{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T10:50:07Z","timestamp":1777891807947,"version":"3.51.4"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T00:00:00Z","timestamp":1777593600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Fc-mediated antibody effector functions play key roles in both antiviral immunity and immunopathology in COVID-19. While antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) contribute to pathogen clearance, they may also be associated with inflammatory responses. The contribution of these pathways\u2014particularly antibody-dependent enhancement (ADE)\u2014to severe COVID-19 remains incompletely understood. We prospectively investigated relationships among ADE, ADCC, and ADCP across multiple SARS-CoV-2 variants from 64 patients with laboratory-confirmed SARS-CoV-2 infection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patient Fc-mediated effector activities were profiled. Disease severity was classified using National Institutes of Health criteria. ADE was assessed using pseudotyped SARS-CoV-2 entry into THP-1 cells, whereas Fc gamma receptors (Fc\u03b3R)IIIa- and Fc\u03b3RIIa-mediated reporter activities (reflecting ADCC and ADCP surrogate responses, respectively) were assessed using spike-expressing A549 target cells and Fc\u03b3R-expressing Jurkat-Lucia reporter cells. Functional responses were measured against wild-type SARS-CoV-2 and Omicron sublineages (B.1.1.529, BA.4\/BA.5, XBB.1.5).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 64 participants (40 with mild, 24 with severe COVID-19; median age, 58 years [interquartile range, 45\u201371], 56% men), anti-spike IgG binding did not differ by severity. ADE activity was significantly higher in severe than mild COVID-19 and remained independently associated with severity in multivariable analysis. Fc\u03b3RIIa-mediated reporter activity was higher in severe cases in descriptive and univariate analyses, but lost statistical significance after adjustment for age, sex, comorbidities, and variant period. Fc\u03b3RIIIa-mediated reporter activity did not differ by severity but was reduced against Omicron variants. Plasma from severe cases promoted enhanced Fc\u03b3R-dependent viral entry in pseudovirus assays; yet, subsequent live Omicron virus infection did not lead to an increase in viral RNA replication\u2014consistent with an abortive infection without evidence of productive viral replication.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our findings suggest that ADE activity is associated with dysregulated Fc-mediated immune responses in severe COVID-19. Although multiple Fc\u03b3 receptor\u2013mediated pathways were observed, the independent association of ADE with disease severity supports a potential link with excessive Fc\u03b3R-mediated myeloid activation. Fc\u03b3RIIa reporter activity likely reflects overlapping immune signatures rather than an independent pathogenic contribution, whereas Fc\u03b3RIIIa reporter activity showed no clear relationship with clinical outcomes. These findings highlight the complexity of Fc-effector immunity and support further investigation into therapeutic strategies targeting Fc\u2013Fc\u03b3R interactions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1797975","type":"journal-article","created":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T06:09:15Z","timestamp":1777615755000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fc-mediated antibody functions are associated with disease severity in COVID-19"],"prefix":"10.3389","volume":"17","author":[{"given":"Sungim","family":"Choi","sequence":"first","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital","place":["Goyang-si, Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Su","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital","place":["Goyang-si, Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaehwan","family":"You","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute for Viral Diseases, College of Medicine, Korea University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Man-Seong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Institute for Viral Diseases, College of Medicine, Korea University","place":["Seoul, Republic of Korea"]},{"name":"Department of Microbiology, Vaccine Innovation Center, Institute for Viral Diseases, College of Medicine, Korea University","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hee Bum","family":"Jo","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Incheon Sejong Hospital","place":["Incheon, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ji-Soo","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung-Han","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seong Yeon","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Infectious Diseases, Department of Internal Medicine, Dongguk University Ilsan Hospital","place":["Goyang-si, Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1146\/annurev-med-042921-020956","article-title":"COVID-19: Challenges of viral variants","volume":"74","author":"Jacobs","year":"2023","journal-title":"Annu Rev Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMcp2009249","article-title":"Mild or moderate covid-19","volume":"383","author":"Gandhi","year":"2020","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2020.557453","article-title":"Prognostic factors for COVID-19 pneumonia progression to severe symptoms based on earlier clinical features: A retrospective analysis","volume":"7","author":"Huang","year":"2020","journal-title":"Front Med (Laus)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2600-6","article-title":"Association of COVID-19 inflammation with activation of the C5a-C5aR1 axis","volume":"588","author":"Carvelli","year":"2020","journal-title":"Nature"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-0320-7","article-title":"Complement as a target in COVID-19","volume":"20","author":"Risitano","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jamainternmed.2020.3313","article-title":"Is a \u2018cytokine storm\u2019 relevant to COVID-19","volume":"180","author":"Sinha","year":"2020","journal-title":"JAMA Intern Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01377-8","article-title":"Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection","volume":"27","author":"Khoury","year":"2021","journal-title":"Nat Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03696-9","article-title":"Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection","volume":"595","author":"Wang","year":"2021","journal-title":"Nature"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2372","DOI":"10.1016\/j.cell.2021.03.013","article-title":"Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity","volume":"184","author":"Garcia-Beltran","year":"2021","journal-title":"Cell"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04386-2","article-title":"Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift","volume":"602","author":"Cameroni","year":"2022","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04385-3","article-title":"Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies","volume":"602","author":"Cao","year":"2022","journal-title":"Nature"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-020-00410-0","article-title":"The role of IgG Fc receptors in antibody-dependent enhancement","volume":"20","author":"Bournazos","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04388-0","article-title":"Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2","volume":"602","author":"Liu","year":"2022","journal-title":"Nature"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1508","DOI":"10.1016\/j.cell.2020.10.052","article-title":"Compromised humoral functional evolution tracks with SARS-CoV-2 mortality","volume":"183","author":"Zohar","year":"2020","journal-title":"Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1016\/j.immuni.2020.10.012","article-title":"Distinctive humoral elicitation patterns of SARS-CoV-2 antibody-dependent cellular cytotoxicity and phagocytosis in COVID-19","volume":"53","author":"Atyeo","year":"2020","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00828-7","article-title":"Pro-inflammatory IgG Fc structures in patients with severe COVID-19","volume":"22","author":"Chakraborty","year":"2021","journal-title":"Nat Immunol."},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00026.2020","article-title":"The pathogenesis of COVID-19","volume":"101","author":"Sch\u00e4fer","year":"2021","journal-title":"Physiol Rev"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms21207746","article-title":"Antibody-dependent enhancement and SARS-CoV-2: Principles and predictions","volume":"21","author":"Lee","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2538-8","article-title":"A perspective on potential antibody-dependent enhancement of SARS-CoV-2","volume":"584","author":"Arvin","year":"2020","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2021.109570","article-title":"Longitudinal analysis of the humoral immune response to SARS-CoV-2 Spike in convalescent individuals and its ability to neutralize variants of concern","volume":"36","author":"Khurana","year":"2021","journal-title":"Cell Rep"},{"key":"B21","volume-title":"Coronavirus disease 2019 (COVID-19) treatment guidelines","year":"2024"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/ofid\/ofac248","article-title":"Transmission potential of the omicron variant of severe acute respiratory syndrome coronavirus 2 in South Korea, 25 November 2021\u20138 January 2022","volume":"9","author":"Shim","year":"2022","journal-title":"Open Forum Infect Dis"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.virol.2023.109869","article-title":"Genomic epidemiology of SARS-CoV-2 variants in South Korea between January 2020 and February 2023","volume":"587","author":"Kim","year":"2023","journal-title":"Virology"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.2807\/1560-7917.ES.2020.25.3.2000045","article-title":"Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR","volume":"25","author":"Corman","year":"2020","journal-title":"Euro Surveill"},{"key":"B25","doi-asserted-by":"publisher","first-page":"23713","DOI":"10.1038\/s41598-021-03273-0","article-title":"The potential of COVID-19 patients\u2019 sera to cause antibody-dependent enhancement of infection and IL-6 production","volume":"11","author":"Shimizu","year":"2021","journal-title":"Sci Rep"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-020-00789-5","article-title":"Antibody-dependent enhancement and SARS-CoV-2 vaccines and therapies","volume":"5","author":"Lee","year":"2020","journal-title":"Nat Microbiol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-04702-4","article-title":"Fc\u03b3R-mediated SARS-CoV-2 infection of monocytes activates inflammation","volume":"606","author":"Junqueira","year":"2022","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/microbiolspec.MCHD-0045-2016","article-title":"The role and function of Fc\u03b3 receptors on myeloid cells","volume":"4","author":"Bournazos","year":"2016","journal-title":"Microbiol Spectr"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00281-21","article-title":"COVID-19 severity is associated with differential antibody Fc-mediated innate immune functions","volume":"12","author":"Adeniji","year":"2021","journal-title":"mBio"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.901217","article-title":"Evaluation of antibody-dependent Fc-mediated viral entry, as compared with neutralization, in SARS-CoV-2 infection","volume":"13","author":"Wieczorek","year":"2022","journal-title":"Front Immunol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/j.immuni.2022.01.001","article-title":"mRNA-1273 vaccine-induced antibodies maintain Fc effector functions across SARS-CoV-2 variants of concern","volume":"55","author":"Kaplonek","year":"2022","journal-title":"Immunity"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4174","DOI":"10.1038\/s41467-023-39189-8","article-title":"Waning and boosting of antibody Fc-effector functions upon SARS-CoV-2 vaccination","volume":"14","author":"Tong","year":"2023","journal-title":"Nat Commun"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abf8654","article-title":"High titers and low fucosylation of early human anti-SARS-CoV-2 IgG promote inflammation by alveolar macrophages","volume":"13","author":"Hoepel","year":"2021","journal-title":"Sci Transl Med"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/science.abc8378","article-title":"Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity","volume":"371","author":"Larsen","year":"2021","journal-title":"Science"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1804","DOI":"10.1016\/j.cell.2021.02.026","article-title":"Human neutralizing antibodies against SARS-CoV-2 require intact Fc effector functions for optimal therapeutic protection","volume":"184","author":"Winkler","year":"2021","journal-title":"Cell"},{"key":"B36","first-page":"137","article-title":"The threat of COVID-19 resurgence and emergent recombinant variants: The imperative of securing vaccine sovereignty","volume-title":"Institute for National Security Strategy Report","author":"Kim","year":"2025"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2025.106432","article-title":"Immunocompromised individuals remain at risk of COVID-19: 2023 results from the observational INFORM study","volume":"90","author":"Quint","year":"2025","journal-title":"J Infect"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.3390\/v15091926","article-title":"Humoral responses elicited after a fifth dose of SARS-CoV-2 mRNA bivalent vaccine","volume":"15","author":"Tauzin","year":"2023","journal-title":"Viruses"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/v15061274","article-title":"A recent SARS-CoV-2 infection enhances antibody-dependent cellular cytotoxicity against several Omicron subvariants following a fourth mRNA vaccine dose","volume":"15","author":"Beaudoin-Bussi\u00e8res","year":"2023","journal-title":"Viruses"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12367","article-title":"Fc receptors in antibody\u2010dependent enhancement of viral infections","volume":"268","author":"Taylor","year":"2015","journal-title":"Immunol Rev"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1797975\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T06:09:16Z","timestamp":1777615756000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1797975\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,1]]},"references-count":40,"alternative-id":["10.3389\/fimmu.2026.1797975"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1797975","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,1]]},"article-number":"1797975"}}