UVInduced Local Immunosuppression

Application of hapten onto low-dose UVB-exposed human or murine skin leads to inhibition of the induction of CHS. This effect has also been termed "UV-induced local immunosuppression". The UV-induced changes in epidermal Langerhans' cell function, as well as the UV-induced release of soluble immunosuppressive factors (interleukin [IL]-10, tumor necrosis factor [TNF]-a, IL-1a, and cis-urocanic acid), which influence the local micromilieu, have been proposed to be the major players contributing to this phenomenon (Black et al. 1978, Enk et al. 1993,1995, Grewe et al. 1993, Kock et al. 1990, Noonan et al. 1988, Toews et al. 1980, Ullrich 1995a, b).

In the early 1980s, Streilein's research group (Streilein and Bergstresser 1988) observed that low-dose UVB irradiation is capable of suppressing CHS responses to epicutaneously applied haptens in some strains of mice, and later studies revealed that genetic factors influence individual immunologic (un)responsiveness (Toews et al. 1980). Mouse strains in which immunosuppression was observed were designated UVB susceptible (e.g., C3H/HeN and C57BL/6), whereas strains resistant to the adverse effects of UV irradiation were termed "UVB resistant" (C3H/HeJ and BALB/c) (Streilein and Bergstresser 1988, Streilein et al. 1994). Further studies revealed that the genotype can be polygenically inherited and that the relevant autosomal loci controlling these traits can be found in the alleles Ips and tnf (Yoshikawa and Streilein 1990). Further circumstantial evidence for the relevance of the tnf locus was supplied by experiments in which suppression of CHS in UVB-susceptible animals was prevented when its gene product was blocked by neutralizing anti-TNF-a antibodies (Moody-cliffe et al. 1994). In keeping with these results, a diminished capacity to mount a CHS response when hapten was applied to murine skin after injection of subinflammatory doses of TNF-a has also been demonstrated. UV irradiation also induces morphologic alterations in epidermal Langerhans' cells. This leads to their immobilization, whereby the reduction of CHS responses ensues, and similar changes can be observed after injections of TNF-a. The involvement of TNF-a in the emigration of Langerhans' cells from irradiated skin into the regional lymph nodes has also been reported by other research groups (Cumberbatch and Kimber 1992). Nonetheless, the role of TNF-a was made questionable by the report that normal Langerhans' cell migration after hapten application onto unirradiated skin was observable in TNF receptor 1 (p55)-deficient mice but that the treatment of these mice with neutralizing anti-TNF-a antibodies still had the effect of reducing Langerhans'cell migration (Cumberbatch andKimber 1992, Kondo et al. 1995,Wang et al. 1996). This suggests that TNF receptor 1 may not be crucial for this process and indirectly implied that the TNF receptor 2 (p75) is required for Langerhans' cell migration. Because of the possible similarities between UVB- and TNF-a-mediated effects, the same group used these mouse models to study the role of the known TNF-a signaling pathways in UV-induced local suppression (Kondo et al. 1995). UVB irradiation similarly abrogated CHS responses in both mutant and wildtype mice as well as in mice deficient in TNF-a receptor 1+2, once again precluding TNF-a receptor 1 as a integral factor in the effects caused by UV in local cutaneous immunity. Taken together, the data obtained from the studies with these gene-targeted mice put the role of TNF-a signaling into a different perspective and suggest a minor role,if any,for the classic TNF-a signaling pathway in UVB-induced local immunosuppression and point to other factors as key mediators in this process.

UVB susceptibility and UVB resistance are not limited to mice but can also be found to a certain degree in humans (Yoshikawa et al. 1990). In addition, an association between the immunosuppressive effects of UVB and the development of skin cancer is evidenced by the significantly higher incidence of skin cancer in photosen sitive patients. Once again, in accordance with the evidence provided by the mouse models, microsatellite markers and single nucleotide polymorphisms link these phe-notypes to the TNF-a locus, suggesting that TNF-a or other genes contained in this region are plausible determinants of UVB susceptibility in humans (Niizeki et al. 2001). With the advent of human genome sequencing, a better marker(s) for UV susceptibility will be identified in the near future and will help clarify these controversial findings.

It is well documented that exposure to UVB radiation impairs Langerhans' cells in their activity to present antigens (Aberer et al. 1982,1991,Caceres-Dittmar et al. 1995, Greene et al. 1979, Simon et al. 1990, Stingl et al. 1981, 1983, Tang and Udey 1991). Low-dose exposure of Langerhans' cells to UVB also leads to the preferential activation of CD4+ cells of the T helper 2 (Th2) subset but does not result in the activation T helper 1 (Th1) cells (Simon et al. 1990).A follow-up study on this reported that UVB irradiation converts Langerhans' cells from immunogenic to tolerogenic antigen-presenting cells because of induction of specific clonal anergy in CD4+ Th1 cells (Simon et al. 1991). Because hapten sensitization represents a primary syngeneic response and these studies used either allogeneic primary systems or primed syngeneic systems, an extrapolation of these findings to the in vivo situation for hapten sensiti-zation may not be feasible, as neither of these model systems is an appropriate surrogate for suppression of a primary immune response.

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