A Novel Model for Lymphocytic Infiltration of the Thyroid Gland Generated by Transgenic Expression of the CC Chemokine CCL21

Abstract

Lymphocytic infiltrates and lymphoid follicles with germinal centers are often detected in autoimmune thyroid disease (AITD), but the mechanisms underlying lymphocyte entry and organization in the thyroid remain unknown. We tested the hypothesis that CCL21, a chemokine that regulates homeostatic lymphocyte trafficking, and whose expression has been detected in AITD, is involved in the migration of lymphocytes to the thyroid. We show that transgenic mice expressing CCL21 from the thyroglobulin promoter (TGCCL21 mice) have significant lymphocytic infiltrates, which are topologically segregated into B and T cell areas. Although high endothelial venules expressing peripheral lymph node addressin were frequently observed in the thyroid tissue, lymphocyte recruitment was independent of L-selectin or lymphotoxin-α but required CCR7 expression. Taken together, these results indicate that CCL21 is sufficient to drive lymphocyte recruitment to the thyroid, suggest that CCL21 is involved in AITD pathogenesis, and establish TGCCL21 transgenic mice as a novel model to study the formation and function of lymphoid follicles in the thyroid.

CXCR5‐ and CCR7‐dependent lymphoid neogenesis in a murine model of chronic antigen‐induced arthritis

“…Furthermore, expression of CXCL13 was demonstrated in lymphoid aggregates in various chronic inflammatory autoimmune diseases affecting mucosa-associated tissue, the thyroid, and the brain (6)(7)(8)20,21). More direct evidence for a critical role of CXCL13 and CCL21 in the de novo formation of lymphoid tissue has been provided by the finding that ectopic transgenic expression of either chemokine in pancreatic islets or of CCL21 in the thyroid gland is sufficient to trigger lymphoid neogenesis (22)(23)(24).…”

Targeted Expression of the Human Thyrotropin Receptor A-Subunit to the Mouse Thyroid: Insight into Overcoming the Lack of Response to A-Subunit Adenovirus Immunization

“…Transgenic mice expressing IL-12 in the thyroid had moderate primary hypothyroidism due to a direct cytokine effect on thyrocytes (35). Conversely, despite extensive thyroid lymphocytic infiltration, transgenic mice expressing the chemokine CCL21 in the thyroid (36) had normal thyroid function.…”

The unexpected role of lymphotoxin β receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development

“…The role of LT in the context of lymphoid neogenesis, development of autoimmune diseases and inflammatory disorders was further investigated in vivo (Picarella et al, 1992;Kratz et al, 1996;Luther et al, 2000;Drayton et al, 2003Drayton et al, , 2006Gommerman and Browning, 2003;Martin et al, 2004;Heikenwalder et al, 2005Heikenwalder et al, , 2008Haybaeck et al, 2009). These studies revealed that ectopic LT expression suffices to generate lymphoid-like structures (Picarella et al, 1992;Kratz et al, 1996;Gommerman and Browning, 2003;Heikenwalder et al, 2005;Haybaeck et al, 2009), also termed tertiary lymphoid organs or tissues.…”