Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.
Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.
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DOI：
10.1016/j.jaci.2009.06.046
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发表时间：
2009-09
影响因子：
14.2
通讯作者：
Elias, Peter M.
中科院分区：
文献类型：
--
作者：
Scharschmidt, Tiffany C.;Man, Mao-Qiang;Hatano, Yutaka;Crumrine, Debra;Gunathilake, Roshan;Sundberg, John P.;Silva, Kathleen A.;Mauro, Theodora M.;Hupe, Melanie;Cho, Soyun;Wu, Yan;Celli, Anna;Schmuth, Matthias;Feingold, Kenneth R.;Elias, Peter M.
聚丝蛋白（FLG）的突变与特应性皮炎（AD）相关，并被推测引起屏障异常。然而，额外的获得性应激源可能是必要的，因为相同的突变可能导致非炎症性疾病，寻常鱼鳞病。我们在这里研究是否FLG缺陷单独足以产生屏障异常，为假定的异常的基础，其促炎性后果。使用片状尾巴（ft/ft）小鼠，缺乏加工的神经元，由于在前聚丝蛋白的移码突变，模仿人类AD中的一些突变，我们评估是否FLG缺乏引起屏障异常;进一步定位缺陷;确定其亚细胞基础;并评估阈值刺激性和半抗原诱导的皮炎。片状尾小鼠表现出低度炎症，由于板层体分泌受损和角质层细胞外膜改变，水溶性异生物质的双向、细胞旁渗透性增加。这种屏障异常与局部刺激物和半抗原的炎症阈值降低相关。此外，当以在+/+小鼠中不产生炎症的剂量反复暴露于局部半抗原时，ft/ft小鼠发展为严重的AD样皮肤病，屏障功能进一步恶化，并具有th 2免疫表型的特征（CRTH +炎症增加，血清IgE水平升高，抗菌肽[mBD 3]表达降低）。FLG缺陷单独在小鼠中引起细胞旁屏障异常，其降低了局部刺激物/半抗原的炎症阈值，可能是FLG相关AD中抗原渗透增强的原因。
Mutations in filaggrin (FLG) are associated with atopic dermatitis (AD), and are presumed to provoke a barrier abnormality. Yet, additional acquired stressors may be necessary, since the same mutations can result in a non-inflammatory disorder, ichthyosis vulgaris. We examined here whether FLG deficiency alone suffices to produce a barrier abnormality; the basis for the putative abnormality; and its pro-inflammatory consequences. Using the flaky-tail (ft/ft) mouse, which lacks processed flg due to a frame-shift mutation in profilaggrin that mimics some mutations in human AD, we assessed whether FLG deficiency provokes a barrier abnormality; further localized the defect; identified its subcellular basis; and assessed thresholds to irritant and hapten-induced dermatitis. Flaky-tail mice exhibit low-grade inflammation, with increased bidirectional, paracellular permeability of water-soluble xenobiotes due to impaired lamellar body secretion and altered stratum corneum extracellular membranes. This barrier abnormality correlates with reduced inflammatory thresholds to both topical irritants and haptens. Moreover, when exposed repeatedly to topical haptens, at doses that produce no inflammation in +/+ mice, ft/ft mice develop a severe AD-like dermatosis, with a further deterioration in barrier function and features of a th2 immunophenotype (increased CRTH + inflammation, elevated serum IgE levels, and reduced antimicrobial peptide [mBD3] expression). FLG deficiency alone provokes a paracellular barrier abnormality in mice that reduces inflammatory thresholds to topical irritants/haptens, likely accounting for enhanced antigen penetration in FLG-associated AD.
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影响因子：
3.6
作者：
Demerjian, M;Man, MQ;Feingold, KR
通讯作者：
Feingold, KR
影响因子：
6.5
作者：
BOND, JR;BARRY, BW
通讯作者：
BARRY, BW
DOI：
10.1038/jid.2008.442
发表时间：
2009-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
6.5
作者：
Demerjian, Marianne;Crumrine, Debra A.;Elias, Peter M.
通讯作者：
Elias, Peter M.
影响因子：
6.5
作者：
Hachem, JP;Man, MQ;Elias, PM
通讯作者：
Elias, PM