{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T09:21:46Z","timestamp":1775899306112,"version":"3.50.1"},"posted":{"date-parts":[[2026,4,8]]},"group-title":"Allergy and Immunology","reference-count":73,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Multisystem inflammatory syndrome in children (MIS-C) is a pediatric hyperinflammatory disease manifesting 4-6 weeks after SARS-CoV-2 infection. While the immunological hallmarks of MIS-C have been defined, few details regarding the underlying disease pathology have been resolved. To address this, we used a multiomics approach to profile the plasma and peripheral immune cells of 13 acute MIS-C patients, 18 recovered MIS-C follow-ups resampled over multiple time points (1-18 months), and 15 healthy pediatric controls. Despite rapid clinical disease resolution, circulating pro-inflammatory (IL-8, IL-6, IL-1\u03b1, IL-1\u03b2, TNF-\u03b2) and T\n                  <jats:sub>H<\/jats:sub>\n                  2-type cytokines (IL-4, IL-5, IL-13) remained elevated up to three months post-MIS-C onset, revealing a subclinical inflammatory state that endures in recovered children. Surprisingly, the majority of patient-expanded TCRs recognizing SARS-CoV-2 epitopes were cross-reactive (75%, 12\/16 SARS-CoV-2 TCRs) for autoantigens related to prostaglandin biology and insulin metabolism, suggesting a breakdown of self-tolerance via SARS-CoV-2 molecular mimicry. Indeed, autoantibody screening confirmed that 13 gene targets with self-antigen peptides also exhibited elevated autoantibodies in MIS-C patients. Further, autoreactive TCR expansions lasted over time and correlated with cytokines involved in allergic inflammation. Together, our findings point to a mechanism of sustained autoimmunity wherein promiscuous TCRs recognize both viral and self-antigens that are activated during primary SARS-CoV-2 infection in children who develop MIS-C. Upon onset, these circulating cross-reactive T cells drive clinically apparent sterile autoinflammation that persists subclinically into convalescence.\n                <\/jats:p>","DOI":"10.64898\/2026.04.03.26350001","type":"posted-content","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:45:25Z","timestamp":1775695525000},"source":"Crossref","is-referenced-by-count":0,"title":["Cooperative molecular mimicry drives prolonged autoinflammation in multisystem inflammatory syndrome in children"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2044-1180","authenticated-orcid":false,"given":"Haley E","family":"Randolph","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1700-9162","authenticated-orcid":false,"given":"Ashley","family":"Richardson","sequence":"additional","affiliation":[{"name":"Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7662-3851","authenticated-orcid":false,"given":"Sofija","family":"Buta","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5184-0390","authenticated-orcid":false,"given":"Julie","family":"Samuels","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2472-7397","authenticated-orcid":false,"given":"Nina N","family":"Brodsky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Yale University School of Medicine, New Haven, CT, USA"},{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0192-4400","authenticated-orcid":false,"given":"Seunghee","family":"Kim-Schulze","sequence":"additional","affiliation":[{"name":"Human Immune Monitoring Center, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5754-0820","authenticated-orcid":false,"given":"Carrie L","family":"Lucas","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8634-9443","authenticated-orcid":false,"given":"Rebecca","family":"Trachtman","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9277-3232","authenticated-orcid":false,"given":"Dusan","family":"Bogunovic","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA"},{"name":"Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA"},{"name":"Center for Genetic Errors of Immunity, Columbia University Irving Medical Center, New York, NY, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2026041101400922000_2026.04.03.26350001v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2022.01.014"},{"key":"2026041101400922000_2026.04.03.26350001v1.2","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1056\/NEJMoa2021680","article-title":"Multisystem Inflammatory Syndrome in U","volume":"383","year":"2020","journal-title":"S. Children and Adolescents. New England Journal of Medicine"},{"key":"2026041101400922000_2026.04.03.26350001v1.3","doi-asserted-by":"crossref","unstructured":"Acevedo, L. et al. Mortality and clinical characteristics of multisystem inflammatory syndrome in children (MIS-C) associated with covid-19 in critically ill patients: an observational multicenter study (MISCO study). BMC Pediatr 21, 516 (2021).","DOI":"10.1186\/s12887-021-02974-9"},{"key":"2026041101400922000_2026.04.03.26350001v1.4","doi-asserted-by":"publisher","DOI":"10.1038\/s41584-020-0426-0"},{"key":"2026041101400922000_2026.04.03.26350001v1.5","doi-asserted-by":"publisher","DOI":"10.1111\/ped.13614"},{"key":"2026041101400922000_2026.04.03.26350001v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jfma.2013.12.008"},{"key":"2026041101400922000_2026.04.03.26350001v1.7","doi-asserted-by":"crossref","unstructured":"Goswami, N. , Marzan, K. , De Oliveira, E. , Wagner-Lees, S. & Szmuszkovicz, J . Recurrent Kawasaki Disease: A Case Report of Three Separate Episodes at >4-Year Intervals. Children (Basel) 5, 155 (2018).","DOI":"10.3390\/children5110155"},{"key":"2026041101400922000_2026.04.03.26350001v1.8","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2020.09.034"},{"key":"2026041101400922000_2026.04.03.26350001v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2020.09.016"},{"key":"2026041101400922000_2026.04.03.26350001v1.10","doi-asserted-by":"crossref","first-page":"eabh1516","DOI":"10.1126\/sciimmunol.abh1516","article-title":"Polyclonal expansion of TCR V\u03b2 21.3+ CD4+ and CD8+ T cells is a hallmark of multisystem inflammatory syndrome in children","volume":"6","year":"2021","journal-title":"Science Immunology"},{"key":"2026041101400922000_2026.04.03.26350001v1.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-08697-6"},{"key":"2026041101400922000_2026.04.03.26350001v1.12","doi-asserted-by":"crossref","first-page":"4227","DOI":"10.1038\/s41467-024-48699-y","article-title":"Enhanced CD95 and interleukin 18 signalling accompany T cell receptor V\u03b221.3+ activation in multi-inflammatory syndrome in children","volume":"15","year":"2024","journal-title":"Nat Commun"},{"key":"2026041101400922000_2026.04.03.26350001v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2021.04.003"},{"key":"2026041101400922000_2026.04.03.26350001v1.14","doi-asserted-by":"crossref","unstructured":"Porritt, R. A. et al. The autoimmune signature of hyperinflammatory multisystem inflammatory syndrome in children. J Clin Invest 131, (2021).","DOI":"10.1172\/JCI151520"},{"key":"2026041101400922000_2026.04.03.26350001v1.15","doi-asserted-by":"crossref","first-page":"1126","DOI":"10.1038\/s41423-019-0285-2","article-title":"SNX8 modulates the innate immune response to RNA viruses by regulating the aggregation of VISA","volume":"17","year":"2020","journal-title":"Cell Mol Immunol"},{"key":"2026041101400922000_2026.04.03.26350001v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07722-4"},{"key":"2026041101400922000_2026.04.03.26350001v1.17","first-page":"127","article-title":"IL-6 in inflammation, autoimmunity and cancer","volume":"33","year":"2020","journal-title":"Int Immunol"},{"key":"2026041101400922000_2026.04.03.26350001v1.18","doi-asserted-by":"crossref","unstructured":"Migliorini, P. , Italiani, P. , Pratesi, F. , Puxeddu, I. & Boraschi, D . The IL-1 family cytokines and receptors in autoimmune diseases. Autoimmunity Reviews 19, 102617 (2020).","DOI":"10.1016\/j.autrev.2020.102617"},{"key":"2026041101400922000_2026.04.03.26350001v1.19","doi-asserted-by":"publisher","DOI":"10.1007\/BF02786470"},{"key":"2026041101400922000_2026.04.03.26350001v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELL.2021.04.048"},{"key":"2026041101400922000_2026.04.03.26350001v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27544-6"},{"key":"2026041101400922000_2026.04.03.26350001v1.22","doi-asserted-by":"crossref","first-page":"e2456272","DOI":"10.1001\/jamanetworkopen.2024.56272","article-title":"Phenotypic Classification of Multisystem Inflammatory Syndrome in Children Using Latent Class Analysis","volume":"8","year":"2025","journal-title":"JAMA Netw Open"},{"key":"2026041101400922000_2026.04.03.26350001v1.23","doi-asserted-by":"crossref","unstructured":"Yu, J. et al. FABP5 in skin macrophages mediates saturated fat-induced IL-1\u03b2 signaling in psoriatic inflammation. Cell Reports 44, 116254 (2025).","DOI":"10.1016\/j.celrep.2025.116254"},{"key":"2026041101400922000_2026.04.03.26350001v1.24","doi-asserted-by":"crossref","unstructured":"Vecchio, E. et al. FABP5 is a key player in metabolic modulation and NF-\u03baB dependent inflammation driving pleural mesothelioma. Commun Biol 8, 324 (2025).","DOI":"10.1038\/s42003-025-07754-0"},{"key":"2026041101400922000_2026.04.03.26350001v1.25","doi-asserted-by":"crossref","unstructured":"Batal, A. , Garousi, S. , Finnson, K. W. & Philip, A . CD109, a master regulator of inflammatory responses. Front Immunol 15, 1505008 (2025).","DOI":"10.3389\/fimmu.2024.1505008"},{"key":"2026041101400922000_2026.04.03.26350001v1.26","doi-asserted-by":"crossref","unstructured":"Shi, J. et al. Single-Cell Transcriptomic Profiling of MAIT Cells in Patients With COVID-19. Frontiers in Immunology 12, 700152 (2021).","DOI":"10.3389\/fimmu.2021.700152"},{"key":"2026041101400922000_2026.04.03.26350001v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/nature01433"},{"key":"2026041101400922000_2026.04.03.26350001v1.28","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130958"},{"key":"2026041101400922000_2026.04.03.26350001v1.29","first-page":"e20232298","article-title":"MAIT cells: Conserved watchers on the wall","volume":"222","year":"2024","journal-title":"Journal of Experimental Medicine"},{"key":"2026041101400922000_2026.04.03.26350001v1.30","doi-asserted-by":"crossref","unstructured":"Hinks, T. S. C. & Zhang, X.-W. MAIT Cell Activation and Functions. Front. Immunol. 11, (2020).","DOI":"10.3389\/fimmu.2020.01014"},{"key":"2026041101400922000_2026.04.03.26350001v1.31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000054"},{"key":"2026041101400922000_2026.04.03.26350001v1.32","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-08-303339"},{"key":"2026041101400922000_2026.04.03.26350001v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0191-y"},{"key":"2026041101400922000_2026.04.03.26350001v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.b.21858"},{"key":"2026041101400922000_2026.04.03.26350001v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/s41385-021-00391-w"},{"key":"2026041101400922000_2026.04.03.26350001v1.36","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201646300"},{"key":"2026041101400922000_2026.04.03.26350001v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaz0374"},{"key":"2026041101400922000_2026.04.03.26350001v1.38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx760"},{"key":"2026041101400922000_2026.04.03.26350001v1.39","doi-asserted-by":"crossref","first-page":"8124","DOI":"10.1038\/s41467-025-63615-8","article-title":"Structure and transport mechanism of the human prostaglandin transporter SLCO2A1","volume":"16","year":"2025","journal-title":"Nat Commun"},{"key":"2026041101400922000_2026.04.03.26350001v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9343(99)00115-1"},{"key":"2026041101400922000_2026.04.03.26350001v1.41","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.pharmthera.2004.06.003","article-title":"Pharmacology and signaling of prostaglandin receptors: Multiple roles in inflammation and immune modulation","volume":"103","year":"2004","journal-title":"Pharmacology & Therapeutics"},{"key":"2026041101400922000_2026.04.03.26350001v1.42","doi-asserted-by":"crossref","unstructured":"Trapani, S. et al. Thromboembolic complications in children with COVID-19 and MIS-C: A narrative review. Front. Pediatr. 10, (2022).","DOI":"10.3389\/fped.2022.944743"},{"key":"2026041101400922000_2026.04.03.26350001v1.43","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0513-9"},{"key":"2026041101400922000_2026.04.03.26350001v1.44","first-page":"606195","article-title":"Clinical and Pathological Roles of Ro\/SSA Autoantibody System","volume":"2012","year":"2012","journal-title":"Clin Dev Immunol"},{"key":"2026041101400922000_2026.04.03.26350001v1.45","doi-asserted-by":"crossref","unstructured":"Allard-Chamard, H. et al. Interleukin-15 in autoimmunity. Cytokine 136, 155258 (2020).","DOI":"10.1016\/j.cyto.2020.155258"},{"key":"2026041101400922000_2026.04.03.26350001v1.46","doi-asserted-by":"crossref","unstructured":"Hills, L. B. , et al. Pediatric T cell and B cell responses to SARS-CoV-2 infection. JCI Insight 10, (2025).","DOI":"10.1172\/jci.insight.196032"},{"key":"2026041101400922000_2026.04.03.26350001v1.47","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abd5487"},{"key":"2026041101400922000_2026.04.03.26350001v1.48","doi-asserted-by":"crossref","first-page":"1358","DOI":"10.1016\/j.cmet.2021.04.015","article-title":"Food colorants metabolized by commensal bacteria promote colitis in mice with dysregulated expression of interleukin-23","volume":"33","year":"2021","journal-title":"Cell Metabolism"},{"key":"2026041101400922000_2026.04.03.26350001v1.49","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2102968"},{"key":"2026041101400922000_2026.04.03.26350001v1.50","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000000484"},{"key":"2026041101400922000_2026.04.03.26350001v1.51","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abe1670"},{"key":"2026041101400922000_2026.04.03.26350001v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-00870-z"},{"key":"2026041101400922000_2026.04.03.26350001v1.53","unstructured":"van Wilgenburg, B. et al. MAIT cells are activated during human viral infections. Nat Commun 7, 11653 (2016)."},{"key":"2026041101400922000_2026.04.03.26350001v1.54","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201401-0106OC"},{"key":"2026041101400922000_2026.04.03.26350001v1.55","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-07-445429"},{"key":"2026041101400922000_2026.04.03.26350001v1.56","doi-asserted-by":"crossref","unstructured":"Fan, Q. et al. New insights into MAIT cells in autoimmune diseases. Biomedicine & Pharmacotherapy 159, 114250 (2023).","DOI":"10.1016\/j.biopha.2023.114250"},{"key":"2026041101400922000_2026.04.03.26350001v1.57","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.jaci.2025.02.005","article-title":"Autoimmunity in long COVID","volume":"155","year":"2025","journal-title":"Journal of Allergy and Clinical Immunology"},{"key":"2026041101400922000_2026.04.03.26350001v1.58","doi-asserted-by":"crossref","unstructured":"Marrani, E. , Burns, J. C. & Cimaz, R . How Should We Classify Kawasaki Disease? Front. Immunol. 9, (2018).","DOI":"10.3389\/fimmu.2018.02974"},{"key":"2026041101400922000_2026.04.03.26350001v1.59","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06651-y"},{"key":"2026041101400922000_2026.04.03.26350001v1.60","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.a.22826"},{"key":"2026041101400922000_2026.04.03.26350001v1.61","doi-asserted-by":"crossref","unstructured":"Kotecha, N. , Krutzik, P. O. & Irish, J. M . Web-based analysis and publication of flow cytometry experiments. Curr Protoc Cytom Chapter 10, Unit10.17 (2010).","DOI":"10.1002\/0471142956.cy1017s53"},{"key":"2026041101400922000_2026.04.03.26350001v1.62","unstructured":"Zheng, G. X. Y. et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun 8, 14049 (2017)."},{"key":"2026041101400922000_2026.04.03.26350001v1.63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2019.05.031"},{"key":"2026041101400922000_2026.04.03.26350001v1.64","doi-asserted-by":"crossref","unstructured":"Hafemeister, C. & Satija, R . Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biology 20, 296 (2019).","DOI":"10.1186\/s13059-019-1874-1"},{"key":"2026041101400922000_2026.04.03.26350001v1.65","unstructured":"Mouselimis, L. textTinyR: Text Processing for Small or Big Data Files. (2023)."},{"key":"2026041101400922000_2026.04.03.26350001v1.66","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp616"},{"key":"2026041101400922000_2026.04.03.26350001v1.67","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkv007"},{"key":"2026041101400922000_2026.04.03.26350001v1.68","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1530509100"},{"key":"2026041101400922000_2026.04.03.26350001v1.69","doi-asserted-by":"publisher","DOI":"10.18129\/B9.bioc.qvalue"},{"key":"2026041101400922000_2026.04.03.26350001v1.70","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo.10840553"},{"key":"2026041101400922000_2026.04.03.26350001v1.71","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-023-05638-x"},{"key":"2026041101400922000_2026.04.03.26350001v1.72","doi-asserted-by":"crossref","unstructured":"Borcherding, N. et al. Mapping the immune environment in clear cell renal carcinoma by single-cell genomics. Commun Biol 4, 122 (2021).","DOI":"10.1038\/s42003-020-01625-6"},{"key":"2026041101400922000_2026.04.03.26350001v1.73","doi-asserted-by":"publisher","DOI":"10.1016\/j.csbj.2021.06.043"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.04.03.26350001","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,11]],"date-time":"2026-04-11T08:40:22Z","timestamp":1775896822000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.04.03.26350001"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,8]]},"references-count":73,"URL":"https:\/\/doi.org\/10.64898\/2026.04.03.26350001","relation":{},"subject":[],"published":{"date-parts":[[2026,4,8]]},"subtype":"preprint"}}