Th17 cells promote autoimmune anti-myeloperoxidase glomerulonephritis

J Am Soc Nephrol. 2010 Jun;21(6):925-31. doi: 10.1681/ASN.2009070763. Epub 2010 Mar 18.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / metabolism*
  • Antibodies, Antineutrophil Cytoplasmic / metabolism
  • Autoimmune Diseases / etiology
  • Autoimmune Diseases / metabolism*
  • Autoimmune Diseases / pathology
  • Disease Models, Animal
  • Glomerulonephritis / etiology
  • Glomerulonephritis / metabolism*
  • Glomerulonephritis / pathology
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Kidney / drug effects
  • Kidney / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophils / metabolism
  • Neutrophils / pathology
  • Peroxidase / immunology*
  • Peroxidase / pharmacology
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / pathology

Substances

  • Antibodies
  • Antibodies, Antineutrophil Cytoplasmic
  • Interleukin-17
  • Peroxidase