Endocrine Abstracts (2006) 11 S7

Thyroid disease paradigms and problems

AP Weetman

University of Sheffield Medical School, Sheffield, United Kingdom.

It is the 50th anniversary of the discovery of thyroid autoimmunity by Rose and Witebsky in suitably immunised rabbits and then by Doniach and Roitt who identified thyroglobulin antibodies in the serum of patients with Hashimoto’s thyroiditis. This is really the exemplar or paradigm of an autoimmune disease and subsequent discoveries have provided new paradigms. Graves’ disease is a prime example of disease apparently caused exclusively by an autoantibody while unravelling the genetics of thyroid autoimmunity has established the role of immunoregulatory genes such as CTLA-4. An international collaboration has recently shown that there are no major genes conferring susceptibility as revealed by linkage studies in a large cohort of families but by applying the candidate gene approach to this collection we were able clearly to show that TSH-receptor polymorphisms confer susceptibility to Graves’ disease and not autoimmune hypothyroidism, possibly explaining how these clinically distinct conditions occur together in families. Another paradigm has been the demonstration of the important role that T cell suppressor cells play in preventing thyroid autoimmunity, based on the elegant studies of Penhale and others in T cell deficient animals. It is now known that these renamed T regulatory cells are critical in controlling autoreactive T cells that escape thymic tolerance in all individuals. Reconstitution Graves’ disease is a recent example which seems likely to result from an imbalance in T regulatory cells in patients treated with T cell depleting monoclonal antibodies or in those with HIV treated with highly active antiretroviral therapy. The critical role of the target cell in the autoimmune thyroiditis is a final paradigm. The problems that remain to be solved include improved immunological treatments and unravelling the complex interrelationship between thyroid autoimmune responses and those which cause ophthalmopathy, but progress is highly likely in these areas shortly.

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