Yersinia infections and Graves’ disease

Background. The most common thyroid disease, accompanied by thyrotoxicosis syndrome, is Graves' disease (GD). Information about the role of Yersinia in the development of this disease is contradictory.

Aims. To study the significance of Yersinia (Y.) enterocolitica and Y. pseudotuberculosis in the development of Graves' disease.

Materials and methods. 78 patients with GD. Identification of antibodies to Y. was carried out by the following methods: 1. agglutination test (AT) with suspensions of live virulent cultures Y. pseudotuberculosis, Y. enterocolitica O:3 and O:9; 2. indirect hemagglutination test (IHET) with the use of erythrocyte diagnosticum; 3. determination of IgA and IgG antibodies against pathogenicity factors of Y. enterocolitica strains by immunoblotting (30 patients with GD).

Results. Diagnostically significant titers of antibodies to Y. pseudotuberculosis and Y. enterocolitica were obtained in all patients with GD by AT. The greatest total thyroid volume determined by ultrasound investigation (p = 0.010) and the maximum duration of the disease (p = 0.040) were determined in the group of patients with the maximum antibody titer. No significant relation was found between the titer of antibodies to Yersinia and the levels of thyroid hormones stimulating the thyroid antibodies.The test for detection of IgA antibodies by immunoblotting was negative in 30 patients with GD (9 patients with a titer of antibodies by AT 1:800 – 1:1600, 17 – 1:400, 4 – 1:200). In all cases with the maximum antibody titer in AT, the positive IgG antibodies to the antigens YopM (Yop2a), YopH (Yop2b), V-antigen, YopD were found. The GD duration in patients with negative titers of antibodies by the immunoblotting test was less than with the positive one (p = 0.010). The privative clinical and anamnestic data and negative results by IHET confirmed the absence of active and/or transferred Yersinia infections in all the examined patients with GD.

Conclusions. The cross-reacting antibodies to the antigens of Y. enterocolitica are determined in the serum of GD patients by AT and immunoblotting. The diagnostic titer of these antibodies is more often detected in patients with greater GD duration and larger volume of the thyroid gland. The absence of a link between the titer of these antibodies and the levels of thyroid hormones, the antibodies to the thyrotropin receptors of pituitary, as well as negative results by IHET with a diagnosticum that does not contain outer membrane proteins of pathogenic Yersinia, deny the trigger role of Yersinia infections as an initiating factor in the development of GD.

Yersinia infections, Graves’ disease, cross reaction, antibodies

1. Кроненберг Г.М., Мелмед Ш., Полонски К.С., Ларсен П.Р. Заболевания щитовидной железы. / Под ред. Дедова И.И., Мельниченко Г.А. – М.: ООО “Рид Элсивер”; 2010. [Kronenberg GM, Melmed S, Polonski KS, Larsen PR. Dedov II, Melnichenko GA, editors. Zabolevaniyashchitovidnoi zhelezy. Moscow: Reed Elsevier; 2010. (In Russ.)]

2. Bech K, Hannover Larsen J, Mlholm Hansen J, Nerup J. Yersinia enterocolitica infection and thyroid disorders. Lancet. 1974; 304(7886):951-952. doi: 10.1016/s0140-6736(74)91152-0.

3. Weiss M, Rubinstein E, Bottone EJ, et al. Yersinia enterocolitica antibodies in thyroid disorders. Isr J Med Sci. 1979;15(7):553-555.

4. Wenzel BE, Peters A, Zubaschev I. Bacterial virulence antigens and the pathogenesis of autoimmune thyroid diseases (AITD). Exp Clin Endocrinol Diabetes. 1996;104 Suppl 4:75-78. doi: 10.1055/s-0029-1211707.

5. Takuno H, Sakata S, Miura K. Antibodies to Yersinia enterocolitica serotype 3 in autoimmune thyroid diseases. Endocrinol Jpn. 1990;37(4):489-500. doi: 10.1507/endocrj1954.37.489.

6. Gangi E, Kapatral V, El-Azami El-Idrissi M, et al. Characterization of a recombinant Yersinia enterocolitica lipoprotein; implications for its role in autoimmune response against thyrotropin receptor. Autoimmunity. 2004;37(6-7):515-520. doi: 10.1080/08916930410001728074.

7. Guarneri F, Carlotta D, Saraceno G, et al. Bioinformatics support the possible triggering of autoimmune thyroid diseases by Yersinia enterocolitica outer membrane proteins homologous to the human thyrotropin receptor. Thyroid. 2011;21(11):1283-1284. doi: 10.1089/thy.2010.036.

8. Wang Z, Zhang Q, Lu J, et al. Identification of outer membrane porin f protein of Yersinia enterocolitica recognized by antithyrotopin receptor antibodies in Graves' disease and determination of its epitope using mass spectrometry and bioinformatics tools. J Clin EndocrinolMetab. 2010;95(8):4012-4020. doi: 10.1210/jc.2009-2184.

9. Rastawicki W. Humoral response to selected antigens of Yersinia enterocolitica and Yersinia pseudotuberculosis in the course of yersiniosis in humans. IV. Specificity of antigens. Med Dosw Mikrobiol. 2008;60(1):27-37.

10. Hargreaves CE, Grasso M, Hampe CS, et al. Yersinia enterocolitica provides the link between thyroid-stimulating antibodies and their germline counterparts in Graves' disease. J Immunol. 2013;190(11):5373-5381. doi: 10.4049/jimmunol.1203412.

11. Gimenez-Barcons M, Colobran R, Gomez-Pau A, et al. Graves' disease TSHR-stimulating antibodies (TSAbs) induce the activation of immature thymocytes: a clue to the riddle of TSAbs generation? J Immunol. 2015;194(9):4199-4206. doi: 10.4049/jimmunol.1500183.

12. Volpé R. Antibodies to plasmdo-encoated proteins of enteropathogenic Yersinia in patients with autoimmune thyroid disease. Lancet. 1988;331(8586):647. doi: 10.1016/s0140-6736(88)91444-4.

13. Asari S, Amino N, Horikawa M, Miyai K. Incidences of antibodies to Yersinia enterocolitica: High incidence of serotype O5 in autoimmune thyroid diseases in Japan. Endocrinol Jpn. 1989;36(3): 381-386. doi: 10.1507/endocrj1954.36.381.

14. Трошина Е.А., Свириденко Н.Ю., Ванушко В.Э., и др. Клинические рекомендации по диагностике и лечению тиреотоксикоза с диффузным зобом (диффузный токсический зоб, болезнь Грейвса-Базедова), узловым/многоузловым зобом. – М.; 2014. [Troshina EA, Sviridenko NY, Vanushko VE, et al. Klinicheskie rekomendatsii po diagnostike i lecheniyu tireotoksikoza s diffuznym zobom (diffuznyi toksicheskii zob, bolezn' Greivsa-Bazedova), uzlovym/mnogouzlovym zobom. Moscow; 2014. (In Russ.)]

15. Хамнуева Л.Ю., Сизых Т.П., Климов В.Т., Харитончик О.А. Состояние щитовидной железы при псевдотуберкулезе. // Сибирский медицинский журнал (Иркутск). – 1999. – Т. 18. – №3. – С. 32–35. [Khamnueva LY, Sizykh TP, Klimov VT, Kharitonchik OA. Thyroid condition in pseudotuberculesis. Sibirskii meditsinskii zhurnal (Irkutsk, Russia). 1999;18(3):32-35. (In Russ.)]

16. 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(1):38-43. doi: 10.1111/j.1365-2249.2011.04399.x.

17. Серов В.В., Зайратьянц О.В. Аутоиммунизация и аутоиммунные болезни. // Архив патологии. – 1992. – Т. 54. – №3. – С. 5–12. [Serov VV, Zairat'yants OV. Autoimmunizatsiya i autoimmunnye bolezni. Arkh Patol. 1992;54(3):5-12. (In Russ.)]