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. METHODS AND FINDINGS: 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.

Hypothalamic hamartoma with refractory epilepsy: surgical procedures and results in 18 patients.

AIM: To study the surgical procedures and results on seizures, in 18 patients with refractory epilepsy due to hypothalamic hamartoma. PATIENTS AND METHODS: Eighteen patients aged from 9 months to 32 years underwent surgery between 1997 and 2002. The mean age at seizure onset was 15.5 months. Seventeen patients had gelastic seizures, 14 had partial seizures, two had infantile spasms, 10 had tonic or atonic seizures and three had generalized seizures. The mean seizure frequency was 21 per day. Four patients had borderline intellectual disability and the others were mentally retarded. Five patients had precocious puberty, one had acromegaly and four suffered from obesity. Brain MRI, performed at least twice in each patient showed the hamartoma as a stable, homogeneous interpeduncular mass implanted either on the mammillary tubercle or on the wall of the third ventricle, with variable extension to the bottom. Ictal SPECT, performed in four patients, showed hyperperfusion within the hamartoma in two. SURGICAL PROCEDURE: Twenty-six operations were performed in 18 patients. The first patient underwent a total removal of the hamartoma, whereas the following patients underwent a disconnection, either through open surgery (14 patients) or endoscopy (10 patients). RESULTS: Regarding the seizure outcome with a mean follow up of three years four months (one year to 4.5 years), nine patients are seizure-free, one patient has only brief gelastic seizures and eight are dramatically improved. Surgery was uncomplicated in all but two patients: one had transitory hemiplegia and paresis of the third cranial nerve, the other presented with hemiplegia due to ischemia of the middle cerebral artery territory. The quality of life, behavior and school performance were greatly improved in most of the patients. CONCLUSION: Our series illustrates the feasibility and relative safety of disconnecting surgery of hypothalamic hamartomas, with seizure relief in 50% and a dramatic improvement in the others. Endoscopic disconnection seems to be a very safe way to treat the intra-ventricular part of hamartomas.