Expansion of Regulatory T Cells in Patients with Langerhans Cell Histiocytosis

Brigitte Senechal,Natacha Patey-Mariaud De Serre,Arielle Lellouch,Jean Donadieu,Jean Donadieu,Pierre Mary,Francis Jaubert,Patrice Josset,Eric Jeziorski,Eric Jeziorski,Eric Jeziorski,Eric Jeziorski,Liliane Boccon-Gibod,Patrice Josset,Christophe Glorion,Christophe Glorion,Christophe Glorion,Christophe Glorion,Marianne Debré,Natacha Patey-Mariaud De Serre,Kheira Beldjord,Liliane Boccon-Gibod,Marianne Debré,Mohammed Barkaoui,Virginie Grondin,Michel Zerah,Arielle Lellouch,Arielle Lellouch,Arielle Lellouch,Frederic Geissmann,Natacha Patey-Mariaud De Serre,Alain Fischer,Alain Fischer,Alain Fischer,Alain Fischer,Virginie Grondin,Natacha Patey-Mariaud De Serre,Natacha Patey-Mariaud De Serre,Jean Francois Emile,Jean Francois Emile,Virginie Grondin,Pierre Mary,Virginie Grondin,Gaelle Elain,Natacha Patey-Mariaud De Serre

doi:10.1371/journal.pmed.0040253

Abstract

BackgroundLangerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. LCH can involve various tissues such as bone, skin, lung, bone marrow, lymph nodes, and the central nervous system, and is frequently responsible for functional sequelae. The pathophysiology of LCH is unclear, but the uncontrolled proliferation of Langerhans cells (LCs) is believed to be the primary event in the formation of granulomas. The present study was designed to further investigate the nature of proliferating cells and the immune mechanisms involved in the LCH granulomas.Methods and FindingsBiopsies (n = 24) and/or blood samples (n = 25) from 40 patients aged 0.25 to 13 y (mean 7.8 y), were studied to identify cells that proliferate in blood and granulomas. We found that the proliferating index of LCs was low (∼1.9%), and we did not observe expansion of a monocyte or dendritic cell compartment in patients. We found that LCH lesions were a site of active inflammation, tissue remodeling, and neo-angiogenesis, and the majority of proliferating cells were endothelial cells, fibroblasts, and polyclonal T lymphocytes. Within granulomas, interleukin 10 was abundant, LCs expressed the TNF receptor family member RANK, and CD4+ CD25high FoxP3high regulatory T cells (T-regs) represented 20% of T cells, and were found in close contact with LCs. FoxP3+ T-regs were also expanded compared to controls, in the blood of LCH patients with active disease, among whom seven out of seven tested exhibited an impaired skin delayed-type hypersensitivity response. In contrast, the number of blood T-regs were normal after remission of LCH.ConclusionsThese findings indicate that LC accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs. These data suggest that LCs may be involved in the expansion of T-regs in vivo, resulting in the failure of the host immune system to eliminate LCH cells. Thus T-regs could be a therapeutic target in LCH.

Highlights

Langerhans cell histiocytosis (LCH), known as histiocytosis X, affects mainly young children with a peak incidence between the ages of 1 and 3 y, and features granulomas consisting of macrophages, multinucleated giant cells, lymphocytes, eosinophils, and CD1aþ Langerinþ Langerhans-like cells, accumulating within various tissues such as bone, skin, lung, liver, bone marrow, lymph nodes, the gastrointestinal tract, and the central nervous system [1,2,3,4,5,6]
The number of blood regulatory T cell (T-reg) were normal after remission of LCH. These findings indicate that Langerhans cells (LC) accumulation in LCH results from survival rather than uncontrolled proliferation, and is associated with the expansion of T-regs
We performed immunostaining with antibodies against Ki-67, the LC antigen CD1a, CD68, the T cell antigen CD3, and the B cell antigen CD20 in tissue samples from a retrospective series of 16 patients with various clinical forms of LCH

Summary

Introduction

Langerhans cell histiocytosis (LCH), known as histiocytosis X, affects mainly young children with a peak incidence between the ages of 1 and 3 y, and features granulomas consisting of macrophages, multinucleated giant cells, lymphocytes, eosinophils, and CD1aþ Langerinþ Langerhans-like cells, accumulating within various tissues such as bone, skin, lung, liver, bone marrow, lymph nodes, the gastrointestinal tract, and the central nervous system [1,2,3,4,5,6]. LCs have been shown to be clonal by X-inactivation studies [15,16] (reviewed in [10,17]), and proliferation of LCs has been generally proposed as the mechanism responsible for LC accumulation in most [3,16,18,19], but not all [20] studies Cytogenetic abnormalities such as loss of heterozygosity of tumor suppressor genes and chromosomal instability have been described as case reports [21,22,23], no recurrent molecular abnormality has been yet characterized. Langerhans cell histiocytosis (LCH) is a rare clonal granulomatous disease that affects mainly children. Most affected children recover from the disease but the disease can be fatal if multiple organs are affected

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Conclusion