoproteins (snRNP) is a diagnostic finding in patients in whom systemic lupus erythematosus (SLE) is suspected. Endogenous RNA molecules within snRNP trigger Toll-like receptor 7 (TLR-7) activation in B cells and dendritic cells, leading to anti-snRNP antibody production, which is associated with the development of immune complex nephritis in SLE. The purpose of this study was to investigate the role of TLR-7 in anti-snRNP antibody production and renal disease in SLE induced by an exogenous factor in the absence of genetic predisposition, using the pristane-induced murine lupus model.


METHODS
Serum autoantibodies, IgG isotypes, and cytokine levels in pristane-treated wild-type and TLR-7-deficient mice were analyzed by enzyme-linked immunosorbent assay. Histopathologic changes in mouse kidneys were determined by light immunofluorescence microscopy. Cell subsets in splenocytes and peritoneal lavage cells from the mice were examined by flow cytometry.


RESULTS
We found that anti-snRNP antibody production induced by pristane treatment was entirely dependent on the expression of TLR-7, whereas anti-double-stranded DNA antibody production was not affected by a lack of TLR-7. Impaired anti-snRNP antibody production in TLR-7-deficient mice was paralleled by lower levels of glomerular IgG and complement deposits, as well as less severe glomerulonephritis.


CONCLUSIONS
TLR-7 is specifically required for the production of RNA-reactive autoantibodies and the development of glomerulonephritis in pristane-induced murine lupus, a model of environmentally triggered SLE in the absence of genetic susceptibility to autoimmunity. Specific interference with TLR-7 activation by endogenous TLR-7 ligands may therefore be a promising novel strategy for the treatment of SLE.
Savarese
Emina
E
Department of Internal Medicine II, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany.
Steinberg
Christian
C
Pawar
Rahul D
RD
Reindl
Wolfgang
W
Akira
Shizuo
S
Anders
Hans-Joachim
HJ
Krug
Anne
A
D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D008181:Lupus Nephritis / Q000139:chemically induced / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology*; D013729:Terpenes; D051199:Toll-Like Receptor 7 / Q000172:deficiency / Q000276:immunology*
D001323:Autoantibodies; D017411:Ribonucleoproteins, Small Nuclear; D013729:Terpenes; D051199:Toll-Like Receptor 7; C009042:pristane