IL-31 expression by inflammatory cells is preferentially elevated in atopic dermatitis

Interleukin-31 (IL-31) is a recently discovered cytokine expressed in many human tissues, and predominantly by activated CD4+ T cells. IL-31 signals through a heterodimeric receptor consisting of IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMR). Earlier studies have shown involvement of IL-31 and its receptor components IL-31RA and OSMR in atopic dermatitis, pruritus and Th2-weighted inflammation at the mRNA level. The aim of this study was to investigate IL-31 protein expression in skin of such conditions. Immunohisto-chemical staining for IL-31, IL-31RA and OSMR was performed in formalin-fixed paraffin-embedded biopsy specimens. IL-31 expression was increased in the inflammatory infiltrates from skin biopsies taken from subjects with atopic dermatitis, compared with controls (p ≤ 0.05). IL-31, IL-31RA and OSMR protein immunoreactivity was not increased in biopsies from subjects with other Th2-weighted and pruritic skin diseases. Our results confirm, at the protein level, the relationship between IL-31 expression and atopic dermatitis. Our results do not support a general relationship between expression of IL-31/IL-31R and pruritic or Th2-mediated diseases

Prevalence of Merkel cell polyomavirus among Swiss Merkel cell carcinoma patients

We detected viral DNA in 20 out of 30 cases of MCC and in 0 out of 19 control samples. The presence of viral DNA in 66.6% of our MCC tissue specimens confirms the high prevalence of MCPyV in MCC patients described in American, German, French and Hungarian patient collections

Komplexes regionales Schmerzsyndrom (CRPS)

Einleitung: Das komplexe regionale Schmerzsyndrom (CRPS) ist eine relativ seltene, jedoch für die Betroffenen äußerst gravierende Erkrankung, welche meist distal einer Extremitätenverletzung auftritt. Die klinischen Symptome sowie die Schmerzen stehen in keinem Verhältnis zum auslösenden Ereignis. Bei etwa 10% der Patienten liegt gar kein auslösendes Ereignis vor. Bei ungefähr der Hälfte der Patienten führt CRPS zu dauerhafter Arbeitsunfähigkeit und hohen Behandlungs- und Folgekosten. Klinik: Es werden zwei Formen unterschieden. Beim CRPS 1 lässt sich keine Nervenläsion nachweisen, wohingegen es beim CRPS 2 zu einer Verletzung eines Nerven oder Nervenhauptstamms gekommen ist. Im klinischen Verlauf gibt es jedoch keinen Unterschied zwischen den beiden Formen. In ca. 90 % aller Fälle handelt es sich um ein CRPS 1, früher als „Morbus Sudeck“ bekannt. Das Leitsymptom sind Schmerzen. Zudem können auch trophische Störungen wie Schwelllungen, lokale Verfärbungen der Haut oder asymmetrische Hauttemperaturen auftreten. Häufig finden sich auch eine eingeschränkte Beweglichkeit und Funktionseinbuße der betroffenen Extremität, welche sehr schwer zu therapieren sind. Diagnostik: Initial kann die Unterscheidung eines CRPS von einem normalen posttraumatischen Verlauf schwierig sein. Im weiteren Verlauf stehen die gravierenden Symptome in keinem Verhältnis mehr zum auslösenden Ereignis. Die Diagnose eines CRPS wird primär klinisch gestellt. Die Budapest-Kriterien helfen, die Diagnose zu sichern. Therapie: Eine frühe und interdisziplinäre Rehabilitation ist zentral in der Therapie des CRPS. Ergo- und physiotherapeutische Maßnahmen werden ergänzt mit einer guten medikamentösen Schmerzeinstellung sowie gegebenenfalls auch psychologischer Unterstützung. Medikamentös kommt das analgetische Stufenschema der WHO zum Einsatz, bei starken Hyperalgesien zeigte Methadon gute Erfolge, bei therapieresistenten Schmerzen auch Gabapentin oder Pregabalin. Biphosphonate zeigten einen guten analgetischen Effekt, insbesondere bei nachgewiesenen ossären Läsionen. Die chronischen Ödeme und Entzündungen können einen vorübergehenden Einsatz von Steroiden erfordern. Weiter gilt es, Folgeschäden wie Osteoporose zu verhindern. Patienten, bei welchen der Verdacht auf ein CRPS geäußert wird, sollten durch ein multidisziplinäres Behandlungsteam mit möglicher großer Erfahrung in der Betreuung dieses Krankheitsbildes überwiesen werden. Ein Arzt sollte die Betreuung des Patienten koordinieren. Je früher die Behandlung begonnen wird, desto besser ist die Prognose

Immunosuppression affects CD4+ mRNA expression and induces Th2 dominance in the microenvironment of cutaneous squamous cell carcinoma in organ transplant recipients

Squamous cell carcinoma (SCC) is the most frequent cancer in organ transplant recipients (OTRs). The immune system plays a major role in the fight against SCC, however, little is known about the local inflammatory response in SCC at all. We analyzed quantity and quality of the perineoplastic inflammatory SCC microenvironment in immunocompetent patients and immmunosuppressed OTRs. RNA expression profile of SCC patients was analyzed for 8 different sets of genes relating to Th1 versus Th2 response using Gene Set Enrichment Analysis. SCC from immunocompetent patients and OTRs were analyzed by real-time polymerase chain reactions for CD4, CD8, TBET, GATA-3, FOXP3, RORC, IFN-gamma, IL-4, TGF-beta, IL-10, and IL-17A mRNA expression. Immunohistochemistry was carried out in SCC for CD3, CD4, CD8, and FOXP3 expression. Considerable inflammation was seen in both patient groups. SCC in immunocompetent patients and OTRs was associated with a mixed Th1 and Th2 gene expression signature. CD4(+) mRNA was diminished in immunosuppression. Skin adjacent to SCC in OTRs showed Th2 expression pattern as compared with immunocompetent patients. T-BET and IFN-gamma mRNA expression were decreased in the OTR group. Although Th17-weighted inflammation was unchanged, IL-17A mRNA level was markedly decreased with immunosuppression. Regulatory T cells, characterized by FOX-P3 and TGF-beta mRNA level, were decreased in OTRs. Our findings support the hypothesis that nontumor-bearing skin adjacent to SCC in OTRs is not necessarily normal and that the local microenvironment may contribute to a field effect contributing to higher recurrence rates and more aggressive behavior observed in these patients

Ingenol mebutate signals via PKC/MEK/ERK in keratinocytes and induces interleukin decoy receptors IL1R2 and IL13RA2

Squamous cell carcinoma (SCC) is the second most common human skin cancer and the second leading cause of skin cancer-related death. Recently, a new compound, ingenol mebutate, was approved for treatment of actinic keratosis, a precursor of SCC. As the mechanism of action is poorly understood, we have further investigated the mechanism of ingenol mebutate-induced cell death. We elucidate direct effects of ingenol mebutate on primary keratinocytes, patient-derived SCC cells, and a SCC cell line. Transcriptional profiling followed by pathway analysis was performed on ingenol mebutate-treated primary keratinocytes and patient-derived SCC cells to find key mediators and identify the mechanism of action. Activation of the resulting pathways was confirmed in cells and human skin explants and supported by a phosphorylation screen of treated primary cells. The necessity of these pathways was demonstrated by inhibition of certain pathway components. Ingenol mebutate inhibited viability and proliferation of all keratinocyte-derived cells in a biphasic manner. Transcriptional profiling identified the involvement of PKC/MEK/ERK signaling in the mechanism of action and inhibition of this signaling pathway rescued ingenol mebutate-induced cell death after treatment with 100 nmol/L ingenol mebutate, the optimal concentration for the first peak of response. We found the interleukin decoy receptors IL1R2 and IL13RA2 induced by ingenol mebutate in a PKC/MEK/ERK-dependent manner. Furthermore, siRNA knockdown of IL1R2 and IL13RA2 partially rescued ingenol mebutate-treated cells. In conclusion, we have shown that ingenol mebutate-induced cell death is mediated through the PKCδ/MEK/ERK pathway, and we have functionally linked the downstream induction of IL1R2 and IL13RA2 expression to the reduced viability of ingenol mebutate-treated cells. Mol Cancer Ther; 14(9); 2132-42. ©2015 AACR