| First Author | Huber AK | Year | 2012 |
| Journal | J Immunol | Volume | 189 |
| Issue | 6 | Pages | 3043-53 |
| PubMed ID | 22888137 | Mgi Jnum | J:189814 |
| Mgi Id | MGI:5447088 | Doi | 10.4049/jimmunol.1200311 |
| Citation | Huber AK, et al. (2012) Genetically driven target tissue overexpression of CD40: a novel mechanism in autoimmune disease. J Immunol 189(6):3043-53 |
| abstractText | 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 beta 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. |
