Markus Grewe

A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis.

Abstract Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by intensely pruritic subacute and chronic eczematous plaques, the pathogenesis of which appears to involve a complex interplay of genetic, pharmacological, environmental and psychological factors. Here, Markus Grewe and colleagues propose that the development of skin lesions in AD patients results from sequential activation of T helper 2 (Th2)- and Th1-type cells.

High-dose UVA1 radiation therapy for localized scleroderma

BACKGROUND Fibrotic skin lesions in patients with localized scleroderma can cause muscle atrophy, disfigurement, and flexion contractures. There is no effective therapy for this disease. Skin fibrosis is thought to be caused by decreased collagenase activity. Collagenase activity can be induced in dermal fibroblasts by UVA1 irradiation. OBJECTIVE Our purpose was to assess whether UVA1 radiation therapy is effective for patients with localized scleroderma. METHODS Patients with localized scleroderma (n = 17) were exposed 30 times to 130 J/cm2 UVA1 (high-dose UVA1 therapy; n = 10) or 20 J/cm2 UVA1 (low-dose UVA1 therapy; n = 7). Therapeutic effectiveness was assessed by evaluation of (1) clinical features, (2) thickness of sclerotic plaques, and (3) cutaneous elastometry. Sequential biopsy specimens from treated lesions were analyzed for collagenase I messenger RNA (mRNA) expression by semiquantitative reverse transcriptase-polymerase chain reaction. RESULTS In all patients, high-dose UVA1 therapy softened sclerotic plaques, and complete clearance was observed in four of 10 patients. High-dose UVA1 therapy significantly reduced thickness and increased elasticity of plaques. These changes could not be detected in unirradiated control plaques and were still present in 9 of 10 patients 3 months after cessation of therapy. For all factors assessed, high-dose UVA1 was superior to low-dose UVA1 therapy (p = 0.001). High-dose UVA1 therapy increased collagenase I mRNA expression about 20-fold in treated plaques. CONCLUSION High-dose UVA1 therapy is effective in the treatment of localized scleroderma. Effectiveness is UVA1 dose dependent and is associated with induction of collagenase I expression.

Successful monotherapy of severe and intractable atopic dermatitis by photopheresis

BACKGROUND Patients with chronic atopic dermatitis can become unresponsive to standard immunosuppressive therapy and thus pose a serious therapeutic problem. OBJECTIVE Our purpose was to evaluate the therapeutic effectiveness of photopheresis in the management of patients with severe and intractable atopic dermatitis. METHODS Photopheresis was used as monotherapy in patients (n = 3) who previously did not respond to treatment with glucocorticosteroids, cyclosporine, phototherapy, or photochemotherapy. Patients were treated at 2-week intervals (total number of treatments = 10). RESULTS In all patients, photopheresis induced clinical improvement and reduction of elevated serum levels of eosinophil cationic protein and total IgE. Prolongation of the intervals between treatments from 2 to 4 weeks caused worsening in one patient, whereas shortening of treatment-free intervals improved both clinical and laboratory findings. CONCLUSION These studies indicate that photopheresis may be used as monotherapy for the treatment of patients with severe atopic dermatitis that has become intractable to standard therapeutic modalities.

Induction of proinflammatory cytokines in human epidermoid carcinoma cells by in vitro ultraviolet A1 irradiation.

Abstract— 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)‐a and interleukin (IL)‐8 expression in KB cells at the mRNA and protein level. Upregulation of cytokine mRNA levels followed a Diphasic pattern. This effect was specific for TNFa and IL‐8 because UVA1 radiation did not induce expression of IL‐la or IL‐6 in these cells. Ultraviolet Al 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‐1α 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.

Inhibition of intercellular adhesion molecule-1 (ICAM-1) expression in ultraviolet B-irradiated human antigen-presenting cells is restored after repair of cyclobutane pyrimidine dimers

Abstract: The present study assessed the molecular mechanism underlying ultraviolet (UV) B radiation‐induced inhibition of the expression of the adhesion molecule ICAM‐1 in human antigen‐presenting cells (APC). UVB radiation‐induced inhibition of ICAM‐1 expression in human peripheral blood monocytes was associated with the generation of cyclobutane pyrimidine dimers (CPD). CPD were reduced by 60% after treatment with liposomal packed photolyase, an enzyme which removes CPD after absorption of photoreactivating light. Although incomplete, reduction of CPD was associated with complete restoration of ICAM‐1 expression at the mRNA and protein level. Neither reduction of CPD level nor restoration of ICAM‐1 expression were observed, if monocytes were treated with empty liposomes, or if they were irradiated with photoreactivating light prior to application of photolyase. DNA damage might also induce soluble mediators capable of autocrine inhibition of ICAM‐1 expression. UVB irradiation of monocytes did not induce IL‐10 production, but resulted in release of prostaglandin (PG) E2. Treatment of unirradiated monocytes with PGE2 completely inhibited ICAM‐1 expression, thus mimicking the UVB effect. Inhibition of monocytic PGE2 production by indomethacin, however, did not restore ICAM‐1 expression. These results suggest that formation of CPD is necessary and sufficient for UVB radiation‐induced inhibition of ICAM‐1 expression. In contrast, PGE2 might serve a paracrine role in UVB radiation‐induced immunosuppression.