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TLR7 modulates anti-nucleosomal autoantibody isotype and renal complement deposition in mice exposed to syngeneic late apoptotic cells
  1. Zi-jian Pan (zi-jian-pan{at}omrf.org)
  1. Oklahoma Medical Research Foundation, United States
    1. Shannon Maier (shannon-maier{at}omrf.org)
    1. OMRF and OUHSC, United States
      1. Karen Schwarz (daviska{at}hotmail.com)
      1. None, United States
        1. Jennifer Azbill (jenniferazbill{at}yahoo.com)
        1. None, United States
          1. Shizuo Akira (sakira{at}biken.osaka-u.ac.jp)
          1. The Department of Host Defense, Research Institute for Microbial Diseases, Japan
            1. Satoshi Uematsu (uemattsu{at}biken.osaka-u.ac.jp)
            1. The Department of Host Defense, Research Institute for Microbial Diseases, Japan
              1. A Darise Farris (darise-farris{at}omrf.org)
              1. Oklahoma Medical Research Foundation, United States

                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 d0, 10, 24 and 37. Sera were tested for IgG antibodies to histones and 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 co-localized 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 TLR9. Moreover, TLR7 promotes glomerular C3 deposition, possibly through a mechanism of altered antibody isotype switching.

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