title: Langerhans cell histiocytosis reveals a new IL-17A-dependent pathway of dendritic cell fusion.
abstract: 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.
authors.affiliation: INSERM, U851, 21 Avenue Tony Garnier, Lyon 5-69007, France.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Coury
authors.forename: Nicola
authors.initials: N
authors.lastname: Annels
authors.forename: Aymeric
authors.initials: A
authors.lastname: Rivollier
authors.forename: Selma
authors.initials: S
authors.lastname: Olsson
authors.forename: Alessandra
authors.initials: A
authors.lastname: Santoro
authors.forename: Carole
authors.initials: C
authors.lastname: Speziani
authors.forename: Olga
authors.initials: O
authors.lastname: Azocar
authors.forename: Monique
authors.initials: M
authors.lastname: Flacher
authors.forename: Sophia
authors.initials: S
authors.lastname: Djebali
authors.forename: Jacques
authors.initials: J
authors.lastname: Tebib
authors.forename: Maria
authors.initials: M
authors.lastname: Brytting
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.forename: Chantal
authors.initials: C
authors.lastname: Rabourdin-Combe
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Maurizio
authors.initials: M
authors.lastname: Arico
authors.forename: Christine
authors.initials: C
authors.lastname: Delprat
mesh_terms: D000818:Animals; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D002459:Cell Fusion; D003713:Dendritic Cells / Q000378:metabolism*; D006646:Histiocytosis, Langerhans-Cell / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism*; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009161:Mycobacterium / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D020381:Interleukin-17; D007371:Interferon-gamma