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Possible involvement of CXCR3-CXCR6 + CD4 + T cells in Langerhans cell histiocytosis

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Abstract

Introduction

Langerhans cell histiocytosis (LCH) is a condition characterized by proliferation of Langerhans cells and wide-range pathologies, ranging from single granulomatous lesions to multi-organ involvement, associated with tissue destruction. LCH pathogenesis remains obscure although association with interleukin (IL)-17A has been reported. We report here a case that illustrates the potential pathogenic role of helper T17 (Th17) cells in LCH-related bone destruction.

Materials and Methods

The patient was a 66-year-old woman. The clinical course included craniectomy and bone mass excision in X-9, diagnosis of LCH confirmed by histopathology, followed by 26-month chemotherapy. In August X, the patient was diagnosed with complete central diabetes insipidus. Symptoms improved after treatment with desmopressin. Pituitary magnetic resonance imaging showed swelling extending from the suprasellar region to the pituitary stalk, suggestive of LCH recurrence. This was followed by chemotherapy combined with mercaptopurine hydrate. 

Results

Subsequent peripheral blood lymphocyte analysis showed marked increase in activated Th17 cells (CXCR3−CXCR6+ CD4+ T cells). Double staining for CD4 and IL-17 by immunofluorescence of pathological tissue samples obtained during temporal bone mass excision, which confirmed the diagnosis of LCH in X-9, showed areas of combined presence of CD4-positive cells and IL-17-positive cells. Chemotherapy resulted in size reduction of the pituitary lesion and decrease in peripheral blood-activated Th17 cells.

Conclusions

We found abundant peripheral blood-activated Th17 cells and high percentages of IL-17-producing cells in osteolytic bone lesions in LCH. This finding, together with the decrease in peripheral blood-activated Th17 cells following chemotherapy, suggests the potential involvement of activated Th17 cells in LCH-related osteolysis.

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Data availability

Not applicable.

Abbreviations

LCH:

Langerhans cell histiocytosis

Th17:

Helper T17

IL:

Interleukin

VBL:

Vinblastine

PSL:

Prednisolone

MTX:

Methotrexate

ELISA:

Enzyme-linked immunosorbent assay

OPN:

Osteopontin

TRACP5b:

Tartrate-resistant acid phosphatase 5b

NTX:

Cross-linked N-telopeptide of type 1 collagen

References

  1. Liechtenstein L (1953) Histiocytosis X: integration of eosinophilic granuloma, “Letterer-Siwe disease”, and ”Schuller-Christian dis- ease” as related manifestations of a single nosologic entity. AMA Arch Pathol 56:84–102

    Google Scholar 

  2. Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C et al (2013) Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis 8:72. https://doi.org/10.1186/1750-1172-8-72

    Article  PubMed  PubMed Central  Google Scholar 

  3. Lian C, Lu Y, Shen S (2016) Langerhans cell histiocytosis in adults: a case report and review of the literature. Oncotarget 7:18678–18683. https://doi.org/10.18632/oncotarget.7892

    Article  PubMed  PubMed Central  Google Scholar 

  4. Baumgartner I, von Hochstetter A, Baumert B, Luetolf U, Follath F (1997) Langerhans’-cell histiocytosis in adults. Med Pediatr Oncol 28:9–14. https://doi.org/10.1002/(sici)1096-911x(199701)28:1%3c9::aid-mpo3%3e3.0.co;2-p

    Article  CAS  PubMed  Google Scholar 

  5. Grana N (2014) Langerhans cell histiocytosis. Cancer Control 21:328–334. https://doi.org/10.1177/107327481402100409

    Article  PubMed  Google Scholar 

  6. Cao XX, Duan MH, Zhao AL, Cai H, Chen J et al (2022) Treatment outcomes and prognostic factors of patients with adult Langerhans cell histiocytosis. Am J Hematol 97:203–208. https://doi.org/10.1002/ajh.26412. (Epub 2021 Nov 23)

    Article  CAS  PubMed  Google Scholar 

  7. Malpas JS (1998) Langerhans cell histiocytosis in adults. Hematol Oncol Clin North Am 12:259–268. https://doi.org/10.1016/s0889-8588(05)70509-8

    Article  CAS  PubMed  Google Scholar 

  8. Kubo S, Nakayamada S, Yoshikawa M, Miyazaki Y, Sakata K et al (2017) Peripheral Immunophenotyping identifies three subgroups based on T Cell heterogeneity in lupus patients. Arthritis Rheumatol 69:2029–2037. https://doi.org/10.1002/art.40180

    Article  CAS  PubMed  Google Scholar 

  9. Maecker HT, McCoy JP, Nussenblatt R (2012) Standardizing immunophenotyping for the human immunology project. Nat Rev Immunol 12:191–200. https://doi.org/10.1038/nri3158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Morimoto A, Shioda Y, Imamura T, Kudo K, Kawaguchi H et al (2016) Intensified and prolonged therapy comprising cytarabine, vincristine and prednisolone improves outcome in patients with multisystem Langerhans cell histiocytosis: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study. Int J Hematol 104:99–109. https://doi.org/10.1007/s12185-016-1993-3

    Article  CAS  PubMed  Google Scholar 

  11. Egeler RM, Favara BE, van Meurs M, Laman JD, Claassen E (1999) Differential In situ cytokine profiles of Langerhans-like cells and T cells in Langerhans cell histiocytosis: abundant expression of cytokines relevant to disease and treatment. Blood 94:4195–4201

    CAS  PubMed  Google Scholar 

  12. Kobayashi M, Tojo A (2018) Langerhans cell histiocytosis in adults: advances in pathophysiology and treatment. Cancer Sci 109:3707–3713. https://doi.org/10.1111/cas.13817

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ismail MB, Åkefeldt SO, Lourda M, Gavhed D, Aricò M et al (2020) High levels of plasma interleukin-17A are associated with severe neurological sequelae in Langerhans cell histiocytosis. Cytokine 126:154877. https://doi.org/10.1016/j.cyto.2019.154877

    Article  CAS  PubMed  Google Scholar 

  14. Singh SP, Zhang HH, Foley JF, Hedrick MN, Farber JM (2008) Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. J Immunol 180:214–221. https://doi.org/10.4049/jimmunol.180.1.214

    Article  CAS  PubMed  Google Scholar 

  15. Aggarwal S, Gurney AL (2002) IL-17: Prototype member of an emerging cytokine family. J Leukoc Biol 71:1–8

    Article  CAS  PubMed  Google Scholar 

  16. Kolls JK, Linden A (2004) Interleukin-17 family members and inflammation. Immunity 21:467–476. https://doi.org/10.1016/j.immuni.2004.08.018

    Article  CAS  PubMed  Google Scholar 

  17. Pöllinger B, Junt T, Metzler B, Walker UA, Tyndall A et al (2011) Th17 cells, not IL-17+ γδ T cells, drive arthritic bone destruction in mice and humans. J Immunol 186:2602–2612. https://doi.org/10.4049/jimmunol.1003370

    Article  CAS  PubMed  Google Scholar 

  18. Kamizono J, Okada Y, Shirahata A, Tanaka Y (2002) Bisphosphonate induces remission of refractory osteolysis in Langerhans cell histiocytosis. J Bone Miner Res 17:1926–1928. https://doi.org/10.1359/jbmr.2002.17.11.1926

    Article  PubMed  Google Scholar 

  19. Oh Y, Morimoto A, Shioda Y, Imamura T, Kudo K, Imashuku S, Japan LCH Study Group (2014) High serum osteopontin levels in pediatric patients with high risk Langerhans cell histiocytosis. Cytokine 70:194–197. https://doi.org/10.1016/j.cyto.2014.07.002

    Article  CAS  PubMed  Google Scholar 

  20. Li N, Cui L, Ma H, Gong Z, Lian H et al (2020) Osteopontin is highly secreted in the cerebrospinal fluid of patient with posterior pituitary involvement in Langerhans cell histiocytosis. Int J Lab Hematol 42:788–795. https://doi.org/10.1111/ijlh.13304

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We would like to express our sincere gratitude to Dr. Shimajiri Shohei, who performed the pathological staining for this paper.

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Authors and Affiliations

  1. First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushyu-shi, Kitakyushu, 807-8555, Japan

    Akemi Tokutsu, Yosuke Okada, Akira Kurozumi, Kenichi Tanaka, Satoshi Kubo & Yoshiya Tanaka

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  1. Akemi Tokutsu
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  2. Yosuke Okada
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  3. Akira Kurozumi
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  4. Kenichi Tanaka
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  5. Satoshi Kubo
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  6. Yoshiya Tanaka
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Contributions

KT obtained consent forms. AT and AK collected data. AT wrote the manuscript. YO, AK, KT, SK, and YT reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Yoshiya Tanaka.

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Tokutsu, A., Okada, Y., Kurozumi, A. et al. Possible involvement of CXCR3-CXCR6 + CD4 + T cells in Langerhans cell histiocytosis. J Bone Miner Metab 41, 212–219 (2023). https://doi.org/10.1007/s00774-022-01397-5

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  • DOI: https://doi.org/10.1007/s00774-022-01397-5

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