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

W.T. Quispel, J.A. Stegehuis-Kamp, S.J. Santos, A. van Wengen, E. Dompeling, R.M. Egeler, E. van de Vosse, A.G.S. van Halteren*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

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


  • Langerhans cell histiocytosis
  • mendelian susceptibility to mycobacterial disease
  • diagnostic approaches
  • interferon-gamma
  • interferon-gamma receptor-1
  • autosomal dominant IFN-gamma R1 deficiency


Dive into the research topics of 'Intact IFN-gammaR1 Expression and Function Distinguishes Langerhans Cell Histiocytosis From Mendelian Susceptibility to Mycobacterial Disease'. Together they form a unique fingerprint.

Cite this