Functional autoantibodies against G-protein coupled receptors in patients with persistent Long-COVID-19 symptoms

Impairment of health after overcoming the acute phase of COVID-19 is being observed more and more frequently. Here different symptoms of neurological and/or cardiological origin have been reported. With symptoms, which are very similar to the ones reported but are not caused by SARS-CoV-2, the occurrence of functionally active autoantibodies (_fAABs) targeting G-protein coupled receptors (GPCR-_fAABs) has been discussed to be involved. We, therefore investigated, whether GPCR-_fAABs are detectable in 31 patients suffering from different Long-COVID-19 symptoms after recovery from the acute phase of the disease. The spectrum of symptoms was mostly of neurological origin (29/31 patients), including post-COVID-19 fatigue, alopecia, attention deficit, tremor and others. Combined neurological and cardiovascular disorders were reported in 17 of the 31 patients. Two recovered COVID-19 patients were free of follow-up symptoms. All 31 former COVID-19 patients had between 2 and 7 different GPCR-_fAABs that acted as receptor agonists. Some of those GPCR-_fAABs activate their target receptors which cause a positive chronotropic effect in neonatal rat cardiomyocytes, the read-out in the test system for their detection (bioassay for GPCR-_fAAB detection). Other GPCR-_fAABs, in opposite, cause a negative chronotropic effect on those cells. The positive chronotropic GPCR-_fAABs identified in the blood of Long-COVID patients targeted the β₂-adrenoceptor (β₂-_fAAB), the α₁-adrenoceptor (α₁-_fAAB), the angiotensin II AT1-receptor (AT1-_fAAB), and the nociceptin-like opioid receptor (NOC-_fAAB). The negative chronotropic GPCR-_fAABs identified targeted the muscarinic M₂-receptor (M₂-_fAAB), the MAS-receptor (MAS-_fAAB), and the ETA-receptor (ETA-_fAAB). It was analysed which of the extracellular receptor loops was targeted by the autoantibodies.