The role of pendrin and NIS antibodies in the pathogenesis of AITD is conflicting, which suggests that these antibodies are present in some patients with AITD, notwithstanding that their clinical importance in the pathogenesis of AITD and on thyroid function is yet to be determined. So far, their measurement does not seem to offer any diagnostic, treatment, or prognostic benefits [
AITD is triggered by a variety of factors (genetic, nongenetic, epigenetic, and environmental). Among the susceptibility genes associated with the immune system, the following stand out: HLA-DR3; PTPN22; CD40; FOXP3; CTLA-4; and IL-2Rα, although thyroid-specific susceptibility genes have been described (TSHR, Tg, and TPO). Some SNPs in these genes play key roles that help explain (at least in part) the increased risk for AITD. For example, the SNPs in FOXP3 and IL-2Rα are involved in peripheral tolerance mechanisms, while the SNPs in the CD40, CTLA-4, and HLA genes compromise the activation of TLs and the antigenic presentation; therefore, the SNPs in immunoregulatory genes can potentially alter the functioning or normal development of the central and peripheral tolerance mechanisms and the interaction of TLs with APCs. Some SNPs in other genes involved in the synthesis of cytokines with potential inflammatory effects have also been described and associated with an increased risk of AITD.
Although genetic susceptibility can potentially explain the pathogenesis of AITD, the genetic risk by itself is low; however, this risk is increased when there is synergism with some components or epigenetic modifications in the region’s regulators that are capable of controlling the gene expression. These epigenetic modifications include the XCI SNPs of the genes involved in DNA methylation, DNMT genes, or MTHFR and MTRR genes. Histone modifications and the impaired expressions of noncoding RNAs have also been implicated.
Environmental factors can be infectious and noninfectious and, in turn, nutritional and nonnutritional. These factors can, by mechanisms not yet elucidated, increase the susceptibility to AITD. However, the key point for the development of AITD is the infiltration of the thyroid by APCs, which may be induced by environmental factors.
Considering that the thyroid follicular cells from individuals with AITD can also abnormally express HLA-II (induced by IFN-γ), the phenomenon of thyroid autoantigen presentation, which facilitates the activation of TLs, is feasible. Likewise, there is also the thyroid infiltration of BLs, cytotoxic TLs, and TLs (CD4+). The interaction with APCs leads to the activation of TLs (CD4+) and the differentiation towards Tregs and Th (Th1, Th2, and Th17), with an imbalance in the Th1:Th2 ratio. For HT, the predominance is towards a Th1 response, whereas in GBD, the predominance is towards a Th2 response.
In addition, an attenuated Treg response has also been found, which may increase the proinflammatory activity of Th17. These mechanisms involve cytokines/chemokines and/or cytotoxins. For HT, apoptosis and subsequent fibrosis lead to the presence of hypothyroidism, while in GBD, the persistent stimulation of the TSHR by its autoantibody (TRAb) induces hyperthyroidism, goiter, and extrathyroidal manifestations (Figure 4).
Figure 4. Summary of the mechanisms that lead to AITD. AITD is the product of multiple environmental factors that act on the basis of genetic susceptibility, together with some epigenetic mechanisms, leading to a loss of immune tolerance, with destruction of thyroid tissue and increased synthesis and secretion of autoantibodies. Finally, the Th1:Th2 imbalance directs the clinical and biochemical manifestations towards HT or GBD. Abbreviations: AITD: autoimmune thyroid disease, GBD: Graves-Basedow disease, HT: Hashimoto’s disease, Tg: thyroglobulin, TgAb: Tg autoantibodies, TPO: thyroid peroxidase, TPOAbs: TPO autoantibodies, TRAbs: thyroid stimulating hormone receptor autoantibodies.
9. References
1. Bieber, K.; Hundt, J.E.; Yu, X.; Ehlers, M.; Petersen, F.; Karsten, C.M.; Köhl, J.; Kridin, K.; Kalies, K.; Kasprick, A.; et al.
Autoimmune pre-disease. Autoimmun. Rev. 2023, 22, 103236. [CrossRef]
2. Wang, L.; Wang, F.S.; Gershwin, M.E. Human autoimmune diseases: A comprehensive update. J. Intern. Med. 2015, 278, 369–395.
[CrossRef] [PubMed]
3. Selmi, C.; Leung, P.S.; Sherr, D.H.; Diaz, M.; Nyland, J.F.; Monestier, M.; Rose, N.R.; Gershwin, M.E. Mechanisms of environmental
influence on human autoimmunity: A National Institute of Environmental Health Sciences expert panel workshop. J. Autoimmun.
2012, 39, 272–284. [CrossRef] [PubMed]
4. Ngo, S.T.; Steyn, F.J.; McCombe, P.A. Gender differences in autoimmune disease. Front. Neuroendocrinol. 2014, 35, 347–369.
[CrossRef]
5. Moroncini, G.; Calogera, G.; Benfaremo, D.; Gabrielli, A. Biologics in Inflammatory Immune-mediated Systemic Diseases. Curr.
Pharm. Biotechnol. 2017, 18, 1008–1016. [CrossRef]
6. Ceccarelli, F.; Govoni, M.; Piga, M.; Cassone, G.; Cantatore, F.P.; Olivieri, G.; Cauli, A.; Favalli, E.G.; Atzeni, F.; Gremese, E.; et al.
Arthritis in Systemic Lupus Erythematosus: From 2022 International GISEA/OEG Symposium. J. Clin. Med. 2022, 11, 6016.
[CrossRef]
Cells 2023, 12, 918 25 of 37
7. Bach, J.F. The hygiene hypothesis in autoimmunity: The role of pathogens and commensals. Nat. Rev. Immunol. 2018, 18, 105–120.
[CrossRef]
8. McLeod, D.S.; Cooper, D.S. The incidence and prevalence of thyroid autoimmunity. Endocrine 2012, 42, 252–265. [CrossRef]
9. Ralli, M.; Angeletti, D.; Fiore, M.; D’Aguanno, V.; Lambiase, A.; Artico, M.; de Vincentiis, M.; Greco, A. Hashimoto’s thyroiditis:
An update on pathogenic mechanisms, diagnostic protocols, therapeutic strategies, and potential malignant transformation.
Autoimmun. Rev. 2020, 19, 102649. [CrossRef]
10. Hoang, T.D.; Stocker, D.J.; Chou, E.L.; Burch, H.B. 2022 Update on Clinical Management of Graves Disease and Thyroid Eye
Disease. Endocrinol. Metab. Clin. North Am. 2022, 51, 287–304. [CrossRef]
11. Bartalena, L.; Piantanida, E.; Gallo, D.; Ippolito, S.; Tanda, M.L. Management of Graves’ hyperthyroidism: Present and future.
Expert Rev. Endocrinol. Metab. 2022, 17, 153–166. [CrossRef]
12. Ragusa, F.; Fallahi, P.; Elia, G.; Gonnella, D.; Paparo, S.R.; Giusti, C.; Churilov, L.P.; Ferrari, S.M.; Antonelli, A. Hashimotos’
thyroiditis: Epidemiology, pathogenesis, clinic and therapy. Best Pract. Res. Clin. Endocrinol. Metab. 2019, 33, 101367. [CrossRef]
13. Qiu, K.; Li, K.; Zeng, T.; Liao, Y.; Min, J.; Zhang, N.; Peng, M.; Kong, W.; Chen, L.L. Integrative Analyses of Genes Associated with
Hashimoto’s Thyroiditis. J. Immunol. Res. 2021, 2021, 8263829. [CrossRef]
14. Ku´s, A.; Chaker, L.; Teumer, A.; Peeters, R.P.; Medici, M. The Genetic Basis of Thyroid Function: Novel Findings and New
Approaches. J. Clin. Endocrinol. Metab. 2020, 105, dgz225. [CrossRef]
15. Lee, H.J.; Li, C.W.; Hammerstad, S.S.; Stefan, M.; Tomer, Y. Immunogenetics of autoimmune thyroid diseases: A comprehensive
review. J. Autoimmun. 2015, 64, 82–90. [CrossRef]
16. Guarneri, F.; Benvenga, S. Environmental factors and genetic background that interact to cause autoimmune thyroid disease.
Curr. Opin. Endocrinol. Diabetes Obes. 2007, 14, 398–409. [CrossRef] [PubMed]
17. Koch, C.A.; Antonelli, A. Immunoendocrinology: When (neuro)endocrinology and immunology meet. Rev. Endocr. Metab. Disord.
2018, 19, 277–282. [CrossRef] [PubMed]
18. Yu, X.; Petersen, F. A methodological review of induced animal models of autoimmune diseases. Autoimmun. Rev. 2018, 17,
473–479. [CrossRef] [PubMed]
19. Topping, L.M.; Romero-Castillo, L.; Urbonaviciute, V.; Bolinsson, H.; Clanchy, F.I.; Holmdahl, R.; Bäckström, B.T.; Williams, R.O.
Standardization of Antigen-Emulsion Preparations for the Induction of Autoimmune DiseaseModels. Front. Immunol. 2022, 13, 892251.
[CrossRef] [PubMed]
20. Lam-Tse, W.K.; Lernmark, A.; Drexhage, H.A. Animal models of endocrine/organ-specific autoimmune diseases: Do they really
help us to understand human autoimmunity? Springer Semin. Immunopathol. 2002, 24, 297–321. [CrossRef] [PubMed]
21. Kong, Y.M. Experimental models for autoimmune thyroid disease: Recent developments. In Autoimmune Endocrinopathies
(Contemporary Endocrinology); Volpe´, R., Ed.; Humana Press: Totowa, NJ, USA, 2004; pp. 91–111.
22. Ng, H.P.; Banga, J.P.; Kung, A.W. Development of a murine model of autoimmune thyroiditis induced with homologous mouse
thyroid peroxidase. Endocrinology 2004, 145, 809–816. [CrossRef]
23. Braley-Mullen, H.; Sharp, G.C.; Medling, B.; Tang, H. Spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J. Autoimmun.
1999, 12, 157–165. [CrossRef]
24. Yu, S.; Medling, B.; Yagita, H.; Braley-Mullen, H. Characteristics of inflammatory cells in spontaneous autoimmune thyroiditis of
NOD.H-2h4 mice. J. Autoimmun. 2001, 16, 37–46. [CrossRef]
25. Ng, H.P.; Kung, A.W. Induction of autoimmune thyroiditis and hypothyroidism by immunization of immunoactive T cell epitope
of thyroid peroxidase. Endocrinology 2006, 147, 3085–3092. [CrossRef]
26. Jaume, J.C.; Guo, J.;Wang, Y.; Rapoport, B.; McLachlan, S.M. Cellular thyroid peroxidase (TPO), unlike purified TPO and adjuvant,
induces antibodies in mice that resemble autoantibodies in human autoimmune thyroid disease. J. Clin. Endocrinol. Metab. 1999,
84, 1651–1657.
27. Jacobson, E.M.; Concepcion, E.; Ho, K.; Kopp, P.; Vono Toniolo, J.; Tomer, Y. cDNA immunization of mice with human
thyroglobulin generates both humoral and T cell responses: A novel model of thyroid autoimmunity. PLoS ONE 2011, 6, e19200.
[CrossRef] [PubMed]
28. Penhale, W.J.; Farmer, A.; McKenna, R.P.; Irvine, W.J. Spontaneous thyroiditis in thymectomized and irradiated Wistar rats. Clin.
Exp. Immunol. 1973, 15, 225–236. [PubMed]
29. Badami, E.; Maiuri, L.; Quaratino, S. High incidence of spontaneous autoimmune thyroiditis in immunocompetent self-reactive
human T cell receptor transgenic mice. J. Autoimmun. 2005, 24, 85–91. [CrossRef] [PubMed]
30. McLachlan, S.M.; Aliesky, H.A.; Rapoport, B. To Reflect Human Autoimmune Thyroiditis, Thyroid Peroxidase (Not Thyroglobulin)
Antibodies Should be Measured in Female (Not Sex-Independent) NOD.H2(h4) Mice. Clin. Exp. Immunol. 2019, 196, 52–58.
[CrossRef]
31. Ellis, J.S.; Wan, X.; Braley-Mullen, H. Transient depletion of CD4+ CD25+ regulatory T cells results in multiple autoimmune
diseases in wild-type and B-cell-deficient NOD mice. Immunology 2013, 139, 179–186. [CrossRef] [PubMed]
32. Sharma, R.B.; Fan, X.; Caturegli, P.; Rose, N.R.; Burek, C.L. Invariant NKT Cell Lines Derived From the NOD.H2 Mouse Enhance
Autoimmune Thyroiditis. J. Thyroid Res. 2011, 2011, 895923. [CrossRef] [PubMed]
33. Horie, I.; Abiru, N.; Sakamoto, H.; Iwakura, Y.; Nagayama, Y. Induction of Autoimmune Thyroiditis by Depletion of CD4+CD25+
Regulatory T Cells in Thyroiditis-Resistant IL-17, But not Interferon-Gamma Receptor, Knockout Nonobese Diabetic-H2h4 Mice.
Endocrinology 2011, 152, 4448–4454. [CrossRef]
Cells 2023, 12, 918 26 of 37
34. Aubin, A.M.; Lombard-Vadnais, F.; Collin, R.; Aliesky, H.A.; McLachlan, S.M.; Lesage, S. The NOD Mouse Beyond Autoimmune
Diabetes. Front. Immunol. 2022, 13, 874769. [CrossRef]
35. Cheng, C.W.; Fang, W.F.; Tang, K.T.; Lin, J.D. The pathogenic role of IFN- in thyroiditis mouse models. Life Sci. 2022, 288, 120172.
[CrossRef]
36. Braley-Mullen, H.; Johnson, M.; Sharp, G.C.; Kyriakos, M. Induction of experimental autoimmune thyroiditis in mice with in vitro
activated splenic T cells. Cell. Immunol. 1985, 93, 132–143. [CrossRef]
37. Martin, A.P.; Coronel, E.C.; Sano, G.; Chen, S.C.; Vassileva, G.; Canasto-Chibuque, C.; Sedgwick, J.D.; Frenette, P.S.; Lipp, M.;
Furtado, G.C.; et al. A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC
chemokine CCL21. J. Immunol. 2004, 173, 4791–4798. [CrossRef] [PubMed]
38. Braley-Mullen, H.; Yu, S. NOD.H-2h4 mice: An important and underutilized animal model of autoimmune thyroiditis and
Sjogren’s syndrome. Adv. Immunol. 2015, 126, 1–43.
39. Braley-Mullen, H.; Yu, S. Early Requeriment for B Cells for Development of Spontaneous Autoimmune Thyroiditis in NOD.H-2h4
Mice. J. Immunol. 2000, 165, 7262–7269. [CrossRef]
40. Nagayama, Y.; Nakahara, M.; Abiru, N. Animal models of Graves’ Disease and Graves’ orbitopathy. Curr. Opin. Endocrinol.
Diabetes Obes. 2015, 22, 381–386. [CrossRef]
41. Chen, C.R.; Hamidi, S.; Braley-Mullen, H.; Nagayama, Y.; Bresee, C.; Aliesky, H.A.; Rapoport, B.; McLachlan, S.M. Antibodies to
thyroid peroxidase arise spontaneously with age in NOD.H-2h4 mice and appear after thyroglobulin antibodies. Endocrinology
2010, 151, 4583–4593. [CrossRef]
42. Zhang,M.; Jiang,W.; Lu, G.;Wang, R.; Lv, Z.; Li, D. Insight IntoMouseModels of Hyperthyroidism. Front. Endocrinol. 2022, 13, 929750.
[CrossRef]
43. Hall, R.; Stanbury, J.B. Familial studies of autoimmune thyroiditis. Clin. Exp. Immunol. 1967, 2, 719–725.
44. Carey, C.; Skosey, C.; Pinnamaneni, K.M.; Barsano, C.P.; DeGroot, L.J. Thyroid abnormalities in children of parents who have
Graves’ disease: Possible pre-Graves’ disease. Metabolism 1980, 29, 369–376. [CrossRef]
45. Burek, C.L.; Hoffman,W.H.; Rose, N.R. The presence of thyroid autoantibodies in children and adolescents with, A.I.TD and in
their siblings and parents. Clin. Immunol. Immunopathol. 1982, 25, 395–404. [CrossRef] [PubMed]
46. Brix, T.H.; Kyvik, K.O.; Christensen, K.; Hegedüs, L. Evidence for a major role of heredity in Graves’ disease: A population-based
study of two Danish twin cohorts. J. Clin. Endocrinol. Metab. 2001, 86, 930–934. [CrossRef] [PubMed]
47. Hansen, P.S.; Brix, T.H.; Iachine, I.; Kyvik, K.O.; Hegedüs, L. The relative importance of genetic and environmental effects for the
early stages of thyroid autoimmunity: A study of healthy Danish twins. Eur. J. Endocrinol. 2006, 154, 29–38. [CrossRef]
48. Skov, J.; Eriksson, D.; Kuja-Halkola, R.; Höijer, J.; Gudbjörnsdottir, S.; Svensson, A.M.; Magnusson, P.K.E.; Ludvigsson, J.F.;
Kämpe, O.; Bensing, S. Co-aggregation and heritability of organ-specific autoimmunity: A population-based twin study. Eur. J.
Endocrinol. 2020, 182, 473–480. [CrossRef] [PubMed]
49. Tomer, Y.; Ban, Y.; Concepcion, E.; Barbesino, G.; Villanueva, R.; Greenberg, D.A.; Davies, T.F. Common. and unique susceptibility
loci in Graves and Hashimoto diseases: Results of whole-genome screening in a data set of 102 multiplex families. Am. J. Hum.
Genet. 2003, 73, 736–747. [CrossRef]
50. Aust, G.; Krohn, K.; Morgenthaler, N.G.; Schröder, S.; Schütz, A.; Edelmann, J.; Brylla, E. Graves’ disease and Hashimoto’s
thyroiditis in monozygotic twins: Case study as well as transcriptomic and immunohistological analysis of thyroid tissues. Eur. J.
Endocrinol. 2006, 154, 13–20. [CrossRef]
51. Monteiro, J.; Hingorani, R.; Choi, I.-H.; Silver, J.; Pergolizzi, R.; Gregersen, P.K. Oligoclonality in the human CD8+ T cell repertoire
in normal subjects and twins: Implications for studies of infectious and autoimmune diseases. Mol. Med. 1995, 1, 614–624.
[CrossRef]
52. Brix, T.H.; Christensen, K.; Holm, N.V.; Harvald, B.; Hegedus, L. A population-based study of Graves’ diseases in Danish twins.
Clin. Endocrinol. 1998, 48, 397–400. [CrossRef]
53. Ringold, D.A.; Nicoloff, J.T.; Kesler, M.; Davis, H.; Hamilton, A.; Mack, T. Further evidence for a strong genetic influence on the
development of autoimmune thyroid disease: The California twin study. Thyroid 2002, 12, 647–653. [CrossRef]
54. Brix, T.H.; Kyvik, K.O.; Hegedus, L. A population-based study of chronic autoimmune hypothyroidism in Danish twins. J. Clin.
Endocrinol. Metab. 2000, 85, 536–539. [CrossRef]
55. Thomsen, H.; Li, X.; Sundquist, K.; Sundquist, J.; Försti, A.; Hemminki, K. Familial risks between Graves disease and Hashimoto
thyroiditis and other autoimmune diseases in the population of Sweden. J. Transl. Autoimmun. 2020, 3, 100058. [CrossRef]
56. Ramos, P.S.; Shedlock, A.M.; Langefeld, C.D. Genetics of autoimmune diseases: Insights from population genetics. J. Hum. Genet.
2015, 60, 657–664. [CrossRef]
57. Villanueva, R.; Greenberg, D.A.; Davies, T.F.; Tomer, Y. Sibling recurrence risk in autoimmune thyroid disease. Thyroid 2003, 13,
761–764. [CrossRef] [PubMed]
58. Tomer, Y.; Davies, T.F. Searching for the autoimmune thyroid disease susceptibility genes: From gene mapping to gene function.
Endocr. Rev. 2003, 24, 694–717. [CrossRef] [PubMed]
59. Frommer, L.; König, J.; Chatzidou, S.; Chionos, G.; Längericht, J.; Kahaly, G.J. Recurrence risk of autoimmune thyroid and
endocrine diseases. Best Pract. Res. Clin. Endocrinol. Metab. 2022, 101636. [CrossRef]
Cells 2023, 12, 918 27 of 37
60. Phillips, D.; McLachlan, S.; Stephenson, A.; Roberts, D.; Moffitt, S.; McDonald, D.; Ad’Hiah, A.; Stratton, A.; Young, E.; Clark, F.
Autosomal dominant transmission of autoantibodies to thyroglobulin and thyroid peroxidase. J. Clin. Endocrinol. Metab. 1990, 70,
742–746. [CrossRef] [PubMed]
61. Pauls, D.L.; Zakarija, M.; McKenzie, J.M.; Egeland, J.A. Complex segregation analysis of antibodies to thyroid peroxidase in old
order Amish families. Am. J. Med. Genet. 1993, 47, 375–379. [CrossRef]
62. Jaume, J.C.; Guo, J.; Pauls, D.L.; Zakarija, M.; McKenzie, J.M.; Egeland, J.A.; Burek, C.L.; Rose, N.R.; Hoffman, W.H.; Rapoport, B.;
et al. Evidence for genetic transmission of thyroid peroxidase autoantibody epitopic “fingerprints”. J. Clin. Endocrinol. Metab.
1999, 84, 1424–1431.
63. Polster, A. Rethinking Complex Diseases: A High-Dimensional Representation of Individual Disease Burden and Global Disease
Landscape. Preprints 2022, 2022010228.
64. Hwangbo, Y.; Park, Y.J. Genome-Wide Association Studies of Autoimmune Thyroid Diseases, Thyroid Function, and Thyroid
Cancer. Endocrinol. Metab. 2018, 33, 175–184. [CrossRef]
65. Jacobson, E.M.; Huber, A.; Tomer, Y.; The, H.L. A gene complex in thyroid autoimmunity: From epidemiology to etiology. J.
Autoimmun. 2008, 30, 58e62. [CrossRef]
66. Ban, Y.; Tomer, Y. Genetic susceptibility in thyroid autoimmunity. Pediatr. Endocrinol. Rev. 2005, 3, 20–32. [PubMed]
67. Sollid, L.M.; Pos, W.; Wucherpfennig, K.W. Molecular Mechanisms for contribution of MHC molecules to autoimmune diseases.
Curr. Opin. Immunol. 2014, 31, 24–30. [CrossRef]
68. Wamala, D.; Buteme, H.K.; Kirimunda, S.; Kallenius, G.; Joloba, M. Association between human leukocyte antigen class II and
pulmonary tuberculosis due to mycobacterium tuberculosis in Uganda. BMC Infect. Dis. 2016, 16, 23. [CrossRef] [PubMed]
69. Mehraji, Z.; Farazmand, A.; Esteghamati, A.; Noshad, S.; Sadr, M.; Amirzargar, S.; Yekaninejad, M.S.; Amirzargar, A. Association
of Human Leukocyte Antigens Class I and II with Graves’ Disease in Iranian Population. Iran. J. Immunol. 2017, 14, 223–230.
70. Stasiak, M.; Zawadzka-Starczewska, K.; Tymoniuk, B.; Stasiak, B.; Lewi´ nski, A. Significance of HLA in the development of Graves’
orbitopathy. Genes Immun. 2023, 24, 32–38. [CrossRef]
71. Du, P.; Zhu, J.; Yao, Q.; Cai, T.; Xu, J.; Fang, Y.;Wu, Y.; Zhang,W.; Zhang, J.A. HLA-DRA Gene Polymorphisms Are Associated
with Graves’ Disease as an Autoimmune Thyroid Disease. Biomed. Res. Int. 2022, 2022, 6839634. [CrossRef]
72. Zawadzka-Starczewska, K.; Tymoniuk, B.; Stasiak, B.; Lewi´ nski, A.; Stasiak, M. Actual Associations between HLA Haplotype and
Graves’ Disease Development. J. Clin. Med. 2022, 11, 2492. [CrossRef]
73. Huang, X.; Liu, G.; Mei, S.; Cai, J.; Rao, J.; Tang, M.; Zhu, T.; Chen, W.; Peng, S.; Wang, Y.; et al. Human leucocyte antigen alleles
confer susceptibility and progression to Graves’ ophthalmopathy in a Southern Chinese population. Br. J. Ophthalmol. 2021, 105,
1462–1468. [CrossRef] [PubMed]
74. Zakharova, M.Y.; Belyanina, T.A.; Sokolov, A.V.; Kiselev, I.S.; Mamedov, A.E. The Contribution of Major Histocompatibility
Complex Class I Genes to an Association with Autoimmune Diseases. Acta Nat. 2019, 11, 4–12. [CrossRef]
75. Cohen, S.; Dadi, H.; Shaoul, E.; Sharfe, N.; Roifman, C.M. Cloning and characterization of a lymphoid-specific, inducible human
protein tyrosine phosphatase, Lyp. Blood 1999, 93, 2013–2024. [CrossRef] [PubMed]
76. Siminovitch, K.A. PTPN22 and autoimmune disease. Nat. Genet. 2004, 36, 1248–1249. [CrossRef]
77. Tizaoui, K.; Kim, S.H.; Jeong, G.H.; Kronbichler, A.; Lee, K.S.; Lee, K.H.; Shin, J.I. Association of PTPN22 1858C/T Polymorphism
with Autoimmune Diseases: A Systematic Review and Bayesian Approach. J. Clin. Med. 2019, 8, 347. [CrossRef]
78. Jassim, B.A.; Lin, J.; Zhang, Z.Y. PTPN22, structure, function, and developments in inhibitor discovery with applications for
immunotherapy. Expert Opin. Drug. Discov. 2022, 17, 825–837. [CrossRef] [PubMed]
79. Ban, Y.; Tozaki, T.; Taniyama, M.; Nakano, Y.; Ban, Y.; Ban, Y.; Hirano, T. Association of the protein tyrosine phosphatase
nonreceptor 22 haplotypes with autoimmune thyroid disease in the Japanese population. Thyroid 2010, 20, 893–899. [CrossRef]
80. Ban, Y.; Tozaki, T.; Taniyama, M.; Tomita, M.; Ban, Y. The codon 620 single nucleotide polymorphism of the protein tyrosine
phosphatase-22 gene does not contribute to autoimmune thyroid disease susceptibility in the Japanese. Thyroid 2005, 15, 1115–1118.
[CrossRef]
81. Lee, H.S.; Kang, J.; Yang, S.; Kim, D.; Park, Y. Susceptibility influence of a PTPN22 haplotype with thyroid autoimmunity in
Koreans. Diabetes Metab. Res. Rev. 2011, 27, 878–882. [CrossRef] [PubMed]
82. Alkhateeb, A.; Marzouka, N.A.; Tashtoush, R. Variants in PTPN22 and SMOC2 genes and the risk of thyroid disease in the
Jordanian Arab population. Endocrine 2013, 44, 702–709. [CrossRef]
83. Krupi´ nska, J.; Urbanowicz, W.; Kaczmarczyk, M.; Kulig, G.; Sowi´ nska-Przepiera, E.; Andrysiak-Mamos, E.; Syrenicz, A.
Association between genetic mutations and the development of autoimmune thyroiditis in patients with chronic hepatitis C
treated with interferon alpha. Thyroid Res. 2012, 5, 10. [CrossRef] [PubMed]
84. Dultz, G.; Matheis, N.; Dittmar, M.; Röhrig, B.; Bender, K.; Kahaly, G.J. The protein tyrosine phosphatase non-receptor type 22
C1858T polymorphism is a joint susceptibility locus for immune thyroiditis and autoimmune diabetes. Thyroid 2009, 19, 143–148.
[CrossRef]
85. Hamza, R.T.; Awwad, K.S.; Temsah, K.A.; Hamed, A.I. R620W polymorphism of protein tyrosine phosphatase PTPN22 in
Egyptian children and adolescents with systemic lupus erythematosus: Relation to thyroid autoimmunity. Int. J. Adolesc. Med.
Health 2013, 25, 143–149. [CrossRef]
86. Luo, L.; Cai, B.; Liu, F.; Hu, X.; Wang, L. Association of protein tyrosine phosphatase nonreceptor 22 (PTPN22) C1858T gene
polymorphism with susceptibility to autoimmune thyroid diseases: A meta-analysis. Endocr. J. 2012, 59, 439–445. [CrossRef]
Cells 2023, 12, 918 28 of 37
87. Smyth, D.; Cooper, J.D.; Collins, J.E.; Heward, J.M.; Franklyn, J.A.; Howson, J.M.; Vella, A.; Nutland, S.; Rance, H.E.; Maier, L.;
et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and
evidence for its role as a general autoimmunity locus. Diabetes 2004, 53, 3020–3023. [CrossRef] [PubMed]
88. Heward, J.M.; Brand, O.J.; Barrett, J.C.; Carr-Smith, J.D.; Franklyn, J.A.; Gough, S.C. Association of, P.T.PN22 haplotypes with
Graves’ disease. J. Clin. Endocrinol. Metab. 2007, 92, 685–690. [CrossRef]
89. Jurecka-Lubieniecka, B.; Ploski, R.; Kula, D.; Krol, A.; Bednarczuk, T.; Kolosza, Z.; Tukiendorf, A.; Szpak-Ulczok, S.; Stanjek-
Cichoracka, A.; Polanska, J.; et al. Association between age at diagnosis of Graves’ disease and variants in genes involved in
immune response. PLoS ONE 2013, 8, e59349. [CrossRef] [PubMed]
90. Velaga, M.R.;Wilson, V.; Jennings, C.E.; Owen, C.J.; Herington, S.; Donaldson, P.T.; Ball, S.G.; James, R.A.; Quinton, R.; Perros,
P.; et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major determinant of Graves’
disease. J. Clin. Endocrinol. Metab. 2004, 89, 5862–5865. [CrossRef] [PubMed]
91. Skórka, A.; Bednarczuk, T.; Bar-Andziak, E.; Nauman, J.; Ploski, R. Lymphoid tyrosine phosphatase (PTPN22/LYP) variant and
Graves’ disease in a Polish population: Association and gene dose-dependent correlation with age of onset. Clin. Endocrinol. 2005,
62, 679–682. [CrossRef]
92. Wawrusiewicz-Kurylonek, N.; Koper-Lenkiewicz, O.M.; Go´scik, J.; My´sliwiec, J.; Pawłowski, P.; Kr˛etowski, A.J. Association of
PTPN22 polymorphism and its correlation with Graves’ disease susceptibility in Polish adult population-A preliminary study.
Mol. Genet. Genomic Med. 2019, 7, e661. [CrossRef]
93. Shehjar, F.; Misgar, R.A.; Malik, S.A.; Laway, B.A. PTPN22 1858 C/T Exon Polymorphism is not Associated with Graves’ Disease
in Kashmiri population. Indian J. Endocrinol. Metab. 2018, 22, 457–460. [PubMed]
94. López-Cano, D.J.; Cadena-Sandoval, D.; Beltrán-Ramírez, O.; Barbosa-Cobos, R.E.; Sánchez-Muñoz, F.; Amezcua-Guerra, L.M.;
Juárez-Vicuña, Y.; Aguilera-Cartas, M.C.; Moreno, J.; Bautista-Olvera, J.; et al. The PTPN22 R263Q polymorphism confers
protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves’
disease in a Mexican population. Inflamm. Res. 2017, 66, 775–781. [CrossRef]
95. Zheng, J.; Ibrahim, S.; Petersen, F.; Yu, X. Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases,
which depends on the localization of the affected tissue. Genes Immun. 2012, 13, 641–652. [CrossRef] [PubMed]
96. Wu, H.;Wan, S.; Qu, M.; Ren, B.; Liu, L.; Shen, H. The Relationship between PTPN22 R620W Polymorphisms and the Susceptibility
to Autoimmune Thyroid Diseases: An Updated Meta-analysis. Immunol. Investig. 2022, 51, 438–451. [CrossRef]
97. Burn, G.L.; Svensson, L.; Sanchez-Blanco, C.; Saini, M.; Cope, A.P. Why is PTPN22 a good candidate susceptibility gene for
autoimmune disease? FEBS Lett. 2011, 585, 3689–3698. [CrossRef] [PubMed]
98. Tizaoui, K.; Shin, J.I.; Jeong, G.H.; Yang, J.W.; Park, S.; Kim, J.H.; Hwang, S.Y.; Park, S.J.; Koyanagi, A.; Smith, L. Genetic
Polymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. Medicina 2022, 58, 1034. [CrossRef] [PubMed]
99. Bogusławska, J.; Godlewska, M.; Gajda, E.; Piekiełko-Witkowska, A. Cellular and molecular basis of thyroid autoimmunity. Eur.
Thyroid J. 2022, 11, e210024. [CrossRef]
100. Pyzik, A.; Grywalska, E.; Matyjaszek-Matuszek, B.; Rolinski, J. Immune disorders in Hashimoto’s thyroiditis: What do we know
so far? J. Immunol. Res. 2015, 2015, 979167. [CrossRef]
101. Criswell, L.A.; Pfeiffer, K.A.; Lum, R.F.; Gonzales, B.; Novitzke, J.; Kern, M.; Moser, K.L.; Begovich, A.B.; Carlton, V.E.; Li, W.; et al.
Analysis of families in the multiple autoimmune disease genetics consortium (MADGC) collection: The PTPN22 620W allele
associates with multiple autoimmune phenotypes. Am. J. Hum. Genet. 2005, 76, 561–571. [CrossRef]
102. Salomon, R.; Dahan, R. Next Generation CD40 Agonistic Antibodies for Cancer Immunotherapy. Front. Immunol. 2022, 13, 940674.
[CrossRef]
103. Karnell, J.L.; Rieder, S.A.; Ettinger, R.; Kolbeck, R. Targeting the CD40-CD40L pathway in autoimmune diseases: Humoral
immunity and beyond. Adv. Drug. Deliv. Rev. 2019, 141, 92–103. [CrossRef]
104. Laman, J.D.; Claassen, E.; Noelle, R.J. Functions of CD40 and Its Ligand, gp39 (CD40L). Crit. Rev. Immunol. 2017, 37, 371–420.
[CrossRef] [PubMed]
105. Tomer, Y.; Concepcion, E.; Greenberg, D.A. A C/T Single-Nucleotide Polymorphism in the Region of the CD40 Gene Is Associated
With Graves’ Disease. Thyroid 2002, 12, 1129–1135. [CrossRef] [PubMed]
106. Ban, Y.; Tozaki, T.; Taniyama, M.; Tomita, M.; Ban, Y. Association of a C/T single-nucleotide polymorphism in the 50-untranslated
region of the CD40 gene with Graves’ disease in Japanese. Thyroid 2006, 16, 443–446. [CrossRef] [PubMed]
107. Kurylowicz, A.; Kula, D.; Ploski, R.; Skorka, A.; Jurecka-Lubieniecka, B.; Zebracka, J.; Steinhof-Radwanska, K.; Hasse-Lazar, K.;
Hiromatsu, Y.; Jarzab, B.; et al. Association of CD40 gene polymorphism (C-1T) with susceptibility and phenotype of Graves’
disease. Thyroid 2005, 15, 1119–1124. [CrossRef]
108. Kim, T.Y.; Park, Y.J.; Hwang, J.K.; Song, J.Y.; Park, K.S.; Cho, B.Y.; Park, D.J. A C/T polymorphism in the 50-untranslated region of
the CD40 gene is associated with Graves’ disease in Koreans. Thyroid 2003, 13, 919–925. [CrossRef]
109. Wang, D.; Chen, J.; Zhang, H.; Zhang, F.; Yang, L.; Mou, Y. Role of Different CD40 Polymorphisms in Graves’ Disease and
Hashimoto’s Thyroiditis. Immunol. Investig. 2017, 46, 544–551. [CrossRef]
110. Li, M.; Sun, H.; Liu, S.; Yu, J.; Li, Q.; Liu, P.; Shen, H.; Sun, D. CD40 C/T-1 polymorphism plays different roles in Graves’ disease
and Hashimoto’s thyroiditis: A meta-analysis. Endocr. J. 2012, 59, 1041–1050. [CrossRef]
Cells 2023, 12, 918 29 of 37
111. Chand Dakal, T.; Dhabhai, B.; Agarwal, D.; Gupta, R.; Nagda, G.; Meena, A.R.; Dhakar, R.; Menon, A.; Mathur, R.; Mona; et al.
Mechanistic basis of co-stimulatory CD40-CD40L ligation mediated regulation of immune responses in cancer and autoimmune
disorders. Immunobiology 2020, 225, 151899. [CrossRef]
112. Chennamadhavuni, A.; Abushahin, L.; Jin, N.; Presley, C.J.; Manne, A. Risk Factors and Biomarkers for Immune-Related Adverse
Events: A Practical Guide to Identifying High-Risk Patients and Rechallenging Immune Checkpoint Inhibitors. Front. Immunol.
2022, 13, 779691. [CrossRef] [PubMed]
113. Van Coillie, S.;Wiernicki, B.; Xu, J. Molecular and Cellular Functions of CTLA-4. Adv. Exp. Med. Biol. 2020, 1248, 7–32.
114. Finck, B.K.; Linsley, P.S.;Wofsy, D. Treatment of murine lupus with CTLA4Ig. Science 1994, 265, 1225–1227. [CrossRef]
115. Lenschow, D.J.; Herold, K.C.; Rhee, L.; Patel, B.; Koons, A.; Qin, H.Y.; Fuchs, E.; Singh, B.; Thompson, C.B.; Bluestone, J.A.
CD28/B7 regulation of Th1 and Th2 subsets in the development of autoimmune diabetes. Immunity 1996, 5, 285–293. [CrossRef]
116. Kouki, T.; Sawai, Y.; Gardine, C.A.; Fisfalen, M.E.; Alegre, M.L.; DeGroot, L.J. CTLA-4 gene polymorphism at position 49 in
exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease. J. Immunol. 2000, 165,
6606–6611. [CrossRef]
117. Ban, Y.; Davies, T.F.; Greenberg, D.A.; Kissin, A.; Marder, B.; Murphy, B.; Concepcion, E.S.; Villanueva, R.B.; Barbesino, G.; Ling,
V.; et al. Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease. Genes Immun.
2003, 4, 586–593. [CrossRef] [PubMed]
118. Mäurer, M.; Loserth, S.; Kolb-Mäurer, A.; Ponath, A.; Wiese, S.; Kruse, N.; Rieckmann, P. A polymorphism in the human cytotoxic
T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 2002, 54, 1–8. [PubMed]
119. Takara, M.; Kouki, T.; DeGroot, L.J. CTLA-4 AT-repeat polymorphism reduces the inhibitory function of CTLA-4 in Graves’
disease. Thyroid 2003, 13, 1083–1089. [CrossRef] [PubMed]
120. Anjos, S.; Nguyen, A.; Ounissi-Benkalha, H.; Tessier, M.C.; Polychronakos, C. A common autoimmunity predisposing signal
peptide variant of the cytotoxic T-lymphocyte antigen 4 results in inefficient glycosylation of the susceptibility allele. J. Biol. Chem.
2002, 277, 46478–46486. [CrossRef] [PubMed]
121. Linsley, P.S.; Golstein, P. Lymphocyte activation: T-cell regulation by CTLA-4. Curr. Biol. 1996, 6, 398–400. [CrossRef]
122. Bossowski, A.; Stasiak-Barmuta, A.; Urban, M. Relationship between CTLA-4 and CD28 molecule expression on T lymphocytes
and stimulating and blocking autoantibodies to the TSH-receptor in children with Graves’ disease. Horm. Res. 2005, 64, 189–197.
[CrossRef]
123. Vaidya, B.; Pearce, S. The emerging role of the CTLA-4 gene in autoimmune endocrinopathies. Eur. J. Endocrinol. 2004, 150,
619–626. [CrossRef] [PubMed]
124. Kavvoura, F.K.; Akamizu, T.; Awata, T.; Ban, Y.; Chistiakov, D.A.; Frydecka, I.; Ghaderi, A.; Gough, S.C.; Hiromatsu, Y.; Ploski,
R.; et al. Cytotoxic T-lymphocyte associated antigen 4 gene polymorphisms and autoimmune thyroid disease: A meta-analysis.
J. Clin. Endocrinol. Metab. 2007, 92, 3162–3170. [CrossRef] [PubMed]
125. Heward, J.M.; Allahabadia, A.; Armitage, M.; Hattersley, A.; Dodson, P.M.; Macleod, K.; Carr-Smith, J.; Daykin, J.; Daly, A.;
Sheppard, M.C.; et al. The development of Graves’ disease and the CTLA-4 gene on chromosome 2q33. J. Clin. Endocrinol. Metab.
1999, 84, 2398–2401. [CrossRef]
126. Buzzetti, R.; Nisticò, L.; Signore, A.; Cascino, I. CTLA-4 and, H.L. A gene susceptibility to thyroid-associated orbitopathy. Lancet
1999, 354, 1824. [CrossRef]
127. Ikegami, H.; Awata, T.; Kawasaki, E.; Kobayashi, T.; Maruyama, T.; Nakanishi, K.; Shimada, A.; Amemiya, S.; Kawabata, Y.;
Kurihara, S.; et al. The association of CTLA4 polymorphism with type 1 diabetes is concentrated in patients complicated
with autoimmune thyroid disease: A multicenter collaborative study in Japan. J. Clin. Endocrinol. Metab. 2006, 91, 1087–1092.
[CrossRef]
128. Fang, W.; Zhang, Z.; Zhang, J.; Cai, Z.; Zeng, H.; Chen, M.; Huang, J. Association of the CTLA4 gene CT60/rs3087243 singlenucleotide
polymorphisms with Graves’ disease. Biomed. Rep. 2015, 3, 691–696. [CrossRef]
129. Ni, J.; Qiu, L.J.; Zhang, M.; Wen, P.F.; Ye, X.R.; Liang, Y.; Pan, H.F.; Ye, D.Q. CTLA-4 CT60 (rs3087243) polymorphism and
autoimmune thyroid diseases susceptibility: A comprehensive meta-analysis. Endocr. Res. 2014, 39, 180–188. [CrossRef] [PubMed]
130. Huang, F.; He, Q.; Jiao, X.; Zhang, H.; Chang, Q. Meta-Analysis of CTLA-4 +49 Gene Polymorphism and Susceptibility to Graves’
Disease. Crit. Rev. Eukaryot. Gene Expr. 2020, 30, 377–390. [CrossRef]
131. Eriksson, N.; Tung, J.Y.; Kiefer, A.K.; Hinds, D.A.; Francke, U.; Mountain, J.L.; Do, C.B. Novel associations for hypothyroidism
include known autoimmune risk loci. PLoS ONE 2012, 7, e34442. [CrossRef]
132. Zhao, S.X.; Pan, C.M.; Cao, H.M.; Han, B.; Shi, J.Y.; Liang, J.; Gao, G.Q.; Peng, Y.D.; Su, Q.; Chen, J.L.; et al. Association of the
CTLA4 gene with Graves’ disease in the Chinese Han population. PLoS ONE 2010, 5, e9821. [CrossRef] [PubMed]
133. Narooie-Nejad, M.; Taji, O.; Kordi Tamandani, D.M.; Kaykhaei, M.A. Association of CTLA-4 gene polymorphisms -318C/T and
+49A/G and Hashimoto’s thyroidits in Zahedan, Iran. Biomed. Rep. 2017, 6, 108–112. [CrossRef]
134. Xiaoheng, C.; Yizhou, M.; Bei, H.; Huilong, L.; Xin, W.; Rui, H.; Lu, L.; Zhiguo, D. General and Specific Genetic Polymorphism of
Cytokines-Related Gene in AITD. Mediat. Inflamm. 2017, 2017, 3916395. [CrossRef] [PubMed]
135. Mazzieri, A.; Montanucci, P.; Basta, G.; Calafiore, R. The role behind the scenes of Tregs and Th17s in Hashimoto’s thyroiditis:
Toward a pivotal role of FOXP3 and BACH2. Front. Immunol. 2022, 13, 1098243. [CrossRef]
136. Ramirez, R.N.; Chowdhary, K.; Leon, J.; Mathis, D.; Benoist, C. FoxP3 associates with enhancer-promoter loops to regulate
Treg-specific gene expression. Sci. Immunol. 2022, 7, eabj9836.
Cells 2023, 12, 918 30 of 37
137. Lee, M.G.; Bae, S.C.; Lee, Y.H. Association between FOXP3 polymorphisms and susceptibility to autoimmune diseases: A
meta-analysis. Autoimmunity 2015, 48, 445–452. [CrossRef] [PubMed]
138. Tan, G.; Wang, X.; Zheng, G.; Du, J.; Zhou, F.; Liang, Z.; Wei, W.; Yu, H. Meta-analysis reveals significant association between
FOXP3 polymorphisms and susceptibility to Graves’ disease. J. Int. Med. Res. 2021, 49, 3000605211004199. [CrossRef]
139. Li, H.N.; Li, X.R.; Du, Y.Y.; Yang, Z.F.; Lv, Z.T. The Association Between Foxp3 Polymorphisms and Risk of Graves’ Disease: A
Systematic Review and Meta-Analysis of Observational Studies. Front. Endocrinol. 2020, 11, 392. [CrossRef]
140. Kalantar, K.; Khansalar, S.; Eshkevar Vakili, M.; Ghasemi, D.; Dabbaghmanesh, M.H.; Amirghofran, Z. Association of foxp3 gene
variants with risk of hashimoto’s thyroiditis and correlation with anti-tpo antibody levels. Acta Endocrinol. 2019, 15, 423–429.
[CrossRef]
141. Inoue, N.;Watanabe, M.; Morita, M.; Tomizawa, R.; Akamizu, T.; Tatsumi, K.; Hidaka, Y.; Iwatani, Y. Association of functional
polymorphisms related to the transcriptional level of FOXP3 with prognosis of autoimmune thyroid diseases. Clin. Exp. Immunol.
2010, 162, 402–406. [CrossRef]
142. Effraimidis, G.; Wiersinga, W.M. Mechanisms in endocrinology: Autoimmune thyroid disease: Old and new players. Eur. J.
Endocrinol. 2014, 170, R241–R252. [CrossRef]
143. Frommer, L.; Kahaly, G.J. Type 1 Diabetes and Autoimmune Thyroid Disease-The Genetic Link. Front. Endocrinol. 2021, 12, 618213.
[CrossRef]
144. Li, Y.; Li, X.; Geng, X.; Zhao, H. The IL-2A receptor pathway and its role in lymphocyte differentiation and function. Cytokine
Growth Factor Rev. 2022, 67, 66–79. [CrossRef]
145. Damoiseaux, J. The IL-2-IL-2 receptor pathway in health and disease: The role of the soluble IL-2 receptor. Clin. Immunol. 2020,
218, 108515. [CrossRef] [PubMed]
146. Sawicka, B.; Borysewicz-Sa ´ nczyk, H.; Wawrusiewicz-Kurylonek, N.; Aversa, T.; Corica, D.; Go´scik, J.; Kr˛etowski, A.; Wa´sniewska,
M.; Bossowski, A. Analysis of Polymorphisms rs7093069-IL-2RA, rs7138803-FAIM2, and rs1748033-PADI4 in the Group of
Adolescents with Autoimmune Thyroid Diseases. Front. Endocrinol. 2020, 11, 544658. [CrossRef] [PubMed]
147. Cooper, J.D.; Simmonds, M.J.;Walker, N.M.; Burren, O.; Brand, O.J.; Guo, H.;Wallace, C.; Stevens, H.; Coleman, G.;Wellcome
Trust Case Control Consortium; et al. Seven newly identified loci for autoimmune thyroid disease. Hum. Mol. Genet. 2012, 21,
5202–5208. [CrossRef]
148. Chistiakov, D.A.; Chistiakova, E.I.; Voronova, N.V.; Turakulov, R.I.; Savost’anov, K.V. A variant of the Il2ra/Cd25 gene predisposing
to graves’ disease is associated with increased levels of soluble interleukin-2 receptor. Scand. J. Immunol. 2011, 74, 496–501.
[CrossRef]
149. Du, J.;Wang, X.; Tan, G.;Wei,W.; Zhou, F.; Liang, Z.; Li, H.; Yu, H. Predisposition to Graves’ disease and Graves’ ophthalmopathy
by genetic variants of IL2RA. J. Mol. Med. 2021, 99, 1487–1495. [CrossRef]
150. Brand, O.J.; Lowe, C.E.; Heward, J.M.; Franklyn, J.A.; Cooper, J.D.; Todd, J.A.; Gough, S.C. Association of the interleukin-2
receptor alpha (IL-2Ralpha)/CD25 gene region with Graves’ disease using a multilocus test and tag SNPs. Clin. Endocrinol. 2007,
66, 508–512.
151. Song, Z.Y.; Liu, W.; Xue, L.Q.; Pan, C.M.; Wang, H.N.; Gu, Z.H.; Yang, S.Y.; Cao, H.M.; Zuo, C.L.; Zhang, X.N.; et al. Dense
mapping of IL2RA shows no association with Graves’ disease in Chinese Han population. Clin. Endocrinol. 2013, 79, 267–274.
[CrossRef] [PubMed]
152. Borysewicz-Sa´ nczyk, H.; Sawicka, B.; Wawrusiewicz-Kurylonek, N.; Głowi´nska-Olszewska, B.; Kadłubiska, A.; Go´scik, J.;
Szadkowska, A.; Łosiewicz, A.; Młynarski, W.; Kretowski, A.; et al. Genetic Association Study of IL2RA, IFIH1, and CTLA-4
Polymorphisms With Autoimmune Thyroid Diseases and Type 1 Diabetes. Front. Pediatr. 2020, 8, 481. [CrossRef]
153. Kyrgios, I.; Fragou, A.; Kotanidou, E.P.; Mouzaki, K.; Efraimidou, S.; Tzimagiorgis, G.; Galli-Tsinopoulou, A. DNA methylation
analysis within the IL2RA gene promoter in youth with autoimmune thyroid disease. Eur. J. Clin. Investig. 2020, 50, e13199.
[CrossRef] [PubMed]
154. Schuppert, F.; Deiters, S.; Rambusch, E.; Sierralta,W.; Dralle, H.; Mühlen, A.V.Z. TSH-receptor expression and human thyroid
disease: Relation to clinical, endocrine, and molecular thyroid parameters. Thyroid 1996, 6, 575–587. [CrossRef] [PubMed]
155. Szkudlinski, M.W.; Fremont, V.; Ronin, C.; Weintraub, B.D. Thyroid-stimulating hormone and thyroid-stimulating hormone
receptor structure-function relationships. Physiol. Rev. 2002, 82, 473–502. [CrossRef] [PubMed]
156. Chu, Y.D.; Yeh, C.T. The Molecular Function and Clinical Role of Thyroid Stimulating Hormone Receptor in Cancer Cells. Cells
2020, 9, 1730. [CrossRef]
157. Akamizu, T. Antithyrotropin Receptor Antibody: An Update. Thyroid 2001, 11, 1123–1134. [CrossRef]
158. Kleinau, G.;Worth, C.L.; Kreuchwig, A.; Biebermann, H.; Marcinkowski, P.; Scheerer, P.; Krause, G. Structural-Functional Features
of the Thyrotropin Receptor: A Class A G-Protein-Coupled Receptor at Work. Front. Endocrinol. 2017, 8, 86. [CrossRef]
159. Davies, T.F.; Ando, T.; Lin, R.Y.; Tomer, Y.; Latif, R. Thyrotropin receptor-associated diseases: From adenomata to Graves disease.
J. Clin. Investig. 2005, 115, 1972–1983. [CrossRef]
160. Karponis, D.; Ananth, S. The role of thyrostimulin and its potential clinical significance. Endocr. Regul. 2017, 51, 117–128.
[CrossRef]
161. van Zeijl, C.J.; Surovtseva, O.V.; Kwakkel, J.; van Beeren, H.C.; Bassett, J.H.; Williams, G.R.; Wiersinga, W.M.; Fliers, E.; Boelen, A.
Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness. Am. J. Physiol.
Endocrinol. Metab. 2014, 307, E527–E537. [CrossRef]
Cells 2023, 12, 918 31 of 37
162. Sun, S.C.; Hsu, P.J.;Wu, F.J.; Li, S.H.; Lu, C.H.; Luo, C.W. Thyrostimulin, but not thyroid-stimulating hormone (TSH), acts as a
paracrine regulator to activate the TSH receptor in mammalian ovary. J. Biol. Chem. 2010, 285, 3758–3765. [CrossRef]
163. Brand, O.J.; Barrett, J.C.; Simmonds, M.J.; Newby, P.R.; McCabe, C.J.; Bruce, C.K.; Kysela, B.; Carr-Smith, J.D.; Brix, T.; Hunt, P.J.;
et al. Association of the thyroid stimulating hormone receptor gene (TSHR) with Graves’ disease. Hum. Mol. Genet. 2009, 18,
1704–1713. [CrossRef]
164. Liu, L.; Wu, H.Q.; Wang, Q.; Zhu, Y.F.; Zhang, W.; Guan, L.J.; Zhang, J.A. Association between thyroid stimulating hormone
receptor gene intron polymorphisms and autoimmune thyroid disease in a Chinese Han population. Endocr. J. 2012, 59, 717–723.
[CrossRef]
165. Gong, J.; Jiang, S.J.; Wang, D.K.; Dong, H.; Chen, G.; Fang, K.; Cui, J.R.; Lu, F.E. Association of polymorphisms of rs179247
and rs12101255 in thyroid stimulating hormone receptor intron 1 with an increased risk of Graves’ disease: A meta-analysis.
J. Huazhong Univ. Sci. Technol. Med. Sci. 2016, 36, 473–479. [CrossRef] [PubMed]
166. Xiong, H.;Wu, M.; Yi, H.;Wang, X.;Wang, Q.; Nadirshina, S.; Zhou, X.; Liu, X. Genetic associations of the thyroid stimulating
hormone receptor gene with Graves diseases and Graves ophthalmopathy: A meta-analysis. Sci. Rep. 2016, 6, 30356. [CrossRef]
[PubMed]
167. Bufalo, N.E.; Dos Santos, R.B.; Marcello, M.A.; Piai, R.P.; Secolin, R.; Romaldini, J.H.; Ward, L.S. TSHR intronic polymorphisms
(rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves’ disease and Graves’
ophthalmopathy. J. Endocrinol. Investig. 2015, 38, 555–561. [CrossRef] [PubMed]
168. Płoski, R.; Brand, O.J.; Jurecka-Lubieniecka, B.; Franaszczyk, M.; Kula, D.; Krajewski, P.; Karamat, M.A.; Simmonds, M.J.;
Franklyn, J.A.; Gough, S.C.; et al. Thyroid stimulating hormone receptor (TSHR) intron 1 variants are major risk factors for
Graves’ disease in three European Caucasian cohorts. PLoS ONE 2010, 5, e15512. [CrossRef]
169. Qian, W.; Xu, K.; Jia, W.; Lan, L.; Zheng, X.; Yang, X.; Cui, D. Association between TSHR gene polymorphism and the risk of
Graves’ disease: A meta-analysis. J. Biomed. Res. 2016, 30, 466–475.
170. Pujol-Borrell, R.; Giménez-Barcons, M.; Marín-Sánchez, A.; Colobran, R. Genetics of Graves’ Disease: Special Focus on the Role of
TSHR Gene. Horm. Metab. Res. 2015, 47, 753–766. [CrossRef]
171. Pujol-Borrell, R.; Álvarez-Sierra, D.; Jaraquemada, D.; Marín-Sánchez, A.; Colobran, R. Central Tolerance Mechanisms to TSHR in
Graves’ Disease: Contributions to Understand the Genetic Association. Horm. Metab. Res. 2018, 50, 863–870.
172. Marín-Sánchez, A.; Álvarez-Sierra, D.; González, O.; Lucas-Martin, A.; Sellés-Sánchez, A.; Rudilla, F.; Enrich, E.; Colobran, R.;
Pujol-Borrell, R. Regulation of TSHR Expression in the Thyroid and Thymus May Contribute to TSHR Tolerance Failure in Graves’
Disease Patients via Two Distinct Mechanisms. Front. Immunol. 2019, 10, 1695. [CrossRef]
173. Stefan, M.;Wei, C.; Lombardi, A.; Li, C.W.; Concepcion, E.S.; Inabnet,W.B., 3rd; Owen, R.; Zhang,W.; Tomer, Y. Genetic-epigenetic
dysregulation of thymic TSH receptor gene expression triggers thyroid autoimmunity. Proc. Natl. Acad. Sci. USA 2014, 111,
12562–12567. [CrossRef]
174. Coscia, F.; Taler-Verˇciˇc, A.; Chang, V.T.; Sinn, L.; O’Reilly, F.J.; Izoré, T.; Renko, M.; Berger, I.; Rappsilber, J.; Turk, D.; et al. The
structure of human thyroglobulin. Nature 2020, 578, 627–630. [CrossRef]
175. Di Jeso, B.; Arvan, P. Thyroglobulin From Molecular and Cellular Biology to Clinical Endocrinology. Endocr. Rev. 2016, 37, 2–36.
[CrossRef]
176. Vono-Toniolo, J.; Rivolta, C.M.; Targovnik, H.M.; Medeiros-Neto, G.; Kopp, P. Naturally occurring mutations in the thyroglobulin
gene. Thyroid 2005, 15, 1021–1033. [CrossRef] [PubMed]
177. Zhang, X.; Young, C.; Morishita, Y.; Kim, K.; Kabil, O.O.; Clarke, O.B.; Di Jeso, B.; Arvan, P. Defective Thyroglobulin: Cell Biology
of Disease. Int. J. Mol. Sci. 2022, 23, 13605. [CrossRef] [PubMed]
178. Tomer, Y.; Greenberg, D.A.; Concepcion, E.; Ban, Y.; Davies, T.F. Thyroglobulin is a thyroid specific gene for the familial
autoimmune thyroid diseases. J. Clin. Endocrinol. Metab. 2002, 87, 404–407. [CrossRef]
179. Ban, Y.; Tozaki, T.; Taniyama, M.; Tomita, M.; Ban, Y. Association of a thyroglobulin gene polymorphism with Hashimoto’s
thyroiditis in the Japanese population. Clin. Endocrinol. 2004, 61, 263–268. [CrossRef] [PubMed]
180. Hsiao, J.Y.; Hsieh, M.C.; Tien, K.J.; Hsu, S.C.; Lin, S.R.; Ke, D.S. Exon 33 T/T genotype of the thyroglobulin gene is a susceptibility
gene for Graves’ disease in Taiwanese and exon 12 C/C genotype protects against it. Clin. Exp. Med. 2008, 8, 17–21. [CrossRef]
181. Maierhaba, M.; Zhang, J.A.; Yu, Z.Y.; Wang, Y.; Xiao, W.X.; Quan, Y.; Dong, B.N. Association of the thyroglobulin gene
polymorphism with autoimmune thyroid disease in Chinese population. Endocrine 2008, 33, 294–299. [CrossRef]
182. Ban, Y.; Tozaki, T.; Taniyama, M.; Skrabanek, L.; Nakano, Y.; Ban, Y.; Hirano, T. Multiple SNPs in intron 41 of thyroglobulin gene
are associated with autoimmune thyroid disease in the Japanese population. PLoS ONE 2012, 7, e37501. [CrossRef]
183. Wang, L.Q.; Wang, T.Y.; Sun, Q.L.; Qie, Y.Q. Correlation between thyroglobulin gene polymorphisms and autoimmune thyroid
disease. Mol. Med. Rep. 2015, 12, 4469–4475. [CrossRef]
184. Lahooti, H.; Edirimanne, S.;Walsh, J.P.; Delbridge, L.; Hibbert, E.J.;Wall, J.R. Single nucleotide polymorphism 1623 A/G (rs180195)
in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy.
Clin. Ophthalmol. 2017, 11, 1337–1345. [CrossRef] [PubMed]
185. Mizuma, T.; Watanabe, M.; Inoue, N.; Arakawa, Y.; Tomari, S.; Hidaka, Y.; Iwatani, Y. Association of the polymorphisms in
the gene encoding thyroglobulin with the development and prognosis of autoimmune thyroid disease. Autoimmunity 2017, 50,
386–392. [CrossRef] [PubMed]
Cells 2023, 12, 918 32 of 37
186. Zhang, M.L.; Zhang, D.M.;Wang, C.E.; Chen, X.L.; Liu, F.Z.; Yang, J.X. Association between thyroglobulin polymorphisms and
autoimmune thyroid disease: A systematic review and meta-analysis of case-control studies. Genes Immun. 2019, 20, 484–492.
[CrossRef] [PubMed]
187. Latrofa, F.; Fiore, E.; Rago, T.; Antonangeli, L.; Montanelli, L.; Ricci, D.; Provenzale, M.A.; Scutari, M.; Frigeri, M.; Tonacchera, M.;
et al. Iodine contributes to thyroid autoimmunity in humans by unmasking a cryptic epitope on thyroglobulin. J. Clin. Endocrinol.
Metab. 2013, 98, E1768–E1774. [CrossRef]
188. Dai, Y.D.; Rao, V.P.; Carayanniotis, G. Enhanced iodination of thyroglobulin facilitates processing and presentation of a cryptic
pathogenic peptide. J. Immunol. 2002, 168, 5907–5911. [CrossRef]
189. Williams, D.E.; Le, S.N.; Godlewska, M.; Hoke, D.E.; Buckle, A.M. Thyroid Peroxidase as an Autoantigen in Hashimoto’s Disease:
Structure, Function, and Antigenicity. Horm. Metab. Res. 2018, 50, 908–921. [CrossRef]
190. Le, S.N.; Porebski, B.T.; McCoey, J.; Fodor, J.; Riley, B.; Godlewska, M.; Góra, M.; Czarnocka, B.; Banga, J.P.; Hoke, D.E.; et al.
Modelling of Thyroid Peroxidase Reveals Insights into Its Enzyme Function and Autoantigenicity. PLoS ONE 2015, 10, e0142615.
[CrossRef]
191. Faam, B.; Daneshpour, M.S.; Azizi, F.; Salehi, M.; Hedayati, M. Association between TPO gene polymorphisms and Anti-TPO
level in Tehranian population: TLGS. Gene 2012, 498, 116–119. [CrossRef]
192. Balmiki, N.; Bankura, B.; Guria, S.; Das, T.K.; Pattanayak, A.K.; Sinha, A.; Chakrabarti, S.; Chowdhury, S.; Das, M. Genetic analysis
of thyroid peroxidase (TPO) gene in patients whose hypothyroidism was found in adulthood inWest Bengal, India. Endocr. J.
2014, 61, 289–296. [CrossRef] [PubMed]
193. Brˇci´c, L.; Bari´c, A.; Graˇcan, S.; Brdar, D.; Torlak Lovri´c, V.; Vidan, N.; Zemunik, T.; Polašek, O.; Barbali´c, M.; Punda, A.; et al.
Association of established thyroid peroxidase autoantibody (TPOAb) genetic variants with Hashimoto’s thyroiditis. Autoimmunity
2016, 49, 480–485. [CrossRef]
194. Tomari, S.; Watanabe, M.; Inoue, N.; Mizuma, T.; Yamanaka, C.; Hidaka, Y.; Iwatani, Y. The polymorphisms in the thyroid
peroxidase gene were associated with the development of autoimmune thyroid disease and the serum levels of anti-thyroid
peroxidase antibody. Endocr. J. 2017, 64, 1025–1032. [CrossRef] [PubMed]
195. Khoshi, A.; Sirghani, A.; Ghazisaeedi, M.; Mahmudabadi, A.Z.; Azimian, A. Association between TPO. Asn698Thr and Thr725Pro
gene polymorphisms and serum anti-TPO levels in Iranian patients with subclinical hypothyroidism. Hormones 2017, 16, 75–83.
196. Ahmed, H.S.; Nsrallah, A.A.M.; Abdel-Fatah, A.H.; Mahmoud, A.A.; Fikry, A.A. Association of Thyroid Peroxidase Gene
Polymorphisms and Serum Anti- TPO Levels in Egyptian Patients with Autoimmune Hypothyroidism. Endocr. Metab. Immune
Disord. Drug Targets 2021, 21, 734–742. [CrossRef] [PubMed]
197. Medici, M.; Porcu, E.; Pistis, G.; Teumer, A.; Brown, S.J.; Jensen, R.A.; Rawal, R.; Roef, G.L.; Plantinga, T.S.; Vermeulen, S.H.; et al.
Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease. PLoS Genet. 2014,
10, e1004123. [CrossRef]
198. Simmonds, M.J.; Heward, J.M.; Carr-Smith, J.; Foxall, H.; Franklyn, J.A.; Gough, S.C. Contribution of single nucleotide polymorphisms
within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves’ disease. J. Clin. Endocrinol. Metab. 2006, 91, 1056–1061.
[CrossRef]
199. Fang, Y.; Li, Y.; Zeng, J.; Wang, J.; Liu, R.; Cao, C. Genetic association of Fc receptor-like glycoprotein with susceptibility to Graves’
disease in a Chinese Han population. Immunobiology 2016, 221, 56–62. [CrossRef] [PubMed]
200. Bari´c, A.; Brˇci´c, L.; Graˇcan, S.; Torlak Lovri´c, V.; Gunjaˇca, I.; Šimunac, M.; Brekalo, M.; Boban, M.; Polašek, O.; Barbali´c, M.; et al.
Association of established hypothyroidism-associated genetic variants with Hashimoto’s thyroiditis. J. Endocrinol. Invest. 2017, 40,
1061–1067. [CrossRef]
201. Zaaber, I.; Mestiri, S.; Hammedi, H.; Marmouch, H.; Mahjoub, S.; Tensaout, B.B.; Said, K. Association of Interleukin-1B and
Interleukin-4 Gene Variants with Autoimmune Thyroid Diseases in Tunisian Population. Immunol. Investig. 2016, 45, 284–297.
[CrossRef]
202. Heidari, Z.; Salimi, S.; Rokni, M.; Rezaei, M.; Khalafi, N.; Shahroudi, M.J.; Dehghan, A.; Saravani, M. Association of IL-1 , NLRP3,
and COX-2 Gene Polymorphisms with Autoimmune Thyroid Disease Risk and Clinical Features in the Iranian Population.
Biomed. Res. Int. 2021, 2021, 7729238. [CrossRef] [PubMed]
203. Blakemore, A.I.; Watson, P.F.; Weetman, A.P.; Duff, G.W. Association of Graves’ disease with an allele of the interleukin-1 receptor
antagonist gene. J. Clin. Endocrinol. Metab. 1995, 80, 111–115.
204. Mühlberg, T.; Kirchberger, M.; Spitzweg, C.; Herrmann, F.; Heberling, H.J.; Heufelder, A.E. Lack of association of Graves’ disease
with the A2 allele of the interleukin-1 receptor antagonist gene in a white European population. Eur. J. Endocrinol. 1998, 138,
686–690. [CrossRef]
205. Kammoun-Krichen, M.; Bougacha-Elleuch, N.; Makni, K.; Mnif, M.; Jouida, J.; Abid, M.; Rebai, A.; Ayadi, H. A potential role of
TNFR gene polymorphisms in autoimmune thyroid diseases in the Tunisian population. Cytokine 2008, 43, 110–113. [CrossRef]
206. Ito, C.; Watanabe, M.; Okuda, N.; Watanabe, C.; Iwatani, Y. Association between the severity of Hashimoto’s disease and the
functional +874A/T polymorphism in the interferon-gamma gene. Endocr. J. 2006, 53, 473–478. [CrossRef]
207. Okada, Y.; Terao, C.; Ikari, K.; Kochi, Y.; Ohmura, K.; Suzuki, A.; Kawaguchi, T.; Stahl, E.A.; Kurreeman, F.A.; Nishida, N.; et al.
Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population. Nat. Genet. 2012, 44,
511–516. [CrossRef] [PubMed]
Cells 2023, 12, 918 33 of 37
208. Tomer, Y.; Hasham, A.; Davies, T.F.; Stefan, M.; Concepcion, E.; Keddache, M.; Greenberg, D.A. Fine mapping of loci linked to
autoimmune thyroid disease identifies novel susceptibility genes. J. Clin. Endocrinol. Metab. 2013, 98, E144–E152. [CrossRef]
209. Lin, J.D.; Wang, Y.H.; Fang, W.F.; Hsiao, C.J.; Chagnaadorj, A.; Lin, Y.F.; Tang, K.T.; Cheng, C.W.; Serum, B.A. FF and thyroid
autoantibodies in autoimmune thyroid disease. Clin. Chim. Acta. 2016, 462, 96–102. [CrossRef]
210. Lin, J.D.; Yang, S.F.; Wang, Y.H.; Fang, W.F.; Lin, Y.C.; Lin, Y.F.; Tang, K.T.; Wu, M.Y.; Cheng, C.W. Analysis of Associations of
Human BAFF Gene Polymorphisms with Autoimmune Thyroid Diseases. PLoS ONE 2016, 11, e0154436. [CrossRef]
211. Lane, L.C.; Allinson, K.R.; Campbell, K.; Bhatnagar, I.; Ingoe, L.; Razvi, S.; Cheetham, T.; Cordell, H.J.; Pearce, S.H.; Mitchell, A.L.
Analysis of BAFF gene polymorphisms in UK Graves’ disease patients. Clin. Endocrinol. 2019, 90, 170–174. [CrossRef] [PubMed]
212. Jungel, A.; Ospelt, C.; Gay, S. What can we learn from epigenetics in the year 2009? Curr. Opin. Rheumatol. 2010, 22, 284–292.
[CrossRef] [PubMed]
213. Yan, N.; Mu, K.; An, X.F.; Li, L.; Qin, Q.; Song, R.H.; Yao, Q.M.; Shao, X.Q.; Zhang, J.A. Aberrant Histone Methylation in Patients
with Graves’ Disease. Int. J. Endocrinol. 2019, 2019, 1454617. [CrossRef] [PubMed]
214. Coppedè, F. Epigenetics and Autoimmune Thyroid Diseases. Front. Endocrinol. 2017, 8, 149. [CrossRef] [PubMed]
215. Zhou, F.; Wang, X.; Wang, L.; Sun, X.; Tan, G.; Wei, W.; Zheng, G.; Ma, X.; Tian, D.; Yu, H. Genetics, Epigenetics, Cellular
Immunology, and Gut Microbiota: Emerging Links With Graves’ Disease. Front. Cell. Dev. Biol. 2022, 9, 794912. [CrossRef]
[PubMed]
216. Karagianni, P.; Tzioufas, A.G. Epigenetic Perspectives on Systemic Autoimmune Disease. J. Autoimmun. 2019, 104, 102315.
[CrossRef]
217. Santiwatana, S.; Mahachoklertwattana, P.; Limwongse, C.; Khlairit, P.; Pongratanakul, S.; Roothumnong, E.; Prangphan, K.;
Choubtum, L.; Songdej, D.; Poomthavorn, P. Skewed X chromosome inactivation in girls and female adolescents with autoimmune
thyroid disease. Clin. Endocrinol. 2018, 89, 863–869. [CrossRef]
218. Simmonds, M.J.; Kavvoura, F.K.; Brand, O.J.; Newby, P.R.; Jackson, L.E.; Hargreaves, C.E.; Franklyn, J.A.; Gough, S.C. Skewed X
chromosome inactivation and female preponderance in autoimmune thyroid disease: An association study and meta-analysis.
J. Clin. Endocrinol. Metab. 2014, 99, E127–E131. [CrossRef]
219. Arakawa, Y.;Watanabe, M.; Inoue, N.; Sarumaru, M.; Hidaka, Y.; Iwatani, Y. Association of polymorphisms in DNMT1, DNMT3A,
DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clin.
Exp. Immunol. 2012, 170, 194–201. [CrossRef]
220. Sarumaru, M.; Watanabe, M.; Inoue, N.; Hisamoto, Y.; Morita, E.; Arakawa, Y.; Hidaka, Y.; Iwatani, Y. Association between
functional, S.I.RT1 polymorphisms and the clinical characteristics of patients with autoimmune thyroid disease. Autoimmunity
2016, 49, 329–337. [CrossRef]
221. Yang, H.; Lee, S.M.; Gao, B.; Zhang, J.; Fang, D. Histone deacetylase sirtuin 1 deacetylates IRF1 protein and programs dendritic
cells to control Th17 protein differentiation during autoimmune inflammation. J. Biol. Chem. 2013, 288, 37256–37266. [CrossRef]
222. Liu, T.; Sun, J.; Wang, Z.; Yang, W.; Zhang, H.; Fan, C.; Shan, Z.; Teng, W. Changes in the DNA Methylation and Hydroxymethylation
Status of the Intercellular Adhesion Molecule 1 Gene Promoter in Thyrocytes from Autoimmune Thyroiditis Patients. Thyroid
2017, 27, 838–845. [CrossRef] [PubMed]
223. Yan, N.; Zhou, J.Z.; Zhang, J.A.; Cai, T.; Zhang, W.; Wang, Y.; Muhali, F.S.; Guan, L.; Song, R.H. Histone hypoacetylation and
increased histone deacetylases in peripheral blood mononuclear cells from patients with Graves’ disease. Mol. Cell. Endocrinol.
2015, 414, 143–147. [CrossRef] [PubMed]
224. Chen, J.Q.; Papp, G.; Szodoray, P.; Zeher, M. The role of microRNAs in the pathogenesis of autoimmune diseases. Autoimmun.
Rev. 2016, 15, 1171–1180. [CrossRef]
225. Seddiki, N.; Brezar, V.; Ruffin, N.; Levy, Y.; Swaminathan, S. Role of miR-155 in the regulation of lymphocyte immune function
and disease. Immunology 2014, 142, 32–38. [CrossRef]
226. Cai, T.T.; Muhali, F.S.; Song, R.H.; Qin, Q.; Wang, X.; Shi, L.F.; Jiang, W.J.; Xiao, L.; Li, D.F.; Zhang, J.A. Genome-wide DNA
methylation analysis in Graves’ disease. Genomics 2015, 105, 204–210. [CrossRef]
227. Limbach, M.; Saare, M.; Tserel, L.; Kisand, K.; Eglit, T.; Sauer, S.; Axelsson, T.; Syvänen, A.C.; Metspalu, A.; Milani, L.; et al.
Epigenetic profiling in CD4+ and CD8+ T cells from Graves’ disease patients reveals changes in genes associated with T cell
receptor signaling. J. Autoimmun. 2016, 67, 46–56. [CrossRef] [PubMed]
228. Li, K.; Du, Y.; Jiang, B.L.; He, J.F. Increased microRNA-155 and decreased microRNA-146a may promote ocular inflammation and
proliferation in Graves’ ophthalmopathy. Med. Sci. Monit. 2014, 20, 639–643.
229. Wei, H.; Guan, M.; Qin, Y.; Xie, C.; Fu, X.; Gao, F.; Xue, Y. Circulating levels of miR-146a and IL-17 are significantly correlated
with the clinical activity of Graves’ ophthalmopathy. Endocr. J. 2014, 61, 1087–1092. [CrossRef]
230. Luty, J.; Ruckemann-Dziurdzi ´ nska, K.; Witkowski, J.M.; Bryl, E. Immunological aspects of autoimmune thyroid disease-Complex
interplay between cells and cytokines. Cytokine 2019, 116, 128–133. [CrossRef]
231. Li, Q.; Wang, B.; Mu, K.; Zhang, J.A. The pathogenesis of thyroid autoimmune diseases: New T lymphocytes-Cytokines circuits
beyond the Th1-Th2 paradigm. J. Cell. Physiol. 2019, 234, 2204–2216. [CrossRef]
232. Bargiel, P.; Szczuko, M.; Stachowska, L.; Prowans, P.; Czapla, N.; Markowska, M.; Petriczko, J.; Kledzik, J.; J˛edrzejczyk-Kledzik,
A.; Palma, J.; et al. Microbiome Metabolites and Thyroid Dysfunction. J. Clin. Med. 2021, 10, 3609. [CrossRef]
233. Benvenga, S.; Guarneri, F. Molecular mimicry and autoimmune thyroid disease. Rev. Endocr. Metab. Disord. 2016, 17, 485–498.
[CrossRef]
Cells 2023, 12, 918 34 of 37
234. Hou, Y.; Sun, W.; Zhang, C.; Wang, T.; Guo, X.; Wu, L.; Qin, L.; Liu, T. Meta-analysis of the correlation between Helicobacter
pylori infection and autoimmune thyroid diseases. Oncotarget 2017, 8, 115691–115700. [CrossRef]
235. Choi, Y.M.; Kim, T.Y.; Kim, E.Y.; Jang, E.K.; Jeon, M.J.; Kim, W.G.; Shong, Y.K.; Kim, W.B. Association between thyroid
autoimmunity and Helicobacter pylori infection. Korean J. Intern. Med. 2017, 32, 309–313. [CrossRef]
236. Wang, L.; Cao, Z.M.; Zhang, L.L.; Dai, X.C.; Liu, Z.J.; Zeng, Y.X.; Li, X.Y.; Wu, Q.J.; Lv, W.L. Helicobacter Pylori and Autoimmune
Diseases: Involving Multiple Systems. Front. Immunol. 2022, 13, 833424. [CrossRef] [PubMed]
237. Jadali, Z. Autoimmune thyroid disorders in hepatitis C virus infection: Effect of interferon therapy. Indian J. Endocrinol. Metab.
2013, 17, 69–75. [CrossRef] [PubMed]
238. Dalgard, O.; Bjøro, K.; Hellum, K.; Myrvang, B.; Bjøro, T.; Haug, E.; Bell, H. Thyroid dysfunction during treatment of chronic
hepatitis C with interferon alpha: No association with either interferon dosage or efficacy of therapy. J. Intern. Med. 2002, 251,
400–406. [CrossRef] [PubMed]
239. Wasserman, E.E.; Nelson, K.; Rose, N.R.; Rhode, C.; Pillion, J.P.; Seaberg, E.; Talor, M.V.; Burek, L.; Eaton, W.; Duggan, A.;
et al. Infection and thyroid autoimmunity: A seroepidemiologic study of TPOaAb. Autoimmunity 2009, 42, 439–446. [CrossRef]
[PubMed]
240. Tozzoli, R.; Barzilai, O.; Ram, M.; Villalta, D.; Bizzaro, N.; Sherer, Y.; Shoenfeld, Y. Infections and autoimmune thyroid diseases:
Parallel detection of antibodies against pathogens with proteomic technology. Autoimmun. Rev. 2008, 8, 112–115. [CrossRef]
241. Micali, C.; Russotto, Y.; Celesia, B.M.; Santoro, L.; Marino, A.; Pellicanò, G.F.; Nunnari, G.; Venanzi Rullo, E. Thyroid Diseases and
Thyroid Asymptomatic Dysfunction in People Living with HIV. Infect. Dis. Rep. 2022, 14, 655–667. [CrossRef]
242. Nagata, K.; Nakayama, Y.; Higaki, K.; Ochi, M.; Kanai, K.; Matsushita, M.; Kuwamoto, S.; Kato, M.; Murakami, I.; Iwasaki, T.; et al.
Reactivation of persistent Epstein-Barr virus (EBV) causes secretion of thyrotropin receptor antibodies (TRAbs) in EBV-infected B
lymphocytes with, T.R.Abs on their surface. Autoimmunity 2015, 48, 328–335. [CrossRef]
243. Houen, G.; Trier, N.H. Epstein-Barr Virus and Systemic Autoimmune Diseases. Front. Immunol. 2021, 11, 587380. [CrossRef]
[PubMed]
244. Murugan, A.K.; Alzahrani, A.S. SARS-CoV-2, Emerging Role in the Pathogenesis of Various Thyroid Diseases. J. Inflamm. Res.
2021, 14, 6191–6221. [CrossRef] [PubMed]
245. Naguib, R. Potential relationships between COVID-19 and the thyroid gland: An update. J. Int. Med. Res. 2022, 50, 3000605221082898.
[CrossRef]
246. Zangiabadian, M.; Mirsaeidi, M.; Pooyafar, M.H.; Goudarzi, M.; Nasiri, M.J. Associations of Yersinia Enterocolitica Infection with
Autoimmune Thyroid Diseases: A Systematic Review and Meta-Analysis. Endocr. Metab. Immune Disord. Drug Targets 2021, 21,
682–687. [CrossRef]
247. Corapçio˘ glu, D.; Tonyukuk, V.; Kiyan, M.; Yilmaz, A.E.; Emral, R.; Kamel, N.; Erdo˘gan, G. Relationship between thyroid
autoimmunity and Yersinia enterocolitica antibodies. Thyroid 2002, 12, 613–617. [CrossRef]
248. Benvenga, S.; Guarneri, F.; Vaccaro, M.; Santarpia, L.; Trimachi, F. Homologies between proteins of borrelia burgdorferi and
thyroid autoantigens. Thyroid 2004, 14, 964–966. [CrossRef] [PubMed]
249. Jin, H.Y.; Kang, S.M.; Kim, S.Y.; Park, J.H.; Baek, H.S. Park TS A case of Graves’ disease combined with hantaan virus infection.
J. Korean Med. Sci. 2009, 24, 158–161. [CrossRef]
250. Mäkelä, S.; Jaatinen, P.; Miettinen, M.; Salmi, J.; Ala-Houhala, I.; Huhtala, H.; Hurme, M.; Pörsti, I.; Vaheri, A.; Mustonen, J.
Hormonal deficiencies during and after Puumala hantavirus infection. Eur. J. Clin. Microbiol. Infect. Dis. 2010, 29, 705–713.
[CrossRef]
251. Mankai, A.; Thabet, Y.; Manoubi, W.; Achour, A.; Sakly, W.; Ghedira, I. Anti-Saccharomyces cerevisiae antibodies are elevated in
Graves’ diseases but not in Hashimoto’s thyroiditis. Endocr. Res. 2013, 38, 98–104. [CrossRef]
252. Yazıcı, D.; Aydın, S.Z.; Yavuz, D.; Tarçın, O.; Deyneli, O.; Direskeneli, H.; Akalın, S. Anti-Saccaromyces Cerevisiae antibodies
(ASCA) are elevated in autoimmune thyroid disease, A.S.CA in autoimmune thyroid disease. Endocrine 2010, 38, 194–198.
[CrossRef]
253. Gong, B.; Wang, C.; Meng, F.; Wang, H.; Song, B.; Yang, Y.; Shan, Z. Association Between Gut Microbiota and Autoimmune
Thyroid Disease: A Systematic Review and Meta-Analysis. Front. Endocrinol. 2021, 12, 774362. [CrossRef] [PubMed]
254. Zhao, H.; Yuan, L.; Zhu, D.; Sun, B.; Du, J.; Wang, J. Alterations and Mechanism of Gut Microbiota in Graves’ Disease and
Hashimoto’s Thyroiditis. Pol. J. Microbiol. 2022, 71, 173–189. [CrossRef]
255. Rayman, M. Multiple nutritional factors and thyroid disease, with particular reference to autoimmune thyroid disease. Proc. Nutr.
Soc. 2019, 78, 34–44. [CrossRef] [PubMed]
256. Zhang, H.Y.; Teng, X.C.; Shan, Z.Y.; Wang, Z.J.; Li, C.Y.; Yu, X.H.; Mao, J.Y.; Wang, W.W.; Xie, X.C.; Teng, W.P. Association
between iron deficiency and prevalence of thyroid autoimmunity in pregnant and non-pregnant women of childbearing age: A
cross-sectional study. Chin. Med. J. 2019, 132, 2143–2149. [CrossRef]
257. Vargas-Uricoechea, H.; Pinzón-Fernández, M.V.; Bastidas-Sánchez, B.E.; Jojoa-Tobar, E.; Ramírez-Bejarano, L.E.; Murillo-Palacios,
J. Iodine Status in the Colombian Population and the Impact of Universal Salt Iodization: A Double-Edged Sword? J. Nutr. Metab.
2019, 2019, 6239243. [CrossRef] [PubMed]
258. Luo, Y.; Kawashima, A.; Ishido, Y.; Yoshihara, A.; Oda, K.; Hiroi, N.; Ito, T.; Ishii, N.; Suzuki, K. Iodine excess as an environmental
risk factor for autoimmune thyroid disease. Int. J. Mol. Sci. 2014, 15, 12895–12912. [CrossRef] [PubMed]
Cells 2023, 12, 918 35 of 37
259. Vargas-Uricoechea, H.; Mera-Mamian, A.; Bastidas-Sanchez, B.; Pinzon-Fernandez, M.; Murillo-Palacios, J.; Ramirez-Bejarano, L.
Population Status of Iodine and Its Potential Effects on Thyroid Function and Autoimmunity in Southwestern Colombia. J. Clin.
Med. Res. 2022, 14, 126–135. [CrossRef]
260. Huang, Z.; Rose, A.H.; Hoffmann, P.R. The role of selenium in inflammation and immunity: From molecular mechanisms to
therapeutic opportunities. Antioxid. Redox Signal. 2012, 16, 705–743. [CrossRef]
261. Ferrari, S.M.; Fallahi, P.; Antonelli, A.; Benvenga, S. Environmental Issues in Thyroid Diseases. Front. Endocrinol. 2017, 8, 50.
[CrossRef]
262. Vargas-Uricoechea, H.; Bastidas, B.; Pinzón, M.V. Population status of selenium in Colombia and associated factors: A crosssectional
study. Horm. Mol. Biol. Clin. Investig. 2022. [CrossRef] [PubMed]
263. Tamer, G.; Arik, S.; Tamer, I.; Coksert, D. Relative vitamin D insufficiency in Hashimoto’s thyroiditis. Thyroid 2011, 21, 891–896.
[CrossRef] [PubMed]
264. Wang, J.; Lv, S.; Chen, G.; Gao, C.; He, J.; Zhong, H.; Xu, Y. Meta-analysis of the association between vitamin D and autoimmune
thyroid disease. Nutrients 2015, 7, 2485–2498. [CrossRef]
265. Ashok, T.; Patni, N.; Fatima, M.; Lamis, A.; Siddiqui, S.W. Celiac Disease and Autoimmune Thyroid Disease: The Two Peas in a
Pod. Cureus 2022, 14, e26243. [CrossRef]
266. Naiyer, A.J.; Shah, J.; Hernandez, L.; Kim, S.Y.; Ciaccio, E.J.; Cheng, J.; Manavalan, S.; Bhagat, G.; Green, P.H. Tissue transglutaminase
antibodies in individuals with celiac disease bind to thyroid follicles and extracellular matrix and may contribute to thyroid
dysfunction. Thyroid 2008, 18, 1171–1178. [CrossRef] [PubMed]
267. Brent, G.A. Environmental exposures and autoimmune thyroid disease. Thyroid 2010, 20, 755–761. [CrossRef]
268. Shukla, S.K.; Singh, G.; Ahmad, S.; Pant, P. Infections, genetic and environmental factors in pathogenesis of autoimmune thyroid
diseases. Microb. Pathog. 2018, 116, 279–288. [CrossRef]
269. Benvenga, S.; Elia, G.; Ragusa, F.; Paparo, S.R.; Sturniolo, M.M.; Ferrari, S.M.; Antonelli, A.; Fallahi, P. Endocrine disruptors and
thyroid autoimmunity. Best Pract. Res. Clin. Endocrinol. Metab. 2020, 34, 101377. [CrossRef]
270. Benvenga, S.; Vigo, M.T.; Metro, D.; Granese, R.; Vita, R.; Le Donne, M. Type of fish consumed and thyroid autoimmunity in
pregnancy and postpartum. Endocrine 2016, 52, 120–129. [CrossRef]
271. Tajtáková, M.; Semanová, Z.; Tomková, Z.; Szökeová, E.; Majoros, J.; Rádiková, Z.; Seböková, E.; Klimes, I.; Langer, P. Increased
thyroid volume and frequency of thyroid disorders signs in schoolchildren from nitrate polluted area. Chemosphere 2006, 62,
559–564. [CrossRef]
272. Colucci, R.; Lotti, F.; Arunachalam, M.; Lotti, T.; Dragoni, F.; Benvenga, S.; Moretti, S. Correlation of Serum Thyroid Hormones
Autoantibodies with Self-Reported Exposure to Thyroid Disruptors in a Group of Nonsegmental Vitiligo Patients. Arch. Environ.
Contam. Toxicol. 2015, 69, 181–190. [CrossRef]
273. de Freitas, C.U.; Grimaldi Campos, R.A.; Rodrigues Silva, M.A.; Panachão, M.R.; de Moraes, J.C.;Waissmann,W.; Roberto Chacra,
A.; Maeda, M.Y.; Minazzi Rodrigues, R.S.; Gonçalves Belchor, J.; et al. Can. living in the surroundings of a petrochemical complex
be a risk factor for autoimmune thyroid disease? Environ. Res. 2010, 110, 112–117. [CrossRef]
274. Freire, C.; Koifman, R.J.; Sarcinelli, P.N.; Simões Rosa, A.C.; Clapauch, R.; Koifman, S. Long-term exposure to organochlorine
pesticides and thyroid status in adults in a heavily contaminated area in Brazil. Environ. Res. 2013, 127, 7–15. [CrossRef] [PubMed]
275. Schell, L.M.; Gallo, M.V.; Ravenscroft, J.; DeCaprio, A.P. Persistent organic pollutants and anti-thyroid peroxidase levels in
Akwesasne Mohawk young adults. Environ. Res. 2009, 109, 86–92. [CrossRef] [PubMed]
276. Langer, P.; Tajtáková, M.; Fodor, G.; Kocan, A.; Bohov, P.; Michálek, J.; Kreze, A. Increased thyroid volume and prevalence of
thyroid disorders in an area heavily polluted by polychlorinated biphenyls. Eur. J. Endocrinol. 1998, 139, 402–409. [CrossRef]
[PubMed]
277. Fallahi, P.; Foddis, R.; Elia, G.; Ragusa, F.; Patrizio, A.; Frenzilli, G.; Benvenga, S.; Cristaudo, A.; Antonelli, A.; Ferrari, S.M.
Differential modulation by vanadium pentoxide of the secretion of CXCL8 and CXCL11 chemokines in thyroid cells. Mol. Med.
Rep. 2018, 17, 7415–7420. [CrossRef] [PubMed]
278. Fallahi, P.; Foddis, R.; Elia, G.; Ragusa, F.; Patrizio, A.; Benvenga, S.; Cristaudo, A.; Antonelli, A.; Ferrari, S.M. Vanadium
pentoxide induces the secretion of CXCL9 and CXCL10 chemokines in thyroid cells. Oncol. Rep. 2018, 39, 2422–2426. [CrossRef]
279. Babi´c Leko, M.; Gunjaˇca, I.; Plei´c, N.; Zemunik, T. Environmental Factors Affecting Thyroid-Stimulating Hormone and Thyroid
Hormone Levels. Int. J. Mol. Sci. 2021, 22, 6521. [CrossRef]
280. Vestergaard, P. Smoking and thyroid disorders- a meta-analysis. Eur. J. Endocrinol. 2002, 146, 153–161. [CrossRef]
281. Attard, C.C.; Sze, W.C.C.; Vella, S. Predictors of autoimmune thyroid disease. Proc. Bayl. Univ. Med. Cent. 2022, 35, 608–614.
[CrossRef]
282. Fukayama, H.; Nasu, M.; Murakami, S.; Sugawara, M. Examination of antithyroid effects of smoking products in cultured thyroid
follicles: Only thiocyanate is a potent antithyroid agent. Acta Endocrinol. 1992, 127, 520–525. [CrossRef] [PubMed]
283. Carlé, A.; Pedersen, I.B.; Knudsen, N.; Perrild, H.; Ovesen, L.; Rasmussen, L.B.; Jørgensen, T.; Laurberg, P. Moderate alcohol
consumption may protect against overt autoimmune hypothyroidism: A population-based case-control study. Eur. J. Endocrinol.
2012, 167, 483–490. [CrossRef]
284. Effraimidis, G.; Tijssen, J.G.;Wiersinga,W.M. Alcohol consumption as a risk factor for autoimmune thyroid disease: A prospective
study. Eur. Thyroid J. 2012, 1, 99–104. [CrossRef]
Cells 2023, 12, 918 36 of 37
285. Carlé, A.; Bülow Pedersen, I.; Knudsen, N.; Perrild, H.; Ovesen, L.; Rasmussen, L.B.; Jørgensen, T.; Laurberg, P. Graves’
hyperthyroidism and moderate alcohol consumption: Evidence for disease prevention. Clin. Endocrinol. 2013, 79, 111–119.
[CrossRef]
286. Caslin, B.; Mohler, K.; Thiagarajan, S.; Melamed, E. Alcohol. as friend or foe in autoimmune diseases: A role for gut microbiome?
Gut Microbes 2021, 13, 1916278. [CrossRef]
287. Mizokami, T.; Wu Li, A.; El-Kaissi, S.; Wall, J.R. Stress and thyroid autoimmunity. Thyroid 2004, 14, 1047–1055. [CrossRef]
[PubMed]
288. Vonk, R.; van der Schot, A.C.; Kahn, R.S.; Nolen, W.A.; Drexhage, H.A. Is autoimmune thyroiditis part of the genetic vulnerability
(or an endophenotype) for bipolar disorder? Biol. Psychiatry 2007, 62, 135–140. [CrossRef]
289. Yang, W.; Qu, M.; Jiang, R.; Lang, X.; Zhang, X.Y. Association between thyroid function and comorbid anxiety in first-episode and
drug naïve patients with major depressive disorder. Eur. Arch. Psychiatry Clin. Neurosci. 2023, 273, 191–198. [CrossRef]
290. Bogazzi, F.; Tomisti, L.; Bartalena, L.; Aghini-Lombardi, F.; Martino, E. Amiodarone and the thyroid: A 2012 update. J. Endocrinol.
Investig. 2012, 35, 340–348. [PubMed]
291. Lazarus, J.H. Lithium and thyroid. Best. Pract. Res. Clin. Endocrinol. Metab. 2009, 23, 723–733. [CrossRef] [PubMed]
292. Rotondi, M.; Lazzeri, E.; Romagnani, P.; Serio, M. Role for interferon-gamma inducible chemokines in endocrine autoimmunity:
An expanding field. J. Endocrinol. Investig. 2003, 26, 177–180. [CrossRef] [PubMed]
293. Duntas, L.H. Environmental factors and thyroid autoimmunity. Ann. Endocrinol. 2011, 72, 108–113. [CrossRef] [PubMed]
294. Khosrotehrani, K.; Johnson, K.L.; Cha, D.H.; Salomon, R.N.; Bianchi, D.W. Transfer of fetal cells with multilineage potential to
maternal tissue. J. Am. Med. Assoc. 2004, 292, 75–80. [CrossRef] [PubMed]
295. O’Donoghue, K.; Chan, J.; de la Fuente, J.; Kennea, N.; Sandison, A.; Anderson, J.R.; Roberts, I.A.; Fisk, N.M. Microchimerism in
female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy. Lancet 2004, 364, 179–182.
[CrossRef]
296. Lambert, N.; Nelson, J.L. Microchimerism in autoimmune disease: More questions than answers? Autoimmun. Rev. 2003, 2,
133–139. [CrossRef]
297. Klintschar, M.; Immel, U.D.; Kehlen, A.; Schwaiger, P.; Mustafa, T.; Mannweiler, S.; Regauer, S.; Kleiber, M.; Hoang-Wu, C. Fetal
microchimerism in Hashimoto’s thyroiditis: A quantitative approach. Eur. J. Endocrinol. Eur. Fed. Endocr. Soc. 2006, 154, 237–241.
[CrossRef]
298. Ando, T.; Imaizumi, M.; Graves, P.N.; Unger, P.; Davies, T.F. Intrathyroidal fetal microchimerism in Graves’ disease. J. Clin.
Endocrinol. Metab. 2002, 87, 3315–3320.
299. Renné, C.; Ramos Lopez, E.; Steimle-Grauer, S.A.; Ziolkowski, P.; Pani, M.A.; Luther, C.; Holzer, K.; Encke, A.; Wahl, R.A.;
Bechstein, W.O.; et al. Thyroid fetal male microchimerisms in mothers with thyroid disorders: Presence of Y-chromosomal
immunofluorescence in thyroid-infiltrating lymphocytes is more prevalent in Hashimoto’s thyroiditis and Graves’ disease than in
follicular adenomas. J. Clin. Endocrinol. Metab. 2004, 89, 5810–5814. [CrossRef]
300. Cirello, V.; Rizzo, R.; Crippa, M.; Campi, I.; Bortolotti, D.; Bolzani, S.; Colombo, C.; Vannucchi, G.; Maffini, M.A.; de Liso, F.; et al.
Fetal cell microchimerism: A protective role in autoimmune thyroid diseases. Eur. J. Endocrinol. 2015, 173, 111–118. [CrossRef]
301. Jimenez, S.A.; Artlett, C.M. Microchimerism and systemic sclerosis. Curr. Opin. Rheumatol. 2005, 17, 86–90. [CrossRef]
302. Brix, T.H.; Hansen, P.S.; Kyvik, K.O.; Hegedüs, L. Aggregation of thyroid autoantibodies in twins from opposite-sex pairs suggests
that microchimerism may play a role in the early stages of thyroid autoimmunity. J. Clin. Endocrinol. Metab. 2009, 94, 4439–4443.
[CrossRef]
303. Nelson, J.L. Maternal-fetal immunology and autoimmune disease: Is some autoimmune disease auto-alloimmune or alloautoimmune?
Arthritis Rheum. 1996, 39, 191–194. [CrossRef]
304. Kremer Hovinga, I.C.; Koopmans, M.; de Heer, E.; Bruijn, J.A.; Bajema, I.M. Chimerism in systemic lupus erythematosus-three
hypotheses. Rheumatology 2007, 46, 200–208. [CrossRef] [PubMed]
305. Klonisch, T.; Drouin, R. Fetal-maternal exchange of multipotent stem/progenitor cells: Microchimerism in diagnosis and disease.
Trends Mol. Med. 2009, 15, 510–518. [CrossRef]
306. Wang, Y.; Iwatani, H.; Ito, T.; Horimoto, N.; Yamato, M.; Matsui, I.; Imai, E.; Hori, M. Fetal cells in mother rats contribute to the
remodeling of liver and kidney after injury. Biochem. Biophys. Res. Commun. 2004, 325, 961–967. [CrossRef] [PubMed]
307. Walsh, J.P.; Bremner, A.P.; Bulsara, M.K.; O’Leary, P.; Leedman, P.J.; Feddema, P.; Michelangeli, V. Parity and the risk of
autoimmune thyroid disease: A community-based study. J. Clin. Endocrinol. Metab. 2005, 90, 5309–5312. [CrossRef]
308. Bülow Pedersen, I.; Laurberg, P.; Knudsen, N.; Jørgensen, T.; Perrild, H.; Ovesen, L.; Rasmussen, L.B. Lack of association between
thyroid autoantibodies and parity in a population study argues against microchimerism as a trigger of thyroid autoimmunity.
Eur. J. Endocrinol. 2006, 154, 39–45. [CrossRef] [PubMed]
309. Sgarbi, J.A.; Kasamatsu, T.S.; Matsumura, L.K.; Maciel, R.M. Parity is not related to autoimmune thyroid disease in a populationbased
study of Japanese-Brazilians. Thyroid 2010, 20, 1151–1156. [CrossRef]
310. Lepez, T.; Vandewoestyne, M.; Deforce, D. Fetal microchimeric cells in autoimmune thyroid diseases: Harmful, beneficial or
innocent for the thyroid gland? Chimerism 2013, 4, 111–118. [CrossRef]
311. Ajjan, R.A.; Weetman, A.P. Autoimmune thyroid disease and autoimmune polyglandular syndrome. In Samter’s Immunological
Diseases, 6th ed.; Austin, K.F., Frank, M.M., Canton, H.I., Atkinson, J.P., Samter, M., Eds.; Lippincott Williams & Wilkins:
Philadelphia, PA, USA, 2001; pp. 605–626.
Cells 2023, 12, 918 37 of 37
312. Dwivedi, S.N.; Kalaria, T.; Buch, H. Thyroid autoantibodies. J. Clin. Pathol. 2023, 76, 19–28. [CrossRef]
313. Gupta, A.K.; Kumar, S. Utility of Antibodies in the Diagnoses of Thyroid Diseases: A Review Article. Cureus 2022, 14, e31233.
[CrossRef]
314. Napolitano, G.; Bucci, I.; Di Dalmazi, G.; Giuliani, C. Non-Conventional Clinical Uses of TSH Receptor Antibodies: The Case of
Chronic Autoimmune Thyroiditis. Front. Endocrinol. 2021, 12, 769084. [CrossRef]
315. McLachlan, S.M.; Rapoport, B. Discoveries in Thyroid Autoimmunity in the Past Century. Thyroid 2022. [CrossRef] [PubMed]
316. Weetman, A.P. Autoimmune thyroid disease: Propagation and progression. Eur. J. Endocrinol. 2003, 148, 1–9. [CrossRef] [PubMed]
317. Walsh, J.P.; Bremner, A.P.; Feddema, P.; Leedman, P.J.; Brown, S.J.; O’Leary, P. Thyrotropin and thyroid antibodies as predictors of
hypothyroidism: A 13-year, longitudinal study of a community-based cohort using current immunoassay techniques. J. Clin.
Endocrinol. Metab. 2010, 95, 1095–1104. [CrossRef]
318. Suzuki, S.; Mitsunaga, M.; Miyoshi, M.; Hirakawa, S.; Nakagawa, O.; Miura, H.; Ofuji, T. Cytophilic antithyroglobulin antibody
and antibody-dependent monocyte-mediated cytotoxicity in Hashimoto’s thyroiditis. J. Clin. Endocrinol. Metab. 1980, 51, 446–453.
[CrossRef]
319. Sundick, R.S.; Herdegen, D.M.; Brown, T.R.; Bagchi, N. The incorporation of dietary iodine into thyroglobulin increases its
immunogenicity. Endocrinology 1987, 120, 2078–2084. [CrossRef] [PubMed]
320. Czarnocka, B. Thyroperoxidase, thyroglobulin, Na(+)/I(-) symporter, pendrin in thyroid autoimmunity. Front. Biosci. Landmark
Ed. 2011, 16, 783–802. [CrossRef]
321. Eleftheriadou, A.M.; Mehl, S.; Renko, K.; Kasim, R.H.; Schaefer, J.A.; Minich,W.B.; Schomburg, L. Re-visiting autoimmunity to
sodium-iodide symporter and pendrin in thyroid disease. Eur. J. Endocrinol. 2020, 183, 571–580. [CrossRef]
322. Waliszewska-Prosół, M.; Ejma, M. Hashimoto Encephalopathy-Still More Questions than Answers. Cells 2022, 11, 2873.