title: Transcriptional Analysis of Intravenous Immunoglobulin Resistance in Kawasaki Disease Using an Induced Pluripotent Stem Cell Disease Model.
abstract: Approximately 10-20% of Kawasaki disease (KD) patients are resistant to intravenous immunoglobulin (IVIG) treatment. Further, these patients are at a particularly high risk of having coronary artery abnormalities. The mechanisms of IVIG resistance in KD have been analyzed using patient leukocytes, but not patient vascular endothelial cells (ECs). The present study clarifies the mechanisms of IVIG resistance in KD using an induced pluripotent stem cell (iPSC) disease model.
  
  
  
  Dermal fibroblasts or peripheral blood mononuclear cells from 2 IVIG-resistant and 2 IVIG-responsive KD patients were reprogrammed by the episomal vector-mediated transduction of 6 reprogramming factors. KD patient-derived iPSCs were differentiated into ECs (iPSC-ECs). The gene expression profiles of iPSC-ECs generated from IVIG-resistant and IVIG-responsive KD patients were compared by RNA-sequencing analyses. We found that the expression ofCXCL12was significantly upregulated in iPSC-ECs from IVIG-resistant KD patients. Additionally, Gene Set Enrichment Analysis (GSEA) revealed that gene sets involved in interleukin (IL)-6 signaling were also upregulated.
  
  
  
  The first iPSC-based model for KD is reported here. Our mechanistic analyses suggest thatCXCL12, which plays a role in leukocyte transmigration, is a key molecule candidate for IVIG resistance and KD severity. They also indicate that an upregulation of IL-6-related genes may be involved in this pathogenesis.
authors.affiliation: Department of Pediatric Cardiology and Nephrology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Mizoro
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ameku
authors.forename: Yui
authors.initials: Y
authors.lastname: Nomiya
authors.forename: Shin-Ichi
authors.initials: SI
authors.lastname: Mae
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsui
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuchitsu
authors.forename: Chinatsu
authors.initials: C
authors.lastname: Suzuki
authors.forename: Akiko
authors.initials: A
authors.lastname: Hamaoka-Okamoto
authors.forename: Tomoyo
authors.initials: T
authors.lastname: Yahata
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Sone
authors.forename: Keisuke
authors.initials: K
authors.lastname: Okita
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Osafune
authors.forename: Kenji
authors.initials: K
authors.lastname: Hamaoka
mesh_terms: D000293:Adolescent; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000096:biosynthesis; D002648:Child; D004351:Drug Resistance; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D008954:Models, Biological; D009080:Mucocutaneous Lymph Node Syndrome / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; C508600:IL6 protein, human; D016756:Immunoglobulins, Intravenous; D015850:Interleukin-6