Review and Hypothesis: Does Graves' Disease Develop in Non-Human Great Apes?

McLachlan, Sandra M.; Alpi, Kristine M.; Rapoport, Basil

doi:10.1089/thy.2011.0209

Cited by 23 publications

(13 citation statements)

References 49 publications

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“…Additionally, there was a significant decrease in the weight of hyperthyroid monkeys, which more closely approximates human GD. It has been uncertain for a long time whether GD could occur in nonhuman primates (McLachlan et al 2011), and we have demonstrated in this study that GD could be induced in rhesus monkeys. Tregs are involved in the maintenance of homeostatic mechanisms that suppress autoreactive T cell proliferation and promote autoreactive T cell anergy (Wang et al 2009).…”

Section: Discussionmentioning

confidence: 62%

Hyperthyroid monkeys: a nonhuman primate model of experimental Graves' disease

Wang

et al. 2013

Journal of Endocrinology

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Graves' disease (GD) is a common organ-specific autoimmune disease with the prevalence between 0.5 and 2% in women. Several lines of evidence indicate that the shed A-subunit rather than the full-length thyrotropin receptor (TSHR) is the autoantigen that triggers autoimmunity and leads to hyperthyroidism. We have for the first time induced GD in female rhesus monkeys, which exhibit greater similarity to patients with GD than previous rodent models. After final immunization, the monkeys injected with adenovirus expressing the A-subunit of TSHR (A-sub-Ad) showed some characteristics of GD. When compared with controls, all the test monkeys had significantly higher TSHR antibody levels, half of them had increased total thyroxine (T 4 ) and free T 4 , and 50% developed goiter. To better understand the underlying mechanisms, quantitative studies on subpopulations of CD4CT helper cells were carried out. The data indicated that this GD model involved a mixed Th1 and Th2 response. Declined Treg proportions and increased Th17:Treg ratio are also observed. Our rhesus monkey model successfully mimicked GD in humans in many aspects. It would be a useful tool for furthering our understanding of the pathogenesis of GD and would potentially shorten the distance toward the prevention and treatment of this disease in human.

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Section: Discussionmentioning

confidence: 62%

Hyperthyroid monkeys: a nonhuman primate model of experimental Graves' disease

Wang

et al. 2013

Journal of Endocrinology

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“…The relatively low OVA antibody response versus the strong response to the h TSHR A-subunit in this mouse strain may relate to glycosylation, which plays a role in antigen uptake and internalization (for example (39). Thus, OVA has a single N-linked glycosylation site (32) whereas the hTSHR A-subunit has 5 N-linked glycosylation sites (40). …”

Section: Discussionmentioning

confidence: 99%

Critical Differences between Induced and Spontaneous Mouse Models of Graves’ Disease with Implications for Antigen-Specific Immunotherapy in Humans

Rapoport

Banuelos

Aliesky

et al. 2016

The Journal of Immunology

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Graves’ hyperthyroidism, a common autoimmune disease caused by pathogenic autoantibodies to the thyrotropin (TSH) receptor, can be treated but not cured. This single autoantigenic target makes Graves’ disease a prime candidate for antigen-specific immunotherapy. Previously, in an induced mouse model, injecting TSHR A-subunit protein attenuated hyperthyroidism by diverting pathogenic TSHR antibodies to a non-functional variety. Here we explored the possibility of a similar diversion in a mouse model that spontaneously develops pathogenic TSHR autoantibodies, NOD.H2h4 mice with the human(h) TSHR A-subunit transgene expressed in the thyroid and (shown here) the thymus. We hypothesized that such diversion would occur following injection of “inactive” hTSHR A-subunit protein recognized only by non-pathogenic (not pathogenic) TSHR antibodies. Surprisingly, rather than attenuating the pre-existing pathogenic TSHR level, in TSHR/NOD.H2h4 mice inactive hTSHR antigen injected without adjuvant enhanced the levels of pathogenic TSH-binding inhibition (TBI) and thyroid stimulating antibodies, as well as non-pathogenic antibodies detected by ELISA. This effect was TSHR-specific as spontaneously occurring autoantibodies to thyroglobulin and thyroid peroxidase were unaffected. As controls, non-transgenic NOD.H2h4 mice similarly injected with inactive hTSHR A-subunit protein unexpectedly developed TSHR antibodies, but only of the non-pathogenic variety detected by ELISA. Our observations highlight critical differences between induced and spontaneous mouse models of Graves’ disease with implications for potential immunotherapy in humans. In hTSHR/NOD.H2h4 mice with ongoing disease, injecting inactive hTSHR A-subunit protein fails to divert the autoantibody response to a non-pathogenic form. Indeed, such therapy is likely to enhance pathogenic antibody production and exacerbate Graves’ disease in humans.

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“…The contribution of glycosylation changes to disease progress was shown also in autoimmunity processes [66], among others those taking place in the thyroid gland [72,75]. It was hypothesised that TSHR glycans are involved in breaking the self-tolerance state in GD [57]. The detailed analysis of TSHR glycosylation alterations in AITD is crucial for verification of this hypothesis and is necessary to better understand the pathological mechanism of thyroid autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

“…One hypothesis assumes that the presence of six N-glycans on the surface of human TSHR is one of the factors influencing GD development. There are only four sites of N-glycosylation in fish TSHR, and GD has never been observed in cats, dogs, and mice with five N-glycosylation sites; therefore, it is possible that the higher TSHR N-glycosylation may correlate with the degree of receptor immunogenicity and have an affect on the breakdown of immunological tolerance [57,58].…”

Section: Prace Poglądowementioning

confidence: 99%

“…U ryb istnieją tylko 4 miejsca N-glikozylacji w receptorze TSH, a 5 wykazano u kotów, psów i myszy, w przypadku których nigdy nie stwierdzono autoimmunizacji typowej dla choroby GD występującej u ludzi. Z tego powodu jedna z hipotez zakłada, że intensywniejsza N-glikozylacja TSHR u ludzi, wynikająca z obecności 6 motywów Asn-X-Ser/Thr w sekwencji aminokwasowej, może korelować ze stopniem immunogenności receptora i mieć wpływ na utratę tolerancji immunologicznej [57,58].…”

Section: Prace Poglądoweunclassified

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Glycosylation of thyroid-stimulating hormone receptor

Korta

Pocheć

2019

Endokrynologia Polska

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Thyroid-stimulating hormone receptor (TSHR) is a typical membrane receptor with 7-transmembrane helix domain (7TMR), coupled to the G protein. The mature receptor, present in the cell membrane, is composed of the A subunit comprising a large extracellular domain, and the B subunit, which consists of a short extracellular fragment anchored in the cell membrane and an intracellular part. The TSH receptor is subject to numerous post-translational modifications that determine its final structure and significantly affect its activity. One of them is glycosylation. TSHR is abundantly N-glycosylated, due to the presence of six N-glycosylation sites in the extracellular domain (Asn77, Asn99, Asn113, Asn177, Asn198, Asn302), mostly evolutionarily conserved. N-glycans constitute 30-40% of the receptor molecular weight. The glycans are necessary for the receptor trafficking to the plasma membrane and binding of TSH to the receptor. Fucosylated and sialylated N-oligosaccharides were found on TSHR molecules. The increased sialylation of TSHR glycans correlates positively with the receptor binding ability and prolongs the time of receptor incorporation into the cell membrane. TSHR is the main autoantigen in Graves' disease (GD), one of the thyroid autoimmune diseases. One hypothesis assumes that the higher N-glycosylation of THSR in human compared to animals influences the breaking of autotolerance and GD development. N-oligosaccharides are the important part of THSR molecule, necessary for the proper functioning of receptors and probably involved in thyroid autoimmunity in GD.

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Review and Hypothesis: Does Graves' Disease Develop in Non-Human Great Apes?

Cited by 23 publications

References 49 publications

Hyperthyroid monkeys: a nonhuman primate model of experimental Graves' disease

Hyperthyroid monkeys: a nonhuman primate model of experimental Graves' disease

Critical Differences between Induced and Spontaneous Mouse Models of Graves’ Disease with Implications for Antigen-Specific Immunotherapy in Humans

Glycosylation of thyroid-stimulating hormone receptor

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