{"doi":"10.31038/edmj.2021511","title":"Severe COVID-19 Pneumonia is Associated with Increased Plasma Immunoglobulin G Agonist Autoantibodies Targeting the 5-Hydroxytryptamine 2A Receptor","abstract":"AIMS: To test whether plasma autoantibodies targeting the 5-hydroxytryptamine 2A receptor increase in COVID-19 infection; and to characterize the pharmacologic specificity, and signaling pathway activation occurring downstream of receptor binding in mouse neuroblastoma N2A cells and cell toxicity of the autoantibodies. METHODS: Plasma obtained from nineteen, older COVID-19 patients having mild or severe infection was subjected to protein-A affinity chromatography to obtain immunoglobulin G fraction. One-fortieth dilution of the protein-A eluate was tested for binding to a linear synthetic peptide QN.18 corresponding to the second extracellular loop of the human 5-hydroxytryptamine 2A receptor. Mouse neuroblastoma N2A cells were incubated with COVID-19 IgG autoantibodies in the presence or absence of selective inhibitors of G-protein coupled receptors, signaling pathway antagonists, or a novel decoy receptor peptide. RESULTS: 5-hydroxytryptamine 2A receptor autoantibody binding occurred in 17 of 19 (89%) patients with acute COVID-19 infection and increased level was significantly correlated with increased severity of COVID-19 infection. The agonist autoantibodies mediated acute neurite retraction in mouse neuroblastoma cells by a mechanism involving Gq11/PLC/IP3R/Ca2+ activation and RhoA/Rho kinase pathway signaling occurring downstream of receptor binding which had pharmacologic specificity consistent with binding to the 5-HT2A receptor. A novel synthetic peptide 5-HT2AR fragment, SN..8, dose-dependently blocked autoantibody-induced neurotoxicity. The COVID-19 autoantibodies displayed acute toxicity in bovine pulmonary artery endothelial cells (stress fiber formation, contraction) and modulated proliferation in a manner consistent with known 'biased agonism' on the 5-HT2A receptor. CONCLUSION: These data suggest that 5-HT2AR targeting autoantibodies are highly prevalent may contribute to pathophysiology in acute, severe COVID-19 infection.","journal":"PubMed","year":2021,"id":200999,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.8879,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":377755,"name":"Mark B. Zimering","orcid":null,"position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-18T23:50:52.535403Z","pmid":"33680365","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}