UVInduced Systemic Immunosuppression

Exposure of mice to relatively large doses of UVB radiation (>2 kJ/m2) inhibits both CHS responses after application of haptens to sites not exposed to UV and the induction of DTH responses (Beissert 2002, Beissert and Schwarz 1999, Noonan and DeFabo 1990,Toews et al. 1980, Ullrich 1995a). Because the Langerhans' cells critically involved in local immunosuppression were not altered in their number or morphology in non-UVB-exposed skin areas, this was indicative of effector mechanisms other than those involved in UV-induced local immunosuppression. Various mechanisms are considered to be involved in this so-called UV-induced systemic immuno-suppression, including aberrant signaling due to damage of the photoreceptor DNA, conformational changes in the photoreceptor urocanic acid, and the release of a plethora of soluble factors with suppressive properties, such as IL-1a, TNF-a, PGE2 and IL-10 (Beissert et al. 1995a, b, Black et al. 1978, Enk et al. 1995, Grewe et al. 1993, Köck et al. 1990,Niizeki and Streilein 1997,Noonan et al. 1988,Schwarz et al. 1994, Tan and Stoughton 1969, Ullrich et al. 1990,Yamawaki et al. 1998).

In particular, the role of IL-10 in UV-induced immunosuppression and regulation of cutaneous immune responses has been emphasized by several research groups (Beissert et al. 1995a, b, Enk et al. 1995, Niizeki and Streilein 1997, Ullrich 1994, Yamawaki et al. 1998). Intraperitoneal IL-10 administration was found to inhibit the elicitation phase but not the induction phase of CHS responses (Schwarz et al. 1994). On the other hand, both the induction and the elicitation of DTH immunity are suppressed by IL-10 treatment, indicating that CHS and DTH responses are related but distinct immune reactions. Increased concentrations of IL-10 were detected in the serum of UVB-exposed mice, and application of neutralizing anti-IL-10 antibodies significantly inhibited the UV-induced suppression of DTH responses to alloanti-gens, suggesting that IL-10 functions as a main mediator of UV-induced systemic immunosuppression (Beissert and Schwarz 1999, Beissert et al. 1996, Ullrich 1994). These findings are in agreement with the observation that spleen cells from UVB-treated mice are unable to present antigen to Th1 cells, whereas antigen presentation to Th2 cells was even enhanced (Ullrich 1994). Abrogation of both effects was achieved by application of neutralizing anti-IL-10 antibodies. To directly address the role of IL-10 in UV-induced systemic immunosuppression, IL-10-deficient mice were used (Beissert et al. 1996). The induction of DTH responses in IL-10-deficient mice could not be suppressed by UVB irradiation, whereas the induction of CHS responses was suppressed after UVB exposure. These data clearly demonstrate the in vivo relevance of IL-10 as a key mediator of UV-induced systemic immunosuppression. Furthermore, because IL-10 is one of the key cytokines involved in skewing the immune balance toward Th2-like immunity, such findings support the concept that UV exposure inhibits Th1-type immune responses.

The concept of a Th2 shift in systemic immunosuppression is further supported by the observation that immune suppression is blocked in mice treated with neutralizing anti-IL-4 antibodies (Shreedhar et al. 1998a). Although UVB irradiation does not directly induce the release of this key Th2 cytokine, the IL-4 effects might be mediated indirectly via the UVB-induced release of prostaglandin E2 by ker-atinocytes. Accordingly, this concept was substantiated by the observation that cyclooxygenase-2 inhibitors block IL-4 production after UV treatment. This alludes to the activation of a cytokine cascade (prostaglandin E2 ^ IL-4 ^ IL-10) after UVB exposure that finally results in systemic immunosuppression (Shreedhar et al. 1998a). Recent observations in humans revealed that UVB irradiation stimulates the immigration of neutrophils into the skin, which could give rise to type 2 T-cell responses in UVB-exposed skin via secretion of IL-4 (Teunissen et al. 2002). Hence, there is substantial evidence that exposure to UVB radiation generates a shift toward a Th2 immune response in vivo, thus explaining the fact that mostly Th1-mediated cellular immune reactions are impaired by UVB irradiation.

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