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Integrin-modulating therapy prevents fibrosis and autoimmunity in mouse models of scleroderma

机译：整合素调节疗法可预防硬皮病小鼠模型的纤维化和自身免疫

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摘要

In systemic sclerosis (SSc), a common and aetiologically mysterious form of scleroderma (defined as pathological fibrosis of the skin), previously healthy adults acquire fibrosis of the skin and viscera in association with autoantibodies. Familial recurrence is extremely rare and causal genes have not been identified. Although the onset of fibrosis in SSc typically correlates with the production of autoantibodies, whether they contribute to disease pathogenesis or simply serve as a marker of disease remains controversial and the mechanism for their induction is largely unknown. The study of SSc is hindered by a lack of animal models that recapitulate the aetiology of this complex disease. To gain a foothold in the pathogenesis of pathological skin fibrosis, we studied stiff skin syndrome (SSS), a rare but tractable Mendelian disorder leading to childhood onset of diffuse skin fibrosis with autosomal dominant inheritance and complete penetrance. We showed previously that SSS is caused by heterozygous missense mutations in the gene (FBN1) encoding fibrillin-1, the main constituent of extracellular microfibrils. SSS mutations all localize to the only domain in fibrillin-1 that harbours an Arg-Gly-Asp (RGD) motif needed to mediate cell-matrix interactions by binding to cell-surface integrins. Here we show that mouse lines harbouring analogous amino acid substitutions in fibrillin-1 recapitulate aggressive skin fibrosis that is prevented by integrin-modulating therapies and reversed by antagonism of the pro-fibrotic cytokine transforming growth factor β (TGF-β). Mutant mice show skin infiltration of pro-inflammatory immune cells including plasmacytoid dendritic cells, T helper cells and plasma cells, and also autoantibody production; these findings are normalized by integrin-modulating therapies or TGF-β antagonism. These results show that alterations in cell-matrix interactions are sufficient to initiate and sustain inflammatory and pro-fibrotic programmes and highlight new therapeutic strategies.
机译：在全身性硬化病（SSc）中，硬皮病是一种常见且病因学上神秘的形式（定义为皮肤的病理性纤维化），以前健康的成年人会与自身抗体相关联地获得皮肤和内脏的纤维化。家族性复发极少见，尚未发现病因基因。尽管SSc中纤维化的发作通常与自身抗体的产生有关，但它们是否促成疾病发病机理或仅充当疾病标志物仍存在争议，其诱导机理在很大程度上尚不清楚。 SSc的研究由于缺乏能够概括这种复杂疾病的病因的动物模型而受到阻碍。为了在病理性皮肤纤维化的发病机理中立足，我们研究了硬性皮肤综合症（SSS），这是一种罕见但难治的孟德尔疾病，导致儿童期弥漫性皮肤纤维化的发作，具有常染色体显性遗传和完全外显。我们以前表明SSS是由编码fibrillin-1（细胞外微纤维的主要成分）的基因（FBN1）中的杂合错义突变引起的。 SSS突变均位于原纤维蛋白1中唯一一个具有Arg-Gly-Asp（RGD）基序的结构域，该基序是通过与细胞表面整合素结合来介导细胞-基质相互作用的。在这里，我们显示在原纤维蛋白1中包含相似氨基酸取代的小鼠品系概括了侵袭性皮肤纤维化，该蛋白被整联蛋白调节疗法所预防，并被促纤维化细胞因子转化生长因子β（TGF-β）的拮抗作用所逆转。突变小鼠表现出促炎性免疫细胞（包括浆细胞样树突状细胞，T辅助细胞和浆细胞）的皮肤浸润，以及自身抗体的产生；这些发现通过整合素调节疗法或TGF-β拮抗作用得以标准化。这些结果表明，细胞-基质相互作用的改变足以启动和维持炎症和促纤维化程序，并突出了新的治疗策略。

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  • 来源
    《Nature》 |2013年第7474期|126-130|共5页
  • 作者

    Elizabeth E. Gerber; Elena M. Gallo; Stefani C. Fontana; Elaine C. Davis; Fredrick M. Wigley; David L. Huso; Harry C. Dietz;

  • 作者单位

    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    McGill University, Montreal, Quebec H3A 2K6, Canada;

    Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA;

    McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA,Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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