Number Of Langerhans Cells Research Articles

Stromal CD10 expression, as well as increased dermal macrophages and decreased Langerhans cells, are associated with malignant transformation of keratinocytes

It has become evident that resident stromal cells, such as fibroblasts and inflammatory cells, are involved in the metastatic process, including proliferation or migration of malignant neoplasms. We analyzed CD10+ stromal cells, dermal macrophages and Langerhans cells (LCs) in skin tumors. Immunohistological staining was performed with markers for macrophages (CD68), LC (CD1a), stromal fibroblasts (CD10) and cell proliferation (Ki67) in 12 normal skins (NSs) and 15 cases each of seborrheic keratosis (SK), actinic keratosis (AK), keratoacanthoma (KA), Bowen's disease (BD) and squamous cell carcinoma (SCC). All SCCs showed weak to strong stromal CD10 expression, while all NS, SK and AK were negative. Weak CD10 expression was observed in only 2 of 15 samples in both BD and KA. The number of CD68+ cells and Ki67 labeling index in SCC and BD were significantly higher than that in KA, AK and SK. In contrast, the number of LC was lower in SCC and BD. The stromal CD10 expression was significantly correlated with the Ki67 labeling indices and CD68+ cells and negatively correlated with decreased LC. The stromal CD10 expression is associated with malignant transformation of keratinocytes together with infiltration of dermal macrophages and loss of LC.

Cutaneous immune responses to 2, 4-dinitrochlorobenzene (DNCB): role of interleukin (IL)-2 (97.15)

Abstract Prolonged topical exposure of BALB/c strain mice to the contact allergen DNCB, or to the respiratory sensitiser trimellitic anhydride, results in T helper (h) 1 and Th2 cell polarisation, respectively. In addition, a single application of allergen results in discrete cutaneous cytokine profiles and the migration of Langerhans' cells (LC) with different tempos. Of note, DNCB only induced a rapid and transient increase in cutaneous IL-2. We have now explored the role of IL-2 in DNCB-induced LC migration. BALB/c mice received an intradermal injection of recombinant IL-2 or IL-1β (50ng/ear); the latter is known to provoke LC migration. LC densities were determined in epidermal sheets by immunofluorescence staining. Cytokine production by skin explants was measured by protein array. Intradermal injection of IL-1β decreased epidermal LC numbers significantly after 4 and 16h whereas IL-2 was without effect. Prior systemic administration of neutralising anti-IL-2 antibody failed to influence LC migration monitored 6h after DNCB treatment. Migration was blocked by treatment with an anti-tumor necrosis factor-α antibody, a cytokine regulator of LC migration. Administration of IL-2 did result in increased expression of cutaneous IL-17. These data show that IL-2 is not involved in LC migration, however, the selective up-regulation of IL-2 by DNCB may play a role in the subsequent polarisation of the immune response.

Epidermal Langerhans cells in actinic prurigo: a comparison between lesional and non-lesional skin

Actinic Prurigo (AP) is a chronic pruritic dermatosis of unknown cause affecting sun exposed skin in defined ethnic groups with characteristic MHC alleles. However, the cutaneous dendritic cells have not been assessed. To assess in situ the epidermal Langerhans Cell (LC) status in Actinic Prurigo. Fresh skin samples from three AP patients were used to evaluate in situ the epidermal LC, comparing lesional and non-lesional sites in each subject. AP patients attending the Dermatology Department at the Hospital M. Gea-Gonzalez in Mexico city. Lesional and non-lesional skin samples were taken from each subject to prepare both epidermal sheets and conventional tissue sections. Three markers restricted to LC in epidermis (CD1a, ATPase, MHC-II) were used to quantify the LC per area in epidermal sheets. Compared to non-lesional skin from the same subject, a significant reduction in the number of LC per area of epidermis was found in lesional skin; with any of the three markers evaluated. The frequency of epidermal LC decreases importantly in lesional skin from AP patients.

Decreased number of Langerhans cells in basal cell carcinoma

Journal of the European Academy of Dermatology and VenereologyVolume 23, Issue 4 p. 471-473 Decreased number of Langerhans cells in basal cell carcinoma H Rotsztejn, Corresponding Author H Rotsztejn Section of Dermatology, Research Institute of the Polish Mother's Memorial Hospital, Lodz, Poland, Correspondence: H Rotsztejn. E-mail: [email protected]Search for more papers by this authorD Jesionek-Kupnicka, D Jesionek-Kupnicka Department of Tumor Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland,Search for more papers by this authorE Trznadel-Budźko, E Trznadel-Budźko Department of Dermatology and Pediatric Dermatology, Military-Medical Faculty, Medical University of Lodz, Lodz, PolandSearch for more papers by this author H Rotsztejn, Corresponding Author H Rotsztejn Section of Dermatology, Research Institute of the Polish Mother's Memorial Hospital, Lodz, Poland, Correspondence: H Rotsztejn. E-mail: [email protected]Search for more papers by this authorD Jesionek-Kupnicka, D Jesionek-Kupnicka Department of Tumor Pathology, Chair of Oncology, Medical University of Lodz, Lodz, Poland,Search for more papers by this authorE Trznadel-Budźko, E Trznadel-Budźko Department of Dermatology and Pediatric Dermatology, Military-Medical Faculty, Medical University of Lodz, Lodz, PolandSearch for more papers by this author First published: 17 March 2009 https://doi.org/10.1111/j.1468-3083.2008.02913.xCitations: 5 DOI: 10.1111/j.1468-3083.2008.02913.x Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume23, Issue4April 2009Pages 471-473 RelatedInformation

Langerhans cells in lichen sclerosus of the vulva and lichen sclerosus evolving in vulvar squamous cell carcinoma.

Vulvar lichen sclerosus (LS) represents a benign chronic inflammatory skin lesion that carries a risk for development of vulvar squamous cell carcinoma (SCC). We aimed at determining whether premalignant changes in vulvar LS, a multifactorial disease, presenting a welter of evidence implicating the immune system in its pathogenesis, could be identified by analysing the Langerhans' cells (LCs), the primary cell responsible for antigen recognition and presentation. The relationship existing between inflammation and cancer due to chronic infection, and demonstrated in many solid tumors, led us to study LCs in eight cases of vulvar LS, which showed an evolution to carcinoma of the vulva and in ten cases of unchanged vulvar LS in matched patients by immunohistochemistry for antibodies CD1a and S100. We did not find a statistically significantly different number of LCs counted either in S100 stained specimens, nor in CD1a stained specimens of LS epithelium in unchanged or evolving cases. The data emerging in our study do not support the hypothesis that the variation in the number of LCs may be related to the development of SCC in late stage LS cases.

IL-10-Producing Langerhans Cells and Regulatory T Cells Are Responsible for Depressed Contact Hypersensitivity in Grafted Skin

Although skin grafting is a common surgical technique, the immunological state of grafted skin remains unelucidated. An experimental model has shown that the development of murine contact hypersensitivity (CHS) is depressed when mice are sensitized with a hapten through full-thickness grafted skin. We explored the immunological mechanisms underlying this hyposensitization, focusing on the fate of Langerhans cells (LCs). When FITC was applied to grafted skin, FITC-bearing LCs were capable of migrating to the draining lymph nodes. Epidermal cell suspensions isolated from the grafted skin produced a high amount of IL-10 as assessed by real-time PCR. Adoptive transfer of immune lymph node cells from the sensitized mice suppressed the CHS response of recipients in an antigen-specific manner. CD4(+)CD25(+) but not CD4(+)CD25(-) T cells purified from lymph node cells were responsible for this suppression. Finally, we detected high expression of receptor activators of nuclear factor kappa-B ligand (RANKL) in the grafted skin, and found that recombinant RANKL stimulated LCs to produce IL-10. These findings suggest that the hyposensitization of CHS through the grafted skin is not attributable merely to the reduction of LC number but that IL-10-producing LCs exert a downmodulatory effect by inducing regulatory T cells.

Hypoglycemic effect of crude exopolysaccharides produced by Cerrena unicolor, Coprinus comatus, and Lenzites betulina isolates in streptozotocin- induced diabetic rats

The objective of this study was to investigate the hypoglycemic activity of crude exopolysaccharides (EPS) produced by three mushroom isolates in streptozotocin-induced diabetic rats. The three experimental groups were fed EPS of Cerrena unicolor (Bull.) Murrill (Polyporaceae), Coprinus comatus (O.F. Müll.) Pers. (Agaricaceae), and Lenzites betulina (L.) Fr. (Polyporaceae) for 7 days. The serum glucose levels significantly decreased after oral administration of EPS by 61.23% with Cerrena unicolor, 42.78% with Coprinus comatus, and 42.08% with Lenzites betulina. According to histological observations based on staining in pancreatic tissues, Langerhans islet areas and cell numbers of diabetic animals increased in response to EPS treatment. In conclusion, our findings clearly suggest that exopolysaccharides produced by three mushroom isolates decreased blood glucose levels in STZ-induced diabetic rats. Therefore, the studied mushroom exopolysaccharides might be developed as potential oral hypoglycemic agents in the control of diabetes mellitus. This is the first attempted in vivo study using exopolysaccharides of local mushroom isolates for medicinal purpose in Turkey.

Cytokines as genetic modifiers in K5���/���mice and in human epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a skin disorder caused by fully-penetrant mutations in the keratin genes KRT5 and KRT14, leading to extensive cytolysis and cell fragility of basal keratinocytes. EBS is subject to environmental conditions and displays high intra- and interfamilial variability, suggesting modifying loci. Here, we demonstrate that upregulation of certain cytokines accompanies mutations in keratin 5 (K5) but not in keratin 14 (K14). We find for the first time that cytokines macrophage chemotactic protein (MCP)-1/[chemokine (C-C motif) ligand 2] (CCL2), macrophage inflammatory protein (MIP)-3beta/CCL19 and MIP-3alpha/CCL20, all regulated by nuclear factor kappa B (NFkappaB) and involved in the recruitment, maturation, and migration of Langerhans cells (LCs) in the epidermis, are upregulated in the skin of K5(-/-), but not of K14(-/-) mice. In neonatal K5(-/-) epidermis, the number of LCs was increased two-fold. At the same time, tumor necrosis factor alpha (TNFalpha) remained unaltered, demonstrating the specificity of that process. Most remarkably, enhanced LC recruitment within the epidermis was found in five EBS patients carrying mutations in the KRT5 gene but not in EBS patients with KRT14 gene mutations. In agreement with the NFkappaB-dependent regulation of these cytokines, we found a decrease in p120-catenin in the basal epidermis of K5(-/-) mice. These data provide the first explanation for distinct, keratin-type-specific genotype-phenotype correlations in EBS and represent a rationale to investigate gene loci affecting skin pathology in EBS.

Rat Silicone Hydrogel Contact Lens Model: Effects of High- Versus Low-Dk Lens Wear

This study used a rat contact lens (CL) model to test if high- versus low-Dk lens wear caused changes in (1) conjunctival Langerhans cell (LC) number or location; (2) Bcl-2 expression; and (3) infection risk. Female, Lewis rats wore a high- or low-Dk CL continuously for 2 weeks. Afterward, corneas were harvested and processed for ADPase activity to identify LCs, for immunostaining and for real time-polymerase chain reaction. Contact lens-wearing rats also were challenged with Pseudomonas aeruginosa by placing a bacterial-soaked CL on the eye followed by topical delivery of bacteria. After 48 hrs, slit lamp examination and real time-polymerase chain reaction were used to evaluate the corneal response. Conjunctival LC were significantly increased after low- versus high-Dk CL wear (P<0.0001). In contrast, conjunctival LC in non-lens wearing rats was not significantly different from the high-Dk lens wearing group. Bcl-2 mRNA levels were significantly decreased in low- versus high-Dk CL wearing rats, while Bax, FasL, caspase 3, and caspase 9 levels were unchanged. Immunostaining for Bcl-2 showed fewer positively stained epithelial cells in the low- versus high-Dk lens wearing group. After bacterial challenge, 30% of low- versus none of the high-Dk CL wearing corneas became infected and showed increased mRNA levels for several proinflammatory cytokines/chemokines, inducible nitric oxide synthase and matrix metalloproteinase-9. Low- versus high-Dk or non-CL wear led to an increased number of conjunctival LC, decreased Bcl-2 levels, and increased the risk of bacterial infection.

The impact of Meth A fibrosarcoma derived EMAP II on dendritic cell migration

Studies have suggested that tumors are capable of modulating dendritic cell (DC) phenotype. A soluble protein produced by certain tumors, endothelial monocyte-activating polypeptide II (EMAP II) has been suggested as an anti-tumor agent based on its anti-angiogenic activity. However, this factor has not been evaluated for effects on DC. In this study, we analyzed the effect of Meth A fibrosarcoma supernatant and recombinant human EMAP II on DC migration. This included the migration of Langerhans cells from mouse ear skin sections and the migration of cells of a dendritic cell line (JAWS II) in a transwell culture system. The results of these studies indicated that EMAP II stimulates the migration of DC. Additional studies showed that the presence of the ascites form of the Meth A tumor led to a decrease in Langerhans cell (LC) numbers in the skin, and this decrease could be partially blocked by neutralizing antibody specific for EMAP II. Subcutaneous injection at the base of the ear of recombinant human EMAP II also led to a decrease in epidermal LC similar to that observed in tumor bearing mice. Together, these results suggest novel roles for EMAP II in modulating the migration of DC and suggest that these effects may modify Meth A tumor/host interactions.

American tegumentary leishmaniasis: langerhans cells in montenegro skin test

This work analyzed the histopathology and epidermal Langerhans cells (LC) of Montenegro skin test (MST) in patients with American tegumentary leishmaniasis (ATL) in order to in situ characterize and compare the immunological reaction of the two major clinical forms of ATL, localized cutaneous leishmaniasis (LCL) and mucocutaneous leishmaniasis (MCL). MST histopathology of both LCL and MCL showed superficial and deep perivascular inflammatory infiltrate composed mainly of lymphocytes and histiocytes. Epidermal LC population was higher in MST biopsies taken from LCL patients when compared to MCL group, at 48 and 72 hours after antigen inoculation. Increased number of epidermal LC displayed in MST biopsies of LCL patients represents specific cellular immunity against parasites. The decrease of LC in MST biopsies of MCL patients does not necessarily indicate a worse specific cellular immunity in this clinical form of leishmaniasis.

Imuno-histoquímica para o diagnóstico precoce de vitiligo

O vitiligo e uma doenca de pele frequente que acomete 1% da populacao e e caracterizada por maculas despigmentadas consequentes a perda progressiva e localizada dos melanocitos da epiderme. Na maioria dos pacientes, o diagnostico e feito por exame clinico. A biopsia da pele e realizada quando ha necessidade de diagnostico diferencial com doencas hipocromiantes. O diagnostico histopatologico de vitiligo e dificil nos preparados corados por hematoxilina e eosina (HE). Ha poucos estudos sobre a melhoria da qualidade diagnostica no vitiligo. OBJETIVO: Avaliar a utilidade dos marcadores imuno-histoquimicos proteina S-100, human melanoma black-45 (HMB-45) e Melan-A para o diagnostico precoce em casos clinicamente suspeitos ou duvidosos de vitiligo. Material e metodos: Lâminas histologicas de biopsias de pele sa e lesada de 10 pacientes com suspeita clinica de vitiligo coradas pelos metodos de HE, proteina S-100, HMB-45 e Melan-A. Utilizou-se contracoloracao com Giemsa como modificacao tecnica para diferenciar a melanina da imunomarcacao. RESULTADOS: Seis casos, com manifestacao clinica recente, apresentaram infiltrado linfocitario, do tipo dermatite de interface, na pele lesada na HE. As coloracoes por S-100, HMB-45 e Melan-A marcaram os melanocitos da camada basal da pele sa, e a proteina S-100 evidenciou as celulas de Langerhans. Na pele lesada, os melanocitos estavam ausentes ou diminuidos quando comparados com a pele normal. A proteina S-100 demonstrou maior numero de celulas de Langerhans, o que e caracteristico das lesoes de vitiligo. CONCLUSAO: A imuno-histoquimica pode ser utilizada como metodo auxiliar no diagnostico dos casos duvidosos de vitiligo.

Activin A Induces Langerhans Cell Differentiation In Vitro and in Human Skin Explants

Langerhans cells (LC) represent a well characterized subset of dendritic cells located in the epidermis of skin and mucosae. In vivo, they originate from resident and blood-borne precursors in the presence of keratinocyte-derived TGFβ. Ιn vitro, LC can be generated from monocytes in the presence of GM-CSF, IL-4 and TGFβ. However, the signals that induce LC during an inflammatory reaction are not fully investigated. Here we report that Activin A, a TGFβ family member induced by pro-inflammatory cytokines and involved in skin morphogenesis and wound healing, induces the differentiation of human monocytes into LC in the absence of TGFβ. Activin A-induced LC are Langerin+, Birbeck granules+, E-cadherin+, CLA+ and CCR6+ and possess typical APC functions. In human skin explants, intradermal injection of Activin A increased the number of CD1a+ and Langerin+ cells in both the epidermis and dermis by promoting the differentiation of resident precursor cells. High levels of Activin A were present in the upper epidermal layers and in the dermis of Lichen Planus biopsies in association with a marked infiltration of CD1a+ and Langerin+ cells. This study reports that Activin A induces the differentiation of circulating CD14+ cells into LC. Since Activin A is abundantly produced during inflammatory conditions which are also characterized by increased numbers of LC, we propose that this cytokine represents a new pathway, alternative to TGFβ, responsible for LC differentiation during inflammatory/autoimmune conditions.

Local effects of TL01 phototherapy in psoriasis

The mechanisms whereby narrowband ultraviolet B (UVB) (311-313 nm, TL01) phototherapy are effective in psoriasis may differ from those occurring in broadband UVB phototherapy. In the present study, changes in epidermal cells as a result of TL01 therapy were assessed in the skin of patients with psoriasis. The non-lesional skin of five subjects with plaque psoriasis was biopsied before and after a series of 12 whole-body TL01 treatments. Following appropriate staining of skin sections, the numbers of p53-positive keratinocytes, sunburn cells and Langerhans cells in the epidermis were counted. TL01 therapy induced a threefold increase in the number of p53-positive epidermal cells, a 12-fold increase in sunburn cells and a twofold decrease in Langerhans cells. The increase in epidermal p53 expression and apoptosis of keratinocytes together with the depletion of Langerhans cells in the non-lesional skin of psoriasis patients are likely to contribute to the effectiveness of TL01 phototherapy.

Long-term ultraviolet B-induced impairment of Langerhans cell function: an immunoelectron microscopic study.

The influence of low-dose, long-term ultraviolet B (UVB) light exposure on HLA class II-positive human epidermal Langerhans cells (LC) was studied using a sensitive immunoelectron microscopic technique for the ultrastructural assessment of HLA class II expression on LC and for quantification of these cells in situ. Six healthy Caucasian volunteers participated in the experiments and received thrice weekly UVB treatments for 4 weeks. The initial dose ranged from 30 to 50 mJ/cm2 and the total dose from 600 to 3500 mJ/cm2, depending on skin type. Suction blisters and biopsies were obtained before the start of the UVB protocol and 48 h after the last UVB irradiation, and processed for the mixed epidermal cell-lymphocyte reaction (MECLR) and electronmicroscopy, respectively. The MECLR was used as a measure of the immune response. The distribution of HLA class II molecules on LC was studied by incubating ultrathin cryosections of human skin tissue with an anti-HLA class II MoAb that was conjugated to 10 nm colloidal gold. Furthermore, the number of LC was assessed ultrastructurally, when they could be recognized by their unique cytoplasmic organelle, the Birbeck granule (BG). The UVB protocol that was employed caused a marked suppression of the MECLR responses. This UVB-induced reduction of the immune response was not paralleled by changes in HLA class II expression on LC, nor in the number of epidermal LC. These findings are further support for our hypothesis that UVB-induced immune suppression in the skin is not due to a depletion of local LC.

Skin application of the nonsteroidal anti-inflammatory drug ketoprofen downmodulates the antigen-presenting ability of Langerhans cells in mice

Ketoprofen (KP) is widely used as a topical nonsteroidal anti-inflammatory drug that inhibits prostaglandin (PG) biosynthesis. As PGE(2) upregulates the antigen-presenting activity of Langerhans cells (LCs), i.e. migration to lymph nodes and expression of immunocompetent molecules, modulation of LC functions resulting from topical application of KP is an issue to be clarified. To investigate the in vivo effect of KP application to the skin and the in vitro effect of KP addition to the culture on the antigen-presenting ability of murine LCs. Methods Ears of BALB/c mice were painted with picryl chloride (PCl) hapten, KP or both. An immunofluorescence study of epidermal sheets and a flow cytometric analysis of epidermal cell suspensions from the treated ears were performed. PCl altered the morphology of LCs and reduced their number, and simultaneous application of 10% KP maintained LC morphology and number. KP at 5% or 10% clearly decreased the PCl-augmented expression of major histocompatibility complex class II and CD86 on LCs. In cultivation of freshly isolated epidermal cells, 5 mmol L(-1) KP inhibited the culture-promoted expression of these molecules on LCs, whereas 100 micromol L(-1) indomethacin was not inhibitory. The further addition of PGE(2) to the KP-containing epidermal cell culture did not restore the expression of these molecules. Moreover, topical application of 10% KP to the sensitizing sites suppressed the development of contact hypersensitivity to PCl. KP may have the potential to inhibit the antigen-presenting ability of LCs, in a PGE(2)-independent manner.

Ultrastructural studies bearing on the mechanism of UVB-impaired induction of contact hypersensitivity to DNCB in man.

In both murine and human experimental systems, acute, low dose exposure of skin to ultraviolet B light (UVB) impairs the induction of allergic contact dermatitis (ACD) by haptens such as dinitrochlorobenzene (DNCB) in a significant proportion of individuals. By light microscopy, epidermal Langerhans cells (LC) have been reported to be depleted by UVB exposure as well as by epicutaneous hapten application, implying that LC may be the locus of action of the effects of both UVB and DNCB. However, light microscopy can not readily distinguish cell density changes secondary to LC necrosis from changes resulting from down-modulation of expression of LC surface molecules. Using a highly sensitive immunogold electron microscopic approach, we have evaluated the differential effects of UVB and/or DNCB on human epidermal LC. The results reveal that DNCB alone caused significant up-regulation of cell surface HLA class II expression on a very small number of LC, the major fraction of LC expressing normal levels of HLA class II. Furthermore, DNCB alone caused a modest reduction in the density of LC at the treated sites without evidence of cell necrosis. Treatment with UVB alone or UVB exposure followed by DNCB resulted in a reduction in the density of LC, with widespread evidence of LC necrosis. However, the few remaining intact LC were all intensely HLA class II-positive after UVB exposure followed by DNCB, whereas treatment with UVB alone did not result in changes in LC HLA class II expression. The findings that after DNCB painting only a small proportion of the LC were strongly HLA class II-positive, but after UVB exposure followed by DNCB all intact LC displayed significant up-regulation of cell surface HLA class II expression, imply that UVB exposure inhibits the migration of epidermal LC. This is consistent with the view that DNCB fails to induce ACD when hapten is painted on UVB-exposed skin because insufficient LC are available to initiate T cell activation in the draining lymph node.

Differential Effects of Doses and Forms of Dietary Selenium on Immune Cell Numbers in the Skin of Ultraviolet-irradiated and Unirradiated Mice

The effect of three different doses of dietary L-selenomethionine (SM) and sodium selenite (SS) on skin selenium (Se) content, glutathione peroxidase (GPx) activity, Langerhans cell (LC) and mast cell numbers in ultraviolet radiation-B (UVB)-irradiated and unirradiated C3H/HeN mice was determined. After weaning, groups of mice were given Se-deficient, Se-adequate, or Se-high diets. Six weeks later, some animals in each group were exposed to a single UVB dose (acute), while others were exposed three times weekly for the following 40 weeks (chronic). The skin Se content and GPx activity increased in all the Se-supplemented groups, and the latter was not altered by UVB exposure. Generally, the Se-containing diets caused an increase in LC numbers at 6 weeks and a further rise at 40 weeks, but did not prevent the loss induced by acute or chronic UVB radiation. Skin mast cell numbers were highest in animals fed the Se-deficient diet after 6 and 40 weeks. Acute and chronic UVB radiation decreased the mast cell number and dietary Se did not prevent the reduction. While the present study shows that Se plays an important role in governing the number of LCs and mast cells in the skin, no protective effect against the immunomodulating properties of UVB radiation on these cell types was observed. However, this conclusion may only apply to the experimental conditions chosen, and additional studies at different Se dosages and reduced intensities of chronic UVB exposure are required to confirm the results.

Tacrolimus and TGF-β act synergistically on the generation of Langerhans cells

The proportion of dendritic cell subpopulations in the skin is important for the severity of atopic dermatitis because topical treatment with tacrolimus leads to rapid depletion of inflammatory dendritic epidermal cells, whereas Langerhans cells (LCs) predominate in cured sites. The effects of tacrolimus and TGF-beta1 on LC differentiation and the idea of tacrolimus skewing the differentiation of epidermal precursors to LCs were evaluated. The presence of LC markers, MHC, and costimulatory molecules and stimulatory capacity toward T cells of monocyte-derived LCs were analyzed. Skin samples of patients with atopic dermatitis were assessed by means of immunofluorescence microscopy before and after tacrolimus treatment. TGF-beta production of skin cells was analyzed. Tacrolimus and TGF-beta1 act synergistically on the generation of LCs and the expression of CD40, CD80, CD86, CD83, and MHC II; stabilize TGF-beta receptor II expression; and decrease the stimulatory capacity of LCs toward T cells. In vivo the number of epidermal LCs in tacrolimus-treated skin increased. The synergism between TGF-beta1 and tacrolimus leads to the generation of LCs, reduced expression of costimulatory and MHC II molecules, and reduced stimulatory activity. Shifting the balance of the dendritic cell population to LCs might be of major importance for the therapeutic effect of tacrolimus.

Transforming Growth Factor-β1-Mediated Slug and Snail Transcription Factor Up-Regulation Reduces the Density of Langerhans Cells in Epithelial Metaplasia by Affecting E-Cadherin Expression

Epithelial metaplasia (EpM) is an acquired tissue abnormality resulting from the transformation of epithelium into another tissue with a different structure and function. This adaptative process is associated with an increased frequency of (pre)cancerous lesions. We propose that EpM is involved in cancer development by altering the expression of adhesion molecules important for cell-mediated antitumor immunity. Langerhans cells (LCs) are intraepithelial dendritic cells that initiate immune responses against viral or tumor antigens on both skin and mucosal surfaces. In the present study, we showed by immunohistology that the density of CD1a(+) LCs is reduced in EpM of the uterine cervix compared with native squamous epithelium and that the low number of LCs observed in EpM correlates with the down-regulation of cell-surface E-cadherin. We also demonstrated that transforming growth factor-beta1 is not only overexpressed in metaplastic tissues but also reduces E-cadherin expression in keratinocytes in vitro by inducing the promoter activity of Slug and Snail transcription factors. Finally, we showed that in vitro-generated LCs adhere poorly to keratinocytes transfected with either Slug or Snail DNA. These data suggest that transforming growth factor-beta1 indirectly reduces antigen-presenting cell density in EpM by affecting E-cadherin expression, which might explain the increased susceptibility of abnormal tissue differentiation to the development of cancer by the establishment of local immunodeficiency responsible for EpM tumorigenesis.