Autoimmune thyroid disease

Background

The thyroid gland, located in the neck, produces hormones that regulate metabolism. Autoimmune thyroid disease (AITD) is characterized by the presence of antibodies that attack the thyroid's healthy cells, leading to various thyroid disorders. The most common type of AITDs include Graves' disease (GD) and Hashimoto's thyroiditis (HT)(hyperthyroidism in GD and hypothyroidism in HT). Other types include Atrophic thyroiditis and Postpartum thyroiditis. The three most common thyroid autoantibodies are Thyroid peroxidase (TPO) autoantibodies (TPOAb), Thyroglobulin (Tg) autoantibodies (TgAb), and Thyroid-stimulating hormone (TSH) receptor antibodies (TRAb).

Autoimmune targets

Autoimmune thyroid diseases are usually accompanied by the presence of anti-thyroid peroxidase (TPO), anti-thyroglobulin (Tg), and anti-thyroid-stimulating hormone receptor (TSHR) antibodies. Antibodies against thyroid antigens such as carbonic anhydrase 2, megalin, T3 and T4, sodium iodide symporter (NIS), and pendrin have also been detected, although rarely.

Fig. 2 Summary of the immunological mechanisms of AITD leading to HT and GBD

• Thyroid Peroxidase, TPO

TPO is responsible for iodine (I2) oxidation and iodination of tyrosyl residues of the Tg molecule. Anti-TPO antibodies from AITD patients can fix complement, destroy thyrocytes, and act as competitive inhibitors of enzymatic activity. It can also act as inductors of oxidative stress. Studies indicated a higher prevalence of IgG1 (70%) and IgG4 (66.1%) forms compared to IgG2 and IgG3. Anti-TPO antibodies are detected in 90–95% of AITD patients, 80% of GD, and 10–15% of non-AITD patients.

• Thyroglobulin, Tg

Thyroglobulin is a large (600 kDa) glycoprotein consisting of dimers and containing on average 2–3 molecules of T4 and 0.3 molecules T3. The molecule is heterogeneous regarding hormone content, glycosylation, and size. The production of antibodies against Tg can be induced by massive destruction of the thyroid gland. Anti-Tg antibodies do not fix complement because the epitopes are too widely spaced to allow cross-linking. Anti-Tg antibodies in GD belong mainly to the IgG4 class, and IgG2 class is dominant in HT patients. Anti-Tg antibodies are often measured alongside TPOAb to confirm the diagnosis of HT.

• Thyroid-Stimulating Hormone Receptor (TSHR)

The TSHR binds to thyroid-stimulating hormone (TSH), stimulating the production and release of thyroid hormones (T4 and T3) from the thyroid gland. Anti-TSHR antibodies are primarily associated with Graves' disease. TSHR can bedivided to stimulating TSHR antibody and TSH blocking antibody. In addition, neutral antibodies directed against the "hinge" region exist. Anti-TSHR antibodies are found in 90% of GD patients, 0–20% HT, and 10–75% of atrophic thyroiditis patients. The pleiotropic action of anti-thyroid antibodies is typical for anti-TSHR antibodies. Stimulating antibodies is oligoclonal and belong to IgG1 class, while blocking antibodies are polyclonal. Stimulatory antibodies are detected in 73–100% and blocking anti-TSHR antibodies in 25–75% of GD patients.

Fig. 3 Schematic of functional cell-based bioassays for anti-TSHR antibodies