Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases

Abstract

Autoimmune diseases have a high prevalence in the population, and autoimmune thyroid disease (AITD) is one of the most common representatives. Thyroid autoantibodies are not only frequently detected in patients with AITD but also in subjects without manifest thyroid dysfunction. The high prevalence raises questions regarding a potential role in extra-thyroidal diseases. This review summarizes the etiology and mechanism of AITD and addresses prevalence of antibodies against thyroid peroxidase, thyroid-stimulating hormone receptor (TSHR), and anti-thyroglobulin and their action outside the thyroid. The main issues limiting the reliability of the conclusions drawn here include problems with different specificities and sensitivities of the antibody detection assays employed, as well as potential confounding effects of altered thyroid hormone levels, and lack of prospective studies. In addition to the well-known effects of TSHR antibodies on fibroblasts in Graves' disease (GD), studies speculate on a role of anti-thyroid antibodies in cancer. All antibodies may have a tumor-promoting role in breast cancer carcinogenesis despite anti-thyroid peroxidase antibodies having a positive prognostic effect in patients with overt disease. Cross-reactivity with lactoperoxidase leading to induction of chronic inflammation might promote breast cancer, while anti-thyroid antibodies in manifest breast cancer might be an indication for a more active immune system. A better general health condition in older women with anti-thyroid peroxidase antibodies might support this hypothesis. The different actions of the anti-thyroid antibodies correspond to differences in cellular location of the antigens, titers of the circulating antibodies, duration of antibody exposure, and immunological mechanisms in GD and Hashimoto's thyroiditis.

Keywords: Graves’ orbitopathy; autoimmune thyroiditis; thyroglobulin; thyroid autoantibodies; thyroid peroxidase; thyroid-stimulating hormone receptor.

Figure 1

Promoting factors in Hashimoto’s and Graves’ disease. Abbreviations: chr., chromosome; CTLA4, cytotoxic T-lymphocyte-associated protein 4; Environ., environmental; PTN22, protein tyrosine phosphatase, non-receptor type 22.

Figure 2

Pathogenesis of Hashimoto’s disease (A) and GD (B). (A) Autoreactive CD4⁺ T cells in HT induce antibody production by B cells. The antibodies bind to the basal membrane of the thyroid follicle, activate complement, and induce necrosis of thyrocytes. The activation of cytotoxic CD8⁺ T cells leads to the induction of apoptosis by action of perforin. Finally, the expression of Fas (CD95) and FasL (CD95L) by thyrocytes perpetuates HT. (B) Autoreactive CD4⁺ T cells in GD induce only anti-thyroid-stimulating hormone receptor antibody-producing B cells. These antibodies act stimulatory by increasing I₂ metabolism (cAMP/PKA) and promoting proliferation and survival (PI3K/PKC/ERK) of thyrocytes. Blocking antibodies are characterized by lack of effect (not shown), and neutral antibodies activate various pathways, such as PI3K/Akt, mTOR/p70S6K, and MAPK/ERK1/2 and induce thyrocyte apoptosis. Abbreviations: GD, Graves’ disease; HT, Hashimoto’s thyroiditis; ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; p70S6K, ribosomal protein S6 kinase beta-1; PKC, protein kinase C; PI3K, phosphatidylinositol 3,4,5, triphosphate kinase; PKA, protein kinase; mTOR, mammalian target of rapamycin.

Figure 3

Overview of extra-thyroidal effects of anti-thyroid antibodies.

Figure 4

Autoantibodies in the pathogenesis of Graves’ orbitopathy. Anti-TSHR antibodies bind to the TSHR on orbital fibroblasts, which initiate signaling through Gαs and Gαq subunits. The Gαs complex initiates signaling by the protein kinase A through generation of cAMP by adenylyl kinase (AC). The Gαq pathway mediates activation of phospholipase C (PLC) and leads to activation of phosphatidylinositol 3,4,5 triphosphate by phosphatidylinositol 3,4,5 triphosphate kinase (PI3K) under the influence of insulin receptor substrate 1 (IRS-1). Akt activation results in mammalian target of rapamycin (mTOR) signaling with proliferation and secretion of cytokines, hyaluronic acid, and adipogenesis. Activation of orbital fibroblasts by T cells occurs via binding of the CD154 molecule on the T cell surface to the CD40 on the fibroblast surface. Abbreviations: IGF-1, insulin growth factor 1; IGF-1R, insulin growth factor 1 receptor; MCP-1, monocyte chemotactic protein 1; TNF-α, tumor necrosis factor-alpha; TSHR, thyroid-stimulating hormone receptor.