Pathogenesis

It is widely acknowledged that Graves' disease (GD) arises from autoimmunity due to the production of autoantibodies that attack the thyroid. Excessive stimulation of T-helper lymphocytes over-activates B-lymphocytes to undergo clonal expansion into forming specific plasma cells that secrete thyroid autoantibodies (Nauman, 2013), of which thyroid-stimulating hormone receptor antibodies (TRAb) are the most significant. These antibodies act similarly to the naturally occurring hormone, thyroid-stimulating hormone (TSH), causing hyperactivity of the thyroid gland. This leads to the overproduction of thyroid hormones, triiodothyronine (T3) and thyroxine (T4) (Földes et al., 1983; HealthCentral, 2018), which play important roles in metabolism and growth. This hyperactivity manifests as hyperthyroidism and an enlarged thyroid due to follicular hypertrophy and hyperplasia (Nauman, 2013).

So how are these lymphocytes activated to cause GD? Some pathogenesis pathways of GD have been proposed:

Figure on the left shows the mechanism of antigenic mimicry leading to GD and Graves' orbitopathy (GO) (Hou et al., 2021).

Antigenic Mimicry

Peptides secreted by certain gut bacteria can cross-react with structurally similar self-antigens in our body to produce self-reactive lymphocytes. These lymphocytes will attack the thyroid, resulting in GD. For example, some proteins of Yersinia enterocolitica are encoded by genes that are similar to that of the thyroid-stimulating hormone receptors (TSHRs) in our bodies, therefore can stimulate B-lymphocytes to produce TRAb (Hou et al., 2021).

Th17 and Treg Imbalance

Regulatory T lymphocytes, a.k.a. Tregs, suppress immune responses while T-helper lymphocytes (Th17) facilitate immune responses. Normally, Tregs and Th17 exist in a balanced state to maintain immune homeostasis by promoting pro-inflammatory responses during infections or injuries and then promoting anti-inflammatory responses to prevent immune cells from attacking our own bodies. However, a study by Hou et al. showed that dysbiosis can lead to heightened levels of Th17 but reduced production of Tregs, ultimately prompting AITDs like GD (Hou et al., 2021; Nauman, 2013).

Figure on the right shows how dysbiosis affects the Th17-Tregs balance (Hou et al., 2021).

Loss of Self-Tolerance

Normally, lymphocytes that mistake self-antigens as foreign are destroyed, preventing GD. However, this is not always the case. There are 3 ways in which self-reactive lymphocytes can persist in our system:

Figure above depicts the possible errors in the elimination of self-reactive T-lymphocyte. A: faulty central tolerance, B: increased antigens, C(i):T-lymphocyte defect, C(ii): thyrocyte defect (McIver and Morris, 1998 (modified)).

Faulty central tolerance: Failure of highly self-reactive T-lymphocytes to self-destruct (a.k.a undergo apoptosis ) in the thymus [A].
Increased amount of antigens: Thyrocytes produce abundant amounts of antigens, which are processed and presented by antigen-presenting cells (APCs), activate even weakly self-reactive T-lymphocytes to attack the thyroid [B].
Faulty peripheral tolerance: Thymic elimination of highly self-reactive T-lymphocytes is normal but evaded by some weakly self-reactive T-lymphocytes. They are allowed to be activated due to T-lymphocyte defect (does not secrete cytokines that signal for apoptosis) [C(i)] or thyrocyte defect (does not express enough major histocompatibility complex (MHC) molecules to facilitate apoptosis) [C (ii)].

(McIver and Morris, 1998)

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