On the Pathogenesis of Autoimmune Thyroid Disease: A Unifying Hypothesis

Stelios Fountoulakis; Agathocles Tsatsoulis

Disclosures

Clin Endocrinol. 2004;60(4) 

In This Article

Pathogenesis of Thyroid Autoimmunity

Genetic Susceptibility

Thyroid autoimmune diseases are regarded as polygenic disorders resulting from the combination of a genetic predisposition in conjunction with an environmental trigger. In animal models there are strong indications that genetically determined immune defects lead to intolerance toward presented self-antigens (Ruwhof & Drexhage, 2001). Genetic constitution, including both major MHC and non-MHC genes, determines how prone an individual is to autoimmune diseases. Genes may influence disease in two ways. They may be essential for disease development, or simply increase the susceptibility of the individual to develop the disease. The most important genes are those in the MHC region but other non-MHC genes with a role in regulation of the metabolism and susceptibility of the target tissue may also be involved. Such genes include inflammatory cytokine genes (Badenhoop et al., 1992; Hunt et al., 2001) and co-stimulatory molecule genes (CTLA-4; Yanagawa et al., 1995; Kotsa et al., 1997; Einarsdottir et al., 2003), while TCR variable region genes and immunoglobulin genes do not seem to contribute to AITD susceptibility (Fakhfakh et al., 1999; Pickerill et al., 1993).

The recently discovered AIRE gene may also harbour risk polymorphisms, although studies to date failed to correlate any of the two most frequent AIRE mutations with predisposition to isolated autoimmune endocrinopathies, including AITDs. Nevertheless, these studies were confined to two mutations of the many so far identified, which were also so rare that any susceptibility effect to AITD could not be assessed (Meyer et al., 2001; Nithiyananthan et al., 2002). Therefore other AIRE mutants cannot be ruled out as candidates for genetic susceptibility to AITD.

A large number of studies have reported an increased frequency of different MHC gene alleles among HT and GD patients depending on their ethnic origin (Hunt et al., 2001; Ban et al., 2002; Vaidya et al., 2002; Villanueva et al., 2002). Polymorphisms of CTLA-4 or a closely linked gene (Yanagawa et al., 1995; Kotsa et al., 1997; Einarsdottir et al., 2003) and the newly implicated Pendred syndrome (PDS) gene (Kacem et al., 2003), have also been found in HT and GD patients. However, data from genome-wide scans searching for AITD susceptibility candidate genes indicate that the only real evidence is that for HLA (DR3) and CTLA-4 (Weetman, 2003). Thus, these two major contributors in antigen presentation processes appear to be associated with the pathogenesis of thyroid autoimmunity.

Environmental Factors

Environmental factors postulated to induce autoimmune diseases include iodine, drugs (amiodarone, IFN-α) and infectious organisms. It has been suggested that antibodies produced in response to certain infectious agents (i.e. Yersinia enterocolitica) may also react with human cell proteins, due to their structural resemblance (mechanism of molecular mimicry; Baker, 1997; Corapcioglu et al., 2002; Strieder et al., 2003). However, other studies suggest that molecular mimicry does not play a role in the initiation or induction of autoimmune thyroid diseases (Tomer & Davies, 1993). Other precipitating or predisposing factors include stress (Kung, 1995; Matos-Santos et al., 2001), which has also been demonstrated to affect the outcome of antithyroid drug treatment in GD (Fukao et al., 2003), sex steroids, smoking (Prummel & Wiersinga, 1993) and trauma.

The Role of Iodine

Iodine is considered to be an important environmental agent known to increase the risk of thyroid autoimmunity. Several studies support a role for iodine in the initiation and promotion of AITD. Thus, epidemiological studies have shown that appearance of thyroid autoantibodies has been associated with salt iodination in iodine-deficient regions (Tsatsoulis et al., 1999; Premawardhana et al., 2000; Lind et al., 2002; Zois et al., 2003). In addition, animal studies have confirmed that high iodine intake accelerates autoimmune thyroiditis in autoimmune-prone animal models (Mooij et al., 1993; Bagchi et al., 1995; Rasooly et al., 1996).

Several mechanisms have been suggested for the induction of thyroid autoimmunity by excess iodine. Thyroglobulin (Tg) iodination can increase its immunogenicity by altering stereochemical structure and leading to the production of novel iodine-containing determinants and the loss of some and appearance of other cryptic epitopes (Rasooly et al., 1998; Saboori et al., 1998). All of these may enhance the Tg presentation by APCs and increase the affinity of the TCR for the Tg, leading to specific T lymphocyte activation.

Another mechanism is toxic destruction of thyroid cells possibly through the generation of oxygen radicals (Bagchi et al., 1995). Excessive amounts of the iodide ion are oxidized by TPO producing large amounts of oxidative intermediates and these molecules are capable of oxidizing membrane lipids and proteins, thus damaging thyroid cell membranes (Burikhanov & Matsuzaki, 2000; Vitale et al., 2000).

There is also evidence for direct stimulation effects of iodine on macrophages, DCs, B and T lymphocytes. Enhanced macrophage myeloperoxidase activity, augmentation of dendritic cell maturation, increase in the number of circulating T lymphocytes and stimulation of immunoglobulin production are some of the possible iodine effects on the immune system (Rose et al., 2002).

Mechanisms of Thyroid Autoimmunity

The pathogenetic mechanisms of thyroid autoimmunity have been studied in detail in animal models that spontaneously develop autoimmune thyroiditis. Such studies have shown that the pathogenesis of thyroid autoimmunity is a multistep process (Ruwhof & Drexhage, 2001). In the early phases, two immune processes take place. In the first stage an increased number of intrathyroidal APCs appears to be the most prominent sign of the initiation of an autoimmune reaction (Voorbij et al., 1990). Induction of APC influx in the thyroid of susceptible individuals may result from inflammatory signals following damage or necrosis of target cells by toxins, viral or bacterial infection, or iodine excess. Alterations in the metabolism or the microenvironment of thyroid cells may also be an inducing factor for APC accumulation in the thyroid. During this early phase the APCs migrate and present thyroid autoantigens to T helper lymphocytes in the draining lymph nodes of the thyroid gland.

In the next stage, lymphocytes interact with the presented autoantigens. During this phase, peripheral tolerance mechanisms described above and their regulation by co-stimulatory molecules is important. If immune tolerance is lost, the outcome of this interaction is the activation of antigen-specific T helper lymphocytes. These in turn stimulate, through different cytokine production, the cellular immune response and/or the humoral immune response via B lymphocytes. Thus, instead of reinforcing tolerance, the APCs generate an autoimmune reaction. Initially, the production of autoreactive T lymphocytes and antibodies takes place in the draining lymph nodes, but later lymphoid tissue develops locally in the thyroid itself. Thyroid cells may also express MHC II molecules that are required for antigen presentation to CD4+ T lymphocytes and can also act as APCs (Bottazzo et al., 1983; Sospedra et al., 1995). This expression of MHC II molecules on thyrocytes may be the consequence of cytokine (IFN-γ) production by activated T lymphocytes infiltrating the thyroid gland (Todd et al., 1985). Earlier studies indicated that thyroid cells were unable to express B7·1 or B7·2 molecules (Tandon et al., 1994a; Matsuoka et al., 1996). However, Battifora et al. (1998) found that B7·1 is frequently expressed on thyroid follicular cells in HT patients. CD28 expression by a large number of thyroid infiltrating lymphocytes could, through the interaction with B7·1 on thyroid cells, result in the induction of autoreactive T lymphocyte activation (Battifora et al., 1998). Another role for thyroid cells may involve the recruitment of immune cells in the thyroid gland, through the expression of chemoattractant molecules (Weetman et al., 1990). This expression was also found to be induced by cytokines (IL-1α and IFN-γ) in cultured thyroid cells (Kemp et al., 2003). T lymphocytes can then be restimulated by MHC II expressed on thyrocytes, thus leading to the continuation of the autoimmune process.

Studies regarding sCTLA-4 expression in AITD patients have reported controversial results. Oaks & Hallett (2000) report that sCTLA-4 levels are elevated among patients with AITD, while Ueda et al. (2003) have found reduced mRNA levels of sCTLA-4 in subjects with a CTLA-4 allelic variant, associated with GD and HT disease susceptibility.

In a final phase, the generated autoreactive T and B lymphocytes accumulate in large numbers and infiltrate the thyroid parenchyma. The latter is then turned into a battlefield in which thyrocytes interact with infiltrating lymphocytes, in a struggle for survival. The outcome of this battle will determine the clinical phenotype of the disease. Apoptosis appears to play a major role in this final stage (Andrikoula & Tsatsoulis, 2001; Tsatsoulis, 2002).

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