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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References

A single or a limited number of UVR exposures is recognized to suppress cell-mediated immunity in human subjects. The complex pathway leading from the absorption of photons by chromophores in the skin to the generation of T regulatory cells has been, at least partially, elucidated. However, the effect of repeated UV exposures on immune responses and associated mediators is not well studied, particularly to assess whether they lead, first, to the development of photoprotection so that these immune changes are reduced or no longer occur, and, secondly, to the development of photoprotection against the normal downregulation of immunity induced by a high UV dose. For almost all the parameters evaluated in this review—epidermal DNA damage/erythema, urocanic acid, Langerhans and dendritic cells, natural killer cells, macrophages, mast cells, contact and delayed hypersensitivity responses—none, aside from epidermal DNA damage/erythema and macrophage phagocytic activity, show convincing evidence of photoadaptation or, where appropriate, photoprotection. It is concluded that repeatedly irradiating individuals with UVR is likely to continue to result in downregulation of immunity.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References

Starting with the seminal discoveries of Margaret Kripke and her co-workers some 30 years ago, it has been recognized that exposure to UVR can suppress cell-mediated immunity. Many details, although by no means all, of the complex pathway leading from the absorption of photons by chromophores at or near the surface of the skin to the generation of antigen-specific T regulatory cells have been revealed in the intervening years. The major steps in UV-induced local immunosuppression are outlined in Fig. 1, and further details can be found in the several comprehensive reviews (1–6). However, it should be noted that, in many instances, these details were obtained following a single or a few exposures of a rodent model or human subjects to UVR and that the dose chosen was sufficient to cause burning. In addition, the source used to emit UVR frequently contained more than 50% UVB (waveband 280–315 nm), while sunlight contains at most 6% UVB and frequently less than this depending on the latitude, season of the year, cloud cover, air pollution and time of the day.

image

Figure 1.  Steps in the pathway leading to UV-induced local immunosuppression.

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Human and rodent skins have the capacity to adapt as a result of repeated suberythemal UV exposures. Photoadaptation has been defined as the “diminished future response to equivalent doses of irradiation” (7). The mechanisms involved in this process are multiple and are not entirely clear, but are likely to include cutaneous pigmentation, epidermal hyperplasia and hyperkeratosis of the stratum corneum (8). Most importantly in the context of protection against skin cancer, these processes attenuate the quantity of UVR that reaches the basal and suprabasal cells of the epidermis. In addition, a significant contribution to photoadaptation arises from an enhanced ability to repair UV-induced DNA damage (9,10) and by the induction of protective enzymes such as superoxide dismutase (11). If the skin has photoadapted in response to repeated UVR exposures, then one important consequence might be the development of photoprotection. Here, on “challenge” with what would normally be a high single dose of UVR, the expected acute responses are diminished or avoided.

In real life, most people living in mid-latitudes are thought to photoadapt to solar UVR as a result of being outdoors for short periods of time on a daily basis over the summer months. Their capacity to be photoprotected might be tested if they go on a “sunshine holiday” where their daily sunlight exposure would be considerably higher than that experienced on a regular basis, reaching what would normally be sufficient to cause burning of the skin. Photoadaptation and photoprotection are terms that are usually used in the context of erythema but it is also worthwhile to consider such processes in the context of immune responses (see Table 1). It is the aim of this review to assess whether photoadaptation for several of the immune parameters outlined in Fig. 1 develops following repeated UV exposures of human subjects with a spectrum that mimics that emitted by the sun or, in some cases, with sources emitting predominantly UVB. Information obtained from mouse models will only be included when the human experiments have not been performed or cannot be undertaken for ethical reasons. Where possible, photoprotection will also be considered.

Table 1.   Development of photoadaptation and photoprotection in the context of immunity.
 Suppression in CHS and/or changes in immune cell numbers/function
Single or limited number of exposures to UVR, frequently erythemalYes
Repeated suberythemal UVR exposuresDiminished/absent—photoadaptation
Repeated suberythemal UVR exposures, followed by single erythemal exposureDiminished/absent—photoprotection

The sections below will deal in turn with two of the main chromophores for UV-induced immunosuppression (DNA and trans-urocanic acid [trans-UCA]), immune cell types known to be affected by UVR (Langerhans cells [LCs]/dendritic cells [DCs], natural killer [NK] cells, monocytes/macrophages and mast cells), and, finally, contact hypersensitivity (CHS) and delayed type hypersensitivity (DTH) responses.

Chromophores for UV-Induced Immunosuppression

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References

DNA

On absorption of photons, DNA is damaged with the production of photoproducts, particularly cyclobutane pyrimidine dimers (CPDs). Such changes in DNA are capable of initiating the pathway leading to UV-induced local immunosuppression, mainly through the upregulation of immunomodulating cytokines (reviewed in 12). The action spectrum for CPD formation is very similar to that for erythema with a maximum at 290–300 nm, and thus erythema is thought to result largely from CPD formation (13).

Bataille et al. (14) assessed the level of photoproducts in the skin of patients with psoriasis following UVB phototherapy, administered three times weekly for at least 6 weeks. The photoproducts reached a maximum after three exposures and decreased thereafter, despite the dose increasing by between 20% and 30% on each occasion. Subjects are frequently divided into phototypes on the basis of their sensitivity to sunlight, ranging from Type I (always burns, never tans) to Type VI (burns rarely, tans easily). Phototype was negatively associated with mean levels of CPDs, although there were large interpersonal differences in the accumulation of the DNA photoproducts, even after adjusting for skin phototype. The variation between individuals is probably caused by genetic factors that affect the efficiency of DNA repair (15) and the induction of protective enzymes (11). Bech-Thomson and Wulf (16) demonstrated that photoadaptation as a result of repeated suberythemal UVB or UVA exposures could be attributed largely to increased skin pigmentation initially; however, the contribution of melanogenesis decreased with the number of irradiations and ended up by contributing as little as 10% to the protection against erythema.

Only a few studies to date have assessed photoadaptation regarding erythema and DNA damage in healthy subjects using solar simulating lamps. de Winter et al. (17) irradiated volunteers, who had a range of skin phototypes, three times weekly for 3 weeks using Cleo Natural lamps that emit UV mimicking the spectral output of the sun. The starting dose was 0.5 of the individual’s minimal erythema dose (MED) and this was increased by 20% on each occasion. The exposures resulted in increased epidermal pigmentation and thickness, mainly of the stratum corneum. At the end of 3 weeks, photoprotection was tested by irradiating a small skin site with three times the subject’s initial MED, and then comparing the level of erythema and CPD formation with that induced by three MEDs before solar simulated radiation (SSR) began. The UV sensitivity for erythema decreased by 75% and CPD formation was reduced by 60%. Sheehan et al. (10) showed that photoprotection against erythema and DNA damage induced by two MEDs SSR developed to the same extent in individuals of phototype II and IV as a result of 12 exposures to 0.65 MED SSR over the previous 2 weeks. However there was more rapid DNA repair of thymine dimers in skin Type IV than skin Type II. Such a conclusion was also reached in a study in which the induction of DNA damage (measured by the number of keratinocytes containing thymine dimers) was assessed in chronically sun-exposed and unexposed skin sites following irradiation with artificial UVR and with natural sunlight (18). A smaller number of thymine dimer-positive keratinocytes was found 24 h after the exposure in the chronically sun-exposed site compared with the unexposed site, accounted for by the more rapid repair of the damaged DNA in the former location.

Recently, Narbutt et al. (19) employed a UV regime that attempted to mimic the type of sunlight exposure likely to be experienced by the majority of the population living in mid-latitudes during the summer. They found that whole-body irradiation of healthy human subjects daily for 10 days with SSR resulted in significant photoprotection regarding erythema when tested subsequently with a high UVB dose on a small body area. The SSR dose used was small, only 120 J m−2, which is less than 0.3 MED in subjects with phototype II/III and is equivalent to being in the sun for as little as 10 min around midday in summer in mid-Europe.

Thus several reports provide convincing evidence that, with regard to DNA damage and associated erythema, repeated exposure to UVR leads to the development of significant photoadaptation and photoprotection in the skin of subjects of all phototypes. Similar results in albino hairless mice irradiated daily for 60 days have been obtained, indicating the lack of importance of melanin in this process (20). Because of the link between CDP formation and the generation of immunosuppressive cytokines, the crucial question that follows is whether these attenuation processes might be sufficient to affect the initiation step of the pathway leading to UV-induced downregulation of immunity.

Finally, it may be of interest to note the study of Moller et al. (21) involving the assessment of peripheral blood mononuclear cells from subjects living in Denmark for sun-induced DNA damage throughout a year. Higher levels of DNA damage occurred in the summer compared with the winter months. Sun exposure in the 3–6 days preceding sampling had the most striking effect on the level of DNA damage. Unlike the situation in the skin, these results do not indicate photoadaptation of the blood mononuclear cells to the mutagenic properties of solar UVR during the time of the year that the subjects would be expected to tan and to increase their epidermal thickness.

Urocanic acid

Trans-UCA is synthesized from histidine using histidase which is activated in the upper layers of the epidermis. It accumulates in this site as urocanase, the enzyme that catabolizes it, and is not present in the skin. trans-UCA represents a major cutaneous absorber of UVR and, on exposure, is converted to cis-UCA in a dose-dependent manner until the photostationary state is reached, with approximately equal quantities of the two isomers. The action spectrum for trans to cis-UCA conversion in human skin demonstrates peak effectiveness at 280–310 nm, with isomerization still occurring in the UVA waveband (22). One major unsolved mystery relating to UCA is the large interpersonal variation, up to 10-fold, in the amount found in the skin of healthy subjects (23,24). This quantity does not correlate with pigmentation, MED, stratum corneum thickness or with phototypes I–IV. Limited results indicate that those individuals with black skin have a higher concentration of total UCA than those with white skin (cited in 25). There is little difference in the UCA content at different body sites within an individual, although there is a higher percentage as cis-UCA in areas normally exposed to sunlight than on nonexposed areas (24). UCA does not act as an effective sunscreen (26).

Cis-UCA was first proposed in 1983 as a chromophore for UVR and an initiator of UV-induced immunosuppression (27). This hypothesis has been confirmed in many investigations since then, although the mechanism of action of cis-UCA is still uncertain. It seems likely that the quantity of cis-UCA in the skin could affect the extent of immunosuppression. Such a dose dependence has been shown in a mouse model of DTH where the animals were treated with various doses of cis-UCA prior to infection with herpes simplex virus and then challenged subsequently with inactivated virus (28). Snellman et al. (29) reported that the total UCA content of the skin of subjects with phototype I/II was similar to that of subjects with phenotype III/IV, but there was a lower absolute and relative cis-UCA concentration in the former compared with the latter. On UVR with a range of single doses, no skin phototype-dependent difference in the ability to isomerize from trans to cis-UCA was apparent. Therefore, a link between MED and cis-UCA formation seems unlikely. This conclusion was not corroborated by a later study in which phototype I/II individuals displayed a slightly higher relative rate of isomerization to cis-UCA on exposure to low single doses of UVR than phototype III/IV individuals (30). This indicates that fair-skinned people may be at a relatively higher risk of immunosuppression following suberythemal UVR exposure compared with more pigmented people. A preliminary report involving a limited number of subjects indicated that, following SSR, the quantity of some DNA photoproducts and their rate of repair may correlate with the UCA content of the skin (31). Thus the skin of subjects with high UCA levels produced more photoproducts on exposure with a slower rate of repair of DNA damage. Furthermore, in another study volunteers who had high cutaneous cis-UCA levels developed lower T cell responses to a hepatitis B virus subunit vaccine administered after five daily whole-body UVB exposures (32).

Therefore, it is of interest to measure changes in total UCA and percentage as cis-UCA following repeated UVR to assess whether photoadaptation for this parameter occurs as the epidermis thickens and tans. To our knowledge, such experiments have not been performed. However, de Fine Olivarius et al. (33) assayed the concentration of UCA isomers at six body sites in 30 healthy Danish subjects, phototypes I–IV, on several occasions throughout a calendar year. Some of these sites are normally exposed to sunlight, such as the forehead, and others unexposed, such as the buttocks. Total UCA was slightly lower in the summer months at all body sites when the greatest skin pigmentation had developed. No evidence was obtained for photoadaptation during the summer months regarding the percentage of UCA as cis-UCA—it was at the maximum throughout this time of the year at all sites except the buttock, and fell to a background level in all areas in the winter months, aside from retaining a higher percentage in the forehead.

In conclusion, although there is some, although limited, evidence to suggest that the cis-UCA content of the skin may be a factor in determining the level of immunosuppression induced by UVR, photoadaptation for this parameter has not been convincingly demonstrated. In support of this, three separate studies in patients with a past history of nonmelanoma skin cancer or melanoma revealed that they had very similar cutaneous UCA content and percentage cis-UCA as control subjects without skin cancer (34–36). Chronic exposure to solar UVR or intermittent episodes of sun-burning are major risk factors for skin cancer development, so such a finding argues against an adaptation in UCA concentration or in its isomers over time as a result of repeated UV irradiation. It is impossible to test for the development of photoprotection regarding UCA as the maximal possible quantity of cis-UCA is produced following a dose of UVB that is just higher than 1 MED.

Immune Cell Types

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References

Langerhans cells and dendritic cells

Langerhans cells represent the major antigen presenting cell population of the epidermis. They are phagocytic and dendritic, forming an interdigitating network capable of surveying the skin for antigenic challenges and changes. They internalize antigens, process them and respond to the local production of mediators by migrating from the epidermis to the draining lymph, with associated changes in the expression of various adhesion and costimulatory molecules. On arrival in the paracortical area of the lymph node as DCs, they act as very effective antigen presenting cells for the stimulation of receptor-specific T cells. UVR also leads to the migration of LCs (37,38) and, if antigen is applied to the skin within a few days of the exposure while the numbers are depleted, the remaining LCs induce the generation of antigen-specific T regulatory cells. After the loss in LCs, it takes about 4 days to restore the numbers to their normal level in a mouse model (39).

Both Gilchrest et al. (40) and Czernielewski et al. (41) found that there were fewer epidermal LCs in sun-exposed body sites, such as the face, than in sun-protected sites, such as the buttocks. In another report, subjects were irradiated on each weekday for 6 weeks with 0.5 MED SSR on each occasion (42). There was an approximate 25% reduction in LC numbers compared with an unirradiated body site. A similar result was found by Seite et al. (43) who used 19 repeated exposures of volunteers to 0.5 MED simulated daylight (UVA:UVB = 27:1), delivered over 4 weeks. The number of LCs decreased from 522 to 308 per mm2, as evaluated in epidermal sheets. In addition, Murphy et al. (44) showed that a 1.5 MED dose of monochromatic UVB (295 ± 5 nm) administered in 10 equal fractions on alternate days led to a significant depletion of LCs. Thus all of these studies indicate that there is no photoadaptation regarding the reduction in LC density as a result of chronic UV exposure of human subjects.

Confirmation of this conclusion comes from a mouse model in which the animals were irradiated daily, up to 60 days, with a dose of SSR that, administered as a single dose, did not alter the number of LCs in the epidermis (45). From two exposures onwards, there was a declining number of LCs as the number of irradiations increased. In addition, the number of DCs in the lymph nodes draining the irradiated skin was greater in mice exposed for 20 and 60 consecutive days compared with the unirradiated animals. Therefore, there was no evidence to indicate the development of photoadaptation regarding the UV-induced loss of LCs and increase in lymph node DCs.

Very few publications have assessed the function of epidermal LCs as antigen presenting cells following repeated exposures of human subjects to suberythemal UVR. However, van Praag et al. (46) used suction blister roofs from volunteers UVB irradiated three times weekly for 4 weeks and tested the epidermal cells for their activity in a mixed epidermal cell-lymphocyte reaction. Marked suppression of this response occurred, indicating that photoadaptation had not occurred, at least over the 4 week period of the exposures.

While it is obviously not possible to monitor DC numbers or activity in lymph nodes draining chronically irradiated sites in humans, changes in the populations of DCs in human blood following UV exposure have been examined. Narbutt et al. (47) reported that whole-body suberythemal SSR of volunteers daily for up to 30 days induced an increase in the percentage of DCs within the peripheral blood mononuclear population. In particular there was an increase in DCs characterized as myeloid subtype 1. No evidence of photoadaptation regarding the percentages of DC subtypes in the blood was obtained throughout the 30 days of repeated UV exposures.

Natural killer cells

Natural killer cells are major histocompatibility complex (MHC)-unrestricted cells that are part of the innate immune system, important in the recognition and lysis of both virally infected cells and tumor cells. They also play a part in the development of T helper 1 immune responses via the release of γ-interferon. Only a limited number of reports, using a variety of UV sources, have tested whether changes are induced in either the frequency or activity of this cell type by repeated UVR in human subjects.

Two related studies monitored NK cell activity following solarium exposure; normal subjects were irradiated with approximately 1 MED for 2, 6 or 12 consecutive days (48,49). At least 6 days of exposure were required to induce suppression of NK cell activity and the suppression was more pronounced after 12 days of exposure, indicating that the downregulation may be dose-dependent. There was an associated reduction in circulating NK cell numbers. Following the final UV exposure, it took at least 14 days for the NK cell function to be restored to the preirradiated level. Gilmour et al. (50) assessed NK cell activity in patients with psoriasis who were receiving broadband UVB or narrow band UVB (311 nm) therapy over a 6 week period. Both regimes resulted in suppression and it took several weeks after the cessation of therapy to recover to the initial level of activity. A similar result was obtained by Neill et al. (51) but using healthy subjects where the extent of the decline in NK cell activity correlated with the number of exposures to broadband UVB. Whitmore and Morison (52) examined NK cells in the peripheral blood of normal individuals before and after 10 whole-body exposures over 2 weeks to sunlamps emitting 95% UVA and 5% UVB. The treatment started at 70% MED and increased by 20% on each occasion. No significant change in the number of circulating NK cells occurred. In contrast, in a study involving infants in St. Petersburg, it was demonstrated that, following 20 daily whole-body suberythemal exposures to FS20 lamps emitting predominantly UVB, the percentage of the total peripheral blood mononuclear cell population identified as NK cells dropped from about 21 to about 13 (53). NK cell function was not evaluated in either of these last two reports.

Thus, as far as can be ascertained with the limited information outlined above, repeated UVR is capable of reducing NK cell activity and possibly the numbers circulating in human blood, and photoadaptation does not occur. The development of photoprotection has not been tested.

Monocytes/macrophages

Macrophages play an important role in both the induction and the effector phase of the immune response and in nonspecific resistance to infection caused, in particular, by intracellular microorganisms such as mycobacteria and viruses. Following acute UVR of human subjects, some monocytes infiltrate from the blood into the dermis first, and then into the epidermis, and are partly responsible for UV-induced immunomodulation by producing immunosuppressive cytokines, such as IL-10 (54). These monocytes/macrophages are distinguished from LCs as they are MHC class II+, CD1c, CD11b+, CD11c+ and CD36+ (55). Only one study has monitored the number of such cells in the skin following repeated UV exposures. None were detected following irradiation of subjects with 0.5 MED SSR daily for 6 weeks (42). It is possible that this cell population may only be recruited into the skin in response to erythemal doses of UVR. Regarding macrophage function, very little is known except that, following acute UVR, the phagocytic activity of cells in human blood is reduced (56); the effect of repeated UV exposures on this parameter is not known. As information relating to UVR and macrophages in humans is lacking at present, some mouse data are included below.

Exposing mice to a single erythemal UVB dose or to the same dose administered over 5 days can reduce the phagocytic activity of the peritoneal macrophages, decrease their production of IL-12 on stimulation with lipopolysaccharide in culture, and decrease their active oxygen production, important in the killing of pathogens (57,58). Peritoneal macrophages have been assessed in a chronic UVB experiment that was designed to induce skin tumors (59). The dose given was erythemal and was administered three times weekly for 22–42 weeks. No effect on the phagocytic activity of the macrophages was found when tested at 8 and 16 weeks. We have used suberythemal doses of SSR delivered daily over a period of 30 days (60). There was a reduction in macrophage phagocytic activity initially (at 2 days) but this was reversed as the number of exposures increased. We also tested for the development of photoprotection by irradiating the animals with a single high SSR dose (sufficient to cause suppression in phagocytic activity in previously unirradiated mice) following the repeated low doses. We found that the expected suppression in the phagocytic activity of the peritoneal macrophages did not occur (60). Thus, in mice, limited evidence points to the development of both photoadaptation and photoprotection for peritoneal macrophage activity as a result of repeated UV exposures.

Mast cells

Mast cells are present in large numbers in the skin and are located predominantly in the perivascular region of the dermis. They have a distinct appearance after staining with the dye toluidine blue that makes them readily identifiable in tissue sections, or can be located using a labeled antihistamine antibody. They are derived from progenitor cells in the bone marrow that enter the circulation and differentiate in the peripheral tissues, including the skin, in response to a variety of signals. Skin mast cells are long lived and store a range of mediators that are released on degranulation, thus influencing immune responses both locally and systemically. They are critically important in skin remodeling after photodamage and in initiating UV-induced immunosuppression (reviewed in 61). By examining different mouse strains, a positive correlation has been revealed between dermal mast cell prevalence and susceptibility to systemic suppression of CHS by UVB, i.e. the higher the prevalence of mast cells, the lower the dose of UVB required to induce a 50% reduction in the CHS (62).

Although photoadaptation and photoprotection for mast cell numbers and function have not been tested as such in human subjects, some evidence is available from mouse studies and from comparing body sites in healthy people that are normally exposed to sunlight with others that are normally covered.

In hairless mice, repeated UVB irradiation over a period of 10 weeks led to an increase in mast cell numbers in the lower dermis if the dose was 2 MEDs or above, and in the upper dermis if the dose was 3 MEDs or above (63). This response was attributed to the UV-induced upregulation in epidermal stem factor production. Following a year of irradiation of hairless mice five times weekly with suberythemal narrowband UV, an increase in mast cell numbers occurred, especially in response to the lower wavelengths of UVB (300 and 307 nm) (64). The increased numbers correlated with the degree of elastosis. However, using a lower dose of broadband UVB, Learn and Moloney (65) found no change in dermal mast cell numbers in hairless mice when irradiated over a period of 20 weeks. We monitored mast cell numbers in the dermis of haired C3H/HeN mice irradiated daily with suberythemal SSR for up to 30 days and did not observe any change at three time points throughout the exposure period (P. McLoone and M. Norval, unpublished). It is possible that the quantity of UVB in the administered UVR may be a critical factor in determining whether mast cell numbers increase or not.

With regard to human studies, most conclude that the prevalence of mast cells within a subject is higher in chronically sun-exposed body sites, such as the back of the hand, compared with those receiving intermittent exposure, such as the shoulder or upper arm (66–68). The extent of elastosis in the back of the hand, used as a measure of past cumulative sun exposure, is found to correlate with the density of dermal mast cells so that the higher the degree of elastosis, the higher the density (66). In addition, Grimbaldeston et al. showed that mast cell prevalence in a body site not normally exposed to solar UVR is higher in subjects with a past history of malignant melanoma (69) or basal cell carcinoma (70,71), but not in those with a past history of squamous cell carcinoma (72). This is taken as evidence that the mast cells in the dermis can provide an immunosuppressive environment in response to UVR for the two skin cancer types in which intermittent episodes of sun-burning in childhood are major risk factors. Thus for the mast cell numbers in the dermis, most of the small amount of evidence available to date does not indicate the development of photoadaptation.

Hypersensitivity Responses

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References

Hypersensitivity to a particular antigen is thought to reflect an accurate measure of T cell immunity to that antigen, and has been used extensively to demonstrate and investigate the immune suppression that follows UVR. It can be important clinically, occurring most commonly as allergic CHS. The response normally consists of two phases—the first is called sensitization (or afferent or induction) and occurs in naive subjects on first exposure to an antigen applied to the skin, and the second is called elicitation (or efferent or challenge). Here the same antigen is applied to the skin for a second or subsequent time. Hypersensitivity is then seen as erythema with induration at the site of skin challenge and can be assessed by clinical score, by an erythema meter or by measuring edema with high-frequency ultrasound or histopathology of skin biopsies. In some cases there is an observed inflammation 1–2 weeks after the first exposure to the antigen. This is called the primary allergic response (PAR) and is most likely due to the persistence of the antigen in the skin, thus allowing time for both the sensitization and elicitation phases to occur.

Contact hypersensitivity and DTH differ in several respects although the final visual response in the skin is similar. In CHS, the antigen is a low molecular weight molecule called a hapten, such as nickel; it binds to self-antigens in the skin on topical application and the same antigen is applied topically in the elicitation phase. In DTH, the antigen is complex, often consisting of several proteins such as a microorganism. Here the first exposure can be through the skin or systemic and the antigen is reintroduced intradermally in the elicitation phase. Thus different antigen presenting cells and other immune mediators are involved in the two phases of CHS and DTH. Although both can be suppressed by a single, often erythemal UV exposure, the details of the pathways involved are likely to differ (e.g. 73,74). In addition, there are other variables to consider when studying hypersensitivity responses. First the UVR can be experienced prior to the first exposure to the antigen in which case any effect will be on the generation of the primary immune response. Alternatively it can be experienced after the sensitization phase in which case any effect will be on the activation of memory or recall immunity. Secondly, hypersensitivity can be used to test whether the UVR has affected immune responses locally if the test antigen is applied directly to an irradiated body site, or systemically if the antigen is applied to a nonexposed distant body site in an irradiated individual. CHS and DTH are considered separately below in the context of chronic UVR of human subjects.

Contact hypersensitivity

Because of ethical and other difficulties in selecting a suitable hapten, few studies have assessed the effect of repeated UVR on the generation of CHS. Whitmore and Morison (52) irradiated volunteers with 10 whole-body UV exposures (95% UVA, 5% UVB) over 2 weeks, starting at 0.7 MED and increasing on each occasion, although remaining suberythemal throughout. The sensitizer, dinitrochlorobenzene (DNCB), was applied to an irradiated site immediately following the final UVR. Twelve days later, DNCB was re-applied to both an irradiated site to test for local immunosuppression and one that had been protected during the exposures to test for systemic immunosuppression. The repeated UVR led to a reduction in the percentage of subjects who developed PAR compared with a control unirradiated group. In addition, local suppression of CHS occurred, with less marked, but still significant, systemic suppression. Narbutt et al. (75) attempted to mimic “natural” sunlight exposure of people during the summer months by irradiation daily with small doses of SSR, equivalent to being out in the sun for about 10 min in mid-Europe on a clear day around noon. Volunteers were whole-body irradiated with approximately 0.3 MED SSR daily for up to 30 days before application of the sensitizer diphenylcyclopropenone on an exposed body site and reapplication on a UV-protected site 3 weeks later. In comparison with an unirradiated control group, suppression of PAR and systemic CHS occurred, as assessed by clinical score and epidermal spongiosis. This downregulation increased as the number of days of SSR increased, indicating that photoadaptation for CHS did not develop.

With regard to the effect of chronic UVR on the CHS to recall antigens, as part of a study evaluating phototherapy linked to hyposensitization in subjects with nickel-allergic contact dermatitis, Troost et al. (76) monitored the clinical response during whole-body exposure with suberythemal UVB three times weekly for 4 months. A distinct clinical improvement occurred as assessed by affected area, severity and frequency of symptoms. Sjovall and Christensen (77) also demonstrated that whole-body irradiation of nickel-sensitive patients with suberythemal UVB four times weekly for 3 weeks led to a 61% reduction in the CHS response on challenge with a range of nickel concentrations on an irradiated site, and to a 32% reduction on challenge on a site that had been protected from UVR. Damian et al. (78) irradiated a 6 × 4 cm body area of nickel-allergic volunteers on 4 days per week for up to 4 weeks with approximately 0.5 MED SSR on each occasion. Challenge with a range of nickel concentrations took place on an exposed and an unexposed site. UVR significantly suppressed CHS in the 1, 2 and 3 week groups when the nickel-induced erythema at the irradiated site was compared with the unirradiated site but, although a 25% decrease in the CHS response occurred in the 4 week group, this was not considered a significant change. However, it should be noted that any downregulation might have been masked as a result of various factors—irradiation took place on a limited body area, the dose remained the same throughout the experimental period, there were only five subjects in each group and there was considerable interpersonal variation in the CHS response.

It is concluded from the limited evidence available to date that photoadaptation of the CHS response to primary or recall haptens is unlikely to develop. Studies conducted in mice reach the same general conclusion (79,80).

Delayed type hypersensitivity

It is obviously not ethically acceptable, say, to infect human volunteers with a microorganism or to administer tumor extracts following repeated UVR in order to test any effect on the subsequent DTH. However, several studies have examined what happens to this response if the UV exposures are given after the generation of the primary immune response and prior to the experimental elicitation challenge.

In one of the first of such reports, Fuller et al. (81) whole-body irradiated subjects with suberythemal UV (UVB + UVA) on 12 occasions in 16 days, before administration of Multitest kits containing seven test antigens on an unexposed (protected) body site. The antigens were tetanus toxoid, diphtheria toxoid, tuberculin, inactivated Streptococcus, Candida albicans, Trichophyton mentagrophytes and Proteus mirabilis, all of which most individuals have been immunized against or have come into contact with in the past. The diameter of each positive test was measured and added together for each subject to give a total score. Compared with the preirradiation value, UVR induced a 39% suppression in the total score. A similar result was recorded by Moyal et al. (82) and Moyal and Fourtanier (83). Here volunteers underwent 10 SSR exposures on the back or the abdomen over 2 weeks, starting at 0.8 MED and increasing by 10% on each occasion to 2 MED. The Multitest antigens were subsequently applied to an irradiated and an unirradiated site. The total score was reduced by 68–71% in the irradiated site and by 53–59% in the unirradiated site, compared with the preirradiation score. Damian et al. (84) recruited subjects who had been vaccinated in the past with bacille Calmette-Guerin and were known to give a positive Mantoux reaction when tested by intradermal injection of purified protein derivative (PPD). Initially they were irradiated with 0.7 MED SSR on a small body area (6 cm2) on 5 consecutive days before PPD injection into the irradiated site and a distant unirradiated site. The subsequent Mantoux reaction was evaluated by an erythema meter. It was suppressed by 42% on the irradiated site compared with the unirradiated site and, by comparing the Mantoux reaction in a group of unirradiated controls with the irradiated subjects, it was concluded that no suppression had occurred at the distant unirradiated site. In a second set of experiments, the number of SSR exposures was increased to 5 days per week for 4–5 weeks before testing the Mantoux reaction at the irradiated site. The suppression was reduced to 17%, thus indicating the possible development of photoadaptation. This study contained the longest period of irradiation so far undertaken before testing the DTH to the recall antigen, but it should be noted that the body area irradiated was limited, the dose remained the same throughout, and only six subjects were tested of whom one did demonstrate greater suppression with the longer irradiation period.

Two further reports are of relevance here. In the first Cestari et al. (85) monitored the effect of repeatedly irradiating a small body area of subjects who were contacts of leprosy patients and who had demonstrated a positive DTH on intradermal injection of lepromin, a cell-mediated immune response to Mycobacterium leprae antigens. They were tested with lepromin on two sites followed by exposure to 2 MED UVR at one of these sites every 4 days on five occasions. The granuloma that formed was 20% smaller in the irradiated site than in the unirradiated site. In the second, O’Dell et al. (86) compared the DTH response to the common skin test antigens, Candida albicans, mumps and tuberculin, in a sun-damaged site (back of the neck) with a sun-protected site (upper back). Greater responses were found on the back than on the neck indicating that one consequence locally of chronic solar UVR is a reduction in DTH. Thus the majority of studies published to date show that DTH responses to a range of recall antigens are suppressed by chronic UV exposures and that photoadaptation for this parameter is unlikely to occur.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References

As may be seen from the sections above, it is difficult to draw definitive conclusions at this stage regarding the effects of chronic UVR on human immune responses as there are considerable gaps in our knowledge and many variables involved, including the acknowledged genetic diversity in the response of individuals to UVR, whether primary or memory immune responses are being considered, the source of UV used, the dose on each occasion, the frequency of exposures and the area of the body that is irradiated. However, Table 2 attempts to summarize the present position regarding several parameters known to be involved in immune regulation in human skin and systemically. Evidence for the development of photoadaptation and photoprotection is apparent in a few instances only. More work is required to investigate these and other immune aspects, especially regarding function, such as mast cell activity and antigen presentation. It is important to obtain this information as, in normal life, many people go out into the sun for short periods of time during the summer months and most will adapt at least to some extent so that the chance of being burnt is reduced. However, it appears that protection against sunburn/erythema does not generally provide protection against immune changes in the skin and the immunosuppression induced by UV exposure. Therefore it would seem prudent to take personal protective measures, even if the skin is tanned, to lessen the potential risks that follow from immunomodulation, such as the lack of control of skin tumors and infectious diseases.

Table 2.   Development of photoadaptation and photoprotection for several immune parameters involved in UV-induced immunosuppression of human subjects (relevant references indicated).
 PhotoadaptationPhotoprotection
  1. UCA = urocanic acid.

Epidermal DNA damage/erythemaYes (14,16–19)Yes (10,17)
Total UCA content and isomerization to cis-UCANo (33)Cannot be tested
Langerhans and dendritic cell numbers and functionNo (40–44,46,47)Not known
Natural killer cell numbers and functionNo (48–51,53)Not known
Peritoneal macrophage activity (mouse)Yes (59,60)Yes (60)
Dermal mast cell numbersNo (66–68)Not known
Contact hypersensitivityNo (52,74,76–78)Not known
Delayed type hypersensitivityNo (81–86)Not known

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Chromophores for UV-Induced Immunosuppression
  5. Immune Cell Types
  6. Hypersensitivity Responses
  7. Conclusions
  8. References
  • 1
    Clydesdale, G. J., G. W. Dandie and H. K. Muller (2001) Ultraviolet light induced injury: Immunological and inflammatory effects. Immunol. Cell Biol. 79, 547568.
    Direct Link:
  • 2
    Schwarz, T. (2005) Mechanisms of UV-induced immunosuppression. Keio J. Med. 54, 165171.
  • 3
    Ullrich, S. E. (2005) Mechanisms underlying UV-induced immune suppression. Mutat. Res. 571, 185205.
  • 4
    Schade, N., C. Esser and J. Krutmann (2005) Ultraviolet B radiation-induced immunosuppression: Molecular mechanisms and cellular alterations. Photochem. Photobiol. Sci. 4, 699798.
  • 5
    Hanneman, K. K., K. D. Cooper and E. D. Baron (2006) Ultraviolet immunosuppression: Mechanisms and consequences. Dermatol. Clin. 24, 1925.
  • 6
    Norval, M. (2006) Photoimmunosuppression of contact hypersensitivity. Expert Rev. Dermatol. 1, 227239.
  • 7
    Oh, C., A. Hennessy, T. Ha, Y. Bisset, B. Diffey and J. L. Rees (2004) The time course of photoadaptation and pigmentation studied using a novel method to distinguish pigmentation from erythema. J. Invest. Dermatol. 123, 965972.
  • 8
    Meischer, G. (1930) Das problems des lichtchutzes und der lichtgewohnung. Strahlentherapie 35, 403443.
  • 9
    Young, A. R., C. S. Potten, C. A. Chadwick, G. M. Murphy, J. L. Hawk and A. J. Cohen (1991) Photoprotection and 5-MOP photochemoprotection from UVR-induced DNA damage in humans: The role of skin type. J. Invest. Dermatol. 97, 942948.
  • 10
    Sheehan, J. M., N. Cragg, C. A. Chadwick, C. S. Potten and A. R. Young (2002) Repeated ultraviolet exposure affords the same protection against DNA photodamage and erythema in human skin types II and IV but is associated with faster DNA repair in skin type IV. J. Invest. Dermatol. 118, 825829.
  • 11
    Poswig, A., J. Wenk, P. Brenneisen, M. Wlaschek, C. Hommel, G. Quel, K. Faisst, J. Dissemond, K. Briviba, T. Kreig and K. Scharffetter-Kochanek (1999) Adaptive antioxidant response of manganese-superoxide dismutase following repetitive UVA irradiation. J. Invest. Dermatol. 112, 1318.
  • 12
    Vink, A. A. and L. Roza (2001) Biological consequences of cyclobutane pyrimidine dimers. J. Photochem. Photobiol. B, Biol. 65, 101104.
  • 13
    Young, A. R., C. A. Chadwick, G. I. Harrison, O. Nikaido, J. Ramsden and C. S. Potten (1998) The similarity of action spectra for thymine dimers in human epidermis and erythema suggests that DNA is the chromophore for erythema. J. Invest. Dermatol. 111, 982988.
  • 14
    Bataille, V., V. J. Bykov, P. Sasieni, S. Harulow, J. Cuzick and K. Hemminki (2000) Photoadaptation to ultraviolet (UV) radiation in vivo: Photoproducts in epidermal cells following UVB therapy for psoriasis. Br. J. Dermatol. 143, 477483.
  • 15
    Bykov, V. J., J. M. Sheehan, K. Hemminki and A. R. Young (1999) In situ repair of cyclobutane pyrimidine dimers and 6-4 photoproducts in human skin exposed to solar simulating radiation. J. Invest. Dermatol. 112, 326331.
  • 16
    Bech-Thomsen, N. and H. C. Wulf (1996) Photoprotection due to pigmentation and epidermal thickness after repeated exposure to ultraviolet light and psoralen plus ultraviolet A therapy. Photodermatol. Photoimmunol. Photomed. 11, 213218.
  • 17
    De Winter, S., A. A. Vink, L. Roza and S. Pavel (2001) Solar-simulated skin adaptation and its effect on subsequent UV-induced epidermal DNA damage. J. Invest. Dermatol. 117, 678682.
  • 18
    Wassberg, C., H. Backvall, B. Diffey, F. Ponten and B. Berne (2003) Enhanced ultraviolet responses in chronically sun-exposed skin are dependent on previous sun exposure. Acta Derm. Venereol. 83, 254261.
  • 19
    Narbutt, J., A. Lesiak, J. Boncela, A. Wozniacka and M. Norval (2007) Repeated exposures of humans to low doses of solar simulated radiation lead to limited photoadaptation and photoprotection against UVB-induced erythema and cytokine mRNA up-regulation. J. Dermatol. Sci. 45, 210212.
  • 20
    Mitchell, D. L., M. Byrom, S. Chiarello and M. G. Lowery (2001) Attenuation of DNA damage in the dermis and epidermis of the albino hairless mouse by chronic exposure to ultraviolet-A and -B radiation. Photochem. Photobiol. 73, 8389.
  • 21
    Moller, P., H. Wallin, E. Holst and L. E. Knudsen (2002) Sunlight-induced DNA damage in human mononuclear cells. FASEB J. 16, 4553.
  • 22
    McLoone, P., E. Simics, A. Barton, M. Norval and N. K. Gibbs (2005) An action spectrum for the production of cis-urocanic acid in human skin in vivo. J. Invest. Dermatol. 124, 10711074.
  • 23
    Kavanagh, G., J. Crosby and M. Norval (1995) Urocanic acid isomers in human skin: Analysis of site variation. Br. J. Dermatol. 133, 728731.
  • 24
    De Fine Olivarius, F., H. C. Wulf, P. Therkildsen, T. Poulsen, J. Crosby and M. Norval (1997) Urocanic acid isomers: Relation to body site, pigmentation, stratum corneum thickness and photosensitivity. Arch. Dermatol. Res. 289, 501505.
  • 25
    Hug, D. H. (2004) Association of nonmelanoma skin cancer with second malignancy. Cancer 101, 206207.
  • 26
    De Fine Olivarius, F., H. C. Wulf, J. Crosby and M. Norval (1996) The sunscreening effect of urocanic acid. Photodermatol. Photoimmunol. Photomed. 12, 9399.
  • 27
    De Fabo, E. C. and F. P. Noonan (1983) Mechanism of immune suppression by ultraviolet irradiation in vivo. I. Evidence for the existence of a unique photoreceptor in skin and its role in photoimmunology. J. Exp. Med. 158, 8498.
  • 28
    Ross, J. A., S. E. M. Howie, M. Norval, J. Maingay and T. J. Simpson (1986) Ultraviolet-irradiated urocanic acid suppresses delayed-type hypersensitivity to herpes simplex virus. J. Invest. Dermatol. 87, 630633.
  • 29
    Snellman, E., C. T. Jansen, J. K. Laihia, T. Milan, L. Koulu, K. Leszczynski and P. Pasanen (1997) Urocanic acid concentration and photoisomerisation in Caucasian skin phototypes. Photochem. Photobiol. 65, 862865.
  • 30
    De Fine Olivarius, F., H. C. Wulf, J. Crosby and M. Norval (1999) Isomerization of urocanic acid after ultraviolet radiation is influenced by skin pigmentation. J. Photochem. Photobiol. B, Biol. 48, 4247.
  • 31
    Snellman, E., C. T. Jansen, G. Xu, P. Pasanen, J. Laihia and K. Hemminki (2002) Correlation analysis of production and photoisomerisation of epidermal urocanic acid versus induction and repair of DNA photoproducts in the human skin in situ. J. Invest. Dermatol. 118, 893895.
  • 32
    Sleijffers, A., A. Kammeyer, F. R. De Gruijl, G. J. Boland, J. Van Hattum, W. A. Van Vloten, H. Van Loveren, M. B. Teunissen and J. Garssen (2003) Epidermal cis-urocanic acid levels correlate with lower specific cellular immune responses after hepatitis B vaccination of ultraviolet B-exposed humans. Photochem. Photobiol. 77, 271275.
  • 33
    De Fine Olivarius, F., H. C. Wulf, J. Crosby and M. Norval (1997) Seasonal variation in urocanic acid isomers in human skin. Photochem. Photobiol. 66, 119123.
  • 34
    Snellman, E., C. T. Jansen, T. Rantanen and P. Pasanen (1997) Epidermal urocanic acid concentration and photoisomerization reactivity in patients with cutaneous malignant melanoma or basal cell carcinoma. Acta Derm. Venereol. 79, 200203.
  • 35
    De Fine Olivarius, F., J. Lock-Andersen, F. Gronhoj Larsen, H. C. Wulf, J. Crosby and M. Norval (1998) Urocanic acid isomers in patients with basal cell carcinoma and cutaneous malignant melanoma. Br. J. Dermatol. 138, 986992.
    Direct Link:
  • 36
    De Simone, C., C. Masini, M. S. Cattaruzza, C. Guerriero, D. Cerimele and M. Norval (2001) Urocanic acid isomers in patients with non-melanoma skin cancer. Br. J. Dermatol. 144, 858861.
  • 37
    Alcalay, J., J. N. Craig and M. L. Kripke (1989) Alterations in Langerhans cells and Thy-1+ dendritic epidermal cells in murine epidermis during the evolution of ultraviolet radiation-induced skin cancers. Cancer Res. 49, 45914596.
  • 38
    Moodycliffe, A. M., I. Kimber and M. Norval (1992) The effect of ultraviolet B irradiation and urocanic acid isomers on dendritic cell migration. Immunology 77, 394399.
  • 39
    Duthie, M. S., I. Kimber, R. J. Dearman and M. Norval (2000) Differential effects of UVAI and UVB radiation on Langerhans cell migration in mice. J. Photochem. Photobiol. B, Biol. 57, 123131.
  • 40
    Gilchrest, B. A., G. Szabo, E. Flynn and R. M. Goldwyn (1983) Chronologic and actinically induced aging in human facial skin. J. Invest. Dermatol. 80(Suppl.), 81s85s.
  • 41
    Czernielewski, J. M., I. Masouye, A. Pisani, J. Ferracin, D. Auvolat and J. P. Ortonne (1988) Effect of chronic sun exposure on human Langerhans cell density. Photodermatology 5, 116120.
  • 42
    Lavker, R. M., G. F. Gerberick, D. Veres, C. J. Irwin and K. H. Kaidbey (1995) Cumulative effects from repeated exposures to suberythemal doses of UVB and UVA in human skin. J. Am. Acad. Dermatol. 32, 5362.
  • 43
    Seite, S., C. Medaisko, F. Christiaens, C. Bredoux, D. Compan, H. Zucchi, D. Lombard and A. Fourtanier (2006) Biological effects of simulated ultraviolet daylight: A new approach to investigate daily photoprotection. Photodermatol. Photoimmunol. Photomed. 22, 6777.
  • 44
    Murphy, G. M., P. G. Norris, A. R. Young, M. F. Corbett and J. L. Hawk (1993) Low-dose ultraviolet-B irradiation depletes human epidermal Langerhans cells. Br. J. Dermatol. 129, 674677.
  • 45
    McLoone, P., G. M. Woods and M. Norval (2005) Decrease in Langerhans cells and increase in lymph node dendritic cells following chronic exposure of mice to suberythemal doses of solar simulated radiation. Photochem. Photobiol. 81, 11681173.
  • 46
    Van Praag, M. C., A. A. Mulder, F. H. Claas, B. J. Vermeer and A. M. Mommaas (1994) Long-term ultraviolet B-induced impairment of Langerhans cell function: An immunoelectron microscope study. Clin. Exp. Immunol. 95, 7377.
  • 47
    Narbutt, J., M. Skibinska, A. Lesiak, A. Wozniacka, A. Sysa-Jedrzewska, B. Cebula, T. Robak and P. Smolewski (2004) Exposure to low doses of solar-simulated radiation induces an increase in the myeloid subtype of blood dendritic cells. Scand. J. Immunol. 60, 429435.
  • 48
    Hersey, P., M. MacDonald, C. Burns, S. Schibeci, H. Matthews and F. J. Wilkinson (1987) Analysis of the effect of a sunscreen agent on the suppression of natural killer cell activity induced in human subjects by radiation from solarium lamps. J. Invest. Dermatol. 88, 271276.
  • 49
    Hersey, P., M. MacDonald, C. Henderson, S. Schibeci, G. D’Alessandro, M. Pryor and F. J. Wilkinson (1988) Suppression of natural killer cell activity in humans by radiation from solarium lamps depleted of UVB. J. Invest. Dermatol. 90, 305310.
  • 50
    Gilmour, J. W., J. P. Vestey, S. George and M. Norval (1993) Effect of phototherapy and urocanic acid isomers on natural killer cell function. J. Invest. Dermatol. 101, 169174.
  • 51
    Neill, W. A., K. E. Halliday and M. Norval (1998) Differential effect of phototherapy on the activities of human natural killer cells and cytotoxic T cells. J. Photochem. Photobiol. B, Biol. 47, 129135.
  • 52
    Whitmore, S. E. and W. L. Morison (2000) The effect of suntan parlor exposure on delayed and contact hypersensitivity. Photochem. Photobiol. 71, 700705.
  • 53
    Snopov, S. A., S. M. Kharit, M. Norval and V. V. Ivanova (2005) Circulating leukocyte and cytokine responses to measles and poliovirus vaccination in children after ultraviolet radiation exposures. Arch. Virol. 150, 17291743.
  • 54
    Hammerberg, C., N. Duraiswamy and K. D. Cooper (1996) Temporal correlation between UV radiation locally-induced tolerance and the sequential appearance of dermal, then epidermal, class II MHC+CD11b+ monocytic/macrophagic cells. J. Invest. Dermatol. 107, 755763.
  • 55
    Meunier, L., Z. Bata-Csorgo and K. D. Cooper (1995) In human dermis, ultraviolet radiation induces expansion of a CD36+ CD11b+ CD1- macrophage subset by infiltration and proliferation; CD1+ Langerhans-like dendritic antigen-presenting cells are concomitantly depleted. J. Invest. Dermatol. 105, 782788.
  • 56
    Leino, L., K. Saarinen, K. Kiviso, L. Koulu, C. T. Jansen and K. Punnonen (1999) Systemic suppression of human peripheral blood phagocytic leukocytes after whole-body UVB irradiation. J. Leukoc. Biol. 65, 573582.
  • 57
    Jeevan, A., C. D. Bucana, Z. Dong, V. V. Dixon, S. L. Thomas, T. E. Lloyd and M. L. Kripke (1995) Ultraviolet radiation reduces phagocytosis and intracellular killing of mycobacteria and inhibits nitric oxide production by macrophages in mice. J. Leukoc. Biol. 57, 883890.
  • 58
    Kasahara, S., K. Aizawa, M. Okamiya, N. Kazuno, S. Mutoh, H. Fugo, E. L. Cooper and H. Wago (2001) UVB irradiation suppresses cytokine production and innate cellular immune functions in mice. Cytokine 14, 104111.
  • 59
    Norbury, K. C., M. L. Kripke and M. B. Budmen (1977) In vitro reactivity of macrophages and lymphocytes from ultraviolet-irradiated mice. J. Natl Cancer Inst. 59, 12311235.
  • 60
    McLoone, P. and M. Norval (2005) Adaptation to the UV-induced suppression of phagocytic activity in murine peritoneal macrophages following chronic exposure to solar simulated radiation. Photochem. Photobiol. Sci. 4, 783788.
  • 61
    Grimbaldeston, M. A., J. J. Finlay-Jones and P. H. Hart (2006) Mast cells in photodamaged skin: What is their role in skin cancer? Photochem. Photobiol. 5, 177183.
  • 62
    Hart, P. H., M. A. Grimbaldeston, G. J. Swift, A. Jaksic, F. P. Noonan and J. J. Finlay-Jones (1998) Dermal mast cells determine susceptibility to UVB-induced systemic suppression of contact hypersensitivity. J. Exp. Med. 187, 20452053.
  • 63
    Kligman, L. H. and G. F. Murphy (1996) Ultraviolet B radiation increases hairless mouse mast cells in a dose-dependent manner and alters distribution of UV-induced mast cell growth factor. Photochem. Photobiol. 63, 123127.
  • 64
    Kaarsen, L. L., T. D. Poulsen, F. De Fine Olivarius and H. C. Wulf (1995) Mast cells and elastosis in ultraviolet-irradiated hairless mice. Photodermatol. Photoimmunol. Photomed. 11, 15.
  • 65
    Learn, D. B. and S. J. Moloney (1991) Numbers of murine mast cells remain unchanged during chronic ultraviolet B irradiation. Photodermatol. Photoimmunol. Photomed. 8, 195199.
  • 66
    Grimbaldeston, M. A., A. Simpson, J. J. Finlay-Jones and P. H. Hart (2003) The effect of ultraviolet radiation exposure on the prevalence of mast cells in human skin. Br. J. Dermatol. 148, 300306.
  • 67
    Weber, A., J. Knop and M. Maurer (2003) Pattern analysis of human cutaneous mast cell populations by total body surface mapping. Br. J. Dermatol. 148, 224228.
  • 68
    Janssens, A. S., R. Heide, J. C. Den Hollander, P. G. M. Mulder, B. Tank and A. P. Oranje (2005) Mast cell distribution in normal adult skin. J. Clin. Pathol. 58, 285289.
  • 69
    Grimbaldeston, M. A., A. L. Pearce, B. O. Robertson, B. J. Coventry, G. Marshman, J. J. Finlay-Jones and P. H. Hart (2004) Association between melanoma and dermal mast cell prevalence in sun-unexposed skin. Br. J. Dermatol. 150, 895903.
  • 70
    Grimbaldeston, M. A., A. Green, S. Darlington, B. O. Robertson, G. Marshman, J. J. Finlay-Jones and P. H. Hart (2003) Susceptibility to basal cell carcinoma is associated with high dermal mast cell prevalence in non-sun-exposed skin for an Australian population. Photochem. Photobiol. 78, 633639.
  • 71
    Grimbaldeston, M. A., L. Skov, O. Baadsgaard, B. G. Skov, G. Marshman, J. J. Finlay-Jones and P. H. Hart (2000) High dermal mast cell prevalence is a predisposing factor for basal cell carcinoma in humans. J. Invest. Dermatol. 115, 317320.
  • 72
    Grimbaldeston, M. A., L. Skov, J. J. Finlay-Jones and P. H. Hart (2002) Squamous cell carcinoma is not associated with high dermal mast cell prevalence in humans. J. Invest. Dermatol. 119, 12041206.
  • 73
    Kim, T. H., S. E. Ullrich, H. N. Ananthaswamy, S. Zimmerman and M. L. Kripke (1998) Suppression of delayed and contact hypersensitivity responses in mice have different UV dose responses. Photochem. Photobiol. 68, 738744.
  • 74
    El-Ghorr, A. A. and M. Norval (1999) The UV waveband dependencies in mice differ for the suppression of contact hypersensitivity, delayed-type hypersensitivity and cis-urocanic acid formation. J. Invest. Dermatol. 112, 757762.
  • 75
    Narbutt, J., A. Lesiak, M. Skibinska, A. Wozniacka, H. Van Loveren, A. Sysa-Jedrzejowska, I. Lewy-Trenda, A. Omulscka and M. Norval (2005) Suppression of contact hypersensitivity after repeated exposures of humans to low doses of solar simulated radiation. Photochem. Photobiol. Sci. 4, 517522.
  • 76
    Troost, R. J. J., M. M. A. Kozel, C. G. Van Helden-Meeuwsen, T. Van Joost, P. G. H. Mulder, R. Benner and E. P. Prens (1995) Hyposensitization in nickel allergic contact dermatitis: Clinical and immunologic monitoring. J. Am. Acad. Dermatol. 32, 576583.
  • 77
    Sjovall, P. and O. B. Christensen (1986) Local and systemic effect of ultraviolet irradiation (UVB and UVA) on human allergic contact dermatitis. Acta Derm. Venereol. 66, 290294.
  • 78
    Damian, D. L., R.StC. Barnetson and G. M. Halliday (1999) Low-dose UVA and UVB have different time courses for suppression of contact hypersensitivity to a recall antigen in humans. J. Invest. Dermatol. 112, 939944.
  • 79
    Alcalay, J. and M. L. Kripke (1991) Antigen-presenting activity of draining lymph node cells from mice painted with a contact allergen during ultraviolet carcinogenesis. J. Immunol. 146, 17171721.
  • 80
    Steerenberg, P. A., F. Daamen, E. Weesendorp and H. Van Loveren (2006) No adaptation to UV-induced immunosuppression and DNA damage following exposure to mice to chronic UV-exposure. J. Photochem. Photobiol. B, Biol. 84, 2837.
  • 81
    Fuller, C. J., H. Faulkner, A. Bendich, R. S. Parker and D. A. Roe (1992) Effect of β-carotene supplementation on photosuppression of delayed-type hypersensitivity in normal young men. Am. J. Clin. Nutr. 56, 684690.
  • 82
    Moyal, D., C. Courbiere, Y. Le Corre, O. De Lacharriere and C. Hourseau (1997) Immunosuppression induced by chronic solar-simulated irradiation in humans and its prevention by sunscreens. Eur. J. Dermatol. 7, 223225.
  • 83
    Moyal, D. D. and A. M. Fourtanier (2001) Broad-spectrum sunscreens provide better protection from the suppression of the elicitation phase of delayed-type hypersensitivity response in humans. J. Invest. Dermatol. 117, 11861192.
  • 84
    Damian, D. L., G. M. Halliday, C. A. Taylor and R.StC. Barnetson (1998) Ultraviolet radiation induced suppression of Mantoux reactions in humans. J. Invest. Dermatol. 110, 824827.
  • 85
    Cestari, T. F., M. L. Kripke, P. L. Baptista, L. Bakos and C. D. Bucana (1995) Ultraviolet radiation decreases the granulomatous response to lepromin in humans. J. Invest. Dermatol. 105, 813.
  • 86
    O’Dell, B. L., R. T. Jessen, L. E. Becker, R. T. Jackson and E. B. Smith (1980) Diminished immune responses in sun-damaged skin. Arch. Dermatol. 116, 559561.