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

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-κB 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-γ and led to giant cells expressing three major tissue-destructive enzymes: tartrate resistant acidic phosphatase and matrix metalloproteinases 9 and 12. IFN-γ 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.

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Figure 1: Study of IL-17A in serums, lesions, peripheral blood T lymphocytes, monocytes and monocyte-derived DCs (Mo-DCs) from subjects with LCH.
Figure 2: Fusion of Mo-DCs from healthy donors or individuals with LCH, in the presence of IL-17A, with or without IFN-γ.
Figure 3: Functional characterization of the IL-17A–stimulated DC in vitro, and in vivo implications.

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Acknowledgements

We thank S. Lebecque for fruitful scientific discussions on IL-17A autoantibodies, J.J. Pin (Dendritics SAS, http://www.dendritics.net) for technical discussions and IL-17A antibodies, O. Gillet, D. Gavhed, J. Lachuer and B. Blanquier for technical assistance, F. Archer and K. Gallay for the management of the Level 3 security laboratory, and M. Faure and G. Meiffren for critical reading of the manuscript. This work was supported by recurrent grants from the Institut National de la Santé Et de la Recherche Médicale, Université Claude Bernard de Lyon and grants from the Histiocytosis Association of America 2006, Fondation pour la Recherche Médicale DEQ2005120572, Émergence project of Rhône-Alpes Region, Ligue Contre le Cancer Ardèche Drome and Rhône, Institut National contre le Cancer-cancéropole 2004-2005, Association pour la Recherche sur le Cancer 3637, Association de Recherche sur la Polyarthrite and French Ministry of Research ACI8BC05H, the Italian Ministry of Health, Progetto di Ricerca Finalizzata 2004: “Istiocitosi e Tumori”, Associazione Italiana Ricerca Istiocitosi, the Swedish Children's Cancer Foundation, the Swedish Research Council, the Cancer and Allergy Foundation of Sweden and the Stockholm County Council (ALF project).

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Contributions

C.D. conceived and wrote the initial study proposal and supervised the project. N.A. (immunohistological studies), S.O., A.S. and M.B. (Herpesvirus detections), and C.D., F.C., A.R. and C.S. made substantial contributions to acquisition of data with the technical assistance of O.A., M.F. and S.D. C.D., F.C., N.A., A.R., S.O., A.S. and M.B. carried out the data analysis. F.C. and J.T. conducted the sampling and clinical study of the rheumatoid arthritis patients, and M.A. (Table 1), J.-I.H. (Table 1) and R.M.E. (immunohistological samples) did likewise for the LCH patients. C.D. wrote the manuscript. C.R.-C., J.-I.H., M.A. and R.M.E. participated in the interpretation of the results and the editing of the manuscript.

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Correspondence to Christine Delprat.

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Supplementary Figs. 1–6, Table 1 and Supplementary Methods (PDF 12744 kb)

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Coury, F., Annels, N., Rivollier, A. et al. Langerhans cell histiocytosis reveals a new IL-17A–dependent pathway of dendritic cell fusion. Nat Med 14, 81–87 (2008). https://doi.org/10.1038/nm1694

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