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

29 Scopus citations

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Huber, A. K., Finkelman, F. D., Li, C. W., 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, 189(6), 3043-3053. https://doi.org/10.4049/jimmunol.1200311