Adhesion Molecules as Susceptibility Factors in Spontaneous Autoimmune Thyroiditis in the NOD-H2 h4 Mouse Raphael E. Bonita,* ,1 Noel R. Rose,* , † Linda Rasooly,* ,2 Patrizio Caturegli,† and C. Lynne Burek* , † ,3 *Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, and †Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205 Received July 2, 2002 Mononuclear cell infiltration of the thyroid is a prominent feature of chronic lymphocytic thyroiditis. Adhesion molecules play a major role in determining the localization of inflammatory mononuclear cells in the thyroid. Previous reports from animal models and human studies have described the thyroidal expression of adhesion molecules only late in clinical disease. In this study, we examined the distribution and kinetics of expression of E-selectin, VCAM-1, LFA-1, and ICAM-1 in the NOD-H2 h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by dietary iodine. Mice were fed 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin– biotin–peroxidase assay. We found a dramatic in- crease in E-selectin and VCAM-1 expression on intrathyroidal endothelial cells after 16 weeks of iodine treatment. In addition, we describe for the first time that thyrocytes from the NOD-H2 h4 mouse, and the parental NOD, constitutively express ICAM-1 independent of iodine treatment and prior to mononuclear cell infiltration of the thyroid gland. ICAM-1 was not detected on the thyrocytes of other untreated strains of mice, implicating expression of this adhesion molecule as a critical event in the recruitment of inflammatory mononuclear cells to the thyroid. © 2002 Elsevier Science (USA) Key Words: adhesion molecules; ICAM-1; immunohistochemistry; io- dine; autoimmune thyroiditis. INTRODUCTION Chronic lymphocytic (Hashimoto’s) thyroiditis (HT) is an organ-specific autoimmune disorder characterized by the production of autoantibodies to thyroglobulin (Tg) and thy- roid peroxidase (TPO) and mononuclear cell infiltration of the thyroid, culminating in the destruction of thyroid folli- cles and clinical hypothyroidism (Weetman and McGregor, 1994). Studies in humans and in animal models of HT have reported an increased prevalence of thyroiditis with the administration of supplementary dietary iodine (Allen et al., 1986; Bagchi et al., 1985; Boukis et al., 1983; Harach et al., 1985). A marked rise in mononuclear cell infiltration and serum Tg and TPO autoantibodies has been observed in individuals from iodine-deficient geographical areas with the introduction of iodine supplementation (Boukis et al., 1983; Harach et al., 1985). To further investigate the role of iodine in the pathogenesis of chronic lymphocytic thyroid- itis, studies in our laboratory have focused on the NOD- H2 h4 mouse. This mouse strain was produced by crossing the NOD strain, which spontaneously develops type 1 dia- betes and a low incidence of mononuclear cell infiltration of the thyroid gland, with the B10.A(4R) strain. The result of this genetic backcross is the expression of I-A k on the NOD background, which favors the development of autoimmune thyroiditis (Vladutiu and Rose, 1971). The NOD-H2 h4 mouse does not develop diabetes but retains a low sponta- neous incidence of autoimmune thyroiditis, which can be significantly increased by the administration of NaI in the drinking water (Braley-Mullen et al., 1999; Rasooly et al., 1996). Considerable effort has been devoted toward understand- ing how lymphocytes infiltrate the thyroid gland of patients with HT, but the mechanism remains undefined. Studies investigating the events involved in the initial recruitment of lymphocytes into the thyroid have been hampered by the availability of human thyroid tissue only late in clinical disease, but previous reports have suggested that the up- 1 Current address: MCP Hahnemann University School of Medicine, Philadelphia, PA 19129. 2 Current address: Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem 91120, Israel. 3 To whom correspondence should be addressed. Fax: 410-614-3548. E-mail: lburek@jhmi.edu. Experimental and Molecular Pathology 73, 155–163 (2002) doi:10.1006/exmp.2002.2470 155 0014-4800/02 $35.00 © 2002 Elsevier Science (USA) All rights reserved.