Article

Effects of ultraviolet radiation on Langerhans cells

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Abstract

Research on penetration of ultraviolet (UV) radiation into human skin shows that about 20% of UVA and 10% of UVB can reach the basal layer of the epidermis. As a consequence, Langerhans cells (LCs), located in suprabasal layers, are subject to the influence of the two types of UV radiation. This phenomenon leads to quantitative and qualitative alterations in LCs, including reduction in their number in the epidermis and modifications in morphology and immune functions. Studies show that two mechanisms may be responsible for their depletion from epidermis, namely, migration to the lymph nodes or induction of cell necrosis or apoptosis. UV radiation also affects the phenotype of LCs and their functions as antigen presenting cells. In recent years, the role of LCs in the UV-dependent immunosuppression and immune tolerance has been emphasized. The aim of the study is to review the literature about the influence of ultraviolet radiation on Langerhans cells.

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... The results of such studies will lead the way to the solution of some problems related to the future of human health. Upon exposure to UV radiation, skin reactions such as pigmentation, lesion, erythema and changes in the ultrastructure of cells in the epidermis and dermis have been examined on Monodelphis domestica, hairless mice, guinea pig and volunteer people (Applegate, Stuart, & Ley, 1985; Bivik, Larsson, Kå gedal, Rosdahl, & € Ollinger, 2006; Brody, 1959; Browman et al., 2003; Chomiczewska-Sk ora, Adamus, Trznadel-Grodzka, & Rotsztejn, 2013; Johnston, Oikarinen, Lowe, Clark, & Uitto, 1984; McMillan et al., 2008; Sayed, Ahmed, Imam, & Mekkawy, 2007). Our aim was to determine the effect of UVC radiation on the stratum corneum of mole rats epidermis by the electron microscope. ...
... These data were corroborated by previous studies done on human and animals epidermis (Matsumura & Ananthaswamy, 2004; Nix et al., 1964; Raknerud, Hovig, & Iversen, 1971). Although the general effects of UV radiation were studied on the epidermis of human, mice and guinea pig (Bivik et al., 2006; Brody, 1959; Chomiczewska-Sk ora et al., 2013; Johnston et al., 1984; McMillan et al., 2008), some further different changes in the epidermis were seen. The typical appearances of desmosomes disappeared in the basale and spinosum layers of mole rats epidermis (Schwartz, LeRoux, Schaller, & Neurand, 1979 ). ...
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It is likely that the UV rays will affect the epidermis of mammals. All these negative effects justify the studies on the relation between the UV rays and epidermis. The purpose of this study was to investigate the ultrastructural effects of ultraviolet C radiation (UVC) on the stratum corneum of mole rats epidermis. Mole rats were divided into two as the control and experiment groups. The control group did not receive any radiation while the other groups were irradiated with UV radiation for 52, 112 and 168 h. The skin samples were prepared and analyzed by transmission electron microscopy. After the examination, stratum basale, stratum spinosum, stratum granulosum and stratum corneum layers were distinguished. The most drastic effects of UVC were noted in stratum corneum. Lacunae formations and unkeratinized cytoplasmic residues were observed within the horny cells. Depending on dosage and exposal period of the UVC radiation, ultrastructural changes occurred in the stratum corneum on mole rats epidermis.
... Moreover, UVR is able to influence DCs function, maturation, migration, and cooperation with Tregs. A study has revealed that the effectiveness of UVA1 phototherapy in the treatment of morphea was associated with an increase in the number of CD34+ DCs in the dermis [36][37][38][39]. No one has yet studied the potential effects of UVA1 phototherapy on the number of Treg in skin and blood of morphea patients. ...
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Morphea is one of diseases characterised by fibrosis of the skin and subcutaneous tissue. It is a chronic disease that does not shorten the life of the patient, yet significantly affects its quality. The group of factors responsible for its pathogenesis is thought to include disturbed functioning of endothelial cells as well as immune disturbances leading to chronic inflammatory conditions, accompanied by increased production of collagen and of other extracellular matrix components. Dendritic cells (DC) are a type of professional antigen-presenting cells and can be found in almost all body tissues. Individual investigations have demonstrated high numbers of plasmacytoid DC (pDC) in morphoeic skin lesions, within deeper dermal layers, around blood vessels, and around collagen fibres in subcutaneous tissue. It appears that DC has a more pronounced role in the development of inflammation and T cell activation in morphea, as compared to systemic sclerosis (SSc). Regulatory T (Treg) cells represent a subpopulation of T cells with immunosuppressive properties. Recent studies have drawn attention to the important role played by Treg in the process of autoimmunisation. Just a few studies have demonstrated a decrease in the number and activity of Treg in patients with SSc, and only such studies involve morphea. This article reviews recent studies on the role of DC and regulatory T cells in the pathogenesis of morphea. Moreover, mechanisms of phototherapy and potential therapeutic targets in the treatment of morphea are discussed in this context.
... With increasing radiation time and intensity, the number and functionality of LCs decreases. LCs from irradiated skin show a reduced expression of major histocompatibility complex (MHC) proteins of class II and have reduced antigen-presenting ability, probably due to a UV-induced reduction of co-stimulatory molecules like cluster of differentiation antigens (CD 80 and CD 86) [137,138]. Thus, malignant, degenerated cells cannot be detected and aren't rejected by the immune system [139]. ...
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... None. Bivik Larsson, Kågedal, Rosdahl, & € Ollinger, 2006, Chomiczewska-Sk ora, Adamus, Trznadel-Grodzka, & Rotsztejn, 2013, Edwards et al., 1999, De Gruijl, 1999, Matsumura & Ananthaswamy, 2004, Mekkawy, Mahmoud, Osman, & Sayed, 2010, Stolarski et al., 1992, Zare, Hashemi, & Salari, 2007 . ...
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The ultrastructure of the epidermis of mole rats (Spalax leucodon) was studied after irradiation with ultraviolet (UV) light (λmax = 254 nm; 0.00147 J cm−2 s−1; for periods of 52, 112 and 168 h) by using transmission electron microscope (TEM). After irradiation, Vacuolation in cytoplasm and mitochondria, and wrinkled nucleus were found in the stratum basal cells. Also, pathological aggregations of tonofilaments are formed in the desmosomes in these cells. These findings clearly demonstrated the harmful effects of ultraviolet C radiation on the stratum basale. The degree of pathological changes occurred depending on exposure time and radiation dosage applied.
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Literature data indicate the beneficial therapeutic effect of UVA1 irradiation, whose biological properties are significantly different from those of other UV light waves, which is connected with their deeper penetration into the skin. Taking into account immunomodulatory mechanisms of UVA1 action, which mostly influences the apoptosis of fibroblasts, mast cells, Langerhans cells, and T lymphocytes, UVA1 radiation is indicated in the treatment of four major groups of skin diseases: T-cell and mast-cell mediated skin diseases, connective tissue diseases, and dermatoses in HIV positive patients sensitive to phototherapy. This publication presents a review of the literature concerning indications for UVA irradiation, recommended doses, as well as the most often observed adverse events.
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Langerhans cells (LCs) have long been considered to be the major sensitizing cells in the skin by initiating productive immunity in naive resting T cells. This picture has changed over the past decade. We now know (i) that the skin also harbors other types of dendritic antigen-presenting cells and (ii) that the genetically driven removal of the LC population results in increased T-cell immunity against haptens and infectious agents. It is not clear at present whether the situation in genetically modified mice is in any way indicative of the actual in vivo function of LCs. Exciting and challenging years lie ahead of the LC research community.
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Irradiation with ultraviolet-B light (UV-B) suppresses some cell-mediated immune responses to a variety of antigens, including contact sensitizers. Following UV irradiation there is modulation of Langerhans' cells' markers and keratinocytes are induced to synthesize and secrete tumour necrosis factor-alpha (TNF-alpha). Cis-urocanic acid (cis-UCA) has been suggested as a photoreceptor for UV and has been demonstrated to suppress immune responses in several experimental systems. UCA is found naturally in the stratum corneum as the trans-isomer and converts to the cis-isomer on irradiation. In the present study the migration of dendritic cells (DC) to lymph nodes following UV-B irradiation or epicutaneous application of UCA isomers was examined in unsensitized mice and mice sensitized with fluorescein isothiocyanate (FITC). It was found that UV-B irradiation alone induced DC migration to draining lymph nodes (DLN) and that UV-B irradiation prior to skin sensitization at the same site enhanced DC migration. A maximum number of DC was present in DLN 48 hr following irradiation. In sensitized mice, the percentage of DC bearing FITC and the quantity of FITC per DC was unaltered by prior UV exposure. In contrast, neither isomer of UCA had any significant effect on DC numbers in sensitized or unsensitized mice. It was concluded that UV-B irradiation induced the migration of DC from the epidermis to draining lymph nodes, an effect possibly mediated by TNF-alpha release, while UCA may act by a different mechanism, perhaps via histamine-like receptors in the epidermis.
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We have examined the effects of low-dose monochromatic UVB irradiation (295 +/- 5 nm), biologically equivalent to that generally incident on the skin during a 12-session sun-bed course, on the expression of the CD1a epidermal Langerhans cell surface marker in human skin in vivo. In five subjects, 1.5 minimal erythema doses (MEDs) at 295 nm depleted its expression by 50%. In five further subjects, a single 1.5 MED dose, 1.5 MEDs in 10 equal fractions on alternate days, and a single 1.5 MED dose at one-tenth the previously used irradiance, delivered to separate sites, also led to variable but significant depletion of CD1a expression of around 30-50%. Thus, low-dose UVB irradiation, whether received rapidly or slowly, appears significantly and approximately equally to deplete human epidermal Langerhans cell numbers as measured by CD1a expression.
Article
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Article
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.
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Professional antigen-presenting cells (APCs) are required for the initiation of an immune response. Dendritic cells (DCs) are the most potent APCs identified thus far and can present antigen in the context of co-stimulatory signals required for the stimulation of both primed and naïve T cells. Cytotoxic T lymphocytes (CTLs) are critical to the immune response against tumors or virally infected cells. Optimal stimulation of antigen-specific CTLs is the goal of evolving immunization strategies for the prevention or therapy of viral infections and tumors. Epidermal dendritic cells (eDCs), or Langerhans cells, can present antigens for the stimulation of CD4+ T cell dependent anti-tumor immunity and may play a role in tumor surveillance. The capacity of eDCs to induce tumor-specific CD8+ CTL immunity has not been determined. We have previously shown that DCs derived from bone marrow precursors (BmDCs) under the influence of cytokines can induce protective, antigen-specific CTL-mediated anti-tumor immunity. Here we show that subcutaneous immunization with ovalbumin (OVA) peptide (SIINFEKL(257-264))-pulsed eDCs induced OVA-specific, CD8+ CTLs that lyse the OVA-expressing target. Furthermore, mice vaccinated with OVA peptide-pulsed eDCs were completely protected from subsequent challenge by the OVA-expressing melanoma MO5. The capacity of peptide-pulsed eDCs to induce CTL-mediated immunity is directly dependent on the dose of eDCs administered. Importantly, the APC capacity of eDCs is comparable to that of BmDCs, as mice immunized with eDC populations containing at least as many class II+/B7.2+ cells as populations of BmDCs were equally protected against challenge with MO5. These results demonstrate that eDCs can be potent inducers of antigen-specific CD8+ CTL-mediated immunity. They suggest that eDCs may be important targets for antigen delivery strategies aimed at inducing antiviral or anti-tumor immunity.
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We have reported previously that low-dose UVB radiation (UVBR, 50-200 J/m2) perturbs the antigen-presenting cell (APC) function of murine Langerhans cells (LC) by interfering with yet undefined costimulatory signals. In this study, we investigated (1) the effects of UVBR on the expression of the costimulatory molecules B7-1 and B7-2 on murine LC, (2) the functional consequences of defective B7-1 and B7-2 signalling on primary and secondary T-cell responses induced by LC and (3) the mechanism by which UVBR interferes with B7-1 and B7-2 expression. Ultraviolet-B radiation dose-dependently inhibited the culture-induced upregulation of B7-1 and B7-2 on LC from both UVB-susceptible (UVBs, C57BL/6) and UVB-resistant (UVBR, Balb/c) mice and abrogated their capacity to stimulate proliferation of naive alloreactive T cells and of the KLH (keyhole limpet hemocyanin)-specific T helper (Th)1 clone HDK-1. The UVBR-induced suppression of B7-1 and B7-2 on LC and their perturbed APC function were related, because exogenous triggering of the B7/CD28 pathway with a stimulatory monoclonal antibody (mAb) for CD28 to UVB-irradiated LC partially restored T-cell proliferation. Such reconstitution was not observed when the mAb was added to killed LC, indicating that the UVBR-induced suppression of APC function was not due to lethal effects on LC. Conditioned supernatants from UVB-irradiated epidermal cells did not inhibit the functional upregulation of B7-1 and B7-2, suggesting that UVBR inhibits B7-1 and B7-2 upregulation by acting directly on LC and not by altering LC costimulatory function via release of soluble immunosuppressive factors. In conclusion, UVBR distorts the functional expression of B7-1 and B7-2 on LC from both UVBS and UVBR mice, thereby contributing to the failure of UVB-irradiated LC to stimulate resting alloreactive T cells or KLH-specific Th1 cells.
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Experimental data are reviewed that lend support to the hypothesis that formation of DNA damage is the initiation event of local suppression of contact hypersensitivity (CHS) after exposure to ultraviolet (UV) radiation and that the antigen-presenting cell (APC) is an important target for this DNA damage.
Article
Acute, low-dose ultraviolet B (UVB) radiation impairs contact hypersensitivity induction in mice by a mechanism due at least in part to Langerhans cells alterations. To better define the effects of UVB on Langerhans cells, we have compared the action of this agent on the skin of intact mice and in skin explants incubated in vitro up to 24 h. Using immunofluorescence, we detected a reduction in the length of the dendrites of Langerhans cells and a significant reduction in the number of Ia-positive Langerhans cells per unit area within 2 h of UVB; these changes reversed within 24 h in vivo, but not in vitro. By electron microscopy, the number of dendritic cells per 100 basal keratinocytes increased in vivo, but decreased in vitro by 2 h after UVB, a discordance that was significant. On the contrary, the number of dendrite profiles per dendritic cell body decreased significantly 2 h after UVB, both in vivo and in vitro. Many epidermal dendritic cells, 2 h after UVB in vivo, were deficient in cytoplasmic organelles, whereas the few cells that remained after UVB in vitro retained their Birbeck granules, and displayed many, dilated cytoplasmic vesicles. We interpret these data to mean that low doses of UVB radiation destroy the functional and morphologic integrity of epidermal Langerhans cells, and that these cells are rapidly replaced by precursor cells that mature in situ into normal-appearing Langerhans cells.
Article
Ultraviolet B (UVB, 290-320 nm) radiation is known to suppress the immune function of epidermal Langerhans cells. We have recently described that in vitro UVB irradiation perturbs the antigen-presenting cell function of Langerhans cells by inhibiting their expression of functional B7 costimulatory molecules (B7-1, B7-2). The aim of this study was to determine wavelength-specific UV effects on Langerhans cells function in vivo, specifically UVB and UVA-1. To address this issue, volunteers were irradiated on the sun protected volar aspects of their forearms with 3 x minimal erythema dose of UVB (Philips TL-12) and UVA-1 (UVASUN 5000 Mutzhaas). Langerhans cells were isolated from suction blister roofs immediately following irradiation. Langerhans cells isolated from UVB- but not from UVA-1-irradiated skin failed to activate naïve resting allogeneic T cells (mixed epidermal cell leukocyte reaction) or primed tetanus toxoid reactive autologous T cells. Langerhans cells isolated from sham-irradiated or UVA-1-irradiated skin strongly upregulated B7-2 molecules during short-term tissue culture. By contrast, Langerhans cells from UVB-irradiated skin did not upregulate B7-2 molecules. Furthermore, exogenous stimulation of the B7 pathway by anti-CD28 stimulatory monoclonal antibodies restored the capacity of UVB-irradiated Langerhans cells to activate both alloreactive and tetanus toxoid-reactive T cells, implying suppressed antigen-presenting cell activities and perturbed B7 expression of Langerhans cells isolated from UVB-irradiated skin are related. Those studies demonstrate that in vivo UVB, but not UVA-1, interferes with the activation-dependent upregulation of B7 molecules on Langerhans cells, which in turn is of functional relevance for the perturbed antigen-presenting cell function of Langerhans cells within UVB- but not UVA-1-irradiated skin.
Article
UVB irradiation of the skin causes immunosuppression and Ag-specific tolerance in which Langerhans cells (LC) are involved. We tested the effect of UVB on LC that had migrated out of cultured epidermal sheets derived from the skin that was irradiated ex vivo (200, 400, 800, or 1600 J/m2). Two separate subpopulations of LC were distinguished: large-sized LC with high HLA-DR expression, and HLA-DR-low, small LC. UVB stimulated the maturation of the former LC subset as demonstrated by enhanced up-regulation of CD80, CD86, CD54, CD40, and CD83 and reduced CD1a expression in comparison with unirradiated controls. In contrast, the latter LC exhibited little or no up-regulation of these molecules except for high CD1a expression and high binding of annexin V, indicating that they were apoptotic, although their CD95 expression was relatively low. Stimulation of enriched LC with CD40 ligand-transfected cells and IFN-gamma revealed that the release of IL-1beta, IL-6, IL-8, and TNF-alpha was enhanced by UVB. In comparison with HLA-DR-low LC, HLA-DR-high LC were the principal IL-8 producers as demonstrated by intracellular cytokine staining, and they retained more accessory function. There was no detectable secretion of IL-12 p70, and IL-18 production was neither affected by any stimulus nor by UVB. These results suggest a dual action of UVB on LC when irradiated in situ: 1) immunosuppression by preventing maturation and inducing apoptotic cell death in part of LC, and 2) immunopotentiation by enhancing the up-regulation of costimulatory molecules and the production of proinflammatory cytokines in another part.
Article
Two major components of epidermal cells, keratinocytes and Langerhans cells, are injured by ultraviolet light B radiation, resulting in sunburn cell (apoptotic cell) formation, impaired function, and a reduced number of Langerhans cells. Quantitative analysis of Langerhans cell damage is usually performed using epidermal sheets, whereas that of keratinocytes has been performed by counting the number of sunburn cells in vertical tissue sections. In this study we assessed the influences of ultraviolet light B radiation on epidermal cells by apoptotic cell formation, using murine epidermal sheets stained by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique. Ten to 75 mJ per cm2 of ultraviolet light B radiation induced apoptotic cells in abdominal skin of C3H mice. The cells were induced in 6 h after 50 mJ per cm2 of ultraviolet light B irradiation with the peak in number in 24 h, 18.8 +/- 5.0 per mm2 and 97.7 +/- 7.4 per mm2, respectively. One week later, the apoptotic cells were not visualized. As C3H/He, BALB/C, and C57BL/6 mice showed almost the same frequency of apoptosis in epidermal sheets from 50 mJ per cm2 ultraviolet light B-irradiated skin, the induction of the cells by ultraviolet light B radiation did not depend on the genetic trait of the mouse. Xeroderma pigmentosum type A gene-deficient mice, however, showed a greater induction of apoptotic cells (216.9 +/- 25.2 per mm2) by ultraviolet light B radiation than xeroderma pigmentosum type A wild-type mice (89.5 +/- 13.6 per mm2) and conventional mice. Pretreatment with a SPF 60 sunscreen agent was quite effective in reducing the induction of apoptotic cells. Using confocal laser scanning microscopy and double staining, 1.5 +/- 2.7% of apoptotic cells were Ia-positive cells in 24 h after 50 mJ per cm2 of ultraviolet light B radiation. Apoptotic Ia-positive cells were not observed 48 h after the radiation. On the other hand, no apoptotic dendritic epidermal T cells were observed in up to 75 mJ per cm2 of ultraviolet light B radiated skin. Thus, nearly all apoptotic cells were keratinocytes, and Langerhans cells and dendritic epidermal T cells appeared resistant to ultraviolet light B-induced apoptosis. Compared with the assessment in vertical tissue sections, the terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling technique with epidermal sheets appeared to be a more physiologically relevant method for quantitative evaluation of apoptotic epidermal cells induced by ultraviolet light B radiation.
Article
Ultraviolet (UV) B-induced effects on the skin immune system have been extensively investigated, but little is known regarding the immunological changes induced by UVA exposure of human skin. Recent data assessing the protection afforded by sunscreens against photoimmunosuppression stress the need for broad-spectrum sunscreens with an adequate UVA protection. The purpose of this study was first to determine the changes observed in epidermal Langerhans cells (ELC) density and epidermal antigen-presenting cell (APC) activity after exposure of human skin to UVAI (340-400 nm) radiation, and secondly to assess the immune protection afforded in vivo by a sunscreen formulation containing a long wavelength UVA filter with a low UVA protection factor (UVA-PF = 3). Epidermal cell (EC) suspensions were prepared from skin biopsies 3 days after exposure to a single dose of UVAI (either 30 or 60 J cm(-2)). Flow-cytometric analysis of EC suspensions revealed that exposure to 60 J cm(-2) UVAI resulted in a decreased number of ELC without infiltration of CD36+ DR+ CD1a- antigen-presenting macrophages into the epidermis, and a significant reduction of HLA-DR expression on viable ELC. In vivo exposure to both 30 and 60 J cm(-2) resulted in a decreased allogeneic CD4+ T-cell proliferation induced by UVAI-irradiated ECs. The sunscreen application partially prevented (57 +/- 9%) the decrease in epidermal allogeneic APC activity induced by 60 J cm(-2) UVAI. In vivo UVAI exposure of human skin results in a decreased number of ELC and in a downregulation of epidermal APC activity. This last effect is partially prevented by prior application of a sunscreen with a low UVAI-PF value. These results indicate that increasing the absorption of UV filters for long UVA wavelengths may lead to an improved immune protection.
Article
There are few human studies investigating the immunosuppressive effects of exposure to solar-simulated radiation (SSR) and its relationship with sunburn/erythema, and few comparative data on the importance of SSR exposure regimens. To evaluate whether SSR-induced erythema is a reliable end-point for assessing damage to antigen-presenting cells (APCs) in human skin. We compared the relationship between SSR-induced erythema and alterations in epidermal CD1a+ Langerhans cells (LCs) and CD11b+ macrophages in human volunteers after single exposures to 0, 0.5, 1, 2 or 3 minimal erythema doses (MED). We also investigated whether SSR exposure leads to an accumulation or accommodation of the same end-points by comparing the effects of a relatively low cumulative SSR dose (3 MED) given in varying daily dose fractions (4 x 0.75 MED, 2 x 1.5 MED and 1 x 3 MED). Single SSR exposures induced a dose-dependent increase in erythema. CD1a+ LCs remaining in the irradiated epidermis showed a dose-dependent increase in cell size and altered morphology. Significant depletion of CD1a+ LCs and presence of CD11b+ macrophages only occurred in sites irradiated with 2 MED and 3 MED. Dose fractionation had no effect on the final erythemal response but the 4 x 0.75 MED and 1 x 3 MED protocols were better tolerated than 2 x 1.5 MED for alterations in CD1a+ LC and CD11b+ cell numbers. In contrast, dose fractionation protected against alterations in CD1a+ LC morphology or cell size. We found that erythema is a poor indicator of alterations in epidermal APCs and that dose fractionation is an important parameter in the immunological effects of ultraviolet radiation.
Article
This article reviews many of the complex events that occur after cutaneous ultraviolet (UV) exposure. The inflammatory changes of acute exposure of the skin include erythema (sunburn), the production of inflammatory mediators, alteration of vascular responses and an inflammatory cell infiltrate. Damage to proteins and DNA accumulates within skin cells and characteristic morphological changes occur in keratinocytes and other skin cells. When a cell becomes damaged irreparably by UV exposure, cell death follows via apoptotic mechanisms. Alterations in cutaneous and systemic immunity occur as a result of the UV-induced inflammation and damage, including changes in the production of cytokines by keratinocytes and other skin-associated cells, alteration of adhesion molecule expression and the loss of APC function within the skin. These changes lead to the generation of suppressor T cells, the induction of antigen-specific immunosuppression and a lowering of cell-mediated immunity. These events impair the immune system's capacity to reject highly antigenic skin cancers. This review gives an overview of the acute inflammatory and immunological events associated with cutaneous UV exposure, which are important to consider before dealing with the complex interactions that occur with chronic UV exposure, leading to photocarcinogenesis.
Article
Ultraviolet B radiation can suppress cellular immunity. One of the mechanisms related to this immunosuppression is the disappearance of Langerhans cells from the epidermis. The aim of this study was to establish the mechanism of ultraviolet B-induced Langerhans cell disappearance in healthy individuals. The two most likely mechanisms for Langerhans cell disappearance are apoptosis and migration. Apoptosis was assessed in vivo by exposing buttock skin of 10 healthy volunteers to six minimal erythema doses of ultraviolet B. Only very few apoptotic Langerhans cells could be observed in sections from the ultraviolet B-exposed skin. Migration of Langerhans cells cannot be established in skin sections and suction blisters were therefore raised in an attempt to trap migrating Langerhans cells in the sub-basal membrane blister fluid. Blisters were raised on the flexor side of the lower arm of 30 healthy volunteers at several time points after exposure of the skin to six minimal erythema doses of ultraviolet B. Blister fluid was collected and blister roofs were removed to check for Langerhans cell disappearance. Langerhans cells were detected in the blister fluid of the ultraviolet B-exposed skin and not of the unexposed skin. The number of Langerhans cells in the blister fluid peaked at about 18 h after ultraviolet exposure, which coincided with the largest depletion of Langerhans cells in the blister roof. A fraction (20-30%) of the Langerhans cells in the blister fluid stained positive for DNA damage (cyclobutyl pyrimidine dimers), showing that they originated from the epidermis. Ultraviolet B-induced Langerhans cell disappearance appears to be mainly attributable to migration.
Article
Background: Ultraviolet (UV) exposure of human skin induces local and systemic immune suppression. This phenomenon has been well documented when UVB radiation (290-320 nm) is used. The mechanism is thought to involve Langerhans cells (LCs), the epidermal dendritic cells that play a crucial role in antigen presentation. A variety of studies have clearly demonstrated that UVB radiation decreases LC density and alters their morphology and immunological function, but little is known about the effects of the entire UV spectrum (ultraviolet solar simulated radiation, UV-SSR or UVB + UVA) or UVA (320-400 nm) radiation alone. Objectives: The purpose of this study was to analyse and compare the effects of a single exposure of human volunteers to UV-SSR, total UVA or UVA1 (340-400 nm) in the human epidermal LC density and morphology. Methods: Immunohistochemistry on epidermal sheets with various antibodies and transmission electron microscopy (TEM) were used. Results: Immunostaining for class II antigen revealed that a single UV-SSR exposure, corresponding to twice the minimal erythemal dose (MED), induced a significant reduction in LC density with only slight morphological alterations of remaining cells. After a single UVA exposure, LC density showed a dose-dependent reduction with a significant effect at 60 J cm(-2) (well above the MED). Moreover, the reduction of LC dendricity was also dose-dependent and significant for doses exceeding 30 J cm(-2). UVA1 radiation was as effective as total UVA for the later endpoint. As demonstrated by TEM, the location of Birbeck granules containing epidermal cells was modified in UVA-exposed areas. They were located in the spinous rather than in the suprabasal layer. In addition, the morphology of these cells was altered. We observed a rounding up of the cell body with a reduction of dendricity. Alterations of mitochondrial membrane and ridges were also seen. Conclusions: A single exposure of human skin in vivo to UV-SSR, UVA or UVA1 radiation results in different alterations of density and/or morphology of LCs. All these alterations may impair the antigen-presenting function of LCs leading to an alteration of immune response.
Article
The influence of repeated low-dose ultraviolet B (UVB) radiation, to which we are exposed in daily life, has not been fully clarified, although the damage caused by exposure to high-dose UVB radiation has been well-studied in recent years. To investigate skin damage caused by repeated low-dose exposure, we evaluated the extent of injury to the Langerhans cells which are known to be involved in the cutaneous immune system. The backs of hairless mice were exposed to the following doses of UVB radiation: 100 mJ/cm(2) once, 50 mJ/cm(2) twice, 25 mJ/cm(2) four times or 10 mJ/cm(2) ten times. Skin specimens were taken for histochemical and electron microscopic examination 24 h after the final irradiation. Epidermis exposed to UVB radiation demonstrated a decrease in the number of Langerhans cells which showed less dendricity. The population of these cells in specimens exposed to repeated suberythemal doses was reduced to 40%, whereas exposure to a single high dose of UVB with the same energy resulted in a reduction of only 33%. These results indicate that repeated suberythemal doses injure Langerhans cells more than a single high-dose exposure. Furthermore, Birbeck granules in Langerhans cells of UVB-irradiated epidermis were reduced and tended to show shortening of their rod portion. The present study suggested that repeated challenge with suberythemal UVB radiation, to which we are all exposed in daily life, can cause substantial damage to Langerhans cells.
Article
Immune suppression following UVB irradiation is partly attributed to the effects of the exposure on antigen-presenting cells. Following a single UVB irradiation, there is a decrease in epidermal Langerhans cell numbers; this is accompanied by an increase in the number of dendritic cells (DC) in lymph nodes draining the irradiated site. We investigated whether a similar effect occurred following multiple UVB exposures. Mice were irradiated on their ears and shaved dorsal skin twice a week for 3 weeks. After the final exposure, the number of ATPase(+) Langerhans cells in epidermal sheets prepared from the ears was found to be decreased by 33% compared to unirradiated controls. The number of DC in the draining lymph nodes (DLN) did not increase as might have been expected; rather, a significant decrease of approximately 30% in DC numbers in the DLN of UVB-irradiated mice compared with unirradiated controls occurred. This decrease in antigen-presenting cells in both the epidermis and the DLN may be an important contributing factor to the immune suppression that follows multiple UVB exposures.
Article
Langerhans cells capture exogenous antigens through fluid phase pinocytosis and receptor-mediated endocytosis and migrate to lymph nodes, where they present processed antigen to T cells. Ultraviolet B radiation impairs the antigen-presenting function of Langerhans cells, resulting in antigen-specific immunosuppression of contact hypersensitivity. We tested the notion that ultraviolet B radiation inhibits the endocytic activity of Langerhans cells, leading to impaired migration and maturation. Human monocyte-derived Langerhans cell-like dendritic cells that took up lucifer yellow or fluorescein isothiocyanate dextran exclusively migrated in response to 6Ckine/secondary lymphoid chemokine, and matured, as evidenced by an increase in CD54 and CD86 expression and potent stimulatory activity in allogeneic mixed lymphocyte reaction. Exposing Langerhans cell-like dendritic cells to 20-40 mJ per cm2 of ultraviolet B radiation reduced their endocytic activity in fluid phase pinocytosis (measured by uptake of lucifer yellow) and in receptor-mediated endocytosis (measured by uptake of fluorescein isothiocyanate dextran). Membrane ruffling and CD32 expression were also suppressed by ultraviolet B radiation. Ultraviolet B-irradiated, endocytosing Langerhans cell-like dendritic cells had less movement towards 6Ckine, expressed less CD54 and CD86, and had less effective stimulatory activity in allogeneic mixed lymphocyte reaction than nonirradiated, endocytosing Langerhans cell-like dendritic cells. Endocytosis upregulated tumor necrosis factor alpha production by Langerhans cell-like dendritic cells, but prior ultraviolet B radiation inhibited this enhancement. These data suggested that impaired endocytosis and subsequent inhibitory migration and maturation of Langerhans cells by ultraviolet B radiation could contribute to local immunosuppression of contact hypersensitivity.
Article
Exposure of certain strains of mice to ultraviolet radiation (UVR) causes suppression of some innate and adaptive immune responses. One such consequence of acute UVB exposure is a reduction in the number of Langerhans cells (LC) in the epidermis and an increase in dendritic cells (DC) in lymph nodes draining the irradiated skin sites. Exposure to chronic UVB irradiation also has effects on the immune system, but it is unknown what effects are caused by repeated doses of solar simulated radiation (SSR). Consequently, the main aims of the present study were to determine whether repeated exposure to low doses of SSR would lead to similar changes in these cell populations and whether chronic doses of SSR activate a protective photoadaptation mechanism. Groups of C3H/HeN mice were irradiated daily with 3.7 J/cm(2) SSR from Cleo Natural lamps for 2, 10, 20, 30 or 60 days. Further groups of mice received an additional dose of 7.4 J/cm(2) SSR on days 2, 10, 30 or 60 to test for photoadaptation. The numbers of LC in the epidermis and DC in the lymph nodes draining irradiated skin sites were counted 24 h after the final irradiation. With the exception of mice irradiated for only 2 days, LC were significantly reduced throughout the chronic irradiation protocol, and no recovery occurred. DC numbers were significantly increased in the draining lymph nodes of mice irradiated for 20 days and 60 days.
Article
Regulatory T cells belong to a subset of T lymphocytes which suppress immune reactions in an antigen-specific fashion. They play an important role in the prevention of autoimmune diseases. Ultraviolet (UV) radiation was also found to suppress the immune system in an antigen-specific fashion mediated by UV-induced regulatory T cells. Induction of these cells by UV radiation is an active process which requires antigen presentation by UV-damaged but still viable Langerhans cells in the lymph nodes. UV-induced regulatory T cells have been recently characterized to express CD4 and CD25 and to release the immunosuppressive cytokine interleukin-10 upon activation. Once activated in an antigen-specific fashion, they suppress immune responses in a general fashion via the release of interleukin-10, a phenomenon called bystander suppression. Upon intravenous injection, UV-induced regulatory T cells primarily migrate into the lymph nodes, explaining why they preferentially suppress sensitization. Recently, the development of regulatory T cells was demonstrated in an experimental model of photopheresis, a therapeutic regimen which is used for the therapy of autoimmune diseases, transplant rejection and graft-versus-host disease. Further characterization of these cells will determine whether they can be applied therapeutically in the future with the ultimate aim to induce specific immunosuppression.
Article
Exposure to ultraviolet radiation (UVR) can result in immune suppression to antigens encountered within a few days of the irradiation. The process leading to the down-regulation in immune responses is complex. It is initiated by several photoreceptors located in the skin surface, namely DNA, trans-urocanic acid and membrane components. The absorption of UVR by these chromophores then leads to the release of a wide range of mediators that can affect antigen presenting cells locally or systemically. The final steps include the generation of antigen-specific T cells capable of regulating immunity. The consequences of the UV-induced changes in the skin immune system for the control of skin cancers, infectious diseases including vaccination, and autoimmune diseases are considered. Finally, the effects of active vitamin D, synthesised in the epidermis following UVR, are discussed in the context of the skin immune response.
Article
The irradiance of standard ultraviolet daylight (UV-DL) is representative of most frequently encountered UV exposure conditions and simulators of UV-DL can now be used to properly investigate the biological effects of a non-extreme UV radiation. One of the characteristics of the simulated UV-DL used in this study is its dUVA to dUVB irradiance ratio, which amounts to 24, instead of close to 10, for the simulated zenithal UV radiation (UV-SSR). The aim of our study was to compare photobiological effects induced, in human skin, by acute and semi-chronic exposure to simulated UV-DL with those induced by UV-SSR. Differences between UV doses needed to induce given biological effects after exposure to simulated UV-DL compared with UV-SSR indicate that the spectral distribution of the UV spectrum is of primary importance with regard to biological endpoints in the epidermis (SBC, p53, thymine dimers, Langerhans cells, and melanocyte alterations, etc.) and in the dermis (collagen, tenascin, etc.). Significant biological damage was noticed after 19 cumulative exposures to 0.5 minimum erythemal dose (MED) of UV-DL over 4 weeks. 0.5 MED of UV-DL corresponds to 1/9 of the daily typical dose received in Paris in April, emphasizing the need for an efficient daily UV protection. Simulated UV daylight is a relevant new tool for daily photoprotection studies.
Article
Ultraviolet B (UVB) radiation affects the migration and function of epidermal Langerhans cells (LC) and causes immunosuppression of contact hypersensitivity. It is known that LC leaves the epidermis after exposure to UVB. To know the behavior of LC in the dermis after UVB radiation, we studied the effect of UVB radiation on the expression of integrin families on freshly isolated or cultured murine LC. We also examined whether UVB radiation affects the migration of LC to secondary lymphoid tissue chemokine (SLC/6Ckine). Integrin expressions of murine LC cultured in epidermal cell suspension were analyzed using flowcytometry. We used murine LC sorted flowcytometrically for binding assay to extracellular matrix and for migration assay to chemokine. Skin explant assay and immnohistochemical staining for 'cords formation' were performed as previously described. Twenty and 40 mJ/cm2 of UVB radiation down-regulated the expression of alpha4 integrin on 24 h-cultured LC, but not that of alpha6, beta1, or beta4 integrin. The number of cultured LC adhered to fibronectin, a ligand for alpha4 integrin, was decreased after UVB irradiation, while that to laminin, a ligand for alpha6 integrin, was not influenced. UVB radiation reduced the number of migrating LC to SLC. Furthermore, skin sheet explant experiments showed that UVB radiation inhibited the 'cords' formation in dermal vessels of the 48 h-cultured skin. These data suggest that UVB radiation may suppress the migration of LC from the dermis to lymphatic vessels. UVB radiation may downregulate the adherence of LC to dermal fibronectin and migration to SLC, and consequently suppress the migration of LC from the UVB-irradiated dermis to lymphatics.
Article
Dendritic cells (DC) have a unique capacity to present external antigens to CD8(+) T cells, i.e. cross-presentation. However, it is not fully established whether the ability to cross-presentation is restricted to a unique subset of DC in humans. Here, we show that two major myeloid DC subsets, i.e. Langerhans cells (LC) and interstitial DC (Int-DC), have the ability to cross-present antigens to CD8(+) T cells in vitro. LC and Int-DC were obtained from DC generated by culturing human CD34(+)-hematopoietic progenitor cells with GM-CSF, FLT3-L, and TNF-alpha (CD34-DC). Both DC subsets were able to capture necrotic/apoptotic allogeneic melanoma cells and present antigens to CD8(+) T cells, resulting in efficient priming of naive CD8(+) T cells into CTL capable of killing melanoma cells. Strikingly, a single stimulation with either subset (LC or Int-DC) or total CD34-DC loaded with necrotic/apoptotic melanoma cells was sufficient to activate melanoma-specific memory CD8(+) T cells obtained from patients with metastatic melanoma to become effective CTL. Thus, this study provides the rationale to use CD34-DC loaded with necrotic/apoptotic allogeneic melanoma cells in a clinical trial.
Article
A single or a limited number of UVR exposures is recognized to suppress cell-mediated immunity in human subjects. The complex pathway leading from the absorption of photons by chromophores in the skin to the generation of T regulatory cells has been, at least partially, elucidated. However, the effect of repeated UV exposures on immune responses and associated mediators is not well studied, particularly to assess whether they lead, first, to the development of photoprotection so that these immune changes are reduced or no longer occur, and, secondly, to the development of photoprotection against the normal downregulation of immunity induced by a high UV dose. For almost all the parameters evaluated in this review--epidermal DNA damage/erythema, urocanic acid, Langerhans and dendritic cells, natural killer cells, macrophages, mast cells, contact and delayed hypersensitivity responses--none, aside from epidermal DNA damage/erythema and macrophage phagocytic activity, show convincing evidence of photoadaptation or, where appropriate, photoprotection. It is concluded that repeatedly irradiating individuals with UVR is likely to continue to result in downregulation of immunity.
Article
Solar UVR is highly mutagenic but is only partially absorbed by the outer stratum corneum of the epidermis. UVR can penetrate into the deeper layers of the epidermis, depending on melanin content, where it induces DNA damage and apoptosis in epidermal cells, including those in the germinative basal layer. The cellular decision to initiate either cellular repair or undergo apoptosis has evolved to balance the acute need to maintain skin barrier function with the long-term risk of retaining precancerous cells. Langerhans cells (LCs) are positioned suprabasally, where they may sense UV damage directly, or indirectly through recognition of apoptotic vesicles and soluble mediators derived from surrounding keratinocytes. Apoptotic vesicles will contain UV-induced altered proteins that may be presented to the immune system as foreign. The observation that UVR induces immune tolerance to skin-associated antigens suggests that this photodamage response has evolved to preserve the skin barrier by protecting it from autoimmune attack. LC involvement in this process is not clear and controversial. We will highlight some basic concepts of photobiology and review recent advances pertaining to UV-induced DNA damage, apoptosis regulation, novel immunomodulatory mechanisms and the role of LCs in generating antigen-specific regulatory T cells.