Epithelial-intrinsic defects in TGFβR signaling drive local allergic inflammation manifesting as eosinophilic esophagitis

被引:18
作者
Laky, Karen [1 ]
Kinard, Jessica L. [1 ]
Li, Jenny Min [1 ]
Moore, Ian N. [2 ]
Lack, Justin [3 ,4 ]
Fischer, Elizabeth R. [5 ]
Kabat, Juraj [6 ]
Latanich, Rachel [7 ]
Zachos, Nicholas C. [7 ]
Limkar, Ajinkya R. [8 ]
Weissler, Katherine A. [1 ]
Thompson, Robert W. [9 ]
Wynn, Thomas A. [9 ]
Dietz, Harry C. [10 ,11 ]
Guerrerio, Anthony L. [12 ]
Frischmeyer-Guerrerio, Pamela A. [1 ]
机构
[1] NIAID, Food Allergy Res Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA
[2] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA
[3] NIAID, Collaborat Bioinformat Resource, NIH, Bethesda, MD 20892 USA
[4] Frederick Natl Lab Canc Res, Adv Biomed Computat Sci, Frederick, MD 21701 USA
[5] NIAID, Electron Microscopy Unit, Res Technol Branch, NIH, Hamilton, MT 59840 USA
[6] NIAID, Biol Imaging Sect, Res Technol Branch, NIH, Bethesda, MD 20892 USA
[7] Johns Hopkins Univ, Sch Med, Dept Med, Div Gastroenterol & Hepatol, Baltimore, MD 21205 USA
[8] NIAID, Inflammat Immunobiol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA
[9] NIAID, Immunopathogenesis Sect, Lab Parasit Dis, NIH, Bethesda, MD 20892 USA
[10] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Sch Med, Baltimore, MD 21205 USA
[11] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA
[12] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Gastroenterol Hepatol & Nutr, Baltimore, MD 21287 USA
关键词
GROWTH-FACTOR-BETA; INNATE LYMPHOID-CELLS; NECROSIS-FACTOR-ALPHA; LOEYS-DIETZ SYNDROME; EPIDERMAL-KERATINOCYTES; ATOPIC-DERMATITIS; TRANSFORMING GROWTH-FACTOR-BETA-1; TRANSENDOTHELIAL MIGRATION; EXPRESSION PROFILE; MOUSE MODEL;
D O I
10.1126/sciimmunol.abp9940
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Allergic diseases are a global health challenge. Individuals harboring loss-of-function variants in transforming growth factor-3 receptor (TGF3R) genes have an increased prevalence of allergic disorders, including eosino-philic esophagitis. Allergic diseases typically localize to mucosal barriers, implicating epithelial dysfunction as a cardinal feature of allergic disease. Here, we describe an essential role for TGF3 in the control of tissue-specific immune homeostasis that provides mechanistic insight into these clinical associations. Mice expressing a TGF3R1 loss-of-function variant identified in atopic patients spontaneously develop disease that clinically, im-munologically, histologically, and transcriptionally recapitulates eosinophilic esophagitis. In vivo and in vitro, TGF3R1 variant-expressing epithelial cells are hyperproliferative, fail to differentiate properly, and overexpress innate proinflammatory mediators, which persist in the absence of lymphocytes or external allergens. Together, our results support the concept that TGF3 plays a fundamental, nonredundant, epithelial cell-intrinsic role in controlling tissue-specific allergic inflammation that is independent of its role in adaptive immunity.
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页数:18
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