UV-induced tolerance to a contact allergen is impaired in polymorphic light eruption.

Polymorphic light eruption (PLE) is a common skin disorder provoked by exposure to UVR. Its clinical symptoms resemble those of a contact allergic reaction. PLE is generally considered a T-cell-mediated autoimmune reaction toward a yet unidentified antigen formed in UVR-exposed skin. Predisposition to such an immune reaction may result from aberrant epitope formation, increased immune reactivity to a universal epitope, or diminished propensity to UVR-induced immunosuppression or to the induction of tolerance. In a study comprising a total of 24 PLE patients and 24 healthy sex- and age-matched controls, we found that both groups demonstrated similar immunosuppression of contact sensitization to diphenylcyclopropenone by earlier exposure to solar-simulating UVR. However, only 1 out of 13 PLE patients (8%) versus 6 out of 11 controls (55%) that had been immunosuppressed by UVR exhibited a state of immunotolerance toward the same allergen after 10-24 months (P=0.023). We conclude that the impaired propensity to UVR-induced allergen-specific immunotolerance may promote recurrent PLE.

Stimulation of Langerhans cells with ketoprofen plus UVA in murine photocontact dermatitis to ketoprofen.

BACKGROUND: Ketoprofen (KP) clinically evokes the allergic type of photocontact dermatitis when applied to the skin and irradiated with ultraviolet A (UVA). We have established a murine model of photocontact dermatitis to KP, which is a T cell-mediated delayed type hypersensitivity. OBJECTIVE: To further explore the mechanism underlying this sensitivity, we investigated whether KP plus UVA activates the antigen-presenting ability of Langerhans cells (LCs). METHODS: We analyzed the expression of surface molecules on LCs in the murine epidermis treated with KP plus UVA by immunohistochemistry and flow cytometry. Changes in the cytokine expression of epidermal cells from KP-phototreated skin were also examined by real-time PCR. RESULTS: LCs became larger after treatment with KP plus UVA. The number of LCs was significantly decreased 2-3 days after KP phototreatment and recovered on day 5. A flow cytometric analysis revealed that KP plus UVA increased the percentage of LCs that highly expressed MHC class II, CD86, CD80, CD54 and CD40, whereas neither KP nor UVA alone enhanced the expression. KP phototreatment augmented the expression of I-A and CD86 on LCs in KP and UVA dose-dependent manners. A real-time PCR analysis of KP-phototreated skin showed that the expression of mRNA for IL-1alpha and GM-CSF was immediately increased after treatment. CONCLUSION: A photosensitizing regimen of KP plus UVA activates LCs at least partly by stimulating keratinocytes to produce cytokines. Two strains of mice (BALB/c and AKR) differ in responsiveness to KP and the difference is not related to the activation of keratinocytes.

Ultraviolet radiation causes less immunosuppression in patients with polymorphic light eruption than in controls.

It is hypothesized that polymorphic light eruption is characterized by a partial failure of ultraviolet radiation-induced immunosuppression, resulting in a delayed-type hypersensitivity response to photo-induced antigens. We aimed to study the susceptibility of PLE patients to UVR-induced immunosuppression, by measuring the strength of sensitization to 2,4-dinitrochlorobenzene after UVR exposure, and to diphenylcyclopropenone without UVR exposure, in subjects with PLE and controls. Thirteen PLE patients and 11 controls were exposed to 1 minimum erythema dose (MED) of UVR delivered from Waldmann UV-6 bulbs to the upper inner arm. Twenty-four hours later at the same site they were exposed to a sensitizing dose of 2,4-dinitrochlorobenzene. One week later they were exposed to a sensitizing dose of diphenylcyclopropenone at a nonirradiated site. Three weeks later all subjects were challenged with four doses of 2,4-dinitrochlorobenzene and four doses of diphenylcyclopropenone. The resulting increase in skin thickness was measured with Harpenden callipers and summed over the four doses, to give a single value representing the reactivity of the subject to 2,4-dinitrochlorobenzene (Sigma DN) and diphenylcyclopropenone (Sigma DP). Among all subjects, there was a very strong correlation between Sigma DN and Sigma DP (Pearson correlation 0.56, p=0.004). The strength of the reaction to 2,4-dinitrochlorobenzene relative to the reaction to diphenylcyclopropenone was significantly greater among PLE patients than controls (p=0.04 independent samples t test of Sigma DP-Sigma DN). We conclude that induction of sensitization by 2,4-dinitrochlorobenzene is suppressed less by UVR in patients with PLE than in healthy controls.

Ultraviolet-radiation-induced erythema and suppression of contact hypersensitivity responses in patients with polymorphic light eruption.

Ultraviolet-radiation suppresses cell-mediated immunity in healthy humans. It has been postulated that, in the short term, this immunosuppression prevents autoimmune responses to ultraviolet-radiation damaged skin. Patients with polymorphic light eruption (PLE) demonstrate abnormal responses to ultraviolet-radiation suggestive of an immune response to an ultraviolet-radiation-induced antigen. We investigated whether PLE patients (n=22) were resistant to ultraviolet-radiation-induced immunosuppression compared to skin-type, aged-matched controls (n=23). Groups of patients and controls (six subjects per group) received a single dose of solar-simulated ultraviolet-radiation of either 0, 0.6, 1 or 2 minimal erythema doses (MED). Erythema was quantified using a reflectance meter and all volunteers were sensitised on the irradiated site with dinitrochlorobenzene. Contact hypersensitivity responses (CHS) to dinitrochlorobenzene were quantified after challenge using ultrasound. Ultraviolet-radiation-induced erythema was comparable in patients and controls. CHS was comparable in unirradiated patients and controls. UVR-induced a dose-dependent suppression of CHS in all volunteers but patients were more resistant to immunosuppression after 1MED. Exposure to 1MED suppressed CHS by 78% in controls but induced less suppression in patients (44%, p < 0.01). Our data suggest that PLE patients have a flaw in their immunoregulatory response to ultraviolet-radiation it is only apparent over a narrow dose range around 1 MED.

Distribution of naive and memory T-cells in photoprovoked and spontaneous skin lesions of discoid lupus erythematosus and polymorphous light eruption.

Immune response to ultraviolet radiation-modified skin antigens has been suggested as a pathomechanism of skin lesions in discoid lupus erythematosus and polymorphous light eruption. In order to elucidate the role of T-lymphocyte subsets in this response, we studied the distribution of CD45RO+, CD45RA+ and CD31+ cells and the endothelial expression of adhesion molecules E-selectin/P-selectin, intercellular adhesion molecule-1 and CD31 antigen in photoprovoked and spontaneous skin lesions. Typically, CD45RA+ cells were the prevailing inflammatory cell population of discoid lupus erythematosus, whereas CD45RO+ cells prevailed in both diseases and in healthy controls. Epidermotrophism of any T-cell subsets was more typical of discoid lupus erythematosus, whereas no major differences in endothelial adhesion molecule expression was found between the 2 diseases. Strong keratinocyte ICAM-1 expression was associated with adjacent CD45RO+ cell infiltrates, not with CD45RA+ or CD31+ cell infiltrates. We conclude that the cellular immune response to UV radiation is dissimilar in discoid lupus erythematosus and polymorphous light eruption.

Photoallergic skin reaction to ribavirin.

A 65-yr-old woman with chronic hepatitis C was treated with three million units interferon-alpha t.i.w. and 1000 mg ribavirin daily. At wk 16 of combination therapy the patient developed an itchy eczematous erythema, partly of urticarial character, which was almost confined to ultraviolet (UV)-exposed sites. Histopathological examination of the skin lesions was consistent with a photoallergic reaction. The minimal erythematous dose for UVA and UVB was assessed on healthy skin. After 24 h, a distinct erythema at the UVB irradiated site was found, whereas no reaction was seen with UVA provocation up to a dose of 10 J/cm2. Correspondingly, determination of the absorption spectrum of ribavirin revealed maximum absorption within UVB at 282.5 nm. Ribavirin was stopped, and the cutaneous lesions and pruritus completely disappeared without subsequent hyperpigmentation. This case indicates that ribavirin is a potential photosensitizer for UVB, which may become increasingly relevant in patients with chronic hepatitis C undergoing combination therapy for 6-12 months with interferon-alpha and ribavirin.

Sunscreens and vitamin E provide some protection to the skin immune system from solar-simulated UV radiation.

Previous studies have indicated that sunscreens designed to protect from erythema do not adequately prevent immunosuppression. Mice were irradiated with suberythemal doses of solar-simulated ultraviolet radiation (ssUVR) to assess the immunoprotective ability of sunscreens. Whereas C3H/HeJ and BALB/c mice had similar sensitivities to ssUVR-induced inflammation, C3H/HeJ mice were more sensitive to ssUVR-induced immunosuppression. Octyl dimethyl-p-aminobenzoic acid did not protect from immunosuppression and, thus, had an immune protection factor (IPF) of 1. 2-Ethylhexyl-p-methoxycinnamate and microfine titanium dioxide provided limited protection, both having IPF values of 1.127. Immune protection by the sunscreens appeared to be dependent upon absorption of UVA as well as UVB, and was much less than predicted from the sun protection factor. Vitamin E, an inhibitor of lipid peroxidation, also protected the immune system, with an IPF of 1.2, indicating that oxidation of lipids is involved in UVR-induced immunosuppression, and that it should be possible to develop sunscreens which protect the immune system.

Evaluation of ultraviolet-A protection by sunscreen agents using a mouse model of contact photoallergy.

This study was conducted to investigate in vivo evaluation of protectiveness by sunscreens in the UVA range using a mouse model of contact photoallergy (CPS) to 3,3',4',5-tetrachlorosalicylanilide (TCSA). Mice were sensitized with TCSA painting plus UVA irradiation (TCSA/UVA) on the abdomen and, 5 days later, challenged with TCSA/UVA on the earlobe. Each of four sunscreen agents, benzophenone-3, Parsol 1789, p-aminobenzoic acid, and 2-ethyl-hexyl-p-methoxycinnamate, was applied to the earlobes before irradiation. Their protective efficacy was evaluated in the degree of inhibition of both ear swelling responses and TCSA-epidermal cell photoadduct formation. Two UVA-absorbing sunscreens, benzophenone-3 and Parsol 1789, dramatically inhibited the ear swelling response, while the two UVB-absorbers exhibited a much less suppressive effect. The UVA-absorbing agents functioned via inhibiting the formation of TCSA-epidermal cell photoadducts. This method is thought to be useful for in vivo estimation of UVA protection provided by sunscreens against the exquisite sensitivity involved in photoallergy.

Piroxicam has at least two epitopes for contact photoallergy.

We have demonstrated previously in guinea pigs that the induction of photocontact sensitivity to piroxicam (PXM) also induces a state of cross-reactive contact hypersensitivity to two compounds having structurally related elements, thimerosal (TMS) and thiosalicylate (TOS). The present study was conducted to determine whether oral administration of TOS would desensitize guinea pigs previously photosensitized with PXM. At the same time, the spectrum of reactivities against these compounds and against tenoxicam (TXM) which resembles only piroxicam was assessed by appropriate sensitizing and eliciting protocols. As expected, animals photosensitized to PXM developed reactivities against all four compounds, PXM and TXM (photosensitivity) and TMS and TOS (contact sensitivity). By contrast, photosensitization with TXM induced cross-reactivity only against PXM. Moreover, the induction of contact sensitivity against TMS or TOS induced photosensitive cross-reactivity to PXM, but not to TXM. Finally, the oral administration of TOS produced a transient desensitization only for TMS and TOS. These results suggest that photosensitization with PXM induces two distinct reactivities. The first reactivity cross-reacts with TMS and TOS and is suppressible with orally administered TOS. The second cross-reacts only with TXM and is not suppressible with oral TOS. We conclude that PXM acquires at least two distinct immunogenic epitopes when exposed to UVA irradiation.