Autonomic dysfunction and vasoregulation in long COVID-19 are linked to anti-GPCR autoantibodies - 15/12/25

Doi : 10.1016/j.jaci.2025.10.034

Boris Schmitz, PhD ^a,^b, René Garbsch, PhD ^a,^b, Hendrik Schäfer, MSc ^a,^b, Christian Bär, PhD ^c,^d,^e, Shambhabi Chatterjee, PhD ^c,^d,^e, Gabriela Riemekasten, MD ^f, Kai Schulze-Forster, PhD ^g, Harald Heidecke, PhD ^g, Christoph Schultheiß, PhD ^h,ⁱ, Mascha Binder, MD ^h,ⁱ, Frank C. Mooren, MD ^a,^b,^⁎

^a Department of Rehabilitation Sciences, Faculty of Health, University of Witten/Herdecke, Witten, Germany

^b DRV Clinic Königsfeld, Center for Medical Rehabilitation, Ennepetal, Germany

^c Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany

^d Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Hannover, Germany

^e Fraunhofer Cluster of Excellence Immune-Mediated Diseases (CIMD), Hannover, Germany

^f Klinik Für Rheumatologie Und Klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany

^g CellTrend GmbH, Luckenwalde, Germany

^h Division of Medical Oncology, University Hospital Basel, Basel, Switzerland

ⁱ Laboratory of Translational Immuno-Oncology, Department of Biomedicine, University Hospital Basel, Basel, Switzerland

^∗ Corresponding author: Frank C. Mooren, MD, DRV Clinic Königsfeld, Center for Medical Rehabilitation, Holthauser Talstraße 2, Ennepetal 58256, Germany. DRV Clinic Königsfeld Center for Medical Rehabilitation Holthauser Talstraße 2 Ennepetal 58256 Germany

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Graphical abstract

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Abstract

Background

Severe acute respiratory syndrome coronavirus 2–triggered autoantibodies (AABs) targeting G protein–coupled receptors have been suggested to contribute to the post–acute sequelae of coronavirus disease 2019 (or post–COVID-19 syndrome [PCS]).

Objective

We sought to characterize AABs involved in autonomic dysfunction such as rhythm control and vasoregulation in patients with PCS and profile the peripheral B- and T-cell receptor (BCR/TCR) architecture to identify immunogenetic imprints of autoimmunity.

Methods

Anti–G protein–coupled receptor AABs were characterized in patients with PCS with known alteration in autonomic nervous system functions assessed by heart rate variability. Adaptive immune receptor repertoire sequencing was used to profile peripheral BCR and TCR architecture. Patients with COVID-19 with severe or moderate acute disease, after recovery, and prepandemic healthy individuals served as controls. Cardio- and vasoactive effects of AABs were analyzed using 24-hour and exercise test blood pressure measurements. The direct effect of AABs on electromechanical coupling was tested in human-induced pluripotent stem cell cardiomyocytes.

Results

AABs including autoantibody against angiotensin II receptor type 1/2, autoantibody against adrenoceptor beta 1/2, autoantibody against muscarinic acetylcholine receptor M1/M3, and autoantibody against C-X-C motif chemokine receptor 3 (CXCR3ab) were associated with heart rate variability alterations. Analysis of the broad BCR repertoire metrics revealed high similarity between patients with PCS and healthy controls for clonality and diversity measures. The level of somatic hypermutation as proxy for antigen experience was equal to that of healthy controls. Elevated CXCR3ab levels were linked to higher 24-hour mean arterial pressure, whereas patients with elevated autoantibody against muscarinic acetylcholine receptor M1 and CXCR3ab levels showed higher blood pressure during stress tests. AABs had no effect on beat frequency and amplitude of cardiomyocyte contraction in vitro .

Conclusions

These findings suggest that AABs play a modulatory role in sympathetic nervous system–mediated regulation of cardiac rhythm and vascular function in PCS. AAB levels did not correlate with BCR and TCR repertoire metrics or T-cell receptor beta variable gene usage.

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Key words : Post–acute sequelae of COVID-19, dysautonomia, autoimmunity, heart rate variability, G protein–coupled receptors

Abbreviations used : AAB, ADRA1ab/ADRA2ab, ADRB1ab/ADRB2ab, AGT1Rab/AGT2Rab, AIRR-seq, BCR, BP, COVID-19, CPET, CXCR3, CXCR3ab, ECG, GPCR, HF, HFnu, hiPSC, HR, HRV, IGH, IGHV, IGHVJ, IP-10, LF, LF/HF, LFnu, MAP, ME/CFS, M1Rab/M2Rab/M3Rab/M4Rab/M5Rab, NN, NN50, PAR1ab, PCS, SARS-CoV-2, SPO ₂ , TCR, TRBV, VO ₂