Herpes-Virus Infection in Patients with Langerhans Cell Histiocytosis: A Case-Controlled Sero-Epidemiological Study, and In Situ Analysis

Eric Jeziorski,Ludovic Mansuy,Thierry Jo Molina,Jean-Marie Seigneurin,Frederic Geissmann,Patrice Morand,Francis Devez,Marianne Leruez-Ville,Christophe Glorion,Francis Jaubert,Marianne Debre,Jean Donadieu,Joel Gaudelus,Caroline Thomas,Brigitte Senechal,Irene Joab,Maria G Masucci

doi:10.1371/journal.pone.0003262

Abstract

BackgroundLangerhans cell histiocytosis (LCH) is a rare disease that affects mainly young children, and which features granulomas containing Langerhans-type dendritic cells. The role of several human herpesviruses (HHV) in the pathogenesis of LCH was suggested by numerous reports but remains debated. Epstein-barr virus (EBV, HHV-4), & Cytomegalovirus (CMV, HHV-5) can infect Langerhans cells, and EBV, CMV and HHV-6 have been proposed to be associated with LCH based on the detection of these viruses in clinical samples.MethodologyWe have investigated the prevalence of EBV, CMV and HHV-6 infection, the characters of antibody response and the plasma viral load in a cohort of 83 patients and 236 age-matched controls, and the presence and cellular localization of the viruses in LCH tissue samples from 19 patients.Principal FindingsThe results show that prevalence, serological titers, and viral load for EBV, CMV and HHV-6 did not differ between patients and controls. EBV was found by PCR in tumoral sample from 3/19 patients, however, EBV small RNAs EBERs –when positive-, were detected by in situ double staining in bystander B CD20+ CD79a+ lymphocytes and not in CD1a+ LC. HHV-6 genome was detected in the biopsies of 5/19 patients with low copy number and viral Ag could not be detected in biopsies. CMV was not detected by PCR in this series.Conclusions/SignificanceTherefore, our findings do not support the hypothesis of a role of EBV, CMV, or HHV-6 in the pathogenesis of LCH, and indicate that the frequent detection of Epstein-barr virus (EBV) in Langerhans cell histiocytosis is accounted for by the infection of bystander B lymphocytes in LCH granuloma. The latter observation can be attributed to the immunosuppressive micro environment found in LCH granuloma.

Highlights

FoxP3+ CD25 + CD4+ regulatory T cells both in granuloma and Langerhans cell histiocytosis (LCH, a.k.a. histiocytosis X), is a rare disease that affects mainly young children, and features granulomas consisting of Langerhans-like cells (LC), mixed with macrophages, eosinophiles, multinucleated giant cells, and lymphocytes, that can be found within various tissues [1,2]
We performed a casecontrolled sero-epidemiological study to investigate a relationship between the onset of LCH in young children and the antibody response to infection with Epstein-Barr virus (EBV), CMV, or human herpesviruses (HHV)-6, and second we searched for the presence of viruses in the serum of patients, and in Langerhans cells in tumor samples, by PCR and, when positive, we investigated the cellular target of the viruses by immunolabeling and in situ hybridization
Defective control of infection by Herpesviruses such as EBV, CMV and HHV-6 results in replicative infection and viremia [35]

Summary

Introduction

Langerhans cell histiocytosis (LCH, a.k.a. histiocytosis X), is a rare disease that affects mainly young children, and features granulomas consisting of Langerhans-like cells (LC), mixed with macrophages, eosinophiles, multinucleated giant cells, and lymphocytes, that can be found within various tissues [1,2].The presence of LC in granuloma is a key diagnostic feature of LCH. Langerhans cell histiocytosis (LCH, a.k.a. histiocytosis X), is a rare disease that affects mainly young children, and features granulomas consisting of Langerhans-like cells (LC), mixed with macrophages, eosinophiles, multinucleated giant cells, and lymphocytes, that can be found within various tissues [1,2]. Environmental agents and viruses, in particular Epstein-Barr virus (EBV), or vaccination, have been proposed to trigger, or to play a role in the pathogenesis of the disease [11,12]. Langerhans cell histiocytosis (LCH) is a rare disease that affects mainly young children, and which features granulomas containing Langerhans-type dendritic cells. Epstein-barr virus (EBV, HHV-4), & Cytomegalovirus (CMV, HHV-5) can infect Langerhans cells, and EBV, CMV and HHV-6 have been proposed to be associated with LCH based on the detection of these viruses in clinical samples

Methods

Results

Conclusion