Hiroko Miyauchi-Hashimoto

The clinical and photobiological characteristics of solar urticaria in 40 patients.

Forty patients with solar urticaria, 16 male and 24 female, were examined personally during the past 25u2003years. The median age at onset of symptoms was 32u2003years, ranging from 13 to 76u2003years. Most commonly (45%) solar urticaria first appeared during the third decade. The mean duration of the disease was 3·6u2003years at presentation. The action spectrum was found in the visible light range in 24 patients (60%), in the ultraviolet (UV) A range in four, in the UVB in four, from the UVA to UVB in three, from the UVA to visible light in one and in a broad range from UVB to visible light in four patients. An inhibition spectrum was detected in 13 of 19 patients (68%), occurring at longer wavelengths than the action spectrum in 12 of these cases. The augmentation spectrum was found in only four of 14 patients (29%) examined. Twenty‐four of 31 patients (77%) developed an urticarial reaction to autologous serum, which had been previously irradiated in vitro at the action spectrum for that patient. In a single patient, solar urticaria was caused by a drug, namely chlorpromazine. In two patients, polymorphic light eruption occurred in association with solar urticaria. No single modality of treatment was satisfactory, but combined use of antihistamines, sunbathing, psoralen UVA photochemotherapy and/or sunscreening agents partially suppressed the symptoms.

UV-induced skin carcinogenesis in xeroderma pigmentosum group A (XPA) gene-knockout mice with nucleotide excision repair-deficiency.

Nucleotide excision repair (NER) removes a wide variety of lesions from the genome and is deficient in the genetic disorder, xeroderma pigmentosum (XP). In this paper, an in vitro analysis of the XP group A gene product (XPA protein) is reported. Results of an analysis on the pathogenesis of ultraviolet (UV)-B-induced skin cancer in the XPA gene-knockout mouse are also described: (1) contrary to wild type mice, significant bias of p53 mutations to the transcribed strand and no evident p53 mutational hot spots were detected in the skin tumors of XPA-knockout mice. (2) Skin cancer cell lines from UVB-irradiated XPA-knockout mice had a decreased mismatch repair activity and an abnormal cell cycle checkpoint, suggesting that the downregulation of mismatch repair helps cells escape killing by UVB and that mismatch repair-deficient clones are selected for during the tumorigenic transformation of XPA (-/-) cells. (3) The XPA-knockout mice showed a higher frequency of UVB-induced mutation in the rpsL transgene at a low dose of UVB-irradiation than the wild type mice. CC-->TT tandem transition, a hallmark of UV-induced mutation, was detected at higher frequency in the rpsL transgene in the XPA-knockout mice than the wild type mice. This rpsL/XPA mouse system will be useful for further analysing the role of NER in the mutagenesis induced by various carcinogens. (4) The UVB-induced immunosuppression was greatly enhanced in the XPA-knockout mice. It is possible that an enhanced impairment of the immune system by UVB irradiation is involved in the high incidence of skin cancer in XP.

Protective effects of sunscreening agents on photocarcinogenesis, photoaging, and DNA damage in XPA gene knockout mice

Abstract We investigated the protective effects of commercial sunscreening agents against UVB-induced photoresponses in group A xeroderma pigmentosum (XPA) model mice. XPA gene-deficient mice are defective in nucleotide excision repair and show a high incidence of skin tumors and severe acute inflammation in response to UVB irradiation, in a similar manner to XP patients. SPF 10 and SPF 60 sunscreens protected partially and almost completely, respectively, ear swelling responses produced by UVB up to 200 mJ/cm 2 in (–/–) mice. XPA (–/–) mice were irradiated three times a week to a cumulative dose of 2.6 J/cm 2 UVB for a period of 24 weeks with or without SPF 10 or SPF 60 sunscreen. UV-induced skin tumors had developed in all unprotected (–/–) mice (13.3 tumors per mouse) at the completion of UVB irradiation. The SPF 60 sunscreen afforded stronger protection against photocarcinogenesis (1.0 tumors per mouse) than the SPF 10 sunscreen (4.4 tumors per mouse). Regarding photoaging, SPF 60 sunscreen also protected against mast cell infiltration (79% inhibition), elastic fiber accumulation, and dermal cyst proliferation in XPA (–/–) mice compared with unprotected (–/–) mice. In (–/–) mice, the SPF 60 sunscreen provided stronger protection against cyclobutane pyrimidine dimer formation shown immunohistologically following irradiation with 200 mJ/¶cm 2 UVB than the SPF 10 sunscreen. The XPA model mouse is a useful animal for the evaluation of the photoprotective ability of sunscreens because photoresponses, even chronic changes, can be easily and quickly induced experimentally.

Carcinogen-Induced Inflammation and Immunosuppression Are Enhanced in Xeroderma Pigmentosum Group A Model Mice Associated with Hyperproduction of Prostaglandin E2

Xeroderma pigmentosum group A (XPA) gene-deficient mice easily developed skin cancers by the application of topical chemical carcinogens as well as by UV irradiation. As certain chemical carcinogens have been shown to be immunosuppressive, we examined the inflammatory and immunosuppressive effects of dimethylbenz(a)anthracene (DMBA) on XPA mice. Compared with wild-type mice, XPA mice showed greater ear swelling and reduction of epidermal Langerhans cells after DMBA application. Topical application of DMBA impaired the induction of contact hypersensitivity, initiated either locally or at distant sites. These DMBA-induced local and systemic immunosuppressions were more greatly enhanced in XPA mice than in wild-type mice. DMBA application induced pronounced production of PGE2, IL-10, and TNF-α in the skin of XPA mice. Treatment with indomethacin, a potent inhibitor of PG biosynthesis, inhibited DMBA-induced inflammation and local immunosuppression. In XPA mice, increased serum IL-10 was detected after DMBA treatment. Excess production of PGE2, TNF-α, and IL-10 after DMBA application may be involved in the enhanced local and systemic immunosuppression in DMBA-treated XPA mice. Susceptibility to DMBA-induced skin tumors in XPA mice may be due to easy impairment of the immune system by DMBA in addition to a defect in the repair of DMBA-DNA adduct. Enhanced immunosuppression by chemical carcinogens as well as the mutagenicity of these mutagens might be associated with the high incidence of internal malignancies seen in XP patients. Moreover, these results supported the hypothesis that persistent DNA damage is a trigger for the production of immunoregulatory cytokines.

Cockayne syndrome without typical clinical manifestations including neurologic abnormalities

Although patients with mild symptoms of atypical Cockayne syndrome (CS) have been described, there has not been a report of a patient with CS whose only clinical manifestation was cutaneous photosensitivity. Cells from patients with CS show UV sensitivity, reduced recovery of RNA synthesis, but normal UV-induced unscheduled DNA synthesis. On the other hand, the patients with UV-sensitive syndrome have only cutaneous photosensitivity and skin freckles, whereas those cells respond to UV radiation in a similar fashion to the CS cells. We describe a patient with CS who showed only photosensitivity without typical clinical manifestations of CS, but his cells showed UV sensitivity, reduced recovery of RNA synthesis, and normal unscheduled DNA synthesis after UV radiation similar to CS cells. Furthermore, the patient was assigned to complementation group B of CS on the basis of the results of complementation analysis. The present report suggests that CS has a wider spectrum than that considered previously.

Therapeutic and prophylactic effects of PUVA photochemotherapy on atopic dermatitis‐like lesions in NC/Nga mice

Background: Psoralens and ultraviolet A radiation (PUVA) photochemotherapy has been used for severe cases of atopic dermatitis (AD). To understand the mechanisms of action is important for the choice of treatments. AD‐like lesions can be induced experimentally in NC/Nga mice.

Xeroderma pigmentosum variant associated with multiple cancers

A 62‐year‐old Japanese man with xeroderma pigmentosum (XP) variant is reported. The patient had developed at least 6 basal cell carcinomas, a squamous cell carcinoma, and a malignant melanoma on sun‐exposed areas, and an atypical carcinoid on the right lung. In vivo phototesting showed a normal response. The minimal erythema dose of ultraviolet B (UVB) was not lowered and no delayed peaking of the erythema reaction was observed. His skin fibroblasts exhibited higher sensitivity to UV irradiation, but a normal level of unscheduled DNA and RNA synthesis. Cell fusions with XP group A, C, D, E, F, and G cells after UV irradiation were all complemented. Previous reports together with this case suggest that older XP variant patients have a high frequency of not only skin cancers, but also internal malignancies.

DNA damage initiates photobiologic reactions in the skin

Ultraviolet (UV) radiation can induce acute and chronic photobiologic reactions in the absence of exogenous chromophores. Nuclear DNA is a major chromophore to initiate UV-induced physiologic reactions. The XPA-gene deficient mouse, an animal model of xeroderma pigmentosum, develops increased photobiologic reactions including acute inflammation, immunosuppression and skin cancers, because of the defect in the excision repair of UV-induced DNA lesions.

Suppressive effect of ultraviolet B radiation on contact sensitization in mice. II. Systemic immunosuppression is modulated by ultraviolet irradiation and hapten application

Irradiation of mice with ultraviolet B (UVB) can suppress contact hypersensitivity “systemically”, even if hapten is applied to the non‐irradiated skin site. We previously reported the factors influencing UVB‐induced “local” immunosuppression. To obtain the most effective systemic immunosuppression, we further investigated the effect of the following factors on contact hypersensitivity to dinitrofluorobenzene (DNFB): UVB dose, dividing exposure, timing of sensitization after irradiation, area of exposure, hapten concentration, age, and genetic basis. The suppression was enhanced by increasing UVB dose. When 1 J/cm2 of UVB was exposed, 4 daily divided exposures (0.25 J/cm2x4) was more suppressive than a single (1 J/cm2x1) or double divided (0.5 J/cm2x2) exposure. Five or 10 day intervals between irradiation and sensitization induced stronger suppression than 1 or 3 day intervals. When the total energy (Joule, J) was kept constant, the exposure of low dose‐UVB to a large area (0.5 J/ cm2 × 16.45 cm2) suppressed contact hypersensitivity more strongly than did high dose‐UVB to a small area (2 J/cm2x4.11 cm2). When 25 ml of DNFB solution was applied, high concentration induced lower suppression. The stronger suppression was most prominant in the young (7 week) than in the old (22 week) mice. No difference was found in the systemic immunosuppression between C3H/HeN and Balb/c mice. These results suggest that not only UVB dose but also various factors should be taken into consideration to effectively induce systemic immunosuppression.

Photobiological Information Obtained from XPA Gene‐deficient Mice†

The XPA gene‐deficient mouse, an animal model of xeroderma pigmentosum (XP), develops enhanced photobiologic reactions including acute inflammation, immunosuppression and skin carcinogenesis, because of the defect in the excision repair of ultraviolet‐induced DNA lesions. The results strongly suggest that nuclear DNA is an important chromophore to initiate acute and chronic skin damages. The model mouse is a useful experimental animal not only to investigate the mechanisms of photosensitivity in XP, but also to study physiological photobiology in humans, because photobiologic reactions are greatly intensified in this mouse.