Photoimmunosuppression

Ultraviolet (UV) radiation can exert a variety of biological effects, including induction of skin cancer, premature skin ageing and inhibition of the immune system. The immunosuppressive properties of UV radiation are of major biological relevance since suppression of the immune system by UV radiation is not only responsible for the exacerbation of infectious diseases following UV exposure, but also contributes to the induction of skin cancer. Hence, understanding of the mechanisms by which UV radiation compromises the immune system is of primary importance. UV radiation suppresses the immune system in multiple ways. It inhibits antigen presentation, stimulates the release of immunosuppressive cytokines and induces the generation of lymphocytes of the suppressor subtype. In the following, some of the basic mechanisms underlying UV-induced immunosuppression will be discussed.     

Lichtschutz: Möglichkeiten und Grenzen

Protection against ultraviolet (UV) irradiation prevents from the development of acute skin damage such as erythema formation and chronic skin changes such as premature skin ageing. Especially those sunscreens with higher sun protection factors do not only protect against solar dermatitis but also inhibit UV‐induced immunosuppression by blocking the release of immunosuppressive mediators from UV‐exposed epidermis. In particular, the protection against UV‐induced immunosuppression by sunscreens is supposed to reduce the development of UV‐induced skin cancer. Besides immunosuppression UV‐irradiation is also able to induce “UV signature” mutations within UV‐exposed DNA. Topical application of DNA repair enzymes induces nucleotide excision repair and corrections of DNA damages. Thereby, the risk to develop UV‐induced skin malignancies is markedly reduced. Accordingly, future perspectives in the development of sunscreens include DNA repair enzymes or factors, which can induce the endogenous cellular DNA repair system. Until these developments come to practice reasonable sun protection according to the skin complexion is of primary importance.     

Mechanisms involved in ultraviolet light-induced immunosuppression

Ultraviolet radiation (UV) represents one of the most important environmental factors affecting human health, especially with regard to its hazardous effects on the generation of skin cancer, suppression of the immune system and premature skin aging. At molecular level, various chromophores have been identified, and DNA remains the major chromophore in the skin. Epidermal Langerhans cells (LC) are considered as the main targets of UV, as UV inhibits their antigen-presenting activity and their capacity to stimulate allogeneic type 1 T cells. Keratinocytes are also a target of UV light and they produce and release numerous soluble and immunosuppressive mediators. In human skin, IL-10 is mainly produced by dermis CD11b + macrophages and neutrophils that infiltrate epidermis after intense UV. UV-induced immunosuppression is transferable with suppressor T cells whose phenotype is still debated (Natural Killer T cells and T regulatory type 1 cells). Although the mechanisms by which immune regulatory suppressor T cells act still remain unclear, there is increasing evidence that apoptosis of epidermal LC or reactive T cells may play an important role through the Fas/FasL system.     

UV‐induzierte regulatorische T‐Zellen

Regulatory T cells belong to a subset of T lymphocytes which suppress immune reactions in an antigen‐specific fashion. Regulatory T cells play an important role in the prevention of autoimmune diseases. Ultraviolet (UV) radiation suppresses the immune system in antigen‐specific fashion. This effect is mediated by UV‐induced regulatory T cells. UV‐induced regulatory T cells express CD4 and CD25 and upon activation release the immunosuppressive cytokine interleukin‐10. 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. The further characterisation of these cells will determine whether they can be applied in the future therapeutically with the ultimate aim to induce specific immunosuppression.     

Roles of the immune system in skin cancer

Over the past several decades, there has been increasing interest in understanding the roles of the immune system in the development and progression of cancer. The importance of the immune system in human skin cancer has been long recognized based primarily upon the increased incidence of skin cancers in organ transplant recipients and mechanisms of ultraviolet (UV) radiation-mediated immunomodulation. In this review, we integrate multiple lines of evidence highlighting the roles of the immune system in skin cancer. First, we discuss the concepts of cancer immunosurveillance and immunoediting as they might relate to human skin cancers. We then describe the clinical and molecular mechanisms of skin cancer development and progression in the contexts of therapeutic immunosuppression in organ transplant recipients, viral oncogenesis, and UV radiation-induced immunomodulation with a primary focus on basal cell carcinoma and squamous cell carcinoma. The clinical evidence supporting expanding roles for immunotherapy is also described. Finally, we discuss recent research examining the functions of particular immune cell subsets in skin cancer and how they might contribute to both antitumour and protumour effects. A better understanding of the biological mechanisms of cancer immunosurveillance holds the promise of enabling better therapies.     

Ultraviolet irradiation, systemic immunosuppression and skin cancer: role of urocanic acid

Ultraviolet (UV) radiation, particularly in the UVB region (280-320 nm), is immunosuppressive. This modulation of the immune response to antigens following UV irradiation allows the outgrowth of UV-induced skin cancers. Because UV irradiation penetrates only a few millimetres into the skin, yet can induce not only a local but also a systemic immunosuppression, the transducing mechanisms must be superficially located. Three mechanisms have been put forward, one which identifies epidermal urocanic acid as the photoreceptor, one that identifies DNA, and one that identifies cell membrane lipid peroxidation as initiating immunomodulation. While a number of mechanisms may operate (or cooperate), and do so differentially for local vs systemic suppression, considerable evidence supports urocanic acid as a key photoreceptor for immunosuppression. This review examines the immunomodulatory effects of urocanic acid, as well as its role in facilitating the outgrowth of UV-induced skin cancer.     

Ultraviolet-induced alloantigen-specific immunosuppression in transplant immunity

After the first observation of the immunosuppressive effects of ultraviolet(UV) irradiation was reported in 1974, therapeutic modification of immune responses by UV irradiation began to be investigated in the context immunization. UV-induced immunosuppression is via the action of regulatory T cells(Tregs). Antigen-specific Tregs were induced by high-dose UV-B irradiation before antigen immunization in many studies, as it was considered that functional alteration and/or modulation of antigen-presenting cells by UV irradiation was required for the induction of antigen-specific immunosuppression. However, it is also reported that UV irradiation after immunization induces antigen-specific Tregs. UV-induced Tregs are also dominantly transferable, with interleukin-10 being important for UV-induced immunosuppression. Currently, various possible mechanisms involving Treg phenotype and cytokine profile have been suggested. UV irradiation accompanied by alloantigen immunization induces alloantigen-specific transferable Tregs, which have potential therapeutic applications in the transplantation field. Here we review the current status of UV-induced antigen-specific immunosuppression on the 40th anniversary of its discovery.     

Skin Immune Systems and Inflammation: Protector of the Skin or Promoter of Aging?

The immune system may either have a protective role against sunburn and skin cancer or, conversely, promote solar damage. The skin is poised to react to infections and injury, such as sunburn, with rapidly acting mechanisms (innate immunity) that precede the development of acquired immunity and serve as an immediate defense system. Some of these mechanisms, including activation of defensins and complement, modify subsequent acquired immunity. An array of induced immune-regulatory and pro-inflammatory mediators is evident, at the gene expression level, from the microarray analysis of both intrinsically aged and photoaged skin. Thus, inflammatory mechanisms may accentuate the effect of UV radiation to amplify direct damaging effects on molecules and cells, including DNA, proteins, and lipids, which cause immunosuppression, cancer, and photoaging. A greater understanding of the cutaneous immune system's response to photo-skin interactions is essential to comprehensively protect the skin from adverse solar effects. Sunscreen product protection measured only as reduction in redness (current "sun" protection factor) may no longer be sufficient, as it is becoming clear that protection against UV-induced immune changes is of equal if not of greater importance. Greater knowledge of these processes will also enable the development of improved strategies to repair photodamaged skin.     

Molecular determinants of UV-induced immunosuppression

Abstract: It is almost three decades ago that it was discovered that ultraviolet radiation (UV) can compromise the immune system. UV suppresses immune responses in several ways. It inhibits the function of antigen-presenting cells, induces T cells with suppressor activity and induces the release of immunosuppressive cytokines. The latter phenomenon is mainly responsible for systemic immunosuppression. Although UV can also target cytoplasmic and cell membrane components, UV-induced DNA damage has been recognized as the most important molecular structure in mediating UV-induced immunosuppression. Recently, it was observed that interleukin-12 (IL-12), which antagonizes UV-induced immunosuppression, can accelerate the removal of UV-induced DNA lesions, probably via inducing DNA repair. Hence, it is tempting to speculate that the activity of IL-12 to reduce UV-induced immunosuppression may be due at least partially to this new biological activity of IL-12.     

Calcineurin inhibitor (CNI)-associated skin cancers: New insights on exploring mechanisms by which CNIs downregulate DNA repair machinery

The use of the calcineurin inhibitors (CNI) cyclosporine (CsA) and tacrolimus remains a cornerstone in post-transplantation immunosuppression. Although these immunosuppressive agents have revolutionized the field of transplantation medicine, its increased skin cancer risk poses a major concern. A key contributor to this phenomenon is a reduced capacity to repair DNA damage caused by exposure to ultraviolet (UV) wavelengths of sunlight. CNIs decrease DNA repair by mechanisms that remain to be fully explored. Though CsA is known to decrease the abundance of key DNA repair enzymes, less is known about how tacrolimus yields this effect. CNIs hold the capacity to inhibit both of the main catalytic calcineurin isoforms (CnAα and CnAβ). However, it is unknown which isoform regulates UV-induced DNA repair, which is the focus of this review. It is with hope that this insight spurs investigative efforts that conclusively addresses these gaps in knowledge. Additionally, this research also raises the possibility that newer CNIs can be developed that effectively blunt the immune response while mitigating the incidence of skin cancers with immunosuppression.     

Dermal mast cells affect the development of sunlight-induced skin tumours

Ultraviolet (UV) radiation contained in sunlight is considered a major risk in the induction of skin cancer. While mast cells are best known for their role in allergic responses, they have also been shown to play a crucial role in suppressing the anti-tumour immune response following UV exposure. Evidence is now emerging that UV may also trigger mast cell release of cutaneous tissue remodelling and pro-angiogenic factors. In this review, we will focus on the cellular and molecular mechanisms by which UV recruits and then activates mast cells to initiate and promote skin cancer development.     

An action spectrum for ultraviolet radiation-induced immunosuppression in humans

Background The immune‐suppressive effects of sunlight play a central role in skin carcinogenesis. Ultraviolet (UV) B radiation is highly immunosuppressive even at suberythemal doses, and longwave UVA is now also recognized to cause immunosuppression in humans. The relative contributions of UVA and UVB to immunosuppression by incidental daily sun exposure are, however, unclear. Objectives We previously determined wavelength dependencies for immunosuppression by UVB and UVA wavebands in humans. We now aimed to calculate relative and solar immune‐suppressive effectiveness across the UVB and UVA spectra. Methods We used the nickel model of recall contact hypersensitivity to determine UV immunosuppression dose responses and minimum immune suppression doses (MISDs) at 11 narrowbands from 289 to 392 nm. The relative immune‐suppressive effectiveness of each narrowband was then determined as 1/MISD vs. wavelength. This curve was multiplied by the solar spectrum to show the relative immune‐suppressive effectiveness of each waveband in sunlight. Results We found peaks of immune‐suppressive effectiveness in the UVB waveband at 300 nm and in the UVA at 370 nm. Because of the far greater amount of longwave UVA in sunlight, the relative solar immune‐suppressive effectiveness of UVA was threefold higher than that of UVB at doses equivalent to sun exposure from normal daily activities. Conclusions Longwave UVA, which abuts the visible light spectrum and is less effectively filtered by sunscreens than UVB, is likely to be the largest contributor to immunosuppression resulting from incidental daily sun exposure.     

Topical calcitriol protects from UV‐induced genetic damage but suppresses cutaneous immunity in humans

Please cite this paper as: Topical calcitriol protects from UV‐induced genetic damage but suppresses cutaneous immunity in humans. Experimental Dermatology 2010; 19 : e23‐e30. Abstract: Calcitriol, the biologically active form of vitamin D, has been reported to cause both suppressive and protective immune effects in mice. Its immune effects in vivo in humans are unclear. We investigated the in vivo effects of topical calcitriol on minimal erythema dose and skin immune responses in healthy volunteers. We found that calcitriol did not protect from ultraviolet (UV)‐induced erythema (sunburn) when applied either 24 h before or immediately after irradiation, although it decreased the density of sunburn cells and thymine dimers seen on biopsy when applied 24 h before and again immediately after irradiation. Using the Mantoux reaction as a model of skin immunity, we found that topical calcitriol applied at high total doses reduced the Mantoux responses of nearby untreated, unirradiated skin, suggesting a para‐local or systemic immunosuppressive effect not observed with lower calcitriol doses. We then measured UV‐induced suppression of Mantoux reactions at vehicle‐treated sites and sites treated with low‐dose calcitriol, and found that calcitriol neither reduced nor enhanced UV‐induced immunosuppression. Despite calcitriol reducing UV‐induced DNA damage, which should protect the immune system, it has immunosuppressive effects in our model which may help to explain the efficacy of analogues such as calcipotriol in the treatment of psoriasis.     

Photoschädigung und Photoalterung – Prävention und Behandlung

The exposure of human skin to environmental and artificial ultraviolet irradiation has increased significantly. This is not only due to an increased solar UV irradiation as a consequence of the stratospheric ozone depletion, but also the result of an inappropriate social behaviour with the use of tanning parlors being very popular. Besides this, leisure activities and living style with travelling to equatorial regions also add to the individual annual UV load. Since the population in industrialised countries shows an increasing total life span, in parallel the cumulative life time dose of solar and artificial UV‐irradiation is dramatically augmented. In addition to the common longterm detrimental effects like immunosuppression and skin cancer, the photooxidative damage due to energy absorption of UV photons in an oxygenized environment leads to alterations of cells, subcellular compartments and macromolecules. The clinical manifestations of UV/ROS induced disturbances result in photoaged skin with wrinkle formation, laxity, leathery appearence as well as fragility, impaired wound healing and higher vulnerability. Strategies to prevent or to minimize photoaging and intrinsic aging of the skin necessarily include protection against UV irradiation and antioxidant homoeostasis. New developments of therapeutic interventions including DNA repair enzymes will be discussed.     

Immune protective effect of a moisturizer with DNA repair ingredients

Ultraviolet (UV) light damages DNA and impairs immune surveillance. The faulty repair of DNA after UV exposure is associated with immune suppression and facilitates photodamage that leads to photoaged skin and the growth of skin cancer. Sunscreens have been developed to filter UV light from entering the skin, but are not beneficial once DNA damage has occurred. Enhancing DNA repair after UV radiation may provide added advantage and prevent UV immunosuppression. This study was performed to determine whether a product with DNA repair ingredients prevents UV-induced suppression of contact hypersensitivity responses in vivo . Solar simulated radiation was delivered on skin with and without topical treatment with a moisturizer containing DNA repair enzymes (Advanced Night Repair Concentrate). Subjects were then sensitized to the hapten dinitrochlorobenzene, and the level of resultant contact hypersensitivity response was elicited 2 weeks later. Contact hypersensitivity response measured by skin fold thickness was significantly suppressed in untreated UV-irradiated subjects but not in subjects treated with DNA repair moisturizer after solar simulated radiation. Our results indicate that DNA repair ingredients significantly prevent UV-induced immune suppression.     

The beneficial role of functional food components in mitigating ultraviolet‐induced skin damage

Excessive exposure to ultraviolet (UV) radiation can chemically alter biological molecules and is one of the major environmental health risks with potential to damage the structure and function of the skin. Numerous dietary supplements are known to optimize the skin's defenses against radiation exposure. Several studies in which the beneficial roles of functional food components, that can protect against UV‐induced skin damage, have been demonstrated. Supplemental dietary sphingomyelin maintains covalently bound ω‐hydroxy ceramides to avert skin barrier defects after UVB irradiation. The oral administration of collagen hydrolysates has been shown to limit decreases in skin elasticity via increases in the dermal hyaluronic acid content. Milk fermented with lactic acid bacteria has been shown to augment DNA repair mechanisms and improve skin immunity in the aftermath of UVB damage. Furthermore, long‐term ingestion of fermented milk containing lactic acid bacteria, collagen hydrolysates and sphingomyelin increases the minimal erythema dose (MED) in human subjects with moderate sunburn or redness and tanned skin after exposure to UV solar radiation. Thus, products containing these functional food components are one means by which the adverse effects of UV radiation on the skin can be mitigated.     

Role of IL‐10 and TGF‐β in melanoma

IL‐10 and TGF‐β are immunosuppressive cytokines expressed in tumors including melanoma and, therefore, deemed major cause for failing antitumor immune responses. Re‐evaluating their role, we compared their expression by quantitative RT‐PCR in melanoma and skin of healthy individuals, tested their induction in dendritic cells and T cells co‐cultured with tumor cells, and their effects on the immune cells. Both cytokines as well as their receptors were expressed in melanoma at significantly lower levels than in healthy skin. Consequently, the expressions of IL‐10‐responsive SOCS‐3 and TGF‐β‐responsive Smad‐7 were low in tumors but high in healthy skin. T cells co‐cultured with tumor cells developed an anergic state without increased IL‐10 or TGF‐β expression. In vitro tumor‐induced immature dendritic cells produced high IL‐10 levels and less efficiently induced T‐cell proliferation. Nonetheless, they could be induced to mature, and blocking IL‐10 did not alter the capacity of the resulting mature dendritic cells to stimulate T cells. Mature dendritic cells co‐cultured with tumor cells produced increased IL‐10 but decreased TGF‐β and more efficiently induced T‐cell proliferation. The lack of correlation of IL‐10 and TGF‐β with immune deficits in situ and in vitro suggests re‐evaluating their roles in cancer.     

Klinik und Pathogenese UV‐induzierter Pigmentveränderungen

Solar and ultraviolet (UV) radiation, respectively, are the strongest stimuli for the induction of pigmentation in human skin. UV radiation induces pigmentation by exerting direct and indirect effects on melanocytes. Melanogenesis is a very complex process whose molecular mechanisms are not yet completely understood. Acute UV exposure induces the non‐protective immediate pigment darkening as well as delayed tanning which exerts photoprotective effects. Chronic UV exposure causes permanent pigmentary changes by inducing solar lentigines and pigmented actinic keratoses as well hypopigmentated areas. Artificial UV irradiation (UVA, PUVA) can also induce pigmentary disorders, including lentigines. Since the therapeutic options for UV‐induced pigmentary changes are limited consequent protection as a prophylactic measure is recommended.     

Oral and systemic photoprotection

Photoprotection can be provided not only by ultraviolet (UV) blockers but also by oral substances. Epidemiologically identified associations between foods and skin cancer and interventional experiments have discovered mechanisms of UV skin damage. These approaches have identified oral substances that are photoprotective in humans. UV inhibits adenosine triphosphate (ATP) production causing an energy crisis, which prevents optimal skin immunity and DNA repair. Enhancing ATP production with oral nicotinamide protects from UV immunosuppression, enhances DNA repair and reduces skin cancer in humans. Reactive oxygen species also contribute to photodamage. Nontoxic substances consumed in the diet, or available as oral supplements, can protect the skin by multiple potential mechanisms. These substances include polyphenols in fruit, vegetables, wine, tea and caffeine‐containing foods. UV‐induced prostaglandin E₂ (PGE₂) contributes to photodamage. Nonsteroidal anti‐inflammatory drugs and food substances reduce production of this lipid mediator. Fish oils are photoprotective, at least partially by reducing PGE₂. Orally consumed substances, either in the diet or as supplements, can influence cutaneous responses to UV. A current research goal is to develop an oral supplement that could be used in conjunction with other sun protective strategies in order to provide improved protection from sunlight.