Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells

<jats:sec><jats:title>Objectives</jats:title><jats:p>The objectives of this study were to determine whether late apoptotic cell material directly induces autoantibodies characteristic of systemic lupus erythematosus (SLE) and to investigate the innate recognition pathways involved.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>B6, B6.MyD88<jats:sup>–/–</jats:sup>, B6.TLR7<jats:sup>–/–</jats:sup> and B6.TLR9<jats:sup>–/–</jats:sup> mice were subcutaneously injected with B6 syngeneic late apoptotic thymocytes (SLATs) without adjuvant on days 0, 10, 24 and 37. Sera were tested for IgG antibodies to histones and double-stranded DNA (dsDNA) by ELISA and <jats:italic>Crithidia luciliae</jats:italic> indirect immunofluorescence. IgG and C3 deposition in kidney glomeruli was assessed by immunostaining and fluorescence microscopy.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>SLAT injections induced anti-dsDNA and anti-histone antibodies of the IgG1 and IgG2b isotypes in B6 but not MyD88<jats:sup>–/–</jats:sup> mice. TLR7<jats:sup>–/–</jats:sup> and TLR9<jats:sup>–/–</jats:sup> mice injected with SLATs produced delayed or slightly more robust responses, respectively. SLAT injections induced IgG deposits in renal glomeruli of B6, TLR7<jats:sup>–/–</jats:sup> and TLR9<jats:sup>–/–</jats:sup> mice that were absent in MyD88<jats:sup>–/–</jats:sup> mice. Unlike B6 and TLR9<jats:sup>–/–</jats:sup> animals, TLR7<jats:sup>–/–</jats:sup> mice failed to exhibit IgG colocalised glomerular C3 deposits and demonstrated autoantibodies of primarily the IgG2a isotype.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Late apoptotic cell-induced anti-histone and anti-dsDNA antibodies require MyD88 but not Toll-like receptor (TLR)9. Moreover, TLR7 promotes glomerular C3 deposition, possibly through a mechanism of altered antibody isotype switching.</jats:p></jats:sec>