Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells

Hutter, Caroline; Kauer, Max; Simonitsch‐Klupp, Ingrid; Jug, Gunhild; Schwentner, Raphaela; Leitner, Judith; Böck, Peter; Schmitz, Peter; Bauer, Wolfgang; Carlesso, Nadia; Minkov, Milen; Gadner, Helmut; Stingl, Georg; Kovar, Heinrich; Kriehuber, Ernst

doi:10.1182/blood-2012-02-410241

Cited by 82 publications

(104 citation statements)

References 49 publications

(68 reference statements)

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“…In the present study, we indeed demonstrated that E-cadherin expression was readily induced on MDLCs when cocultured with primary KCs and that this was partly due to the Notch signaling pathway activation as suggested by the DAPT blockade (28). Moreover, we provided further evidence that E-cadherin-dependent interactions between MDLCs and KCs were crucial to generate fully differentiated MDLCs as reported by others in two-dimensional cultures (45,58). Noticeably, to our knowledge, DLL1 does not exist as a clinical-grade reagent whereas GM-CSF, TGF-b1, and human albumin do, thus precluding the development of preclinical or clinical applications involving human LC-like cells using the DLL1 approach reported by Hoshino et al (28).…”

Section: Discussionsupporting

confidence: 66%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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Langerhans cells (LCs) are epithelial APCs that sense danger signals and in turn trigger specific immune responses. In steady-state, they participate in the maintenance of peripheral tolerance to self-antigens whereas under inflammation LCs efficiently trigger immune responses in secondary lymphoid organs. It has been demonstrated in mice that LC-deprived epithelia are rapidly replenished by short half-life langerin-expressing monocyte-derived LCs (MDLCs). These surrogate LCs are thought to be progressively replaced by langerinhigh LCs arising from self-renewing epithelial precursors of hematopoietic origin. How LCs arise from blood monocytes is not fully understood. Hence, we sought to characterize key factors that induce differentiation of langerinhigh-expressing monocyte-derived Langerhans-like cells. We identified GM-CSF and TGF-β1 as key cytokines to generate langerinhigh-expressing cells but only in serum-free conditions. These cells were shown to express the LC-specific TROP-2 and Axl surface markers and contained Birbeck granules. Surprisingly, E-cadherin was not spontaneously expressed by these cells but required a direct contact with keratinocytes to be stably induced. MDLCs induced stronger allogeneic T cell proliferations but released low amounts of inflammatory cytokines upon TLR stimulation compared with donor-paired monocyte-derived dendritic cells. Immature langerinhigh MDLCs were responsive to MIP-3β/CCL20 and CTAC/CCL27 chemokine stimulations. Finally, we demonstrated that those cells behaved as bona fide LCs when inserted in a three-dimensional rebuilt epithelium by becoming activated upon TLR or UV light stimulations. Collectively, these results prompt us to propose these langerinhigh MDLCs as a relevant model to address LC biology–related questions.

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Section: Discussionsupporting

confidence: 66%

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Picarda

Chéneau

Humbert

et al. 2016

The Journal of Immunology

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“…36,37 Intrinsic notch signaling was previously suggested as a key mechanism promoting LCH pathogenesis, through expression of Jagged 2 by lesional histiocytes. 28 Taken together, these observations do not support a simple dichotomous model that LCH arises from the DC pathway and ECD from the monocyte-macrophage pathway of myeloid cell development. Classical monocytes appear able to contribute to histiocytes of both disorders, depending on the signals they receive.…”

Section: V600ementioning

confidence: 69%

Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults

Milne

Bigley

Bacon

et al. 2017

Blood

159

132

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Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are rare histiocytic disorders induced by somatic mutation of MAPK pathway genes. BRAF V600E mutation is the most common mutation in both conditions and also occurs in the hematopoietic neoplasm hairy cell leukemia (HCL). It is not known if adult LCH or ECD arises from hematopoietic stem cells (HSCs), nor which potential blood borne precursors lead to the formation of histiocytic lesions. In this study, BRAF V600E allele-specific polymerase chain reaction was used to map the neoplastic clone in 20 adults with LCH, ECD, and HCL. BRAF V600E was tracked to classical monocytes, nonclassical monocytes, and CD1c 1 myeloid dendritic cells (DCs) in the blood, and mutations were observed in HSCs and myeloid progenitors in the bone marrow of 4 patients. The pattern of involvement of peripheral blood myeloid cells was indistinguishable between LCH and ECD, although the histiocytic disorders were distinct to HCL. As reported in children, detection of BRAF V600E in peripheral blood of adults was a marker of active multisystem LCH. The healthy counterparts of myeloid cells affected by BRAF mutation had a range of differentiation potentials depending on exogenous signals. CD1c 1 DCs acquired high langerin and CD1a with granulocyte-macrophage colony-stimulating factor and transforming growth factor b alone, whereas CD14 1 classical monocytes required additional notch ligation. Both classical and nonclassical monocytes, but not CD1c 1 DCs, made foamy macrophages easily in vitro with macrophage colony-stimulating factor and human serum. These studies are consistent with a hematopoietic origin and >1 immediate cellular precursor in both LCH and ECD. (Blood. 2017;130(2):167-175)

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“…Various metalloproteinases have been identified in LCH granulomas and could account for LCH-induced tissue destruction [49,50,60]. Recently, the activation of the Notch1 signalling pathway has been shown to be at least partly responsible for the specific profile of LCH cells [49].…”

Section: Pathogenesismentioning

confidence: 99%

“…The cell-specific gene expression signature in Langerin (CD207) + cells within LCH lesions has shown that these cells are more consistent with immature myeloid dendritic cell precursors than Langerhans cells [49,50].…”

Section: Pathogenesismentioning

confidence: 99%

How I manage pulmonary Langerhans cell histiocytosis

Lorillon

Tazi

2017

Eur Respir Rev

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Pulmonary Langerhans cell histiocytosis (PLCH) is a rare sporadic cystic lung disease of unknown aetiology that is characterised by the infiltration and destruction of the wall of distal bronchioles by CD1a + Langerhans-like cells. In adults, PLCH is frequently isolated and affects young smokers of both sexes. Recent multicentre studies have led to the more standardised management of patients in clinical practice. Smoking cessation is essential and is occasionally the only suitable intervention. Serial lung function testing is important because a significant proportion of patients may experience an early decline in forced expiratory volume in 1 s and develop airflow obstruction. Cladribine was reported to dramatically improve progressive PLCH in some patients. Its efficacy and tolerance are currently being evaluated. Patients who complain of unexplained dyspnoea with decreased diffusing capacity of the lung for carbon monoxide should be screened for pulmonary hypertension by Doppler echocardiography, which must be confirmed by right heart catheterisation. Lung transplantation is a therapeutic option for patients with advanced PLCH.The identification of the BRAF V600E mutation in approximately half of Langerhans cell histiocytosis lesions, including PLCH, and other mutations of the mitogen-activated protein kinase (MAPK) pathway in a subset of lesions has led to targeted treatments (BRAF and MEK (MAPK kinase) inhibitors). These treatments need to be rigorously evaluated because of their potentially severe side-effects.

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Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells

Abstract: Langerhans cell histiocytosis (LCH) is an enigmatic disease defined by the accumulation of Langerhans cell-like dendritic cells (DCs

Cited by 82 publications

References 49 publications

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Functional Langerinhigh-Expressing Langerhans-like Cells Can Arise from CD14highCD16− Human Blood Monocytes in Serum-Free Condition

Hematopoietic origin of Langerhans cell histiocytosis and Erdheim-Chester disease in adults

How I manage pulmonary Langerhans cell histiocytosis

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