Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis.
Interleukin-13-producing CD8+ T cells mediate dermal fibrosis in patients with systemic sclerosis.
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DOI：
10.1002/art.37706
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发表时间：
2013-01
影响因子：
--
通讯作者：
Medsger, Thomas A., Jr.
中科院分区：
文献类型：
--
作者：
Fuschiotti, Patrizia;Larregina, Adriana T.;Ho, Johnan;Feghali-Bostwick, Carol;Medsger, Thomas A., Jr.
纤维化是导致系统性硬化症(SSC)发病率和死亡率的主要因素。T细胞是受影响组织中的主要炎性细胞，被认为能产生细胞因子，驱动成纤维细胞合成细胞外基质蛋白，导致过度纤维化。我们发现SSC患者外周血中CD8+T细胞异常产生IL-13与皮肤纤维化程度相关。在这里，我们研究了CD8+T细胞产生IL-13在真皮纤维化中的作用，真皮纤维化是SSC的一种早期和特殊的表现。用定量聚合酶链式反应和免疫印迹法检测正常真皮成纤维细胞与SSC CD8+T细胞培养上清液共培养时细胞外基质的产生。流式细胞仪检测外周血中SSC CD8+T细胞的皮肤归巢受体表达和IL-13的产生，免疫组织化学检测硬化皮肤中IL-13+和CD8+细胞的表达。产生IL-13的循环SSC CD8+T细胞表达皮肤归巢受体，并在正常真皮成纤维细胞中诱导促纤维化表型，该表型可被抗IL-13抗体抑制。在患者的皮损中发现大量的CD8+T细胞和IL-13+细胞，尤其是在疾病的早期炎症阶段。因此，产生IL-13的CD8+T细胞直接参与调节SSC的真皮纤维化。我们通过显示CD8+T细胞在疾病早期归巢于皮肤与IL-13的积聚相关，为理解SSC的真皮纤维化的发病机制做出了重要的机制贡献，并可能成为未来治疗干预的重要靶点。
Fibrosis is a major contributor to morbidity and mortality in systemic sclerosis (SSc). T cells are the predominant inflammatory infiltrate in affected tissues and are thought to produce cytokines that drive the synthesis of extracellular matrix proteins by fibroblasts, resulting in excessive fibrosis. We showed that aberrant IL-13 production by peripheral blood effector CD8+ T cells from SSc patients correlates with the extent of skin fibrosis. Here we investigate the role of IL-13 production by CD8+ T cells in dermal fibrosis, an early and specific manifestation of SSc. Extracellular matrix production by normal dermal fibroblasts co-cultured with SSc CD8+ T-cell-supernatants was determined by quantitative PCR and Western blot. Skin-homing receptor expression and IL-13 production by peripheral blood SSc CD8+ T cells were measured by flow cytometry, whereas immunohistochemistry identified IL-13+ and CD8+ cells in sclerotic skin. IL-13-producing circulating SSc CD8+ T cells express skin-homing receptors and induce a pro-fibrotic phenotype in normal dermal fibroblasts that is inhibited by an anti-IL-13 antibody. High numbers of CD8+ T cells and IL-13+ cells are found in the skin lesions of patients, particularly in the early inflammatory phase of the disease. Thus, IL-13-producing CD8+ T cells are directly involved in modulating dermal fibrosis in SSc. We make an important mechanistic contribution to understanding the pathogenesis of dermal fibrosis in SSc by showing that CD8+ T cells homing to the skin early in the disease are associated with accumulation of IL-13 and may represent an important target for future therapeutic intervention.
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DOI：
10.1073/pnas.0700021104
发表时间：
2007-02-20
影响因子：
11.1
作者：
Aliprantis, Antonios O.;Wang, Jingsong;Glimcher, Laurie H.
通讯作者：
Glimcher, Laurie H.
DOI：
10.1006/clin.1996.4322
发表时间：
1997-04-01
期刊：
CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY
影响因子：
--
作者：
Kahaleh, MB;Fan, PS
通讯作者：
Fan, PS
影响因子：
64.8
作者：
Fuhlbrigge, RC;Kieffer, JD;Kupper, TS
通讯作者：
Kupper, TS
影响因子：
--
作者：
Chizzolini, C;Parel, Y;Dayer, JM
通讯作者：
Dayer, JM
影响因子：
82.9
作者：
Fichtner-Feigl, S;Strober, W;Kitani, A
通讯作者：
Kitani, A