Low molecular weight fragmentation products of the polysaccharide of Hyaluronic acid (sHA) produced during inflammation have been shown to be potent activators of immunocompetent cells such as dendritic cells (DCs) and macrophages. Here we report that sHA induces maturation of DCs via the Toll-like receptor (TLR)-4, a receptor complex associated with innate immunity and host defense against bacterial infection. Bone marrow–derived DCs from C3H/HeJ and C57BL/10ScCr mice carrying mutant TLR-4 alleles were nonresponsive to sHA-induced phenotypic and functional maturation. Conversely, DCs from TLR-2–deficient mice were still susceptible to sHA. In accordance, addition of an anti–TLR-4 mAb to human monocyte–derived DCs blocked sHA-induced tumor necrosis factor α production. Western blot analysis revealed that sHA treatment resulted in distinct phosphorylation of p38/p42/44 MAP-kinases and nuclear translocation of nuclear factor (NF)-κB, all components of the TLR-4 signaling pathway. Blockade of this pathway by specific inhibitors completely abrogated the sHA-induced DC maturation. Finally, intravenous injection of sHA-induced DC emigration from the skin and their phenotypic and functional maturation in the spleen, again depending on the expression of TLR-4. In conclusion, this is the first report that polysaccharide degradation products of the extracellular matrix produced during inflammation might serve as an endogenous ligand for the TLR-4 complex on DCs.
A 68-year-old man presented with a one month history of painful blue-red papules and nodules on an erythematous base on the top of his feet, as well as dystrophic toenails. He had undergone renal transplantation six months previously for membranous glomerulonephritis, and was immunosuppressed with tacrolimus 3 g, mycophenolate mofetil 1500 mg and prednisolone 5 mg daily. His tacrolimus level was 29.8 ng/ml (expected level 6-8 ng/ml). Even though the cutaneous lesions strongly suggested Kaposi sarcoma, the histological examination revealed a dermal abscess in which hyphae and spores were seen with PAS staining. ELISA-PCR of the biopsy identified Trichophyton rubrum, which was also grown on culture of the biopsy tissue. The diagnosis of Majocchi granuloma secondary to excessive immunosuppression was made. Systemic treatment with terbinafine 250 mg per day and topical ciclopirox olamine completely cured the granulomatous skin lesions, and later the nails.
Phototherapy with ultraviolet (UV) radiation of wavelengths between 280 and 320 nm (UVB) is a safe and effective treatment for a variety of diseases. In addition to standard broadband UVB (bUVB), narrowband phototherapy with fluorescent bulbs emitting near monochromatic UV around 311 nm (nUVB) has become an important treatment for diseases such as psoriasis, atopic dermatitis and vitiligo. In addition to these indications, the number of diseases for which nUVB phototherapy is reported to be effective is continuously growing. The differential effects of nUVB phototherapy in comparison to other UV wavelengths as well as established and new indications for this treatment modality are reviewed.
A 23-year-old woman presented with recurrent herpetiform vesicles of the lower lip, but all diagnostic measures for herpes virus infection including herpes viridae specific PCR were negative. Medical history revealed that she also had chronic recurrent vulvovaginal candidiasis, which had been treated with various regimes, including repetitive applications of fluconazole. Consequently, fluconazole-induced fixed drug eruption was suspected, but skin tests performed with fluconazole remained with-out response. Consecutive repeated oral provocation tests with fluconazole were carried out and resulted in the development of burning herpetiform vesicles of the lower lip. Histopathology revealed a subepidermal and superficial perivascular infiltrate, basal vacuolated and apoptotic keratinocytes, intra-epidermal lymphocytes and intra-epidermal multilocular vesicles. Together with the clinical history and picture, fluconazole-induced fixed drug eruption mimicking labial herpes simplex virus infection was diagnosed. Oral provocation tests with an alternative systemic antifungal treatment, itraconazole, were well tolerated, systemic therapy with itraconazole was initiated, and no further labial vesicles developed.
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