Current concepts in the pathogenesis of autoimmune thyroid disease
In the 46 years since the discovery of thyroid autoimmunity, the same questions have recurred: why does it start, why does it progress, albeit slowly, to disease and what is the nature of the interaction between the autoantigen(s) and the immune system? Answers to these should allow us to address the most important question, namely, can we improve present treatment, especially in the case of Graves' disease with ophthalmopathy? Susceptibility to thyroid autoimmunity and progression to autoimmune thyroid disease (AITD) are determined by genetic, environmental and endogenous contributions, which vary in their strength between individuals. The only genes solidly associated with AITD are in the HLA-D region and either CTLA-4 or a gene in linkage disequilibrium. At least 8 other loci have been proposed by genome scans and linkage analysis of small numbers of families with affected sib pairs: none of these loci have been confirmed using a large data set of over 600 sib pairs (Thyroid Autoimmunity Genetics Consortium, submitted). Similarly the environmental risk factors for AITD remain elusive, although iodine intake, smoking and, for Graves' disease, stress are all contributory.
Whilst the 3 main thyroid autoantigens have long been cloned, we remain unclear about the role of other potential autoantigens such as the sodium iodide symporter. Since B cells are excellent and specific presenters of autoantigen, even minor autoantigens causing autoantibody formation could contribute significantly to the autoimmune process. Current attention is focussed on two areas; the generation of monoclonal TSH-receptor antibodies, to establish how the stimulating antibodies that cause Graves' disease interact with the receptor, and the identification of the autoantigen(s) involved in ophthalmopathy, for which the TSH-receptor is one but not the only candidate