Publications (7)0 Total impact
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ABSTRACT: Canineatopic dermatitis (AD), a chronic inflammatory skin disease, shares characteristics with its human counterpart. To get insight into the role of enzymes involved in production of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4), potent inflammatory mediators originating from membrane-derived arachidonic acid (AA), expression of genes encoding these enzymes and receptors was quantified by qPCR in non-lesional and lesional skin from atopic dogs and in healthy skin. Significantly higher mRNA expression of the key enzymes 5-lipoxygenase (5-LO), 5-LO activating protein (FLAP), leukotriene A4 hydrolase (LTA4H) and prostaglandin E synthase 1 (mPGES-1) and their receptors (PGE receptors 2 and 3) were observed. Being responsible for elevated levels of metabolites of the 3-series prostaglandins and the 5-series leukotrienes these enzymes may be interesting targets for therapy that should result in amelioration of clinical signs in canine atopic dermatitis
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ABSTRACT: GLI1 oncogene mediates the effects of the signalling molecule Sonic Hedgehog, involved in the control of differentiation and morphogenesis during embryonic development and postnatal life [1,2]. Methods to modulate GLI1 expression without knocking out the gene have not yet been devised. Since GLI1 is specifically expressed by basal cell carcinoma (BCC) [2,3], which expression is considered a diagnostic hallmark and a pathogenetically meaningful event [4], BCC cells might be valuable to investigate on GLI1 modulation and its consequences.
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Y.M. Schlotter
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ABSTRACT: Atopic dermatitis in dogs Novel insights into mechanisms of disease Atopic dermatitis in dogs is the most important canine pruritic disorder, described for the first time in 1971. It is defined as a genetically-predisposed inflammatory and pruritic allergic skin disease with characteristic clinical features, associated with IgE antibodies specific for environmental allergens such as house dust mites and grass pollen. Atopic dermatitis in dogs harbors many similarities with its human counterpart such as the young age of onset, the clinical presentation and the genetic predisposition to develop the disease. Atopic dermatitis in human and dogs has been largely viewed as a disease of immunologic etiology. Key roles are played by dendritic cell signaling, the Th1/T2 cell dysregulation, IgE production, and mast cell hyperreactivity in the development of the pruritic inflammatory dermatosis. However, more recently it has been proposed that an intrinsic defect in the epithelial cell leads to a dysfunction in the epidermal barrier followed by immune system activation. In this thesis major research questions addressed, concern the role of fatty acids and their metabolic enzymes in the inflammation in canine atopic dermatitis and their possible modulatory effect. In addition, we have characterized the immunologic phenotype of atopic skin, particularly at the level of mRNA expression. It is concluded that spontaneous atopic dogs show a mixed Th1/Th2 inflammatory pattern which is consistent with human findings. In addition, it was found that lesional skin of atopic dogs contains a significant higher amount of arachidonic acid, which metabolism results primarily in inflammatory metabolites, the 2-series prostaglandins and the 4-series leukotrienes. This likely contributes to the inflammatory reaction seen in lesional skin. A question for future research is how the arachidonic content in lesional skin becomes this high. Several explanations for this high arachidonic acid content are discussed, whereas one of these have been addressed in this thesis and concern the cell infiltrates in lesional atopic skin. As atopic skin inhabits increased amounts of inflammatory cells and as arachidonic acid is the main fatty acid in the membranes of these cells, this might explain our finding of the high amount of AA in lesional skin. It is further reasoned that these cell infiltrates in lesional (and non-lesional) skin explain the high levels found for 5-lipoxygenase, 5-lipoxygenase-activating protein, leukotriene A4 hydrolase and microsomal prostaglandin-E synthase. These observations support future therapies with anti-leukotriene drugs in atopic dogs. It is very likely that in dogs, as in human, an epidermal barrier dysfunction together with an immunologic disturbance leads to atopic dermatitis; however it is not yet known which of these two systems initiate disease development. Based on the currently known similarities between human and canine atopic dermatitis now supplemented with our findings, there is strong evidence that the dog might serve as a good model for further research into human atopic dermatitis as well.
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ABSTRACT: Lipid antigens are presented to T cells by the CD1 family of proteins. In this study, we characterize the complete dog (Canis familiaris) CD1 locus, which is located on chromosome 38. The canine locus contains eight CD1A genes (canCD1A), of which five are pseudogenes, one canCD1B, one canCD1C, one canCD1D, and one canCD1E gene. In vivo expression of canine CD1 proteins was shown for canCD1a6, canCD1a8, and canCD1b, using a panel of anti-CD1 monoclonal antibodies (mAbs). CanCD1a6 and canCD1a8 are recognized by two distinct mAbs. Furthermore, we show differential transcription of the three canCD1A genes in canine tissues. In canine skin, the transcription level of canCD1A8 was higher than that of canCD1A6, and no transcription of canCD1A2 was detected. Based on protein modeling and protein sequence alignment, we predict that both canine CD1a proteins can bind different glycolipids in their groove. Besides differences in ectodomain structure, we observed the unique presence of three types of cytoplasmic tails encoded by canCD1A genes. cDNA sequencing and expressed sequence tag sequences confirmed the existence of a short, human CD1a-like cytoplasmic tail of four amino acids, of an intermediate length form of 15 amino acids, and of a long form of 31 amino acids.
