Photohardening of polymorphic light eruption patients decreases baseline epidermal Langerhans cell density while increasing mast cell numbers in the papillary dermis.

The pathogenesis of polymorphic light eruption (PLE) has been linked to a lack of UV-induced immune suppression. To determine the role of Langerhans cells (LC), mast cells and regulatory T cells, biopsies from PLE patients were taken from exposed sites in spring before and after photohardening with 311 nm or PUVA as well as again in summer. Skin sections were assessed for the presence of Langerin/CD1a+ LC and CD3+, CD4+, CD25+ or FoxP3+ T cells and mast cells. Photohardening transiently decreased the density of epidermal LC and significantly increased a low baseline mast cell density in the papillary dermis of PLE patients. Baseline T cell numbers in the skin were low, and there was no difference in PLE patients among any time point. This suggests that LC suppression together with recruitment of mast cells into photohardened skin may be a key cellular event underlying the mechanism by which phototherapy protects from PLE.

Infrequent p53 gene mutation but UV gradient-like p53 protein positivity in keloids.

Keloids are characterized by extreme fibroblastic overgrowth of unknown pathogenesis after skin injury. Previous studies, mostly in non-Caucasian populations, suggest that p53 mutations may be involved. To substantiate this, we performed DNA sequence analysis of exons 4-8 of the p53 gene and immunohistochemical staining of p53 protein in archived keloidal tissue samples from 23 Caucasian patients. In contrast to previous reports, we found mutated p53 in keloidal tissue in a minority of cases (2/23; 12%). The G allele frequency and C allele frequency at the p53 polymorphic codon 72 were 0.72 (33/46) and 0.28 (13/46), respectively, in our study, a finding that was similar to the 0.77 (184/240) vs. 0.23 (56/240) (P = 0.4580; chi-squared test) observed in the Hap Map data of a European population but statistically significantly different from the 0.43 (547/1258) vs. 0.57 (711/1258) (P = 0.0002; chi-squared test) observed in the 1000 Genome project [Database of Single Nucleotide Polymorphisms (dbSNP). Bethesda (MD): National Center for Biotechnology Information, National Library of Medicine. dbSNP accession:rs1042522, (dbSNP Build ID: 132). Available from: (http://www.ncbi.nlm.nih.gov/SNP/] a difference most likely due to the different genetic background of the populations enrolled. However, one-third of the keloidal samples showed lesional nuclear p53 staining with a UV penetration gradient-like positivity (P ≤ 0.0084). Staining with an anti-cyclobutane pyrimidine dimer antibody revealed the total absence of short-term photoproducts in the epidermis as well as keloidal tissue. Furthermore, all fibroblasts expressing p53 stained negative for Ki-67, indicating that these cells were in a quiescent stage and p53 upregulation did not contribute to keloidal proliferation. We conclude that p53 plays no major role in the pathogenesis of keloids in the Caucasian population.

8-methoxypsoralen plus ultraviolet A therapy acts via inhibition of the IL-23/Th17 axis and induction of Foxp3+ regulatory T cells involving CTLA4 signaling in a psoriasis-like skin disorder.

To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5.hTGF-beta1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4+CD25+ regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORgammat. PUVA induced the Th2 pathway and IL-10-producing CD4+CD25+Foxp3+Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA.

Profiles of chemokine receptors in melanocytic lesions: de novo expression of CXCR6 in melanoma.

Selective expression of certain chemokine receptors by melanoma cells and the presence of their ligands in tissues might govern organ site-specific metastasis. Because the expression profile of chemokine receptors in tissues of melanocytic origin is unknown, we performed a comprehensive study on melanocytic tissue samples investigating the expression of 18 chemokine receptors at the mRNA level by real-time polymerase chain reaction, using a semiquantitative approach, and of 3 chemokine receptors (CXCR6, CCR9, and XCR1) at the protein level. We report on the de novo expression of CXCR6 in primary melanomas and melanoma metastases, but absence in melanoma cell lines and congenital nevi. CXCR4 and CCR1 were the only 2 chemokine receptors that were consistently expressed in melanocytes, melanoma cell lines, primary, and metastatic melanoma; CCR1 expression increased significantly over progression. CCR9 and XCR1 transcripts were found in melanocytic lesions, and expression was confirmed by immunohistochemistry. Transcripts for CCR10 were not found in any of the lesions, but in some melanoma cell lines. Expression of CCR7 was observed in primary melanomas and some metastases. CCR5 was exclusively expressed in primary melanomas and some cutaneous metastases. Results revealed a restricted and differential pattern of chemokine receptor expression in melanoma tissue, which varies substantially from the expression profile of melanoma cell lines and warrants functional studies on some receptors.