Graves' disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Seyedmahdi Pahlavani, M.D. [2]
Overview
Pathophysiology
Several factors may contribute in Graves' disease pathogenesis. Followings are the main aspects of Graves' diseases pathophysiology.
Initiating factors
Genetic factors are important in developing Graves' disease. These factors include genes encoding for,[1]
- Thyroglobulin
- Thyrotropin receptor
- HLA-DRβ-Arg74
- The protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
- Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)
- CD25
- CD40
Hypermethylation of genes involved in encoding thyrotropin receptor and proteins involved in T-cell signaling is another important factor.[2]
Anti Thyrotropin Receptor Antibodies
Graves' disease is an autoimmune disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.[3]
These antibodies cause hyperthyroidism because they bind to the TSH receptor and chronically stimulate it. The TSH receptor is expressed on the follicular cells of the thyroid gland (the cells that produce thyroid hormone), and the result of chronic stimulation is an abnormally high production of T3 and T4. This in turn causes the clinical symptoms of hyperthyroidism, and the enlargement of the thyroid gland visible as goiter.
These antibodies stimulate thyroid hormone production that is uncontrolled by the hypothalamic pituitary axis.[4][5]
T Cells and B Cells
Both T cells and B cells are necessary for the development of Graves' disease.
T Cells
In Graves’ disease, autoreactive T cells against the thyrotropin receptor have escaped both central (thymic) and peripheral editing.
Receptors on these CD4+ helper T cells interact with MHC class II molecules through which thyrotropin-receptor peptides are presented.
Intrathyroidal T cells are particularly reactive to thyroid antigens and predominantly have the Th2 phenotype.[6]
B Cells
B cells develop into antibody-producing plasma cells in a process requiring second signals.
The first of these signals is provided by antigen binding to the B cell receptor and the second by CD40 on the B cell surface interacting with CD40 ligand on T cells.
These interactions result in the production of critical cytokines, such as interleukin-4, which promote antibody secretion and T-cell support of class switching.
B cells initially produce IgM, which can be class-switched to IgG or IgE. Intrathyroidal B cells have reduced mitogenic responses but spontaneously secrete anti–thyrotropin-receptor antibodies. [7]
Thyroid Epithelial Cell Involvement
These cells express important organ specific antigens, such as the thyrotropin receptor, thyroglobulin, and thyroperoxidase.
Thyroid epithelial cells release several chemokines and thus may participate in the recruitment of immune cells.[8]
In addition, they act as MHC class II and have the potential to present thyroid antigens to T cells. Also, their CD40 expression suggests the potential for direct, productive interactions between thyroid epithelium and antigen-specific T cells in Graves’ disease.[9][10]
Pathogenesis of Extrathyroidal Manifestations
The immune pathogenesis of ophthalmopathy and hyperthyroidism are similar. The orbital process primarily targets fibroblasts. T cells may contribute to ophtalmopathy through their interaction with fibroblasts.[11] The infiltrative exophthalmos that is frequently encountered has been explained by postulating that the thyroid gland and the extraocular muscles share a common antigen which is recognized by the antibodies. Antibodies binding to the extraocular muscles would cause swelling behind the eyeball.
The ocular manifestations of Graves disease are more common in smokers and tend to worsen (or develop for the first time) following radioiodine treatment of the thyroid condition. Thus, they are not caused by hyperthyroidism per se; this common misperception may result from the fact that hyperthyroidism from other causes may cause eyelid retraction or eyelid lag (so-called hyperthyroid stare) which can be confused with the general appearance of proptosis/exophthalmos, despite the fact that the globes do not actually protrude in other causes of hyperthyroidism. Also, both conditions (globe protrusion and hyperthyroid lid retraction) may exist at the same time in the hyperthyroid patient with Graves disease.
References
- ↑ Tomer Y (2014). "Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics". Annu Rev Pathol. 9: 147–56. doi:10.1146/annurev-pathol-012513-104713. PMC 4128637. PMID 24460189.
- ↑ Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P (2016). "Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling". J. Autoimmun. 67: 46–56. doi:10.1016/j.jaut.2015.09.006. PMID 26459776.
- ↑ Weetman AP, Yateman ME, Ealey PA, Black CM, Reimer CB, Williams RC, Shine B, Marshall NJ (1990). "Thyroid-stimulating antibody activity between different immunoglobulin G subclasses". J. Clin. Invest. 86 (3): 723–7. doi:10.1172/JCI114768. PMC 296786. PMID 2168443.
- ↑ Morshed SA, Latif R, Davies TF (2009). "Characterization of thyrotropin receptor antibody-induced signaling cascades". Endocrinology. 150 (1): 519–29. doi:10.1210/en.2008-0878. PMC 2630889. PMID 18719020.
- ↑ Pujol-Borrell R, Giménez-Barcons M, Marín-Sánchez A, Colobran R (2015). "Genetics of Graves' Disease: Special Focus on the Role of TSHR Gene". Horm. Metab. Res. 47 (10): 753–66. doi:10.1055/s-0035-1559646. PMID 26361261.
- ↑ Martin A, Schwartz AE, Friedman EW, Davies TF (1989). "Successful production of intrathyroidal human T cell hybridomas: evidence for intact helper T cell function in Graves' disease". J. Clin. Endocrinol. Metab. 69 (6): 1104–8. doi:10.1210/jcem-69-6-1104. PMID 2531154.
- ↑ Smith TJ, Hegedüs L (2016). "Graves' Disease". N. Engl. J. Med. 375 (16): 1552–1565. doi:10.1056/NEJMra1510030. PMID 27797318.
- ↑ Armengol MP, Cardoso-Schmidt CB, Fernández M, Ferrer X, Pujol-Borrell R, Juan M (2003). "Chemokines determine local lymphoneogenesis and a reduction of circulating CXCR4+ T and CCR7 B and T lymphocytes in thyroid autoimmune diseases". J. Immunol. 170 (12): 6320–8. PMID 12794165.
- ↑ Faure GC, Bensoussan-Lejzerowicz D, Bene MC, Aubert V, Leclere J (1997). "Coexpression of CD40 and class II antigen HLA-DR in Graves' disease thyroid epithelial cells". Clin. Immunol. Immunopathol. 84 (2): 212–5. PMID 9245555.
- ↑ Smith TJ, Sciaky D, Phipps RP, Jennings TA (1999). "CD40 expression in human thyroid tissue: evidence for involvement of multiple cell types in autoimmune and neoplastic diseases". Thyroid. 9 (8): 749–55. doi:10.1089/thy.1999.9.749. PMID 10482365.
- ↑ Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ (1998). "Activation of human orbital fibroblasts through CD40 engagement results in a dramatic induction of hyaluronan synthesis and prostaglandin endoperoxide H synthase-2 expression. Insights into potential pathogenic mechanisms of thyroid-associated ophthalmopathy". J. Biol. Chem. 273 (45): 29615–25. PMID 9792671.