Is There Evidence for IGF1R-Stimulating Abs in Graves’ Orbitopathy Pathogenesis?

Krieger, Christine C; Neumann, Susanne; Gershengorn, Marvin C.

doi:10.3390/ijms21186561

Cited by 12 publications

(6 citation statements)

References 54 publications

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“… 37 However, the interactions between TSHR and IGF-1R are complex, with immunoglobulins binding directly to TSHR. 9 , 38 Based on its important role in TAO, this study selected TSHR as the positive target during SELEX. Aptamer detection of TSHR expression showed that this receptor correlated positively with disease activity of disease, with results consistent with those obtained using anti-TSHR antibody, but at much lower cost.…”

Section: Discussionmentioning

confidence: 99%

A TSHR-Targeting Aptamer in Monocytes Correlating with Clinical Activity in TAO

Cao,

Zhang,

Chen

et al. 2024

IJN

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Background Manifestations of thyroid-associated ophthalmopathy (TAO) vary greatly. Few tools and indicators are available to assess TAO, restricting personalized diagnosis and treatment. Aim To identify an aptamer targeting thyroid-stimulating hormone receptor (TSHR) and utilize this aptamer to evaluate clinical activity in patients with TAO. Methods An aptamer targeting TSHR was developed by exponential enrichment and systematic evaluation of TSHR ligands. After truncation and optimization, the affinity, equilibrium dissociation constant, and serum stability of this aptamer were evaluated. The affinity of the TSHR-targeting aptamer to isolated fibrocytes was assessed, as was aptamer internalization by fibrocytes. The mechanism of binding was determined by molecular docking. The correlation between disease manifestations and the percentage of TSHR-positive cells was assessed by correlation analysis. Results The aptamer TSHR-21-42 was developed to bind to TSHR, with the equilibrium dissociation constant being 71.46 Kd. Isolated fibrocytes were shown to bind TSHR-21-42 through TSHR, with its affinity maintained at various temperatures and ion concentrations. TSHR-21-42 could compete with anti-TSHR antibody, both for binding site to TSHR and uptake by cells after binding. In addition, TSHR-21-42 could bind to leukocytes in peripheral blood, with this binding differing in patients with TAO and healthy control subjects. The percentage of TSHR-positive monocytes, as determined by binding of TSHR-21-42, correlated positively with clinical activity score in patients with TAO, indicating that TSHR-21-42 binding could assess the severity of TAO. Conclusion This aptamer targeting TSHR may be used to objectively assess disease activity in patients with TAO, by evaluating the percentages of TSHR positive cells in peripheral blood.

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Section: Discussionmentioning

confidence: 99%

A TSHR-Targeting Aptamer in Monocytes Correlating with Clinical Activity in TAO

Cao,

Zhang,

Chen

et al. 2024

IJN

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“…A role for IGF-1R in the pathogenesis of GO has been proposed, but the presence and function of IGF-1R antibodies (IGF-1R Abs) are controversial ( 82 ). The findings of Marcus-Samuels et al.…”

Section: Autoantibodies In Go Pathogenesismentioning

confidence: 99%

A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves’ orbitopathy

2023

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Graves’ orbitopathy (GO) is an organ-specific autoimmune disease, but its pathogenesis remains unclear. There are few review articles on GO research from the perspective of target cells and target antigens. A systematic search of PubMed was performed, focusing mainly on studies published after 2015 that involve the role of target cells, orbital fibroblasts (OFs) and orbital adipocytes (OAs), target antigens, thyrotropin receptor (TSHR) and insulin-like growth factor-1 receptor (IGF-1R), and their corresponding antibodies, TSHR antibodies (TRAbs) and IGF-1R antibodies (IGF-1R Abs), in GO pathogenesis and the potentially effective therapies that target TSHR and IGF-1R. Based on the results, OFs may be derived from bone marrow-derived CD34+ fibrocytes. In addition to CD34+ OFs, CD34- OFs are important in the pathogenesis of GO and may be involved in hyaluronan formation. CD34- OFs expressing Slit2 suppress the phenotype of CD34+ OFs. β-arrestin 1 can be involved in TSHR/IGF-1R crosstalk as a scaffold. Research on TRAbs has gradually shifted to TSAbs, TBAbs and the titre of TRAbs. However, the existence and role of IGF-1R Abs are still unknown and deserve further study. Basic and clinical trials of TSHR-inhibiting therapies are increasing, and TSHR is an expected therapeutic target. Teprotumumab has become the latest second-line treatment for GO. This review aims to effectively describe the pathogenesis of GO from the perspective of target cells and target antigens and provide ideas for its fundamental treatment.

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“…As the study progressed, researchers found that IGF-1R can also be involved in GO pathogenesis through the IGF-1R/TSHR crosstalk pathway, where GO Igs activate crosstalk by binding to TSHR on OFs ( 46 ). Kriege et al.…”

Section: Immune Factorsmentioning

confidence: 99%

“…Thus, TSHR and IGF-1R can form physical and functional protein complexes. It has been shown that IGF-1R and TSHR can interact to increase signaling when activated by their respective ligands, and that inhibition of IGF-1R activity blocks signaling downstream of TSHR ( 46 ). IGF-1R/TSHR signaling also boosts the production of hyaluronan in GO OFs and other glycosaminoglycan components in the ECM ( 48 ) ( Figure 2 ).…”

Section: Immune Factorsmentioning

confidence: 99%

Research progress on the pathogenesis of Graves’ ophthalmopathy: Based on immunity, noncoding RNA and exosomes

et al. 2022

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Graves’ ophthalmopathy (GO), also known as thyroid-associated ophthalmopathy, is a common potentially vision-threatening organ-specific autoimmune disease and the most common extrathyroidal manifestation of Graves’ disease. It can happen to those who have hyperthyroidism or euthyroidism. At present, the pathogenesis of GO has not been fully elucidated, and the majority of clinical treatments are symptomatic. Therefore, we are eager to discover any new therapeutic strategies that target the etiology of GO. To provide fresh ideas for the creation of new therapeutic techniques, this study primarily discusses the research state and progress of GO-related pathogenesis from the perspectives of GO’s cellular immunity, autoantigens, non-coding RNAs, and exosomes.

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Is There Evidence for IGF1R-Stimulating Abs in Graves’ Orbitopathy Pathogenesis?

Cited by 12 publications

References 54 publications

A TSHR-Targeting Aptamer in Monocytes Correlating with Clinical Activity in TAO

A TSHR-Targeting Aptamer in Monocytes Correlating with Clinical Activity in TAO

A review of TSHR- and IGF-1R-related pathogenesis and treatment of Graves’ orbitopathy

Research progress on the pathogenesis of Graves’ ophthalmopathy: Based on immunity, noncoding RNA and exosomes

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