Article Text

other Versions

PDF
Extended report
Toll-like receptor 7 (TLR7) modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells
  1. Zi-jian Pan1,
  2. Shannon Maier1,2,
  3. Karen Schwarz1,
  4. Jennifer Azbill1,
  5. Shizuo Akira3,
  6. Satoshi Uematsu3,
  7. A Darise Farris1
  1. 1Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA
  2. 2Department of Endocrinology and Diabetes, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
  3. 3Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
  1. Correspondence to Dr A Darise Farris, Arthritis and Immunology Program, Oklahoma Medical Research Foundation, 825 NE 13th Street, Oklahoma City, Oklahoma 73104, USA; farrisd{at}omrf.ouhsc.edu

Abstract

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.

Statistics from Altmetric.com

Footnotes

  • 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.

Request permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.