Changes In Langerhans Cells Research Articles

016 Phenotypic Changes of a Monocyte Cell Line depend on the Culture Temperature

Although the body temperature is mainteined at around 37 °C, the temperature of skin, which is facing directly to external environment, is affected by external climate. Since epidermal Langerhans cells reside in upper most layers of skin, they must be affected with temperature shift. But most of the in vitro experiments are conducted at 37 °C. In this study, threfore, the phenotypic changes of Langerhans cells were examined using a model cell line, THP-1 cells. Since the skin surface temperture goes down to 25 °C when people go in to a room at 10 °C, we chose the culture temperature at 29 °C, 33 °C, and regular 37 °C. The proliferation rate declined as temperature went down. The amount of RNA extracted from the same number of cells cultured at lower temperature was smaller than at 37 °C. These results suggest that cellular activity is lower at lower temperature. However, when gene expression was examined, some specific genes were detected at lower temperature, including inhibitor of NFκB, inhibitor of growth family2, B cell anti-translocator gene antiproliferative, while inflammatory genes were expressed at 37 °C, demonstrating that cells are not simply inactive but actively responding to lower temperature. The expression of CD86 examined by flowcytometry was same or a little bit lower at lower temperature compared to 37 °C, but higher after stimulation with dinitrochlorobenzene. These results suggest that epidermal Langerhans cells actively stay quiet at regular physiological condition. These results anyway tell us to consider the culture condition of in vitro experimants when extraporating to in vivo.

Interleukin-32 promotes detachment and activation of human Langerhans cells in a human skin explant model.

Cross-talk between skin keratinocytes (KCs) and Langerhans cells (LCs) plays a fundamental role in the body's first line of immunological defences. However, the mechanism behind the interaction between these two major epidermal cells is unknown. Interleukin (IL)-32 is produced in inflammatory skin disorders. We questioned the role of IL-32 in the epidermis. We aimed to determine the role of IL-32 produced by KCs on surrounding LCs. We used an ex vivo human explant model from healthy donors and investigated the role of IL-32 on LC activation using imaging, flow cytometry, reverse transcriptase quantitative polymerase chain reaction and small interfering (si)RNA treatment. Modified vaccinia virus ankara (MVA) infection induced KC death alongside the early production of the proinflammatory cytokine IL-32. We demonstrated that IL-32 produced by MVA-infected KCs induced modest but significant morphological changes in LCs and downregulation of adhesion molecules, such as epithelial cell adhesion molecule and very late antigen-4, and CXCL10 production. The treatment of KCs with IL-32-specific siRNA, and anti-IL-32 blocking antibody significantly inhibited LC activation, demonstrating the role of IL-32 in LC activation. We also found that some Toll-like receptor ligands induced a very high level of IL-32 production by KCs, which initiated LC activation. We propose, for the first time, that IL-32 is a molecular link between KCs and LCs in healthy skin, provoking LC migration from the epidermis to the dermis prior to their migration to the draining lymph nodes.

Changes in intraepidermal nerve fiber and Langerhans cell densities in the plantar skin of rats after mercuric chloride exposure.

Mercury and its compounds possess strong neurotoxicity and patients with mercury poisoning often report pain and numbness in the distal extremities that conform to the "stocking-glove" pattern. However, no study has investigated whether damage to small nerve fibers is associated with mercury poisoning. The aims of the present study were to evaluate the effects of different doses of mercury chloride (HgCl2 ) on intraepidermal nerve fibers density (IENFD) and Langerhans cells (LCs) in the plantar skin of rats and to assess the possible relationship between changes in IENFD and sensory testing. Male Sprague-Dawley rats were divided into three experimental groups and administered HgCl2 solutions via gavage at three different doses (4.25, 8.5, and 17 mg/kg/day) for 21 days. Subsequently, behavioral tests and pathological changes in IENFD and LCs were assessed at three different time points (1, 2, and 3weeks). Rats in all three HgCl2 groups exhibited varying degrees of weight and hair loss. Thermal hypersensitivity was evident in all the HgCl2 groups (for middle-2w subgroup, p<0.05). Mechanical sensitivity tests revealed hyposensitivity in all the HgCl2 groups except the high-1w subgroup. Significant decreases in IENFD (for the high-1w, middle-1w, low-2w, and low-3w subgroups, p < 0.05) and significant increases in the density of LCs (except for the low-1w and high-2w subgroups, all p<0.05) were found in all groups after HgCl2 exposure. An association analysis revealed a significant correlation between the decrease in IENFD and the increase in LCs densities (r = -0.573, p < 0.01). The present study demonstrated a decrease in IENFD and an increase in LCs density in the plantar skin of rats after HgCl2 poisoning, indicating that damage of the small nerve fibers occurs after mercury poisoning.

Langerhans cell: exciting developments in health and disease.

Langerhans cells (LCs) have been the subject of much research since their discovery in 1868. LCs belong to the subset of leucocytes called dendritic cells. They are present in the epidermis and the pilosebaceous apparatus and monitor the cutaneous environment for changes in homeostasis. During embryogenesis, a wave of yolk sac macrophages seed the fetal skin. Then, fetal liver monocytes largely replace the yolk sac macrophages and comprise the majority of adult LCs. In the presence of skin irritation, LCs process antigen and travel to regional lymph nodes to present antigen to reactive T lymphocytes. Changes in LCs' surface markers during the journey occur under the influence of cytokines. The difference in expression of surface markers and the ability to resist radiation have allowed researchers to differentiate LCs from the murine Langerin-positive dermal dendritic cells. Exciting discoveries have been made recently regarding their role in inflammatory skin diseases, cancer and HIV. New research has shown that antibodies blocking CD1a appear to mitigate inflammation in contact hypersensitivity reactions and psoriasis. While it has been established that LCs have the potential to induce effector cells of the adaptive immune system to counter oncogenesis, recent studies have demonstrated that LCs coordinate with natural killer cells to impair development of squamous cell carcinoma caused by chemical carcinogens. However, LCs may also physiologically suppress T cells and permit keratinocyte transformation and tumorigenesis. Although long known to play a primary role in the progression of HIV infection, it is now understood that LCs also possess the ability to restrict the progression of the disease. There is a pressing need to discover more about how these cells affect various aspects of health and disease; new information gathered thus far seems promising and exciting.

Langerhans cells prevent subbasal nerve damage and upregulate neurotrophic factors in dry eye disease.

The functional role of Langerhans cells (LCs) in ocular surface inflammation and nerve damage in dry eye (DE) disease has yet to be determined. This study was performed to investigate this relationship through both clinical study on DE patients and in vivo mouse models with induced DE disease. In a cross-sectional case-control study (54 eyes of DE patients; 34 eyes of control patients), average cell density, area, and process length of LCs were measured using confocal microscopy. Data were analyzed to determine whether changes in LCs are correlated with subbasal nerve plexus (SNP) parameters (nerve density, beading, and tortuosity). In DE patients, SNP density marginally decreased and nerve beading and tortuosity were significantly increased compared to the control group. The total number of LCs significantly increased in DE patients, and some LCs with elongated processes were found to be attached to nerve fibers. Interestingly, nerve loss and deformation were correlated with inactivation of LCs. In an in vivo experiment to elucidate the role of LCs in ocular surface inflammation and corneal nerve loss, we used a genetically modified mouse model (CD207-DTR) that reduced the population of CD207 (Langerin) expressing cells by injection of diphtheria toxin. In CD207-depleted mice with DE disease (CD207-dDTR+DE), corneal nerves in the central region were significantly decreased, an effect that was not observed in wild-type (WT)+DE mice. In CD207-dDTR+DE mice, infiltration of CD4+, CD19+, CD45+, and CD11b+ cells into the ocular surface was increased, as confirmed by flow cytometry. Increased IL-17 and IFN-γ mRNA levels, and decreased expression of neurotrophic factors and neurotransmitters, were also found in the CD207-dDTR+DE mice. These data support a functional role for LCs in negatively regulating ocular surface inflammation and exhibiting a neuroprotective function in DE disease.

019 Functional changes in Langerhans cells (LCs) may partially explain alterations in skin immunity with aging

019 Functional changes in Langerhans cells (LCs) may partially explain alterations in skin immunity with aging

Changes of Langerhans cells during skin ageing.

IntroductionDuring the process of skin ageing, changes occur in all skin layers and all cells, including the Langerhans cells.AimTo assess whether any quantitative difference in the number of CD1a+ LC cells/mm2 and HLA-DR+ LC cells/mm2 as well as in their morphological features can be observed during the course of different types of skin ageing.Material and methodsThe study was conducted in a group of 60 women, which was divided into three independent groups: group I with symptoms of menopausal skin ageing, group II with symptoms of photoageing, group III with symptoms of chronological ageing. Skin biopsy samples were taken from the pre-auricular region from all of the participants. The number of CD1a+ LC cells/mm2 and HLA-DR+ LC cells/mm2 as well as their morphological features were evaluated.ResultsThe frequency of CD1a+ LC and HLA-DR+ LC in all the studied groups was diverse. In groups I and III, the LC with large cell bodies and long, multi-branched processes were the majority. In group II, the LC had small cell bodies and their processes were mainly short and unbranched.ConclusionsThe obtained results indicate the presence of quantitative and morphological changes of the CD1a+ LC and HLA-DR+ LC during the course of different types of skin ageing.

Topical steroid therapy induces pro-tolerogenic changes in Langerhans cells in human skin.

We have investigated the efficacy of conditioning skin Langerhans cells (LCs) with agents to promote tolerance and reduce inflammation, with the goal of improving the outcomes of antigen-specific immunotherapy. Topical treatments were assessed ex vivo, using excised human breast skin maintained in organ bath cultures, and in vivo in healthy volunteers by analysing skin biopsies and epidermal blister roof samples. Following topical treatment with a corticosteroid, tumour necrosis factor-α levels were reduced in skin biopsy studies and blister fluid samples. Blister fluid concentrations of monocyte chemoattractant protein-1, macrophage inflammatory proteins -1α and 1β and interferon-γ inducible protein-10 were also reduced, while preserving levels of interleukin-1α (IL-1α), IL-6, IL-8 and IL-10. Steroid pre-treatment of the skin reduced the ability of LCs to induce proliferation, while supernatants showed an increase in the IL-10/interferon-γ ratio. Phenotypic changes following topical steroid treatment were also observed, including reduced expression of CD83 and CD86 in blister-derived LCs, but preservation of the tolerogenic signalling molecules immunoglobulin-like transcript 3 and programmed death-1. Reduced expression of HLA-DR, CD80 and CD86 were also apparent in LCs derived from excised human skin. Topical therapy with a vitamin D analogue (calcipotriol) and steroid, calcipotriol alone or vitamin A elicited no significant changes in the parameters studied. These experiments suggest that pre-conditioning the skin with topical corticosteroid can modulate LCs by blunting their pro-inflammatory signals and potentially enhancing tolerance. We suggest that such modulation before antigen-specific immunotherapy might provide an inexpensive and safe adjunct to current approaches to treat autoimmune diseases.

Jorge Lobo's disease: immunohistochemical characterization of dendritic cells in cutaneous lesions.

Jorge Lobo's disease (JLD) is a cutaneous chronic mycosis caused by Lacazia loboi. We studied Factor XIIIa + dermal dendrocytes (FXIIIa + DD), Langerhans cells (LC) through the expression of langerin and the expression of S100 protein. A total of 41 biopsies and 10 normal skins (control) were developed with a polymer-based immunohistochemical method. Lesions presented infiltrate comprising macrophages, some asteroid corpuscles, lymphocytes, multinucleated giant cells and a large number of fungi. LCs presented short dendrites and were scarcely distributed. Dermal langerin + cells were detected in nine JLD lesions. FXIIIa + DD were hypertrophic, visualized in the inflammatory infiltrate of JLD lesions. Cells S100+ were present in JLD and control group with a similar number of cells. A total of 14 specimens did not express FXIIIa, and this considerable number probably contributed to the statistical similarity with the control group. The results indicate that LCs are present in the immune response against Lacazia loboi. Some dermal langerin + cells could be another subset of dendritic cells. Our data indicate changes of LCs in JLD cutaneous lesions and present, for the first time, results that show langerin + cells in the dermis and corroborate previous observations on the participation of FXIIIa + DD in the in situ immune response in JLD.

A study of the correlation between acantholysis and apoptosis for the pathogenesis of pemphigus vulgaris

The goal of the study is to determine the particular features of pemphigus vulgaris (PV) morphogenesis and keratinocytes in the patients’ skin having morphological signs of acantholysis and apoptosis as well as changes in Langerhans cells. Materials and methods. Skin tissue samples taken from 46 PV patients were examined. The skin tissue samples underwent cytology, histopathology and immunohistochemistry examinations as well as transmission electronic microscopy. An increased number of CD1a+ (dendritic) cells and apoptotic Cpp3+ keratinocytes was revealed in the skin of the PV patients. According to the electronic microscopy data, keratinocytes with signs of apoptosis are present in fresh vesicles in the acantholysis area at early PV stages quite seldom; at the same time, Langerhans cells had morphologic signs of activation. As the number of keratinocytes with desmosome lysis signs grew, the number of apoptotic keratinocytes was increasing reliably. Conclusion. In case of PV, apoptosis has a secondary nature and develops as anoikis.

Early events after skin injury: Observations on changes in Langerhans cells and Birbeck granules with role of phosphorylase kinase in the injury pathway

Background and Aim: To evaluate the role of Langerhans cells (LCs) in the early events of the injury pathway, we studied activated and unactivated LCs in sequential biopsies from uninvolved skin of psoriatic and nonpsoriatic individuals using immunocytochemistry and electron microscopy. Methods: Tape-stripping injury was used for cell activation. Changes suggestive of LC activation were observed as early as 5-30 min following tape-stripping. These consisted of abundant Golgi cisternae, proliferation of rough endoplasmic reticulum consistent with increased protein synthesis, increased folds and waviness of the nuclear membranes, and development of migratory status as shown by shortening of dendritic processes and presence of spaces around the LCs from detachment of the cell-membranes from the adjacent keratinocytes. Results: There were notable changes in Birbeck granules (BGs) in LCs, with an inverse correlation of BG density with cell activation as early as 5 min after tape-stripping. The BG was most abundant in the unactivated LCs, and least numerous after activation. With cell activation, BG was observed to be few and unstacked, with isolated granules opening to the cell surface. The presence of T6 antigen (CD1a) 30 min after tape-stripping, with loss of epidermal T6+ LCs and presence of T6+ LCs within the dermal blood vessels 24 h after tape-stripping, strongly suggest development of LCs' migratory status, followed by amplification of the immune response 7 days after tape-stripping. Conclusion: Because BG contain both C-type lectin (langerin) and T6 antigen (CD1a), BG in activated LCs may provide a mechanism whereby presynthesized molecules (langerin, T6/CD1a, toll receptors) necessary for early LC activation and migration may be simultaneously delivered to the cell surface membrane for rapid enhancement of activated cell function by nonpeptide antigens.

Depletion of Langerhans cells in the tongue from patients with advanced‐stage acquired immune deficiency syndrome: relation to opportunistic infections

To quantify and compare the expression of Langerhans cells (LCs) in the tongue mucosa of AIDS patients with different opportunistic infections, and from acquired immune deficiency syndrome (AIDS) and non-AIDS patients with normal tongues, using autopsy material. Human leucocyte antigen D-related (HLA-DR), CD1a and CD83 antibodies were used to identify and quantify LCs by immunohistochemistry in tongue tissue of 40 AIDS patients (10 with lingual candidiasis, 10 with lingual herpes, 10 with oral hairy leukoplakia and 10 with no lesions) and 23 tongues from human immunodeficiency virus (HIV)-negative control patients. Quantification was performed by means of conventional morphometry in four different regions (anterior, middle, posterior and lateral) of the tongue. The results were expressed as positive cells per area of epithelium. The AIDS patients presented a lower density of CD1a(+) cells (P < 0.001), HLA-DR (P < 0.003) and CD83 (P < 0.001) in all regions of the tongue compared to the non-AIDS control group. However, no differences in any of the markers were found when AIDS patients with different opportunistic infections were compared with AIDS patients without tongue infection. Advanced stage AIDS patients showed a depletion of LCs in the tongue mucosa. HIV infection induces cytopathic changes in LCs, contributing to their depletion regardless of the presence of oral infections.

Effects of pimecrolimus versus triamcinolone on Langerhans cells after UV exposure

Pimecrolimus is a topical immunomodulator for atopic dermatitis. Concerns regarding malignancy risk resulted in its black box warning in 2006. The purpose of this study is to determine the effects of pimecrolimus on Langerhans cells (LC), mediators of the cutaneous immunity UV-irradiated skin. A RCT was conducted investigating pimecrolimus 1% cream vs triamcinolone 0.1% cream on UV-irradiated epidermal LC on 20 healthy volunteers. Punch biopsies were stained with antibodies to CD1a, HLADR and CD83. Triamcinolone caused more depletion in UV-irradiated CD1a(+) epidermis relative to pimecrolimus treatment. (P=0.030). Using HLA-DR as a pan-marker for APCs, pimecrolimus caused marginally less depletion than triamcinolone (P=0.013). Using anti-CD83 as a maturation marker, UV-irradiated skin treated with pimecrolimus showed more mature LC than skin treated with triamcinolone (P=0.00090). UV-induced changes in LC are minimally affected by pimecrolimus, compared with triamcinolone.

Changes in Human Langerhans Cells Following Intradermal Injection of Influenza Virus-Like Particle Vaccines

There is a significant gap in our fundamental understanding of early morphological and migratory changes in human Langerhans cells (LCs) in response to vaccine stimulation. As the vast majority of LCs studies are conducted in small animal models, substantial interspecies variation in skin architecture and immunity must be considered when extrapolating the results to humans. This study aims to determine whether excised human skin, maintained viable in organ culture, provides a useful human model for measuring and understanding early immune response to intradermally delivered vaccine candidates. Excised human breast skin was maintained viable in air-liquid-interface organ culture. This model was used for the first time to show morphological changes in human LCs stimulated with influenza virus-like particle (VLP) vaccines delivered via intradermal injection. Immunohistochemistry of epidermal sheets and skin sections showed that LCs in VLP treated skin lost their typical dendritic morphology. The cells were more dispersed throughout the epidermis, often in close proximity to the basement membrane, and appeared vertically elongated. Our data provides for increased understanding of the complex morphological, spatial and temporal changes that occur to permit LC migration through the densely packed keratinocytes of the epidermis following exposure to vaccine. Significantly, the data not only supports previous animal data but also provides new and essential evidence of host response to this vaccination strategy in the real human skin environment.

Células de Langerhans CD1a+ en la epidermis peritumoral del carcinoma basocelular

BackgroundBasal cell carcinoma (BCC) is a common malignant tumor and its incidence has risen in recent decades. Research has shown the relationship between ultraviolet (UV) radiation, the skin immune system, and BCC. The role of Langerhans cells (LC) in the immune response to tumors has prompted research into LC density and morphology in response to UV radiation and BCC. However, the data are inconsistent due to differences in research methodology. ObjectiveTo study the density and morphology of LCs in the peritumoral epidermis of BCC using immunohistochemistry and image processing software and compare the results with those from the epidermis overlying the tumor. Material and methodsTwelve samples from patients with BCC were prepared with a CD1a stain. Areas of epidermis overlying and adjacent to the tumor were defined using light microscopy and the Image J image processing software. The LCs in each area were counted and the cell densities were calculated and compared. Morphological features of LCs were also evaluated in each epidermal areas. ResultsThe results showed a lower density of LCs in the epidermis overlying the tumor than in the peritumoral epidermis (p<0.05). There were also differences in the size, shape, and dendritic pattern of the LCs between the epidermal areas. ConclusionsThe lower density and fewer morphological changes of LCs in the epidermis overlying BCC may give rise to alterations in the immune response to BCC. Digital image analysis is a reliable method for the morphometric evaluation of LCs.

CD1a + Langerhans Cells in the Peritumoral Epidermis of Basal Cell Carcinoma

Background Basal cell carcinoma (BCC) is a common malignant tumor and its incidence has risen in recent decades. Research has shown the relationship between ultraviolet (UV) radiation, the skin immune system, and BCC. The role of Langerhans cells (LC) in the immune response to tumors has prompted research into LC density and morphology in response to UV radiation and BCC. However, the data are inconsistent due to differences in research methodology. Objective To study the density and morphology of LCs in the peritumoral epidermis of BCC using immunohistochemistry and image processing software and compare the results with those from the epidermis overlying the tumor. Material and methods Twelve samples from patients with BCC were prepared with a CD1a stain. Areas of epidermis overlying and adjacent to the tumor were defined using light microscopy and the Image J image processing software. The LCs in each area were counted and the cell densities were calculated and compared. Morphological features of LCs were also evaluated in each epidermal area. Results The results showed a lower density of LCs in the epidermis overlying the tumor than in the peritumoral epidermis (P < 0.05). There were also differences in the size, shape, and dendritic pattern of the LCs between the epidermal areas. Conclusions The lower density and fewer morphological changes of LCs in the epidermis overlying BCC may give rise to alterations in the immune response to BCC. Digital image analysis is a reliable method for the morphometric evaluation of LCs.

Reduction of the DTH response is related to morphological changes of Langerhans cells in mice exposed to acute immobilization stress.

There is a large body of evidence indicating that stress influences immune competence. For example, psoriasis and atopic dermatitis may be exacerbated by psychic stress and related to abnormalities in the cellular constituents of the immune system in the skin. However, the underlying mechanisms remain unclear. We therefore investigated the potential of acute immobilization stress to affect the DTH response in BALB/c mice. DTH was significantly reduced in an immobilization time-dependent manner when stress exposure was just before sensitization. Although the number of Langerhans cells (LC) did not change under these conditions, marked alteration of LC morphology was observed with a significant decrease in area. Recovery of LC was observed within 24 h when the DTH response was also restored. Expression of the calcitonin gene-related peptide (CGRP), which inhibits LC antigen presentation, was significantly increased up to 1.6-fold in nerve fibres of immobilized mice. We conclude that stress-induced suppression of DTH could be due to reduction of LC antigen presentation with morphological change in association with CGRP elevation.

IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: evidence for enhanced cutaneous immunity.

p40, the common subunit of the proinflammatory cytokines IL-12 and IL-23, is produced by resident skin cells. Whereas the in vivo effects of IL-12 are well established, little is known about the role of IL-23 in cutaneous immune responses. In this study we show that p40 transgenic (TG) mice constitutively produce IL-23 (p19/p40), but not IL-12 (p35/p40), in basal keratinocytes by cosecretion of TG p40 with endogenous p19. Repeated injections of rIL-23 in littermate (LM) mice result in an inflammatory skin disease similar to that of p40 TG mice, confirming the proinflammatory activity of IL-23. Furthermore, IL-23 secretion by p40 TG keratinocytes induces elevated numbers of Langerhans cells (LC) with a marked up-regulation of costimulatory molecules, indicating advanced maturation of keratin 14 (K14)/p40 LC when compared with LM LC. At the functional level, freshly isolated K14/p40 LC greatly exceeded LC from LM animals in their capacity to stimulate allogeneic T cell proliferation. To assess whether IL-23 regulates cutaneous immune responses in vivo, we used an allogeneic skin transplantation model. Full thickness skin grafts from K14/p40 donors (H-2(q)) transplanted across a MHC class I and class II barrier onto BALB/c (H-2(d)) recipients were rejected in a significantly accelerated fashion (mean survival time: 8.8 days) when compared with skin grafts from non-TG LM (H-2(q)) (mean survival time: 10.7 days, p < 0.01). Based on these results we propose that IL-23-induced changes of LC may be an important mechanism in directing the outcome of cutaneous immune responses.

Numerical, morphological and phenotypic changes in Langerhans cells in the course of murine graft-versus-host disease.

In the course of graft-versus-host disease (GVHD) or diseases that histologically mimic GVHD (e.g. toxic epidermal necrolysis, Stevens-Johnson syndrome), it is known that epidermal Langerhans cells (LCs) are depleted from the epidermis. However, the mechanism and significance of LC depletion is not well known. To investigate the numerical, morphological and phenotypic changes in LCs and apoptosis of LCs in the course of GVHD using a non-irradiated mouse GVHD model. BALB/c nu/nu mice and C57BL/6 mice were used as recipients and donors, respectively. Recipient mice were injected with T-cell-enriched donor spleen cells. Skin samples were harvested at various times after the inoculation. The numerical and morphological changes were examined by an immunofluorescence study of epidermal sheets. Apoptosis was studied by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labelling method and flow cytometric analysis using annexin V. Phenotypic change was studied by flow cytometric analysis of epidermal cell suspensions. The mixed epidermal cell lymphocyte reaction (MELR) was performed to examine functional changes in the epidermal cells. Five days after inoculation, a graft-versus-host reaction occurred. Epidermal LCs began to decrease from the sixth day. On the fifth day, the LCs became larger and had prominent dendrites. Immediately before the LCs began to decrease, many LCs became round in shape, with scanty dendrites. LC apoptosis was not observed in the epidermis either on the fifth or seventh day. Phenotypically, the expression of CD40, CD80, CD86 and major histocompatibility complex class II antigen on the LCs was upregulated on the fifth and seventh day. Epidermal cells from GVHD mice showed an increased allostimulatory capacity in the secondary MELR. These results suggest that at early GVHD onset, most LCs may not undergo apoptosis in the epidermis but are phenotypically activated, resulting in further activation of alloreactive T cells and aggravation of the disease.

Chronological ageing and photoageing of dendritic cells.

Ageing involves the whole organism, including the immune system. Age-dependent alterations of immune functions are located in both the adaptive and innate parts of the immune system. The most important cell type of the innate immune system are the dendritic cells, because their capacity to induce primary immune responses via professional antigen presentation is crucial for the initiation of the adaptive immune response. Evidence exists that dendritic cells of the systemic immune system, represented by lymph-node and blood-derived dendritic cells, as well as of local immunity, represented by Langerhans cells of the skin, participate in ageing processes. In animal models of older mice, dendritic cells of lymph nodes show degenerative characteristics with decreased adhesion molecule expression, less dendrite formation, and reduced antigen trapping capacity, which together imply disruption of functional activity. In contrast, dendritic cells generated from peripheral blood of elderly people were not impaired in their capacity to induce T-cell responses. Together, these findings indicate that in old individuals in vivo dendritic cells of the systemic immune system are reduced in their functional capacity to stimulate immune responses, whereas in vitro generated dendritic cells are fully functional, and therefore might be used in therapeutic approaches to treat age-associated malfunctions of the immune system. Thus far, only morphological descriptions about age-associated changes of dendritic cells (in particular the Langerhans cells) of the skin exist. In the skin, effects of naturally occurring ageing have to be differentiated from UV-radiation-induced ageing processes. The hallmark of Langerhans cell changes in natural as well as UV-induced skin ageing is their reduction in cell number within the epidermis. In addition, they show an atrophic morphology with less dendrites, and less Birbeck granules. It is assumed that these morphological changes are associated with loss of dendritic cell functions, and that this contributes to age-associated development of skin cancer. Therapeutic strategies against natural and UV-induced skin ageing should include a reduction of these changes of Langerhans cells in order to strengthen the immunological functions of the body's outer surface.