{"doi":"10.1002/ajh.26868","title":"Factor H autoantibodies contribute to complement dysregulation in multisystem inflammatory syndrome in children (<scp>MIS‐C</scp>)","abstract":"While most children are asymptomatic or have mild symptoms from SARS-CoV-2 infection, some progress to severe coronavirus disease 2019 (COVID-19). After pediatric SARS-CoV-2 infection, a subset of patients develops multisystem inflammatory syndrome in children (MIS-C), manifested by respiratory failure, myocardial injury, and hemodynamic shock. The specific immune pathways and distinct immunologic responses underlying endothelial and multiorgan damage in children with MIS-C are not well described. Understanding the pathophysiology of MIS-C is critical to identifying targeted therapies and providing novel insights into the pathogenesis of similar pediatric hyperinflammatory syndromes (e.g., Kawasaki disease). The complement system serves a vital role in the innate immune defense against pathogens, including viruses, with sequential activation in response to the recognition of molecular components of microorganisms or tissue injury. Complement pathway (CP) hyperactivation may contribute to endothelial cell dysfunction, hypercoagulability, and consequential thrombus formation in COVID-19.1 Adults with severe COVID-19 demonstrate evidence of complement activation, and complement fragments are deposited in the lungs, kidneys, and microvasculature.2 Furthermore, case reports describe the successful use of anti-C5 and anti-C3 targeted complement inhibitors in the treatment of adult and pediatric patients with severe COVID-19 lung injury, leading to clinical improvement, improved lung oxygenation, and decreased systemic inflammation.3, 4 Despite studies suggesting broad complement dysregulation in MIS-C, a comprehensive analysis of complement dysregulation has not been undertaken. We aimed to elucidate the complement-mediated immune mechanisms underlying MIS-C compared to COVID-19 in pediatric patients, with the goal of providing further insights and potential treatment targets to improve clinical outcomes. We hypothesized that CP dysregulation caused by SARS-CoV-2 infection contributes to acute COVID-19 organ injury and MIS-C pathogenesis. Blood samples were collected from March 2020 through October 2020 from hospitalized children (0–21 years of age) at Children's Healthcare of Atlanta with either COVID-19 (n = 44) or MIS-C (n = 37). Participants were enrolled after consent and age-appropriate assent were obtained. Additional clinical information was obtained from the medical records (Table S1). All samples with sufficient quantity for testing were included. The research was performed with Institutional Review Board approval. For detailed Methods, please see Supplemental information (Appendix S1). As shown in Table S1, patients with MIS-C had similar demographics and comorbidities. Many of these patients had significant systemic inflammation requiring intravenous immunoglobulin, steroids, and cardiorespiratory support including oxygen therapy and the need for vasopressors, all concerning endothelial damage. Furthermore, patients with MIS-C had lower hemoglobin and platelets, evidence of organ injury (higher creatinine, B-type natriuretic peptide, troponin), and higher markers of inflammation (white blood cells, c-reactive protein) when compared to patients with COVID-19 (Table S2). We initially investigated for correlation of viral serology with the disease process and severity in relation to complement activation, by testing for IgM and IgG antibodies against the RBD of the SARS-CoV-2 virus (Figure S1A,B). Consistent with previous findings, higher IgG levels were present in patients with MIS-C when compared to patients with acute COVID-19.5 Likewise, patients with MIS-C had significantly higher neutralizing antibody titers, but IgM antibodies did not statistically differ (Figure S1A,C). To examine the dysregulation of key complement components in patients with COVID-19 or MIS-C, plasma was evaluated for levels of the three CPs as shown in Figure 1A (respective complement proteins highlighted under each CP). C4d is a split product of","journal":"American Journal of Hematology","year":2023,"id":363472,"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":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":848506,"name":"Jennifer Stowell","orcid":"0000-0001-6879-7149","position":1,"is_corresponding":false},{"id":226159,"name":"Hans Verkerke","orcid":"0000-0002-5152-0095","position":2,"is_corresponding":false},{"id":677790,"name":"James McCoy","orcid":null,"position":3,"is_corresponding":false},{"id":580890,"name":"Jayre Jones","orcid":null,"position":4,"is_corresponding":false},{"id":673070,"name":"Sara Graciaa","orcid":null,"position":5,"is_corresponding":false},{"id":895556,"name":"Austin Lu","orcid":null,"position":6,"is_corresponding":false},{"id":94483,"name":"Laila Hussaini","orcid":null,"position":7,"is_corresponding":false},{"id":94484,"name":"Evan J. Anderson","orcid":"0000-0002-1576-4420","position":8,"is_corresponding":false},{"id":94488,"name":"Christina A. Rostad","orcid":"0000-0001-8439-0592","position":9,"is_corresponding":false},{"id":226169,"name":"Sean R. Stowell","orcid":"0000-0002-1130-9551","position":10,"is_corresponding":false},{"id":402916,"name":"Satheesh Chonat","orcid":"0000-0002-5909-0800","position":11,"is_corresponding":false},{"id":402915,"name":"Patricia E. Zerra","orcid":"0000-0003-3675-2725","position":0,"is_corresponding":true}],"reference_count":10,"raw_metadata":null,"created_at":"2026-07-19T01:14:28.054440Z","pmid":"36715424","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":[]}