Trial Report Circulating Autoantibodies Against G-Protein-Coupled Receptors as Potential Biomarkers for Long COVID: Preliminary Investigations, 2026, Camici rt al

[John Mac]

Full title:

Prevalence of Circulating Autoantibodies Against G-Protein-Coupled Receptors as Potential Biomarkers for Long COVID: Preliminary Investigations​

Abstract​

This prospective, single-center, case-control study investigated circulating autoantibodies (AAbs) targeting G protein-coupled receptors (GPCRs) in Long COVID (LC) patients to identify potential diagnostic biomarkers and therapeutic targets.

Fifteen participants were enrolled at the LC clinic in Rome: eleven with severe LC—defined as >4 persistent symptoms (fatigue, cognitive impairment, poor exercise tolerance, dyspnea, arthralgia, or dysautonomic manifestations) >3 months post-infection—and four asymptomatic post-COVID (APC) individuals.

Fatigue was assessed using the Fatigue Assessment Scale (FAS ≥ 22; severe ≥ 35). Auto-Abs against AT1R, endothelin receptor A, adrenergic (α1, α2, β1, β2), and muscarinic (M1–M5) receptors were quantified, along with blood cortisol and ACTH levels. SARS-CoV-2-specific T-cell responses to Spike and Nucleocapsid proteins were evaluated by ELISpot assay.

In our small cohort, LC patients were younger, had fewer comorbidities (p = 0.03), fewer vaccine doses (p = 0.03), and higher FAS scores (33 vs. 12; p = 0.001).

Mean GPCR AAbs levels were higher in LC than in APC (8.88 vs. 5.45 Units/mL; p = 0.17), indicating a coherent autoimmune signature in LC that correlates with symptom development.

Morning cortisol was lower in LC (12.7 vs. 17 mg/dL; p = 0.01), and T-cell responses tended to be weaker.

These findings suggest GPCR AAbs may serve as biomarkers and therapeutic targets for a subset of patients, guiding diagnosis and treatments with IV immunoglobulin or immunoadsorption.

Long COVID (LC) is a multisystemic post-viral syndrome that can persist for months or even years after the acute SARS-CoV-2 infection [1]. It comprises heterogeneous clinical subsets, and it fits within the broader category of the infection-associated chronic conditions sharing numerous clinical and pathophysiological features with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

My bolding

https://www.mdpi.com/1422-0067/27/4/1787

 

[Jonathan Edwards]

Mean GPCR AAbs levels were higher in LC than in APC (8.88 vs. 5.45 Units/mL; p = 0.17), indicating a coherent autoimmune signature in LC that correlates with symptom development.

If p=0.17 no way is this a 'coherent signature'.

 

[EndME]

This has been looked at over and over again. I'm sure one needed an additional study of laughable sample size with insufficient patient characterisation. I can understand when people want to be in on a trend, but seems like they're a bit late?

 

[ryanc97]

Can someone explain why only these antibodies pop up when talking about AABs? There are probably many other unknown ones that might be causing ME. Why are these the only ones with a test?

 

[Jonathan Edwards]

Can someone explain why only these antibodies pop up when talking about AABs? There are probably many other unknown ones that might be causing ME. Why are these the only ones with a test?

They are just trendy.

And people have been publishing shaky studies on associations with GPCR antibodies in all sort of conditions for a couple of decades. Maybe they are attractive because it seems you can weave all sorts of stories around them about symptom mechanisms.

The difference from normal are tiny and no way pathogenic.

 

[Utsikt]

The figures in the main text:

Figure 1. Levels of autoantibodies targeting G-protein-coupled receptors in Long COVID (LC) and asymptomatic post-COVID (APC) patients. Autoantibodies were measured in serum samples from both groups (LC and APC) using ELISA (CellTrend GmbH, Luckenwalde, Germany). Asymptomatic Post-COVID, LC: LongCOVID. AT1R-Ab: anti-Angiotensin II type 1 receptor-Ab. ETAR-Ab: anti-Endothelin receptor-Ab. α1R-Ab: anti-α-Adrenergic receptors Ab. α2R-Ab: anti-α2-Adrenergic receptors Ab. β1R-Ab: anti-β1-Adrenergic receptor Ab. β2R-Ab: anti-β2 adrenergic receptor Ab. M1R-Ab: anti Muscarinic Cholinergic receptors-1 Ab. M2R-Ab: anti-Muscarinic Cholinergic Receptors-2 Ab. M3R-Ab: anti-Muscarinic Cholinergic Receptors-3 Ab. M4R-Ab: anti Muscarinic Cholinergic receptors-4 Ab. M5R-Ab anti-Muscarinic Cholinergic receptors-5 Ab. Data were shown as mean values (standard deviation). Units are arbitrary units decided by the kit manufacturer and reported as is from test readout. We report data points, mean mean ±- SD; N(LC) = 11, N(APC) = 4.

Figure 2. SARS-CoV-2-specific T cell response to Spike and Nucleocapsid proteins in Long COVID and asymptomatic post-COVID patients. The Elispot assay assessed the SARS-CoV-2-specific T-cell response against the Spike and Nucleocapsid proteins. PBMC were stimulated with S and N peptides (1 µg/mL) for 20 h. Data were shown as median values. APC: Asymptomatic Post-COVID, LC: LongCOVID. We report data points as well as 5th, 25th, 50th, 75th, and 95th percentile ranges. N(LC) = 11, N(APC) = 4.

Figure 3. Correlation matrix of clinical, immunological, and endocrine parameters in Long COVID and asymptomatic post-COVID patients. Clustered heatmap showing pairwise Pearson correlations among GPCR autoantibody levels, FAS score, cytokine concentrations, hormonal parameters, and demographic variables. Positive correlations are represented in red and negative correlations in blue, with color intensity proportional to the correlation coefficient. Hierarchical clustering reveals that GPCR autoantibodies (β1-, β2-, α1-, α2-, M1–M4-, AT1R-, and ETAR-Abs) cluster together with fatigue-related symptoms and dysautonomic manifestations, supporting the presence of a shared and biologically meaningful autoimmune signature underlying Long COVID. Cortisol, age, and vaccine dose number inversely correlated with GPCR autoantibody levels and defined the APC group. Sample size of this pilot study was 15 participants. Correlation coefficients are reported in Supplementary Table S1.