{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T20:01:41Z","timestamp":1779998501272,"version":"3.53.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":17,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004423","name":"WHO","doi-asserted-by":"publisher","award":["1013487-0"],"award-info":[{"award-number":["1013487-0"]}],"id":[{"id":"10.13039\/100004423","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Arboviral infections are characterized by heterogeneity in inflammatory responses and clinical outcomes. While antibodies are essential for protection, antibody\u2013antigen immune complexes may modulate innate immune signaling through Fc receptor engagement. The extent to which immune complex signaling contributes to coordinated cytokine responses in human arboviral infection remains incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a mechanistic immunology study nested within a prospective cohort of patients with acute arboviral infection in southern India. Using paired ex vivo stimulation assays, we compared cytokine responses following antigen-only and antibody\u2013antigen immune complex stimulation. Fc dependence was interrogated using Fc\u03b3 receptor blockade and immunoglobulin G (IgG) subclass depletion. Cytokines were quantified using the LEGENDplex Human Inflammation Panel (BioLegend). Principal component analysis was applied to identify coordinated cytokine response patterns, and multivariable regression models were used to assess associations with humoral immune state.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 80 participants, immune complex stimulation was associated with higher concentrations of pro-inflammatory cytokines compared with antigen alone. This difference was attenuated by Fc\u03b3 receptor blockade and was influenced by antibody subclass composition. Principal component analysis revealed a coordinated cytokine pattern characterized by positive contributions from interleukin-6 (IL-6), tumor necrosis factor, IL-1\u03b2, and CXCL10, with an inverse contribution from IL-10. In multivariable analysis, individuals with lower neutralization capacity or altered IgG subclass profiles exhibited higher inflammatory cytokine program scores (\u03b2 = +1.80 standard deviation; 95% confidence interval 1.54\u20132.06; P = 7.18 \u00d7 10\u221222).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings suggest that antibody-dependent immune complex signaling may contribute to inflammatory cytokine responses during acute arboviral and leptospiral infection.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ofid\/ofag300","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T11:55:53Z","timestamp":1778673353000},"source":"Crossref","is-referenced-by-count":0,"title":["Antibody-Dependent Immune Complex Signaling and Inflammatory Cytokine Responses in Acute Febrile Illness: A Mechanistic Study in Arboviral and Leptospiral Infection"],"prefix":"10.1093","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0038-8896","authenticated-orcid":false,"given":"Peter Mac","family":"Asaga","sequence":"first","affiliation":[{"name":"Institute for Infection Prevention and Control, Medical Center, University of Freiburg , Breisacher str 115b, 79106 Freiburg ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijeesh","family":"Kadukkatti","sequence":"additional","affiliation":[{"name":"RWTH Uniklinik, Aachen, Institute of Occupational Health , Social and Enviromental Medicine, Pauwelsstr 30, 52074 Aachen ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philomena","family":"Airiohuodion","sequence":"additional","affiliation":[{"name":"Special Programme for Research and Training in Tropical Diseases, World Health Organization , Geneva ,","place":["Switzerland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brijil","family":"Mathew","sequence":"additional","affiliation":[{"name":"Aster MIMS Hospital , Kannur 670621, Kerala ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunday","family":"Omilabu","sequence":"additional","affiliation":[{"name":"CHAHZY Central Research Laboratory, College of Medicine, University of Lagos , Lagos ,","place":["Nigeria"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,5,14]]},"reference":[{"key":"2026052815024449500_ofag300-B1","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/S0140-6736(18)32560-1","article-title":"Dengue","volume":"393","author":"Wilder-Smith","year":"2019","journal-title":"Lancet"},{"key":"2026052815024449500_ofag300-B2","doi-asserted-by":"crossref","first-page":"1508","DOI":"10.1038\/s41564-019-0476-8","article-title":"The current and future global distribution and population at risk of dengue","volume":"4","author":"Messina","year":"2020","journal-title":"Nat Microbiol"},{"key":"2026052815024449500_ofag300-B3","article-title":"Global expansion and redistribution of Aedes-borne virus transmission risk with climate change","volume":"15","author":"Ryan","year":"2021","journal-title":"PLoS Negl Trop Dis"},{"key":"2026052815024449500_ofag300-B4","first-page":"339","article-title":"Pathogenesis of severe dengue infection","volume":"16","author":"Malavige","year":"2021","journal-title":"Annu Rev Pathol"},{"key":"2026052815024449500_ofag300-B5","first-page":"531","article-title":"Immune-mediated cytokine storm and its role in severe dengue","volume":"42","author":"Srikiatkhachorn","year":"2020","journal-title":"Semin Immunopathol"},{"key":"2026052815024449500_ofag300-B6","article-title":"Dengue virus NS1 disrupts the endothelial glycocalyx, leading to hyperpermeability","volume":"17","author":"Puerta-Guardo","year":"2021","journal-title":"PLoS Pathog"},{"key":"2026052815024449500_ofag300-B7","first-page":"e815","article-title":"Higher plasma viremia in the febrile phase is associated with adverse dengue outcomes","volume":"72","author":"Vuong","year":"2021","journal-title":"Clin Infect Dis"},{"key":"2026052815024449500_ofag300-B8","first-page":"210262","article-title":"Immune responses to dengue virus in the skin","volume":"12","author":"Rathore","year":"2022","journal-title":"Open Biol"},{"key":"2026052815024449500_ofag300-B9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1186\/s40249-021-00908-2","article-title":"Clinical predictors of severe dengue: a systematic review and meta-analysis","volume":"10","author":"Tsheten","year":"2021","journal-title":"Infect Dis Poverty"},{"key":"2026052815024449500_ofag300-B10","first-page":"733","article-title":"Systems immunology approaches to metabolism\u2013immune axis","volume":"207","author":"Tsai","year":"2021","journal-title":"J Immunol"},{"key":"2026052815024449500_ofag300-B11","doi-asserted-by":"crossref","first-page":"375","DOI":"10.1038\/s41577-020-0285-6","article-title":"Defining trained immunity and its role in health and disease","volume":"20","author":"Netea","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"2026052815024449500_ofag300-B12","first-page":"102","article-title":"The use of longitudinal cohorts for studies of dengue viral pathogenesis and protection","volume":"43","author":"Katzelnick","year":"2020","journal-title":"Curr Opin Virol"},{"key":"2026052815024449500_ofag300-B13","first-page":"a038570","article-title":"Which dengue vaccine approach is the most promising?","volume":"13","author":"Screaton","year":"2021","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2026052815024449500_ofag300-B14","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1126\/science.aan6836","article-title":"Antibody-dependent enhancement of severe dengue disease in humans","volume":"358","author":"Katzelnick","year":"2020","journal-title":"Science"},{"key":"2026052815024449500_ofag300-B15","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1056\/NEJMoa1800820","article-title":"Effect of dengue serostatus on dengue vaccine safety and efficacy","volume":"379","author":"Sridhar","year":"2021","journal-title":"N Engl J Med"},{"key":"2026052815024449500_ofag300-B16","article-title":"Dengue antibody-dependent enhancement: knowns and unknowns","volume":"2","author":"Halstead","year":"2020","journal-title":"Microbiol Spectr"},{"key":"2026052815024449500_ofag300-B17","doi-asserted-by":"crossref","first-page":"633","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":"2026052815024449500_ofag300-B18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/nri.2017.106","article-title":"Beyond binding: antibody effector functions in infectious diseases","volume":"18","author":"Lu","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"2026052815024449500_ofag300-B19","first-page":"1","article-title":"Boosting therapeutic potency of antibodies by taming Fc domain functions","volume":"51","author":"Kang","year":"2022","journal-title":"Exp Mol Med"},{"key":"2026052815024449500_ofag300-B20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/nri2206","article-title":"Fc\u03b3 receptors as regulators of immune responses","volume":"8","author":"Nimmerjahn","year":"2020","journal-title":"Nat Rev Immunol"},{"key":"2026052815024449500_ofag300-B21","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/ni.2939","article-title":"Type I and type II Fc receptors regulate innate and adaptive immunity","volume":"15","author":"Pincetic","year":"2021","journal-title":"Nat Immunol"},{"key":"2026052815024449500_ofag300-B22","first-page":"218","article-title":"Fc\u03b3 receptor function and the design of vaccination strategies","volume":"47","author":"Bournazos","year":"2022","journal-title":"Immunity"},{"key":"2026052815024449500_ofag300-B23","first-page":"520","article-title":"IgG subclasses and allotypes: from structure to effector functions","volume":"5","author":"Vidarsson","year":"2020","journal-title":"Front Immunol"},{"key":"2026052815024449500_ofag300-B24","doi-asserted-by":"crossref","first-page":"877","DOI":"10.3389\/fimmu.2017.00877","article-title":"Decoding the human immunoglobulin G-glycan repertoire","volume":"8","author":"Dekkers","year":"2021","journal-title":"Front Immunol"},{"key":"2026052815024449500_ofag300-B25","article-title":"Afucosylated IgG characterizes enveloped viral responses and correlates with COVID-19 severity","volume":"371","author":"Larsen","year":"2022","journal-title":"Science"},{"key":"2026052815024449500_ofag300-B26","doi-asserted-by":"crossref","first-page":"B55","DOI":"10.1016\/j.vaccine.2015.03.058","article-title":"Beyond adjuvants: antagonizing inflammation to enhance vaccine immunity","volume":"33","author":"Alter","year":"2022","journal-title":"Vaccine"},{"key":"2026052815024449500_ofag300-B27","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.cell.2015.10.027","article-title":"Dissecting polyclonal vaccine-induced humoral immunity against HIV using systems serology","volume":"163","author":"Chung","year":"2021","journal-title":"Cell"},{"key":"2026052815024449500_ofag300-B28","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1038\/s41467-021-21336-8","article-title":"Discrete SARS-CoV-2 antibody titers track with functional humoral stability","volume":"12","author":"Bartsch","year":"2021","journal-title":"Nat Commun"},{"key":"2026052815024449500_ofag300-B29","doi-asserted-by":"crossref","first-page":"107642","DOI":"10.1016\/j.celrep.2020.107642","article-title":"Maternal anti-dengue IgG fucosylation predicts susceptibility to dengue disease in infants","volume":"31","author":"Thulin","year":"2020","journal-title":"Cell Rep"},{"key":"2026052815024449500_ofag300-B30","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1126\/science.aai8128","article-title":"IgG antibodies to dengue enhanced for Fc\u03b3RIIIA binding determine disease severity","volume":"355","author":"Wang","year":"2022","journal-title":"Science"},{"key":"2026052815024449500_ofag300-B31","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abm7853","article-title":"Early non-neutralizing, afucosylated antibody responses are associated with COVID-19 severity","volume":"14","author":"Chakraborty","year":"2022","journal-title":"Sci Transl Med"},{"key":"2026052815024449500_ofag300-B32","doi-asserted-by":"crossref","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":"2026052815024449500_ofag300-B33","doi-asserted-by":"crossref","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":"2026052815024449500_ofag300-B34","doi-asserted-by":"crossref","first-page":"e1002726","DOI":"10.1371\/journal.pmed.1002726","article-title":"Prior dengue virus infection and risk of Zika: a pediatric cohort in Nicaragua","volume":"16","author":"Gordon","year":"2021","journal-title":"PLoS Med"},{"key":"2026052815024449500_ofag300-B35","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1146\/annurev-immunol-042617-053142","article-title":"Immune response to dengue and Zika","volume":"36","author":"Ngono","year":"2022","journal-title":"Annu Rev Immunol"},{"key":"2026052815024449500_ofag300-B36","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/s41590-018-0210-3","article-title":"The immune response against flaviviruses","volume":"19","author":"Slon Campos","year":"2022","journal-title":"Nat Immunol"},{"key":"2026052815024449500_ofag300-B37","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1038\/s41577-019-0123-x","article-title":"Adaptive immune responses to primary and secondary dengue virus infections","volume":"19","author":"St John","year":"2023","journal-title":"Nat Rev Immunol"}],"container-title":["Open Forum Infectious Diseases"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ofid\/advance-article-pdf\/doi\/10.1093\/ofid\/ofag300\/68289010\/ofag300.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/13\/5\/ofag300\/68289010\/ofag300.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ofid\/article-pdf\/13\/5\/ofag300\/68289010\/ofag300.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T19:02:51Z","timestamp":1779994971000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ofid\/article\/doi\/10.1093\/ofid\/ofag300\/8678479"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,28]]},"references-count":37,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2026,4,28]]}},"URL":"https:\/\/doi.org\/10.1093\/ofid\/ofag300","relation":{},"ISSN":["2328-8957"],"issn-type":[{"value":"2328-8957","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,4,28]]},"article-number":"ofag300"}}