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ALTEX 2016Here we describe a reconstructed full thickness human oral mucosa (gingiva) equivalent with integrated Langerhans Cells (GE-LC) and use it to compare LC activation and...
Here we describe a reconstructed full thickness human oral mucosa (gingiva) equivalent with integrated Langerhans Cells (GE-LC) and use it to compare LC activation and migration from oral versus skin epithelium. The physiologically representative models consist of differentiated reconstructed epithelium (keratinocytes and Langerhans-like cells derived from the MUTZ-3 cell line) on a fibroblast-populated collagen hydrogel which serves as a lamina propria for gingiva and dermis for skin. Topical exposure of GE-LC and the skin equivalent (SE-LC) to sub-toxic concentrations of the allergens cinnamaldehyde, resorcinol and nickel sulphate, resulted in LC migration out of the epithelia. Neutralizing antibody to CXCL12 blocked allergen-induced LC migration in SE-LC but not in GE-LC. Also, gingival fibroblasts secreted very low amounts of CXCL12 compared to skin fibroblasts even when stimulated with rhTNFα or rhIL-1α. Surprisingly, cinnamaldehyde exposure of GE-LC resulted in an increase in MUTZ-3 LC and CD83 mRNA in the hydrogel but did not result in an increase in CD1a+ cells in the collagen hydrogel (as was observed for SE-LC. These results indicate that in gingiva, upon allergen exposure, MUTZ-3 LC migrate in a CXCL12 independent manner from epithelium-to-lamina propria and in doing so mature become CD1a- and increase CD83+ mRNA. These physiologically relevant in vitro models which not only are human but which also resemble specific tissues, may aid in the identification of factors regulating immune stimulation which in turn will aid the development of therapeutic interventions for allergy and inflammation, anti-cancer vaccines as well as improving diagnostics for skin and oral allergy.
Topics: Allergens; Antibodies; Cell Differentiation; Cell Line; Cell Movement; Chemokine CXCL12; Chemotaxis; Gene Expression Regulation; Gingiva; Humans; Langerhans Cells; Tissue Engineering
PubMed: 27196738
DOI: 10.14573/altex.1510301 -
Seminars in Cell & Developmental Biology May 2015Langerhans cells (LC), the skin epidermal contingent of dendritic cells (DC), possess an exceptional life cycle and developmental origin. LC, like all mature blood... (Review)
Review
Langerhans cells (LC), the skin epidermal contingent of dendritic cells (DC), possess an exceptional life cycle and developmental origin. LC, like all mature blood cells, develop from haematopoietic stem cells (HSC) through successive steps of lineage commitment and differentiation. However, LC development is different to that of other DC subsets and not yet fully understood. Haematopoietic cell fate decisions are instructed by specific growth factors and cytokines produced in specialized microenvironments or niches. Upon ligand binding the cognate surface receptors on HSC and further restricted progenitor cells regulate the signalling pathways that eventually leads to the execution of lineage-determining genetic programs. In this review we focus on a specific set of surface receptor kinases that have been identified as critical regulators of LC development using genetically modified mice. Recent studies suggest for some of these kinases to impact on LC/LC progenitor interaction with the local niche by regulating adhesion and/or migration. During embryonic development, in wound healing and aberrantly in tumour invasion the same kinase receptors control a genetic program known as epithelial-to-mesenchymal-transition (EMT). We will discuss how EMT and its reverse program of mesenchymal-to-epithelial-transition (MET) can serve as universal concepts operating also in LC development.
Topics: Cell Adhesion; Cell Differentiation; Cell Movement; Epithelial-Mesenchymal Transition; Hematopoietic Stem Cells; Homeostasis; Humans; Langerhans Cells; Receptor Protein-Tyrosine Kinases; Skin
PubMed: 24613914
DOI: 10.1016/j.semcdb.2014.02.009 -
Cell Apr 2021Sensory neurons have surfaced as key instigators of skin inflammation. In this issue of Cell, Zhang et al. define an anti-inflammatory Langerhans cell (LC)-neuron-mast...
Sensory neurons have surfaced as key instigators of skin inflammation. In this issue of Cell, Zhang et al. define an anti-inflammatory Langerhans cell (LC)-neuron-mast cell (MC) circuit that underlies skin immune homeostasis. They uncover a role for LCs in maintaining innervation of MrgprD nonpeptidergic neurons that restrain MC activation via glutamate secretion.
Topics: Homeostasis; Langerhans Cells; Mast Cells; Sensory Receptor Cells; Skin
PubMed: 33861962
DOI: 10.1016/j.cell.2021.03.040 -
The Journal of Investigative... Aug 1997Morphologic studies have indicated that Langerhans cells (LC) are frequently in anatomic apposition with epidermal nerves containing the neuropeptide calcitonin... (Review)
Review
Morphologic studies have indicated that Langerhans cells (LC) are frequently in anatomic apposition with epidermal nerves containing the neuropeptide calcitonin gene-related peptide (CGRP). Experiments were undertaken to examine whether CGRP modulates LC function. The effect of pre-exposure of LC to CGRP in vitro on alloantigen presentation and specific protein presentation to a responsive T-cell line were studied using freshly prepared murine epidermal cell populations enriched for LC content (EC) by treatment with antibody to Thy-1 and complement. The ability of EC to present tumor-associated antigens for induction and elicitation of delayed-type hypersensitivity (DTH) in tumor-immune mice was also examined. Inhibitory effects of CGRP on antigen presentation were observed in each of these assays. Experiments were also performed examining the ability of intradermally administered CGRP to modulate induction of contact hypersensitivity (CHS) to a hapten applied at the injected site. Administration of CGRP led to a decrease in the CHS response after immunization at the site of injection. Intracellular cAMP was significantly increased in freshly prepared LC after exposure to CGRP, and this process could be inhibited by a specific inhibitor of the CGRP receptor, demonstrating the existence of CGRP receptors on LC. B7-2 expression induced by LPS and GM-CSF in the LC-like line XS52, and by LPS in peritoneal macrophages, was suppressed by CGRP. This suppression may account, in part, for the inhibitory effect of CGRP. As a whole, these observation suggest that regulation of antigen presentation by nerves may occur in the epidermis.
Topics: Afferent Pathways; Animals; Antibody Formation; Antigen-Presenting Cells; Calcitonin Gene-Related Peptide; Cell Line; Efferent Pathways; Humans; Hypersensitivity, Delayed; Langerhans Cells
PubMed: 9487021
DOI: 10.1038/jidsymp.1997.16 -
British Journal of Haematology Apr 2015Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A(+) /CD207(+) mononuclear phagocytes within... (Review)
Review
Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A(+) /CD207(+) mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells.
Topics: Antigens, CD; Antigens, CD1; Cell Differentiation; Histiocytosis, Langerhans-Cell; Humans; Langerhans Cells; Lectins, C-Type; MAP Kinase Signaling System; Mannose-Binding Lectins; Models, Biological; Myeloid Cells; Neoplasms
PubMed: 25430560
DOI: 10.1111/bjh.13247 -
Diagnostic Pathology Aug 2012To study the clinico-pathological characteristics of Langerhans cell sarcoma (LCS) which involving epidermis. (Review)
Review
OBJECTIVE
To study the clinico-pathological characteristics of Langerhans cell sarcoma (LCS) which involving epidermis.
METHODS
A case of primary multifocal LCS was analyzed in histopathology and immunophenotype.
RESULTS
A 41-year-old man with multifocal cutaneous LCS involving the inguina and waist was reported. Clinical and pathology data were available. Neoplastic cells with markedly malignant cytological features were observed. Tumor cells exhibited irregular shape with abundant and eosinophilic red staining cytoplasm; large, irregular-shaped, showing lobulated or dented nucleus and some cells with a longitudinal nuclear groove and prominent nucleoli. The tumor cells expressed CD1a, Langerin (CD207), S-100 protein, CD68 and vimentin, and did not express pan-T or B cell markers and epithelial markers. The patient died less than 1 year after diagnosis due to local recurrence and metastasis to the lung, despite the administration of local radiation and chemotherapy.
CONCLUSIONS
LCS is a tumor with markedly malignant cytological features that originates from Langerhans cells. Primary multifocal neoplasms involving epidermis is even rare. Accurate diagnosis is based on the histopathological and immunohistochemical of the tumor cells.
VIRTUAL SLIDE
The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1182345104754765.
Topics: Adult; Biomarkers, Tumor; Biopsy; Epidermis; Fatal Outcome; Humans; Immunophenotyping; Langerhans Cell Sarcoma; Langerhans Cells; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Skin Neoplasms; Time Factors; Treatment Outcome
PubMed: 22889043
DOI: 10.1186/1746-1596-7-99 -
The Journal of Investigative Dermatology Mar 2023
Topics: Humans; Langerhans Cells; Mitochondria; Transcription Factors; Mitochondrial Diseases; Mitochondrial Proteins; DNA, Mitochondrial; DNA-Binding Proteins
PubMed: 36049540
DOI: 10.1016/j.jid.2022.08.035 -
Science Translational Medicine Aug 2018Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the...
Photosensitivity, or skin sensitivity to ultraviolet radiation (UVR), is a feature of lupus erythematosus and other autoimmune and dermatologic conditions, but the mechanistic underpinnings are poorly understood. We identify a Langerhans cell (LC)-keratinocyte axis that limits UVR-induced keratinocyte apoptosis and skin injury via keratinocyte epidermal growth factor receptor (EGFR) stimulation. We show that the absence of LCs in Langerin-diphtheria toxin subunit A (DTA) mice leads to photosensitivity and that, in vitro, mouse and human LCs can directly protect keratinocytes from UVR-induced apoptosis. LCs express EGFR ligands and a disintegrin and metalloprotease 17 (ADAM17), the metalloprotease that activates EGFR ligands. Deletion of ADAM17 from LCs leads to photosensitivity, and UVR induces LC ADAM17 activation and generation of soluble active EGFR ligands, suggesting that LCs protect by providing activated EGFR ligands to keratinocytes. Photosensitive systemic lupus erythematosus (SLE) models and human SLE skin show reduced epidermal EGFR phosphorylation and LC defects, and a topical EGFR ligand reduces photosensitivity. Together, our data establish a direct tissue-protective function for LCs, reveal a mechanistic basis for photosensitivity, and suggest EGFR stimulation as a treatment for photosensitivity in lupus erythematosus and potentially other autoimmune and dermatologic conditions.
Topics: ADAM17 Protein; Animals; Apoptosis; Cytoprotection; Disease Models, Animal; Epidermis; ErbB Receptors; Humans; Keratinocytes; Langerhans Cells; Ligands; Lupus Erythematosus, Systemic; Mice, Inbred C57BL; Phosphorylation; Ultraviolet Rays
PubMed: 30111646
DOI: 10.1126/scitranslmed.aap9527 -
The Journal of Investigative Dermatology Jul 1980Properties of epidermal Langerhans cell were compared with those of a number of other dendritic cells in lymphoid organs and of mononuclear phagocytes. Among the... (Comparative Study)
Comparative Study Review
Properties of epidermal Langerhans cell were compared with those of a number of other dendritic cells in lymphoid organs and of mononuclear phagocytes. Among the dendritic "reticulum" cells included were indeterminate cells from the epidermis, interdigitating "reticulum" cells from T-dependent areas of lymphoid tissue and thymus, follicular dendritic cells of Nossal, and the dendritic cells described by Steinman and Cohn. Interdigitating cells with typical Birbeck granules, in the thymus and in the paracortices of lymph nodes, which are morphologically indistinguishable from Langerhans cells and indeterminate dendritic cells in the epidermis, appear to belong to the same system and possibly represent a subpopulation of "macrophages." On the basis of their similarity to these other dendritic cells, we believe Langerhans cells may function in antigen presentation, lymphokine production, provision of a microenvironment for T lymphocytes, and prostaglandin secretion.
Topics: Animals; Bone Marrow Cells; Guinea Pigs; Haptens; Histocompatibility Antigens; Humans; Langerhans Cells; Lymph Nodes; Lymphocytes; Lymphoid Tissue; Lymphoma; Macrophages; Mice; Monocytes; Prostaglandins; Skin; Spleen
PubMed: 6993584
DOI: 10.1111/1523-1747.ep12521083 -
Scientific Reports Jun 2019Corneal confocal microscopy (CCM) has been used to identify corneal nerve damage and increased Langerhans cell (LC) density in adults with Type 1 diabetes mellitus... (Clinical Trial)
Clinical Trial
Corneal confocal microscopy (CCM) has been used to identify corneal nerve damage and increased Langerhans cell (LC) density in adults with Type 1 diabetes mellitus (T1DM). The purpose of this study was to evaluate whether corneal confocal microscopy can identify early corneal nerve damage and change in LC density in children and adolescents with T1DM. 64 participants with T1DM (age-14.6 ± 2.5 years, duration of diabetes-9.1 ± 2.7 years, HbA1c-75.66 ± 2.53 mmol/mol [9.1 ± 1.8%]) and 48 age-matched healthy control subjects underwent CCM. Sub-basal corneal nerve morphology and the density of mature and immature LCs was quantified. Corneal nerve fibre length and branch density were lower, whilst fibre density and tortuosity did not differ and both immature and mature LC density was significantly higher in T1DM compared to control subjects. There was no association between HbA1c and duration of diabetes with nerve fibre parameters or LC's density. Children and adolescents with T1DM demonstrate early immune activation and nerve degeneration.
Topics: Adolescent; Child; Cornea; Diabetes Mellitus, Type 1; Diabetic Neuropathies; Female; Glycated Hemoglobin; Humans; Langerhans Cells; Male; Nerve Fibers
PubMed: 31217448
DOI: 10.1038/s41598-019-45116-z