The role of TgAbs in the pathogenesis of AITD is less conclusive than those found with TRAbs and TPOAbs; however, more than 90% of HT patients are TgAbs-positive. One explanatory hypothesis is antibody-dependent cell-mediated cytotoxicity, in which cells containing the antigen are killed by TLs (NK) and macrophages. Furthermore, in animal models of AITD, TgAbs are detected earlier (leading to the subsequent discovery of the presence of TPOAbs), which suggests that the tolerances of BLs and TLs are likely initially altered towards Tg and later towards TPO
The role of pendrin and NIS antibodies in the pathogenesis of AITD is conflicting, which suggests that these antibodies are present in some patients with AITD, notwithstanding that their clinical importance in the pathogenesis of AITD and on thyroid function is yet to be determined. So far, their measurement does not seem to offer any diagnostic, treatment, or prognostic benefits 
7. Summary of Molecular Mechanisms Leading to AITD
AITD is triggered by a variety of factors (genetic, nongenetic, epigenetic, and environmental). Among the susceptibility genes associated with the immune system, the following stand out: HLA-DR3; PTPN22; CD40; FOXP3; CTLA-4; and IL-2Rα, although thyroid-specific susceptibility genes have been described (TSHR, Tg, and TPO). Some SNPs in these genes play key roles that help explain (at least in part) the increased risk for AITD. For example, the SNPs in FOXP3 and IL-2Rα are involved in peripheral tolerance mechanisms, while the SNPs in the CD40, CTLA-4, and HLA genes compromise the activation of TLs and the antigenic presentation; therefore, the SNPs in immunoregulatory genes can potentially alter the functioning or normal development of the central and peripheral tolerance mechanisms and the interaction of TLs with APCs. Some SNPs in other genes involved in the synthesis of cytokines with potential inflammatory effects have also been described and associated with an increased risk of AITD.
Although genetic susceptibility can potentially explain the pathogenesis of AITD, the genetic risk by itself is low; however, this risk is increased when there is synergism with some components or epigenetic modifications in the region’s regulators that are capable of controlling the gene expression. These epigenetic modifications include the XCI SNPs of the genes involved in DNA methylation, DNMT genes, or MTHFR and MTRR genes. Histone modifications and the impaired expressions of noncoding RNAs have also been implicated.
Environmental factors can be infectious and noninfectious and, in turn, nutritional and nonnutritional. These factors can, by mechanisms not yet elucidated, increase the susceptibility to AITD. However, the key point for the development of AITD is the infiltration of the thyroid by APCs, which may be induced by environmental factors.
Considering that the thyroid follicular cells from individuals with AITD can also abnormally express HLA-II (induced by IFN-γ), the phenomenon of thyroid autoantigen presentation, which facilitates the activation of TLs, is feasible. Likewise, there is also the thyroid infiltration of BLs, cytotoxic TLs, and TLs (CD4+). The interaction with APCs leads to the activation of TLs (CD4+) and the differentiation towards Tregs and Th (Th1, Th2, and Th17), with an imbalance in the Th1:Th2 ratio. For HT, the predominance is towards a Th1 response, whereas in GBD, the predominance is towards a Th2 response.
In addition, an attenuated Treg response has also been found, which may increase the proinflammatory activity of Th17. These mechanisms involve cytokines/chemokines and/or cytotoxins. For HT, apoptosis and subsequent fibrosis lead to the presence of hypothyroidism, while in GBD, the persistent stimulation of the TSHR by its autoantibody (TRAb) induces hyperthyroidism, goiter, and extrathyroidal manifestations (Figure 3).
Figure 3. Summary of the mechanisms that lead to AITD. AITD is the product of multiple environmental factors that act on the basis of genetic susceptibility, together with some epigenetic mechanisms, leading to a loss of immune tolerance, with destruction of thyroid tissue and increased synthesis and secretion of autoantibodies. Finally, the Th1:Th2 imbalance directs the clinical and biochemical manifestations towards HT or GBD. Abbreviations: AITD: autoimmune thyroid disease, GBD: Graves-Basedow disease, HT: Hashimoto’s disease, Tg: thyroglobulin, TgAb: Tg autoantibodies, TPO: thyroid peroxidase, TPOAbs: TPO autoantibodies, TRAbs: thyroid stimulating hormone receptor autoantibodies.