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Current Opinion in Hematology Jan 2016This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions. (Review)
Review
PURPOSE OF REVIEW
This article summarizes recent research on the ontogeny of Langerhans cells and regulation of their homeostasis in quiescent and inflamed conditions.
RECENT FINDINGS
Langerhans cells originate prenatally and may endure throughout life, independently of bone marrow-derived precursors. Fate-mapping experiments have recently resolved the relative contribution of primitive yolk sac and fetal liver hematopoiesis to the initial formation of Langerhans cells. In postnatal life, local self-renewal restores Langerhans cell numbers following chronic or low-grade inflammatory insults. However, severe inflammation recruits de-novo bone marrow-derived precursors in two waves; a transient population of classical monocytes followed by uncharacterized myeloid precursors that form a stable self-renewing Langerhans cell network as inflammation subsides. Human CD1c⁺ dendritic cells have Langerhans cell potential in vitro, raising the possibility that dendritic cell progenitors provide the second wave. Langerhans cell development depends upon transforming growth factor beta receptor signaling with distinct pathways active during differentiation and homeostasis. Langerhans cell survival is mediated by multiple pathways including mechanistic target of rapamycin and extracellular signal-regulated kinase signaling, mechanisms that become highly relevant in Langerhans cell neoplasia.
SUMMARY
The study of Langerhans cells continues to provide novel and unexpected insights into the origin and regulation of myeloid cell populations. The melding of macrophage and dendritic cell biology, shaped by a unique habitat, is a special feature of Langerhans cells.
Topics: Animals; Cell Differentiation; Cell Lineage; Cell Self Renewal; Fetus; Histiocytosis, Langerhans-Cell; Homeostasis; Humans; Inflammation; Langerhans Cells; Liver; Macrophages; Monocytes; Stem Cells; Yolk Sac
PubMed: 26554892
DOI: 10.1097/MOH.0000000000000202 -
Immunity Oct 2021Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state...
Langerhans cells (LCs) play a pivotal role in skin homeostasis, and the heterogeneity of LCs has long been considered. In this study, we have identified two steady-state (LC1 and LC2) and two activated LC subsets in the epidermis of human skin and in LCs derived from CD34 hemopoietic stem cells (HSC-LCs) by utilizing single-cell RNA sequencing and mass cytometry. Analysis of HSC-LCs at multiple time-points during differentiation revealed that EGR1 and Notch signaling were among the top pathways regulating the bifurcation of LC1 and LC2. LC1 were characterized as classical LCs, mainly related to innate immunity and antigen processing. LC2 were similar to monocytes or myeloid dendritic cells, involving in immune responses and leukocyte activation. LC1 remained stable under inflammatory microenvironment, whereas LC2 were prone to being activated and demonstrated elevated expression of immuno-suppressive molecules. We revealed distinct human LC subsets that require different developmental regulation and orchestrate reciprocal functions.
Topics: Antigen Presentation; Cell Differentiation; Hematopoietic Stem Cells; Humans; Immunity, Innate; Langerhans Cells; Skin
PubMed: 34508661
DOI: 10.1016/j.immuni.2021.08.012 -
Cell Communication and Signaling : CCS Aug 2018The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The relationship between various external agents such as pollen, food, and infectious agents and human sensitivity exists and is variable depending upon individual's health conditions. For example, we believe that the pathogenetic potential of the Merkel cell polyomavirus (MCPyV), the resident virus in skin, is variable and depends from the degree of individual's reactivity. MCPyV as well as Epstein-Barr virus, which are normally connected with humans under the form of subclinical infection, are thought to be involved at various degrees in several neoplastic and inflammatory diseases. In this review, we cover two types of Langerhans cell neoplasms, the Langerhans cell sarcoma (LCS) and Langerhans cell histiocytosis (LCH), represented as either neoplastic or inflammatory diseases caused by MCPyV.
METHODS
We meta-analyzed both our previous analyses, composed of quantitative PCR for MCPyV-DNA, proteomics, immunohistochemistry which construct IL-17 endocrine model and interleukin-1 (IL-1) activation loop model, and other groups' data.
RESULTS
We have shown that there were subgroups associated with the MCPyV as a causal agent in these two different neoplasms. Comparatively, LCS, distinct from the LCH, is a neoplastic lesion (or sarcoma) without presence of inflammatory granuloma frequently observed in the elderly. LCH is a proliferative disease of Langerhans-like abnormal cells which carry mutations of genes involved in the RAS/MAPK signaling pathway. We found that MCPyV may be involved in the development of LCH.
CONCLUSION
We hypothesized that a subgroup of LCS developed according the same mechanism involved in Merkel cell carcinoma pathogenesis. We proposed LCH developed from an inflammatory process that was sustained due to gene mutations. We hypothesized that MCPyV infection triggered an IL-1 activation loop that lies beneath the pathogenesis of LCH and propose a new triple-factor model.
Topics: Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Merkel cell polyomavirus; Models, Biological; Sarcoma
PubMed: 30134914
DOI: 10.1186/s12964-018-0261-y -
Oncology (Williston Park, N.Y.) Feb 2016Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell... (Review)
Review
Langerhans cell histiocytosis is a disorder characterized by lesions that include CD207+ dendritic cells along with an inflammatory infiltrate. Langerhans cell histiocytosis has a highly variable clinical presentation, ranging from a single lesion to potentially fatal disseminated disease. The uncertainty as to whether Langerhans cell histiocytosis is a reactive or a neoplastic disease has resulted in a long-standing debate on this question, and the limited understanding of the pathogenesis of the disease has impeded clinical improvement for patients. The current standard of care for multisystem Langerhans cell histiocytosis, empirically derived chemotherapy with vinblastine and prednisone, cures fewer than 50% of patients, and optimal therapies for relapse and neurodegenerative disease remain uncertain. Recent research advances support a model in which Langerhans cell histiocytosis arises due to pathologic activation of the mitogen-activated protein kinase (MAPK) pathway in myeloid precursors. Redefinition of Langerhans cell histiocytosis as a myeloid neoplastic disorder driven by hyperactive ERK supports the potential of chemotherapy with efficacy against immature myeloid cells, as well as mutation-specific targeted therapy.
Topics: Animals; Antigens, CD; Disease Progression; Enzyme Activation; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Lectins, C-Type; Mannose-Binding Lectins; Mitogen-Activated Protein Kinases; Molecular Targeted Therapy; Prednisone; Protein Kinase Inhibitors; Signal Transduction; Treatment Outcome; Vinblastine
PubMed: 26888790
DOI: No ID Found -
The New England Journal of Medicine Jun 2000
Review
Topics: Adrenal Cortex Hormones; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Prognosis; Smoking; Smoking Cessation
PubMed: 10877650
DOI: 10.1056/NEJM200006293422607 -
Clinical and Experimental Dermatology Jul 2000Epidermal Langerhans cells (LC) play pivotal roles in the induction of cutaneous immune responses. Encounter with antigen in the skin, or other stimuli, cause the... (Review)
Review
Epidermal Langerhans cells (LC) play pivotal roles in the induction of cutaneous immune responses. Encounter with antigen in the skin, or other stimuli, cause the mobilization of LC and their migration, via afferent lymphatics, to draining lymph nodes where they localize within the paracortex. During their movement from the skin LC acquire the characteristics of immunostimulatory dendritic cells (DC) such that the antigen-bearing cells which accumulate in lymph nodes are able to provoke specific T-lymphocyte responses. Epidermal cytokines initiate and regulate LC migration (and maturation), of particular importance being interleukin-1beta and tumour necrosis factor-alpha. Collectively, these cytokines, together with relevant chemokine receptor-ligand interactions, effect the liberation of LC from the epidermis and their directed movement to, and localization within, peripheral lymph nodes. Described here are the phenotypic changes induced during the activation of LC and the mechanisms through which their migration is regulated.
Topics: Antigen-Presenting Cells; Cell Count; Cell Movement; Humans; Interleukins; Langerhans Cells; T-Lymphocytes; Tumor Necrosis Factor-alpha; Wounds and Injuries
PubMed: 11012599
DOI: 10.1046/j.1365-2230.2000.00678.x -
The British Journal of Dermatology Oct 1988
Review
Topics: Humans; Langerhans Cells; Microscopy, Electron
PubMed: 3056492
DOI: 10.1111/j.1365-2133.1988.tb03249.x -
European Cytokine Network Sep 2011Langerhans cell histiocytosis (LCH) is a rare disorder characterized by an abnormal accumulation and/or proliferation of cells with a Langerhans cell phenotype. Although... (Review)
Review
Langerhans cell histiocytosis (LCH) is a rare disorder characterized by an abnormal accumulation and/or proliferation of cells with a Langerhans cell phenotype. Although no clear cause of LCH has been identified, it has been postulated that LCH might be the consequence of an immune dysregulation, causing Langerhans cells to migrate to and accumulate at various sites. Production of cytokines and chemokines is a central feature of immune regulation. Cytokines are abundantly present within LCH lesions. We review here the potential role of cytokines and chemokines in the pathogenesis of LCH. The type, distribution, and number of different cytokines released within lesions can provide clues to the possible aetiology of LCH and, ultimately, might offer therapeutic possibilities using recombinant cytokines or antagonists for this disorder.
Topics: Animals; Chemokines; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Models, Immunological
PubMed: 22001902
DOI: 10.1684/ecn.2011.0290 -
Orphanet Journal of Rare Diseases Mar 2012Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic... (Review)
Review
Pulmonary Langerhans Cell Histiocytosis (PLCH) is a relatively uncommon lung disease that generally, but not invariably, occurs in cigarette smokers. The pathologic hallmark of PLCH is the accumulation of Langerhans and other inflammatory cells in small airways, resulting in the formation of nodular inflammatory lesions. While the overwhelming majority of patients are smokers, mechanisms by which smoking induces this disease are not known, but likely involve a combination of events resulting in enhanced recruitment and activation of Langerhans cells in small airways. Bronchiolar inflammation may be accompanied by variable lung interstitial and vascular involvement. While cellular inflammation is prominent in early disease, more advanced stages are characterized by cystic lung destruction, cicatricial scarring of airways, and pulmonary vascular remodeling. Pulmonary function is frequently abnormal at presentation. Imaging of the chest with high resolution chest CT scanning may show characteristic nodular and cystic abnormalities. Lung biopsy is necessary for a definitive diagnosis, although may not be required in instances were imaging findings are highly characteristic. There is no general consensus regarding the role of immunosuppressive therapy in smokers with PLCH. All smokers must be counseled on the importance of smoking cessation, which may result in regression of disease and obviate the need for systemic immunosuppressive therapy. The prognosis for most patients is relatively good, particularly if longitudinal lung function testing shows stability. Complications like pneumothoraces and secondary pulmonary hypertension may shorten life expectancy. Patients with progressive disease may require lung transplantation.
Topics: Adult; Child, Preschool; Female; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Infant; Langerhans Cells; Lung Diseases; Male; Pneumothorax; Prognosis; Respiratory Function Tests; Smoking; Young Adult
PubMed: 22429393
DOI: 10.1186/1750-1172-7-16 -
Seminars in Cell & Developmental Biology Feb 2019Human Langerhans cells (LC) can be generated ex vivo from hematopoietic precursor cells in response to cytokines and cell-membrane associated ligands. These in vitro... (Review)
Review
Human Langerhans cells (LC) can be generated ex vivo from hematopoietic precursor cells in response to cytokines and cell-membrane associated ligands. These in vitro differentiation models provided mechanistic insights into the molecular and cellular pathways underlying the development of this unique, epithelia-associated dendritic cell subset. Notably, the human epidermal microenvironment is fully sufficient to induce LC differentiation from hematopoietic progenitors. Hence, dissecting the molecular characteristics of the human epithelial/epidermal LC niche, and testing defined ligands for their capacity to induce LC differentiation, led to a refined molecular model of LC lineage commitment. During epidermal ontogeny, spatially and temporally regulated availability of TGF-β family members cooperate with other keratinocyte-derived signals, such as E-cadherin and Notch ligands, for instructing LC differentiation. In this review, we discuss the signals known to instruct human hematopoietic progenitor cells and myelomonocytic cells to undergo LC lineage commitment. Additionally, the current methods for generation of large numbers of human LC-like cells ex vivo in defined serum-free media are discussed.
Topics: Cell Differentiation; Humans; Kruppel-Like Factor 4; Langerhans Cells; Signal Transduction; Transforming Growth Factor beta
PubMed: 29448069
DOI: 10.1016/j.semcdb.2018.02.016