The CD40, CTLA-4, Thyroglobulin, TSH Receptor, and PTPN22 Gene Quintet and Its Contribution to Thyroid Autoimmunity: Back to the Future

Overview

Journal J Autoimmun

Specialty Allergy & Immunology

Date 2007 Mar 21

PMID 17369021

Citations 64

Authors

Eric M Jacobson

Yaron Tomer

Affiliations

Soon will be listed here.

Abstract

Autoimmune thyroid diseases (AITD) are common autoimmune diseases, affecting up to 5% of the general population. Thyroid-directed autoimmunity is manifested in two classical autoimmune conditions, Hashimoto's thyroiditis, resulting in hypothyroidism and Graves' disease resulting in hyperthyroidism. Autoimmune thyroid diseases arise due to an interplay between environmental and genetic factors. In the past decade significant progress has been made in our understanding of the genetic contribution to the etiology of AITD. Indeed, several AITD susceptibility genes have been identified. Some of these susceptibility genes are specific to either Graves' disease or Hashimoto's thyroiditis, while others confer susceptibility to both conditions. Both immunoregulatory genes and thyroid specific genes contribute to the pathogenesis of AITD. The time is now ripe to examine the mechanistic basis for the contribution of genetic factors to the etiology of AITD. In this review, we will focus on the contribution of non-MHC II genes.

Citing Articles

Autoimmune Thyroid Disease and Pregnancy: The Interaction Between Genetics, Epigenetics and Environmental Factors.

Bogovic Crncic T, Curko-Cofek B, Baticic L, Girotto N, Tomas M, Krsek A J Clin Med. 2025; 14(1.

PMID: 39797274 PMC: 11721206. DOI: 10.3390/jcm14010190.

HLA Class II Allele Groups Involved in Autoimmune Thyroid Diseases: Hashimoto's Thyroiditis and Basedow-Graves Disease.

Chiorean A, Nicula G, Balici S, Vica M, Loga L, Dican L Life (Basel). 2024; 14(4).

PMID: 38672712 PMC: 11050925. DOI: 10.3390/life14040441.

Human T-cell leukemia virus type 1 is associated with dysthyroidism in the French Amazon.

Dugardin J, Demar M, Hafsi N, Amroun H, Aurelus J, Alsibai K Front Cell Infect Microbiol. 2023; 13:1164526.

PMID: 37293205 PMC: 10244722. DOI: 10.3389/fcimb.2023.1164526.

HLA typing of patients who developed subacute thyroiditis and Graves' disease after SARS-CoV-2 vaccination: a case report.

Yasuda S, Suzuki S, Yanagisawa S, Morita H, Haisa A, Satomura A BMC Endocr Disord. 2023; 23(1):54.

PMID: 36879263 PMC: 9988595. DOI: 10.1186/s12902-023-01287-5.

Effective Inhibition of Thyroid Antigen Presentation Using Retro-Inverso Peptides in Experimental Autoimmune Thyroiditis: A Pathway Toward Immune Therapies of Thyroid Autoimmunity.

Li C, Osman R, Menconi F, Hou H, Schechter C, Kozhakhmetova A Thyroid. 2023; 33(4):492-500.

PMID: 36762945 PMC: 10325802. DOI: 10.1089/thy.2022.0511.

References

Stafford E, Rose N . Newer insights into the pathogenesis of experimental autoimmune thyroiditis. Int Rev Immunol. 2000; 19(6):501-33. DOI: 10.3109/08830180009088510. View

Begovich A, Carlton V, Honigberg L, Schrodi S, Chokkalingam A, Alexander H . A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet. 2004; 75(2):330-7. PMC: 1216068. DOI: 10.1086/422827. View

Ban Y, Davies T, Greenberg D, Kissin A, Marder B, Murphy B . Analysis of the CTLA-4, CD28, and inducible costimulator (ICOS) genes in autoimmune thyroid disease. Genes Immun. 2003; 4(8):586-93. DOI: 10.1038/sj.gene.6364018. View

Smyth D, Cooper J, Collins J, Heward J, Franklyn J, Howson J . 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(11):3020-3. DOI: 10.2337/diabetes.53.11.3020. View

Tomer Y, Ban Y, Concepcion E, Barbesino G, Villanueva R, Greenberg D . 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(4):736-47. PMC: 1180598. DOI: 10.1086/378588. View

Wucherpfennig K . MHC-linked susceptibility to type 1 diabetes: a structural perspective. Ann N Y Acad Sci. 2003; 1005:119-27. DOI: 10.1196/annals.1288.013. View

Clark E, Lane P . Regulation of human B-cell activation and adhesion. Annu Rev Immunol. 1991; 9:97-127. DOI: 10.1146/annurev.iy.09.040191.000525. View

Collins J, Heward J, Carr-Smith J, Daykin J, Franklyn J, Gough S . Association of a rare thyroglobulin gene microsatellite variant with autoimmune thyroid disease. J Clin Endocrinol Metab. 2003; 88(10):5039-42. DOI: 10.1210/jc.2003-030093. View

Chistiakov D, Savostanov K, Turakulov R, Efremov I, Demurov L . Genetic analysis and functional evaluation of the C/T(-318) and A/G(-1661) polymorphisms of the CTLA-4 gene in patients affected with Graves' disease. Clin Immunol. 2005; 118(2-3):233-42. DOI: 10.1016/j.clim.2005.09.017. View

10.

Brix T, Kyvik K, Hegedus L . A population-based study of chronic autoimmune hypothyroidism in Danish twins. J Clin Endocrinol Metab. 2000; 85(2):536-9. DOI: 10.1210/jcem.85.2.6385. View

11.

Fries K, Sempowski G, Gaspari A, Blieden T, Looney R, Phipps R . CD40 expression by human fibroblasts. Clin Immunol Immunopathol. 1995; 77(1):42-51. DOI: 10.1016/0090-1229(95)90135-3. View

12.

Tomer Y . Genetic dissection of familial autoimmune thyroid diseases using whole genome screening. Autoimmun Rev. 2003; 1(4):198-204. DOI: 10.1016/s1568-9972(02)00053-8. View

13.

Gentile F, Conte M, Formisano S . Thyroglobulin as an autoantigen: what can we learn about immunopathogenicity from the correlation of antigenic properties with protein structure?. Immunology. 2004; 112(1):13-25. PMC: 1782462. DOI: 10.1111/j.1365-2567.2004.01861.x. View

14.

Bielekova B, Martin R . Antigen-specific immunomodulation via altered peptide ligands. J Mol Med (Berl). 2001; 79(10):552-65. DOI: 10.1007/s001090100259. View

15.

Metcalfe R, McIntosh R, Lombardi G, Lechler R, Weetman A . Detection of CD40 on human thyroid follicular cells: analysis of expression and function. J Clin Endocrinol Metab. 1998; 83(4):1268-74. DOI: 10.1210/jcem.83.4.4732. View

16.

Gordon J, Millsum M, Guy G, Ledbetter J . Resting B lymphocytes can be triggered directly through the CDw40 (Bp50) antigen. A comparison with IL-4-mediated signaling. J Immunol. 1988; 140(5):1425-30. View

17.

Libert F, Ruel J, Ludgate M, Swillens S, Alexander N, Vassart G . Complete nucleotide sequence of the human thyroperoxidase-microsomal antigen cDNA. Nucleic Acids Res. 1987; 15(16):6735. PMC: 306137. DOI: 10.1093/nar/15.16.6735. View

18.

Mukai T, Hiromatsu Y, Fukutani T, Ichimura M, Kaku H, Miyake I . A C/T polymorphism in the 5' untranslated region of the CD40 gene is associated with later onset of Graves' disease in Japanese. Endocr J. 2005; 52(4):471-7. DOI: 10.1507/endocrj.52.471. View

19.

Godelaine D, Spiro M, Spiro R . Processing of the carbohydrate units of thyroglobulin. J Biol Chem. 1981; 256(19):10161-8. View

20.

Finck B, Linsley P, Wofsy D . Treatment of murine lupus with CTLA4Ig. Science. 1994; 265(5176):1225-7. DOI: 10.1126/science.7520604. View