title: Transglutaminase 2 expressed in mast cells recruited into skin or bone marrow induces the development of pediatric mastocytosis.
abstract: BACKGROUND
  Mastocytosis is characterized by a pathological increase in mast cells in organs such as skin and bone marrow. Transglutaminase 2 (TG2) expressed in mast cells contributes to allergic diseases, but its role in mastocytosis has not been investigated. This study aimed to investigate whether TG2 contributes to pediatric mastocytosis.
  
  
  METHODS
  Serum, various skin tissues or bone marrow (BM) biopsy and aspirates were obtained from pediatric normal control or patients with indolent systemic mastocytosis (SM), mastocytoma, and urticaria pigmentosa (UP). Tryptase, individual cytokines, leukotriene C4 (LTC4 ), and TG2 activity in the serum were determined by enzyme-linked immunosorbent assay, mast cell population by May-Grünwald-Giemsa, CD 117 by immunofluorescence, cell surface molecules by Western blot, and colocalization of c-kit and TG2 or IL-10-expressing cells, CD25, and FOXP3 by immunohistochemistry.
  
  
  RESULTS
  Infiltration of CD25(+) CD117(+) CD2(-) mast cells into BM and scalp/trunk/ear dermis; expression of FcεRI, tryptase, c-kit, FOXP3, CCL2/CCR2, and vascular cell adhesion molecule-1; and colocalization of c-kit and TG2 were enhanced in patient's skin tissues or BM, particularly SM, but colocalization of c-kit and IL-10-expressing cells was decreased vs. normal tissues. Amounts of LTC4 and inflammatory cytokines, expression of tryptase or TG2 activity were increased in patient's serum, BM aspirates, or ear/scalp skin tissues, respectively, vs. normal persons, but IL-10 level was decreased.
  
  
  CONCLUSIONS
  The data suggest that mast cells, recruited in the skin and BM by CCL2/CCR, may induce the development of pediatric mastocytosis through reducing IL-10 due to upregulating TG2 activity via transcription factor nuclear factor-κB. Thus, TG2 may be used in diagnosis of pediatric mastocytosis, particularly SM.
authors.affiliation: Department of Pediatrics, Eulji Hospital, Eulji University School of Medicine, Seoul, Korea.
authors.forename: Young Min
authors.initials: YM
authors.lastname: Ahn
authors.affiliation: Department of Pharmacology and SBRI, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Gwan Ui
authors.initials: GU
authors.lastname: Hong
authors.affiliation: Department of Internal Medicine, Eulji Hospital, Eulji University School of Medicine, Seoul, Korea.
authors.forename: Sang Hoon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Pathology, Eulji Hospital, Eulji University School of Medicine, Seoul, Korea.
authors.forename: Ho Jung
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea.
authors.forename: Hey Sung
authors.initials: HS
authors.lastname: Baek
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea.
authors.forename: Myung Nam
authors.initials: MN
authors.lastname: Kim
authors.affiliation: Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea.
authors.forename: Kui Young
authors.initials: KY
authors.lastname: Park
authors.affiliation: Department of Pharmacology and SBRI, Sungkyunkwan University School of Medicine, Suwon, Korea.
authors.forename: Jai Youl
authors.initials: JY
authors.lastname: Ro
mesh_terms: D000799:Angioedema / Q000201:enzymology / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D001842:Bone and Bones / Q000201:enzymology* / Q000276:immunology; D002633:Chemotaxis; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003937:Diagnosis, Differential; D005155:Facial Nerve Diseases / Q000201:enzymology / Q000276:immunology; D005260:Female; D019204:GTP-Binding Proteins / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D017997:Leukotriene C4 / Q000276:immunology / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000201:enzymology* / Q000276:immunology; D034721:Mastocytosis, Systemic / Q000097:blood / Q000175:diagnosis / Q000201:enzymology* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011237:Predictive Value of Tests; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction; D012867:Skin / Q000201:enzymology* / Q000276:immunology; D011503:Transglutaminases / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D053802:Tryptases / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D018836:Inflammation Mediators; D016328:NF-kappa B; D017997:Leukotriene C4; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D053802:Tryptases; D019204:GTP-Binding Proteins
keywords: IL-10; c-kit; cutaneous mastocytosis; mastocytoma; recurrent facial nerve palsy; systemic mastocytosis; transglutaminase 2 (TG2); tryptase; urticaria pigmentosa