Possible pathogenetic relevance of interleukin-1 beta in "destructive" organ-specific autoimmune disease (Hashimoto's thyroiditis).

Thyroid follicular cells (TFC) abundantly express a variety of immunologically relevant surface molecules in Hashimoto's thyroiditis (HT), for example, MHC antigens and adhesion molecules such as ICAM-1. Cytokines produced by infiltrating type 1 helper and cytotoxic T cells are importantly involved in de novo expression or up-regulation of such molecules. We recently demonstrated that TFC from HT patients almost invariably bear on their surface two additive functional molecules: Fas/Apo1/CD95, an important participant in apoptosis, and B7.1, a member of a family of "co-stimulatory" molecules that are crucial for efficient antigen presentation. To date, 12 out of 14 surgical HT thyroid specimens that we studied by immunohistochemistry showed B7.1-positive TFC, and all showed Fas-positive TFC, different from Graves' disease (GD) or nonautoimmune specimens. We have investigated the role of a number of cytokines (IL-1 beta, TNF-alpha, IL-4, IL-6, IL-10, IL-12, TGF-beta 1, IFN-gamma) in regulating B7.1 and Fas expression. The experiments were performed by immunofluorescence flow cytometry on TFC purified from nontoxic goiter specimens which were Fas- and B7.1-negative at baseline, and one B7.1/Fas-positive HT specimen. IFN-gamma (500 U/mL) and TNF-alpha (200 ng/mL) were unable to induce de novo expression of B7.1 or Fas on cultured TFC. At higher doses (2000 U/mL and 800 ng/mL, respectively), they were unable to induce B7.1, but potentiated the spontaneous expression of Fas. Type 2 cytokines (IL-4 and IL-10) were unable to induce Fas or B7.1 on TFC at all, or to down-regulate Fas or B7.1 when expressed. On the other hand, IL-1 beta was the only cytokine able to induce Fas expression on Fas-negative TFC at doses ranging from 100 to 1000 pg/mL. Moreover, at a dose of 400 pg/mL, it was also able to induce B7.1. We demonstrated by immunohistochemistry that IL-1 beta is abundantly present on HT thyroids, including follicular structures. It is conceivable that IFN-gamma, or other cytokines secreted by infiltrating T-lymphocytes, are able to promote IL-1 beta secretion by TFC. In conclusion, a crucial role of IL-1 beta in "destructive" organ-specific autoimmunity may be suggested both for the perpetuation of the autoimmune reaction (induction of efficient autoantigen presentation by TFC, via co-stimulatory molecules) and in induction of tissue damage via "suicide" Fas/FasL-mediated TFC interaction.