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==Overview==
==Overview==
Genetic factors, anti [[thyrotropin receptor]] [[Antibody|antibodies]], [[T cells]], [[B cells]] and thyroid [[epithelial]] cells involvement are the main [[Pathological|pathologic]] features of Graves' disease.


==Pathophysiology==
==Pathophysiology==
Several factors may contribute in Graves' disease pathogenesis. Followings are the main aspects of Graves' diseases pathophysiology.
Several factors may contribute to Graves' disease pathogenesis. The following are the main aspects of Graves' diseases pathophysiology.<ref name="pmid24460189">{{cite journal |vauthors=Tomer Y |title=Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics |journal=Annu Rev Pathol |volume=9 |issue= |pages=147–56 |year=2014 |pmid=24460189 |pmc=4128637 |doi=10.1146/annurev-pathol-012513-104713 |url=}}</ref>


===Initiating factors===
===Initiating factors===
Genetic factors are important in developing Graves' disease. These factors include genes encoding for,<ref name="pmid24460189">{{cite journal |vauthors=Tomer Y |title=Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics |journal=Annu Rev Pathol |volume=9 |issue= |pages=147–56 |year=2014 |pmid=24460189 |pmc=4128637 |doi=10.1146/annurev-pathol-012513-104713 |url=}}</ref>
Genetic factors are important in the development of Graves' disease. These factors include genes encoding for:<ref name="pmid9440642">{{cite journal| author=Hahn BA, Saunders WB, Maier WC| title=Differences between individuals with self-reported irritable bowel syndrome (IBS) and IBS-like symptoms. | journal=Dig Dis Sci | year= 1997 | volume= 42 | issue= 12 | pages= 2585-90 | pmid=9440642 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9440642  }} </ref><ref name="pmid24460189">{{cite journal |vauthors=Tomer Y |title=Mechanisms of autoimmune thyroid diseases: from genetics to epigenetics |journal=Annu Rev Pathol |volume=9 |issue= |pages=147–56 |year=2014 |pmid=24460189 |pmc=4128637 |doi=10.1146/annurev-pathol-012513-104713 |url=}}</ref>
*Thyroglobulin  
*[[Thyroglobulin]]
*Thyrotropin receptor
*[[Thyrotropin receptor]]
*HLA-DRβ-Arg74
*[[HLA|HLA-DRβ-Arg74]]
*The protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
*The protein tyrosine phosphatase nonreceptor type 22 (PTPN22)
*Cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)
*[[CTLA-4|Cytotoxic T-lymphocyte–associated antigen 4]] (CTLA4)
*CD25
*[[CD25]]
*CD40
*[[CD40]]
Hypermethylation of genes involved in encoding thyrotropin receptor and proteins involved in T-cell signaling is another important factor.<ref name="pmid26459776">{{cite journal |vauthors=Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P |title=Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling |journal=J. Autoimmun. |volume=67 |issue= |pages=46–56 |year=2016 |pmid=26459776 |doi=10.1016/j.jaut.2015.09.006 |url=}}</ref>
Hypermethylation of genes involved in encoding thyrotropin receptor and proteins involved in T-cell signaling is another important factor.<ref name="pmid26459776">{{cite journal |vauthors=Limbach M, Saare M, Tserel L, Kisand K, Eglit T, Sauer S, Axelsson T, Syvänen AC, Metspalu A, Milani L, Peterson P |title=Epigenetic profiling in CD4+ and CD8+ T cells from Graves' disease patients reveals changes in genes associated with T cell receptor signaling |journal=J. Autoimmun. |volume=67 |issue= |pages=46–56 |year=2016 |pmid=26459776 |doi=10.1016/j.jaut.2015.09.006 |url=}}</ref>


===Anti Thyrotropin Receptor Antibodies===
===Anti Thyrotropin Receptor Antibodies===
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 [[IgG|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 a [[Goitre|goiter]]. The stimulation of thyroid hormone production by these antibodies 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>
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>


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.
===T Cells and B Cells===
Both [[T cells]] and [[B cells]] are necessary for the development of Graves' disease.<ref name="pmid5358896">{{cite journal |vauthors=Weaver DH, Maxwell JG, Castleton KB |title=Mallory-Weiss syndrome |journal=Am. J. Surg. |volume=118 |issue=6 |pages=887–92 |year=1969 |pmid=5358896 |doi= |url=}}</ref>
====T Cells====
* In Graves’ disease, autoreactive T cells against the thyrotropin receptor have escaped both [[Thymus#Phases of thymocyte maturation|central (thymic)]] and [[Thymus#Phases of thymocyte maturation|peripheral]] editing.
* Receptors on these [[CD4+ T cells|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.<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>


The "orange peel" skin has been explained by the infiltration of antibodies under the skin, causing an inflammatory reaction and subsequent fibrous plaques.
====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. <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>


There are 3 types of autoantibodies to the TSH receptor currently recognized:
===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.<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>
* 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.<ref name="pmid9245555">{{cite journal |vauthors=Faure GC, Bensoussan-Lejzerowicz D, Bene MC, Aubert V, Leclere J |title=Coexpression of CD40 and class II antigen HLA-DR in Graves' disease thyroid epithelial cells |journal=Clin. Immunol. Immunopathol. |volume=84 |issue=2 |pages=212–5 |year=1997 |pmid=9245555 |doi= |url=}}</ref><ref name="pmid10482365">{{cite journal |vauthors=Smith TJ, Sciaky D, Phipps RP, Jennings TA |title=CD40 expression in human thyroid tissue: evidence for involvement of multiple cell types in autoimmune and neoplastic diseases |journal=Thyroid |volume=9 |issue=8 |pages=749–55 |year=1999 |pmid=10482365 |doi=10.1089/thy.1999.9.749 |url=}}</ref>


* ''TSI'', Thyroid stimulating immunoglobulins: these antibodies (mainly IgG) act as LATS (Long Acting Thyroid Stimulants), activating the cells in a longer and slower way than TSH, leading to an elevated production of thyroid hormone.
==Pathogenesis of Extrathyroidal Manifestations==
*The immune pathogenesis of ophthalmopathy and hyperthyroidism are similar. The orbital process primarily targets [[fibroblasts]].


* ''TGI'', Thyroid growth immunoglobulins: these antibodies bind directly to the TSH receptor and have been implicated in the growth of thyroid follicles.
* T cells may contribute to ophthalmopathy through their interaction with fibroblasts.<ref name="pmid9792671">{{cite journal |vauthors=Cao HJ, Wang HS, Zhang Y, Lin HY, Phipps RP, Smith TJ |title=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 |journal=J. Biol. Chem. |volume=273 |issue=45 |pages=29615–25 |year=1998 |pmid=9792671 |doi= |url=}}</ref>
* Orbital fat and extraocular muscles expand from accumulating [[hyaluronidase]]-digestible material and adipogenesis.<ref name="pmid20181974">{{cite journal |vauthors=Bahn RS |title=Graves' ophthalmopathy |journal=N. Engl. J. Med. |volume=362 |issue=8 |pages=726–38 |year=2010 |pmid=20181974 |pmc=3902010 |doi=10.1056/NEJMra0905750 |url=}}</ref>


* ''TBII'', Thyrotrophin Binding-Inhibiting Inmunoglobulins: these antibodies inhibit the normal union of TSH with its receptor. Some will actually act as if TSH itself is binding to its receptor, thus inducing thyroid function. Other types may not stimulate the thyroid gland, but will prevent TSI and TSH from binding to and stimulating the receptor.
*Fibrocytes present antigens to T cells and when activated by thyrotropin or thyroid-stimulating immunoglobulins, fibrocytes release cytokines that have been implicated in Graves’ disease, they can differentiate into [[Adipocyte|adipocytes]] or [[Myofibroblast|myofibroblasts]] and thus might contribute to the tissue remodeling in ophthalmopathy.
 
*[[Insulin-like growth factor 1]] (IGF-1) receptor is involved in Graves' disease ophthalmopathy.<ref name="pmid18832736">{{cite journal |vauthors=Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, Kamat S, Smith TJ |title=B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis |journal=J. Immunol. |volume=181 |issue=8 |pages=5768–74 |year=2008 |pmid=18832736 |pmc=2562248 |doi= |url=}}</ref>
The trigger for auto-antibody production is not known. There appears to be a [[genetics|genetic]] predisposition for Graves' disease, suggesting that some people are more prone than others to develop TSH receptor activating antibodies due to a genetic cause. [[Human leukocyte antigen|HLA]] DR (especially DR3) appears to play a significant role.<!--
  --><ref name="EndocrReview1993">{{cite journal | author = Tomer Y, Davies T | title = Infection, thyroid disease, and autoimmunity. | journal = Endocr Rev | volume = 14 | issue = 1 | pages = 107-20 | year = 1993 | id = PMID 8491150 | url=http://edrv.endojournals.org/cgi/reprint/14/1/107.pdf | format=PDF}}</ref>
 
Since Graves' disease is an autoimmune disease which appears suddenly, often quite late in life, it is thought that a [[Virus|viral]] or [[Bacteria|bacterial]] infection may trigger antibodies which cross-react with the human TSH receptor (a phenomenon known as antigenic mimicry, also seen in some cases of type I [[diabetes]]).  
 
One possible culprit is the bacterium ''[[Yersinia enterocolitica]]'' (a cousin of ''[[Yersinia pestis]]'', the agent of bubonic plague). However, although there is indirect evidence for the structural similarity between the bacteria and the human thyrotropin receptor, direct causative evidence is limited.<!--
  --><ref name="EndocrReview1993"/>
''Yersinia'' seems not to be a major cause of this disease, although it may contribute to the development of thyroid autoimmunity arising for other reasons in genetically susceptible individuals.<!--
  --><ref>{{cite journal | author = Toivanen P, Toivanen A | title = Does Yersinia induce autoimmunity? | journal = Int Arch Allergy Immunol | volume = 104 | issue = 2 | pages = 107-11 | year = 1994 | id = PMID 8199453}}</ref>
It has also been suggested that ''Y. enterocolitica'' infection is not the cause of auto-immune thyroid disease, but rather is only an associated condition; with both having a shared inherited susceptibility.<!-- yes this is true
  --><ref>{{cite journal | author = Strieder T, Wenzel B, Prummel M, Tijssen J, Wiersinga W | title = Increased prevalence of antibodies to enteropathogenic ''Yersinia enterocolitica'' virulence proteins in relatives of patients with autoimmune thyroid disease. | journal = Clin Exp Immunol | volume = 132 | issue = 2 | pages = 278-82 | year = 2003 | id = PMID 12699417}}</ref>
More recently the role for ''Y. enterocolitica'' has been disputed.<!--
  --><ref>{{cite journal | author = Hansen P, Wenzel B, Brix T, Hegedüs L | title = Yersinia enterocolitica infection does not confer an increased risk of thyroid antibodies: evidence from a Danish twin study. | journal = Clin Exp Immunol | volume = 146 | issue = 1 | pages = 32-8 | year = 2006 | id = PMID 16968395}}</ref>
 
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==
==References==

Latest revision as of 20:34, 16 November 2017

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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

Genetic factors, anti thyrotropin receptor antibodies, T cells, B cells and thyroid epithelial cells involvement are the main pathologic features of Graves' disease.

Pathophysiology

Several factors may contribute to Graves' disease pathogenesis. The following are the main aspects of Graves' diseases pathophysiology.[1]

Initiating factors

Genetic factors are important in the development of Graves' disease. These factors include genes encoding for:[2][1]

Hypermethylation of genes involved in encoding thyrotropin receptor and proteins involved in T-cell signaling is another important factor.[3]

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.[4]

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 a goiter. The stimulation of thyroid hormone production by these antibodies is uncontrolled by the hypothalamic pituitary axis.[5][6]

T Cells and B Cells

Both T cells and B cells are necessary for the development of Graves' disease.[7]

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.[8]

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. [9]

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.[10]
  • 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.[11][12]

Pathogenesis of Extrathyroidal Manifestations

  • The immune pathogenesis of ophthalmopathy and hyperthyroidism are similar. The orbital process primarily targets fibroblasts.
  • T cells may contribute to ophthalmopathy through their interaction with fibroblasts.[13]
  • Orbital fat and extraocular muscles expand from accumulating hyaluronidase-digestible material and adipogenesis.[14]
  • Fibrocytes present antigens to T cells and when activated by thyrotropin or thyroid-stimulating immunoglobulins, fibrocytes release cytokines that have been implicated in Graves’ disease, they can differentiate into adipocytes or myofibroblasts and thus might contribute to the tissue remodeling in ophthalmopathy.
  • Insulin-like growth factor 1 (IGF-1) receptor is involved in Graves' disease ophthalmopathy.[15]

References

  1. ↑ 1.0 1.1 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.
  2. ↑ Hahn BA, Saunders WB, Maier WC (1997). "Differences between individuals with self-reported irritable bowel syndrome (IBS) and IBS-like symptoms". Dig Dis Sci. 42 (12): 2585–90. PMID 9440642.
  3. ↑ 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.
  4. ↑ 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Weaver DH, Maxwell JG, Castleton KB (1969). "Mallory-Weiss syndrome". Am. J. Surg. 118 (6): 887–92. PMID 5358896.
  8. ↑ 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.
  9. ↑ Smith TJ, Hegedüs L (2016). "Graves' Disease". N. Engl. J. Med. 375 (16): 1552–1565. doi:10.1056/NEJMra1510030. PMID 27797318.
  10. ↑ 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.
  11. ↑ 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.
  12. ↑ 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.
  13. ↑ 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.
  14. ↑ Bahn RS (2010). "Graves' ophthalmopathy". N. Engl. J. Med. 362 (8): 726–38. doi:10.1056/NEJMra0905750. PMC 3902010. PMID 20181974.
  15. ↑ Douglas RS, Naik V, Hwang CJ, Afifiyan NF, Gianoukakis AG, Sand D, Kamat S, Smith TJ (2008). "B cells from patients with Graves' disease aberrantly express the IGF-1 receptor: implications for disease pathogenesis". J. Immunol. 181 (8): 5768–74. PMC 2562248. PMID 18832736.

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