Kess Daniel, Peters Thorsten, Zamek Jan, Wickenhauser Claudia, Tawadros Samir, Loser Karin, Varga Georg, Grabbe Stephan, Nischt Roswitha, Sunderkötter Cord, Müller Werner, Krieg Thomas, Scharffetter-Kochanek Karin
Department of Dermatology, University of Cologne, Cologne, Germany.
J Immunol. 2003 Dec 1;171(11):5697-706. doi: 10.4049/jimmunol.171.11.5697.
In a CD18 hypomorphic polygenic PL/J mouse model, the severe reduction of CD18 (beta(2) integrin) to 2-16% of wild-type levels leads to the development of a psoriasiform skin disease. In this study, we analyzed the influence of reduced CD18 gene expression on T cell function, and its contribution to the pathogenesis of this disease. Both CD4(+) and CD8(+) T cells were significantly increased in the skin of affected CD18 hypomorphic mice. But only depletion of CD4(+) T cells, and not the removal of CD8(+) T cells, resulted in a complete clearance of the psoriasiform dermatitis. This indicates a central role of CD4(+) T cells in the pathogenesis of this disorder, further supported by the detection of several Th1-like cytokines released predominantly by CD4(+) T cells. In contrast to the CD18 hypomorphic mice, CD18 null mutants of the same strain did not develop the psoriasiform dermatitis. This is in part due to a lack of T cell emigration from dermal blood vessels, as experimental allergic contact dermatitis could be induced in CD18 hypomorphic and wild-type mice, but not in CD18 null mutants. Hence, 2-16% of CD18 gene expression is obviously sufficient for T cell emigration driving the inflammatory phenotype in CD18 hypomorphic mice. Our data suggest that the pathogenic involvement of CD4(+) T cells depends on a gene dose effect with a reduced expression of the CD18 protein in PL/J mice. This murine inflammatory skin model may also have relevance for human polygenic inflammatory diseases.
在一个CD18低表达的多基因PL/J小鼠模型中，CD18（β2整合素）严重减少至野生型水平的2%-16%会导致银屑病样皮肤病的发生。在本研究中，我们分析了CD18基因表达降低对T细胞功能的影响及其对该疾病发病机制的作用。在受影响的CD18低表达小鼠的皮肤中，CD4+和CD8+ T细胞均显著增加。但只有清除CD4+ T细胞，而不是去除CD8+ T细胞，才能使银屑病样皮炎完全消退。这表明CD4+ T细胞在该疾病的发病机制中起核心作用，检测到主要由CD4+ T细胞释放的几种Th1样细胞因子进一步支持了这一点。与CD18低表达小鼠不同，同一品系的CD18基因敲除突变体未发生银屑病样皮炎。部分原因是缺乏T细胞从真皮血管的迁出，因为实验性变应性接触性皮炎可在CD18低表达和野生型小鼠中诱导，但在CD18基因敲除突变体中则不能。因此，2%-16%的CD18基因表达显然足以驱动CD18低表达小鼠中T细胞迁出并引发炎症表型。我们的数据表明，CD4+ T细胞的致病作用取决于基因剂量效应，即PL/J小鼠中CD18蛋白表达降低。这种小鼠炎症性皮肤模型可能也与人类多基因炎症性疾病有关。
