Toll-like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll-like receptor 9 drives Th1 autoimmunity in murine vasculitis
Article first published online: 30 MAR 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 4, pages 1124–1135, April 2011
How to Cite
Summers, S. A., Steinmetz, O. M., Gan, P.-Y., Ooi, J. D., Odobasic, D., Kitching, A. R. and Holdsworth, S. R. (2011), Toll-like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll-like receptor 9 drives Th1 autoimmunity in murine vasculitis. Arthritis & Rheumatism, 63: 1124–1135. doi: 10.1002/art.30208
- Issue published online: 3 MAR 2011
- Article first published online: 30 MAR 2011
- Accepted manuscript online: 28 DEC 2010 04:02PM EST
- Manuscript Accepted: 14 DEC 2010
- Manuscript Received: 10 AUG 2010
- Program grant from the National Health and Medical Research Council of Australia
- National Health and Medical Research Council of Australia postgraduate research scholarship
Autoantibodies constitute the hallmark of antineutrophil cytoplasmic antibody–associated vasculitis (AAV); however, CD4+ T cells play an essential role in the development of autoimmunity. Infection is associated with vasculitis, with Toll-like receptors (TLRs) a potential link between infection and autoimmunity. This study was undertaken to investigate the role of TLR ligation on cellular and humoral autoimmunity and glomerular injury in experimental myeloperoxidase (MPO)–induced AAV.
We analyzed autoimmune responses in wild-type mice immunized with MPO alone or coimmunized with MPO and a TLR-2 or TLR-9 ligand. The major vascular injury found in human disease, glomerulonephritis with focal necrosis, was triggered by administering a subnephritogenic dose of nephrotoxic serum.
MPO alone induced low-titer antineutrophil cytoplasmic antibodies (ANCAs) without delayed-type hypersensitivity or CD4 cytokine responses. However, when MPO was given with either TLR ligand, cellular and humoral autoimmunity was enhanced, but with distinctly different CD4 subsets and IgG ANCA isotypes. TLR-2 ligand induced Th17 autoimmunity, with retinoic acid receptor–related orphan nuclear receptor γt–dependent interleukin-17A (IL-17A) production. TLR-9 ligand promoted Th1 autoimmunity, with enhanced production of interferon-γ (IFNγ) and Th1-associated IgG subclasses. Glomerular vasculitis developed only after the administration of nephrotoxic serum in mice immunized with either TLR ligand and MPO. Glomerulonephritis directed by MPO and TLR-2 ligation was attenuated when IL-17A was neutralized, while glomerulonephritis induced by MPO and TLR-9 ligation was attenuated when IFNγ was neutralized.
Our findings indicate a pathogenic role of TLRs in initiating autoimmune AAV. TLR-2 induces Th17 CD4 cells while TLR-9 can also direct vasculitis, by directing Th1 autoimmunity.