Severe Autoimmune Thyroiditis in Transgenic NOD.H2h4 Mice Expressing Interleukin-4 in the Thyroid
- 1 March 2023
- journal article
- research article
- Published by Mary Ann Liebert Inc in Thyroid®
- Vol. 33 (3), 351-364
- https://doi.org/10.1089/thy.2022.0448
Abstract
Background: Hashimoto’s thyroiditis is a common autoimmune thyroid disorder characterized by thyroid lymphocytic infiltrates and autoreactive antibodies against thyroglobulin (TgAbs) and thyroperoxidase. Final evolution of the disease can lead to hypothyroidism with destruction of the thyroid architecture. Interleukine-4 (IL-4) is involved in the humoral immune response and B cell activation required in autoimmune thyroiditis (AT) progression. We used our mouse model overexpressing IL-4 by thyrocytes (Thyr-IL4) to study the impact of a local IL-4 expression in AT using transgenic NOD.H2h4 derived animals treated with iodide-supplemented water to increase the incidence of spontaneous AT (SAT). Methods: Thyr-IL4 NOD.H2h4 and nonpathogenic C57BL/6 animals aged 8 weeks were exposed to 0.05% sodium iodide (NaI) in their drinking water for 8 and 16 weeks. Circulating TgAbs and expression of intrathyroidal cytokines were quantified. Thyroid inflammation was assessed by classical histological analyses including identification of some immune cell populations. The most sensitive parameter to evaluate the thyroid function, serum thyrotropin (TSH), was also measured at the end of the treatment. Results: Relative to WT animals, Thyr-IL4 NOD.H2h4 mice developed severe accelerated SAT with elevated serum TgAbs and numerous thyroid infiltrates mainly composed of CD4+/CD8+ T cells, B lymphocytes and monocytes/macrophages. Thyroid expression of T helper (Th) Th1/Th2 cytokines was also enhanced as well as IL-17. In contrast, excessive iodide supply did not induced TgAbs in WT and Thyr-IL4 SAT-resistant C57BL/6 animals. However, moderate leukocyte infiltrations in transgenic thyroids were evident compared to WT, but associated with a limited number of T and B cells and a different cytokine profile from Thyr-IL4 NOD.H2h4 mice. Finally and despite their diverse immune responses, both transgenic strains presented marked thyroid enlargement and elevated serum TSH at the end of the treatment in contrast to their WT littermates. Conclusions: These findings demonstrated that ectopic expression of IL-4 from thyrocytes enhanced the severity of accelerated SAT in disease-prone Thyr-IL4 NOD.H2h4 animals and promoted thyroid leukocyte infiltration in SAT-resistant transgenic C57BL/6 mice. Moreover, impaired thyroid function emerged in both transgenic strains during the progression of the disease.Keywords
This publication has 55 references indexed in Scilit:
- Iodine-induced thyroid dysfunctionCurrent Opinion in Endocrinology, Diabetes and Obesity, 2012
- Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin AntibodiesEndocrinology, 2010
- Environmental triggers of autoimmune thyroiditisJournal of Autoimmunity, 2009
- A new mathematical model for relative quantification in real-time RT-PCRNucleic Acids Research, 2001
- Characteristics of Inflammatory Cells in Spontaneous Autoimmune Thyroiditis of NOD.H-2h4 MiceJournal of Autoimmunity, 2001
- Spontaneous Autoimmune Thyroiditis in NOD.H-2h4 MiceJournal of Autoimmunity, 1999
- Iodine-Induced Autoimmune Thyroiditis in NOD-H-2h4MiceClinical Immunology and Immunopathology, 1996
- Follicular thyroid cells of autoimmune thyroiditis may coexpress ICAM-1 (CD54) and its natural ligand LFA-1 (CD11a/CD18)Journal of Allergy and Clinical Immunology, 1995
- The effects of a monoclonal antibody to interferon‐γ on experimental autoimmune thyroiditis (EAT): prevention of disease and decrease of EAT‐specific T cellsEuropean Journal of Immunology, 1993
- Stable expression of the human TSH receptor in CHO cells and characterization of differentially expressing clonesBiochemical and Biophysical Research Communications, 1990