Solid experimental data links human autoimmune thyroid disease (AITD) and expression of chemokines, but the studies to date have been mostly descriptive. We have developed transgenic models to investigate the role of chemokines in AITD. We have reported that expression of CCL21, a chemokine expressed in AITD, leads to recruitment of lymphocytes and dendritic cells (DC) into the thyroid. As is found in AITD, lymphocytes organize in structures resembling lymphoid follicles, in which vascular structures such as high endothelial venules (HEV) and lymphatics are present. Deletion of CCR7, the receptor for CCL21, in the autoimmune-prone NOD background favors development of thyroiditis, suggesting a regulatory role for CCL21 in AITD.
Our specific aims i n this proposal are: 1) to define the mechanisms favoring the formation of thyroid lymphoid follicles, and their relevance to development of EAT;and 2), to define the mechanisms favoring development of thyroiditis in NODCCR7ko/ko mice. Many types of thyroid diseases are caused by destruction of the cells of the thyroid by cells of the immune system. PUBLLIC

Public Health Relevance

We will investigate the mechanisms whereby these immune cells arrive in the thyroid and will determine if blocking some of these mechanisms will alter thyroid disease. This work should define the role of immune components in the pathogenesis of thyroid diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067989-09
Application #
8280445
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Spain, Lisa M
Project Start
2004-07-01
Project End
2013-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
9
Fiscal Year
2012
Total Cost
$346,541
Indirect Cost
$142,092
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Furtado, Glaucia C; Marinkovic, Tatjana; Martin, Andrea P et al. (2007) Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc Natl Acad Sci U S A 104:5026-31
Marinkovic, Tatjana; Garin, Alexandre; Yokota, Yoshifumi et al. (2006) Interaction of mature CD3+CD4+ T cells with dendritic cells triggers the development of tertiary lymphoid structures in the thyroid. J Clin Invest 116:2622-32
Furtado, Glaucia C; Pina, Beatrice; Tacke, Frank et al. (2006) A novel model of demyelinating encephalomyelitis induced by monocytes and dendritic cells. J Immunol 177:6871-9
Lira, Sergio A; Martin, Andrea P; Marinkovic, Tatjana et al. (2005) Mechanisms regulating lymphocytic infiltration of the thyroid in murine models of thyroiditis. Crit Rev Immunol 25:251-62
Martin, Andrea P; Coronel, Elizabeth C; Sano, Gen-ichiro et al. (2004) A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. J Immunol 173:4791-8