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

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.

Human Herpesvirus-6 DNA and Langerhans Cell Histiocytosis

“…We failed to find any statistically significant differences between patients with LCH and the control group with regard to the presence of HHV-6 DNA. This is in concordance with previous negative results reported in the literature (17)(18)(19).…”

“…The positive result in six (12.5%) of the control samples could be attributed to coincidence. P = 0.11, which shows no significant difference in HHV-6 detection results between the LCH patients and the controls, does not support the hypothesis of a possible role for HHV-6 in the pathogenesis of LCH disease, which is in keeping with some other reports in the literature (17)(18)(19).…”

“…The etiologic role of HHV-6 in LCH is debated, with conflicting results in the literature (14)(15)(16)(17)(18)(19). Jeziorski et al (17) demonstrated no significant association between EBV, CMV, or HHV-6 in the pathogenesis of LCH.…”

“…In previous studies (14)(15)(16)(17)(18)(19), authors have declared no limitations, and their methods included serology, IHC, ISH, and PCR. However, the limitations of our study were that IHC and ISH for HHV-6 were not available for use and the patients could not be checked for the evidence of HHV-6 infections serologically.…”

Langerhans cell histiocytosis: malignancy or inflammatory disorder doing a great job of imitating one?

“…This seems unlikely because, at least so far, no microbial genomes have been identified in pathologic LCs and no epidemiological studies have suggested an infectious or environmental cause. Herpesviruses had been associated anecdotally with LCH but a recent study showed that the prevalence of antibodies against these viruses, as well as their titers, were the same in LCH patients and age-matched controls (Jeziorski et al, 2008).…”