Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2011-04, Vol.63 (4), p.1124-1135
• Main Authors: Summers, Shaun A., Steinmetz, Oliver M., Gan, Poh‐Yi, Ooi, Joshua D., Odobasic, Dragana, Kitching, A. Richard, Holdsworth, Stephen R.
• Format: Article
• Language: English
• Subjects: Adeno-associated virus; Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - metabolism; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - pathology; Antibodies, Monoclonal - therapeutic use; Autoantibodies; Autoimmunity - physiology; Biological and medical sciences; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - pathology; Disease Models, Animal; Diseases of the osteoarticular system; Glomerulonephritis - immunology; Glomerulonephritis - metabolism; Glomerulonephritis - prevention & control; Immune system; Immunity, Humoral - physiology; Interferon-gamma - metabolism; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Ligands; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Peroxidase - adverse effects; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Th1 Cells - immunology; Th1 Cells - metabolism; Th1 Cells - pathology; Th17 Cells - immunology; Th17 Cells - metabolism; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 9 - metabolism
• ISSN: 0004-3591; 2326-5191; 1529-0131; 1529-0131; 2326-5205
• DOI: 10.1002/art.30208

Objective 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. Methods 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. Results 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. Conclusion 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.