Autoantibodies Directed Against the Endothelin A Receptor in Patients With Benign Prostatic Hyperplasia

Wallukat, Gerd; Jandrig, Burkhard; Kunze, Rudolf; Wendler, Johann Jakob; Müller, Johannes; Schostak, Martin; Schimke, Ingolf

doi:10.1002/pros.23284

Cited by 12 publications

(13 citation statements)

References 38 publications

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“…ETA-AAB were found in the majority (68%) of patients with prostate cancer, targeting the second extracellular receptor loop, an epitope located in the middle region of the loop. This is insigni cantly different from our ndings with a 60% ETA-AAB positivity in patients with BPH/LUTS in whom the ETA-AAB target was comparably localized [20].…”

Section: Discussioncontrasting

confidence: 99%

“…Recently we published that patients with benign prostatic hyperplasia/low urinary tract syndrome (BPH/LUTS) carry GPCR-AAB, especially those directed against the endothelin receptor A (ETA-AAB), and have discussed this nding in the context of vascular pathophysiology and cell growth [20]. In the present study we took a look at the GPCR-AAB situation in patients with prostate cancer where we found ETA-AAB as for patients with BPH/LUTS, but additionally GPCR-AAB directed against the α1-adrenergic receptor (α1-AAB).…”

Section: Introductionmentioning

confidence: 99%

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Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Wallukat

Jandrig

Becker

et al. 2020

Preprint

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Abstract Background: For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called "functional autoantibodies" bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods: Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56-78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48-82 years, median 64) with urinary stone disorders (controls). Results: Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007.Conclusions: We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Wallukat

Jandrig

Becker

et al. 2020

Preprint

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“…Our study demonstrates for the first time that serum antibodies against the ETA-R are relatively common in patients with vascular dementia. ETA-AABs have already been found in patients with pulmonary hypertension [ 17 ], scleroderma [ 18 ], thromboangiitis obliterans [ 19 ] and benign prostate hyperplasia [ 20 ]. The ETA-AABs of patients with dementia targeted a more terminal epitope located on the second extracellular receptor loop, which is different from the epitope targeted by the ETA-AABs in benign prostate hyperplasia [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

“…ETA-AABs have already been found in patients with pulmonary hypertension [ 17 ], scleroderma [ 18 ], thromboangiitis obliterans [ 19 ] and benign prostate hyperplasia [ 20 ]. The ETA-AABs of patients with dementia targeted a more terminal epitope located on the second extracellular receptor loop, which is different from the epitope targeted by the ETA-AABs in benign prostate hyperplasia [ 20 ]. For the ETA-AABs’ pathophysiologic function, their pathology driving or at least supporting role was intensively discussed for systemic scleroderma [ 18 ].…”

Section: Discussionmentioning

confidence: 99%

Functional autoantibodies in patients with different forms of dementia

Wallukat¹,

Prüß²,

Müller³

et al. 2018

PLoS ONE

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Dementia in general and Alzheimer’s disease in particular is increasingly seen in association with autoimmunity being causatively or supportively involved in the pathogenesis. Besides classic autoantibodies (AABs) present in dementia patients, there is the new autoantibody class called functional autoantibodies, which is directed against G-protein coupled receptors (GPCRs; GPCR-AABs) and are seen as pathogenic players. However, less is known about dementia patients’ burden with functional autoantibodies. We present here for the first time a study analyzing the prevalence of GPCR-AABs in patients with different dementia forms such as unclassified, Lewy body, vascular and Alzheimer’s dementia. We identified the GPCR-AABs’ specific targets on the receptors and introduced a neutralization strategy for GPCR-AABs. Patients with Alzheimer’s and vascular dementia carried GPCR-AABs targeting the first loop of the alpha1- and the second loop of the beta2-adrenergic receptors (α1-AABs; β2-AABs). Nearly all vascular dementia patients also carry autoantibodies targeting the endothelin A receptor (ETA-AABs). The majority of patients with Lewy body dementia lacked any of the GPCR-AABs. In vitro, the function of the dementia-associated GPCR-AABs could be neutralized by the aptamer BC007. Due to the presence of GPCR-AABs in dementia patients mainly in those suffering from Alzheimer’s and vascular dementia, the orchestra of immune players in these dementia forms, so far preferentially represented by the classic autoantibodies, should be supplemented by functional autoantibodies. As dementia-associated functional autoantibodies could be neutralized by the aptamer BC007, the first step was taken for a new in vivo treatment option in dementia patients who were positive for GPCR-AABs.

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“…Recently we published that patients with benign prostatic hyperplasia/low urinary tract syndrome (BPH/LUTS) carry GPCR-AAB, especially those directed against the endothelin receptor A (ETA-AAB), and have discussed this finding in the context of vascular pathophysiology and cell growth [20]. In the present study we took a look at the GPCR-AAB situation in patients with prostate cancer where we found ETA-AAB as for patients with BPH/LUTS, but additionally GPCR-AAB directed against the α1adrenergic receptor (α1-AAB).…”

Section: Introductionmentioning

confidence: 99%

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Wallukat

Jandrig

Becker

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Background: For prostate cancer, signaling pathways induced by over-boarding stimulation of G-protein coupled receptors (GPCR) such as the endothelin, α1- and β-adrenergic, muscarinic and angiotensin 1 receptors were accused to support the carcinogenesis. However, excessive receptor stimulation by physiological receptor ligands is minimized by a control system that induces receptor sensitization and down-regulation. This system is missing when so-called "functional autoantibodies" bind to the GPCR (GPCR-AAB). If GPCR-AAB were found in patients with prostate cancer, uncontrolled GPCR stimulation could make these autoantibodies an additional supporter in prostate cancer. Methods: Using the bioassay of spontaneously beating cultured rat neonatal cardiomyocytes, GPCR-AAB were identified, quantified and characterized in the serum of 25 patients (aged 56-78 years, median 70 years) with prostate cancer compared to 10 male patients (aged 48-82 years, median 64) with urinary stone disorders (controls). Results: Of the cancer patients, 24 (96%) and 17 (68%), respectively, carried autoantibodies directed against the α1-adrenergic receptor (α1-AAB) and endothelin receptor A (ETA-AAB). No patient was negative for both GPCR-AAB. In contrast, ETA-AAB and α1-AAB were absent in all (100%) and 9 (90%) of the 10 control patients, respectively. While α1-AAB targeted a specific epitope of the first extracellular loop of the α1-adrenergic receptor subtype A, an epitope of the second extracellular loop of the ETA receptor was identified as a target of ETA-AAB. As demonstrated in vitro, the functional activity of both autoantibodies found in prostate cancer can be neutralized by the aptamer BC007. Conclusions: We hypothesized that α1-AAB and ETA-AAB, which are highly present in prostate cancer patients, could by their functional activity support carcinogenesis by excessive receptor stimulation. The in vitro demonstrated neutralization of α1- and ETA-AAB by the aptamer BC007 could open the door to complement the treatments already available for prostate cancer.

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Autoantibodies Directed Against the Endothelin A Receptor in Patients With Benign Prostatic Hyperplasia

Cited by 12 publications

References 38 publications

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

Functional autoantibodies in patients with different forms of dementia

Autoantibodies directed against α1-adrenergic receptor and endothelin receptor A in patients with prostate cancer

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