title: Intact IFN-γR1 expression and function distinguishes Langerhans cell histiocytosis from mendelian susceptibility to mycobacterial disease.
abstract: OBJECTIVE
  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-γR1 gene, in particular in exon 6, lead to autosomal dominant IFN-γ receptor 1 deficiency (ADIFNGR1) and can mimic LCH. We hypothesized that similar defects might underlie the pathogenesis of LCH.
  
  
  METHODS
  IFN-γR1 expression was immunohistochemically determined at disease onset in biopsies from 11 LCH-patients and four ADIFNGR1-patients. IFN-γR1 function was analyzed in 18 LCH-patients and 13 healthy controls by assessing the IFN-γ-induced upregulation of Fc-gamma-receptor I (FcγRI) expression on monocytes. Pro-inflammatory cytokine production was measured after stimulation of whole blood with LPS and IFN-γ. Exon 6 of the IFN-γR1 gene was sequenced in 67 LCH-patients to determine whether mutations were present.
  
  
  RESULTS
  IFN-γR1 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-γ signaling were detected between LCH-patients with active or non-active disease and healthy controls. No germline mutations in exon 6 of the IFN-γR1 gene were detected in any of the 67 LCH-patients.
  
  
  CONCLUSIONS
  In contrast to ADIFNGR1-patients, IFN-γ 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.
authors.affiliation: Immunology Laboratory, Willem Alexander Children's Hospital, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Willemijn T
authors.initials: WT
authors.lastname: Quispel
authors.forename: Janine A
authors.initials: JA
authors.lastname: Stegehuis-Kamp
authors.forename: Susy J
authors.initials: SJ
authors.lastname: Santos
authors.forename: Annelies
authors.initials: A
authors.lastname: van Wengen
authors.forename: Edward
authors.initials: E
authors.lastname: Dompeling
authors.forename: R Maarten
authors.initials: RM
authors.lastname: Egeler
authors.forename: Esther
authors.initials: E
authors.lastname: van de Vosse
authors.forename: Astrid G S
authors.initials: AG
authors.lastname: van Halteren
mesh_terms: D002675:Child, Preschool; D003937:Diagnosis, Differential; D005091:Exons; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005854:Germ Cells; D006646:Histiocytosis, Langerhans-Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D009154:Mutation; D009164:Mycobacterium Infections / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D009928:Organ Specificity; D017471:Receptors, Interferon / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor