Date Published: August 14, 2007
Publisher: Public Library of Science
Author(s): Brigitte Senechal, Gaelle Elain, Eric Jeziorski, Virginie Grondin, Natacha Patey-Mariaud de Serre, Francis Jaubert, Kheira Beldjord, Arielle Lellouch, Christophe Glorion, Michel Zerah, Pierre Mary, Mohammed Barkaoui, Jean Francois Emile, Liliane Boccon-Gibod, Patrice Josset, Marianne Debré, Alain Fischer, Jean Donadieu, Frederic Geissmann, Berhard Malissen
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.
Partial Text: Langerhans cell histiocytosis (LCH), also 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 CD1a+ Langerin+ 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 [1–6]. The clinical course of LCH is remarkably varied, ranging from lesions that spontaneously resolve, to a chronic disease, or even to a widespread and sometimes lethal disease [1,7,8]. The pathophysiology of LCH remains enigmatic, but seems to be associated with abnormalities in the biology of Langerhans cells (LCs) and macrophages [5,9,10]. Genetic factors are suspected because of the existence of familial cases [11–13], suggesting that predisposing mutations could be present at least in some patients. Serum cytokines that may promote the growth of dendritic cells (DCs), such as GM-CSF (granulocyte macrophage-colony stimulating factor), M-CSF (macrophage-colony stimulating factor), and FLT3-L (FMS-like tyrosin kinase 3 ligand), have been shown to be increased in the blood of patients with the more severe form of the disease [9,14]. 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  studies. Cytogenetic abnormalities such as loss of heterozygosity of tumor suppressor genes and chromosomal instability have also been described as case reports [21–23], although no recurrent molecular abnormality has been yet characterized. Active viral infections such as herpesvirus infections may worsen the disease ; a possible causative role of herpesviruses in LCH has been debated [25–28].
The results from the present study indicate that fibroblasts, endothelial cells, and T cells account for the bulk of proliferating cells in LCH granulomas. This result is in line with the pathological description of the disease as a granuloma. LCs themselves exhibited a proliferation index of only 1.9%, and represented only 6% of proliferating granuloma cells. Putative LC precursors such as blood monocytes and DCs were not expanded in the blood of patients. Therefore, the accumulation of LCs in granulomas is mainly the consequence of increased survival rather than proliferation.