Antagonistic Autoantibodies to Insulin-Like Growth Factor-1 Receptor Associate with Poor Physical Strength

Schwiebert, Christian; Kühnen, Peter; Becker, Niels-Peter; Welsink, Tim; Keller, Theresa; Minich, Waldemar B.; Wiegand, Susanna; Schomburg, Lutz

doi:10.3390/ijms21020463

Cited by 10 publications

(12 citation statements)

References 33 publications

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“…Using the same technique of constructing an antigen receptor fusion protein with luciferase as reporter at the intracellular C-terminus, we identified around 10% of subjects positive for aAb to the IGF1-receptor (IGF1R-aAb) [ 28 ]. The IGF1R-aAb proved to inhibit growth hormone signaling and proliferation in vitro [ 28 ], and were associated with low muscle strength in adolescent subjects [ 35 ]. Due to the very small number of positive samples identified in the current study, a similar analysis on a potential physiological role of natural GnRH-R-aAb is not possible.…”

Section: Discussionmentioning

confidence: 99%

Natural autoantibodies to the gonadotropin-releasing hormone receptor in polycystic ovarian syndrome

et al. 2021

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Context Polycystic ovarian syndrome (PCOS) is a complex disease with different subtypes and unclear etiology. Among the frequent comorbidities are autoimmune diseases, suggesting that autoantibodies (aAb) may be involved in PCOS pathogenesis. Objective As the gonadal axis often is dysregulated, we tested the hypothesis that aAb to the gonadotropin-releasing hormone receptor (GnRH-R) are of diagnostic value in PCOS. Design An in vitro assay for quantifying aAb to the GnRH-R (GnRH-R-aAb) was established by using a recombinant fusion protein of full-length human GnRH-R and firefly luciferase. A commercial rabbit antiserum to human GnRH-R was used for standardization. Serum samples of control subjects and different cohorts of European PCOS patients (n = 1051) were analyzed. Results The novel GnRH-R-aAb assay was sensitive, and signals were linear on dilution when tested with the commercial GnRH-R antiserum. Natural GnRH-R-aAb were detected in one control (0.25%) and two PCOS samples (0.31%), and 12 samples were slightly above the threshold of positivity. The identification of samples with positive GnRH-R-aAb was reproducible and the signals showed no matrix interferences. Conclusion Natural GnRH-R-aAb are present in a very small fraction of adult control and PCOS subjects of European decent. Our results do not support the hypothesis that the GnRH-R constitutes a relevant autoantigen in PCOS.

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Section: Discussionmentioning

confidence: 99%

Natural autoantibodies to the gonadotropin-releasing hormone receptor in polycystic ovarian syndrome

et al. 2021

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“…Fortunately, therapeutic measures have been improved, and disease severity can successfully be controlled by pharmacological intervention [52]. We have recently studied aAb to the IGF1-receptor (IGF1R), impairing IGF1 signalling [18], and related the presence of IGF1R-aAb to poor physical strength in young subjects [20]. Additional physiological effects are likely, given the broad relevance of IGF1 in development and disease.…”

Section: Discussionmentioning

confidence: 99%

“…The open reading frames encoding human MCT8 and human MCT10, respectively, were amplified by PCR and fused in frame to a firefly luciferase gene (Luc), essentially as described [18][19][20]. The resulting composite reading frame was inserted into the expression vector pIRESneo, generating the expression vectors pIRESneo-MCT8-Luc and pIRESneo-MCT10-Luc, respectively.…”

Section: Construction Of Mct8 and Mct10 Luciferase Fusion Proteins Fomentioning

confidence: 99%

“…The suspension was cleared by centrifugation (2,000 g, 5 min, 4 °C), the supernatant was collected, stored at -80 C in aliquots, and thawed when needed for the measurements. Precipitation assays were established with the transporter fusion proteins, essentially as described previously [18][19][20].…”

Section: Construction Of Mct8 and Mct10 Luciferase Fusion Proteins Fomentioning

confidence: 99%

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Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10

Porst¹,

Johannes²,

Gluschke³

et al. 2021

Preprint

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The monocarboxylate transporters 8 (MCT8) and 10 (MCT10) are important for thyroid hormone (TH) uptake and signaling. Reduced TH activity is associated with impaired development, weight gain and discomfort. We hypothesized that autoantibodies (aAb) to MCT8 or MCT10 are prevalent in thyroid disease and obesity. Analytical tests for MCT8-aAb and MCT10-aAb were developed and characterized with commercial antiserum. Serum samples from healthy controls, thyroid patients and young overweight subjects were analyzed, and prevalence of the aAb was compared. MCT8-aAb were additionally tested for biological effects on thyroid hormone uptake in cell culture. Positive MCT8-aAb and MCT10-aAb were detected in all three clinical cohorts analyzed. MCT8-aAb were most prevalent in thyroid patients (11.9%) as compared to healthy controls (3.8%) and overweight adolescents (4.2%). MCT8-aAb positive serum reduced T4 uptake in cell culture in comparison to MCT8-aAb negative control serum. Prevalence of MCT10-aAb was highest in the group of thyroid patients as compared to healthy subjects or overweight adolescents (9.0% versus 4.5% and 6.3%, respectively). We conclude that MCT8 and MCT10 represent autoantigens in humans, and that MCT8-aAb may interfere with regular TH uptake and signaling. The increased prevalence of MCT8-aAb and MCT10-aAb in thyroid disease suggests that their presence may be of pathophysiological relevance. This hypothesis deserves an analysis in large prospective studies.

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“…Of note, the authors of two other studies measuring IGF1R phosphorylation as an indication of direct IGF1R activation by GO-Igs found only very small levels of phosphorylation, although one group concluded that there was no evidence of stimulating IGF1RAbs [12], whereas the other concluded that there may be evidence that a subset of GO patients express stimulating IGF1RAbs [13]. Similarly, Schwiebert et al [40] found naturally occurring IGF1RAbs in young, overweight children, however, these IGF1RAb were antagonists not stimulators.…”

Section: Evidence That Go-igs Activate Tshr/igf1r Crosstalk Via Bindimentioning

confidence: 97%

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

Krieger

Neumann

Gershengorn

2020

IJMS

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In this review, we summarize the evidence against direct stimulation of insulin-like growth factor 1 receptors (IGF1Rs) by autoantibodies in Graves’ orbitopathy (GO) pathogenesis. We describe a model of thyroid-stimulating hormone (TSH) receptor (TSHR)/IGF1R crosstalk and present evidence that observations indicating IGF1R’s role in GO could be explained by this mechanism. We evaluate the evidence for and against IGF1R as a direct target of stimulating IGF1R antibodies (IGF1RAbs) and conclude that GO pathogenesis does not involve directly stimulating IGF1RAbs. We further conclude that the preponderance of evidence supports TSHR as the direct and only target of stimulating autoantibodies in GO and maintain that the TSHR should remain a major target for further development of a medical therapy for GO in concert with drugs that target TSHR/IGF1R crosstalk.

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Antagonistic Autoantibodies to Insulin-Like Growth Factor-1 Receptor Associate with Poor Physical Strength

Cited by 10 publications

References 33 publications

Natural autoantibodies to the gonadotropin-releasing hormone receptor in polycystic ovarian syndrome

Natural autoantibodies to the gonadotropin-releasing hormone receptor in polycystic ovarian syndrome

Natural Autoimmunity to the Thyroid Hormone Monocarboxylate Transporters MCT8 and MCT10

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

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