EUROPEAN THYROID ASSOCIATION MERCK PRIZE LECTURE – Goteborg, 9 September 2002
Autoimmune thyroid disease: propagation and progression
Anthony P Weetman
University of Shefﬁeld Clinical Sciences Centre, Northern General Hospital, Shefﬁeld, S5 7AU, UK (Correspondence should be addressed to A P Weetman; Email:k.f.watson@shefﬁeld.ac.uk)
Autoimmune thyroid disease is the archetype for organ-speciﬁc autoimmune disorders. Progress in treating these disorders lies in improvements of our understanding of the predisposing factors responsible, the mechanisms responsible for progression of disease, and the interaction between thyroid antigens and the immune system at the level of the T cell and antibody. In commonwith other autoimmune diseases, genetic, environmental and endogenous factors are required in an appropriate combination to initiate thyroid autoimmunity. At present the only genetic factors which have been conﬁrmed lie in the HLA complex and CTLA-4 or a closely linked gene. Identifying other predisposing genes will require large-scale family studies, or further insights into likely candidategenes. A number of environmental factors are known to predispose to autoimmune thyroid disease, including smoking, stress and iodine intake, while immunomodulatory treatments are revealing new pathways for disease emergence. The thyroid cell itself appears to play a major role in disease progression, interacting with the immune system through expression of a number of immunologically active moleculesincluding HLA class I and II, adhesion molecules, cytokines, CD40 and complement regulatory proteins. New techniques, in particular phage display libraries, are providing the methods with which to identify autoantibody diversity in autoimmune thyroid disease and to provide tools for mapping autoantigenic epitopes. Application of these techniques is likely to lead to an understanding of how TSHreceptor antibodies interact with the receptor to cause Graves’ disease and also to the identiﬁcation of novel orbital autoantigens in thyroid-associated ophthalmopathy. European Journal of Endocrinology 148 1–9
It is now 46 years since the original delineation of thyroid autoimmunity, ﬁrst in rabbits immunised with thyroglobulin in adjuvant (1), and then in man, with the descriptionof antibodies to thyroglobulin in the serum of patients with Hashimoto’s thyroiditis (2). In the same annus mirabilis, the abnormal thyroid stimulator which turned out to be the cause of Graves’ disease was also identiﬁed (3). As then, there are four important questions which have only partially been answered over the intervening period: (i) why does autoimmune thyroid disease (AITD) start; (ii)why does it progress; (iii) what is the nature of the interaction between thyroid autoantigens and the immune system; and (iv) how can these disorders be better treated? The answer to the last depends on clear answers being obtained to the ﬁrst three questions, which is why treatment has not progressed greatly over the last 60 years, most tellingly in the case of thyroid-associated ophthalmopathy(TAO). This paper is based on the Merck Lecture given at ¨ the European Thyroid Association meeting in Goteborg
2002, and as a result is biased largely to the work from my own group. Nonetheless, it may provide some insight into the way these four questions have been and continue to be addressed. Extensive historical reviews of the subject can be found elsewhere (4 –6).
Incommon with probably all autoimmune disorders, the interplay of genetic, environmental and endogenous factors is required in the right combination to initiate thyroid autoimmunity. Combinations will vary between individuals, and some factors are shared by all AITDs, while others are unique to the individual disorders. In very general terms predisposing factors operate by disturbing immunological...