Genetically driven target tissue overexpression of CD40: a novel mechanism in autoimmune disease.
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.
Division of Endocrinology, Mount Sinai School of Medicine, New York, NY 10029, USA. hubera@umich.edu
Amanda K
AK
Huber
Fred D
FD
Finkelman
Cheuk Wun
CW
Li
Erlinda
E
Concepcion
Eric
E
Smith
Eric
E
Jacobson
Rauf
R
Latif
Mehdi
M
Keddache
Weijia
W
Zhang
Yaron
Y
Tomer
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D019013:CD40 Antigens / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018390:Gene Targeting / Q000379:methods*; D006111:Graves Disease / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D061251:Primary Cell Culture; D011828:Radiation Chimera / Q000276:immunology; D011989:Receptors, Thyrotropin / Q000276:immunology; D013961:Thyroid Gland / Q000276:immunology / Q000378:metabolism / Q000473:pathology
D001323:Autoantibodies; D019013:CD40 Antigens; D011989:Receptors, Thyrotropin