Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin Antibodies

Chen, Chun-Rong; Hamidi, Sepehr; Braley‐Mullen, Helen; Nagayama, Yuji; Bresee, Catherine; Aliesky, Holly A.; Rapoport, Basil; McLachlan, Sandra M.

doi:10.1210/jcem.95.8.9976

Cited by 9 publications

(30 citation statements)

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“…2A). These data confirm previous observations for thyroglobulin autoantibodies that dietary iodide enhances (or accelerates) but is not responsible for the development of thyroid autoimmunity in NOD.H2 h4 mice (18,23). In particular, TgAb are detectable much earlier than TPOAb in NOD.…”

Section: Resultssupporting

confidence: 92%

“…First, unlike the conventional NOD mouse that develops diabetes, the NOD. H2 h4 strain develops spontaneous, iodine-accelerated, autoimmune thyroiditis in association with autoantibodies to thyroglobulin (Tg)(22–24) and, at a later stage, to thyroid peroxidase (TPO) (18), but not to the TSHR. Second, we previously generated transgenic BALB/c mice with the human TSHR A-subunit selectively expressed in the thyroid gland, a ‘self’ antigen as evident by tolerance to human TSHR A-subunit immunization (13).…”

Section: Resultsmentioning

confidence: 99%

“…Thyroglobulin was isolated from murine thyroid glands as previously described (18). ELISA wells (Immulon 4HBX, Thermo Scientific, Rochester NY) were coated with mouse thyroglobulin (1.5μg/ml) and incubated with test sera (duplicate aliquots, 1:100 dilution).…”

Section: Methodsmentioning

confidence: 99%

“…TPOAb were measured using CHO cells stably expressing mouse-TPO (18). Sera (1:50 dilution) were incubated with mouse TPO-CHO cells and binding was detected with fluorescein isothyocyanate-conjugated affinity purified goat anti-mouse IgG (M30101, Invitrogen, Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

“…H2 h4 mice. Positive controls were mouse monoclonal antibodies #15 and #64 to human TPO (20), provided to us by Dr. P. Carayon and Dr. J Ruf (Marseille, France), that recognize mouse TPO (18,20). Flow cytometry was performed (10,000 events) using a FACScan with CELLQUEST Software (Becton Dickinson, San Jose, CA).…”

Section: Methodsmentioning

confidence: 99%

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A Unique Mouse Strain That Develops Spontaneous, Iodine-Accelerated, Pathogenic Antibodies to the Human Thyrotrophin Receptor

Rapoport

Aliesky

Banuelos

et al. 2015

The Journal of Immunology

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Antibodies that stimulate the thyrotropin receptor (TSHR), the cause of Graves’ hyperthyroidism, only develop in humans. TSHR antibodies can be induced in mice by immunization but studying pathogenesis and therapeutic intervention requires a model without immunization. Spontaneous, iodine-accelerated, thyroid autoimmunity develops in NOD.H2h4 mice associated with thyroglobulin and thyroid-peroxidase, but not TSHR, antibodies. We hypothesized that transferring the human (h)TSHR A-subunit to NOD.H2h4 mice would result in loss of tolerance to this protein. BALB/c hTSHR A-subunit mice were bred to NOD.H2h4 mice and transgenic offspring were repeatedly backcrossed to NOD.H2h4 mice. All offspring developed antibodies to thyroglobulin and thyroid-peroxidase. However, only TSHR-transgenic NOD.H2h4 mice (TSHR/NOD.H2h4) developed pathogenic TSHR antibodies as detected using clinical Graves’ disease assays. As in humans, TSHR/NOD.H2h4 females were more prone than males to developing pathogenic TSHR antibodies. Fortunately, in view of the confounding effect of excess thyroid hormone on immune responses, spontaneously arising pathogenic (h)TSHR antibodies cross-react poorly with the mouse TSHR and do not cause thyrotoxicosis. In summary, the TSHR/NOD.H2h4 mouse strain develops spontaneous, iodine-accelerated, pathogenic TSHR antibodies in females, providing a unique model to investigate disease pathogenesis and test novel TSHR-antigen specific immunotherapies aimed at curing Graves’ disease in humans.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 3 more Smart Citations

A Unique Mouse Strain That Develops Spontaneous, Iodine-Accelerated, Pathogenic Antibodies to the Human Thyrotrophin Receptor

Rapoport

Aliesky

Banuelos

et al. 2015

The Journal of Immunology

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A multifunctional long‐term release system for treatment of hypothyroidism

Kaya

Gümrükçü

Saraç

et al. 2019

J Biomedical Materials Res

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Hypothyroidism is an autoimmune disease associated with underactive thyroid gland. In this study, a dual effect polymeric system was designed to release Cepharanthine (CEP) to block T cell activation and Selenium (Se) to decrease the anti-thyroid peroxidase (TPOAb) concentration in order to treat hypothyroidism. For this purpose, poly(ethylenevinyl acetate) (PEVA) and polyethylene glycol (PEG) nanoparticles (NPs) including CEP were synthesized by emulsion solvent evaporation method and they were loaded to polyurethane (PU)/PEG-PUSe-PEG block copolymer blends which were fabricated by particulate leaching technique as porous sponges. Fourier-Transform Infrared (FTIR), Raman, and Nuclear Magnetic Resonance (NMR) analysis showed successful synthesis of PEG-PUSe-PEG block copolymer. A long-term zero-order release profile was obtained for CEP. Se release rate from matrices showed an oxidative stress-mediated release which can be used to adjust Se amount. According to MTS results conducted by NIH 3T3 fibroblasts, both NPs and matrices have no adverse effect on cell viability. Fluorescence microscopy and SEM images confirm the MTS results. The dual release system has potential to be effectively used in long-term treatment of hypothyroidism by addressing both auto-immune response and hormone regulation. K E Y W O R D SCepharanthine, controlled release system, hypothyroidism, selenium, thyroid hormones

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An Attempt to Induce “Graves' Disease of the Gonads” by Immunizing Mice with the Luteinizing Hormone Receptor Provides Insight into Breaking Tolerance to Self-Antigens

Chen

Aliesky²,

Rapoport³

et al. 2011

Thyroid

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Our investigations provide insight into antibody responses to self-antigens. First, antibodies are induced to large self-antigens like mouse-TPO when membrane bound. Second, lesser amino acid homology between the immunogen and mouse protein (91% vs. 97% for the human-TSHR and rat-LHR, respectively) favors antibody induction. Finally, from previous studies demonstrating the immunogenicity of the highly glycosylated human TSHR A-subunit versus our present data for the nonimmunogenic less glycosylated rat LHR, we suggest that the extent of glycosylation contributes to breaking self-tolerance.

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Antibodies to Thyroid Peroxidase Arise Spontaneously with Age in NOD.H-2h4 Mice and Appear after Thyroglobulin Antibodies

Cited by 9 publications

References 0 publications

A Unique Mouse Strain That Develops Spontaneous, Iodine-Accelerated, Pathogenic Antibodies to the Human Thyrotrophin Receptor

A Unique Mouse Strain That Develops Spontaneous, Iodine-Accelerated, Pathogenic Antibodies to the Human Thyrotrophin Receptor

A multifunctional long‐term release system for treatment of hypothyroidism

An Attempt to Induce “Graves' Disease of the Gonads” by Immunizing Mice with the Luteinizing Hormone Receptor Provides Insight into Breaking Tolerance to Self-Antigens

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