Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis

Poh-Yi Gan, Oliver Steinmetz, Diana Shu Yee Tan, Kim O'Sullivan, Joshua Ooi, Yichiro Iwakura, Arthur Richard Kitching, Stephen Roger Holdsworth

Research output: Contribution to journalArticleResearchpeer-review

126 Citations (Scopus)

Abstract

A major target autoantigen in anti-neutrophil cytoplasmic antibody-associated vasculitis is myeloperoxidase (MPO). Although MPO-specific CD4+ Th cells seem to orchestrate renal injury, the role of the Th17 subset is unknown. We hypothesized that Th17 cells direct injurious anti-MPO autoimmunity in experimental murine anti-MPO-induced glomerulonephritis (GN). We immunized mice with MPO to establish autoimmunity, resulting in systemic IL-17A production with MPO-specific dermal delayed-type hypersensitivity. We triggered disease using antibodies to the glomerular basement membrane to induce glomerular deposition of MPO by neutrophils. Wild-type mice developed necrotizing GN with an influx of glomerular leukocytes and albuminuria. In contrast, mice deficient in the key Th17 effector cytokine IL-17A were nearly completely protected. The protective effects resulted partly from reduced neutrophil recruitment, which led to less disposition of glomerular MPO. To test whether IL-17A also drives autoimmune delayed-type hypersensitivity in the kidney, we injected MPO into the kidneys of MPO-sensitized mice. IL-17A deficiency reduced accumulation of renal macrophages and renal CCL5 mRNA expression. In conclusion, IL-17A contributes to the pathophysiology of autoimmune anti-MPO GN, suggesting that it may be a viable therapeutic target for this disease.
Original languageEnglish
Pages (from-to)925 - 931
Number of pages7
JournalJournal of the American Society of Nephrology
Volume21
Issue number6
DOIs
Publication statusPublished - 2010

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