Ultraviolet A Irradiation of C57BL/6 Mice Suppresses Systemic Contact Hypersensitivity or Enhances Secondary Immunity Depending on Dose
2002; Elsevier BV; Volume: 119; Issue: 4 Linguagem: Inglês
10.1046/j.1523-1747.2002.00261.x
ISSN1523-1747
AutoresScott N. Byrne, Nicole Spinks, Gary M. Halliday,
Tópico(s)Circadian rhythm and melatonin
ResumoUltraviolet radiation is the most common environmental carcinogen humans are exposed to. It is now known that in order for skin cancers to develop, both genetic damage and immunosuppression is required. Ultraviolet-induced immunosuppression is therefore a key contributor to the development of skin cancer. Little is known about the relative contributions of the different ultraviolet spectra (A and B), however. Therefore detailed ultraviolet dose–response curves for systemic suppression of contact hypersensitivity in two mouse strains were determined to examine the relative contributions of each of these spectral components of sunlight to primary and secondary immunity. Whereas ultraviolet B caused a linear dose-related immunosuppression in both C57BL/6 and Balb/c mice, only C57BL/6 mice were immunosuppressed by medium doses of ultraviolet A. At higher ultraviolet A doses, C57BL/6 mice were protected from immunosuppression, suggesting a genetic predisposition to ultraviolet-A-induced immunomodulation. Surprisingly, we found that, in contrast to primary immunosuppression, low dose ultraviolet A enhanced the secondary immune response, whereas ultraviolet B caused antigen-specific tolerance. When ultraviolet A and ultraviolet B were combined to mimic sunlight (solar-simulated ultraviolet), immunosuppression and tolerance were only observed over a narrow dose range as the memory-enhancing effect of low dose ultraviolet A and the immunoprotective effect of higher dose ultraviolet A prevented the suppressive effects of ultraviolet B. These studies suggest that complex relationships between ultraviolet dose, immunomodulation, spectra, and genetic background are likely to be important for skin cancer induction. We also describe for the first time that low doses of ultraviolet A are able to enhance secondary immunity, which has important implications for vaccination strategies. Ultraviolet radiation is the most common environmental carcinogen humans are exposed to. It is now known that in order for skin cancers to develop, both genetic damage and immunosuppression is required. Ultraviolet-induced immunosuppression is therefore a key contributor to the development of skin cancer. Little is known about the relative contributions of the different ultraviolet spectra (A and B), however. Therefore detailed ultraviolet dose–response curves for systemic suppression of contact hypersensitivity in two mouse strains were determined to examine the relative contributions of each of these spectral components of sunlight to primary and secondary immunity. Whereas ultraviolet B caused a linear dose-related immunosuppression in both C57BL/6 and Balb/c mice, only C57BL/6 mice were immunosuppressed by medium doses of ultraviolet A. At higher ultraviolet A doses, C57BL/6 mice were protected from immunosuppression, suggesting a genetic predisposition to ultraviolet-A-induced immunomodulation. Surprisingly, we found that, in contrast to primary immunosuppression, low dose ultraviolet A enhanced the secondary immune response, whereas ultraviolet B caused antigen-specific tolerance. When ultraviolet A and ultraviolet B were combined to mimic sunlight (solar-simulated ultraviolet), immunosuppression and tolerance were only observed over a narrow dose range as the memory-enhancing effect of low dose ultraviolet A and the immunoprotective effect of higher dose ultraviolet A prevented the suppressive effects of ultraviolet B. These studies suggest that complex relationships between ultraviolet dose, immunomodulation, spectra, and genetic background are likely to be important for skin cancer induction. We also describe for the first time that low doses of ultraviolet A are able to enhance secondary immunity, which has important implications for vaccination strategies. contact hypersensitivity minimal edematous dose solar-simulated ultraviolet radiation T helper The ultraviolet (UV) wavelengths in sunlight are the prime etiologic agents responsible for causing both melanoma (Armstrong and Kricker, 1993Armstrong B.K. Kricker A. How much melanoma is caused by sun exposure?.Melanoma Res. 1993; 3: 395-401Crossref PubMed Scopus (367) Google Scholar;Klein-Szanto et al., 1994Klein-Szanto A.J. Silvers W.K. Mintz B. Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice.Cancer Res. 1994; 54: 4569-4572PubMed Google Scholar) and epithelial skin cancer (Kricker et al., 1995Kricker A. Armstrong B.K. English D.R. Heenan P.J. A dose–response curve for sun exposure and basal cell carcinoma.Int J Canc. 1995; 60: 482-488Crossref PubMed Scopus (146) Google Scholar;Li et al., 1995Li G. Ho V.C. Berean K. Tron V.A. Ultraviolet radiation induction of squamous cell carcinomas in p53 transgenic mice.Cancer Res. 1995; 55: 2070-2074PubMed Google Scholar). Sunlight is made up of both UVB (290–320 nm) and UVA (320–400 nm) with the UVB component being at a much lower intensity than UVA. UV radiation-induced suppression of the immune system is an important step in carcinogenesis as it prevents the natural defence against skin cancer. The Food and Drug Administration (FDA, Federal Register, Vol. 64, no. 98, Friday May 21, 1999, pages 27666–27693) have recently acknowledged that both UV-induced genetic mutation and immunosuppression are required to develop skin cancer (Donawho and Kripke, 1991Donawho C.K. Kripke M.L. Evidence that the local effect of ultraviolet radiation on the growth of murine melanomas is immunologically mediated.Cancer Res. 1991; 51: 4176-4181PubMed Google Scholar). Therefore, to understand and protect against skin cancer, it is necessary to determine the doses of UV that influence the immune system as well as the role of different wavebands in sunlight. Controversy surrounds the relative roles of UVA compared to UVB, however, and comparative dose–responses have not been established. UVA can induce immunosuppression in both mice and humans (Halliday et al., 1998Halliday G.M. Bestak R. Yuen K.S. Cavanagh L.L. Barnetson R.S. UVA-induced immunosuppression.Mutation Res. 1998; 422: 139-145Crossref PubMed Scopus (53) Google Scholar;Damian et al., 1999Damian D.L. Barnetson R.S. Halliday G.M. Low-dose UVA and UVB have different time courses for suppression of contact hypersensitivity to a recall antigen in humans.J Invest Derm. 1999; 112: 939-944Crossref PubMed Scopus (92) Google Scholar;Nghiem et al., 2001Nghiem D.X. Kazimi N. Clydesdale G. Ananthaswamy H.N. Kripke M.L. Ullrich S.E. Ultraviolet A radiation suppresses an established immune response: implications for sunscreen design.J Invest Derm. 2001; 117: 1193-1199Crossref PubMed Scopus (96) Google Scholar), and in animal models UVA has been shown to contribute to the development of both squamous cell carcinoma (Kelfkens et al., 1992Kelfkens G. de Gruijl F.R. van der Leun J.C. The influence of ventral UVA exposure on subsequent tumorigenesis in mice by UVA or UVB irradiation.Carcinogenesis. 1992; 13: 2169-2174Crossref PubMed Scopus (5) Google Scholar) and melanoma (Ley, 1997Ley R.D. Ultraviolet radiation A-induced precursors of cutaneous melanoma in Monodelphis domestica.Cancer Res. 1997; 57: 3682-3684PubMed Google Scholar). Others have also found that UVA does not alter immunity, however (Skov et al., 1997Skov L. Hansen H. Barker J. Simon J.C. Baadsgaard O. Contrasting effects of ultraviolet-A and ultraviolet-B exposure on induction of contact sensitivity in human skin.Clin Exp Immunol. 1997; 107: 585-588Crossref PubMed Scopus (55) Google Scholar;Dittmar et al., 1999Dittmar H.C. Weiss J.M. Termeer C.C. et al.In vivo UVA-1 and UVB irradiation differentially perturbs the antigen-presenting function of human epidermal Langerhans cells.J Invest Derm. 1999; 112: 322-325Crossref PubMed Scopus (35) Google Scholar). Conversely, there is evidence that high doses of UVA can protect mice and humans from UVB-induced immunosuppression (Reeve et al., 1998Reeve V.E. Bosnic M. Boehm-Wilcox C. Nishimura N. Ley R.D. Ultraviolet A radiation (320–400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280–320 nm) or cis-urocanic acid.Int Arch Allergy Immunol. 1998; 115: 316-322Crossref PubMed Scopus (89) Google Scholar;Skov et al., 2000Skov L. Villadsen L. Ersboll B.K. Simon J.C. Barker J. Baadsgaard O. Long-wave UVA offers partial protection against UVB-induced immune suppression in human skin.Apmis. 2000; 108: 825-830Crossref PubMed Scopus (16) Google Scholar;Garssen et al., 2001Garssen J. de Gruijl F. Mol D. de Klerk A. Roholl P. Van Loveren H. UVA exposure affects UVB and cis-urocanic acid-induced systemic suppression of immune responses in Listeria monocytogenes-infected Balb/c mice.Photochem Photobiol. 2001; 73: 432-438Crossref PubMed Scopus (34) Google Scholar). The experiments described here aimed to clarify the roles of UVA and UVB in UV-induced systemic suppression and tolerance to contact sensitization by constructing dose–response curves for UVA, UVB, and solar-simulated UV radiation (ssUVR). The results show complex interactions dependent on dose, spectra, and genetic background. Female C57BL/6 and Balb/c mice aged 7–8 wk at the start of irradiations were used in these experiments (Animal Resource Center, Perth, WA, Australia), which were conducted with the approval of the Sydney University animal ethics committee. UVA, UVB, and ssUVR spectra were produced with a 1000 W xenon arc solar simulator (Oriel, Stratford, CT). For ssUVR, two dichroic mirrors that each allow wavelengths between 200 nm and 400 nm to pass through were used in conjunction with an atmospheric attenuation filter to produce a spectrum closely resembling sunlight. By changing this filter for one that blocks UVB radiation, a spectrum containing mostly UVA was produced. Alternatively, by changing the two dichroic mirrors to ones that reflect wavelengths between 260 nm and 320 nm, a spectrum containing mostly UVB was produced. The intensity (mW per cm2) of the UV output was measured continuously using a radiometer (Solar Light Company, PA), and the timing of UV exposure was adjusted with an automated timing device so that accurate UV doses (measured in mJ per cm2) could be delivered to individual mice. Spectral output of the solar simulator (both intensity and wavelength) was measured using an OL-754 spectroradiometer (Optronic Laboratories, Orlando, FL), which was calibrated against standard lamps for spectra and intensity and was used to calibrate the radiometer against the source. Additionally, the spectral output of the sun was measured for comparison on October 10, 2001, at midday on a cloudless day in Sydney, Australia. The minimum dose to induce edema (the minimum edematous dose, MEdD) was determined by exposing groups of six to eight mice to various doses of ssUVR. The pre-UV and 24 h post-UV skin thickness was measured using a hand-held high frequency ultrasound (Longport International, Silchester, U.K.) with the minimum dose of ssUVR required to cause a significant increase in skin thickness being the MEdD. For ethical reasons, mice were not given any dose greater than the MEdD. Irradiation times were short (less than 1 min) and a combination of fans and air-conditioning were used to ensure that the mouse body temperature did not increase during irradiation. For each experiment, seven groups of four to seven C57BL/6 or Balb/c mice each had their back-skin hair removed using animal clippers (Oster, McMinnville, TN) and a close shave electric razor (Remington, Austria). Mice were allowed 24 h to recover from any inflammatory effects of the shaving before they were placed in a black perspex animal-restraining device fitted with a quartz glass lid for exposure to various doses and wavelengths of UV radiation. Additionally, the mice ears and head were shielded from the UV with black perspex. One of six different UV doses ranging from control unirradiated (0 mJ per cm2) to 1 × MEdD were delivered to groups of mice each day for three consecutive days. UV-induced systemic immunosuppression has been produced by many groups using a variety of irradiation protocols ranging from single doses to multiple doses over the course of many weeks. The 3 d irradiation regime used in these experiments was based on previous reports by others using multiple irradiations ranging from 2 to 4 d (Noonan and De Fabo, 1990Noonan F.P. De Fabo E.C. Ultraviolet-B dose–response curves for local and systemic immunosuppression are identical.Photochem Photobiol. 1990; 52: 801-810Crossref PubMed Scopus (83) Google Scholar;Roberts and Beasley, 1997Roberts L.K. Beasley D.G. Sunscreens prevent local and systemic immunosuppression of contact hypersensitivity in mice exposed to solar-simulated ultraviolet radiation.J Photochem Photobiol B – Biol. 1997; 39: 121-129Crossref PubMed Scopus (19) Google Scholar). The seventh group was an unirradiated irritant control. Each experiment was repeated three times with the results normalized and pooled. To determine the UV effects on primary and secondary immunity, CHS was induced (Figure 1). For systemic immunosuppression (primary immunity) studies, mice that received UV exposure to the back-skin were sensitized by applying 50 µl of a 2% wt/vol solution of oxazalone (4-ethoxymethylene-2-pheyl-2-oxazolin-5-one; Sigma Chemical, St. Louis, MO) dissolved in acetone. This hapten was applied to the shaved abdomen 3 d after the final UV exposure, with positive control unirradiated mice being sensitized in the same way. To assess the primary CHS, 5 µl of the 2% oxazalone solution was applied to the right ear of the mice 7 d later. After a further 24 h, the difference in the thickness between the right challenged and left unchallenged ears was measured using engineers' callipers (Mitutoyo, Japan). The increase in ear thickness of negative control unirradiated, unsensitized but challenged only mice (irritant control) were subtracted from the test groups. For evaluation of the effects of UV on the secondary immune response, these same groups of mice were rested for 8–10 wk (Figure 1). Memory and/or regulatory T cell activity induced by the primary sensitization was detected by a second contact sensitization without further UV irradiation. Thus, the mice were re-sensitized by applying 2% wt/vol oxazolone to the shaved abdomen. CHS was then assessed by ear challenge to the previously unchallenged (left) ear 7 d later as described above. For assessment of the MEdD, a paired Student's t test was used and p < 0.05 was considered statistically significant. Differences between the two strains was compared by a repeated measures ANOVA. For CHS experiments testing primary and secondary immune responses, experiments were repeated three times with the same result observed each time. Results were then normalized against the positive control group in each experiment and pooled for final analysis. An unpaired Student's t test was used to test for significance, with p < 0.05 considered statistically significant. Many previous studies on the biologic effects of UV have used banks of fluorescent tubes emitting disproportionately large amounts of UVB (47%) and less UVA (53%) than is found in sunlight (5% and 95%, respectively). The work described here used a xenon arc solar simulator, which provided a better mimic of the solar spectrum comprising 5.9% UVB and 94.1% UVA (Figure 2). When using wavebands within the solar spectrum, it was important for this study that the shape of the waveband remained similar to that band within the solar spectrum. When the UVB component was blocked using a UVB/UVC blocking filter, the UVA spectrum closely approximated the UVA component of sunlight with a sharp cut-off at 320 nm (Figure 2). The percentage of contaminating UVB present in the UVA spectrum was less than 0.001%, which was determined by integrating the area under the spectral curve. Similarly, by changing the dichroic mirrors, a spectrum containing mostly UVB wavelengths was produced with the UVA wavelengths being severely attenuated relative to ssUVR (Figure 2). The relative spectral irradiance of the UVB spectrum between 290 and 320 nm was a very good approximation of the UVB component of the solar spectrum (Figure 2). For wavelengths greater than 320 nm not completely removed, there was a one log reduction in intensity by 340 nm and a one and a half log reduction in intensity compared to the solar-simulated spectrum by 370 nm (note that the figure is on a log scale). Therefore, a wavelength distribution similar to that found in sunlight (ssUVR) as well as the two component spectra (UVA and UVB) could accurately be delivered to mice. The delivery of this high intensity output to immobilized single mice therefore enabled more accurate determination of dose–responses than has previously been described. The lowest dose of ssUVR that caused a significant increase in skin thickness (MEdD) was found to be the same in both mouse strains (Figure 3). In humans, the minimum erythema dose (MED) is commonly used to assess the biologic endpoint of erythema or redness of the skin and is also used to determine the skin type of individuals. Because mouse skin is pink, however, changes in skin color cannot be easily detected. Therefore, instead of erythema, the edemal component of sunburn is commonly used as a way of measuring sunburn in mice (Cole et al., 1983Cole C.A. Davies R.E. Forbes P.D. D'Aloisio L.C. Comparison of action spectra for acute cutaneous responses to ultraviolet radiation: man and albino hairless mouse.Photochem Photobiol. 1983; 37: 623-631Crossref PubMed Scopus (88) Google Scholar). We established the use of a hand-held high frequency ultrasound to accurately determine the MEdD. This is conventionally measured using callipers, but we found the ultrasound gave more reproducible results. The MEdD was 3640 mJ per cm2 of ssUVR, being made up of 280 mJ per cm2 UVB and 3360 mJ per cm2 UVA (Figure 3). Although the MEdD was the same for both C57BL/6 and Balb/c mice, the magnitude of the response between the two strains was significantly different (p < 0.005; repeated measures ANOVA), with C57BL/6 mice showing a greater response than Balb/c mice. All irradiations used for immunosuppression were below the MEdD so that the biologic changes associated with sunburn did not confound the immunosuppression studies. This also meant that this study used ssUVR doses that could be experienced in everyday situations by humans. As the MEdD was indistinguishable between the two mouse strains, they can be considered to be of a similar “skin type”. MEdD does not correlate with sensitivity to immunomodulation, however (Damian et al., 1997Damian D.L. Halliday G.M. Barnetson R.S. Broad-spectrum sunscreens provide greater protection against ultraviolet-radiation-induced suppression of contact hypersensitivity to a recall antigen in humans.J Invest Derm. 1997; 109: 146-151Crossref PubMed Scopus (118) Google Scholar), so this issue does not complicate interpretation of the immunosuppression studies. Results from earlier murine studies demonstrated that single doses of both UVB and UVA radiation induce antigen-specific immunosuppression as well as tolerance (Halliday et al., 1998Halliday G.M. Bestak R. Yuen K.S. Cavanagh L.L. Barnetson R.S. UVA-induced immunosuppression.Mutation Res. 1998; 422: 139-145Crossref PubMed Scopus (53) Google Scholar), which is consistent with results obtained in humans (Damian et al., 1999Damian D.L. Barnetson R.S. Halliday G.M. Low-dose UVA and UVB have different time courses for suppression of contact hypersensitivity to a recall antigen in humans.J Invest Derm. 1999; 112: 939-944Crossref PubMed Scopus (92) Google Scholar) but inconsistent with studies showing that high dose UVA protects from the suppressive effects of UVB (Reeve et al., 1998Reeve V.E. Bosnic M. Boehm-Wilcox C. Nishimura N. Ley R.D. Ultraviolet A radiation (320–400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280–320 nm) or cis-urocanic acid.Int Arch Allergy Immunol. 1998; 115: 316-322Crossref PubMed Scopus (89) Google Scholar). To resolve this issue, dose–response studies were performed that revealed that UVA and UVB, although both immunosuppressive, display different dose–responses in the different mouse strains. C57BL/6 mice showed positive control ear swelling responses of 21.4 ± 1.6 with irritant controls of 3.6 ± 0.6 × 10-2 mm. For C57BL/6 mice, low doses of the UVB portion of sunlight were sufficient to suppress systemic immunity (Figure 4a ). This dose (35 mJ per cm2) was the lowest delivered to mice demonstrating that UVB is potently immunosuppressive. The amount of UVA contaminating this UVB dose was 66 mJ per cm2 UVA, which was 25-fold lower than the minimum immunosuppressive UVA dose (Figure 4b). The level of immunosuppression increased linearly with UVB dose, which is consistent with other studies exploring the dose–response effects of UVB on systemic immunosuppression (Noonan and De Fabo, 1990Noonan F.P. De Fabo E.C. Ultraviolet-B dose–response curves for local and systemic immunosuppression are identical.Photochem Photobiol. 1990; 52: 801-810Crossref PubMed Scopus (83) Google Scholar). Medium dose UVA (1680 mJ per cm2) was also able to suppress CHS in C57BL/6 mice (Figure 4b). This corresponded to approximately half the UVA dose present in the MEdD of ssUVR. It is unlikely that traces of UVB were responsible for this UVA-induced systemic immunosuppression in C57BL/6 mice as the percentage of contaminating UVB in the UVA spectrum was less than 0.001%, thus delivering less than 0.0014 mJ per cm2 UVB. Moreover, if this low dose of UVB was immunosuppressive, then the Balb/c mice would also be expected to be immunosuppressed by 1680 mJ per cm2 of UVA. Interestingly, as the dose of UVA was increased, C57BL/6 mice recovered from immunosuppression (Figure 4b). These two spectra were then combined to produce ssUVR (Figure 4c). Because UVB and UVA were both able to suppress primary immunity to oxazolone at low doses, ssUVR also suppressed immunity at these doses. At higher doses, however, although the UVB portion remained suppressive, the UVA component was not, and therefore appeared to protect C57BL/6 mice from the immunosuppressive effects of UVB. Therefore the dose–response for ssUVR was similar to that of UVA but different to the dose–response for UVB in this mouse strain. Balb/c mice showed positive control ear swelling responses of 27.4 ± 1.4 with irritant controls of 5.9 ± 1.0 × 10-2 mm. Balb/c mice were also suppressed by low doses of UVB and displayed a similar dose responsiveness to C57BL/6 mice (Figure 4a). In contrast to C57BL/6 mice, however, Balb/c mice were unaffected by any dose of UVA (Figure 4b). Because of this, when the two spectra were combined to form ssUVR, UVA protection from the immunosuppressive effects of UVB was not observed; rather, higher doses of ssUVR continued to be immunosuppressive (Figure 4c). Also, because low dose UVA was unable to suppress the CHS response in Balb/c mice (Figure 4b), the magnitude of ssUVR-induced suppression in Balb/c was less than in C57BL/6 mice (24% and 55% suppression, respectively). In experiments to test UVB susceptibility to systemic immunosuppression,Noonan and Hoffman, 1994Noonan F.P. Hoffman H.A. Susceptibility to immunosuppression by ultraviolet B radiation in the mouse.Immunogenetics. 1994; 39: 29-39Crossref PubMed Scopus (78) Google Scholar showed that, compared to Balb/c mice, C57BL/6 mice required much lower doses of UVB to become systemically immunosuppressed, and the mice were therefore classed as having a low and high UVB susceptibility, respectively. This study used a UVB spectrum emitted from unfiltered FS40 sunlamps having a peak at 313 nm and containing mostly UVB (60%-65%) but also wavelengths below 290 nm. This contrasts with our UVB spectrum mimicking the UVB portion of the solar spectrum peaking at 320 nm, with essentially no wavelengths in the UVC region (below 290 nm). Our study showed no differences in susceptibility to UVB-induced systemic immunosuppression between C57BL/6 and Balb/c mice, probably because of the spectrum used. Therefore, previous reports of a genetic susceptibility to UVB is probably dependent on the spectra used and possibly the type of immune response being studied. An earlier study by Noonan et al, however, showed that the dose–response curves for UVB-induced local and systemic immunosuppression were the same, with Balb/c mice requiring 6.4 times more UVB than C57BL/6 to attain identical systemic immunosuppression (Noonan and De Fabo, 1990Noonan F.P. De Fabo E.C. Ultraviolet-B dose–response curves for local and systemic immunosuppression are identical.Photochem Photobiol. 1990; 52: 801-810Crossref PubMed Scopus (83) Google Scholar). Therefore it is likely that genetic susceptibility to UV is very dependent on spectrum and dose, and our spectrum, which closely matched the UVB portion of sunlight, did not differentiate between these strains. C57BL/6 mice are prone to T helper 1 (Th1) immunity in response to antigen (as measured by interferon-γ), whereas Balb/c mice are more likely to produce a Th2-type response [as measured by interleukin-4 (IL-4) secretion] (Kelso et al., 1991Kelso A. Troutt A.B. Maraskovsky E. Gough N.M. Morris L. Pech M.H. Thomson J.A. Heterogeneity in lymphokine profiles of CD4+ and CD8+ T cells and clones activated in vivo and in vitro.Immunol Rev. 1991; 123: 85-114Crossref PubMed Scopus (113) Google Scholar). This genetic predisposition to specific types of immune responses may partially explain some of the contrasting results with the two strains presented here. This is especially true considering that UV irradiation can switch from a Th1- to a Th2-type immune response (Simon et al., 1994Simon J.C. Mosmann T. Edelbaum D. Schopf E. Bergstresser P.R. Cruz Jr, P.D. In vivo evidence that ultraviolet B-induced suppression of allergic contact sensitivity is associated with functional inactivation of Th1 cells.Photoderm Photoimmunol Photomed. 1994; 10: 206-211PubMed Google Scholar;Garssen et al., 1999Garssen J. Vandebriel R.J. De Gruijl F.R. Wolvers D.A. Van Dijk M. Fluitman A. Van Loveren H. UVB exposure-induced systemic modulation of Th1- and Th2-mediated immune responses.Immunology. 1999; 97: 506-514Crossref PubMed Scopus (98) Google Scholar). Therefore, C57BL/6 may be more sensitive to UV-induced immunomodulation of Th1 immunity than Balb/c mice. It has not been previously examined whether there is a genetic susceptibility to ssUVR or UVA, and, despite the lack of evidence for a genetic susceptibility to UVB-induced immunosuppression in this study, a difference was found between C57BL/6 and Balb/c mice with regard to their susceptibility to both ssUVR and the UVA portion of the solar spectrum. These results suggest that there is a genetic dependence on the ability of UVA to modulate immunity and that the mechanisms underlying UVA and UVB immunosuppression may differ. Indeed, although we show here that Balb/c mice are not suppressed by subedemal doses of UVA and C57B/6 mice have a bell-shaped dose–response curve,Nghiem et al., 2001Nghiem D.X. Kazimi N. Clydesdale G. Ananthaswamy H.N. Kripke M.L. Ullrich S.E. Ultraviolet A radiation suppresses an established immune response: implications for sunscreen design.J Invest Derm. 2001; 117: 1193-1199Crossref PubMed Scopus (96) Google Scholar have shown using a delayed type hypersensitivity assay that C3H/HeN mice display a linear dose–response to UVA-induced immunosuppression. These results indicate that the possible reasons why previous studies have found UVA to be immunosuppressive (Halliday et al., 1998Halliday G.M. Bestak R. Yuen K.S. Cavanagh L.L. Barnetson R.S. UVA-induced immunosuppression.Mutation Res. 1998; 422: 139-145Crossref PubMed Scopus (53) Google Scholar;Nghiem et al., 2001Nghiem D.X. Kazimi N. Clydesdale G. Ananthaswamy H.N. Kripke M.L. Ullrich S.E. Ultraviolet A radiation suppresses an established immune response: implications for sunscreen design.J Invest Derm. 2001; 117: 1193-1199Crossref PubMed Scopus (96) Google Scholar) or protective (Reeve et al., 1998Reeve V.E. Bosnic M. Boehm-Wilcox C. Nishimura N. Ley R.D. Ultraviolet A radiation (320–400 nm) protects hairless mice from immunosuppression induced by ultraviolet B radiation (280–320 nm) or cis-urocanic acid.Int Arch Allergy Immunol. 1998; 115: 316-322Crossref PubMed Scopus (89) Google Scholar) could be due to (i) the different doses of UVA being used, (ii) the assay, or (iii) the genetics of the irradiated host. The mechanism of UVB-induced immune suppression is thought to involve alterations to various cytokines, which lead to systemic changes in immune cells. Alterations to IL-4, IL-10, IL-12 (Rivas and Ullrich, 1994Rivas J.M. Ullrich S.E. The role of IL-4, IL-10, and TNF-alpha in the immune suppression induced by ultraviolet radiation.J Leuk Biol. 1994; 56: 769-775PubMed Google Scholar), tumor necrosis factor (Vincek et al., 1993Vincek V. Kurimoto I. Medema J.P. Prieto E. Streilein J.W. Tumor necrosis factor alpha polymorphism correlates with deleterious effects of ultraviolet B light on cutaneous immunity.Cancer Res. 1993; 53: 728-732PubMed Google Scholar), and cis-urocanic acid (De Fabo and Noonan, 1983De Fabo E.C. Noonan F.P. 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. 1983; 158: 84-98Crossref PubMed Scopus (435) Google Scholar) levels are all thought to be involved in this process. These changes affect antigen presentation (Kripke and McClendon, 1986Kripke M.L. McClendon E. Studies on the role of antigen-presenting cells in the systemic suppression of contact hypersensitivity by UVB radiation.J Immunol. 1986; 137: 443-447PubMed Google Scholar) and T cell activation, including the generation of suppressor T cells in UVB-exposed mic
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