Langerhans Cells In Human Skin Research Articles

609 Far ultraviolet-C radiation from a filtered KrCl lamp does not result in migration of Langerhans cells in human skin

There is global interest in both the beneficial and detrimental health effects of ultraviolet-C (UVC) radiation in the wavelength range 200-230 nm (known as Far-UVC). Technology using Far-UVC is proposed as a highly effective control measure for reducing the transmission of COVID-19. Far-UVC, and other wavelengths of UVC, are well-known to efficiently inactivate pathogens in air and on surfaces. Although studies have shown irradiation of skin with 254 nm UV results in DNA damage in the epidermal basal layer, irradiation with Far-UVC (222 nm) shows minimal DNA damage and only in the granular layer, which is comprised of non-proliferating keratinocytes.

Epicutaneous immunotherapy with peanut directly targets Langerhans cells in human skin

Epicutaneous immunotherapy with peanut directly targets Langerhans cells in human skin

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.

UV Radiation Induces the Epidermal Recruitment of Dendritic Cells that Compensate for the Depletion of Langerhans Cells in Human Skin

UVR causes skin injury and inflammation, resulting in impaired immune function and increased skin cancer risk. Langerhans cells (LCs), the immune sentinels of the epidermis, are depleted for several days following a single UVR exposure and can be reconstituted from circulating monocytes. However, the differentiation pathways leading to the recovery of a normal pool of LCs is still unclear. To study the dynamic changes in human skin with UV injury, we exposed a cohort of 29 healthy human volunteers to a clinically relevant dose of UVR and analyzed sequential epidermal biopsies for changes in leukocyte and dendritic cell (DC) subsets. UV-induced depletion of CD1a(high) LC was compensated by sequential appearance of various epidermal leukocytes. CD14(+) monocytes were recruited as early as D1 post exposure, followed by recruitment of two inflammatory DC subsets that may represent precursors of LCs. These CD1a(low) CD207(-) and the heretofore unknown CD1a(low) CD207(+) DCs appeared at day 1 and day 4 post UVR, respectively, and were endowed with T-cell-activating properties similar to those of LCs. We conclude that recruitment of monocytes and inflammatory DCs appear as a physiological response of the epidermis in order to repair UVR-induced LC depletion associated with immune suppression.

Influenza virus-like particles coated onto microneedles can elicit stimulatory effects on Langerhans cells in human skin

Virus-like particles (VLPs) have a number of features that make them attractive influenza vaccine candidates. Microneedle (MN) devices are being developed for the convenient and pain-free delivery of vaccines across the skin barrier layer. Whilst MN-based vaccines have demonstrated proof-of-concept in mice, it is vital to understand how MN targeting of VLPs to the skin epidermis affects activation and migration of Langerhans cells (LCs) in the real human skin environment. MNs coated with vaccine reproducibly penetrated freshly excised human skin, depositing 80% of the coating within 60 s of insertion. Human skin experiments showed that H1 (A/PR/8/34) and H5 (A/Viet Nam/1203/04) VLPs, delivered via MN, stimulated LCs resulting in changes in cell morphology and a reduction in cell number in epidermal sheets. LC response was significantly more pronounced in skin treated with H1 VLPs, compared with H5 VLPs. Our data provides strong evidence that MN-facilitated delivery of influenza VLP vaccines initiates a stimulatory response in LCs in human skin. The results support and validate animal data, suggesting that dendritic cells (DCs) targeted through deposition of the vaccine in skin generate immune response. The study also demonstrates the value of using human skin alongside animal studies for preclinical testing of intra-dermal (ID) vaccines.

Targeting of antigens to skin dendritic cells: possibilities to enhance vaccine efficacy

Vaccinations in medicine are commonly administered through the skin. Therefore, the vaccine is immunologically processed by antigen-presenting cells of the skin. There is recent evidence that the clinically less often used intradermal route is effective; in cases even superior to the conventional subcutaneous or intramuscular route. Professional antigen-presenting cells of the skin comprise epidermal Langerhans cells (CD207/langerin(+)), dermal langerin(-) and dermal langerin(+) dendritic cells (DCs). In human skin, langerin(-) dermal DCs can be further subdivided on the basis of their reciprocal CD1a and CD14 expression. The relative contributions of these subsets to the generation of immunity or tolerance are still unclear. Langerhans cells in human skin seem to be specialized for induction of cytotoxic T lymphocytes. Likewise, mouse Langerhans cells are capable of cross-presentation and of protecting against experimental tumours. It is desirable to harness these properties for immunotherapy. A promising strategy to dramatically improve the outcome of vaccinations is 'antigen targeting'. Thereby, the vaccine is delivered directly and selectively to defined types of skin DCs. Targeting is achieved by means of coupling antigen to antibodies that recognize cell surface receptors on DCs. This approach is being widely explored. Little is known, however, about the events that take place in the skin and the DCs subsets involved therein. This topic will be discussed in this article.

Gram-positive bacteria enhance HIV-1 susceptibility in Langerhans cells, but not in dendritic cells, via Toll-like receptor activation

AbstractAlthough numerous studies have shown a higher risk of acquiring HIV infection in the presence of other sexually transmitted diseases, the biologic mechanisms responsible for enhanced HIV acquisition are unclear. Because Langerhans cells (LCs) are suspected to be the initial HIV targets after sexual exposure, we studied whether microbial components augment HIV infection in LCs by activating Toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) pattern recognition receptors. We found that TLR1/2 and TLR2/6 agonists dramatically enhanced both HIV susceptibility and replication in immature monocyte-derived LCs, whereas TLR3-5, TLR7-9, and NOD1,2 agonists did not significantly affect HIV infection. The same infection-enhancing effects were observed when LCs were incubated with other related bacterial components as well as with whole Gram+ bacteria. In resident LCs in human skin, TLR2 agonists also significantly increased HIV susceptibility. By contrast, TLR2 agonists and related bacterial components decreased HIV susceptibility in monocyte-derived dendritic cells (DCs). We found that TLR2 activation of LCs, but not DCs, resulted in a significant down-regulation of APOBEC3G, which is a cellular restriction factor for HIV. Given these data, we hypothesize that ligation of TLR2 by Gram+ bacterial products may underlie enhanced sexual transmission of HIV that occurs with concomitant bacterial sexually transmitted disease infections.

Effects of neuropeptides and hormones on Langerhans cells

Significant evidence suggests that the nervous and immune systems have regulatory interactions within the skin. Langerhans cells (LCs) are dendritic antigen‐presenting cells that reside within the epidermis. By laser confocal scanning microscopy, LCs in human skin have been found to be frequently in anatomic association with epidermal nerves. Additionally, a minority of LCs have been found by immunohistochemistry to have the neuropeptide calcitonin gene‐related peptide (CGRP) on or near their cell surfaces. Functional studies have demonstrated that CGRP, pituitary adenylate cyclase‐activating polypeptide, and vasoactive intestinal peptide inhibit antigen presentation by LCs, at least in some assays. Epinephrine and norepinephrine also have been shown to inhibit LC antigen presentation in vitro. Some of these agents appear to exert their effects through regulation of the expression of cytokines and costimulatory molecules. Furthermore, some of these agents inhibit the acquisition of contact hypersensitivity after intradermal administration. As a whole, these findings suggest a regulatory locus of interaction between the immune system and the nervous system within the skin.

It Is True that, when Langerhans Cells Migrate from the Skin to the Lymph Node, They Are Transported via Lymph Vessels

Background: Generally, Langerhans cells deliver antigen information from the skin to the draining lymph nodes via lymph vessels. Methods: By immunohistopathology, we investigated the delivery route of Langerhans cells in human skin using CD1a and S-100 protein antibodies. Results: We noted CD1a- and S-100-positive Langerhans cells in the lymph vessels of the dermis. These were shaped like dendritic cells and presented with some lymphocytes, melanophages, melanin granules and lymph in the same vessels. Conclusion: These observations support the concept that Langerhans cells deliver antigen peptides to regional lymph nodes via afferent lymph vessels.

Topical or oral administration with an extract of Polypodium leucotomos prevents acute sunburn and psoralen‐induced phototoxic reactions as well as depletion of Langerhans cells in human skin

Sunburn, immune suppression, photoaging, and skin cancers result from uncontrolled overexposure of human skin to solar ultraviolet radiation (UVR). Preventive measures, including photoprotection, are helpful and can be achieved by topical sunscreening agents. Polypodium leucotomos (PL) has been used for the treatment of inflammatory diseases and has shown some in vitro and in vivo inmunomodulating properties. Its beneficial photoprotective effects in the treatment of vitiligo and its antioxidant properties encouraged us to evaluate in vivo the potentially useful photoprotective property of natural extract of PL after topical application or oral ingestion. Twenty-one healthy volunteers [either untreated or treated with oral psoralens (8-MOP or 5-MOP)] were enrolled in this study and exposed to solar radiation for evaluation of the following clinical parameters: immediate pigment darkening (IPD), minimal erythema dose (MED), minimal melanogenic dose (MMD), and minimal phototoxic dose (MPD) before and after topical or oral administration of PL. Immunohistochemical assessment of CD1a-expressing epidermal cells were also performed. PL was found to be photoprotective after topical application as well as oral administration. PL increased UV dose required for IPD (P < 0.01), MED (P < 0.001) and MPD (P < 0.001). After oral administration of PL, MED increased 2.8 +/- 0.59 times and MPD increased 2.75 +/- 0.5 and 6.8 +/- 1.3 times depending upon the type of psoralen used. Immunohistochemical study revealed photoprotection of Langherhans cells by oral as well as topical PL. The observed photoprotective activities of oral or topical PL reveal a new avenue in examining the potentially useful field of systemic photoprotection and suggests that PL can be used as adjunct treatment and can make photochemotherapy and phototherapy possibly safe and effective when the control of cutaneous phototoxicity to PUVA or UVB is a limiting factor in such phototherapies.

Distributional changes of Langerhans cells in human skin during irritant contact dermatitis.

We used light and electron microscopic immunocytochemistry to study distributional changes in the human Langerhans cell (LC) system during the first 14 days of a mild irritancy caused by sodium lauryl sulphate (SLS). A marked initial decrease in epidermal LC was noted possibly resulting from migration from the epidermis to the dermis and from irreversible cell damage. Several studies have previously found an unchanged number of LC in SLS-induced contact irritant dermatitis, but these studies may not have taken into account the fact that SLS is effectively absorbed from the test chamber. Unless certain precautions are taken the SLS concentration rapidly falls to topical levels that have no effect on the LC system. Simultaneously with the decrease in the epidermis we observed an increase in dermal CD1a+ cells, confirming an often reported finding. There is, however, no consensus as to the identity of these cells, and several authors have reported that such cells lack LC granules and thus these cells have often been classed as indeterminate cells. We found that, during irritant contact dermatitis, provided an adequate number of sections were scrutinized in the electron microscope, all dermal CD1+ cells contained Birbeck granules.

Recovery Process of Langerhans Cells in Human Skin Following Ultraviolet B Irradiation

Ultraviolet B (UVB) irradiation has been shown to diminish the local density of epidermal Langerhans cells in both animals and humans. The methods employed for these studies have varied widely. Variables include the UVB source and dosage, skin preparations such as epidermal sheets or cell suspensions, and the Langerhans cell markers used for enumeration. However, although the immediate adverse effects of UVB irradiation are well documented, information on the recovery time of Langerhans cells in human skin is not readily available.Human volunteer subjects were irradiated with approximately 2 minimal erythema doses (MEDs) of ultraviolet light from a xenon compact arc solar simulator at time periods of 1, 7, 14, 21, 28, and 35 days before biopsy. Langerhans cells were enumerated using epidermal sheets stained for HLA-DR and CD la markers and were also morphologically evaluated. At 24 hr after irradiation, the number of Langerhans cells was markedly decreased to approximately 60% of normal and their morphology severely altered. These changes were observed after 7 days but showed recovery at 2 weeks after irradiation. After 4-5 weeks after irradiation, the number of Langerhans cells in irradiated sites was back to its normal level.

The Effect of Superficial X‐Radiation on Epidermal Langerhans Cells in Human Skin

Abstract:The anti‐inflammatory effects of superficial x‐radiation may be due, in part, to their depleting effect on the Langerhans cell in the epidermis.

Further Evidence for the Self-Reproducing Capacity of Langerhans Cells in Human Skin

The limited number of Langerhans cells (LC) in the epidermis is one of the main reasons for the technical difficulties in resolving the question of LC kinetics. In the present paper, we describe a method to evaluate the LC replication potential in epidermis. The procedure is based on the specific incorporation of bromodeoxyuridine (BrdU), a thymidine analogue, into the DNA during the S-phase of the cell cycle. Mice, bearing human skin grafts, were injected s.c. every 6 h for up to 17 days with BrdU. At different times, the incorporated BrdU as well as the human epidermal LC were revealed on skin sections using anti-BrdU and OKT-6 monoclonal antibodies, respectively. After 6 h, 4.9% of the LC were labeled with BrdU. Then, the number of OKT-6(+) BrdU(+) cells increased in a linear manner and achieved 34% at 120 h, 67% at 240 h, and 94% at 400 h during the course of continuous labeling procedures. Based on this result we calculated a total cell cycle time of 392 h (16.3 days) and 12 h for the S-phase for human epidermal LC. Applying this technique, we were able to show also that 48 h after local treatment with 12-O-tetradecanoylphorbol-13-acetate or after stripping, the number of BrdU-labeled LC was considerably increased. Furthermore, after i.p. injection of colchicine in the nude mouse, human epidermal LC undergoing mitosis were evidenced by electron microscopy in the graft. From these results we conclude that the LC are actively cycling--therewith a self-reproducing cell population in human epidermis.