Functional Autoantibodies Targeting G-Protein-Coupled Receptors and Their Clinical Phenotype in Patients with Long-COVID, 2025, Hofmann, Hohberger+

[SNT Gatchaman]

Functional Autoantibodies Targeting G-Protein-Coupled Receptors and Their Clinical Phenotype in Patients with Long-COVID

Spoiler: Authors

Hofmann, Sophia; Lucio, Marianna; Wallukat, Gerd; Hoffmanns, Jakob; Schröder, Thora; Raith, Franziska; Szewczykowski, Charlotte; Skornia, Adam; Rech, Juergen; Schottenhamml, Julia; Harrer, Thomas; Ganslmayer, Marion; Mardin, Christian; Flecks, Merle; Lakatos, Petra; Hohberger, Bettina

Long-COVID (LC) is characterized by diverse and persistent symptoms, potentially mirroring different molecular pathways. Recent data might offer that one of them is mediated by functional autoantibodies (fAAb) targeting G protein-coupled receptors (GPCR). Thus, the aim of this study was to investigate the clinical phenotype of patients with LC in relation to their GPCR-fAAb seropositivity.

The present study recruited 194 patients with LC and profiled them based on self-reported symptoms. GPCR-fAAb seropositivity was identified by using a cardiomyocyte bioassay, testing the presence and functionality of the AAbs. Logistic regression, clustering, and decision tree analyses were applied to examine associations between GPCR-fAAb profiles and self-reported symptoms considering age and gender.

The most prevalent GPCR-fAAbs in patients with LC were fAAB targeting the β2 adrenergic receptor (β2-fAAb, 92.8%), the muscarinergic M2 receptor (M2-fAAb, 87.1%), the Angiotensin II type 1 receptor (AT1-fAAb, 85.6%), and angiotensin (1–7) Mas receptor (MAS-fAAb, 85.6%). β2-fAAb showed a significant relation with dizziness, lack of concentration, and POTS, while Endothelin Type A receptor functional autoantibody (ET-A-fAAb) was significantly related to deterioration of pre-existing neurological disorders. Statistical analysis indicated a strong positive correlation between M2-and β2-fAAb; as in addition, an association of β2-fAAb and gender was observed to one of the major clinical symptoms (fatigue/PEM), a critical impact of GPCR-fAAb on LC-pathogenesis can be assumed.

Summing up, the present data show that specific GPCR-fAAb are associated with distinct clinical phenotypes. Especially, the combination of M2-and β2-fAAb seemed to be essential for the LC-phenotype with a combination of fatigue/PEM and lack of concentration as major clinical symptoms.

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[Hutan]

The first issue from the abstract is no healthy controls. Given we have seen little difference between the prevalence of some of these autoantibodies in healthy and ME/CFS cohorts so far, the paper needs to explain why that is so. It may do, I haven't read it yet.

Those are very high prevalences, so I guess it's possible that many people (healthy and not healthy) have the autoantibodies, but there is some lack of a mechanism to stop them causing harm in the people with symptoms.

I think I'd be looking to see what cutoffs the authors used - I think it's possible to set cutoffs in the usual method for assessing antibodies at a level where basically everyone is testing positive?

And, given the very high prevalences (over 85%), I'm wondering if there is enough variation between participants to really pick out convincing groups.