Sunlight and Skin-Associated Lymphoid Tissues (SALT): If UVB Is the Trigger and TNFa Is its Mediator, What Is the Message?

The damaging effects on cutaneous immunity of Iow-dose ultraviolet B (UVB) radiation in sunlight are genetically determined in mice. Polymorphic alleles at the Tnfa and Lps loci dictate whether mice are UVB susceptible or resistant, i.e., deveIop contact hypersensitivity or not when hapten is painted on UVB-exposed skin. In mice, UVB susceptibility is mediated almost exclusively by tumor necrosis factor-alpha (TNFa). Circumstantial evidence implicates urocanic acid (UCA) in the stratum corneum as the photoreceptor for UVB, and recent results suggest that cis-UCA in turn instigates the intraepidermal accumulation of TNFa. It is hypothesized that TNFa interrupts the induction of contact hypersensitivity by preventing epidermal Langerhans cells from carrying hapten to the draining lymph node, where activation of naive, hapten-specific T cells must first occur. The phenotypic traits of UVB susceptibility (UVB-S) and UVB resistance (UVB-R) have now been documented in human beings, and the frequency of UVB-S is high (approximately 40-45%) in both Caucasians and individuals with deeply pigmented skin. Because the frequency of UVB-S is extremely high in patients with biopsy-proved basai and squamous celI skin cancer, this trait appears to be a risk factor for this disease. The unexpectediy high frequency of UVB-S in human beings, including black-skinned persons, implies that the trait is not perceived by evolutionary processes as deleterious. The possible selective advantages conferred by alleles that determine UVB-S are discussed with respect to cutaneous infections in which mortality and morbidity are primarily mediated by immunopathogenic processes