Development of a murine model of autoimmune thyroiditis induced with homologous mouse thyroid peroxidase

Abstract

Autoimmune thyroid disease (AITD) is a common autoimmune disease. Thyroid peroxidase (TPO) is a well characterized autoantigen in AITD. Autoantibodies and autoreactive T lymphocytes to TPO are believed to play a major role in the pathogenesis of lymphocytic thyroiditis. To understand the pathogenic mechanisms of AITD and the role of TPO, we have established a mouse model of lymphocytic thyroiditis by immunizing C57Bl/6 (H-2(b)), CBA (H-2(k)), and C57Bl/6 x CBA F1 mice with recombinant murine TPO (rmTPO) ectodomain comprising amino acid residue 1-837 produced in Escherichia coli. Mice were immunized with 30 microg purified ectodomain in complete Freund's adjuvant. Antibodies against rmTPO were detected in the serum of all mice from day 21 onward. Draining lymph node cells from rmTPO-immunized animals showed dose-dependent proliferation to TPO stimulation. Mice killed at d 50 and 90 revealed variable degrees of thyroiditis with infiltration of mononuclear cells and destruction of thyroid follicles. C57Bl/6 and the F1 mice, in comparison with CBA mice, showed a greater degree of thyroiditis. There was a lack of correction between the intensity of thyroiditis and the anti-TPO response. Immunotyping of the thyroid cellular infiltrates showed predominantly CD4+ T cells and B220+ B cells but scanty CD8+ T cells. None of the control mice injected with the purified fusion partner developed anti-TPO antibodies and thyroiditis. In conclusion, a genuine autoimmune mouse model of lymphocytic thyroiditis was established using autologous mouse TPO. This new model induced with autologous TPO will lead to a better understanding of the mechanisms in destructive thyroiditis and will assist in the development of new strategies for modulating the pathogenic immune response.