Hypothesized 40 years ago, molecular mimicry has been thereafter demonstrated as an extremely common mechanism by which microbes elude immune response and modulate biosynthetic/metabolic pathways of the host. In genetically predisposed persons and under particular conditions, molecular mimicry between microbial and human antigens can turn a defensive immune response into autoimmunity. Such triggering role and its pathogenetic importance have been investigated and demonstrated for many autoimmune diseases. However, this is not the case for autoimmune thyroid disease, which appears relatively neglected by this field of research. Here we review the available literature on the possible role of molecular mimicry as a trigger of autoimmune thyroid disease. Additionally, we present the results of in silico search for amino acid sequence homologies between some microbial proteins and thyroid autoantigens, and the potential pathogenetic relevance of such homologies. Relevance stems from the overlap with known autoepitopes and the occurrence of specific HLA-DR binding motifs. Bioinformatics data published by our group support and explain the triggering role of Borrelia, Yersinia, Clostridium botulinum, Rickettsia prowazekii and Helicobacter pylori. Our new data suggest the potential pathogenic importance of Toxoplasma gondii, some Bifidobacteria and Lactobacilli, Candida albicans, Treponema pallidum and hepatitis C virus in autoimmune thyroid disease, indicating specific molecular targets for future research. Additionally, the consistency between in silico prediction of cross-reactivity and experimental results shows the reliability and usefulness of bioinformatics tools to precisely identify candidate molecules for in vitro and/or in vivo experiments, or at least narrow down their number.
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Bates HW. Contributions to an insect fauna of the Amazon valley. Lepidoptera: Heliconidae. Trans Linnean Soc. 1862;23:495–566.
Müller F. Ueber die vortheile der mimicry bei schmetterlingen. Zool Anz. 1878;1:54–5.
Emsley MG. The mimetic significance of Erythrolamprus aesculapii ocellatus Peters from Tobago. Evolution. 1966;20:663–4.
Wickler W. Mimicry in plants and animals. New York: McGraw-Hill; 1968.
Lloyd JE. Aggressive mimicry in photuris: firefly femmes fatales. Science. 1965;149:653–4.
Guarneri F, Guarneri C. Molecular mimicry in cutaneous autoimmune diseases. World J Dermatol. 2013;2:36–43.
Grossman Z, Paul WE. Autoreactivity, dynamic tuning and selectivity. Curr Opin Immunol. 2001;13:687–98.
Brower LP, Pough FH, Meck HR. Theoretical investigations of automimicry, I. Single trial learning. Proc Natl Acad Sci U S A. 1970;66:1059–66.
Sturzl M, Hohenadl C, Zietz C, Castanos-Velez E, Wunderlich A, Ascherl G, Biberfeld P, Monini P, Browning PJ, Ensoli B. Expression of K13/v-FLIP gene of human herpesvirus 8 and apoptosis in Kaposi’s sarcoma spindle cells. J Natl Cancer Inst. 1999;91:1725–33.
Shapiro RF, Wiesner KB, Bryan BL, Utsinger PD, Resnick D, Castles JJ. HLA-B27 and modified bone formation. Lancet. 1976;1:230–1.
Ebringer A. Ankylosing spondylitis, immune-response-genes and molecular mimicry. Lancet. 1979;1:1186.
Adams DD. Molecular mimicry and H-Ir genes. Lancet. 1979;2:754.
Ebringer A. Molecular mimicry and H-Ir genes. Lancet. 1979;2:1143.
Fujinami RS, Oldstone MB. Molecular mimicry as a mechanism for virus-induced autoimmunity. Immunol Res. 1989;8:3–15.
Mason D. A very high level of crossreactivity is an essential feature of the T-cell receptor. Immunol Today. 1998;19:395.
Anderton SM, Wraith DC. Selection and fine-tuning of the autoimmune T-cell repertoire. Nat Rev Immunol. 2002;2:487–98.
Sospedra M, Martin R. When T cells recognize a pattern, they might cause trouble. Curr Opin Immunol. 2006;18:697–703.
Ryan KR, Patel SD, Stephens LA, Anderton SM. Death, adaptation and regulation: the three pillars of immune tolerance restrict the risk of autoimmune disease caused by molecular mimicry. J Autoimmun. 2007;29:262–71.
Anderton SM, Radu CG, Lowrey PA, Ward ES, Wraith DC. Negative selection during the peripheral immune response to antigen. J Exp Med. 2001;193:1–11.
Ohashi PS. T-cell signalling and autoimmunity: molecular mechanisms of disease. Nat Rev Immunol. 2002;2:427–38.
Pasare C, Medzhitov R. Toll-like receptors: balancing host resistance with immune tolerance. Curr Opin Immunol. 2003;15:677–82.
Schwartz RH. T cell anergy. Annu Rev Immunol. 2003;21:305.
Anderson CC, Chan WF. Mechanisms and models of peripheral CD4 T cell self-tolerance. Front Biosci. 2004;9:2947–63.
Hildeman DA, Zhu Y, Mitchell TC, Kappler J, Marrack P. Molecular mechanisms of activated T cell death in vivo. Curr Opin Immunol. 2002;14:354–9.
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.
Volpé R. A perspective on human autoimmune thyroid disease: is there an abnormality of the target cell which predisposes to the disorder? Autoimmunity. 1992;13:3–9.
Toivanen P, Toivanen A. Does Yersinia induce autoimmunity? Int Arch Allergy Immunol. 1994;104:107–11.
Tomer Y, Davies TF. Infections and autoimmune endocrine disease. Bailliere Clin Endocrinol Metab. 1995;9:47–70.
Martin A, Barbesino G, Davies TF. T-cell receptors and autoimmune thyroid disease–signposts for T-cell-antigen driven diseases. Int Rev Immunol. 1999;18:111–40.
Rao VP, Kajon AE, Spindler KR, Carayanniotis G. Involvement of epitope mimicry in potentiation but not initiation of autoimmune disease. J Immunol. 1999;162:5888–93.
Carayanniotis G, Kong YC. Pathogenic thyroglobulin peptides as model antigens: insights on the induction and maintenance of autoimmune thyroiditis. Int Rev Immunol. 2000;19:557–72.
Chen CR, Tanaka K, Chazenbalk GD, McLachlan SM, Rapoport B. A full biological response to autoantibodies in Graves’ disease requires a disulfide-bonded loop in the thyrotropin receptor N terminus homologous to a laminin epidermal growth factor-like domain. J Biol Chem. 2001;276:14767–72.
Chen F, Day SL, Metcalfe RA, Sethi G, Kapembwa MS, Brook MG, Churchill D, de Ruiter A, Robinson S, Lacey CJ, Weetman AP. Characteristics of autoimmune thyroid disease occurring as a late complication of immune reconstitution in patients with advanced human immunodeficiency virus (HIV) disease. Medicine (Baltimore). 2005;84:98–106.
Bach JF. Infections and autoimmune diseases. J Autoimmun. 2005;25(Suppl):74–80.
Vaccaro M, Guarneri F, Borgia F, Cannavò SP, Benvenga S. Association of lichen sclerosus and autoimmune thyroiditis: possible role of Borrelia burgdorferi? Thyroid. 2002;12:1147–8.
Benvenga S, Guarneri F, Vaccaro M, Santarpia L, Trimarchi F. Homologies between proteins of Borrelia burgdorferi and thyroid autoantigens. Thyroid. 2004;14:964–6.
Benvenga S, Santarpia L, Trimarchi F, Guarneri F. Human thyroid autoantigens and proteins of Yersinia and Borrelia share amino acid sequence homology that includes binding motifs to HLA-DR molecules and T-cell receptor. Thyroid. 2006;16:225–36.
Guarneri F, Carlotta D, Saraceno G, Trimarchi F, Benvenga S. Bioinformatics support the possible triggering of autoimmune thyroid disease by Yersinia enterocolitica outer membrane proteins homologous to the human thyrotropin receptor. Thyroid. 2011;21:1283–4.
Gregoric E, Gregoric JA, Guarneri F, Benvenga S. Injections of Clostridium botulinum neurotoxin A may cause thyroid complications in predisposed persons based on molecular mimicry with thyroid autoantigens. Endocrine. 2011;39:41–7.
Marangou A, Guarneri F, Benvenga S. Graves’ disease precipitated by rickettsial infection. Endocrine. 2015;50:828–9.
Guarneri F, Guarneri B. Bioinformatic analysis of HLA-linked genetic susceptibility to immunoallergic disease: the MotiFinder software. Ann Ital Dermatol Allergol. 2010;64:69–75.
Paparone PW. Hypothyroidism with concurrent Lyme disease. J Am Osteopath Assoc. 1995;95:435–7.
Völzke H, Werner A, Guertler L, Robinson D, Wallaschofski H, John U. Putative association between anti-Borrelia IgG and autoimmune thyroid disease? Thyroid. 2005;15:1273–7.
Bech K, Larsen JH, Hansen JM, Nerup J. Yersinia enterocolitica infection and thyroid disorders. Lancet. 1974;2:951–2.
Lidman K, Eriksson U, Fagraeus A, Norberg R. Antibodies against thyroid cells in Yersinia enterocolitica infection. Lancet. 1974;2:1449.
Von Bonsdorff M, Friman C. Yersinia enterocolitica infection and thyroid disorders. Lancet. 1974;2:1565–6.
Arscott P, Rosen ED, Koenig RJ, Kaplan MM, Ellis T, Thompson N, Baker Jr JR. Immunoreactivity to Yersinia enterocolitica antigens in patients with autoimmune thyroid disease. J Clin Endocrinol Metab. 1992;75:295–300.
Wenzel BE, Peters A, Zubaschev I. Bacterial virulence antigens and the pathogenesis of autoimmune thyroid disease (AITD). Exp Clin Endocrinol Diabetes. 1996;104(Suppl 4):75–8.
Chatzipanagiotou S, Legakis JN, Boufidou F, Petroyianni V, Nicolaou C. Prevalence of Yersinia plasmid-encoded outer protein (Yop) class-specific antibodies in patients with Hashimoto’s thyroiditis. Clin Microbiol Infect. 2001;7:138–43.
Wang Z, Zhang Q, Lu J, Jiang F, Zhang H, Gao L, Zhao J. Identification of outer membrane porin f protein of Yersinia enterocolitica recognized by antithyrotropin receptor antibodies in Graves’ disease and determination of its epitope using mass spectrometry and bioinformatics tools. J Clin Endocrinol Metab. 2010;95:4012–20.
Hargreaves CE, Grasso M, Hampe CS, Stenkova A, Atkinson S, Joshua GW, Wren BW, Buckle AM, Dunn-Walters D, Banga JP. Yersinia enterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves’ disease. J Immunol. 2013;190:5373–81.
Giménez-Barcons M, Colobran R, Gómez-Pau A, Marín-Sánchez A, Casteràs A, Obiols G, Abella R, Fernández-Doblas J, Tonacchera M, Lucas-Martín A, Pujol-Borrell R. Graves’ disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation? J Immunol. 2015;194:4199–206.
Hansen PS, Wenzel BE, Brix TH, Hegedüs L. Yersinia enterocolitica infection does not confer an increased risk of thyroid antibodies: evidence from a Danish twin study. Clin Exp Immunol. 2006;146:32–8.
Effraimidis G, Tijssen JG, Strieder TG, Wiersinga WM. No causal relationship between Yersinia enterocolitica infection and autoimmune thyroid disease: evidence from a prospective study. Clin Exp Immunol. 2011;165:38–43.
Vita R, Lapa D, Vita G, Trimarchi F, Benvenga S. A patient with stress-related onset and exacerbations of Graves’ disease. Nat Clin Pract Endocrinol Metab. 2009;5:55–61.
Vita R, Lapa D, Trimarchi F, Benvenga S. Stress triggers the onset and the recurrences of hyperthyroidism in patients with Graves’ disease. Endocrine. 2015;48:254–63.
de Luis DA, Varela C, de La Calle H, Cantón R, de Argila CM, San Roman AL, Boixeda D. Helicobacter pylori infection is markedly increased in patients with autoimmune atrophic thyroiditis. J Clin Gastroenterol. 1998;26:259–63.
Figura N, Di Cairano G, Lorè F, Guarino E, Gragnoli A, Cataldo D, Giannace R, Vaira D, Bianciardi L, Kristodhullu S, Lenzi C, Torricelli V, Orlandini G, Gennari C. The infection by Helicobacter pylori strains expressing CagA is highly prevalent in women with autoimmune thyroid disorders. J Physiol Pharmacol. 1999;50:817–26.
Franceschi F, Satta MA, Mentella MC, Penland R, Candelli M, Grillo RL, Leo D, Fini L, Nista EC, Cazzato IA, Lupascu A, Pola P, Pontecorvi A, Gasbarrini G, Genta RM, Gasbarrini A. Helicobacter pylori infection in patients with Hashimoto’s thyroiditis. Helicobacter. 2004;9:369.
Bertalot G, Montresor G, Tampieri M, Spasiano A, Pedroni M, Milanesi B, Favret M, Manca N, Negrini R. Decrease in thyroid autoantibodies after eradication of Helicobacter pylori infection. Clin Endocrinol. 2004;61:650–2.
Tomasi PA, Dore MP, Fanciulli G, Sanciu F, Realdi G, Delitala G. Is there anything to the reported association between Helicobacter pylori infection and autoimmune thyroiditis? Dig Dis Sci. 2005;50:385–8.
Sterzl I, Hrda P, Potuznikova B, Matucha P, Hana V, Zamrazil V. Autoimmune thyroiditis and Helicobacter pylori-is there a connection? Neuro Endocrinol Lett. 2006;27(Suppl 1):41–5.
Sterzl I, Hrdá P, Matucha P, Cerovská J, Zamrazil V. Anti-Helicobacter pylori, anti-thyroid peroxidase, anti-thyroglobulin and anti-gastric parietal cells antibodies in Czech population. Physiol Res. 2008;57(Suppl 1):S135–41.
Bassi V, Santinelli C, Iengo A, Romano C. Identification of a correlation between Helicobacter pylori infection and Graves’ disease. Helicobacter. 2010;15:558–62.
Bassi V, Marino G, Iengo A, Fattoruso O, Santinelli C. Autoimmune thyroid disease and Helicobacter pylori: the correlation is present only in Graves’ disease. World J Gastroenterol. 2012;18:1093–7.
Soveid M, Hosseini Asl K, Omrani GR. Infection by Cag A positive strains of Helicobacter pylori is associated with autoimmune thyroid disease in Iranian patients. Iran J Immunol. 2012;9:48–52.
Shi WJ, Liu W, Zhou XY, Ye F, Zhang GX. Associations of Helicobacter pylori infection and cytotoxin-associated gene A status with autoimmune thyroid disease: a meta-analysis. Thyroid. 2013;23:1294–300.
Aghili R, Jafarzadeh F, Ghorbani R, Khamseh ME, Salami MA, Malek M. The association of Helicobacter pylori infection with Hashimoto’s thyroiditis. Acta Med Iran. 2013;51:293–6.
Arslan MS, Ekiz F, Deveci M, Sahin M, Topaloglu O, Karbek B, Tutal E, Ginis Z, Cakal E, Ozbek M, Yuksel O, Delibasi T. The relationship between cytotoxin-associated gene A positive Helicobacter pylori infection and autoimmune thyroid disease. Endocr Res. 2015;40:211–4.
El-Eshmawy MM, El-Hawary AK, Abdel Gawad SS, El-Baiomy AA. Helicobacter pylori infection might be responsible for the interconnection between type 1 diabetes and autoimmune thyroiditis. Diabetol Metab Syndr. 2011;3:28.
Zekry OA, Abd Elwahid HA. The association between Helicobacter pylori infection, type 1 diabetes mellitus, and autoimmune thyroiditis. J Egypt Public Health Assoc. 2013;88:143–7.
Guarneri F, Alessi A, Trimarchi F, Benvenga S. Helicobacter pylori proteins and thyroid autoantigens share amino acid sequence homology that includes motifs of recognition for HLA molecules and T-cell receptors. 77th Annual meeting of the American Thyroid Association, Phoenix, AZ, USA, October 11–16, 2006. Thyroid. 2006;16:860–1 (Abstract).
Larizza D, Calcaterra V, Martinetti M, Negrini R, De Silvestri A, Cisternino M, Iannone AM, Solcia E. Helicobacter pylori infection and autoimmune thyroid disease in young patients: the disadvantage of carrying the human leukocyte antigen-DRB1*0301 allele. J Clin Endocrinol Metab. 2006;91:176–9.
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;8:112–5.
Shapira Y, Agmon-Levin N, Selmi C, Petríková J, Barzilai O, Ram M, Bizzaro N, Valentini G, Matucci-Cerinic M, Anaya JM, Katz BS, Shoenfeld Y. Prevalence of anti-Toxoplasma antibodies in patients with autoimmune diseases. J Autoimmun. 2012;39:112–6.
Wasserman EE, Nelson K, Rose NR, Rhode C, Pillion JP, Seaberg E, Talor MV, Burek L, Eaton W, Duggan A, Yolken RH. Infection and thyroid autoimmunity: a seroepidemiologic study of TPOaAb. Autoimmunity. 2009;42:439–46.
Kaňková Š, Procházková L, Flegr J, Calda P, Springer D, Potluková E. Effects of latent toxoplasmosis on autoimmune thyroid diseases in pregnancy. PLoS One. 2014;9:e110878.
Kiseleva EP, Mikhailopulo KI, Sviridov OV, Novik GI, Knirel YA, Szwajcer DE. The role of components of Bifidobacterium and Lactobacillus in pathogenesis and serologic diagnosis of autoimmune thyroid disease. Benefic Microbes. 2011;2:139–54.
Felis GE, Dellaglio F, Torriani S. Taxonomy of probiotic microrganisms. In: Charalampopoulos D, Rastall RA, editors. Prebiotics and probiotics science and technology. New York: Springer; 2009. p. 591–637.
Vojdani A, Rahimian P, Kalhor H, Mordechai E. Immunological cross reactivity between Candida albicans and human tissue. J Clin Lab Immunol. 1996;48:1–15.
Khoury EL, Pereira L, Greenspan FS. Induction of HLA-DR expression on thyroid follicular cells by cytomegalovirus infection in vitro. Evidence for a dual mechanism of induction. Am J Pathol. 1991;138:1209–23.
Thomas D, Karachaliou F, Kallergi K, Vlachopapadopoulou E, Antonaki G, Chatzimarkou F, Fotinou A, Kaldrymides P, Michalacos S. Herpes virus antibodies seroprevalence in children with autoimmune thyroid disease. Endocrine. 2008;33:171–5.
Jadali Z, Alavian SM. Autoimmune diseases co-existing with hepatitis C virus infection. Iran J Allergy Asthma Immunol. 2010;9:191–206.
Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev. 2015;14:174–80.
Fallahi P, Ferrari SM, Ruffilli I, Elia G, Giuggioli D, Colaci M, Ferri C, Antonelli A. Incidence of thyroid disorders in mixed cryoglobulinemia: results from a longitudinal follow-up. Autoimmun Rev. 2016. doi:10.1016/j.autrev.2016.03.012.
Ferri S, Muratori L, Lenzi M, Granito A, Bianchi FB, Vergani D. HCV and autoimmunity. Curr Pharm Des. 2008;14:1678–85.
Muratori L, Bogdanos DP, Muratori P, Lenzi M, Granito A, Ma Y, Mieli-Vergani G, Bianchi FB, Vergani D. Susceptibility to thyroid disorders in hepatitis C. Clin Gastroenterol Hepatol. 2005;3:595–603.
Tomer Y. Hepatitis C and interferon induced thyroiditis. J Autoimmun. 2010;34:J322–6.
Menconi F, Hasham A, Tomer Y. Environmental triggers of thyroiditis: hepatitis C and interferon-α. J Endocrinol Investig. 2011;34:78–84.
Martocchia A, Falaschi P. Amino acid sequence homologies between HCV polyprotein and thyroid antigens. Intern Emerg Med. 2007;2:65–7.
Akeno N, Blackard JT, Tomer Y. HCV E2 protein binds directly to thyroid cells and induces IL-8 production: a new mechanism for HCV induced thyroid autoimmunity. J Autoimmun. 2008;31:339–44.
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Benvenga, S., Guarneri, F. Molecular mimicry and autoimmune thyroid disease. Rev Endocr Metab Disord 17, 485–498 (2016). https://doi.org/10.1007/s11154-016-9363-2