MPO-ANCA induces IL-17 production by activated neutrophils in vitro via classical complement pathway-dependent manner

J Autoimmun. 2008 Aug;31(1):79-89. doi: 10.1016/j.jaut.2008.03.006.

Abstract

The elevation of serum anti-neutrophil cytoplasmic autoantibodies (ANCA) is significantly associated with the progression of some patients with systemic vasculitis. Especially, myeloperoxidase-specific ANCA (MPO-ANCA) play a pivotal role in the progression of systemic vasculitis including crescentic glomerulonephritis. Here we demonstrated that MPO-ANCA-activated neutrophils allow the local environment to differentiate Th(17) cells through IL-6, IL-17A, and IL-23 production. We found a variety of elevated serum cytokines, especially IL-17A, in ANCA-mediated systemic vasculitis mice. Furthermore, activated peritoneal neutrophils in vitro also produced IL-17A and IL-23 in response to MPO-ANCA. Co-stimulation of fungal mannoprotein and complements significantly enhanced the MPO-ANCA-mediated IL-17A expression, but F(ab)'(2) fragments of MPO-ANCA diminished the cytokine response. These results suggest that the activated neutrophils produce IL-17A and IL-23 in response to MPO-ANCA via their Fc-region and classical complement pathway, which initiate the first steps of chronic autoimmune inflammation by allowing the local environment to develop Th(17)-mediated autoimmunity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antineutrophil Cytoplasmic / blood
  • Antibodies, Antineutrophil Cytoplasmic / immunology*
  • Antibodies, Antineutrophil Cytoplasmic / pharmacology
  • Autoantibodies / immunology
  • Cells, Cultured
  • Complement Pathway, Classical / drug effects
  • Complement Pathway, Classical / immunology*
  • Interleukin-17 / metabolism*
  • Male
  • Membrane Glycoproteins / immunology
  • Mice
  • Mice, Inbred C57BL
  • Neutrophil Activation / drug effects
  • Neutrophil Activation / immunology*
  • Neutrophils / drug effects
  • Neutrophils / immunology*
  • Peroxidase / immunology
  • Vasculitis / immunology
  • Vasculitis / metabolism

Substances

  • Antibodies, Antineutrophil Cytoplasmic
  • Autoantibodies
  • Interleukin-17
  • Membrane Glycoproteins
  • mannoproteins
  • Peroxidase