title: Expression of Mas-related gene X2 on mast cells is upregulated in the skin of patients with severe chronic urticaria.
abstract: BACKGROUND
  Wheal reactions to intradermally injected neuropeptides, such as substance P (SP) and vasoactive intestinal peptide, are significantly larger and longer lasting in patients with chronic urticaria (CU) than in nonatopic control (NC) subjects. Mas-related gene X2 (MrgX2) has been identified as a receptor for basic neuropeptides, such as SP and vasoactive intestinal peptide. Mast cell (MC) responsiveness to eosinophil mediators contributes to the late-phase reaction of allergy.
  
  
  OBJECTIVE
  We sought to compare the frequency of MrgX2 expression in skin MCs from patients with CU and NC subjects and to identify the receptor for basic eosinophil granule proteins on human skin MCs.
  
  
  METHODS
  MrgX2 expression was investigated by using immunofluorescence in skin tissues from NC subjects and patients with severe CU and on skin-derived cultured MCs. MrgX2 expression in human MCs was reduced by using a lentiviral small hairpin RNA silencing technique. Ca(2+) influx was measured in CHO cells transfected with MrgX2 in response to eosinophil granule proteins. Histamine and prostaglandin D2 levels were measured by using enzyme immunoassays.
  
  
  RESULTS
  The number of MrgX2(+) skin MCs and the percentage of MrgX2(+) MCs in all MCs in patients with CU were significantly greater than those in NC subjects. Eosinophil infiltration in urticarial lesions was observed in 7 of 9 patients with CU. SP, major basic protein, and eosinophil peroxidase, but not eosinophil-derived neurotoxin, induced histamine release from human skin MCs through MrgX2.
  
  
  CONCLUSIONS
  MrgX2 might be a new target molecule for the treatment of wheal reactions in patients with severe CU.
authors: Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
authors: Daisuke
authors: D
authors: Fujisawa
authors: Laboratory for Allergic Disease, RCAI, RIKEN Center for Integrative Medical Sciences (IMS-RCAI), Yokohama, Japan.
authors: Jun-Ichi
authors: J
authors: Kashiwakura
authors: Mayo Clinic College of Medicine, Mayo Clinic, Rochester, Minn.
authors: Hirohito
authors: H
authors: Kita
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Fujisawa, Japan.
authors: Yusuke
authors: Y
authors: Kikukawa
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Fujisawa, Japan.
authors: Yasushi
authors: Y
authors: Fujitani
authors: Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan.
authors: Tomomi
authors: T
authors: Sasaki-Sakamoto
authors: Department of Microbiology, Nihon University School of Medicine, Tokyo, Japan.
authors: Kazumichi
authors: K
authors: Kuroda
authors: Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
authors: Satoshi
authors: S
authors: Nunomura
authors: Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan; Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
authors: Koremasa
authors: K
authors: Hayama
authors: Department of Dermatology, Nihon University School of Medicine, Tokyo, Japan.
authors: Tadashi
authors: T
authors: Terui
authors: Department of Microbiology, Nihon University School of Medicine, Tokyo, Japan.
authors: Chisei
authors: C
authors: Ra
authors: Allergy and Immunology Group, Research Institute of Medical Science, Nihon University School of Medicine, Tokyo, Japan. Electronic address: okayama.yoshimichi@nihon-u.ac.jp.
authors: Yoshimichi
authors: Y
authors: Okayama
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002478:Cells, Cultured; D002908:Chronic Disease; D047091:Eosinophil Granule Proteins / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism*; D012867:Skin / Q000378:metabolism* / Q000473:pathology; D012882:Skin Tests; D013373:Substance P / Q000008:administration & dosage / Q000009:adverse effects; D015854:Up-Regulation; D014581:Urticaria / Q000175:diagnosis* / Q000276:immunology; D014660:Vasoactive Intestinal Peptide / Q000008:administration & dosage / Q000009:adverse effects; D055815:Young Adult
chemical_list: D047091:Eosinophil Granule Proteins; C480039:MRGPRX2 protein, human; D009419:Nerve Tissue Proteins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D013373:Substance P; D014660:Vasoactive Intestinal Peptide
keywords: Chronic urticaria; Mas-related gene X2; eosinophil granule proteins; eosinophil peroxidase; eosinophils; histamine; human skin mast cells; major basic protein; substance P