On the Pathogenesis of Autoimmune Thyroid Disease: A Unifying Hypothesis

Stelios Fountoulakis; Agathocles Tsatsoulis


Clin Endocrinol. 2004;60(4) 

In This Article


It is generally accepted that AITD is a complex and polygenic organ-specific autoimmune disorder. Interaction of environmental, genetic and endogenous factors may play a role in the initiation, progression and clinical outcome of the disease. From the above analysis of current data, a unifying hypothesis for the pathogenesis of AITD may be formulated (Fig. 4).

Figure 4.

An outline of the pathogenesis of AITD.

Environmental factors, including iodine excess, may set the scene by causing thyroid cell damage and release of potential autoantigens. Professional APCs are called upon, take up and present the relevant autoantigens to immune cells in the draining the thyroid lymph nodes. Aberrant regulation of immune response determined by genetic or endogenous factors lead to inappropriate and excessive immune reaction instead of reinforcing immune tolerance towards self-antigens. Consequently, autoreactive T and B lymphocytes accumulate in large numbers, infiltrating the thyroid parenchyma. Thus the thyroid gland is converted into a battlefield with the invading lymphocytes on one side and the defending thyroid cells on the other, fighting for survival. The outcome of this battle determines the phenotypic expression of the disease which is largely dependent on the balance between Th1 and Th2 response and the different profile of inflammatory cytokines released in the local microenvironment. A predominantly Th1 type of response favouring cellular immunity may facilitate a proapoptotic milieu for thyroid cells. Fas and/or TRAIL-dependent pathways are activated by Th1 type inflammatory cytokines and thyroid cells undergo apoptosis leading to HT or its variants (silent thyroiditis). A predominantly Th2 phenotype which favours humoural immunity may induce B lymphocytes to produce anti-TSH receptor antibodies and create an antiapoptotic potential for the thyroid cells and pro-apoptotic milieu for the intrathyroidal lymphocytes. If the prevailing type of anti-TSH antibodies is stimulatory for the TSH receptor, thyroid cell hyperplasia and hyperfunction ensue, leading to Graves' hyperthyroidism. Thus, the potential to produce TSH receptor-stimulating antibodies may be an important branch point towards the development of GD instead of HT. If, on the other hand, TSH receptor inhibitory antibodies predominate, then thyroid cell atrophy and hypofunction develop, leading to atrophic thyroiditis.

A better understanding of how an aberrant immune response against the thyroid gland is initiated and propagated through divergent pathways, leading to different phenotypic expression of AITD, is required. Knowledge of these mechanisms may allow the development of new aetiologically based therapeutic modalities for these common autoimmune disorders.

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