Human Reproduction, Vol. 18, No. 5, 1094-1099,
May 2003
© 2003 European Society of Human Reproduction and Embryology
The pathogenic role of anti-thyroglobulin antibody on pregnancy: evidence from an active immunization model in mice
1 Center for Autoimmune Diseases, Department of Medicine ‘B’, Sheba Medical Center, Tel Hashomer & Sackler Faculty of Medicine, Tel-Aviv, 2 Department of Anatomy, Hadassah Faculty of Medicine, Hebrew University, Jerusalem, 3 Department of Pathology, Rambam Medical Center, Technion University, Haifa, Israel, 4 Departments of Pathology and of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, 5 Department of Medicine, and 6 Department of Pediatrics, University of Chicago, Chicago, Illinois, USA
7 To whom correspondence should be addressed at: Department of Medicine ‘B’, Sheba Medical Center, Tel Hashomer, 52621, Israel. e-mail: shoenfel{at}post.tau.ac.il
BACKGROUND: The presence of antibodies to thyroglobulin (Tg) is associated with fetal loss even in the absence of thyroid dysfunction. The aim of this study was to examine whether active immunization with Tg could elicit anti-Tg autoantibodies and reproductive failure without interfering with thyroid function. METHODS: BALB/c mice that were immunized with human Tg in complete Freund’s adjuvant (CFA) or injected with only CFA were studied for the development of antibodies to Tg, T4, dsDNA, ssDNA and cardiolipin. Total T4, free T4 and thyroid-stimulating hormone (TSH) levels were also assessed before and during pregnancy. Percentages of resorbed fetuses (the equivalent to human missed abortion) were compared and autoantibody presence on the placentae and fetuses was examined. RESULTS: Following immunization, high levels of anti-Tg were observed in mice immunized with Tg, compared with mice injected with CFA [0.83 ± 0.23 versus 0.012 ± 0.016 respectively; mean ± SD optical density (OD) at 405 nm; P < 0.001]. The specificity of binding to Tg was confirmed by competition assay. Although total T4 levels were increased in comparison with control mice, this was associated with the presence of antibodies to T4. Indeed, free T4 levels and TSH were similar to control mice. Mice were killed after 14 days of pregnancy. The thyroid function and the histology of the thyroid glands were normal. Increased fetal wastage was found among the Tg-immunized mice compared with the CFA-injected mice (P = 0.04), with lower fetal and placental weights (fetal weights: 194 ± 4 mg versus 240 ± 6 mg; placental weights: 105 ± 2 mg versus 130 ± 3; P < 0.001 for both). Antibodies to Tg were demonstrated only on the placentae of Tg-immunized mice. CONCLUSION: Immunization with Tg results in the production of Tg antibodies and fetal resorption. These effects occur in the absence of thyroid dysfunction.
Key words: animal model/autoimmunity/fetal loss/thyroglobulin/thyroid
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