TLR2 induces Th17 myeloperoxidase autoimmunity, while TLR9 drives Th1 autoimmunity.

OBJECTIVE:: Autoantibodies constitute the hallmark of antineutrophil cytoplasmic antibody vasculitis (ANCA); however CD4+ T cells play an essential role in the development of autoimmunity. Infection is associated with vasculitis, with Toll like receptors a potential link between infection and autoimmunity. We investigated the role of Toll like receptor (TLR) ligation on cellular and humoral autoimmunity and glomerular injury in experimental myeloperoxidase (MPO) induced ANCA vasculitis. METHODS:: We analysed autoimmune responses in wild type mice immunized with MPO alone, or after co-immunization with MPO and a TLR2 or TLR9 ligand. The major vascular injury found in human disease, glomerulonephritis with focal necrosis was triggered by administering a sub-nephritogenic dose of nephrotoxic serum. RESULTS:: MPO alone induced low titre ANCA without DTH 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. TLR2 ligand induced Th17 autoimmunity, with Ror t dependent IL-17A production. TLR9 ligand promoted Th1 autoimmunity, with enhanced production of IFN 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 TLR2 ligation was attenuated when IL-17A was neutralised, while glomerulonephritis induced by MPO and TLR9 ligation was attenuated when IFN was neutralized. CONCLUSION:: These studies demonstrate a pathogenic role for TLRs in initiating autoimmune ANCA associated vasculitis. TLR2 induces Th17 CD4 cells while TLR9 can also direct vasculitis, by directing Th1 autoimmunity.