Objectives 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.
Methods B6, B6.MyD88–/–, B6.TLR7–/– and B6.TLR9–/– 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 Crithidia luciliae indirect immunofluorescence. IgG and C3 deposition in kidney glomeruli was assessed by immunostaining and fluorescence microscopy.
Results SLAT injections induced anti-dsDNA and anti-histone antibodies of the IgG1 and IgG2b isotypes in B6 but not MyD88–/– mice. TLR7–/– and TLR9–/– mice injected with SLATs produced delayed or slightly more robust responses, respectively. SLAT injections induced IgG deposits in renal glomeruli of B6, TLR7–/– and TLR9–/– mice that were absent in MyD88–/– mice. Unlike B6 and TLR9–/– animals, TLR7–/– mice failed to exhibit IgG colocalised glomerular C3 deposits and demonstrated autoantibodies of primarily the IgG2a isotype.
Conclusions 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.
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ZP and SM contributed equally to this study.
Funding This work was supported by the National Institutes of Health grants R01 AI48097, K02 AI051647 and P50 AR048940-01.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.
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