Ligands to nucleic acid-specific toll-like receptors and the onset of lupus nephritis.
Lupus nephritis develops from a combination of genetic and environmental factors such as microbial infection. A role for microbial nucleic acids (e.g., via nucleic acid-specific Toll-like receptors [TLR]) was hypothesized, in this context, because microbial nucleic acids can trigger multiple aspects of autoimmunity in vitro and in vivo. Eight-week-old MRL(lpr/lpr) and MRL wild-type mice received an injection of pI:C RNA (ligand to TLR-3), imiquimod (ligand to TLR-7), or CpG-DNA (ligand to TLR-9) on alternate days for 2 wk. Only CpG-DNA triggered the onset of lupus nephritis in MRL(lpr/lpr) mice, as defined by diffuse proliferative glomerulonephritis associated with glomerular IgG and complement C3 deposition, proteinuria, and glomerular macrophage infiltrates. None of the compounds caused DNA autoantibody production or glomerulonephritis in MRL wild-type mice. The role of CpG-DNA to trigger lupus nephritis in MRL(lpr/lpr) mice was found to relate to its potent immunostimulatory effects at multiple levels: B cell IL12p40 production, B cell proliferation, double-stranded DNA autoantibody secretion, and dendritic cell IFN-alpha production. The induction of lupus nephritis by CpG-DNA is motif specific and could be prevented by co-injection of inhibitory DNA. In summary, among the ligands tested, CpG-DNA triggers lupus nephritis in genetically predisposed hosts. These data support the concept that systemic lupus erythematosus is triggered by pathogens that release CG-rich DNA.
Pawar
Rahul D
RD
Medical Poliklinik, University of Munich, Munich, Germany.
Patole
Prashant S
PS
Ellwart
Andreas
A
Lech
Maciej
M
Segerer
Stephan
S
Schlondorff
Detlef
D
Anders
Hans-Joachim
HJ
D000276:Adjuvants, Immunologic / Q000009:adverse effects*; D000634:Aminoquinolines / Q000009:adverse effects*; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004269:DNA, Bacterial / Q000009:adverse effects*; D003713:Dendritic Cells / Q000378:metabolism; D005260:Female; D000077271:Imiquimod; D007074:Immunoglobulin G / Q000097:blood; D007369:Interferon Inducers / Q000009:adverse effects*; D016898:Interferon-alpha / Q000097:blood; D053762:Interleukin-12 Subunit p40 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008181:Lupus Nephritis / Q000209:etiology* / Q000821:virology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D011070:Poly I-C / Q000009:adverse effects*; D013154:Spleen / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000634:Aminoquinolines; D001323:Autoantibodies; C472452:CpG-DNA, E coli; D016207:Cytokines; D004269:DNA, Bacterial; D007074:Immunoglobulin G; D007369:Interferon Inducers; D016898:Interferon-alpha; D053762:Interleukin-12 Subunit p40; D015850:Interleukin-6; D051193:Toll-Like Receptors; D011070:Poly I-C; D000077271:Imiquimod