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| Status |
Public on Oct 03, 2012 |
| Title |
Genetically-driven target tissue over-expression of CD40: A novel mechanism in autoimmune disease |
| Organisms |
Homo sapiens; Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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.
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| Overall design |
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.
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| Contributor(s) |
Huber AK, Finkelman FD, Li CW, Concepcion E, Smith EP, Latif R, Keddache M, Zhang W, Tomer Y |
| Citation(s) |
22888137 |
| Submission date |
Jul 03, 2012 |
| Last update date |
May 15, 2019 |
| Contact name |
Weijia Zhang |
| E-mail(s) |
weijia.zhang@mssm.edu
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| Phone |
212-241-2883
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| Organization name |
Mount Sinai School of Medicine
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| Department |
Department of Medicine
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| Lab |
Bioinformatics Lab
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| Street address |
1425 Madison Avenue
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10029 |
| Country |
USA |
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| Platforms (2) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA169916 |
| SRA |
SRP013984 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE39081_RAW.tar |
1.1 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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