ERBIN deficiency links STAT3 and TGF-β pathway defects with atopy in humans

被引：83

作者：

Lyons, J. J. ^{[1
]}

Liu, Y. ^{[1
]}

Ma, C. A. ^{[1
]}

Yu, X. ^{[1
]}

O'Connell, M. P. ^{[1
]}

Lawrence, M. G. ^{[5
]}

Zhang, Y. ^{[1
]}

Karpe, K. ^{[1
]}

Zhao, M. ^{[2
]}

Siegel, A. M. ^{[1
]}

Stone, K. D. ^{[1
]}

Nelson, C. ^{[1
]}

Jones, N. ^{[6
]}

DiMaggio, T. ^{[1
]}

Darnell, D. N. ^{[3
]}

Mendoza-Caamal, E. ^{[7
]}

Orozco, L. ^{[7
]}

Hughes, J. D. ^{[8
]}

McElwee, J. ^{[8
]}

Hohman, R. J. ^{[2
]}

Frischmeyer-Guerrerio, P. A. ^{[4
]}

Rothenberg, M. E. ^{[9
]}

Freeman, A. F. ^{[3
]}

Holland, S. M. ^{[3
]}

Milner, J. D. ^{[1
]}

机构：

[1] NIAID, Genet & Pathogenesis Allergy Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[2] NIAID, Res Technol Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[3] NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[4] NIAID, Food Allergy Res Unit, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[5] Univ Virginia, Dept Med, Div Asthma Allergy & Immunol, Charlottesville, VA 22903 USA

[6] Leidos Biomed Res Inc, Clin Res Directorate CRMP, NCI Campus Frederick, Frederick, MD 21702 USA

[7] Natl Inst Genom Med, Mexico City 14610, DF, Mexico

[8] Merck & Co Inc, Merck Res Labs, Boston, MA 02115 USA

[9] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Div Allergy & Immunol, Cincinnati, OH 45229 USA

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2017年 / 214卷 / 03期

基金：

美国国家卫生研究院;

关键词：

GROWTH-FACTOR-BETA; REGULATORY T-CELLS; EOSINOPHILIC ESOPHAGITIS; NEGATIVE REGULATION; CONNECTIVE-TISSUE; IN-VIVO; MUTATIONS; RECEPTOR; GATA-3; EXPRESSION;

D O I：

10.1084/jem.20161435

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Nonimmunological connective tissue phenotypes in humans are common among some congenital and acquired allergic diseases. Several of these congenital disorders have been associated with either increased TGF-beta activity or impaired STAT3 activation, suggesting that these pathways might intersect and that their disruption may contribute to atopy. In this study, we show that STAT3 negatively regulates TGF-beta signaling via ERBB2-interacting protein (ERBIN), a SMAD anchor for receptor activation and SMAD2/3 binding protein. Individuals with dominant-negative STAT3 mutations (STAT3(mut)) or a loss-of-function mutation in ERBB2IP (ERBB2IP(mut)) have evidence of deregulated TGF-beta signaling with increased regulatory T cells and total FOXP3 expression. These naturally occurring mutations, recapitulated in vitro, impair STAT3-ERBIN-SMAD2/3 complex formation and fail to constrain nuclear pSMAD2/3 in response to TGF-beta. In turn, cell-intrinsic deregulation of TGF-beta signaling is associated with increased functional IL-4R alpha expression on naive lymphocytes and can induce expression and activation of the IL-4/IL-4R alpha/GATA3 axis in vitro. These findings link increased TGF-beta pathway activation in ERBB2IP(mut) and STAT3(mut) patient lymphocytes with increased T helper type 2 cytokine expression and elevated IgE.

引用

页码：669 / 680

页数：12

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