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IL-17A receptor expression differs between subclasses of Langerhans cell histiocytosis, which might settle the IL-17A controversy


Langerhans cell histiocytosis (LCH) is a lymphoproliferative disorder consisting of abnormal Langerhans cell-like cells and other lymphoid cells. LCH presents as either a multisystem LCH (LCH-MS) or a single-system LCH (LCH-SS). Currently, neither the pathogeneses nor the factors that define these disease subclasses have been elucidated. The interleukin (IL)-17A autocrine LCH model and IL-17A-targeted therapies have been proposed and have engendered much controversy. Those authors showed high serum IL-17A levels in LCH and argued that serum IL-17A-dependent fusion activities in vitro, rather than serum IL-17A levels, correlated with LCH severity (i.e. the IL-17A paradox). In contrast, others could not confirm the IL-17A autocrine model. So began the controversy on IL-17A, which still continues. We approached the IL-17A controversy and the IL-17A paradox from a new perspective in considering the expression levels of IL-17A receptor (IL-17RA). We detected higher levels of IL-17RA protein expression in LCH-MS (n = 10) as compared to LCH-SS (n = 9) (P = 0.041) by immunofluorescence. We reconfirmed these data by re-analyzing GSE16395 mRNA data. We found that serum levels of IL-17A were higher in LCH (n = 38) as compared to controls (n = 20) (P = 0.005) with no significant difference between LCH subclasses. We propose an IL-17A endocrine model and stress that changes in IL-17RA expression levels are important for defining LCH subclasses. We hypothesize that these IL-17RA data could clarify the IL-17A controversy and the IL-17A paradox. As a potential treatment of LCH-MS, we indicate the possibility of an IL-17RA-targeted therapy.

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Arbitrary units


False discovery rate controlled by the Benjamini–Hochberg procedure


Enzyme-linked immunosorbent assay


Formalin-fixed paraffin-embedded




Interleukin-17A receptor


Intensity score


Langerhans cell


Langerhans cell histiocytosis

LCH cell:

Langerhans cell-like abnormal cell


Multisystem LCH


Single-system LCH


Liquid chromatography/multiple reaction monitoring-mass spectrometry


Liquid chromatography/mass spectrometry


Matrix metalloproteinase


S100 protein


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This work was partly supported by the Histiocytosis Association of America (HAA grant 2009); a Grant-in-aid for Scientific Research (C) 23590426 from the Japanese Ministry of Education, Science, Sports and Culture; Grant for Research on Measures for Intractable Diseases from the Ministry of Health, Labor and Welfare of Japan; and a 2011 research grant from the Japan LCH Study Group. We thank Dr. Katsumi Higaki and Dr. Katsumi Nagata (Research Center for Bioscience and Technology, Tottori University) for their help with confocal microscopy and LC/MRM-MS.

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Correspondence to Ichiro Murakami.

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Murakami, I., Morimoto, A., Oka, T. et al. IL-17A receptor expression differs between subclasses of Langerhans cell histiocytosis, which might settle the IL-17A controversy. Virchows Arch 462, 219–228 (2013).

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  • Langerhans cell histiocytosis
  • Interleukin-17A
  • Interleukin-17A receptor
  • Photoshop-assisted image analysis
  • Staining intensity
  • Immunofluorescence