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

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Abstract

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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Abbreviations

AU:

Arbitrary units

BH-FDR:

False discovery rate controlled by the Benjamini–Hochberg procedure

ELISA:

Enzyme-linked immunosorbent assay

FFPE:

Formalin-fixed paraffin-embedded

IL-17A:

Interleukin-17A

IL-17RA:

Interleukin-17A receptor

IS:

Intensity score

LC:

Langerhans cell

LCH:

Langerhans cell histiocytosis

LCH cell:

Langerhans cell-like abnormal cell

LCH-MS:

Multisystem LCH

LCH-SS:

Single-system LCH

LC/MRM-MS:

Liquid chromatography/multiple reaction monitoring-mass spectrometry

LC/MS:

Liquid chromatography/mass spectrometry

MMP:

Matrix metalloproteinase

S100:

S100 protein

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Acknowledgments

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.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Division of Molecular Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan

    Ichiro Murakami, Satoshi Kuwamoto, Masako Kato & Kazuhiko Hayashi

  2. Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan

    Akira Morimoto

  3. Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Takashi Oka, Lamia Abd Al-Kadar, Katsuyoshi Takata & Tadashi Yoshino

  4. Department of Pathology, Tottori University Hospital, Tottori, Japan

    Yasushi Horie

  5. Inserm U507 and U1016, Institut Cochin, Paris, France

    Jean Gogusev

  6. University of Paris Descartes (Paris V), Paris, France

    Francis Jaubert

  7. Division of Pediatrics and Hematology, Takasago-seibu Hospital, Hyogo, Japan

    Shinsaku Imashuku

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  1. Ichiro Murakami
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  2. Akira Morimoto
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  3. Takashi Oka
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  8. Jean Gogusev
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  9. Francis Jaubert
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  10. Shinsaku Imashuku
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  11. Lamia Abd Al-Kadar
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  12. Katsuyoshi Takata
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  13. Tadashi Yoshino
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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). https://doi.org/10.1007/s00428-012-1360-6

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