Graves' disease pathophysiology: Difference between revisions
No edit summary |
No edit summary |
||
| Line 21: | Line 21: | ||
Graves' disease is an [[autoimmunity|autoimmune]] disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.<ref name="pmid2168443">{{cite journal |vauthors=Weetman AP, Yateman ME, Ealey PA, Black CM, Reimer CB, Williams RC, Shine B, Marshall NJ |title=Thyroid-stimulating antibody activity between different immunoglobulin G subclasses |journal=J. Clin. Invest. |volume=86 |issue=3 |pages=723–7 |year=1990 |pmid=2168443 |pmc=296786 |doi=10.1172/JCI114768 |url=}}</ref> | Graves' disease is an [[autoimmunity|autoimmune]] disorder, in which the body produces antibodies to the receptor for thyroid-stimulating hormone (TSH). These are IgG1 subclass of antibodies.<ref name="pmid2168443">{{cite journal |vauthors=Weetman AP, Yateman ME, Ealey PA, Black CM, Reimer CB, Williams RC, Shine B, Marshall NJ |title=Thyroid-stimulating antibody activity between different immunoglobulin G subclasses |journal=J. Clin. Invest. |volume=86 |issue=3 |pages=723–7 |year=1990 |pmid=2168443 |pmc=296786 |doi=10.1172/JCI114768 |url=}}</ref> | ||
These antibodies cause [[hyperthyroidism]] because they bind to the TSH receptor and [[chronic (medicine)|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 [[Goitre|goiter]]. | These antibodies cause [[hyperthyroidism]] because they bind to the TSH receptor and [[chronic (medicine)|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 [[Goitre|goiter]].<br> | ||
These antibodies stimulate thyroid hormone production that is uncontrolled by the hypothalamic pituitary axis.<ref name="pmid18719020">{{cite journal |vauthors=Morshed SA, Latif R, Davies TF |title=Characterization of thyrotropin receptor antibody-induced signaling cascades |journal=Endocrinology |volume=150 |issue=1 |pages=519–29 |year=2009 |pmid=18719020 |pmc=2630889 |doi=10.1210/en.2008-0878 |url=}}</ref> | These antibodies stimulate thyroid hormone production that is uncontrolled by the hypothalamic pituitary axis.<ref name="pmid18719020">{{cite journal |vauthors=Morshed SA, Latif R, Davies TF |title=Characterization of thyrotropin receptor antibody-induced signaling cascades |journal=Endocrinology |volume=150 |issue=1 |pages=519–29 |year=2009 |pmid=18719020 |pmc=2630889 |doi=10.1210/en.2008-0878 |url=}}</ref><ref name="pmid26361261">{{cite journal |vauthors=Pujol-Borrell R, Giménez-Barcons M, Marín-Sánchez A, Colobran R |title=Genetics of Graves' Disease: Special Focus on the Role of TSHR Gene |journal=Horm. Metab. Res. |volume=47 |issue=10 |pages=753–66 |year=2015 |pmid=26361261 |doi=10.1055/s-0035-1559646 |url=}}</ref> | ||
===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.<br> | |||
Receptors on these CD4+ helper T cells interact with MHC class II molecules through which thyrotropin-receptor peptides are presented.<br> | |||
Intrathyroidal T cells are particularly reactive to thyroid antigens and predominantly have the Th2 phenotype.<ref name="pmid2531154">{{cite journal |vauthors=Martin A, Schwartz AE, Friedman EW, Davies TF |title=Successful production of intrathyroidal human T cell hybridomas: evidence for intact helper T cell function in Graves' disease |journal=J. Clin. Endocrinol. Metab. |volume=69 |issue=6 |pages=1104–8 |year=1989 |pmid=2531154 |doi=10.1210/jcem-69-6-1104 |url=}}</ref> | |||
====B Cells==== | |||
B cells develop into antibody-producing plasma cells in a process requiring second signals.<br> | |||
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.<br> | |||
These interactions result in the production of critical cytokines, such as interleukin-4, which promote antibody secretion and T-cell support of class switching.<br> | |||
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. <ref name="pmid27797318">{{cite journal |vauthors=Smith TJ, Hegedüs L |title=Graves' Disease |journal=N. Engl. J. Med. |volume=375 |issue=16 |pages=1552–1565 |year=2016 |pmid=27797318 |doi=10.1056/NEJMra1510030 |url=}}</ref> | |||
===Thyroid Epithelial Cell Involvement=== | |||
These cells express important organ specific antigens, such as the thyrotropin receptor, thyroglobulin, and thyroperoxidase.<br> | |||
Thyroid epithelial cells release several chemokines and thus may participate in the recruitment of immune cells.<ref name="pmid12794165">{{cite journal |vauthors=Armengol MP, Cardoso-Schmidt CB, Fernández M, Ferrer X, Pujol-Borrell R, Juan M |title=Chemokines determine local lymphoneogenesis and a reduction of circulating CXCR4+ T and CCR7 B and T lymphocytes in thyroid autoimmune diseases |journal=J. Immunol. |volume=170 |issue=12 |pages=6320–8 |year=2003 |pmid=12794165 |doi= |url=}}</ref> | |||
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. | 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. | ||
Revision as of 16:16, 12 December 2016
|
Graves' disease Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Medical Therapy |
|
Case Studies |
|
Graves' disease pathophysiology On the Web |
|
American Roentgen Ray Society Images of Graves' disease pathophysiology |
|
Risk calculators and risk factors for Graves' disease pathophysiology |
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]
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.