Major climate change-induced risks to human health in South Africa.

There are many climatic changes facing South Africa which already have, or are projected to have, a detrimental impact on human health. Here the risks to health due to several alterations in the climate of South Africa are considered in turn. These include an increase in ambient temperature, causing, for example, a significant rise in morbidity and mortality; heavy rainfall leading to changes in the prevalence and occurrence of vector-borne diseases; drought-associated malnutrition; and exposure to dust storms and air pollution leading to the potential exacerbation of respiratory diseases. Existing initiatives and strategies to prevent or reduce these adverse health impacts are outlined, together with suggestions of what might be required in the future to safeguard the health of the nation. Potential roles for the health and non-health sectors as well as preparedness and capacity development with respect to climate change and health adaptation are considered.

Are there differences in immune responses following delivery of vaccines through acutely or chronically sun-exposed compared with sun-unexposed skin?

The majority of human vaccines are administered above the deltoid muscle of the arm, a site that is chronically sun-exposed in many people. It is known that exposure of the skin to the UV wavelengths in sunlight stimulates systemic immunosuppression, an outcome that is associated with reduced immunity to microbial infections in animal models. Here we consider whether immunization of humans through a UV-irradiated skin site will lead to a less effective immune response compared with immunization through an unexposed site. Studies showing that the efficacy of vaccination can be reduced when surrogates of increased levels of sun exposure, such as latitude of residence and season of the year, are considered. Results from a limited number of intervention experiments in humans demonstrate a similar pattern. To provide an explanation for these findings, changes in the number and functional potential of immune cells in chronically sun-exposed compared with unexposed skin are outlined. UV radiation-induced changes to skin cells are also relevant when considering skin sites for administration of immune-tolerizing peptides. The review provides the basis for further research into the effects of acute and chronic UV radiation exposure on skin cells in the context of vaccination.

Trends in Melanoma Mortality in the Population Groups of South Africa.

The incidence of cutaneous melanoma (CM) is increasing in countries around the world. However, little is known about melanoma trends in African countries by population group. We studied CM mortality in South Africa from 1997 to 2014 to partly address this knowledge gap. Unit record mortality data for all South Africans who died from CM (n = 8,537) were obtained from Statistics South Africa. Join-point regression models were used to assess whether there was a statistically significant change in the direction and/or magnitude of the annual trends in CM mortality. A significant increasing trend of 11% per year was observed in age-adjusted mortality rates in men between 2000 and 2005 (p < 0.01), rising from 2 to 3 per 100,000. There was also a statistically significant increase of 180% per year among White South Africans from 1997 to 1999 (p < 0.05) and of 3% from 1999 to 2014 (p < 0.01). These results may be used to inform CM awareness campaigns and will motivate efforts to improve the collection and analysis of relevant statistics regarding the present burden of CM in South Africa.

Ultraviolet radiation-induced immunosuppression and its relevance for skin carcinogenesis.

The realisation that UV radiation (UVR) exposure could induce a suppressed immune environment for the initiation of carcinogenesis in the skin was first described more than 40 years ago. Van der Leun and his colleagues contributed to this area in the 1980s and 90s by experiments in mice involving UV wavelength and dose-dependency in the formation of such tumours, in addition to illustrating both the local and systemic effect of the UVR on the immune system. Since these early days, many aspects of the complex pathways of UV-induced immunosuppression have been studied and are outlined in this review. Although most experimental work has involved mice, it is clear that UVR also causes reduced immune responses in humans. Evidence showing the importance of the immune system in determining the risk of human skin cancers is explained, and details of how UVR exposure can down-regulate immunity in the formation and progression of such tumours reviewed. With increasing knowledge of these links and the mechanisms of UVR-induced immunosuppression, novel approaches to enhance immunity to skin tumour antigens in humans are becoming apparent which, hopefully, will reduce the burden of UVR-induced skin cancers in the future.

Solar ultraviolet radiation in Africa: a systematic review and critical evaluation of the health risks and use of photoprotection.

Most information on the harmful health effects of solar ultraviolet radiation (UVR) has been obtained in populations in which the majority has fair skin. Here a systematic review of evidence on diseases related to solar UVR in Africa was undertaken, and the appropriateness of effective photoprotection for these people considered. There are few population-based studies on UV-induced skin cancers (melanoma, squamous and basal cell carcinomas) in Africa, although limited reports indicated that they occur, even in people with deeply pigmented skin. The incidence of melanoma is particularly high in the white population living in the Western Cape of South Africa and has increased significantly in recent years. Cataract is extremely common in people of all skin colours and is a frequent cause of blindness, particularly in the elderly. For both skin cancer and cataract, the proportion of the disease risk that is attributable to exposure to solar UVR in African populations, and therefore the health burden caused by UV irradiation is unclear. There was little published information on the use of sun protection in Africa. The potential disease burden attributable to solar UVR exposure of Africans is high, although accurate data to quantify this are sparse. Information is required on the incidence, prevalence and mortality for the range of UV-related diseases in different populations living throughout Africa. Photoprotection is clearly required, at least for those subpopulations at particularly high risk, but may be limited by cost and cultural acceptability.

A systematic review of the influence of skin pigmentation on changes in the concentrations of vitamin D and 25-hydroxyvitamin D in plasma/serum following experimental UV irradiation.

Defining whether skin pigmentation influences vitamin D photosynthesis is important for delivering accurate public health messages. Current evidence is contradictory. We undertook a systematic review of the published literature to examine the association between skin pigmentation and change in blood concentrations of vitamin D and 25-hydroxyvitamin D following experimental UV irradiation. Twelve studies fulfilled the inclusion criteria: human study in vivo with non-diseased participants; controlled artificial UV radiation; vitamin D or 25-hydroxyvitamin D measured in serum or plasma; full text in English. In seven studies, vitamin D photosynthesis was reduced in dark-skinned compared with fairer-skinned individuals. In the remaining five studies, only one of which was published after 1990, there was no difference in vitamin D photosynthesis according to skin type. The disparities in these results may be due to small sample sizes and variations in study methodology, including the source, dose and frequency of UV irradiation, phototype classification, and analysis of vitamin D and 25-hydroxyvitamin D. Of these, the spectrum emitted by the UV lamps may be significant. No study considered potential modifying factors, such as relevant genetic polymorphisms. On balance, we conclude that pigmented skin has less effective photoproduction of vitamin D and 25-hydroxyvitamin D. The quantity of sun exposure needed for dark-skinned, compared with light-skinned, people to achieve vitamin D sufficiency remains uncertain.

Altered immunity and dendritic cell activity in the periphery of mice after long-term engraftment with bone marrow from ultraviolet-irradiated mice.

Alterations to dendritic cell (DC) progenitors in the bone marrow (BM) may contribute to long-lasting systemic immunosuppression (>28 d) following exposure of the skin of mice to erythemal UV radiation (UVR). DCs differentiated in vitro from the BM of mice 3 d after UVR (8 kJ/m(2)) have a reduced capacity to initiate immunity (both skin and airways) when adoptively transferred into naive mice. Studies in IL-10(-/-) mice suggested that UV-induced IL-10 was not significantly involved. To investigate the immune capabilities of peripheral tissue DCs generated in vivo from the BM of UV-irradiated mice, chimeric mice were established. Sixteen weeks after reconstitution, contact hypersensitivity responses were significantly reduced in mice reconstituted with BM from UV-irradiated mice (UV-chimeric). When the dorsal skin of UV-chimeric mice was challenged with innate inflammatory agents, the hypertrophy induced in the draining lymph nodes was minimal and significantly less than that measured in control-chimeric mice challenged with the same inflammatory agent. When DCs were differentiated from the BM of UV-chimeric mice using FLT3 ligand or GM-CSF + IL-4, the cells maintained a reduced priming ability. The diminished responses in UV-chimeric mice were not due to different numerical or proportional reconstitution of BM or the hematopoietic cells in blood, lymph nodes, and skin. Erythemal UVR may imprint a long-lasting epigenetic effect on DC progenitors in the BM and alter the function of their terminally differentiated progeny.

The incidence and body site of skin cancers in the population groups of South Africa.

BACKGROUND/PURPOSE: Data regarding basal cell carcinoma (BCC), squamous cell carcinoma of the skin (SSCC) and cutaneous melanoma (CM) in multiracial populations are sparse. Here the incidence and body site of these tumours in the South African population in 2000-2004 were analysed. METHODS: Annual age-standardized incidences and body sites of BCC, SSCC and CM in black, coloured, Asian and white groups were obtained from histological confirmed cases, reported to the National Cancer Registry. RESULTS: Highest annual incidences of BCC, SSCC and CM occurred in the white group, followed by coloured, then Asian and then black. BCCs and SSCCs were about twice as common in males than females. CM was the least frequent skin tumour, and BCC the most frequent, except in black people. The head was the commonest body site for SSCC and BCC in all groups and both sexes, whereas the lower limb was the predominant site for CM in black people. Mean age at diagnosis was generally mid-50s for CM, and mid-60s for BCC and SSCC. CONCLUSIONS: In South Africa, differences in reported incidence rates and body sites of skin tumours by population group and sex occur. Host characteristics, particularly skin phototype, and personal behaviour are likely to affect the risk of these cancers.

Characterization of regulatory dendritic cells differentiated from the bone marrow of UV-irradiated mice.

When antigen-loaded dendritic cells (DCs) differentiated from the bone marrow (BM) of UV-irradiated mice (UV-BMDCs) were adoptively transferred into naive mice or mice pre-sensitized with that antigen, the recipients exhibited a reduced immune response following antigen challenge. Hence, UV-BMDCs are poorly immunogenic and can suppress pre-existing immunity. The UV-induced effect on BM-derived DCs was rapid (observed 1 day after UV radiation), long-lasting (observed 10 days after UV radiation) and UV dose-dependent. The mechanism by which UV-BMDCs could regulate immunity was investigated. The CD11c(+) cells, differentiated using granulocyte-macrophage colony-stimulating factor + interleukin-4, were confirmed to be DCs because they did not express the myeloid-derived suppressor cell marker, Gr1. UV-BMDCs did not display altered antigen uptake, processing or ability to activate T cells in vitro. When gene expression in UV-BMDCs and DCs differentiated from the BM of non-irradiated mice (control-BMDCs) was examined, Ccl7, Ccl8 and CSF1R (CD115) mRNA transcripts were up-regulated in UV-BMDCs compared with control-BMDCs. However, neutralizing antibodies for Ccl7 and Ccl8 did not abrogate the reduced immunogenicity of UV-BMDCs in vivo. Moreover, the up-regulation of CSF1R transcript did not correspond with increased receptor expression on UV-BMDCs. The phenotypes of UV-BMDCs and control-BMDCs were similar, with no difference in the expression of CD4, CD8α, CD103, B220 or F4/80, or the regulatory molecules CCR7 (CD197), FasL (CD95L), B7H3 (CD276) and B7H4. However, PDL1 (CD274) expression was reduced in UV-BMDCs compared with control-BMDCs following lipopolysaccharide stimulation. In summary, UV-BMDCs do not express the classical phenotypic or gene expression properties of DCs reported by others as 'regulatory' or 'tolerogenic'.

Toward homeostasis: regulatory dendritic cells from the bone marrow of mice with inflammation of the airways and peritoneal cavity.

Inflammatory mediators from peripheral tissues may control dendritic cell (DC) development in the bone marrow. In this study, DCs (CD11c(+) cells) differentiated from the bone marrow of mice with inflammation of the airways, or the peritoneal cavity had poor priming ability resulting in reduced, long-lived responses to that antigen in vivo. This indicates enhancement of regulatory mechanisms of immune responses through a peripheral tissue-bone marrow axis. If CD11c(+) cells, expanded from the bone marrow of mice with tissue inflammation were antigen pre-loaded and injected into mice already sensitized to that antigen, then subsequent contact hypersensitivity responses were significantly reduced. The effects of inflammation were imprinted in vivo and were independent of in vitro culture conditions for DC differentiation. The effect of tissue inflammation on the bone marrow DC precursors was not detected in mice treated subcutaneously with slow-release indomethacin pellets, suggesting a role for prostanoids, including prostaglandin E(2), in differentiation of regulatory CD11c(+) cells from bone marrow. Our study represents an important homeostatic process with potential for therapeutic use in the future.

Photoimmunosuppression: a brief overview.

Exposure to ultraviolet radiation can lead to suppression of many adaptive immune responses, both to antigens encountered within a short period of the irradiation (primary) and to antigens previously encountered (memory). The pathways involved are complex and not completely elucidated. This brief review summarizes the information available currently regarding the multiple steps involved, with the aim of providing a general overview of the main aspects of photoimmunosuppression and its clinical consequences.

Solar Ultraviolet Radiation, Skin Cancer and Photoprotective Strategies in South Africa†.

The most recent data relating to the incidence of, and mortality from, the three commonest forms of skin cancer, namely basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and cutaneous melanoma (CM), in the Black African, Colored, Asian/Indian and White population groups in South Africa are reviewed. While exposure to solar ultraviolet radiation is the major environmental risk factor for BCC in all four groups, for SSC in the White and Asian/Indian groups and for CM in the White group, this is unlikely to be the case for most SCCs in the Black African group and for most CMs in the Black African and Asian/Indian groups. Strategies for practical personal photoprotection in South Africa are discussed with particular emphasis on people at heightened risk of skin cancer including the White population group, those with HIV or oculocutaneous albinism and outdoor workers.

Environmental effects of ozone depletion and its interactions with climate change: progress report, 2011.

The parties to the Montreal Protocol are informed by three panels of experts. One of these is the Environmental Effects Assessment Panel (EEAP), which deals with two focal issues. The first focus is the effects of increased UV radiation on human health, animals, plants, biogeochemistry, air quality, and materials. The second focus is on interactions between UV radiation and global climate change and how these may affect humans and the environment. When considering the effects of climate change, it has become clear that processes resulting in changes in stratospheric ozone are more complex than believed previously. As a result of this, human health and environmental problems will be longer-lasting and more regionally variable. Like the other panels, the EEAP produces a detailed report every four years; the most recent was published in 2010 (Photochem. Photobiol. Sci., 2011, 10, 173-300). In the years in between, the EEAP produces less detailed and shorter progress reports, which highlight and assess the significance of developments in key areas of importance to the parties. The next full quadrennial report will be published in 2014-2015.

Ultraviolet irradiation of mice reduces the competency of bone marrow-derived CD11c+ cells via an indomethacin-inhibitable pathway.

Direct UV irradiation of dendritic cells and Langerhans cells reduces their Ag presenting ability. However, the effects of UV on CD11c(+) cells located distally to the point of irradiation are poorly understood. Three days after UV irradiation (8 kJ/m(2)) of BALB/c mice, bone marrow cells were isolated and cultured for 7 d with IL-4 and GM-CSF for the propagation of CD11c(+) cells. Bone marrow-derived CD11c(+) cells from UV-irradiated or nonirradiated mice were loaded with dinitrobenzene sulfonic acid and injected into the ear pinnas of naive BALB/c mice. After 7 d, the ears were painted with 2,4-dinitro-1-fluorobenzene and the ear swelling determined 24 h later. A reduced contact hypersensitivity response was found in mice injected with CD11c(+) cells from the UV-irradiated animals compared with those injected with cells from the nonirradiated animals. Further, a long-lasting suppression of the memory response to 2,4-dinitro-1-fluorobenzene was created. This suppressed response corresponded to increased IL-10 and PGE(2) secretion by freshly isolated bone marrow cells from UV-irradiated mice, and to increased myelopoiesis. The reduction in competence of bone marrow-derived CD11c(+) cells from UV-irradiated mice was not due to delayed maturation, as it was maintained upon LPS exposure prior to CD11c(+) cell purification. The UV-induced effect was reversed by the administration of indomethacin to mice prior to UV irradiation and could be reproduced by s.c. PGE(2). These results show that UV irradiation of mice can affect the function of bone marrow-derived CD11c(+) cells via a mechanism inhibitable by indomethacin; this pathway is likely to contribute to systemic UV-induced immunosuppression.

An enhanced risk of basal cell carcinoma is associated with particular polymorphisms in the VDR and MTHFR genes.

BACKGROUND: Vitamin D and folate are influenced by ultraviolet radiation (UVR), and both are implicated in skin carcinogenesis. Polymorphisms in the genes involved in the metabolism of these two compounds may alter the risk of basal cell carcinoma (BCC). OBJECTIVE: To assess the frequency of four polymorphisms in the gene encoding the vitamin D receptor (VDR) (FokI, BsmI, TaqI and ApaI) and two in the gene encoding methylenetetrahydrofolate reductase (MTHFR) (677C/T and 1286A/C) in 142 patients of Polish origin with BCC and the same number of controls. The expression of VDR and MTHFR proteins in the skin, and the vitamin D status of a subset of patients and controls were also measured. PATIENTS/METHODS: The polymorphisms were assayed by PCR-RFLP, the VDR and MTHFR proteins by immunoblotting and vitamin D status as 25-hydroxyvitamin D (25(OH)D) level in the serum by RIA. RESULTS: The presence of the TT genotype in the FokI VDR polymorphism resulted in a >10-fold higher risk of BCC development. The CT genotype in 677C/T MTHFR polymorphism and CC genotype in 1286A/C MTHFR polymorphism also significantly increased the risk of BCC development. The expression of the VDR and MTHFR proteins was significantly higher in BCCs of the patients than in the healthy skin of the controls. The median serum level of 25(OH)D was significantly higher in the control group compared with the patients with BCC. CONCLUSIONS: Certain VDR and MTHFR gene polymorphisms increase the risk of BCC development in individuals of Polish origin.

UV-induced immunosuppression and the efficacy of vaccination.

Exposure to ultraviolet radiation (UVR) suppresses immunity by complex pathways, initiated by chromophores located in the skin and ending with the generation of specific subsets of T and B regulatory cells. The primary and memory (recall) immune response to a wide variety of antigens, including microorganisms, can be reduced by UVR, leading to the possibility that the efficacy of vaccination could be similarly reduced. A limited number of animal models of vaccination demonstrate that this may indeed be the case. The situation in human subjects has not been rigorously assessed but there are indications from a variety of sources that UVR adversely affects the immune responses to several vaccines. These studies are reviewed and the implications for vaccine administration discussed. As vaccination represents a major public health measure world-wide for the control of an increasing number of common infections, it is important to maximise its efficacy; therefore further evaluation of UVR in the context of vaccination is required and warranted.

The mechanisms and consequences of ultraviolet-induced immunosuppression in the skin and eye.

Ultraviolet radiation (UVR) of the skin results in immune suppression to antigens encountered shortly after the exposure. The pathways leading to the downregulation in immunity are complex, initiated by chromophores located at the surface of the skin and ending with the generation of immunosuppressive mediators and regulatory cells. Ultraviolet-induced immunosuppression can be considered not only as beneficial, such as in preventing chronic inflammatory responses and allergic and automimmune reactions, but it can also be detrimental, such as in the lack of control of skin tumors and infectious diseases. The eye is an immune privileged site through a wide variety of mechanisms that allow selected immune responses without causing inflammation. The role of UVR in altering immune responses in the eye is not clear and is discussed in relation to photokeratitis, herpetic stromal keratitis, and pterygium.

The Multiple Roles of Urocanic Acid in Health and Disease.

Trans-urocanic acid (trans-UCA) is synthesized in the skin, liver, and brain. It is a major natural moisturizing factor in skin and maintains its acid pH. In skin, it isomerizes to cis-UCA following exposure to UVR. Both isomers fulfill multiple roles in health and disease. Cis-UCA has immunomodulatory properties linked with several cutaneous diseases such as skin cancer, atopic dermatitis, and urticaria and associates with systemic diseases including multiple sclerosis. The levels of UCA in the skin, brain, urine, and feces reflect some physiological processes and may be disease biomarkers. Both isomers of UCA have therapeutic potential for a range of disorders.