Transcriptomics

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Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease


ABSTRACT: The CD40 gene, an important immune regulatory gene, is also expressed and functional on non-myeloid derived cells, many of which are targets for tissue specific autoimmune diseases, including d thyroid follicular cells in Graves’ disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. Here we show for the first time, that target-tissue over-expression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 over-expression augmented the production of thyroid specific antibodies, resulting in more severe experimental autoimmune Graves’ disease (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 over-expression, and showed decreased levels of TSHR stimulating antibodies and frequency of disease. We conclude that target tissue over-expression of CD40 plays a key role in the etiology of organ specific autoimmune disease. CD40 in Thyroid Autoimmunity: 1) Incubation of human thyroid cells with G28.5, a CD40 stimulating antibody, and purification of RNA, conversion to cDNA, measurement of mRNA expression using RNAseq. 2) Removal of thyroid tissues from CD40 over-expressing transgenic mice and wild type mice, purification of RNA, conversion to cDNA measurement of mRNA expression using RNAseq.

ORGANISM(S): Musculus  

SUBMITTER: Erlinda Concepcion   Mehdi Keddache  Fred D Finkelman  Weijia Zhang  Yaron Tomer  Cheuk W Li  Rauf Latif  Amanda K Huber  Eric P Smith 

PROVIDER: E-GEOD-39081 | ArrayExpress | 2012-10-03

SECONDARY ACCESSION(S): SRP013984GSE39081PRJNA169916

REPOSITORIES: GEO, ArrayExpress, ENA

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

Huber Amanda K AK   Finkelman Fred D FD   Li Cheuk Wun CW   Concepcion Erlinda E   Smith Eric E   Jacobson Eric E   Latif Rauf R   Keddache Mehdi M   Zhang Weijia W   Tomer Yaron Y  

Journal of immunology (Baltimore, Md. : 1950) 20120810 6


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  ...[more]

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