IR@PKUHSC  > 北京大学第一临床医学院  > 皮肤性病科
学科主题临床医学
Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens
Scharschmidt, Tiffany C.1,2; Man, Mao-Qiang1,2; Hatano, Yutaka1,2; Crumrine, Debra1,2; Gunathilake, Roshan1,2; Sundberg, John P.3; Silva, Kathleen A.3; Mauro, Theodora M.1,2; Hupe, Melanie1,2; Cho, Soyun4,5; Wu, Yan6; Celli, Anna1,2; Schmuth, Matthias1,2; Feingold, Kenneth R.1,2; Elias, Peter M.1,2
关键词Atopic dermatitis barrier function contact dermatitis filaggrin flaky-tail mouse lamellar body
刊名JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
2009-09-01
DOI10.1016/j.jaci.2009.06.046
124期:3页:496-U164
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Allergy ; Immunology
研究领域[WOS]Allergy ; Immunology
关键词[WOS]HAIRLESS MOUSE SKIN ; EPIDERMAL PERMEABILITY BARRIER ; STRATUM-CORNEUM ACIDIFICATION ; CONTACT-DERMATITIS MODELS ; OF-FUNCTION MUTATIONS ; ATOPIC-DERMATITIS ; ICHTHYOSIS-VULGARIS ; PATHOGENIC MECHANISMS ; LAMELLAR BODIES ; MURINE MODEL
英文摘要

Background: Mutations in the human filaggrin gene (FLG) are associated with atopic dermatitis (AD) and are presumed to provoke a barrier abnormality. Yet additional acquired stressors might be necessary because the same mutations can result in a noninflammatory disorder, ichthyosis vulgaris.

Objective: We examined here whether FLG deficiency alone suffices to produce a barrier abnormality, the basis for the putative abnormality, and its proinflammatory consequences.

Methods: By using the flaky-tail mouse, which lacks processed murine filaggrin because of a frameshift mutation in the gene encoding 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.

Results: Flaky-tail mice exhibit low-grade inflammation with increased bidirectional, paracellular permeability of water-soluble xenobiotes caused by 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 wild-type mice, flaky-tail mice experience a severe AD-like dermatosis with a further deterioration in barrier function and features of a T(H)2 immunophenotype (increased CRTH levels plus inflammation, increased serum IgE levels, and reduced antimicrobial peptide [mBD3] expression).

Conclusions: 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. (J Allergy Clin Immunol 2009;124:496-506.)

语种英语
WOS记录号WOS:000274315900015
项目编号AR019098 ; AG028492 ; AI059311
资助机构National Institutes of Health ; Medical Research Service, Department of Veterans Affairs
引用统计
被引频次:137[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/65500
专题北京大学第一临床医学院_皮肤性病科
作者单位1.Boramae Hosp, Seoul, South Korea
2.Vet Affairs Med Ctr, Dermatol Serv, San Francisco, CA 94121 USA
3.Jackson Lab, Bar Harbor, ME 04609 USA
4.Seoul Natl Univ, Coll Med, Dept Dermatol, Seoul, South Korea
5.Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA
6.Peking Univ, Hosp 1, Dept Dermatol, Beijing 100871, Peoples R China
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GB/T 7714
Scharschmidt, Tiffany C.,Man, Mao-Qiang,Hatano, Yutaka,et al. Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens[J]. JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY,2009,124(3):496-U164.
APA Scharschmidt, Tiffany C..,Man, Mao-Qiang.,Hatano, Yutaka.,Crumrine, Debra.,Gunathilake, Roshan.,...&Elias, Peter M..(2009).Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens.JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY,124(3),496-U164.
MLA Scharschmidt, Tiffany C.,et al."Filaggrin deficiency confers a paracellular barrier abnormality that reduces inflammatory thresholds to irritants and haptens".JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY 124.3(2009):496-U164.
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