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

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.

• Authors: Lisa Harlow, Irina Fernandez, Makoto Soejima, William M Ridgway, Dana P Ascherman
• Journal: Innate immunity (Innate Immun) Vol. 18 Issue 6 Pg. 876-85 (Dec 2012) ISSN: 1753-4267 [Electronic] United States
• PMID: 22582345 (Publication Type: Journal Article)

Chemical References

• Adaptor Proteins, Vesicular Transport
• Autoantibodies
• Myeloid Differentiation Factor 88
• TICAM-1 protein, mouse
• Toll-Like Receptor 4
• Histidine-tRNA Ligase

Topics

• Adaptor Proteins, Vesicular Transport (genetics)
• Animals
• Antibody Formation (genetics)
• Autoantibodies (immunology)
• Cells, Cultured
• Disease Models, Animal
• Histidine-tRNA Ligase (immunology)
• Humans
• Immunoglobulin Class Switching (genetics)
• Mice
• Mice, Inbred C3H
• Mice, Inbred C57BL
• Mice, Knockout
• Mutation (genetics)
• Myeloid Differentiation Factor 88 (genetics)
• Nervous System Autoimmune Disease, Experimental (immunology)
• T-Lymphocytes (immunology)
• Toll-Like Receptor 4 (genetics, immunology, metabolism)