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Milestones in Photoimmunology

      Photoimmunology started almost 40 years ago with the discovery of a link between UVR and immunosuppression during experimental photocarcinogen-esis. Cutaneous UVR-induced tumors appeared to be highly antigenic, as they were rejected upon inoculation into syngeneic mice (
      • Kripke M.L.
      Effects of UV radiation on tumor immunity.
      ). Recipients treated with immuno-suppressive drugs did not reject the transplanted tumors, similar to reci¬pients who had received low doses of UVR instead of pharmacological immunosuppression, indicating that UVR suppresses cellular immunity. The most effective UVR spectrum to alter an immune response turned out to be the mid-wave range (UVB, 290-320 nm). Thus, most of the photoimmunologic studies were conducted with UVB, although UVA (320-400 nm) certainly has an effect on immune reactions as well.
      Besides the development of skin tumors, UVR was found to inhibit contact hypersensitivity (
      • Toews G.B.
      • Bergstresser P.R.
      • Streilein J.W.
      Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB.
      ). As mice that received the contact allergen through UVR-exposed skin could not be resensitized against the same antigen a few weeks later, it was concluded that UVR induces long-term suppression. This appeared to be antigen specific, as no other immune responses were altered. As UVR exposure and sensitization affect the same skin area, this model is also referred to as local immunosuppression. Later studies showed that UVR, although at higher doses, can also affect the immune system in a systemic manner via the release of soluble mediators (IL-10, tumor necrosis factor) from the skin (
      • Ullrich S.E.
      • Schmitt D.A.
      The role of cytokines in UV-induced systemic immune suppression.
      ). Whether the alarmin (endogenous mediators released upon cellular injury) IL-33 contributes to UVR-induced immunosuppression awaits further investigation, although the fact that neutralization of IL-33 blocks UVR-induced immunosuppression is quite convincing (
      • Byrne S.N.
      • Beaugie C.
      • O'Sullivan C.
      • et al.
      The immune-modulating cytokine and endogenous Alarmin interleukin-33 is upregulated in skin exposed to inflammatory UVB radiation.
      ).

      The Changing Role of Langerhans Cells

      Soon thereafter, it was shown that the antigen-specific immunotolerance induced by UVR is attributable to the occurrence of T cells with suppressive activities (
      • Elmets C.A.
      • Bergstresser P.R.
      • Tigelaar R.E.
      • et al.
      Analysis of the mechanism of unresponsiveness produced by haptens painted on skin exposed to low dose ultraviolet radiation.
      ), at that time called ''suppressor T cells'' and these days renamed ''regulatory T cells'' (Tregs) (
      • Schwarz T.
      25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells.
      ;
      • Loser K.
      • Beissert S.
      Regulatory T cells: banned cells for decades.
      ). The same low doses of UVR that suppressed sensiti¬zation depleted the Langerhans cells (LCs) from the epidermis. Initially, it was assumed that LCs are killed by UVR, but later it turned out that they leave the epidermis. As in those days LCs were regarded as the most important antigen-presenting cells in the skin (
      • Romani N.
      • Brunner P.M.
      • Stingl G.
      Changing views of the role of Langerhans cells.
      ) the failure to induce sensitization through UVR-exposed skin was associated with depletion of LCs from the epidermis.
      Nowadays, the functional role of LCs has been redefined. It became clear that LCs are not the primary antigenpresenting cells in the skin, but that this job is mostly done by dermal dendritic cells (
      • Merad M.
      • Ginhoux F.
      • Collin M.
      Origin, homeostasis and function of Langerhans cells and other langerin-expressing dendritic cells.
      ). In contrast, LCs appear to be more involved in downregulating than inducing immune responses, as recently demonstrated in diphtheria toxin receptor knock-in mice in which LCs can be depleted via injection of diphteria toxin (
      • Bennett C.L.
      • Clausen B.E.
      DC ablation in mice: promises, pitfalls, and challenges.
      ). Similarly, it was shown that LCs are crucially involved in UVR-induced immunosuppression, as inhibition of the induction of contact hypersensitivity (CHS) and the generation of Tregs were no longer observed upon UVR in LC-depleted mice (
      • Schwarz A.
      • Noordegraaf M.
      • Maeda A.
      • et al.
      Langerhans cells are required for UVR-induced immunosuppression.
      ). This is in accordance with the previous finding that the appearance of UVR-damaged LCs in the regional lymph nodes was required for the induction of Tregs (
      • Schwarz A.
      • Maeda A.
      • Kernebeck K.
      • et al.
      Prevention of UV radiation-induced immunosuppression by IL-12 is dependent on DNA repair.
      ). This implied that damaged but still alive LCs present the antigen in a nonprofessional manner and thus do not induce T-effector cells, but Tregs. However, additional mechanisms seem to be involved, as it was observed that UVR-induced upregulation of CD254 (RANKL) on keratinocytes activated RANK-stimulated LCs to induce Tregs (
      • Loser K.
      • Mehling A.
      • Loeser S.
      • et al.
      Epidermal RANKL controls regulatory T cell numbers via activation of dendritic cells.
      ).

      UVR-Induced Tregs

      UVR-induced Tregs appear to belong to the CD4+ CD25+ subtype, express CTLA4, and release IL-10 (
      • Schwarz T.
      25 years of UV-induced immunosuppression mediated by T cells-from disregarded T suppressor cells to highly respected regulatory T cells.
      ). They express the lymph node– homing receptor CD62L, migrate into the lymph nodes, and thus primarily inhibit sensitization. However, when present in the periphery, they also suppress the elicitiation of CHS. The pattern of tissue-homing receptors can be altered by tissue-specific antigenpresenting cells (
      • Schwarz A.
      • Navid F.
      • Sparwasser T.
      • et al.
      In vivo reprogramming of UV radiation-induced regulatory T-cell migration to inhibit the elicitation of contact hypersensitivity.
      ). Upon contact with LCs, UVR-Tregs downregulate CD62L and express skinhoming receptors. These cells mediate their effect by migrating into the skin and inhibit the elicitation. Hence, UVR-Tregs can suppress both the induction and the elicitation of CHS, provided they are at the appropriate site.

      Involvement of Cells Beyond T Cells

      When studying T-cell subsets involved in UVR-induced immunosuppression, it became evident that natural killer T (NKT) cells are involved in the suppression of tumor immune responses by UVR (
      • Moodycliffe A.M.
      • Nghiem D.
      • Clydesdale G.
      • et al.
      Immune suppression and skin cancer development: regulation by NKT cells.
      ). NKT cells that express intermediate amounts of T-cell receptor molecules and coexpress surface antigens normally found on NK cells (NK1.1, DX5, and Ly49a) may have a critical role in regulating the growth of UVR-induced skin cancers.
      Mast cells were previously largely ignored in photoimmunology. How¬ever, the prevalence of murine dermal mast cells correlated directly with their susceptibility to UVB-induced systemic immunosuppression, as demonstrated in mast cell-depleted (Wf/Wf) mice (
      • Hart P.H.
      • Grimbaldeston M.A.
      • Swift G.J.
      • et al.
      Dermal mast cells determine susceptibility to ultraviolet B-induced systemic suppression of contact hypersensitivity responses in mice.
      ). In addition, mast cells can be a source for IL-10, which mediates tolerance in UVR-induced immuno¬suppression (Alard et al., 2001). How¬ever, the role of mast cells in regulating CHS requires further elucidation, as depletion of mast cells by using the diphtheria toxin receptor knock-in method was not associated with an enhanced CHS response, but with a decreased CHS response (
      • Dudeck A.
      • Dudeck J.
      • Scholten J.
      • et al.
      Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens.
      ).
      Another quite neglected cell deserving more attention in photoimmunology is the B cell. They appear in increased numbers in the draining lymph nodes upon UVR (
      • Byrne S.N.
      • Halliday G.M.
      B cells activated in lymph nodes in response to ultraviolet irradiation or by interleukin-10 inhibit dendritic cell induction of immunity.
      ) and reveal an activated phenotype (MHCII, B220, IL-10). These cells exert suppressive activity, and thus were suggested to be called UVR-activated regulatory B cells. Studies utilizing inhibitors revealed that serotonin and platelet-activating factor are crucially involved in the activation of this possibly new B-cell subtype (
      • Matsumura Y.
      • Byrne S.N.
      • Nghiem D.X.
      • et al.
      A role for inflammatory mediators in the induction of immunoregulatory B cells.
      ).

      Molecular Events in Photoimmunosuppression

      A major molecular event in UVRmediated immunosuppression is the induction of DNA damage. Reduction of DNA damage via exogenous DNA repair enzymes prevented the suppression of the immune system by UVR, indicating the essential role of DNA damage in signal transduction (
      • Kripke M.L.
      • Cox P.A.
      • Alas L.G.
      • et al.
      Pyrimidine dimers in DNA initiate systemic immunosuppression in UV-irradiated mice.
      ). Similar observations were made when injecting cytokines, such as IL-12, IL-18, and IL-23, which induce DNA repair (
      • Schwarz T.
      • Schwarz A.
      DNA repair and cytokine responses.
      ). Recently, it was shown that UVR-damaged keratinocytes release noncoding RNA, which binds via Toll-like receptor-3 (
      • Bernard J.J.
      • Cowing-Zitron C.
      • Nakatsuji T.
      • et al.
      Ultraviolet radiation damages self noncoding RNA and is detected by TLR3.
      ). Toll-like receptor-3 ligation on keratinocytes induces the expression of tumor necrosis factor-a and IL-6. This pathway appears to be relevant also for UVR-induced immunosuppression, as TLR3— / — mice were found to be resistant to the immunosuppressive effects of UVR in the CHS model
      Beyond DNA, additional chromophores for UVR-induced immunosup-pression were identified. Trans-urocanic acid (UCA) is a histidine-derived molecule present in the stratum corneum. UVR isomerizes trans-UCA to cis-UCA (
      • Mohammad T.
      • Morrison H.
      • Hoengesch H.
      Urocanic acid photochemistry and photobiology.
      ). Removal of the stratum corneum by tape stripping prevented UVR-induced inhibition of CHS, suggesting that a relevant chromophore is removed (
      • DeFabo 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.
      ). Action spectra identified cis-UCA as the hottest candidate. Accordingly, injec¬tion of cis-UCA inhibited CHS. How¬ever, the mechanisms involved in UVR-and cis-UCA-mediated immuno¬suppression do not appear to be exactly the same. For example, anti-IL-10 antibodies blocked the induction of UVR-induced tolerance completely but that of cis-UCA-induced tolerance only partially (
      • Niizeki H.
      • Streilein J.W.
      Hapten-specific tolerance induced by acute, low-dose ultraviolet B radiation of skin is mediated via interleukin-10.
      ).

      Photoimmunologic Findings in Humans

      UVR-induced immunosuppression in humans may represent a risk factor for skin cancer, as the incidence of UVRinduced suppression of CHS is significantly higher in skin cancer patients. A strong association of UVR-susceptible and UVR-resistant phenotypes in humans with single-nucleotide polymorphisms in the tumor necrosis factor region was found, suggesting this region to contain genes that determine the outcome of an UVR response (
      • Yoshikawa T.
      • Rae V.
      • Bruins-Slot W.
      • et al.
      Susceptibility to effects of UVB radiation on induction of contact hypersensitivity as a risk factor for skin cancer in humans.
      ).
      Human volunteers developed tolerance when the hapten was initially painted onto UVR-treated skin (
      • Cooper K.D.
      • Oberhelman L.
      • Hamilton T.A.
      • et al.
      UV exposure reduces immunization rates and promotes tolerance to epicutaneous antigens in humans: relationship to dose, CD1a-DR+epidermal macrophage induction, and Langerhans cell depletion.
      ). UVR not only depleted LCs but also induced CD11b+ macrophages, which released IL-10 (
      • Kang K.
      • Hammerberg C.
      • Meunier L.
      • et al.
      CD11b+ macrophages that infiltrate human epidermis after ultraviolet exposure potently produce IL-10 and present the major secretory source of epidermal IL-10 protein.
      ). The development of tolerance versus suppressed CHS appears to correlate with the timing of antigen application after UVR exposure. Application immediately after UVR exposure resulted in inhibition of CHS but failed to induce tolerance (
      • Hammerberg C.
      • Duraiswamy N.
      • Cooper K.D.
      Active induction of unresponsiveness (tolerance) to DNFB by in vivo ultraviolet-exposed epidermal cells is dependent upon infiltrating class II MHC+ CD11bbright monocytic/macrophagic cells.
      ). The latter was only observed upon antigen application 72 hours after UVR, when LCs were depleted and Ia+CD11bbright macrophages had immigrated into the epidermis. CD11b binds the fragment of the complement component 3, iC3b, which appears to be critically involved, as C3-deficient mice were resistant to UVR-induced tolerance (
      • Hammerberg C.
      • Katiyar S.K.
      • Carroll M.
      • et al.
      Activated complement component 3 (C3) is required for ultraviolet induction of immunosuppression and antigenic tolerance.
      ).

      Consequences of UVR-Induced Immunosuppression

      The characteristic features of UVR-induced immunosuppression are its induction by low/physiologic doses, its antigen specificity, and its influence primarily on T cell-mediated immune reactions (
      • Schwarz A.
      • Noordegraaf M.
      • Maeda A.
      • et al.
      Langerhans cells are required for UVR-induced immunosuppression.
      ). The in vivorelevance and the biological implica¬tions of UVR-induced immunosuppres¬sion have long been, and partially remain, unclear. It is at least partially responsible for the effects of photo¬therapy (
      • Weichenthal M.
      • Schwarz T.
      Phototherapy: how does UV work?.
      ). UVR-induced immunosuppres-sion certainly is involved in photo-carcinogenesis. Chronically immunosuppressed persons reveal a remarkably enhanced risk for skin cancer, which correlates with cumulative UVR exposure (
      • Euvrard S.
      • Kanitakis J.
      • Claudy A.
      Skin cancers after organ transplantation.
      ).
      In addition, it was assumed that UVR-induced immunosuppression supports the exacerbation of skin infections (
      • Chapman R.S.
      • Cooper K.D.
      • De Fabo E.C.
      • et al.
      Solar ultraviolet radiation and the risk of infectious disease: summary of a workshop.
      ). In fact, experimental studies demonstrated the suppression of T-cell reactions against microbial antigens. However, the clinical experience differs. Except herpes simplex, the risk for infections, in particular bacterial infections, after UVR exposure is low. Atopic derma¬titis is frequently superinfected with Staphylococcus aureus, but can be improved by UVR even without anti-septic or antibiotic measures. Hence, the question is obvious: how can an immunosuppressive regimen such as UVR improve superinfected dermatoses without worsening the infection?
      The classical adaptive immune response, which involves antigenpresenting cells, T cells, and B cells, is by far less important for cutaneous antibacterial defense than the evolu-tionary much older innate immune system (
      • Medzhitov R.
      • Janeway Jr, C.
      Innate immunity.
      ). The latter reacts nonspecifically, but in turn is much faster and more effective. It involves neutrophils, NK cells, complement, and also antimicrobial peptides (AMPs), small molecules with effective antimicrobial activity. AMPs are produced in the skin, in particular b-defensins, psoriasin, and RNase7 (
      • Harder J.
      • Schrader J.M.
      Antimicrobial peptides in human skin.
      ). It was recently described that UVR induces AMPs (
      • Glaser R.
      • Navid F.
      • Schuller W.
      • et al.
      UV-B radiation induces the expression of antimicrobial peptides in human keratinocytes in vitro and in vivo.
      ). As UVR disturbs the epidermal barrier (
      • Jiang S.J.
      • Chen J.Y.
      • Lu Z.F.
      • et al.
      Biophysical and morphological changes in the stratum corneum lipids induced by UVB irradiation.
      ), it appears logical that AMPs are induced upon UVR exposure as a counter-regulatory phenomenon, pre-venting bacterial invasion. As AMPs are induced by UVR doses in the same physiologic range as that which sup-presses the adaptive immune response, it is fair to speculate that the downregulation of adaptive immunity in the skin may be beneficial as well.
      The skin is an organ close to (auto)immunity. One of the best routes to immunize is via the skin;many auto-immune diseases affect the skin. The majority of these reactions are T cell-driven (
      • Robert C.
      • Kupper T.S.
      Inflammatory skin diseases, T cells, and immune surveillance.
      ). This gives rise to the hypotheses that T cells in the skin may not always be beneficial, but more often harmful. Thus, it is fair to speculate that a certain level of constant immunosuppression by daily solar exposure may prevent the induction of such adverse immune responses, but this must be confirmed by future studies.

      Conclusion

      In summary, the view of photo-immunology has changed over the past several years (
      • Ullrich S.E.
      • Byrne S.N.
      The immunologic revolution: photoimmunology.
      ). The mechanisms involved are much more complex than initially thought. Previously, activation of the adaptive immune system was always associated with protection. In turn, sup¬pression was regarded as detrimental. Nowadays, we assume that a fine-tuned balance is optimal. Thus, sup¬pression may be as relevant as induc¬tion, and replacing the negatively perceived term ''suppression'' with ''regulation'' may be appropriate. The essential challenge of regulation is the toning down of overshooting immune responses that cause damage. Natural sun exposure may have a role in this scenario. Thus, UVR-induced immunosuppression may be judged from a different angle. Low/physio¬logic doses of UVR inhibit the adap¬tive immune system but induce parts of the innate immune system. This may be beneficial in protecting from microbial attacks, but it also tones down allergic and autoimmune reactions. This is in line with the fact that ambient solar exposure is crucial and physiologic. It will be one of the major future challenges to define the optimal UVR exposure for each individual, as excessive exposure is one of the major environmental threats for human health; this includes artificial UVR exposure as well.

      Conflict of Interest

      The authors state no conflict of interest.

      Acknowledgments

      TS is supported by the Deutsche Forschungsgemeinschaft (SCHW625/4-2).

      To cite this article

      Schwarz T, Beissert S (2013) Milestones in Photoimmunology. J Invest Dermatol 133: E7–E10.

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