Pathogenesis Of Polymorphous Light Eruption Research Articles

Oral administration of a hydrophilic extract of Polypodium leucotomos for the prevention of polymorphic light eruption

Polymorphic light eruption (PLE) is the most common idiopathic photodermatosis. Reactive oxygen species have been implicated in the pathogenesis of PLE. Polypodium leucotomos (PL) is a natural extract from tropical fern leaves with potent antioxidant and anti-inflammatory properties. In this study we sought to evaluate whether a concentrated hydrophilic extract of PL might prevent or delay the photoinduction of typical PLE lesions by artificial ultraviolet (UV) radiation. A total of 35 patients with long-standing PLE were included in this open, uncontrolled bicenter study. PLE was induced by photoprovocation with artificial UVB and UVA light, thereafter oral treatment with PL was initiated. Two weeks later a second photoprovocation was performed while the patients were still taking PL. Thirty patients developed PLE lesions after repeated irradiation with UVA. Of these, 18 patients also responded to UVB. After PL treatment, 9 (30%) and 5 (28%) patients, respectively, were unresponsive to repeated UVA and UVB exposure. In the remaining patients, the mean number of UVA and UVB irradiations required to elicit PLE increased significantly from 1.95 to 2.62 (P = .005) and from 2.38 to 2.92 (P = .047), respectively. The study was open and uncontrolled and included a relatively small number of patients. Our data indicate that oral PL treatment might be beneficial for the prevention of PLE.

Photohardening restores the impaired neutrophil responsiveness to chemoattractants leukotriene B4 and formyl-methionyl-leucyl-phenylalanin in patients with polymorphic light eruption.

A failure to induce immune suppression after UV exposure has been implicated in the pathogenesis of polymorphic light eruption (PLE). This immunological resistance has been linked to an impaired neutrophil infiltration into the skin following UV exposure. Therapeutic photohardening can restore this abnormal neutrophil infiltration in PLE skin and is thought to be responsible for the prophylactic efficacy. The aim of this study was to elucidate the pathogenic mechanism of the described neutrophil deficiency in PLE. Peripheral blood neutrophil responses to the chemoattractants leukotriene B4 (LTB(4)) and formyl-methionyl-leucyl-phenylalanin (fMLP) were investigated in vitro. Samples from 10 patients with PLE before and after 6 weeks of photohardening therapy were assessed. Flow cytometry was used to measure the changes associated with neutrophil activation. We found a significantly reduced neutrophil responsiveness to LTB(4) and fMLP in PLE patients, which was restored to normal levels after phototherapy. Indeed, PLE neutrophil responsiveness to these two chemoattractants after (but not before) phototherapy was similar to that of age- and sex-matched healthy control subjects. This indicates that an abnormal chemotactic potential to neutrophils is a crucial factor in the pathogenesis of PLE. Normalization following photohardening may therefore account for the therapeutic efficacy by restoring UV-induced neutrophil skin infiltration. Our results reveal a completely novel pathogenic mechanism involved in PLE and offer unique targets for therapy.

Advances in the etiology and pathogenesis of polymorphous light eruption

Polymorphous light eruption (PLE) is a chronic, idiopathic, common photoreactive disease associated with sunlight exposure. The etiology and pathogenesis of PLE are still unclear, and reported to be associated with genetic factors, ultraviolet ray-induced internal antigens and external photosensitive materials,immune function disturbance, et al. Recently, there have been increasing reports on the etiology and pathogenesis of PLE, which are mainly related to the direct exposure to ultraviolet B and ultraviolet A,accumulation of oxygen free radicals, delayed type hypersensitivity, cytokines and inherent factors. Besides, the transition of PLE to autoimmune diseases has been reported. Nowadays, it is an important task for clinicians to clarify the pathogenesis of PLE. Key words: Photosensitivity disorders; Etiology; Research

Alpha-glucosylrutin plus licochalcone A: Enhanced protective efficacy in PLE

Polymorphous light eruption (PLE) is the most common photodermatosis with a prevalence of 10-20% in Western Europe1 and in the USA. PLE is characterized by recurrent, delayed reactions to sunlight, resulting in symptoms ranging from erythematous papules and plaques to erythema multiforme. Frequently affected areas are the volar side of arms and hands, the decollete and – less frequently – the face. The visual symptoms are often accompanied by severe pruritus. Thus both factors (skin feel and appearance) engender a substantial psychosocial impact on the patients.2 Exposure to UV-radiation results in the formation of aggressive reactive oxygen species and recent findings suggest a critical role of an impaired cellular defense against reactive oxygen species (ROS) in the pathogenesis of PLE.

Chemokines and cardiac fibrosis

Polymorphic light eruption (PLE) is a photodermatosis (i.e. "sun allergy") with a high prevalence, particularly among young women in temperate climates. It is characterized through itchy skin lesions of variable morphology, occurring in spring or early summer on sun exposed body sites. As yet the exact etiology and pathogenesis of PLE are unknown although a resistance to ultraviolet (UV)-radiation-induced immunosuppression (i.e. a physiologic phenomenon in normal healthy subjects) and a subsequent delayed type hypersensitivity (DTH) response to a UV-modified skin antigen (i.e. neo-antigen) has been suggested as a key factor in the disease. This article reviews the cellular and molecular disturbances associated with and most likely playing a role in pathogenesis of the disease.

A Protective Effect of Glutathione-S-Transferase GSTP1*Val105 against Polymorphic Light Eruption

Polymorphic light eruption (PLE) is a common skin disease, susceptibility to which is genetically determined. The prevalence of PLE is significantly increased in patients with lupus erythematosus (LE) including subacute cutaneous lupus erythematosus (SCLE) and discoid lupus erythematosus (DLE), which may reflect a common genetic background. Experimental evidence supports a role for reactive oxygen species (ROS) in the pathogenesis of PLE, and the family of glutathione-S-transferase (GST) enzymes exerts a critical physiological role in cellular protection against this oxidative damage. Our aim was to look for association between the functional GST gene polymorphisms and PLE, SCLE, and DLE in a case-control study. The carrier frequency of GSTP1 Val(105) in subjects with PLE was 40%, significantly lower than the carrier frequency in controls (54%, P=0.019), although significance was lost on correction for multiple testing. However, the carrier frequency of the GSTP1 Val(105) allele in combined cutaneous LE (SCLE and DLE) patients with PLE was 42%, significantly lower than in those without PLE (72%), which did survive correction (corrected P=0.043). We have identified evidence supporting a protective GSTP1 allele, the first genetic association to be reported for PLE. This supports a role for ROS in the pathogenesis of PLE and may provide a therapeutic target for future treatment of this common, often disabling, condition.

Polymorphic light eruption: an immunopathological study of evolving lesions.

Polymorphic light eruption (PLE) papules were successfully induced on previously affected sites in 11 out of 14 patients with PLE 4-20 h after single exposures to suberythemogenic doses of solar simulated radiation. Histological examination of biopsies performed 1 h, 5 h, 24 h, 72 h and 144 h post-irradiation revealed onset within 5 h of perivascular cellular infiltration. The infiltrate was dominated by lymphocytes in both early and established lesions, without evident epidermal pathology. Immunohistochemistry demonstrated a predominance of CD4+ cells in lesions up to 72 h post-induction, but later biopsies were dominated by a CD8+ infiltrate. Significantly increased numbers of dermal macrophages and CD1b+ cells were detected 1 h and 5 h post-irradiation, respectively. These findings are consistent with a delayed type hypersensitivity response underlying the pathogenesis of polymorphic light eruption.

UVB‐induced leucocyte trafficking in the epidermis of photosensitive lupus erythematosus patients: Normal depletion of Langerhans cells

The pathogenic mechanisms of UV-induced skin lesions of lupus erythematosus (LE) are unknown. In a recent study of pathogenic mechanisms of polymorphic light eruption (PLE), significantly more Langerhans cells (LCs) persisted in the epidermis after UVB overexposure than in healthy individuals. Interestingly, the same phenomenon was observed in one subacute cutaneous lupus erythematosus (SCLE) patient. It could therefore be hypothesized that both photodermatoses share a common pathogenic mechanism of photosensitivity. In the present study, we tested this hypothesis by investigating leucocyte trafficking in the initial phase of cutaneous LE after intense UVB exposure. In 22 photosensitive LE patients (12 chronic discoid lupus erythematosus, seven systemic lupus erythematosus and three SCLE) and nine age/sex-matched controls, uninvolved buttock skin was exposed to six minimal erythemal dose (MED) UVB radiation. Subsequently, biopsies were taken after 24, 48 and 72 h, and one control biopsy was taken from unirradiated skin. Skin sections were stained for the presence of LCs, neutrophils and macrophages. Areal percentages of positively stained cells within the epidermis were quantified and compared between the patients and controls. A gradual decrease of epidermal LCs and a gradual increase of epidermal neutrophils and macrophages at several timepoints after six MED irradiation was observed equally in both LE patients and controls. Immunohistopathology of irradiated uninvolved skin of photosensitive LE patients did not reveal the same pathologic trafficking of LCs and neutrophils as described for PLE patients. We conclude that different mechanisms are operative in the pathogenesis of PLE and photosensitive LE.

Differential expression of cytokines in UV-B-exposed skin of patients with polymorphous light eruption: correlation with Langerhans cell migration and immunosuppression.

Disturbances in UV-induced Langerhans cell migration and T helper (T(H)) 2 cell responses could be early steps in the pathogenesis of PLE. To establish whether UV-B exposure induces aberrant cytokine expression in the uninvolved skin of patients with polymorphous light eruption (PLE). Immunohistochemical staining and comparison of microscopic sections of skin irradiated with 6 times the minimal dose of UV-B causing erythema and the unirradiated skin of patients with PLE and of healthy individuals. University Medical Center (Dutch National Center for Photodermatoses). Patients Patients with PLE (n = 6) with clinically proven pathological responses to UV-B exposure and normal erythemal sensitivity. Healthy volunteers (n = 5) were recruited among students and hospital staff. Expression of cytokines related to Langerhans cell migration (interleukin [IL] 1, IL-18,and tumor necrosis factor [TNF] alpha); T(H)2 responses (IL-4 and IL-10); and T(H)1 responses (IL-6, IL-12, and interferon gamma). Double staining was performed for elastase (neutrophils), tryptase (mast cells), and CD36 (macrophages). The number of cells expressing IL-1beta and TNF-alpha was reduced in the UV-B-exposed skin of patients with PLE compared with the skin of healthy individuals (P<.05 for TNF-alpha). No differences were observed in the expression of T(H)1-related cytokines but fewer cells expressing IL-4 infiltrated the epidermis of patients with PLE 24 hours after irradiation (P =.03). After UV exposure TNF-alpha, IL-4, and, to a lesser extent, IL-10 were predominantly expressed by neutrophils. The reduced expression of TNF-alpha, IL-4, and IL-10 in the UV-B-irradiated skin of patients with PLE appears largely attributable to a lack of neutrophils, and is indicative of reduced Langerhans cell migration and reduced T(H)2 skewing. An impairment of these mechanisms underlying UV-B-induced immunosuppression may be important in the pathogenesis of PLE.

Polymorphic light eruption.

Polymorphic light eruption (PMLE) is the most common photodermatosis. It is typically characterized by nonscarring, pruritic, erythematous papules, plaques, or vesicles on sun-exposed skin that develop 30 minutes to several hours after sun exposure. The eruption may persist for a few hours to as long as 2 weeks. Females are affected two to three times more often than males. PMLE has been reported in all races, but tends to affect fair-skinned individuals with Fitzpatrick skin types I-IV most commonly. The pathogenesis of PMLE has been difficult to define, although it appears to be an immune-mediated delayed-type hypersensitivity reaction. Abnormalities of arachidonic acid metabolism and a possible correlation with lupus are other theories that are reviewed. Treatment options have been explored extensively. While "hardening" or desensitization of the skin through repeated irradiation seems to be the most effective, therapeutic options such as sun avoidance/sun protection, oral carotenoids, and antimalarials are also considered.

Polymorphous light eruption.

Polymorphous light eruption (PLE) is a common idiopathic photosensitivity disorder with an estimated prevalence of 10-20%. It is characterized by an intermittent skin reaction to ultraviolet (UV) radiation exposure, consisting of non-scarring pruritic erythematous papules, vesicles or plaques that develop on light-exposed skin. Despite the different morphology in different individuals, the eruption tends to have a monomorphous presentation in any single subject. The histopathological features of PLE are distinct and comprise a perivascular lymphocytic infiltrate in the dermis, subepidermal oedema and variable epidermal changes. The pathogenesis of PLE is not well known, but findings suggest that it is a delayed-type hypersensitivity reaction to one or more UV-modified cutaneous antigens. The principal action of PLE is mainly in the UVA region, although some subjects exhibit sensitivity to UVB alone or to both UVA and UVB radiation at the same time. Preventive measures in PLE include the regular use of photoprotective methods combined with graduated exposures to natural sunlight. The induction of immune tolerance by phototherapy and photochemotherapy are useful prophylactic methods in moderate to severe cases. The role of systemic agents in the management of PLE is under investigation. This article reviews the epidemiological, pathogenetic and clinical aspects of PLE and discusses recent advances in the diagnostic approach and management of this condition.

Results of photoprovocation and field studies on the efficacy of a novel topically applied antioxidant in polymorphous light eruption

BACKGROUND: UVA-induced photooxidation is considered to play an essential role in the pathogenesis of polymorphous light eruption (PLE), and topical pretreatment of skin with alpha-glucosylrutin (AGR), a potent plant-derived antioxidant, has been shown to significantly suppress photoprovoked PLE eruption. AIM: In order to further elucidate the optimum pretreatment regimen and to investigate the efficacy and skin compatibility of topical preparations containing AGR under field conditions, two controlled clinical studies were conducted in PLE patients. METHODS: In the first study, photoprovocation of PLE was performed in 20 patients, using UVA irradiation (4 2 60-100 J/cm 2 ), applied to four test sites at the individual areas of predilection. One site served as an untreated control. The remaining three sites received treatment with a SPF 15 sunscreen containing 0.25% AGR (Eucerin® Gel Cream Phase 2) 30 minutes before irradiation. Two of these sites were additionally pretreated with the corresponding AGR-containing vehicle (Eucerin® Gel Cream Phase 1) twice daily for 3 and 7 days, respectively. The second study was conducted as a controlled in-use-test in patients with PLE ( n = 27) or acne aestivalis ( n = 3), who had suffered from the disease during their last year's vacation. They were educated to apply the pre-sun preparation to the formerly affected skin areas twice daily for 1 week before their planned vacation and to use the SPF 15 sunscreen 30 minutes before each vacation sun exposure. Symptoms were recorded in patients' diaries throughout the vacation and documented by a physician after their return. RESULTS: In the first study, protection of skin with the SPF 15 sunscreen alone led to a significant prevention of PLE symptoms, especially itch, compared with the control area. Pretreatment further reduced the severity of PLE significantly and led to total prevention in 19 patients. In the second study, whereas 92.6% had reported severe and 7.4% mild PLE in the last year, there were currently only 7.4% severe cases, with 25.9% mild and 29.6% questionable cases; 37% had no symptoms at all. Also, two out of three acne aestivalis patients had diminished symptoms after treatment. CONCLUSION: The results confirm the prophylactic efficacy of the antioxidant AGR in PLE, applied as SPF 15 sunscreen alone or additionally to pretreatment with a corresponding pre-sun preparation, and also show an effect in acne aestivalis patients. ( J Dermatol Treat (2001) 12: 3-8)

Ultraviolet A radiation-induced biological effects in human skin: relevance for photoaging and photodermatosis

There is increasing evidence that longwave ultraviolet (UV) radiation (UVA; 320–400 nm) plays an important role in the pathogenesis of photodermatoses such as polymorphous light eruption as well as photoaging. In order to fully understand these detrimental effects it is critical to analyze the photobiological and molecular mechanisms by which UVA radiation affects the function of human skin cells. In this review, our current knowledge about the signal transduction pathway involved in UVA radiation-induced expression of proinflammatory genes relevant to the pathogenesis of polymorphous light eruption will be summarized. In addition, recent studies on the role of mitochondrial DNA mutations in UVA radiation-induced photoaging of human skin will be discussed. For both biological endpoints the UVA radiation-induced generation of singlet oxygen within human skin appears to be of critical importance. These studies are of enormous clinical relevance because they indicate that prevention of the generation of singlet oxygen or inhibition of singlet oxygen-induced signaling pathways may prove to be critical for effective protection of human skin against UVA radiation-induced damage.

Induction of Proinflammatory Cytokines in Human Epidermoid Carcinoma Cells by in vitro Ultraviolet A1 Irradiation

Ultraviolet radiation-induced expression of cytokines by keratinocytes is important for the pathogenesis of polymorphous light eruption (PLE). Because UVA1 radiation rather than UVB radiation might be a more important trigger for PLE, cells from the human epidermoid carcinoma cell line KB were exposed in vitro to UVA1 radiation (30 J/cm2) and subsequently analyzed for cytokine expression. Ultraviolet A1 irradiation induced tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 expression in KB cells at the mRNA and protein level. Upregulation of cytokine mRNA levels followed a biphasic pattern. This effect was specific for TNF alpha and IL-8 because UVA1 radiation did not induce expression of IL-1 alpha or IL-6 in these cells. Ultraviolet A1 radiation-induced expression of intercellular adhesion molecule-1 in KB cells previously was found to depend on the thiol status of these cells. Therefore, KB cells were treated with DL-buthionine-[S,R]-sulfoximine (BSO), a specific inhibitor of de novo glutathione synthesis. Exposure of BSO-pretreated KB cells to UVA1 radiation significantly induced IL-1 alpha and IL-6 mRNA and protein expression. These studies demonstrate the capacity of UVA1 radiation to induce cytokine expression in human epidermoid carcinoma cells. This immunomodulatory effect may be mediated by thiol-status-dependent and -independent mechanisms.

Immune sensitization against epidermal antigens in polymorphous light eruption

To get further insight into the pathogenesis of polymorphous light eruption, we studied nine patients with polymorphous light eruption and six healthy persons. Two skin biopsy specimens were obtained from each person, one from previously ultraviolet light-irradiated skin and another one from unirradiated skin. An epidermal cell suspension, skin homogenate, or both were prepared from each specimen. Autologous cultures were made with peripheral blood mononuclear cells combined with irradiated or unirradiated skin homogenate and peripheral blood mononuclear cells combined with irradiated or unirradiated epidermal cell suspension. Cell proliferation was assessed by 3H-thymidine incorporation assay. The response of peripheral blood mononuclear cells to unirradiated epidermal cells or unirradiated skin homogenate was similar in both patients and controls. However, peripheral blood mononuclear cells from patients with polymorphous light eruption showed a significantly increased proliferative response to both irradiated epidermal cells and irradiated skin homogenate. Our results indicate that ultraviolet light increases the stimulatory capability of polymorphous light eruption epidermal cells in a unidirectional mixed culture with autologous peripheral blood mononuclear cells. This suggests that an immune sensitization against autologous ultraviolet light-modified skin antigens occurs in polymorphous light eruption.