Characterization of TLR4-mediated auto-antibody production in a mouse model of histidyl-tRNA synthetase-induced myositis

Lisa Harlow, Irina Fernandez, Makoto Soejima, William M. Ridgway, Dana P. Ascherman

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

We have previously shown that intramuscular immunization with a recombinant fragment of murine histidyl-tRNA synthetase (HRS) in the absence of exogenous adjuvant generates Ag-specific, IgG class switched Abs a murine model of myositis. Markedly diminished IgG anti-HRS auto-Ab responses in TLR4 signaling-deficient C3H/HeJ mice indicate that TLR4 is required for auto-Ab formation and/or class switching in this system. Comparative time course assessment of HRS-immunized C3H/HeOuJ (wild type) and C3H/HeJ (TLR4 mutant) mice shows here that despite significant impairment of class switched IgG anti-HRS responses in TLR4-deficient C3H/HeJ mice, production of IgM anti-HRS auto-Abs is relatively preserved-suggesting that TLR4-mediated signals modulate IgG class switching rather than auto-Ab formation in this genetic background. In C57BL/6-derived knockout mice lacking either MyD88 (B6.MyD88-/-) or TRIF (B6.TRIF-/-) adaptor molecules, immunization studies indicate that TRIF exerts a dominant role in the generation of HRS-specific IgG auto-Abs. Complementing these analyses, in vitro stimulation of unfractionated, as well as T cell-depleted, C3H/HeOuJ splenocytes with recombinant murine HRS reveals that TLR4-mediated generation of class switched auto-Abs can occur independently of T cell help. Overall, these findings support a broader role for TLR4 in the breakdown of immune tolerance and development of autoimmunity.

Original languageEnglish (US)
Pages (from-to)876-885
Number of pages10
JournalInnate Immunity
Volume18
Issue number6
DOIs
StatePublished - Dec 1 2012

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Keywords

  • autoantibody
  • classs witching
  • histidyl-tRNA synthetase
  • MyD88
  • TLR4
  • TRIF

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Immunology
  • Microbiology
  • Infectious Diseases

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