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Intact IFN-gammaR1 Expression and Function Distinguishes Langerhans Cell Histiocytosis From Mendelian Susceptibility to Mycobacterial Disease

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Associated researcher

  • Quispel, W. T.
  • Stegehuis-Kamp, J. A.
  • Santos, S. J.
  • van Wengen, A.
  • Dompeling, E.

  • Egeler, R. M.
  • van de Vosse, E.
  • van Halteren, A. G. S.

Associated organisations

Abstract

Poly-ostotic Langerhans Cell Histiocytosis (LCH) can be difficult to distinguish clinically and histologically from disseminated infection in manifesting specific subtypes of Mendelian Susceptibility to Mycobacterial Disease (MSMD). In MSMD-patients, dominant negative germline mutations in the IFN-gamma R1 gene, in particular in exon 6, lead to autosomal dominant IFN-gamma receptor 1 deficiency (ADIFNGR1) and can mimic LCH. We hypothesized that similar defects might underlie the pathogenesis of LCH.

IFN-gamma R1 expression was immunohistochemically determined at disease onset in biopsies from 11 LCH-patients and four ADIFNGR1-patients. IFN-gamma R1 function was analyzed in 18 LCH-patients and 13 healthy controls by assessing the IFN-gamma-induced upregulation of Fc-gamma-receptor I (Fc gamma RI) expression on monocytes. Pro-inflammatory cytokine production was measured after stimulation of whole blood with LPS and IFN-gamma. Exon 6 of the IFN-gamma R1 gene was sequenced in 67 LCH-patients to determine whether mutations were present.

IFN-gamma R1 expression was high in three LCH-affected biopsies, similar to ADIFNGR1-affected biopsies, but varied from negative to moderate in eight other LCH-affected biopsies. No functional differences in IFN-gamma signaling were detected between LCH-patients with active or non-active disease and healthy controls. No germline mutations in exon 6 of the IFN-gamma R1 gene were detected in any of the 67 LCH-patients.

In contrast to ADIFNGR1-patients, IFN-gamma signaling is fully functional in LCH-patients. Either performed before, during or after treatment, these non-invasive functional assays can distinguish LCH-patients from ADIFNGR1-patients and thereby facilitate correct therapy regimens for patients with recurrent osteolytic lesions.

    Research areas

  • Langerhans cell histiocytosis, mendelian susceptibility to mycobacterial disease, diagnostic approaches, interferon-gamma, interferon-gamma receptor-1, autosomal dominant IFN-gamma R1 deficiency, GAMMA RECEPTOR DEFICIENCY, INTERFERON-GAMMA, CLINICAL-FEATURES, CYTOKINE PROFILES, DOMINANT, INFECTION, MUTATION, INTERFERON-GAMMA-RECEPTOR-1, OSTEOMYELITIS, CHILDREN
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Details

Original languageEnglish
Pages (from-to)84-93
Number of pages10
JournalJournal of Clinical Immunology
Volume34
Issue number1
DOIs
Publication statusPublished - 1 Jan 2014