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Staphylococcus δ-toxin induces allergic skin disease by activating mast cells

机译：金黄色葡萄球菌δ毒素通过激活肥大细胞诱导过敏性皮肤病

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摘要

Atopic dermatitis is a chrome inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified δ-toxin as the mast cell degranulation inducing factor produced by S. aureus. Mast cell degranulation induced by δ-toxin depended on phosphoinositide 3-kinase and calcium (Ca~(2+)) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced δ-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of δ-toxin. Skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by 5-toxin was abrogated in Kit~(W-sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify δ-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.
机译：特应性皮炎是一种铬炎性皮肤病，在工业化国家中影响15-30％的儿童和大约5％的成年人。尽管尚未完全了解特应性皮炎的发病机理，但该疾病是由皮肤屏障功能异常引起的异常免疫球蛋白-E免疫反应介导的。肥大细胞促成免疫球蛋白-E介导的过敏性疾病，包括特应性皮炎。激活后，肥大细胞释放其膜结合的胞质颗粒，导致释放在特应性皮炎和宿主防御的发病机理中重要的几种分子。超过90％的特应性皮炎患者在病灶皮肤中被金黄色葡萄球菌定植，而大多数健康人没有病原体。几种葡萄球菌外毒素可以在特应性皮炎模型中充当超抗原和/或抗原。然而，这些葡萄球菌外毒素在疾病发病机理中的作用仍不清楚。在这里我们报道金黄色葡萄球菌的培养上清液含有有效的肥大细胞脱粒活性。生化分析确定δ-毒素是金黄色葡萄球菌产生的肥大细胞脱粒诱导因子。 δ-毒素诱导的肥大细胞脱粒取决于磷酸肌醇3-激酶和钙（Ca〜（2+））的流入。但是，与免疫球蛋白-E交联介导的不同，它不需要脾酪氨酸激酶。此外，在没有抗原的情况下，免疫球蛋白-E增强了δ毒素诱导的肥大细胞脱粒。此外，从特应性皮炎患者中回收的金黄色葡萄球菌分离物产生大量的δ-毒素。金黄色葡萄球菌（S. aureus）的皮肤定植，而不是缺乏δ毒素的突变体，促进了免疫球蛋白E和白介素4的产生，以及炎症性皮肤病。此外，在Kit_（W-sh / W-sh）肥大细胞缺乏的小鼠中，废除了5-毒素对免疫球蛋白-E产生和皮炎的增强作用，并通过肥大细胞重建而恢复。这些研究确定了δ毒素是肥大细胞脱粒的有效诱导剂，并提出了金黄色葡萄球菌定植与过敏性皮肤病之间的机制联系。

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  • 来源
    《Nature》 |2013年第7476期|397-401|共5页
  • 作者

    Yuumi Nakamura; Jon Oscherwitz; Kemp B. Cease; Susana M. Chan; Raul Munoz-Planillo; Mizuho Hasegawa; Amer E. Villaruz; Gordon Y. C. Cheung; Martin J. McGavin; Jeffrey B. Travers; Michael Otto; Naohiro Inohara; Gabriel Nunez;

  • 作者单位

    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, Michigan 48105, USA;

    Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA,VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, Michigan 48105, USA;

    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA;

    Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Microbiology and Immunology, and Centre for Human Immunology, Western University, University of Western Ontario, London, Ontario, N6A 5C1, Canada;

    Department of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;

    Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, Maryland 20892, USA;

    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA;

    Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, 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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