The Immunology of Autoimmune Thyroid Disease in Pregnancy
Abstract
In pregnancy, complex physiologic changes in the immune system alters the environment for the “non-self” fetus allowing it to be tolerated in the maternal womb, while the immune system is still able to counteract external pathogens. The interplay of the immune system and the physiologic changes induced by pregnancy on the thyroid induce changes in the natural history of the autoimmune thyroid diseases (AITD). This review discusses the various players in creating this milieu, including the MHC, the T- and B-cells, sex steroids and the possible role of microchimerism. The participants provide a variety of mechanisms that create the clinical scenarios that we see in patients with AITD – most commonly the improvement in Grave’s Disease during pregnancy and the rebound in thyroid autoantibodies and recurrence, or new onset, of Graves’ and Hashimoto’s diseases in the post-partum.Downloads
References
Munoz-Suano A, Hamilton AB, Betz AG. Gimme shelter: The immune system during pregnancy. Immunological Reviews 2011;241:20-38.
Amino N, Tanizawa O, Mori H, et al. Aggravation of thyrotoxicosis in early pregnancy and after delivery in Graves' disease. Journal of Clinical Endocrinology and Metabolism 1982;55:108-12.
Stagnaro-Green A, Glinoer D. Thyroid autoimmunity and the risk of miscarriage. Best Pract Res Clin Endocrinol Metab 2004;18:167-81.
Gaberscek S, Zaletel K. Thyroid physiology and autoimmunity in pregnancy and after delivery. Expert Review of Clinical Immunology 2011;7:697-706; quiz 7.
Glinoer D. The regulation of thyroid function in pregnancy: Pathways of endocrine adaptation from physiology to pathology. Endocrine Reviews 1997;18:404-33.
Lazarus JH. Thyroid function in pregnancy. British Medical Bulletin 2011;97:137-48.
Poppe K, Velkeniers B, Glinoer D. Thyroid disease and female reproduction. Clinical Endocrinology 2007;66:309-21.
Negro R, Mestman JH. Thyroid disease in pregnancy. Best Pract Res Clin Endocrinol Metab 2011;25:927-43.
Poppe K, Velkeniers B, Glinoer D. The role of thyroid autoimmunity in fertility and pregnancy. Nature Clinical Practice Endocrinology & Metabolism 2008;4:394-405.
Grassi G, Balsamo A, Ansaldi C, Balbo A, Massobrio M, Benedetto C. Thyroid autoimmunity and infertility. Gynecological Endocrinology 2001;15:389-96.
Eisenberg VH, Zolti M, Soriano D. Is there an association between autoimmunity and endometriosis? Autoimmunity Reviews 2012.
Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: Natural immunity dysfunction or autoimmune disease? Trends in Molecular Medicine 2003;9:223-8.
Konova E. The role of NK cells in the autoimmune thyroid disease-associated pregnancy loss. Clinical Reviews in Allergy & Immunology 2010;39:176-84.
Ostensen M, Villiger PM, Forger F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmunity Reviews 2011.
de Man YA, Dolhain RJ, van de Geijn FE, Willemsen SP, Hazes JM. Disease activity of rheumatoid arthritis during pregnancy: Results from a nationwide prospective study. Arthritis and Rheumatism 2008;59:1241-8.
Husby G, Ostensen M, Gran JT. Ankylosing spondylitis and pregnancy. Clinical and Experimental Rheumatology 1988;6:165-7.
Lui NL, Haroon N, Carty A, et al. Effect of pregnancy on ankylosing spondylitis: A case-control study. The Journal of Rheumatology 2011;38:2442-4.
Amino N, Tada H, Hidaka Y. Postpartum autoimmune thyroid syndrome: A model of aggravation of autoimmune disease. Thyroid : official journal of the American Thyroid Association 1999;9:705-13.
Galofre JC, Haber RS, Mitchell AA, Pessah R, Davies TF. Increased postpartum thyroxine replacement in Hashimoto's thyroiditis. Thyroid 2010;20:901-8.
Billington WD. The immunological problem of pregnancy: 50 years with the hope of progress. A tribute to Peter Medawar. J Reprod Immunol 2003;60:1-11.
Pujol-Borrell R, Soldevila G, Buscema M, et al. Inappropriate expression of HLA class II molecules in endocrine epithelial cells: the phenomenon, the new experimental data and comparison with animal models. Journal of Autoimmunity 1989;2 Suppl:163-9.
Levinson W. Review of medical microbiology and immunology. 11th ed. New York: McGraw-Hill Medical; 2010.
Shiina T, Inoko H, Kulski JK. An update of the HLA genomic region, locus information and disease associations: 2004. Tissue Antigens 2004;64:631-49.
Ban Y, Davies TF, Greenberg DA, et al. Arginine at position 74 of the HLA-DR beta1 chain is associated with Graves' disease. Genes and immunity 2004;5:203-8.
Tilburgs T, Scherjon SA, Claas FH. Major histocompatibility complex (MHC)-mediated immune regulation of decidual leukocytes at the fetal-maternal interface. J Reprod Immunol 2010;85:58-62.
Favier B, LeMaoult J, Rouas-Freiss N, Moreau P, Menier C, Carosella ED. Research on HLA-G: An update. Tissue Antigens 2007;69:207-11.
Kuhnert M, Strohmeier R, Stegmuller M, Halberstadt E. Changes in lymphocyte subsets during normal pregnancy. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1998;76:147-51.
Wegmann TG, Lin H, Guilbert L, Mosmann TR. Bidirectional cytokine interactions in the maternal-fetal relationship: Is successful pregnancy a TH2 phenomenon? Immunol Today 1993;14:353-6.
Saito S, Tsukaguchi N, Hasegawa T, Michimata T, Tsuda H, Narita N. Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells. American Journal of Reproductive Immunology 1999;42:240-5.
Golding A, Haque UJ, Giles JT. Rheumatoid arthritis and reproduction. Rheum Dis Clin North Am 2007;33:319-43, vi-vii.
Chaouat G. The Th1/Th2 paradigm: Still important in pregnancy? Semin Immunopathol 2007;29:95-113.
Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium: Aprospective study of 78 pregnancies. Br J Rheumatol 1996;35:133-8.
Shevach EM. From vanilla to 28 flavors: Multiple varieties of T regulatory cells. Immunity 2006;25:195-201.
von Herrath MG, Harrison LC. Antigen-induced regulatory T cells in autoimmunity. Nat Rev Immunol 2003;3:223-32.
Guerin LR, Prins JR, Robertson SA. Regulatory T-cells and immune tolerance in pregnancy: A new target for infertility treatment? Human Reproduction Update 2009;15:517-35.
Leber A, Teles A, Zenclussen AC. Regulatory T cells and their role in pregnancy. American Journal of Reproductive Immunology 2010;63:445-59.
Zenclussen AC, Lim E, Knoeller S, et al. Heme oxygenases in pregnancy II: HO-2 is downregulated in human pathologic pregnancies. American Journal of Reproductive Immunology 2003;50:66-76.
Saito S, Shima T, Nakashima A, Shiozaki A, Ito M, Sasaki Y. What is the role of regulatory T cells in the success of implantation and early pregnancy? Journal of Assisted Reproduction and Genetics 2007;24:379-86.
Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. Th17: An effector CD4 T cell lineage with regulatory T cell ties. Immunity 2006;24:677-88.
Martinez-Garcia EA, Chavez-Robles B, Sanchez-Hernandez PE, et al. IL-17 increased in the third trimester in healthy women with term labor. American Journal of Reproductive Immunology 2011;65:99-103.
Pongcharoen S, Niumsup P, Sanguansermsri D, Supalap K, Butkhamchot P. The effect of interleukin-17 on the proliferation and invasion of JEG-3 human choriocarcinoma cells. American Journal of Reproductive Immunology 2006;55:291-300.
Saito S, Nakashima A, Ito M, Shima T. Clinical implication of recent advances in our understanding of IL-17 and reproductive immunology. Expert Review of Clinical immunology 2011;7:649-57.
Pongcharoen S, Supalap K. Interleukin-17 increased progesterone secretion by JEG-3 human choriocarcinoma cells. American Journal of Reproductive Immunology 2009;61:261-4.
Steinman L. A brief history of T(H)17, the first major revision in the T(H)1/T(H)2 hypothesis of T cell-mediated tissue damage. Nature Medicine 2007;13:139-45.
Loong CC, Hsieh HG, Lui WY, Chen A, Lin CY. Evidence for the early involvement of interleukin 17 in human and experimental renal allograft rejection. Journal of Pathology 2002;197:322-32.
Li J, Simeoni E, Fleury S, et al. Gene transfer of soluble interleukin-17 receptor prolongs cardiac allograft survival in a rat model. European Journal of Cardio-thoracic surgery 2006;29:779-83.
Wang WJ, Hao CF, Yi L, et al. Increased prevalence of T helper 17 (Th17) cells in peripheral blood and decidua in unexplained recurrent spontaneous abortion patients. J Reprod Immunol 2010;84:164-70.
Nakashima A, Ito M, Yoneda S, Shiozaki A, Hidaka T, Saito S. Circulating and decidual Th17 cell levels in healthy pregnancy. American Journal of Reproductive Immunology 2010;63:104-9.
Kincade PW, Medina KL, Smithson G, Scott DC. Pregnancy: A clue to normal regulation of B lymphopoiesis. Immunol Today 1994;15:539-44.
Bouaziz JD, Yanaba K, Tedder TF. Regulatory B cells as inhibitors of immune responses and inflammation. Immunological Reviews 2008;224:201-14.
Weetman AP. Determinants of autoimmune thyroid disease. Nature Immunology 2001;2:769-70.
Yoshida A, Hisatome I, Taniguchi S, et al. Pendrin is a novel autoantigen recognized by patients with autoimmune thyroid diseases. Journal of Clinical Endocrinology and Metabolism 2009;94:442-8.
Raspe E, Costagliola S, Ruf J, Mariotti S, Dumont JE, Ludgate M. Identification of the thyroid Na+/I- cotransporter as a potential autoantigen in thyroid autoimmune disease. European Journal of Endocrinology/European Federation of Endocrine Societies 1995;132:399-405.
Salvatore DD, T., Schlumberger, M., Hay, I., Larsen, P. . Thyroid. In: Melmed SP, K. Larsen, P. Kronenberg, H., ed. Williams Endocrinology. 12th ed. Philadelphia, PA: Elsevier; 2011:327-50.
Feldt-Rasmussen U, Hoier-Madsen M, Rasmussen NG, Hegedus L, Hornnes P. Anti-thyroid peroxidase antibodies during pregnancy and postpartum. Relation to postpartum thyroiditis. Autoimmunity 1990;6:211-4.
Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Alvarez-Marfany M, Davies TF. Detection of at-risk pregnancy by means of highly sensitive assays for thyroid autoantibodies. JAMA 1990;264:1422-5.
Morshed SA, Latif R, Davies TF. Delineating the autoimmune mechanisms in Graves' disease. Immunologic research 2012.Ahead of Print. DOI: 10.1007/s12026-012-8312-8
Zakarija M, McKenzie JM. Pregnancy-associated changes in the thyroid-stimulating antibody of Graves' disease and the relationship to neonatal hyperthyroidism. Journal of Clinical Endocrinology and Metabolism 1983;57:1036-40.
Parker RH, Beierwaltes WH. Thyroid antibodies during pregnancy and in the newborn. Journal of Clinical Endocrinology and Metabolism 1961;21:792-8.
Stagnaro-Green A, Roman SH, Cobin RH, el-Harazy E, Wallenstein S, Davies TF. A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: Evidence of a T-cell etiology for postpartum thyroid dysfunction. Journal of Clinical Endocrinology and Metabolism 1992;74:645-53.
McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992;2:155-9.
Hughes GC, Clark EA. Regulation of dendritic cells by female sex steroids:Relevance to immunity and autoimmunity. Autoimmunity 2007;40:470-81.
Blois SM, Kammerer U, Alba Soto C, et al. Dendritic cells: Key to fetal tolerance? Biology of Reproduction 2007;77:590-8.
Sarkar K, Miller FW. Possible roles and determinants of microchimerism in autoimmune and other disorders. Autoimmunity Reviews 2004;3:454-63.
Bianchi DW, Zickwolf GK, Weil GJ, Sylvester S, DeMaria MA. Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum. Proceedings of the National Academy of Sciences of the United States of America 1996;93:705-8.
Nelson JL, Furst DE, Maloney S, et al. Microchimerism and HLA-compatible relationships of pregnancy in scleroderma. Lancet 1998;351:559-62.
Ando T, Imaizumi M, Graves PN, Unger P, Davies TF. Intrathyroidal fetal microchimerism in Graves' disease. Journal of Clinical Endocrinology and Metabolism 2002;87:3315-20.
Ando T, Davies TF. Clinical Review 160: Postpartum autoimmune thyroid disease:The potential role of fetal microchimerism. Journal of Clinical Endocrinology and Metabolism 2003;88:2965-71.
Brix TH, Hansen PS, Kyvik KO, Hegedus 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. Journal of Clinical Endocrinology and Metabolism 2009;94:4439-43.
Walsh JP, Bremner AP, Bulsara MK, et al. Parity and the risk of autoimmune thyroid disease: A community-based study. Journal of Clinical Endocrinology and Metabolism 2005;90:5309-12.
Friedrich N, Schwarz S, Thonack J, John U, Wallaschofski H, Volzke H. Association between parity and autoimmune thyroiditis in a general female population. Autoimmunity 2008;41:174-80.
Gonzalez DA, Diaz BB, Rodriguez Perez Mdel C, Hernandez AG, Chico BN, de Leon AC. Sex hormones and autoimmunity. Immunology Letters 2010;133:6-13.
Huber SA, Kupperman J, Newell MK. Estradiol prevents and testosterone promotes Fas-dependent apoptosis in CD4+ Th2 cells by altering Bcl 2 expression. Lupus 1999;8:384-7.
Bouman A, Schipper M, Heineman MJ, Faas MM. Gender difference in the non-specific and specific immune response in humans. American Journal of Reproductive Immunology 2004;52:19-26.
Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. Journal of Clinical Investigation 2002;109:1625-33.
Giltay EJ, Fonk JC, von Blomberg BM, Drexhage HA, Schalkwijk C, Gooren LJ. In vivo effects of sex steroids on lymphocyte responsiveness and immunoglobulin levels in humans. Journal of Clinical Endocrinology and Metabolism 2000;85:1648-57.
Pauklin S, Sernandez IV, Bachmann G, Ramiro AR, Petersen-Mahrt SK. Estrogen directly activates AID transcription and function. Journal of Experimental Medicine 2009;206:99-111.
Yovel G, Shakhar K, Ben-Eliyahu S. The effects of sex, menstrual cycle, and oral contraceptives on the number and activity of natural killer cells. Gynecologic Oncology 2001;81:254-62.
Glinoer D, Soto MF, Bourdoux P, et al. Pregnancy in patients with mild thyroid abnormalities: Maternal and neonatal repercussions. Journal of Clinical Endocrinology and Metabolism 1991;73:421-7.
De Vivo A, Mancuso A, Giacobbe A, et al. Thyroid function in women found to have early pregnancy loss. Thyroid : 2010;20:633-7.
Prummel MF, Wiersinga WM. Thyroid autoimmunity and miscarriage. European Journal of Endocrinology_/_European Federation of Endocrine Societies 2004;150:751-5.
Glinoer D, Riahi M, Grun JP, Kinthaert J. Risk of subclinical hypothyroidism in pregnant women with asymptomatic autoimmune thyroid disorders. Journal of Clinical Endocrinology and Metabolism 1994;79:197-204.
Ohara N, Tsujino T, Maruo T. The role of thyroid hormone in trophoblast function, early pregnancy maintenance, and fetal neurodevelopment. Journal of Obstetrics and Gynaecology Canada: 2004;26:982-90.
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: effects on obstetrical complications. Journal of Clinical Endocrinology and Metabolism 2006;91:2587-91.
Berghout A, Wiersinga W. Thyroid size and thyroid function during pregnancy: an analysis. European Journal of Endocrinology_/_European Federation of Endocrine Societies 1998;138:536-42.
Fister P, Gaberscek S, Zaletel K, Krhin B, Gersak K, Hojker S. Thyroid volume and intrathyroidal blood flow increase during pregnancy. Clinical Endocrinology 2006;65:828-9.
LaFranchi SH, Haddow JE, Hollowell JG. Is thyroid inadequacy during gestation a risk factor for adverse pregnancy and developmental outcomes? Thyroid 2005;15:60-71.
Anselmo J, Cao D, Karrison T, Weiss RE, Refetoff S. Fetal loss associated with excess thyroid hormone exposure. JAMA.2004;292:691-5.
Poppe K, Glinoer D. Thyroid autoimmunity and hypothyroidism before and during pregnancy. Human Reproduction Update 2003;9:149-61.
Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocrine Reviews 2010;31:702-55.
Stagnaro-Green A. Overt hyperthyroidism and hypothyroidism during pregnancy. Clinical Obstetrics and Gynecology 2011;54:478-87.
Luewan S, Chakkabut P, Tongsong T. Outcomes of pregnancy complicated with hyperthyroidism: A cohort study. Archives of Gynecology and Obstetrics 2011;283:243-7.
McGrogan A, Seaman HE, Wright JW, de Vries CS. The incidence of autoimmune thyroid disease: a systematic review of the literature. Clinical Endocrinology 2008;69:687-96.
Prummel MF, Strieder T, Wiersinga WM. The environment and autoimmune thyroid diseases. European Journal of Endocrinology / European Federation of Endocrine Societies 2004;150:605-18.
Stagnaro-Green A. Postpartum thyroiditis. Best Pract Res Clin Endocrinol Metab 2004;18:303-16.
Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: Recent insights and consequences for antenatal and postnatal care. Endocrine Reviews 2001;22:605-30.
Zhu J, Paul WE. CD4 T cells: Fates, functions, and faults. Blood 2008;112:1557-69.
Published
How to Cite
Issue
Section
License
Journal of the ASEAN Federation of Endocrine Societies is licensed under a Creative Commons Attribution-NonCommercial 4.0 International. (full license at this link: http://creativecommons.org/licenses/by-nc/3.0/legalcode).
To obtain permission to translate/reproduce or download articles or use images FOR COMMERCIAL REUSE/BUSINESS PURPOSES from the Journal of the ASEAN Federation of Endocrine Societies, kindly fill in the Permission Request for Use of Copyrighted Material and return as PDF file to jafes@asia.com or jafes.editor@gmail.com.
A written agreement shall be emailed to the requester should permission be granted.
