Letter abstract
Nature Medicine 14, 81 - 87 (2008)
Published online: 23 December 2007 | doi:10.1038/nm1694
Langerhans cell histiocytosis reveals a new IL-17A–dependent pathway of dendritic cell fusion
Fabienne Coury1,2,3,4,5, Nicola Annels6, Aymeric Rivollier1,2,3,4, Selma Olsson7, Alessandra Santoro8,9, Carole Speziani1,2,3,4, Olga Azocar1,2,3,4, Monique Flacher1,2,3,4, Sophia Djebali1,2,3,4, Jacques Tebib2,3,4,5, Maria Brytting10, R Maarten Egeler6, Chantal Rabourdin-Combe1,2,3,4,11, Jan-Inge Henter7,11, Maurizio Arico8,11 & Christine Delprat1,2,3,4
Abstract
IL-17A is a T cell–specific cytokine1 that is involved in chronic inflammations, such as Mycobacterium infection2, Crohn's disease3, rheumatoid arthritis4 and multiple sclerosis5. Mouse models have explained the molecular basis of IL-17A production6, 7 and have shown that IL-17A has a positive effect not only on granuloma formation8 and neurodegeneration9 through unknown mechanisms, but also on bone resorption through Receptor activator of NF-
B ligand (RANKL) induction in osteoblasts4, 10. 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 neurodegeneration11, 12. 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-
and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN- expression has been previously documented in LCH13 and observed in IL-17A–related diseases14, 15, 16, 17. 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.
- INSERM, U851, 21 Avenue Tony Garnier, Lyon 5-69007, France.
- Université de Lyon, Lyon F-69007, France.
- Université de Lyon 1, Villeurbanne F-69622, France.
- IFR128, Lyon F-69007, France.
- Hospices Civils de Lyon, Centre Hospitalier Lyon Sud, Pierre Bénite F-69310, France.
- Departments of Pediatric Immunology, Hematology, Oncology, Bone Marrow Transplantation and Autoimmune Diseases, Leiden University Medical Centre, Leiden NL-2300 RC, The Netherlands.
- Childhood Cancer Research Unit, Department of Woman and Child Health, Karolinska Institutet, Karolinska University Hospital, S-171 76 Stockholm, Sweden.
- Onco Ematologia Pediatrica, Ospedale dei Bambini "G. Di Cristina," Palermo I-90134, Italy.
- Hematology I, A.O. Cervello, Palermo I-90134, Italy.
- Department of Virology, Swedish Institute for Infectious Disease Control, Solna S-171 82, Sweden.
- These authors contributed equally to this work.
Correspondence to: Christine Delprat1,2,3,4 e-mail: cdelprat@free.fr
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