Larissa C Faustino1, Cheuk W Li1, Mihaela Stefan-Lifshitz1, Kookjoo Kim2,3, Oliver B Clarke2,3, Yaron Tomer1. 1. Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA. 2. Department of Anesthesiology and Columbia University, New York, New York, USA. 3. Department of Physiology, Columbia University, New York, New York, USA.
Abstract
Background: Thyroglobulin (TG) is a key autoantigen in autoimmune thyroid diseases (AITD). Several single nucleotide polymorphisms (SNPs) in the TG locus were shown to be strongly associated with disease susceptibility in both humans and mice, and autoimmune response to TG is the earliest event in the development of thyroid autoimmunity in mice. The classical model of experimental autoimmune thyroiditis (EAT) is induced by immunizing mice with TG protein together with an adjuvant to break down immune tolerance. The classical EAT model has limited utility in genetic studies of TG since it does not allow testing the effects of TG sequence variants on the development of autoimmune thyroiditis. In this study, we have immunized CBA-J mice, an EAT-susceptible strain, with an adenovirus vector encoding the full-length human TG (hTG) to generate a model of EAT in which the TG sequence can be manipulated to test AITD-associated TG SNPs. Methods: We immunized CBA-J mice with hTG-expressing adenovirus following the well-recognized experimental autoimmune Graves' disease protocol that also uses an adenovirus vector to deliver the immunogen. Results: After hTG adenovirus immunizations, mice developed higher T cell proliferative and cytokine responses to hTG and TG2098 (a major T cell epitope in AITD) and higher titers of TG and thyroperoxidase autoantibodies compared with mice immunized with control LacZ-expressing adenovirus. The mice, however, did not develop thyroidal lymphocytic infiltration and hypothyroidism. Conclusions: Our data describe a novel murine model of autoimmune thyroiditis that does not require the use of adjuvants to break down tolerance and that will allow investigators to test the effects of hTG variants in the pathoetiology of Hashimoto's thyroiditis.
Background: Thyroglobulin (TG) is a key autoantigen in autoimmune thyroid diseases (AITD). Several single nucleotide polymorphisms (SNPs) in the TG locus were shown to be strongly associated with disease susceptibility in both humans and mice, and autoimmune response to TG is the earliest event in the development of thyroid autoimmunity in mice. The classical model of experimental autoimmune thyroiditis (EAT) is induced by immunizing mice with TG protein together with an adjuvant to break down immune tolerance. The classical EAT model has limited utility in genetic studies of TG since it does not allow testing the effects of TG sequence variants on the development of autoimmune thyroiditis. In this study, we have immunized CBA-J mice, an EAT-susceptible strain, with an adenovirus vector encoding the full-length human TG (hTG) to generate a model of EAT in which the TG sequence can be manipulated to test AITD-associated TG SNPs. Methods: We immunized CBA-J mice with hTG-expressing adenovirus following the well-recognized experimental autoimmune Graves' disease protocol that also uses an adenovirus vector to deliver the immunogen. Results: After hTG adenovirus immunizations, mice developed higher T cell proliferative and cytokine responses to hTG and TG2098 (a major T cell epitope in AITD) and higher titers of TG and thyroperoxidase autoantibodies compared with mice immunized with control LacZ-expressing adenovirus. The mice, however, did not develop thyroidal lymphocytic infiltration and hypothyroidism. Conclusions: Our data describe a novel murine model of autoimmune thyroiditis that does not require the use of adjuvants to break down tolerance and that will allow investigators to test the effects of hTG variants in the pathoetiology of Hashimoto's thyroiditis.
Entities:
Keywords:
adenovirus; experimental autoimmune thyroiditis; human thyroglobulin; immunization
Authors: Eric M Jacobson; Heyi Yang; Francesca Menconi; Rong Wang; Roman Osman; Luce Skrabanek; Cheuk Wun Li; Mohammed Fadlalla; Alisha Gandhi; Vijaya Chaturvedi; Eric P Smith; Sandy Schwemberger; Andrew Osterburg; George F Babcock; Yaron Tomer Journal: J Biol Chem Date: 2009-09-23 Impact factor: 5.157
Authors: Alfonso Massimiliano Ferrara; Xiao-Hui Liao; Pilar Gil-Ibáñez; Teresa Marcinkowski; Juan Bernal; Roy E Weiss; Alexandra M Dumitrescu; Samuel Refetoff Journal: Endocrinology Date: 2013-05-21 Impact factor: 4.736
Authors: Francesca Menconi; Maria C Monti; David A Greenberg; Taiji Oashi; Roman Osman; Terry F Davies; Yoshiyuki Ban; Eric M Jacobson; Erlinda S Concepcion; Cheuk Wun Li; Yaron Tomer Journal: Proc Natl Acad Sci U S A Date: 2008-09-08 Impact factor: 11.205
Authors: B R Champion; K R Page; N Parish; D C Rayner; K Dawe; G Biswas-Hughes; A Cooke; M Geysen; I M Roitt Journal: J Exp Med Date: 1991-08-01 Impact factor: 14.307