**3. Etiology and etiopathogenesis of Graves' Disease**

The disease is named after an Irish physician, Robert Graves, who was the first to describe the symptoms of hyperthyrosis. In non-English speaking countries, the two-word term is commonly used as the name of a German doctor, Karl Adolph von Basedow, is added. This is an autoimmune disease, in which stimulating antibodies activate TSH receptor, leading to the thyroid growth as well as to unrestrained production and release of thyroid hormones.

#### *Hyperthyroidism in Children DOI: http://dx.doi.org/10.5772/intechopen.97444*

Last decades have shown a constant increase in the incidence of autoimmune thyroid diseases (AITD). It is estimated that the problem affects approximately 5% of the world population. However, Graves' Disease is rarely diagnosed in the pediatric population. Its prevalence accounts for about 0.02% and children constitute less than 5% of all the patients. Nevertheless, it is Graves' Disease that remains the most common cause of hyperthyreosis in children, being responsible for 10–15% of all thyroid disorders in this group. Among pediatric patients, Graves' Disease may occur at any age but the morbidity rate increases with age, having its peak in adolescence. Its annual incidence among younger patients is 0.1 per 100,000 as compared to 3.0 per 100,000 at puberty. In the USA, Graves' Disease affects 0.2–0.4% of children and adolescents, i.e. 1 per 10,000, whereas in Hongkong it is diagnosed in 14 children per 100,000 a year. Sex distribution in the age group of up to 11 years is comparable, but in the older age group, girls are more frequently affected than boys (6–8,1).

It is estimated based on the research into monozygotic twins that the etiology of AITD has genetic causes in approximately 80% of cases, as compared to 20% due to environmental factors. Hashimoto thyroiditis and Graves' Disease share some of the genes.

Genes likely to be responsible for the development of AITD can be divided into two groups:


Additional genes may also play a role, being involved in the differentiation of AITD phenotypes, disease severity and response to the therapy.

Genes whose mutations may be responsible for the disease onset include:


genes encoding T-bet and GATA3, main regulators of Th1 and Th2 differentiation, respectively, and for the cytokines secreted by (IFNγ) and Th2 (IL4) in patients with Graves' Disease. The levels of the expression of mRNA T-bet and IFNγ are substantially elevated in patients, whereas those of GATA3 and IL4 remain decreased.

Also mutations of the gene encoding the expression of thyroglobulin, located on chromosome 8 and the autoimmune regulator gene located on chromosome 21 predispose to Graves' Disease. Moreover, vulnerability to develop ophthalmopathy in the course of Graves' Disease has been studied, with the involvement of CTLA-4 genes, tumor necrosis factor α (TNFα), adhesion molecule 1 (ICAM-1), interferon γ (IFN-γ), insulin-like growth factor 1 receptor (IGF-1R), protein inhibiting the pathway of signal 3 transduction (SOCS3), thyroid peroxidase (TPO) and calsequestrin 1 (CASQ1) [3–5].

The environmental factors that trigger the cascade leading to AITD include:


○ I -caused by enhanced production of thyroid hormones,

○ II - manifested by inflammation and destruction of thyrocytes.


However, Graves' Disease can be associated with the involvement of a combination of factors. The disease may even appear a long time after contact with a stimulus. Immunologically, the pathogenesis of Hashimoto thyroiditis is based on the predominance of cellular response, whereas the pathogenesis of Graves' Disease is associated with humoral response. This is, however, a gross simplification, as these processes overlap. Up to now, it has been thought that hyperstimulated CD4+ T cells play a major role in the pathogenesis of Hashimoto thyroiditis. T helper 1 cells (Th1) produce interferon γ. Anti-TSHR antibodies against TSH receptor, whose differentiation is induced by Th1 cells, belong mainly to the IgG1 subgroup. Th1 cells can also stimulate the production of antibodies by IL10 secretion, which in turn stimulates B cells. Helper T2 cells (Th2) secrete interleukin 4 (IL4) and lead to the stimulation and production of B cells and plasmatic cells, which produce IgG4 antibodies against thyroid-attacking antigens (**Figure 1**).

Th17 cells originate from Th under the effect of various factors, i.e. TGFB, IL6, IL21, IL23 or STAT3. They produce interleukin 17 (IL17), involved in the promotion of inflammatory processes. Th17 cells show the expression of CCR6, IL23R, IL12Rβ2 and CD161. Their large population has been found in patients with AITD. In turn, Tregs make up an opposite population of lymphocytes that are mainly involved in the inhibition of immune hyperreaction; hence, their function is impaired or their number is decreased in various autoimmune diseases, including AITD. The analysis of the Th17/ Treg proportion in children showed a reduced number of phenotypes characteristic of Treg cells: CD4+ IL17+ /CD4+ CD25+ CD127− and CD4+ IL17+ /CD4+ CD25+ CD127− FoxP3+ in patients with Graves' Disease as compared to the control group.

#### **Figure 1.**

*Model of Graves' Diseases etiopathogenesis; APC – antigen presenting cell; M – macrophages, CD8 – cytotoxic cells; cells – Th1, th2.*

Inflammation is an orderly process that should result in the elimination of a pathogenic factor and recovery of physiological condition, thus reflecting an effective immune response. One of the major traits of inflammatory condition is its selflimiting nature. The impaired suppresive function of lymphocytes leads ultimately to uncontrolled tissue injury and chronic inflammation. In the last few years, the maintenance of immunological tolerance has been ascribed to the subpopulation of B cells called B regulatory cells (Bregs). Their role has been emphasized in many autoimmune diseases which show both abnormal count and disturbed functionality of Bregs. Throughout the decades the knowledge of Bregs was based mainly on the research conducted on mice. The breakthrough was a study by Janeway et al., who in mice deprived of B cells observed a failure to recover after previous experimental autoimmune encephalomyelitis (EAE). Moreover, interleukin 10 (IL10) was found to be responsible for regulatory properties. Immature and mature B cells and plasmoblasts are thought to have a potential to differentiate towards Bregs producing IL10 both in mice and people. There is a strong potentiation of the function between Bregs and Tregs. On the other hand, Bregs inhibit differentiation of Th1 and Th17 cells by suppressing the production of proinflammatory cytokines as well as proliferation of dendritic cells (**Figure 2**).

Apart from IL10 secretion, Bregs are characterized by the production of other factors, i.e. transforming growth factor β (TGFβ) and interleukin 35 (IL35) (**Figure 3**). Through the production of TGF-β, Bregs activated by lipopolysaccharide (LPS) are able to induce the apoptosis of effector CD4+ T cells and inactivity of CD8+ T cells. Another mechanism inhibiting the immune response is due to the effect of IL35 which may inhibit the effector function of T cells; it also induces Bregs, promotes differentiation of B cells to Bregs secreting not only IL35, but also IL10.

Authors still pose a question whether Bregs constitute a separate cell line, in which a specific factor controls the expression of the genes responsible for their suppresive function or appear in response to the action of specific factors that stimulate B cells in a suitable environment. Immature and mature B cells and plasmoblasts and plasmatic cells may act as Bregs. Also B10 cells may differentiate into cells producing antibodies following termination of IL-10 production. In response to the inflammatory process, the level of Bregs increases and they gain the ability to regulate immunity. Thanks to the combination of antigen with B cell receptor (BCR), Bregs detect the inflammatory signal and induce regulatory effects [10–14].

#### **Figure 2.**

*Role of B regulatory cells in inhibiting differentiation of lymphocytes Th1 and Th17 and dendritic cells proliferation.*

#### **Figure 3.**

*Dual role of B lymphocytes. 10% of them release IL10, transforming growth factor beta (TGFβ) and interleukin 35 (IL35).*
