Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion

Nat Med. 2008 Jan;14(1):81-7. doi: 10.1038/nm1694. Epub 2007 Dec 23.


IL-17A is a T cell-specific cytokine that is involved in chronic inflammations, such as Mycobacterium infection, Crohn's disease, rheumatoid arthritis and multiple sclerosis. Mouse models have explained the molecular basis of IL-17A production and have shown that IL-17A has a positive effect not only on granuloma formation and neurodegeneration through unknown mechanisms, but also on bone resorption through Receptor activator of NF-kappaB ligand (RANKL) induction in osteoblasts. Langerhans cell histiocytosis (LCH) is a rare disease of unknown etiology, lacking an animal model, that cumulates symptoms that are found separately in various IL-17A-related diseases, such as aggressive chronic granuloma formation, bone resorption and soft tissue lesions with occasional neurodegeneration. We examined IL-17A in the context of LCH and found that there were high serum levels of IL-17A during active LCH and unexpected IL-17A synthesis by dendritic cells (DCs), the major cell type in LCH lesions. We also found an IL-17A-dependent pathway for DC fusion, which was highly potentiated by IFN-gamma and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-gamma expression has been previously documented in LCH and observed in IL-17A-related diseases. Notably, serum IL-17A-dependent fusion activity correlates with LCH activity. Thus, IL-17A and IL-17A-stimulated DCs represent targets that may have clinical value in the treatment of LCH and other IL-17A-related inflammatory disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / metabolism
  • Cell Fusion
  • Dendritic Cells / metabolism*
  • Histiocytosis, Langerhans-Cell / pathology*
  • Humans
  • Inflammation
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism*
  • Lymphocyte Activation
  • Lymphocytes / metabolism
  • Mice
  • Monocytes / metabolism
  • Mycobacterium / metabolism
  • Oligonucleotide Array Sequence Analysis


  • Interleukin-17
  • Interferon-gamma