Unraveling the pathogenesis of polymorphous light eruption : a comparative study in patients with polymorphous light eruption and healthy individuals

Ultraviolet (UV) radiation, especially UV-B (280-315 nm), can suppress cellular immunity, thereby preventing the occurrence of a disruptive immune reaction against UV-modified organic molecules (e.g. DNA, proteins) whenever the skin is exposed to UV-B radiation. An inadequate immunosuppression could therefore develop into a UV-triggered sun allergy e.g. polymorphous light eruption (PLE). PLE patients included in our experiments reacted pathologically to UV-B radiation, developing papules and/or vesicles on sun-exposed areas of the skin, but had a normal sunburn sensitivity (normal MED (minimal erythema dose)). To study the initial reaction to UV radiation we exposed buttock skin of PLE patients and healthy controls to 6 MED UV-B and took skin biopsies from the (unaffected) UV-exposed skin 24h and 48h post irradiation and from unexposed skin as a control. To investigate our hypothesis that PLE is caused by a disturbance in UV-B-induced immunosuppression we first determined whether immunosuppressive CD11b+ cells were present in the UV-irradiated skin of PLE patients. Dermal CD11b+ cells could be detected in the skin of PLE patients, however, they did not infiltrate the epidermis after UV radiation in contrast to the CD11b+ cells in healthy controls. Furthermore, the majority of the CD11b+ cells in the skin of PLE patients were CD68+ macrophages while the CD11b+ cells in healthy controls were predominantly neutrophils. Langerhans cells disappeared from the skin of healthy individuals after UV-B exposure but, strikingly, persisted in the UV-exposed epidermis of PLE patients. The underlying mechanism, impaired migration, appeared to be attributable to a reduced number of IL-1-? and tumour necrosis factor (TNF)-?-producing cells in the UV-exposed skin of PLE patients in comparison with healthy controls. The persistent Langerhans cells in the UV-exposed epidermis of PLE patients were not activated (CD86, CD40, CD54) or matured (CD83). However, a significant higher number of activated Langerhans cells accumulated in the dermis of the UV-exposed skin of PLE patients in comparison with healthy controls. A simultaneous presence of activated, HLADR+ Langerhans cells together with (potentially type 1) T-cells in the dermis of PLE patients might lead to antigen presentation in the skin, thereby contributing to the pathogenesis of PLE. Neutrophils expressing the Th2-skewing cytokine IL-4 were present in lower numbers in the UV-exposed skin of PLE patients in comparison with healthy individuals. This observation, together with an equal expression of Th1-skewing cytokines (IL-12 and interferon-?) indicated a shift in the cytokine profile in the skin of PLE patients towards a Th1 response in comparison with healthy individuals. Taken together, a hypothetical model can be constructed for the pathogenesis of PLE: A reduced expression of IL-1-? and TNF-? in the UV-exposed skin of PLE patient leads to an impaired and slow Langerhans cell migration, resulting in an accumulation of activated Langerhans cells in the dermis. These Langerhans cells can activate dermal (potentially type 1) T-cells- if present. A reduced number of IL-4-producing neutrophils without a difference in the expression of Th1-skewing cytokines leads to a shift towards a Th1 response in the skin of PLE patients. The normal, healthy immunosuppressive responses are reduced while the erythemal response is increased (slightly lower MED) in PLE patients. This shift in immune responses together with the possibility of an activation of dermal Th1 cells may underlie the pathogenesis of PLE

Association of transcription-coupled repair but not global genome repair with ultraviolet-B-induced Langerhans cell depletion and local immunosuppression.

Exposure to ultraviolet-B radiation impairs cellular immune responses. This immunosuppression seems to be associated with Langerhans cell migration. DNA damage appears to play a key role because enhanced nucleotide excision repair, a pathway essential for elimination of ultraviolet-B-induced DNA lesions, strongly counteracts immunosuppression. To determine the effect of DNA repair on ultraviolet-B-induced local immunosuppression and Langerhans cell disappearance, three mouse strains carrying different defects in nucleotide excision repair were compared. XPC mice, which were defective in global genome repair, were as sensitive to ultraviolet-B-induced local suppression of contact hypersensitivity to picryl chloride as their wild-type littermates. CSB mice, defective in transcription-coupled repair, were far more sensitive for immunosuppression as were XPA mice, defective in both transcription-coupled repair and global genome repair. Only a moderate depletion of Langerhans cells was observed in XPC mice and wild-type littermates. Ultraviolet-B-induced Langerhans cell depletion was enhanced in CSB and XPA mice. Hence, the major conclusion is that local immunosuppression is only affected when transcription-coupled DNA repair is impaired. Furthermore, a defect in transcription-coupled repair was linked to enhanced ultraviolet-B-induced Langerhans cell depletion. In combination with earlier experiments, it can be concluded that Langerhans cell disappearance is related to ultraviolet-B-induced local but not to systemic immunosuppression

The mastocyte: the off switch of UV itch

Dermatology-oncolog