title: Expression of Toll-like receptors and their detection of nuclear self-antigen leading to immune activation in JSLE.
abstract: OBJECTIVE
  Toll-like receptors (TLRs) essential in the functioning of the immune system have been implicated in the development of autoimmunity. TLR3, 7, 8 and 9 are capable of recognizing nucleic autoantigens typical of SLE. Their expression correlates positively with disease activity in adult-onset SLE. This study aimed to determine the role of TLRs in JSLE and whether apoptotic neutrophils are a source of nuclear autoantigen being detected through TLR3, 7, 8 and 9, leading to an inflammatory response.
  
  
  METHODS
  TLR3, 7, 8 and 9 mRNA and protein expression were measured in peripheral blood mononuclear cells (PBMCs) in JSLE patients compared with JIA and non-inflammatory controls. Activation of the TLRs by JSLE serum-induced apoptotic neutrophils was detected by measuring IFN-α mRNA and protein expression, and confirmed using myeloid differentiation factor 88 (MyD88) and TIR domain-containing adapter-inducing IFN-β (TRIF) inhibitors.
  
  
  RESULTS
  JSLE patients have increased TLR3, 8 and 9 mRNA and protein expression compared with controls (P < 0.05). Incubation of PBMCs with apoptotic neutrophils demonstrated a dose-response relationship for IFN-α mRNA expression. Inhibition of TLR signalling by blocking MyD88 and TRIF signalling decreased IFN-α mRNA expression in PBMCs incubated with apoptotic neutrophils (P < 0.05).
  
  
  CONCLUSIONS
  This study demonstrated significantly increased TLR expression in JSLE compared with controls. Our data indicate that apoptotic neutrophils trigger TLR activation through their presentation of autoantigens. The role of TLRs in this inflammatory response was demonstrated by a dose-response relationship to apoptotic neutrophil concentration and confirmed by a decrease in IFN-α production after inhibition of TLR signalling.
authors.affiliation: Department of Women's and Children's Health, Alder Hey Children's NHS Foundation Trust, University of Liverpool, Liverpool L12 2AP, UK. angela.fahey@liv.ac.uk
authors.forename: Angela
authors.initials: A
authors.lastname: Midgley
authors.forename: Colin
authors.initials: C
authors.lastname: Thorbinson
authors.forename: Michael W
authors.initials: MW
authors.lastname: Beresford
mesh_terms: D000293:Adolescent; D034961:Antigens, Nuclear / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000276:immunology; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008297:Male; D015398:Signal Transduction / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism*
chemical_list: D034961:Antigens, Nuclear; D001324:Autoantigens; D051193:Toll-Like Receptors