Expansion of regulatory T cells in patients with Langerhans cell histiocytosis.
BACKGROUND
Langerhans 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.


RESULTS
Biopsies (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 ( approximately 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(+) CD25(high) FoxP3(high) 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.


CONCLUSIONS
These 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.
Senechal
Brigitte
B
INSERM, U838, Laboratory of Biology of the Mononuclear Phagocyte System, Necker Enfants Malades Institute, Paris, France.
Elain
Gaelle
G
Jeziorski
Eric
E
Grondin
Virginie
V
Patey-Mariaud de Serre
Natacha
N
Jaubert
Francis
F
Beldjord
Kheira
K
Lellouch
Arielle
A
Glorion
Christophe
C
Zerah
Michel
M
Mary
Pierre
P
Barkaoui
Mohammed
M
Emile
Jean Francois
JF
Boccon-Gibod
Liliane
L
Josset
Patrice
P
Debré
Marianne
M
Fischer
Alain
A
Donadieu
Jean
J
Geissmann
Frederic
F
D000293:Adolescent; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D006646:Histiocytosis, Langerhans-Cell / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed; D007223:Infant; D007801:Langerhans Cells / Q000276:immunology / Q000502:physiology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000502:physiology*
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