The effects of exposure to solar radiation on human health.

This assessment by the Environmental Effects Assessment Panel (EEAP) of the Montreal Protocol under the United Nations Environment Programme (UNEP) evaluates the effects of ultraviolet (UV) radiation on human health within the context of the Montreal Protocol and its Amendments. We assess work published since our last comprehensive assessment in 2018. Over the last four years gains have been made in knowledge of the links between sun exposure and health outcomes, mechanisms, and estimates of disease burden, including economic impacts. Of particular note, there is new information about the way in which exposure to UV radiation modulates the immune system, causing both harms and benefits for health. The burden of skin cancer remains high, with many lives lost to melanoma and many more people treated for keratinocyte cancer, but it has been estimated that the Montreal Protocol will prevent 11 million cases of melanoma and 432 million cases of keratinocyte cancer that would otherwise have occurred in the United States in people born between 1890 and 2100. While the incidence of skin cancer continues to rise, rates have stabilised in younger populations in some countries. Mortality has also plateaued, partly due to the use of systemic therapies for advanced disease. However, these therapies are very expensive, contributing to the extremely high economic burden of skin cancer, and emphasising the importance and comparative cost-effectiveness of prevention. Photodermatoses, inflammatory skin conditions induced by exposure to UV radiation, can have a marked detrimental impact on the quality of life of sufferers. More information is emerging about their potential link with commonly used drugs, particularly anti-hypertensives. The eyes are also harmed by over-exposure to UV radiation. The incidence of cataract and pterygium is continuing to rise, and there is now evidence of a link between intraocular melanoma and sun exposure. It has been estimated that the Montreal Protocol will prevent 63 million cases of cataract that would otherwise have occurred in the United States in people born between 1890 and 2100. Despite the clearly established harms, exposure to UV radiation also has benefits for human health. While the best recognised benefit is production of vitamin D, beneficial effects mediated by factors other than vitamin D are emerging. For both sun exposure and vitamin D, there is increasingly convincing evidence of a positive role in diseases related to immune function, including both autoimmune diseases and infection. With its influence on the intensity of UV radiation and global warming, the Montreal Protocol has, and will have, both direct and indirect effects on human health, potentially changing the balance of the risks and benefits of spending time outdoors.

Linkages between COVID-19, solar UV radiation, and the Montreal Protocol.

There are several connections between coronavirus disease 2019 (COVID-19), solar UV radiation, and the Montreal Protocol. Exposure to ambient solar UV radiation inactivates SARS-CoV-2, the virus responsible for COVID-19. An action spectrum describing the wavelength dependence of the inactivation of SARS-CoV-2 by UV and visible radiation has recently been published. In contrast to action spectra that have been assumed in the past for estimating the effect of UV radiation on SARS-CoV-2, the new action spectrum has a large sensitivity in the UV-A (315-400 nm) range. If this "UV-A tail" is correct, solar UV radiation could be much more efficient in inactivating the virus responsible for COVID-19 than previously thought. Furthermore, the sensitivity of inactivation rates to the total column ozone would be reduced because ozone absorbs only a small amount of UV-A radiation. Using solar simulators, the times for inactivating SARS-CoV-2 have been determined by several groups; however, many measurements are affected by poorly defined experimental setups. The most reliable data suggest that 90% of viral particles embedded in saliva are inactivated within ~ 7 min by solar radiation for a solar zenith angle (SZA) of 16.5° and within ~ 13 min for a SZA of 63.4°. Slightly longer inactivation times were found for aerosolised virus particles. These times can become considerably longer during cloudy conditions or if virus particles are shielded from solar radiation. Many publications have provided evidence of an inverse relationship between ambient solar UV radiation and the incidence or severity of COVID-19, but the reasons for these negative correlations have not been unambiguously identified and could also be explained by confounders, such as ambient temperature, humidity, visible radiation, daylength, temporal changes in risk and disease management, and the proximity of people to other people. Meta-analyses of observational studies indicate inverse associations between serum 25-hydroxy vitamin D (25(OH)D) concentration and the risk of SARS-CoV-2 positivity or severity of COVID-19, although the quality of these studies is largely low. Mendelian randomisation studies have not found statistically significant evidence of a causal effect of 25(OH)D concentration on COVID-19 susceptibility or severity, but a potential link between vitamin D status and disease severity cannot be excluded as some randomised trials suggest that vitamin D supplementation is beneficial for people admitted to a hospital. Several studies indicate significant positive associations between air pollution and COVID-19 incidence and fatality rates. Conversely, well-established cohort studies indicate no association between long-term exposure to air pollution and infection with SARS-CoV-2. By limiting increases in UV radiation, the Montreal Protocol has also suppressed the inactivation rates of pathogens exposed to UV radiation. However, there is insufficient evidence to conclude that the expected larger inactivation rates without the Montreal Protocol would have had tangible consequences on the progress of the COVID-19 pandemic.

Mass cytometry reveals cladribine-induced resets among innate lymphoid cells in multiple sclerosis.

Here we present a comprehensive mass cytometry analysis of peripheral innate lymphoid cell (ILC) subsets in relapsing/remitting MS (RRMS) patients prior to and after onset of cladribine tablets (CladT). ILC analysis was conducted on CyTOF data from peripheral blood mononuclear cells (PBMC) of MS patients before, 2 and 6 months after onset of CladT, and non-MS controls. Dimensionality reduction was used for immunophenotyping ILC subsets. CladT reduced all ILC subsets, except for CD56bright NK cells and ILC2. Furthermore, CD38+ NK cell and CCR6+ ILC3 were excluded from CladT-induced immune cell reductions. Post-CladT replenishment by immature ILC was noted by increased CD5+ ILC1 proportions at 2 months, and boosted CD38-CD56bright NK cell numbers at 6 months. CladT induce immune cell depletion among ILC but exclude CD56bright NK cells and ILC2 subsets, as well as CD38+ NK cell and CCR6+ ILC3 immunophenotypes. Post-CladT ILC expansions indicate ILC reconstitution towards a more tolerant immune system phenotype.

Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2021.

The Environmental Effects Assessment Panel of the Montreal Protocol under the United Nations Environment Programme evaluates effects on the environment and human health that arise from changes in the stratospheric ozone layer and concomitant variations in ultraviolet (UV) radiation at the Earth's surface. The current update is based on scientific advances that have accumulated since our last assessment (Photochem and Photobiol Sci 20(1):1-67, 2021). We also discuss how climate change affects stratospheric ozone depletion and ultraviolet radiation, and how stratospheric ozone depletion affects climate change. The resulting interlinking effects of stratospheric ozone depletion, UV radiation, and climate change are assessed in terms of air quality, carbon sinks, ecosystems, human health, and natural and synthetic materials. We further highlight potential impacts on the biosphere from extreme climate events that are occurring with increasing frequency as a consequence of climate change. These and other interactive effects are examined with respect to the benefits that the Montreal Protocol and its Amendments are providing to life on Earth by controlling the production of various substances that contribute to both stratospheric ozone depletion and climate change.

Environmental effects of stratospheric ozone depletion, UV radiation, and interactions with climate change: UNEP Environmental Effects Assessment Panel, Update 2020.

This assessment by the Environmental Effects Assessment Panel (EEAP) of the United Nations Environment Programme (UNEP) provides the latest scientific update since our most recent comprehensive assessment (Photochemical and Photobiological Sciences, 2019, 18, 595-828). The interactive effects between the stratospheric ozone layer, solar ultraviolet (UV) radiation, and climate change are presented within the framework of the Montreal Protocol and the United Nations Sustainable Development Goals. We address how these global environmental changes affect the atmosphere and air quality; human health; terrestrial and aquatic ecosystems; biogeochemical cycles; and materials used in outdoor construction, solar energy technologies, and fabrics. In many cases, there is a growing influence from changes in seasonality and extreme events due to climate change. Additionally, we assess the transmission and environmental effects of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the COVID-19 pandemic, in the context of linkages with solar UV radiation and the Montreal Protocol.

Environmental effects of stratospheric ozone depletion, UV radiation and interactions with climate change: UNEP Environmental Effects Assessment Panel, update 2019.

This assessment, by the United Nations Environment Programme (UNEP) Environmental Effects Assessment Panel (EEAP), one of three Panels informing the Parties to the Montreal Protocol, provides an update, since our previous extensive assessment (Photochem. Photobiol. Sci., 2019, 18, 595-828), of recent findings of current and projected interactive environmental effects of ultraviolet (UV) radiation, stratospheric ozone, and climate change. These effects include those on human health, air quality, terrestrial and aquatic ecosystems, biogeochemical cycles, and materials used in construction and other services. The present update evaluates further evidence of the consequences of human activity on climate change that are altering the exposure of organisms and ecosystems to UV radiation. This in turn reveals the interactive effects of many climate change factors with UV radiation that have implications for the atmosphere, feedbacks, contaminant fate and transport, organismal responses, and many outdoor materials including plastics, wood, and fabrics. The universal ratification of the Montreal Protocol, signed by 197 countries, has led to the regulation and phase-out of chemicals that deplete the stratospheric ozone layer. Although this treaty has had unprecedented success in protecting the ozone layer, and hence all life on Earth from damaging UV radiation, it is also making a substantial contribution to reducing climate warming because many of the chemicals under this treaty are greenhouse gases.

Exposure to solar ultraviolet radiation limits diet-induced weight gain, increases liver triglycerides and prevents the early signs of cardiovascular disease in mice.

BACKGROUND AND AIMS: Sunlight exposure is associated with a number of health benefits including protecting us from autoimmunity, cardiovascular disease, obesity and diabetes. Animal studies have confirmed that ultraviolet (UV)-B radiation, independently of vitamin D, can limit diet-induced obesity, metabolic syndrome and atherosclerosis. The aim of this study is to investigate whether exposure to the UV radiation contained in sunlight impacts on these disease parameters. METHODS AND RESULTS: We have trialled an intervention with solar UV in obese and atherosclerosis-prone mice. We have discovered that solar-simulated UV can significantly limit diet-induced obesity and reduce atheroma development in mice fed a diet high in sugar and fat. The optimal regime for this benefit was exposure once a week to solar UV equivalent to approximately 30 min of summer sun. Exposure to this optimal dose of solar UV also led to a significant increase in liver triglycerides which may protect the liver from damage. CONCLUSION: Our results show that the UV contained in sunlight has the potential to prevent and treat chronic disease at sites distant from irradiated skin. A major health challenge going forward will be to harness the power of the sun safely, without risking an increase in skin cancers.

Toll-like receptor-induced expression of epithelial cytokine receptors on haemopoietic progenitors is altered in allergic asthma.

BACKGROUND: Haemopoietic progenitor cells (HPC) migrate to sites of allergic inflammation where, upon stimulation with epithelial cytokines, they produce Th2 cytokines and differentiate into mature eosinophils and basophils. They also express Toll-like receptors (TLR) involved in antimicrobial responses. OBJECTIVE: The objective of this study was to compare TLR expression on peripheral blood HPC and TLR-induced responses, in particular changes in epithelial cytokine receptors, in healthy and asthmatic subjects at baseline and following allergen challenge. METHODS: Ten healthy and 11 allergic asthmatic subjects were studied. HPC-enriched cell populations were stimulated with TLR-2, TLR-4 or TLR-9 ligands. TLR expression by circulating HPC and interleukin (IL)-25 (IL-17RB), IL-33 (ST2) and thymic stromal lymphopoietin receptor (TSLPR) expression after TLR ligation were examined by flow cytometry at baseline and, in asthmatics, following allergen challenge. The effects of dexamethasone (Dex) on TLR-induced responses were also assessed. RESULTS: Asthmatics had significantly lower circulating HPC expressing TLR-2 and TLR-9 with a similar trend for TLR-4. TLR-4 stimulation of HPC yielded higher numbers of TSLPR+ cells in asthmatics compared with healthy subjects. A similar trend was seen for TLR-9 ligation, an effect further augmented by allergen inhalation. Allergen challenge also enhanced TLR-induced ST2 expression on HPC. Treatment with Dex in vitro increased TLR-4-induced TSLPR expression but had no effect on other epithelial cytokine receptors. CONCLUSIONS AND CLINICAL RELEVANCE: These data demonstrate an interaction between allergen and TLR ligand exposure in asthmatics. Allergen inhalation augments the TLR-induced inflammatory response by HPC, possibly leading to increased "in situ haemopoiesis" through up-regulation of TSLPR. These findings show that HPC may be a part of the pro-inflammatory cascade in pathogen-induced asthma exacerbation through their increased responsiveness to TLR stimulation.

Levels and function of regulatory T cells in patients with polymorphic light eruption: relation to photohardening.

BACKGROUND: We hypothesized that regulatory T cells (Tregs) are involved in the immunological abnormalities seen in patients with polymorphic light eruption (PLE). OBJECTIVES: To investigate the number and suppressive function of peripheral Tregs in patients with PLE compared with healthy controls. METHODS: Blood sampling was done in 30 patients with PLE [seeking or not seeking 311-nm ultraviolet (UV)B photohardening] as well as 19 healthy controls at two time points: TP1, March to June (before phototherapy); and TP2, May to August (after phototherapy). We compared the number of CD4(+) CD25(high) CD127(-) FoxP3(+) Tregs by flow cytometry and their function by assessing FoxP3 mRNA levels and effector T cell/Treg suppression assays. RESULTS: Tregs isolated from healthy controls significantly suppressed the proliferation of effector T cells at TP1 by 68% (P = 0·0156). In contrast, Tregs from patients with PLE entirely lacked the capacity to suppress effector T-cell proliferation at that time point. The medical photohardening seen in 23 patients with PLE resulted in a significant increase in the median percentage of circulating Tregs [both as a proportion of all lymphocytes; 65 6% increase (P = 0·0049), and as a proportion of CD4(+) T cells; 32.5% increase (P = 0·0049)]. This was accompanied by an increase in the expression of FoxP3 mRNA (P = 0·0083) and relative immunosuppressive function of Tregs (P = 0·083) comparing the two time points in representative subsets of patients with healthy controls tested. Seven patients with PLE not receiving 311-nm UVB also exhibited an increase in the number of Tregs but this was not statistically significant. No significant differences in Treg numbers were observed in healthy subjects between the two time points. CONCLUSIONS: An impaired Treg function is likely to play a role in PLE pathogenesis. A UV-induced increase in the number of Tregs (either naturally or therapeutically) may be a compensatory mechanism by which the immune system counteracts the susceptibility to PLE.

Randomized double-blinded placebo-controlled intra-individual trial on topical treatment with a 1,25-dihydroxyvitamin D3 analogue in polymorphic light eruption.

BACKGROUND: Polymorphic light eruption (PLE) is a very frequent photodermatosis whose pathogenesis may involve resistance to ultraviolet (UV)-induced immune suppression. Similar to UV radiation, calcitriol (1,25-dihydroxyvitamin D3) and its analogues such as calcipotriol have been shown to exhibit immunosuppressive properties. OBJECTIVES: We performed a randomized double-blinded placebo-controlled intraindividual half-body trial (NCT00871052) to investigate the preventive effect of a calcipotriol-containing cream in PLE. METHODS: Thirteen patients with PLE (10 women, three men; mean age 37 years) pretreated their skin on two symmetrically located test fields with calcipotriol or placebo cream twice daily for 7 days before the start of photoprovocation testing with solar-simulated UV radiation. We established a specific PLE test score [AA + SI + 0·4 P (range 0-12), where AA is affected area score (range 0-4), SI is skin infiltration score (range 0-4) and P is pruritus score on a visual analogue scale (range 0-10)] to quantify PLE severity. RESULTS: Photoprovocation led to PLE lesions in 12/13 (92%) patients. As shown by the PLE test score, compared with placebo calcipotrial pretreatment significantly reduced PLE symptoms in average by 32% (95% confidence interval 21-44%; P = 0·0022, exact Wilcoxon signed-rank test) throughout the observation period starting at 48 h until 144 h after the first photoprovocation exposure. At 48, 72 and 144 h calcipotriol pretreatment resulted in a lower PLE test score in 7 (58%), 9 (75%) and 10 (83%) of the 12 cases, respectively. Considering all time points together, calcipotriol diminished the PLE test score in all 12 photoprovocable patients (P = 0·0005; Wilcoxon signed-rank test). CONCLUSIONS: These results suggest a potential therapeutic benefit of topical 1,25-dihydroxyvitamin D3 analogues as prophylactic treatment in patients with PLE.

Interleukin-1beta but not tumor necrosis factor is involved in West Nile virus-induced Langerhans cell migration from the skin in C57BL/6 mice.

Langerhans cells are bone marrow-derived epidermal dendritic cells. They migrate out of the epidermis into the lymphatics and travel to the draining lymph nodes where they are responsible for the activation of T cells in the primary immune response. Tumor necrosis factor and interleukin-1beta, have previously been shown to be responsible for Langerhans cell migration in response to contact sensitizers in BALB/C mice; however, which cytokines are responsible for mediating Langerhans cell migration in response to a replicating cutaneously acquired virus such as the West Nile Virus, are not known. We have devised a method for identifying Langerhans cells in the draining lymph nodes using E-cadherin labeling and flow cytometry. We infected tumor necrosis factor-deficient gene knockout mice (tumor necrosis factor-/-) intradermally with West Nile Virus and found that levels of Langerhans cell emigration and accumulation in the draining lymph nodes were similar to wild-type C57BL/6 mice. This was borne out by the finding that high levels of systemic neutralizing anti-tumor necrosis factor antibody failed to inhibit the migration of Langerhans cells from the epidermis and their accumulation in the draining lymph nodes in wild-type C57BL/6 mice. In West Nile Virus-infected, tumor necrosis factor-/- mice treated with systemic neutralizing anti-interleukin-1beta antibodies, however, migration of Langerhans cells from the epidermis and their accumulation in the draining lymph nodes were significantly inhibited compared with control antibody-treated, infected animals. The results indicate that Langerhans cell migration, accumulation in the draining lymph nodes and the initiation of lymph node shut-down in response to a cutaneous West Nile Virus infection is dependent on interleukin-1beta and can occur in the absence of tumor necrosis factor.