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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0900275v1 183/5/3073    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Martin, A. P. Articles by Lira, S. A. PubMed PubMed Citation Articles by Martin, A. P. Articles by Lira, S. A.

CCR7 Deficiency in NOD Mice Leads to Thyroiditis and Primary Hypothyroidism¹

Andrea P. Martin^*, Tatjana Marinkovic^2,*, Claudia Canasto-Chibuque^*, Rauf Latif, Jay C. Unkeless^*, Terry F. Davies, Yousuke Takahama, Glaucia C. Furtado^* and Sergio A. Lira^3,*

^* Immunology Institute, Mount Sinai School of Medicine, New York, NY 10029; Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029; and Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, Tokushima, Japan

CCR7 is involved in the initiation of immune responses and has been recently implicated in the control of tolerance. To analyze the role of CCR7 in autoimmunity, we backcrossed CCR7^ko/ko mice (in which ko signifies deficient) onto the autoimmune-prone NOD background. Surprisingly, NODCCR7^ko/ko mice never developed diabetes, but showed severe inflammation in multiple tissues including thyroid, lung, stomach, intestine, uterus, and testis. NODCCR7^ko/ko mice had a marked enlargement of the thyroid gland (goiter) that was associated with circulating autoantibodies against thyroglobulin, and development of primary hypothyroidism (decreased levels of serum thyroxin, and augmented levels of thyroid-stimulating hormone in the pituitary gland), features found in Hashimoto’s thyroiditis. Cells isolated from diseased thyroids and activated splenocytes from NODCCR7^ko/ko animals induced goiter in NOD.SCID recipients, demonstrating that autoreactive cells were generated in the absence of CCR7. Moreover, thyroid disease could be accelerated in young NODCCR7^ko/ko mice by immunization with thyroglobulin. These results demonstrate the complexity in the generation of multiple autoimmune phenotypes in NOD mice and indicate that CCR7 is a key molecule in their development.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant DK067381 (to S.A.L.).

² Current address: Medical-Sanitary School Visan, Tosin bunar 7a, 11000 Belgrade, Serbia.

³ Address correspondence and reprint requests to Dr. Sergio A. Lira, Immunology Institute Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1630, New York, NY 10029-6574. E-mail address: sergio.lira{at}mssm.edu

⁴ Abbreviations used in this paper: DC, dendritic cell; Aire, autoimmune regulator gene; EAT, experimental autoimmune thyroiditis; HT, Hashimoto’s thyroiditis; TSH, thyroid-stimulating hormone; Tg, thyroglobulin; mTg, mouse Tg; TPO, thyroid peroxidase; T4, thyroxin hormone; wt, wild type; ko, knockout (deficient); Treg, regulatory T cell.

⁵ The online version of this article contains supplemental material.