post infectious inflammatory disease in mis c features elevated cytotoxicity signatures CORD-Papers (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: 2020-12-04
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/ https://doi.org/10.1101/2020.12.01.20241364 http://medrxiv.org/cgi/content/short/2020.12.01.20241364v1?rss=1
has_full_text: TRUE
Keywords Extracted from Text Content: IgG1 medRxiv CCR7 human antigens human cardiac microvascular endothelial cells  heart MIS-C convalescent COVID-19 NK  T cell https://doi.org/10.1101 https://doi.org/10 neutrophils cardiogenic shock 12-14 patients IL-10 adult COVID-19 patients gastrointestinal myeloid cells ferritin anti-SARS-CoV2 red blood cells human cardiac microvascular 94 endothelial cells C5b9 dendritic cells rash endothelium interleukin-1β CD86 immune cell CD8 T cell monocyte self-reactive antibodies IgG plasmablasts vascular HLA-DR troponin Multisystem IL-8 CD4 T cells IL-17 endothelial 79 cell C-reactive pulmonary serum CD64 antigen receptor SARS-CoV2 antigen 41 receptor mucocutaneous children CD8 serum IgG PBMCs B cell peripheral blood mononuclear cells IFN-  neutrophil donors IL-6 hematologic monocytes IL-1β IgG3 post-55 SARS-CoV2 medRxiv preprint 53 T cell CD4 cardiac coronary aneurysms heart EBV COVID-19 265 HLA class II MIS-C CD45RO Figure 233 patients Cytomegalovirus 164 CD8 cells myeloid cells superantigen MADCAM1 Ki67+) plasmablasts CD4 T cell ADT dendritic cells PBMC cell CD86 S4d NK cells S100A12 myeloid low-density neutrophils CD8 PBMCs PCs samples S100A9 herpesvirus monocytes GZMA KEGG B cell B cells GZMH naïve 147 T cell endothelial E- abdominal MIS-259 C fold-538 Epstein Barr Virus T high-dose integrin AddModuleScore IgM B cells Figure S1d naïve B cells steroid lymphocyte S100 Figure 3a-b nFeature TCR UMAP ITGB7 SHM T 232 cells medRxiv preprint CD8 T cells peripheral blood plasmablast up-229 PBMC cell-types IgG3 Dead SARS-CoV2 373 CD57 IgG1 medRxiv edge-weights CD4 T neutrophils DMEM antigen post-inflammatory alarmin-183 S5c-d medRxiv preprint CMV proliferating medRxiv preprint 844 845 846 S100A8 CD66d methylprednisolone medRxiv preprint 830 831 gut FBS Figures 4a-b calprotectin S3d mitochondrial COVID-19 CCL4 donors NK cell NK 149 cells Figure 5e ) 13 self-antigens Ki67 BCRs Figure 5a-b T cells alarmin cell medRxiv preprint myeloid cells https://doi.org/10.1101/2020.12.01.20241364 doi proliferating T memory B cells PRF1 cells IGHG1 sub-clustered T CD45RA IGHG3 plasmablasts S4d-e S100A plasmablast IgG clones CD8 T cells medRxiv preprint immune steroid 614 BCR plasmablasts Figures 5d antigen 346 CD4 cells tube S5f serum CD3D A.HD S2a-b Fisher's myeloid-derived inflammatory proteins tissue T cell antigen receptor PBMC endothelial cell
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