title: Viral double-stranded RNA aggravates lupus nephritis through Toll-like receptor 3 on glomerular mesangial cells and antigen-presenting cells.
abstract: How viral infections trigger autoimmunity is poorly understood. A role for Toll-like receptor 3 (TLR3) was hypothesized in this context as viral double-stranded RNA (dsRNA) activates dendritic cells to secrete type I interferons and cytokines that are known to be associated with the disease activity in systemic lupus erythematosus (SLE). Immunostaining of nephritic kidney sections of autoimmune MRL(lpr/lpr) mice revealed TLR3 expression in infiltrating antigen-presenting cells as well as in glomerular mesangial cells. TLR3-positive cultured mesangial cells that were exposed to synthetic polyinosinic-cytidylic acid (pI:C) RNA in vitro produced CCL2 and IL-6. pI:C RNA activated macrophages and dendritic cells, both isolated from MRL(lpr/lpr) mice, to secrete multiple proinflammatory factors. In vivo, a single injection of pI:C RNA increased serum IL-12p70, IL-6, and IFN-alpha levels. A course of 50 microg of pI:C RNA given every other day from weeks 16 to 18 of age aggravated lupus nephritis in pI:C-treated MRL(lpr/lpr) mice. Serum DNA autoantibody levels were unaltered upon systemic exposure to pI:C RNA in MRL(lpr/lpr) mice, as pI:C RNA, in contrast to CpG-DNA, failed to induce B cell activation. It therefore was concluded that viral dsRNA triggers disease activity of lupus nephritis by mechanisms that are different from those of bacterial DNA. In contrast to CpG-DNA/TLR9 interaction, pI:C RNA/TLR3-mediated disease activity is B cell independent, but activated intrinsic renal cells, e.g., glomerular mesangial cells, to produce cytokines and chemokines, factors that can aggravate autoimmune tissue injury, e.g., lupus nephritis.
authors.affiliation: Nephrological Center, Medical Policlinic, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Prashant S
authors.initials: PS
authors.lastname: Patole
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Gröne
authors.forename: Stephan
authors.initials: S
authors.lastname: Segerer
authors.forename: Raluca
authors.initials: R
authors.lastname: Ciubar
authors.forename: Emilia
authors.initials: E
authors.lastname: Belemezova
authors.forename: Anna
authors.initials: A
authors.lastname: Henger
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.forename: Detlef
authors.initials: D
authors.lastname: Schlöndorff
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Anders
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000821:virology; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D019742:Chemokines, CC / Q000097:blood; D005260:Female; D005920:Glomerular Mesangium / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology; D007275:Injections, Intravenous; D016898:Interferon-alpha / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000378:metabolism; D008181:Lupus Nephritis / Q000276:immunology* / Q000821:virology*; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D019463:Mice, Inbred MRL lpr; D010850:Picornaviridae Infections / Q000150:complications / Q000276:immunology*; D021122:Protein Subunits / Q000097:blood; D011507:Proteinuria / Q000276:immunology / Q000821:virology; D012330:RNA, Double-Stranded / Q000276:immunology*; D012367:RNA, Viral / Q000276:immunology / Q000494:pharmacology; D011956:Receptors, Cell Surface / Q000276:immunology* / Q000378:metabolism; D012229:Rhinovirus / Q000235:genetics*; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors
chemical_list: D001323:Autoantibodies; D018932:Chemokine CCL2; D019742:Chemokines, CC; D018836:Inflammation Mediators; D016898:Interferon-alpha; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D021122:Protein Subunits; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D051196:Toll-Like Receptor 3; D051193:Toll-Like Receptors; D018664:Interleukin-12