post infectious inflammatory disease in mis c features elevated cytotoxicity signatures CORD-Papers-2021-10-25 (Version 1)

Title: Post-infectious inflammatory disease in MIS-C features elevated cytotoxicity signatures and autoreactivity that correlates with severity
Abstract: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical illness in children.
Published: 12/4/2020
Journal: medRxiv : the preprint server for health sciences
DOI: 10.1101/2020.12.01.20241364
DOI_URL: http://doi.org/10.1101/2020.12.01.20241364
Author Name: Ramaswamy, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ramaswamy_a
Author Name: Brodsky, N N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/brodsky_n_n
Author Name: Sumida, T S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sumida_t_s
Author Name: Comi, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/comi_m
Author Name: Asashima, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/asashima_h
Author Name: Hoehn, K B
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hoehn_k_b
Author Name: Li, N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_n
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Shah, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/shah_a
Author Name: Ravindra, N G
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ravindra_n_g
Author Name: Bishai, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bishai_j
Author Name: Khan, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/khan_a
Author Name: Lau, W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lau_w
Author Name: Sellers, B
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sellers_b
Author Name: Bansal, N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/bansal_n
Author Name: Sparks, R
Author link: https://covid19-data.nist.gov/pid/rest/local/author/sparks_r
Author Name: Unterman, A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/unterman_a
Author Name: Habet, V
Author link: https://covid19-data.nist.gov/pid/rest/local/author/habet_v
Author Name: Rice, A J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/rice_a_j
Author Name: Catanzaro, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/catanzaro_j
Author Name: Chandnani, H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/chandnani_h
Author Name: Lopez, M
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lopez_m
Author Name: Kaminski, N
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kaminski_n
Author Name: Dela Cruz, C S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dela_cruz_c_s
Author Name: Tsang, J S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/tsang_j_s
Author Name: Wang, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_z
Author Name: Yan, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yan_x
Author Name: Kleinstein, S H
Author link: https://covid19-data.nist.gov/pid/rest/local/author/kleinstein_s_h
Author Name: van Dijk, D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/van_dijk_d
Author Name: Pierce, R W
Author link: https://covid19-data.nist.gov/pid/rest/local/author/pierce_r_w
Author Name: Hafler, D A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hafler_d_a
Author Name: Lucas, C L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/lucas_c_l
Author Name: Guerrerio, Pamela
Author link: https://covid19-data.nist.gov/pid/rest/local/author/guerrerio_pamela
sha: 6f1ff36d7056fd9b5b7accfbad6a5a2e9f17cade
license: medrxiv
source_x: MedRxiv; Medline; WHO
source_x_url: https://www.medline.com/https://www.who.int/
pubmed_id: 33300011
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/33300011
url: https://www.ncbi.nlm.nih.gov/pubmed/33300011/ http://medrxiv.org/cgi/content/short/2020.12.01.20241364v1?rss=1 https://doi.org/10.1101/2020.12.01.20241364
has_full_text: TRUE
Keywords Extracted from Text Content: mucocutaneous endothelium medRxiv red blood cells peripheral blood mononuclear cells interleukin-1β dendritic cells immune cell IFN-  IL-10 IL-6 anti-SARS-CoV2 human antigens pulmonary children PBMCs CD86 endothelial 79 cell https://doi.org/10.1101 https://doi.org/10 Multisystem IgG3 troponin patients serum IgG gastrointestinal donors medRxiv preprint 53 ferritin post-55 SARS-CoV2 C5b9 adult COVID-19 patients heart  T cell CCR7 self-reactive antibodies hematologic IL-8 HLA-DR serum antigen receptor antigen 41 receptor IL-1β CD8 T cell IgG plasmablasts CD4 T cells SARS-CoV2 B cell convalescent COVID-19 NK vascular C-reactive T cell CD8 cardiogenic shock 12-14 human cardiac microvascular 94 endothelial cells  CD4 monocytes neutrophil rash human cardiac microvascular endothelial cells neutrophils CD64 IgG1 coronary aneurysms monocyte myeloid cells cardiac IL-17 MIS-C Figure 5e ) 13 PCs plasmablast IgG clones myeloid CCL4 steroid gut CD57 steroid 614 superantigen PBMC cell-types tissue heart Figure 233 Ki67+) plasmablasts myeloid-derived inflammatory proteins plasmablast AddModuleScore alarmin-183 S100A8 nFeature CD45RO Figure 3a-b ADT up-229 COVID-19 265 methylprednisolone medRxiv preprint 830 831 COVID-19 B cells medRxiv preprint 844 845 846 GZMA FBS Ki67 BCRs peripheral blood Dead integrin IgG3 Epstein Barr Virus HLA class II BCR proliferating T ITGB7 CD4 cells SARS-CoV2 373 TCR CD45RA post-inflammatory calprotectin Figures 5d IGHG1 CD4 T cell naïve B cells IGHG3 plasmablasts GZMH S5c-d CD3D CD8 herpesvirus CD8 cells S5f tube proliferating CD66d Fisher's PBMC CMV S3d T cells Figure S1d myeloid cells PRF1 medRxiv preprint myeloid cells mitochondrial lymphocyte self-antigens samples Figures 4a-b T CD8 T cells PBMCs https://doi.org/10.1101/2020.12.01.20241364 doi patients donors CD4 T cells antigen receptor S100A9 fold-538 S100A12 plasmablasts endothelial E- Cytomegalovirus 164 sub-clustered T medRxiv preprint CD8 T cells low-density neutrophils monocytes MIS-259 C NK 149 cells neutrophils alarmin edge-weights IgG1 S100 Figure 5a-b endothelial cell NK cells MIS-C T 232 cells medRxiv dendritic cells abdominal IgM B cells DMEM CD86 A.HD EBV S4d-e KEGG B cell high-dose NK cell S100A SHM naïve 147 T cell serum medRxiv preprint immune S2a-b antigen 346 UMAP antigen memory B cells T cell S4d PBMC cell cell medRxiv preprint MADCAM1
Extracted Text Content in Record: First 5000 Characters:37 Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-38 infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV2 39 infection in otherwise healthy children. Here, we define immune abnormalities in MIS-C compared 40 to adult COVID-19 and pediatric/adult healthy controls using single-cell RNA sequencing, antigen 41 receptor repertoire analysis, unbiased serum proteomics, and in vitro assays. Despite no 42 evidence of active infection, we uncover elevated S100A-family alarmins in myeloid cells and 43 marked enrichment of serum proteins that map to myeloid cells and pathways including cytokines, 44 complement/coagulation, and fluid shear stress in MIS-C patients. Moreover, NK and CD8 T cell 45 cytotoxicity genes are elevated, and plasmablasts harboring IgG1 and IgG3 are expanded. 46 Consistently, we detect elevated binding of serum IgG from severe MIS-C patients to activated 47 human cardiac microvascular endothelial cells in culture. Thus, we define immunopathology 48 features of MIS-C with implications for predicting and managing this SARS-CoV2-induced critical 49 illness in children. 50 51 : medRxiv preprint 53 Pediatric patients are largely spared of severe respiratory pathology associated with 54 SARS-CoV2 infection; however, recent data has drawn attention to a severe and delayed post-55 SARS-CoV2 inflammatory response in children. This 'multisystem inflammatory syndrome in 56 children' (MIS-C) presents in youth who had a mild or asymptomatic SARS-CoV2 infection roughly 57 4-6 weeks prior 1-9 . Symptoms in MIS-C patients vary and involve a systemic cytokine storm with 58 fever, gastrointestinal, cardiac, vascular, hematologic, mucocutaneous, neurologic, and 59 respiratory pathology, leading to critical illness with distributive/cardiogenic shock in up to 80% of 60 patients and a 2% mortality rate 1 . Most patients with this syndrome are previously healthy with no 61 co-morbidities and recover with supportive care and immune suppressive therapy. Further 62 understanding the pathophysiology of this disease is imperative to predict, prevent, and optimally 63 treat MIS-C in children exposed to SARS-CoV2. 64 Initial reports compared MIS-C with Kawasaki Disease (KD) because of the common 65 presentation with fever, rash, and coronary aneurysms 2,3,5,7,8 . However, MIS-C predominantly 66 affects older children with an increased prevalence among Black and Hispanic/Latino populations, 67 whereas KD affects very young children with higher occurrence in East Asian populations. 68 Moreover, MIS-C has distinct gastrointestinal symptoms, leukopenia, and high B-type natriuretic 69 peptide, troponin, ferritin, and C-reactive protein, and it more frequently leads to shock 2,10 . Acute 70 MIS-C has been further characterized by high systemic inflammatory cytokines such as 71 interleukin-1β (IL-1β), IL-6, IL-8, IL-10, IL-17, IFN-  . Also reported is a cytokine profile indicative 72 of NK, T cell, monocyte and neutrophil recruitment, mucosal immunity, and immune cell negative 73 feedback 12 . Analysis of peripheral blood mononuclear cells (PBMCs) from MIS-C patients has 74 revealed CD4, CD8,  T cell and B cell lymphopenia, with high HLA-DR expression on  and 75 CCR7+ CD4 T cells, elevated CD64 expression on neutrophils and monocytes, and low HLA-DR 76 and CD86 on monocytes and dendritic cells 11 . Neutralizing anti-SARS-CoV2 antibody responses 77 All rights reserved. No reuse allowed without permission. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted December 4, 2020. ; https://doi.org/10.1101 https://doi.org/10. /2020 in MIS-C closely resemble convalescent COVID-19, and recent studies also report higher 78 complement C5b9 in serum and misshapen red blood cells, which are consistent with endothelial 79 cell activation and clinical findings of distributive and cardiogenic shock 12-14 . Using panels of 80 human antigens to screen for autoantibodies, acute MIS-C patients were described to have 81 increased antibody binding to antigens associated with endothelium and heart development and 82 other common autoimmunity targets as compared to healthy controls 12,13 . As such, one of the 83 dominant hypotheses to explain the immunopathology of MIS-C has been autoimmunity triggered 84 by self-reactive antibodies produced in response to SARS-CoV2, as reported in KD where the 85 presumed infectious trigger is often unknown 15-18 . This hypothesis, however, has not yet been 86 directly tested. Here, we report 15 cases of MIS-C and elucidate correlates of immunopathology using 88 single-cell RNA sequencing with antigen receptor repertoire analysis, serum proteomics, and 89 functional studies in a subset of acute and recovered MIS-C patients compared to healthy 90 pediatric donors, adult COVID-19 patients, and healthy adult
PDF JSON Files: document_parses/pdf_json/6f1ff36d7056fd9b5b7accfbad6a5a2e9f17cade.json
G_ID: post_infectious_inflammatory_disease_in_mis_c_features_elevated_cytotoxicity_signatures
S2 ID: 227262185