Upregulation of autoantibodies (aabs) of the immunoglobulin G (IgG) class to GPCRs has been observed in both COVID-19 ^1,2and LC patients ^3,4. Animals experimentally infected with SARS-CoV-2 also generate functional aabs against GPCRs ⁵.

PGE2 has been shown to stimulate the production and class switching of autoantibodies from the immunoglobulin M (IgM) to IgG ⁶ or IgE types ^{7 8,9}, through the cAMP pathway (EP2/EP4) ¹⁰. Aabs can modulate the binding of true ligands. We suggest that PGE2 may hinder ligand binding in COVID-19 and LC through aab production ^11,12. 

1              Sacchi, M. C. et al. SARS-CoV-2 infection as a trigger of autoimmune response. Clin Transl Sci 14, 898-907 (2021). https://doi.org/10.1111/cts.12953

2              Geanes, E. S., McLennan, R., LeMaster, C. & Bradley, T. Autoantibodies to ACE2 and immune molecules are associated with COVID-19 disease severity. Communications Medicine 4, 47 (2024). https://doi.org/10.1038/s43856-024-00477-z

3              Talwar, S., Harker, J. A., Openshaw, P. J. M. & Thwaites, R. S. Autoimmunity in long COVID. Journal of Allergy and Clinical Immunology 155, 1082-1094 (2025). https://doi.org/https://doi.org/10.1016/j.jaci.2025.02.005

4              Sotzny, F. et al. Dysregulated autoantibodies targeting vaso- and immunoregulatory receptors in Post COVID Syndrome correlate with symptom severity. Frontiers in Immunology Volume 13 – 2022 (2022). https://doi.org/10.3389/fimmu.2022.981532

5              Wallukat, G., Wernike, K., Bachamanda Somesh, D., Mettenleiter, T. C. & Müller, J. Animals Experimentally Infected with SARS-CoV-2 Generate Functional Autoantibodies against G-Protein-Coupled Receptors. Biomedicines 11 (2023). https://doi.org/10.3390/biomedicines11102668

6              Stein, S. H. & Phipps, R. P. Antigen-specific IGG2A production in response to prostaglandin E2, immune complexes, and IFN-gamma. The Journal of Immunology 147, 2500-2506 (1991). https://doi.org/10.4049/jimmunol.147.8.2500

7              Fedyk, E. R. & Phipps, R. P. Prostaglandin E2 receptors of the EP2 and EP4 subtypes regulate activation and differentiation of mouse B lymphocytes to IgE-secreting cells. Proc Natl Acad Sci U S A 93, 10978-10983 (1996). https://doi.org/10.1073/pnas.93.20.10978

8              Ishihara, Y. et al. Regulation of Immunoglobulin G2 Production by Prostaglandin E₂ and Platelet-Activating Factor. Infection and Immunity 68, 1563-1568 (2000). https://doi.org/doi:10.1128/iai.68.3.1563-1568.2000

9              Roper, R. L. & Phipps, R. P. Prostaglandin E2 and cAMP inhibit B lymphocyte activation and simultaneously promote IgE and IgG1 synthesis. J Immunol 149, 2984-2991 (1992).

10           Tsuge, K., Inazumi, T., Shimamoto, A. & Sugimoto, Y. Molecular mechanisms underlying prostaglandin E2-exacerbated inflammation and immune diseases. Int Immunol 31, 597-606 (2019). https://doi.org/10.1093/intimm/dxz021

11           Ludwig, R. J. et al. Mechanisms of Autoantibody-Induced Pathology. Frontiers in Immunology Volume 8 – 2017 (2017). https://doi.org/10.3389/fimmu.2017.00603

12           Meyer, C. & Heidecke, H. Antibodies Against GPCR. Front Biosci (Landmark Ed) 23, 2177-2194 (2018). https://doi.org/10.2741/4698