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异位性皮炎(atopic dermatitis),又名特应性皮炎、遗传过敏性皮炎,是一种与特应性(atopy)有关的慢性复发性炎症性皮肤病。特应性是一种以易形成大量变应原特异性IgE作为应答的遗传素质。异位性皮炎多伴有过敏性鼻炎或哮喘。据最近一项流行病学调查报告显示在西欧儿童异位性皮炎发病率高达20%,中国属低发区儿童发病率仅为1.2%左右。特应性皮炎是令人讨厌的疾病,儿童的发病率很高,可以达到15-30%,给患者带来很多麻烦,因此关于特应性皮炎的研究一直受到学者的重视。但关于特应性皮炎的发病机制,过去一直存在争议。
特应性皮炎基本病理生理过程主要是异常IgE免疫反应介导的皮肤屏障功能障碍和肥大细胞激活。研究发现,90%的特应性皮炎患者皮损寄生着金黄色葡萄球菌,而大多数正常人皮肤一般没有该细菌生活。许多金黄色葡萄球菌的外毒素作为超抗原或抗原诱发特应性皮炎。但目前对这些毒素导致皮炎的具体分子机制仍不十分清楚。
来自密歇根大学医学院的研究人员发现,金黄色葡萄球菌生成的δ毒素是引起皮肤免疫系统肥大细胞激活并释放大量细胞因子,进而生成皮疹。而缺乏肥大细胞的动物则不会发生上述反应。这一刊登在《自然》(Nature)杂志上的发现将有助于科学家开发出更好治疗特应性皮炎的药物。据说这一研究完全属于意外,是他们在研究肥大细胞功能时偶然注意到金黄色葡萄球菌δ毒素的强大作用,才导致他们进一步追踪这一细菌毒素在特应性皮炎的作用。
这一研究发现,细菌培养的上清液中包含可以引起肥大细胞脱颗粒的物质,深入生物化学分析确定,金黄色葡萄球菌δ毒素是产生这种作用的最重要成分。研究随后发现,δ毒素诱导肥大细胞脱颗粒依赖于细胞内PI3K激活和游离钙离子内流。奇怪的是,δ毒素诱导肥大细胞脱颗粒和传统的IgE交联不同,这种作用不需要脾脏酪氨酸激酶活性。在没有抗原存在的条件下,IgE可加强δ毒素诱导肥大细胞脱颗粒。从特应性皮炎患者皮肤上分离的金黄色葡萄球菌可大量产生δ毒素,给动物皮肤接种可大量产生δ毒素的金黄色葡萄球菌可以促进IgE和IL-4的产生,并导致皮肤炎症。而存在肥大细胞缺陷的小鼠则不出现IgE和IL-4的增加,如果给动物重新恢复肥大细胞,则上述反应可以重新出现。说明δ毒素导致的皮肤炎症反应决定于肥大细胞。这一研究确定了金黄色葡萄球菌产生δ毒素是造成特应性皮炎皮肤过敏反应的分子基础。
希望将来的深入研究能够确定人类特应性皮炎患者是否存在类似情况,金黄色葡萄球菌无处不在,但过去人们对δ毒素的了解却不太多。关于δ毒素的作用,细菌产生这一毒素的分子细节以及意义都将是十分有价值的研究。和肠道一样,人类皮肤上也存在多种类型的细菌,这些细菌相互制约,共同生活,构成人体皮肤正常屏障的一部分,金黄色葡萄球菌产生δ毒素对其他正常菌群或许会造成抑制,目前还不清楚这是否就是该类患者皮肤上金黄色葡萄球菌占优势的内在原因。
Staphylococcus δ-toxin induces allergic skin disease by activating mast cells.pdf
http://www.nature.com/nature/journal/v503/n7476/full/nature12655.html
a, Activity of β-hexosaminidase released to the extracellular media of BMCMCs stimulated with medium alone (control) or indicated stimuli including different concentrations of culture supernatant of S. aureus 8325-4. b, Activity of β-hexosaminidase in supernatants of MC/9 cells stimulated with 10% of culture supernatant from LAC S. aureus wild type (LAC WT) or isogenic mutants deficient in PSM-α peptides (LAC Δpsmα), PSM-β peptides (LAC Δpsmβ), δ-toxin (LAC Δhld), LAC wild type expressing vector alone (LAC pTXΔ16), LAC deficient in δ-toxin expressing vector alone (LACΔhld pTXΔ16) and strain complemented with δ-toxin plasmid (LACΔhld pTXΔhld). Control represents 10% tryptic soy broth (TSB) medium. c, Histamine concentrations in culture supernatant of FSMCs after stimulation with indicated stimuli including synthetic δ-toxin at 30 μg ml−1 for 15 min. Data represent means ± s.d. of triplicate cultures. Results are representative of at least three independent experiments (a–c). P value refers to comparisons between experimental and control groups (a–c). d, Electromicroscopic images of FSMCs stimulated with synthetic δ-toxin (30 μg ml−1) for 15 min. Images of unstimulated (Control) and ionomycin-treated FSMCs are also shown. Representative of at least 20 images. e, Expression of δ-toxin in Staphylococcus culture supernatants (0.5 μl per well). Loading of lanes with synthetic δ-toxin (10 ng, 100 ng) is shown as reference. Representative of three experiments. f, C57BL6 (WT) and MC-deficient (Kitw-sh/w-sh) mice were injected intradermally into the left and right ears with δ-toxin (100 μg) or PBS, respectively. One representative mouse for each group is shown. Representative of eight mice per group. g, Quantification of Evans blue extracted from skin tissue of WT, Kitw-sh/w-sh and Kitw-sh/w-sh reconstituted with BMCMCs is shown. Dots represent individual ear samples from two independent experiments. NS, not significant; *P < 0.05; **P < 0.01; ***P < 0.001, two-tailed t-test.
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