**1. Introduction**

Graves' hyperthyroidism is characterized by increased thyroid hormone levels (T4 and T3) with the supprimation of TSH levels, diffuse enlargement of thyroid glands and associated symptoms with orbitopathy or/and dermopathy [1, 2]. The course of disease is characterized by duality. The main autoimmune processes are manifested in thyrotoxicosis with a lymphocytic infiltration and diffuse thyroid enlargement, which can be associated with orbitopathy in 15–25% and pretibial myxedema in 0.5–4.5% [3]. The autoimmune processes are associated with the development of autoantibodies against different antigens, such as thyroid antigens [TSH receptor, thyroid peroxidase (TPO) enzyme and thyroglobulin (Tg)] and IGF-1 receptor, as well as against extraocular muscle membrane and cytosol antigens, and intracellular particles (flavoprotein subunit of mitochondrial succinate dehydrogenase, sarcalumenin, calsequestrin, collagen XII)] in thyroid-associated

ophthalmopathy [4–7]. The increased production of proinflammatory cytokines (IL-1, IL-6, TNFα), chemokines and costimulatory ligands on fibroblasts and adipocytes lead to inflammatory and infiltrating processes, and glycosaminoglycan (GAG) accumulation resulting in local tissue enlargements [8, 9]. In orbitopathy, the local infiltrating processes are responsible for the proptosis and sometimes the damage of nervi optici that can reach vision loss in the final stage. TSH receptor stimulating antibodies are kept to be the causative factors for hyperthyroidism. Autoantibodies against IGF-1 nearby receptor are involved in the edematous-infiltrative processes [10]. Antibodies against thyroid peroxidase (TPO) and thyroglobulin (Tg) are the relevant thyroid autoantibodies in Graves' Disease [11]. The binding of IgG and IgA autoantibodies to human extraocular muscle was different: IgG types bound endomysially, while IgA types bound to muscle fibers [12].

Deiodinase enzymes, DIO1, DIO2 and DIO3 are responsible for the conversion of T4 to active T3 hormone, the maintenance of the local T3 levels and the inactivation of T4 and T3 hormones [13, 14]. Deiodinase enzymes show tissue-specific expression, which limits their functions. Many drugs, iodine and selenium supply, proinflammatory cytokines and autoantibodies can influence DIO activities [15, 16]. The increased T4 levels are connected to the acceleration of the physiological degradation of DIO2 enzyme [17]. The common localization of DIO2 enzyme between thyroid and eye muscle tissues suggests that its autoantigenic role can be important in Graves' ophthalmopathy [18, 19]. 5′-deiodinase enzymes (DIO1 and DIO2) play a crucial role in thyroid hormone synthesis. TPO enzyme plays a role in the iodination of tyrosyl residues and their coupling to T3 and T4 in the colloid-embedded Tg with the interaction of hydrogen peroxide (H2O2) at the apical plasma membrane of thyrocytes [20]. The schematically illustrated process of thyroid hormone synthesis is exhibited in **Figure 1** highlighting the role of DIO1 and DIO2 activities.

#### **Figure 1.**

*Schematic illustration of thyroid hormone synthesis and thyroidal deiodinase activities (DIO1 and DIO2). DIO1: Type 1 deiodinase; DIO2: Type 2 deiodinase; Tg: Thyroglobulin; TPO: Thyroid peroxidase; T2, T3 and T4: Iodothyronines with 2, 3 and 4 iodides.*

This review emphasizes the role of deiodinases in the hyperthyroidism of Graves' Disease with respect to the thyroid functional stages and the relationship with antithyroid autoantibodies and autoantibodies against extraocular muscle and peptides corresponding to amino acid sequence of DIO2, as well as with the antithyroid drug (ATD) therapies.
