PRE-AUTOIMMUNE THYROID ABNORMALITIES IN THE BIOBREEDING DIABETES-PRONE (BB-DP) RAT - A POSSIBLE RELATION WITH THE INTRATHYROID ACCUMULATIONOF DENDRITIC CELLS AND THE INITIATION OF THE THYROID AUTOIMMUNE-RESPONSE

Thyroid autoimmune reactions start with an accumulation of mainly dend ritic cells in the thyroid. There is increasing evidence that, apart f rom being antigen-presenting cells, they are also able to control the growth and hormone synthesis of neighbouring endocrine cells. The ques tions thus arise: are dendritic cells accumulating in the pre-autoimmu ne thyroid in response to an altered proliferative or metabolic activi ty of thyrocytes, and do cytokines, monocyte chemoattractants, or both , have a role in their accumulation? We have investigated these questi ons in thyrocytes of the biobreeding diabetes-prone (BB-DP) rat in rel ation to the start of the intrathyroid accumulation of dendritic cells - that is, at about 9 weeks of age. BB-DP rats and Wistar rats (contr ols) were studied from 3 to 20 weeks of age. Hyperplastic goitre devel opment was studied by assessing the thyroid weight and by measuring th e number of thyrocyte nuclei per 0.01 mm(2) thyroid section. In additi on, the in situ expression of interleukin-6 (IL-6), tumour necrosis fa ctor-alpha (TNF-alpha), monocyte-chemotactic protein-1 (MCP-1), and in tercellular adhesion molecule-1 (ICAM-1) were studied by immunohistoch emistry. The in vitro proliferative capacity of BB-DP and Wistar thyro cytes was measured by tridated-thymidine ([H-3]TdR) and bromodeoxyurid ine (BrdU) incorporation into reconstituted, TSH- and non-TSH-stimulat ed, cultured thyroid follicles. Further in vitro studies consisted of measurement of the production of thyroxine (T-4), triiodothyronine (T- 3), thyroglobulin, IL-6, TNF-alpha and MCP-1 by the thyroid follicles. BB-DP rats developed a small hyperplastic goitre between the ages of 9 and 12 weeks. The in vitro proliferative rate of thyrocytes isolated from hyperplastic BB-DP thyroids was significantly lower than that of Wistar thyrocytes. This phenomenon also occurred in follicles isolate d from BB-DP rats before hyperplastic goitre development, which produc ed significantly less T-4, but more T-3, than did Wistar follicles of the same age. At the time of and after hyperplastic goitre development , BB-DP follicles exhibited altered metabolic behaviour and produced s ignificantly more T-4, but equal amounts of T-3 compared with both Wis tar follicles same age and follicles of younger BB-DP rats under basal conditions and TSH-stimulated). In vitro IL-6 production by these BB- DP thyroid follicles was also increased. There was no noteworthy diffe rence in production of thyroglobulin and MCP-1 between BB-DP and Wista r follicles at any age. TNF-alpha was not produced by BB-DP or Wistar thyroid follicles. Immunohistochemistry revealed the expression of IL- 6 by both BB-DP and Wistar thyroid follicle cells at all times of samp ling. MCP-1 and TNF-alpha were expressed only when infiltrates were pr esent in BB-DP thyroids (restricted to leucocytes, ages >18 weeks). Mo dest ICAM-1 expression was restricted to large blood vessels in both B B-DP and Wistar thyroids; in the case of infiltrates (BB-DP rat) alone , high ICAM-1 expression was found on blood vessels and leucocytes in these infiltrations. At the time of intrathyroidal dendritic cells acc umulation, BB-DP rats develop a small hyperplastic goitre. At that tim e there is also in vitro evidence for a shift to a higher production o f thyroxine and IL-6 from thyrocyte follicles. The in vitro proliferat ion rate of BB-DP thyrocytes is, however, abnormally low (both in the: pre-and hyperplastic period). Similar pre-autoimmune thyroid growth a bnormalities have been described in another animal model of thyroid au toimmune disease, the obese strain chicken.