**Abstract**

Graves' Disease is a form of specific autoimmune disorder in the thyroid organ characterized by thyroid-stimulating antibodies (TSAb). Pregnant women are the most susceptible to GD due to hormonal changes and tolerance of immune responses during pregnancy. The incidence of prematurity, low birth weight (LBW), and neonatal thyrotoxicosis risk are the most complications that can be acquired if treatment is late and inadequate. It has implications for increased fetomaternal morbidity and mortality. Apart from being a biomarker for definitive diagnosis, TSAb testing is also beneficial for assessing treatment response and predicting relapse of GD (relapse) after oral anti-thyroid treatment. GD patients with high TPOAb titers also tend to have a high relapse rate. However, the evaluation of both TSAb and TPOAb examinations during and after treatment is rarely done routinely due to the examination's high cost. This works proposed developing TSHR and TPO antigen-based rapid diagnostic tests through the immunochromatography method to address the challenges of financing and limited laboratory facilities in the area. Besides, understanding the importance of examining thyroid antibodies (TSAb and TPOAb) and interpretation in clinical practice is still a matter of debate in clinical circles, so it requires in-depth information.

**Keywords:** Graves' Disease, thyroid-stimulating antibodies, thyroid peroxidase, pregnant women

#### **1. Introduction**

Improved hygiene and technological advances in several developed and developing countries have implications for health improvements marked by a decrease in the population's infectious diseases. However, on the other hand, the tendency of autoimmune disease [1] and cancer [2] is increasingly being found with the availability of early detection screening tools. Genetic susceptibility, nutrition, and environmental factors are risk factors for the increasing prevalence and incidence of autoimmune diseases in the population [3, 4].

Autoimmune cases in specific thyroid organs are the second-highest after rheumatoid arthritis [1], with an incidence rate of about 2–5% affecting the world population [5]. Based on screening data from US and European populations, it was reported that autoimmune thyroid diseases such as Graves' Disease were more dominant in women than men with a ratio of 5: 1 [6, 7]. The cause of the predominant tendency of women to develop autoimmune disorders is still being debated. Several hypotheses are associated with the structure of the X chromosome and hormonal changes. Morphologically, the X chromosome is larger and contains more genes (800–900 genes) than Y chromosomes (50–60 genes). Most of the genes related to immune system response and regulators are present on the X chromosome so that women have a higher risk of developing autoimmune disorders than men who only have one X chromosome [8, 9].

#### **2. Graves' Disease in pregnancy**

Graves' Disease (GD) is a form of specific autoimmune disorder in the thyroid organ characterized by the formation of thyroid-stimulating antibodies (TSAb) and increased thyroid hormone secretion (hyperthyroidism) [10]. This disorder was first introduced by Robert James Graves in 1835, who has clinical features such as goiter, palpitations, and orbitopathy [11]. About 60–80% of hyperthyroid disorders in the population are due to GD [12], with an incidence of 1–2 cases occurring in 1000 pregnancies [13]. GD disorders can affect all age groups, both children [14], reproductive age [15], and the elderly [16], but the most incidence occurs in women aged 20–49 years [6, 17].

Pregnant women are the most susceptible to GD, which is thought to be due to decreased immune tolerance during pregnancy [18] and hormonal changes [19]. Approximately 0.4%-1.0% of women of reproductive age have GD before pregnancy, and 0.2% have it during pregnancy [13]. The American Thyroid Association (ATA) has issued recommendations for routine thyroid health screening in pregnant women, especially the first trimester of pregnancy and postpartum [20]. Besides, all women of reproductive age who are suffering from GD or have a previous history of GD are encouraged to seek counseling when planning pregnancy as an effort to improve fetomaternal health [19].

The high titer of maternal TSAb that can cross the placental barrier will manifest in impaired fetal thyroid function, increasing fetomaternal morbidity, and mortality [18, 21]. Preterm birth (prematurity) [22], low birth weight (LBW) [21, 22], and risk of neonatal thyrotoxicosis [23] are some of the frequently reported fetomaternal complications. Apart from TSAb testing, the ATA also recommends that pregnant women with a positive TPOAb be advised to evaluate serum TSH levels every four weeks during the second trimester [20].

#### **3. TSHR and TPO as autoantigen**

Genetically, polymorphisms in the thyroid-stimulating hormone receptor (TSHR) gene found on chromosome 14q31 [24–26] and the thyroid peroxidase gene on chromosome 2p25 (TPO) [27, 28] are closely related to susceptibility and severity of GD disease in various populations. Both thyroid-specific genes can act as autoantigens and are potential genetic biomarkers for GD [29, 30]. The term autoantigen indicates that a protein originates within the individual's own body, has a highly conserved structure, and is coded for genes with a low mutation rate. Thus, autoantigen is not an abnormal molecule but is coded only for genes that undergo

#### *Thyroid Peroxidase (TPO) and Thyroid Stimulating Hormone Receptor (TSHR) Based… DOI: http://dx.doi.org/10.5772/intechopen.96509*

polymorphisms in the population. Polymorphisms cause variations in protein structure and function so that they are sometimes recognized as foreign antigens that can interact with T lymphocytes and antibodies [31, 32].

Thyroid-stimulating hormone receptor (TSHR) is a protein molecule that plays a vital role in the growth and differentiation of the thyroid gland and is directly involved in signal transduction and regulation of thyroid hormone biosynthesis [33, 34]. TSHR protein is the primary autoantigen that triggers GD and is a target that is attacked by TSAb [35]. T lymphocyte immunotolerance's failure to the TSHR antigen triggers the infiltration of lymphocytes, dendritic cells, and macrophages into the thyroid follicle. Furthermore, lymphocyte infiltration triggers the secretion of several pro-inflammatory cytokines such as interleukin 1ß, IL-6, IL-12 interferon-ƴ, ligand CD40, and tumor necrosis factor-α. Presentation of TSHR peptides by dendritic cells on MHC-II molecules will activate B cells and differentiate plasma cells to synthesize and secrete TSAb into the circulation [10, 36]. TSAb protein, which mimics the action of TSH on the surface of the thyroid follicle cells, is the leading cause of thyroid hyperplasia and hyperfunctioning of T3 and T4 secretion becomes uncontrolled [37].

In the majority of people with GD, other autoantibodies can also be found, such as thyroid peroxidase antibody (TPOAb) [38, 39]. Thyroid peroxidase (TPO) is the main enzyme that assists in the biosynthesis of thyroid hormones. The TPO enzyme catalyzes the organization of iodine (iodination) and the coupling process of iodothyrosine residues in thyroglobulin [40]. In GD, the persistent lymphocyte infiltration of the thyroid follicular cells can also trigger a failure to tolerate the TPO autoantigen's immune response. About 80% of people with GD have positive TPOAb, which can activate the complement cascade, causing thyroid gland damage and dysfunction [38, 41]. Physiologically, the presence of TPOAb can also be found in normal populations around 10%-15% [42, 43], and in thyroid malignancies around 10%-20% [41].

Although both autoantibodies cross the placental barrier, only maternal TSAb titer can interfere with fetal and neonatal thyroid function. In contrast, the presence of TPOAb does not significantly affect neonatal thyroid function [20, 44]. However, monitoring of thyroid antibody titer and regular counseling is necessary during pregnancy due to complications of morbidity in the mother and infant [20, 45].
