Nasal challenge with the relevant antigen can induce a late response characterized by local accumulation of eosinophils, neutrophils and mononuclear cells persisting for 48 h and accompanied by release of ECP, MPO, LTB4 and histamine. These results indicate that a single antigen challenge in patients with allergic rhinitis causes prolonged inflammatory alterations which may contribute to the development of airway hyperreactivity.
At least two signals for proliferation and cytokine secretion by T-cells are required. The first signal is delivered through the interaction of the T-cell receptor with major histocompatibility complex (MHC) molecules expressed on the surface of antigen-presenting cells (APC). The second or costimulatory signal is delivered by cell surface molecules expressed by APC. The interaction of B7.1/B7.2 with CD28 provide the most potent costimulatory signal for T-cell activation. CD40 antigen and its ligand (CD40L) have been shown to play a major role in regulating both humoral and cellular immune responses. In autoimmune thyroid diseases autoantigen presentation could be provided by "professional" APC, such as dendritic cells, as well as "nonprofessional" APC, such as thyroid follicular cells (TFC). In fact, these cells aberrantly express MHC class II molecules in Graves' disease (GD) and Hashimoto's thyroiditis (HT), together with large amounts of MHC class I antigens: moreover, the expression of CD40 on TFC, has been demonstrated. On the other hand B7.1 has been demonstrated in HT, but not in GD TFC. This could provide in HT a local costimulatory signal for T-cell differentiation towards a type 1 cytokine secretion pattern and also result in rescue from apoptosis of infiltrating lymphocytes. The presence of ICAM-1 on the surface of HT TFC may further strengthen contact and facilitate cross-signaling between T-cells and TFC. In contrast, the absence of B7 and ICAM-1 antigens in most GD TFC may more easily be associated with anergy and apoptosis of infiltrating T-cells, preventing the perpetuation and expansion of a "destructive" autoimmune reaction.
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.
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