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Dendritic cells (DCs) are immune cells that arise from different lineages with a shared function of presenting antigen and activating adaptive immunity.
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Langerhans cell histiocytosis (LCH) arises from myeloid DC precursors. Mitogen-activated protein kinase (MAPK) activation is a universal feature of CD1a+ langerin+ LCH cells. The clinical extent of LCH is related to the stage of development in which somatic MAPK mutations arise, either self-renewing progenitors or committed precursors.
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Activating
Cell(s) of Origin of Langerhans Cell Histiocytosis
Section snippets
Key points
The Histiocytoses
The spectrum of histiocytic diseases is characterized by collections of abnormal histiocytes or, literally, tissue cells related to myeloid cells of the mononuclear phagocyte system (MPS).1, 2, 3, 4 LCH is defined by the presence of a large pale-staining histiocyte with high expression of CD1a and langerin (CD207) and containing Birbeck granules (Fig. 1). These features, shared with Langerhans cells (LCs) of the epidermis, are the basis of classifying the disease as an LCH. Prior to this, LCH
Langerhans Cell Histiocytosis: The Debate
The fundamental nature of LCH as neoplastic versus reactive disorder has been an ongoing debate.6, 9 The granulomatous histology with quiescent histiocytes suggested potential autoimmune or infectious etiology10 but the unique appearance of LCH cells and destructive nature of lesions hinted at dysplastic development. Although Nezelof and Basset11 described LCs as the stem cell of LCH, they also acknowledged the prevailing view that elements of the MPS, including LCs, were continually
Branches of dendritic cell differentiation
The insight of Nezelof and Basset32 identified commonality between LCs and LCH but by their own reckoning could not fully explain the histogenesis of LCH. The identification of MAPK pathway mutations provides a genetic neoplastic etiology and an important investigational tool with which to track potential LCH precursor cells. The problem of understanding exactly how potential LCH precursors differentiate abnormally remains, however, unsolved.
Lineage Tracing Langerhans Cell Histiocytosis
Somatic mutations in LCH have provided a foothold with which to study the cell of origin of LCH. As discussed previously, it is evident that LCH cells could arise from more than 1 source. In an attempt to more precisely identify candidate precursor populations, the authors asked whether the mutation encoding BRAF V600E was present in circulating mononuclear cells in patients with active LCH. In the authors’ series of 100 patients, peripheral blood mononuclear cells with the BRAF V600E point
Summary/future directions
LCH is a complex disease with a fascinating history. Individual reports of highly variable intriguing presentations merged into eponymous classifications that were later unified as histiocytosis X, due to common histology. Subsequently, LCH shifted focus to the aberrant development of LCs. New data support a model that once again deconstructs this single diagnosis into its many facets, each caused by a repertoire of mutations acting at multiple stages of myeloid cell development. The common
References (89)
- et al.
Controversies and new approaches to treatment of Langerhans cell histiocytosis
Hematol Oncol Clin North Am
(1998) - et al.
A randomized trial of treatment for multisystem Langerhans' cell histiocytosis
J Pediatr
(2001) - et al.
Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification
Blood
(2008) - et al.
Differentiation of Langerhans cells in Langerhans cell histiocytosis
Blood
(2001) - et al.
Coincident expression of the chemokine receptors CCR6 and CCR7 by pathologic Langerhans cells in Langerhans cell histiocytosis
Blood
(2003) - et al.
Langerhans-cell histiocytosis 'insight into DC biology'
Trends Immunol
(2003) - et al.
The relation of Langerhans cell histiocytosis to acute leukemia, lymphomas, and other solid tumors. The LCH-Malignancy Study Group of the Histiocyte Society
Hematol Oncol Clin North Am
(1998) - et al.
Clonal proliferation of Langerhans cells in Langerhans cell histiocytosis
Lancet
(1994) - et al.
Recurrent BRAF mutations in Langerhans cell histiocytosis
Blood
(2010) - et al.
Somatic activating ARAF mutations in Langerhans cell histiocytosis
Blood
(2014)
Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis
Blood
High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis
Blood
Langerin, a novel C-type lectin specific to Langerhans cells, is an endocytic receptor that induces the formation of Birbeck granules
Immunity
Neither IL-17A mRNA nor IL-17A protein are detectable in Langerhans cell histiocytosis lesions
Mol Ther
BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis
Blood
Stroma-derived interleukin-34 controls the development and maintenance of langerhans cells and the maintenance of microglia
Immunity
Lymphomyeloid contribution of an immune-restricted progenitor emerging prior to definitive hematopoietic stem cells
Cell Stem Cell
Further evidence for the self-reproducing capacity of Langerhans cells in human skin
J Invest Dermatol
Transmission of rosacea from the graft in facial allotransplantation
Am J Transplant
Dendritic cell lineage commitment is instructed by distinct cytokine signals
Eur J Cell Biol
Notch is active in Langerhans cell histiocytosis and confers pathognomonic features on dendritic cells
Blood
Cutaneous CXCL14 targets blood precursors to epidermal niches for Langerhans cell differentiation
Immunity
Human dermal CD14(+) cells are a transient population of monocyte-derived macrophages
Immunity
Generation of human dendritic cells/Langerhans cells from circulating CD34+ hematopoietic progenitor cells
Blood
Human blood BDCA-1 dendritic cells differentiate into Langerhans-like cells with thymic stromal lymphopoietin and TGF-beta
Blood
CD1c+ blood dendritic cells have Langerhans cell potential
Blood
Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells
Immunity
Human CD1c+ dendritic cells drive the differentiation of CD103+ CD8+ mucosal effector T cells via the cytokine TGF-beta
Immunity
Pathological consequence of misguided dendritic cell differentiation in histiocytic diseases
Adv Immunol
High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses
Blood
Recurrent RAS and PIK3CA mutations in Erdheim-Chester disease
Blood
Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation
Blood
Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation
Blood
The origin and kinetics of mononuclear phagocytes
J Exp Med
Dendritic cells, monocytes and macrophages: a unified nomenclature based on ontogeny
Nat Rev Immunol
Development of monocytes, macrophages, and dendritic cells
Science
Human dendritic cell subsets
Immunology
Histiocytosis X histogenetic arguments for a Langerhans cell origin
Biomedicine
Langerhans cell histiocytosis: malignancy or inflammatory disorder doing a great job of imitating one?
Dis Model Mech
Herpes-virus infection in patients with Langerhans cell histiocytosis: a case-controlled sero-epidemiological study, and in situ analysis
PLoS One
An hypothesis Langerhans cell histiocytosis: the failure of the immune system to switch from an innate to an adaptive mode
Pediatr Blood Cancer
Aberrant chemokine receptor expression and chemokine production by Langerhans cells underlies the pathogenesis of Langerhans cell histiocytosis
J Exp Med
Concurrent Langerhans cell histiocytosis and myelodysplasia in children
Med Pediatr Oncol
Langerhans'-cell histiocytosis (histiocytosis X)–a clonal proliferative disease
N Engl J Med
Cited by (0)
The Texas Children’s Cancer Center Histiocytosis Program (C.E. Allen and K.L. McClain) is supported by the HistioCure Foundation. Grant support includes NIH R01 (CA154489) (C.E. Allen and K.L. McClain), NIH SPORE in Lymphoma (P50CA126752) (C.E. Allen), and the St. Baldrick’s Consortium Grant for the North American Consortium for Histiocytosis Research (C.E. Allen and K.L. McClain). M. Collin is supported by the Histiocytosis Research Trust (UK), the Leventis Foundation, and the Histiocytosis Association. V. Bigley is a Wellcome Trust Intermediate Fellow (WT088555MA).
The authors have no conflicting financial interests.