Endocrine Abstracts (2004) 7 S27

Role of cytokines and lymphocytes in Graves' disease

AP Weetman

Division of Clinical Sciences (North); University of Sheffield; Sheffield; UK.

Graves' disease is characterised by a T and B cell lymphocytic infiltrate in the thyroid which can all but disappear after antithyroid drug treatment. The intrathyroidal lymphocytes are a major site of autoantibody synthesis and the disappearance of this population with treatment indicates a direct role for antithyroid drugs in modulating the immune response. The cytokine profile of the infiltrating lymphocytes is a mixture of TH1 and TH2, and altering the balance between these two populations, as a consequence of coincident atopic disease or immunologically active agents, can cause profound effects on the autoimmune process. The cytokines produced by the infiltrating T cells induce a wide variety of responses in the adjacent thyroid cells, including up-regulation of major histocompatibility class I and II molecules, adhesion molecules, CD40 and further cytokines including IL-6, IL-8 and IL-12. Many of these thyroid cell responses are attenuated by antithyroid drugs pointing to the likely importance of the interaction between lymphocytes and thyroid follicular cells in disease pathogenesis.

Despite early observations which suggested a restricted intrathyroidal autoreactive T cell response, in fact this population is polyclonal and directed to a wide variety of thyroid antigenic epitopes, making therapeutic manipulation based on modified epitopes or T cell receptor targeting difficult to envisage unless very early disease stages can be identified in the future. More promising is the realisation of the central role for T cells in the related complication of thyroid-associated ophthalmopathy. Activated T cells infiltrate the extraocular muscles where the cytokines induce enhanced glycosaminoglycan synthesis by orbital fibroblasts. The full identification of the orbital antigens to which T cells respond has not yet been completed although the TSH receptor is a likely target, and animal models using TSH receptor-specific T cell transfer highlights how important this antigen interaction may be. Targeting this population with antigen-specific treatment, or with anticytokine agents, may lead to novel treatment in the near future.

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