Genetically driven target tissue overexpression of CD40: A novel mechanism in autoimmune disease

Amanda K. Huber, Fred D. Finkelman, Cheuk Wun Li, Erlinda Concepcion, Eric Smith, Eric Jacobson, Rauf Latif, Mehdi Keddache, Weijia Zhang, Yaron Tomer

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.

Original languageEnglish (US)
Pages (from-to)3043-3053
Number of pages11
JournalJournal of Immunology
Volume189
Issue number6
DOIs
StatePublished - Sep 15 2012
Externally publishedYes

Fingerprint

Autoimmune Diseases
Graves Disease
Interleukin-6
Thyroid Gland
Thyrotropin Receptors
Regulator Genes
Autoimmunity
Type 1 Diabetes Mellitus
Transcriptome
Chemokines
Crohn Disease
Epithelial Cells
Cytokines
Genes
Thyroid Epithelial Cells
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Genetically driven target tissue overexpression of CD40 : A novel mechanism in autoimmune disease. / Huber, Amanda K.; Finkelman, Fred D.; Li, Cheuk Wun; Concepcion, Erlinda; Smith, Eric; Jacobson, Eric; Latif, Rauf; Keddache, Mehdi; Zhang, Weijia; Tomer, Yaron.

In: Journal of Immunology, Vol. 189, No. 6, 15.09.2012, p. 3043-3053.

Research output: Contribution to journalArticle

Huber, AK, Finkelman, FD, Li, CW, Concepcion, E, Smith, E, Jacobson, E, Latif, R, Keddache, M, Zhang, W & Tomer, Y 2012, 'Genetically driven target tissue overexpression of CD40: A novel mechanism in autoimmune disease', Journal of Immunology, vol. 189, no. 6, pp. 3043-3053. https://doi.org/10.4049/jimmunol.1200311
Huber, Amanda K. ; Finkelman, Fred D. ; Li, Cheuk Wun ; Concepcion, Erlinda ; Smith, Eric ; Jacobson, Eric ; Latif, Rauf ; Keddache, Mehdi ; Zhang, Weijia ; Tomer, Yaron. / Genetically driven target tissue overexpression of CD40 : A novel mechanism in autoimmune disease. In: Journal of Immunology. 2012 ; Vol. 189, No. 6. pp. 3043-3053.
@article{398b133e6d494fb4b6e2c5a71ac83093,
title = "Genetically driven target tissue overexpression of CD40: A novel mechanism in autoimmune disease",
abstract = "The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.",
author = "Huber, {Amanda K.} and Finkelman, {Fred D.} and Li, {Cheuk Wun} and Erlinda Concepcion and Eric Smith and Eric Jacobson and Rauf Latif and Mehdi Keddache and Weijia Zhang and Yaron Tomer",
year = "2012",
month = "9",
day = "15",
doi = "10.4049/jimmunol.1200311",
language = "English (US)",
volume = "189",
pages = "3043--3053",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "6",

}

TY - JOUR

T1 - Genetically driven target tissue overexpression of CD40

T2 - A novel mechanism in autoimmune disease

AU - Huber, Amanda K.

AU - Finkelman, Fred D.

AU - Li, Cheuk Wun

AU - Concepcion, Erlinda

AU - Smith, Eric

AU - Jacobson, Eric

AU - Latif, Rauf

AU - Keddache, Mehdi

AU - Zhang, Weijia

AU - Tomer, Yaron

PY - 2012/9/15

Y1 - 2012/9/15

N2 - The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.

AB - The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.

UR - http://www.scopus.com/inward/record.url?scp=84866184305&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866184305&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1200311

DO - 10.4049/jimmunol.1200311

M3 - Article

C2 - 22888137

AN - SCOPUS:84866184305

VL - 189

SP - 3043

EP - 3053

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 6

ER -