Ultraviolet A (UVA) irradiation is effectively used to treat patients with atopic dermatitis and other T cell mediated, inflammatory skin diseases. In the present study, successful phototherapy of atopic dermatitis was found to result from UVA radiation-induced apoptosis in skin-infiltrating T helper cells, leading to T cell depletion from eczematous skin. In vitro, UVA radiation-induced human T helper cell apoptosis was mediated through the FAS/FAS-ligand system, which was activated in irradiated T cells as a consequence of singlet oxygen generation. These studies demonstrate that singlet oxygen is a potent trigger for the induction of human T cell apoptosis. They also identify singlet oxygen generation as a fundamental mechanism of action operative in phototherapy.

Cells from patients with xeroderma pigmentosum complementation group D (XP-D) and most patients with trichothiodystrophy (TTD) are deficient in excision repair of ultraviolet (UV) radiation-induced DNA damage. Although in both syndromes this defect is based on mutations in the same gene, XPD, only XP-D, not TTD, individuals have an increased risk of skin cancer. Since the reduction in DNA repair capacity is similar in XP-D and TTD patients, it cannot account for the difference in skin cancer risk. The features of XP-D and TTD might therefore be attributable to differences in the immune response following UV-irradiation, a factor which is presumed to be important for photocarcinogenesis. Sunlight-induced skin cancer represents the most prevalent malignancy in the Caucasian population, and its incidence is increasing (1). The pathogenesis of photocarcinogenesis is complex and only partially understood. Sunlight is a complete carcinogen, and it is generally accepted that ultraviolet B (UVB; 290-320 nm) radiation-induced DNA mutations constitute the initiation event for the generation of malignant skin cells (2). Studies in animals, however, provide evidence for a second mechanism for the development of clinically apparent skin cancer following UVB radiation exposure. In these studies, UVB radiation at subcarcinogenic doses was found to inhibit the surveillance function of the skin immune system directed against UVB radiation-induced skin tumors (3, 4). The importance of this second mechanism for photocarcinogenesis was demonstrated in tumor transplantation studies in mice, which cannot be carried out in humans. The evidence for a role of UVB radiation-induced immunosuppression in human skin cancer is therefore inevitably circumstantial and includes the observation that immunosuppressed humans who have received renal transplants have an increased frequency of sunlight-induced skin cancers (5-8).Here we take advantage of two human syndromes associated with defects in excision repair of UV-induced DNA lesions, namely xeroderma pigmentosum complementation group D (XP-D) and trichothiodystrophy (TTD) (9-11). Cells derived from XP-D and the majority of TTD patients have a defect in nucleotide excision repair (12, 13), which results from mutations in the same gene (XPD) (refs. 14-16 and unpublished results of B. C. Broughton and A.R.L.). Despite this similarity and a similar frequency of UV-induced mutations (17), only XP-D patients have an increased risk of developing skin cancer (10, 11). Since the increased risk of skin cancer in XP-D, as compared with TTD patients, cannot be explained simply by differences in DNA repair capacity, we hypothesized that XP-D and TTD cells might differ in some aspect of the immune response after UVB radiation.To test this hypothesis, the capacity of UVB radiation to suppress transcriptional expression of the intercellular adhesion molecule 1 (ICAM-1) was assessed in comparative studies employing XP-D and TTD cells. ICAM-1 serves as a ligand for leukocyte function-associated antige...