title: Molecular characterization of systemic sclerosis esophageal pathology identifies inflammatory and proliferative signatures.
abstract: BACKGROUND
  Esophageal involvement in patients with systemic sclerosis (SSc) is common, but tissue-specific pathological mechanisms are poorly understood. There are no animal scleroderma esophagus models and esophageal smooth muscle cells dedifferentiate in culture prohibiting in vitro studies. Esophageal fibrosis is thought to disrupt smooth muscle function and lead to esophageal dilatation, but autopsy studies demonstrate esophageal smooth muscle atrophy and the absence of fibrosis in the majority of SSc cases. Herein, we perform a detailed characterization of SSc esophageal histopathology and molecular signatures at the level of gene expression.
  
  
  METHODS
  Esophageal biopsies were prospectively obtained during esophagogastroduodenoscopy in 16 consecutive SSc patients and 7 subjects without SSc. Upper and lower esophageal biopsies were evaluated for histopathology and gene expression.
  
  
  RESULTS
  Individual patient's upper and lower esophageal biopsies showed nearly identical patterns of gene expression. Similar to skin, inflammatory and proliferative gene expression signatures were identified suggesting that molecular subsets are a universal feature of SSc end-target organ pathology. The inflammatory signature was present in biopsies without high numbers of infiltrating lymphocytes. Molecular classification of esophageal biopsies was independent of SSc skin subtype, serum autoantibodies and esophagitis.
  
  
  CONCLUSIONS
  Proliferative and inflammatory molecular gene expression subsets in tissues from patients with SSc may be a conserved, reproducible component of SSc pathogenesis. The inflammatory signature is observed in biopsies that lack large inflammatory infiltrates suggesting that immune activation is a major driver of SSc esophageal pathogenesis.
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, 1 Rope Ferry Road, Hanover, NH, 03755, USA. Jaclyn.N.Taroni.GR@dartmouth.edu.
authors.forename: Jaclyn N
authors.initials: JN
authors.lastname: Taroni
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, 1 Rope Ferry Road, Hanover, NH, 03755, USA. Viktor.Martyanov@dartmouth.edu.
authors.forename: Viktor
authors.initials: V
authors.lastname: Martyanov
authors.affiliation: Zilber School of Public Health, University of Wisconsin, 1240 N 10th Street, Milwaukee, WI, 53205, USA. huangcc@uwm.edu.
authors.forename: Chiang-Ching
authors.initials: CC
authors.lastname: Huang
authors.affiliation: Department of Neurological Sciences, College of Medicine, University of Vermont, 89 Beaumont Avenue, Burlington, VT, 05405, USA. John.M.Mahoney@uvm.edu.
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Mahoney
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 1400, Chicago, IL, 60611, USA. i-hirano@northwestern.edu.
authors.forename: Ikuo
authors.initials: I
authors.lastname: Hirano
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Ward- 3-140, Chicago, IL, 60611, USA. Brandon.Shetuni@CadenceHealth.org.
authors.forename: Brandon
authors.initials: B
authors.lastname: Shetuni
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Avenue, Ward- 3-140, Chicago, IL, 60611, USA. g-yang@northwestern.edu.
authors.forename: Guang-Yu
authors.initials: GY
authors.lastname: Yang
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 1400, Chicago, IL, 60611, USA. darren-brenner@northwestern.edu.
authors.forename: Darren
authors.initials: D
authors.lastname: Brenner
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Northwestern University Feinberg School of Medicine, 676 N. Saint Clair Street, Suite 1400, Chicago, IL, 60611, USA. bjung@uic.edu.|Department of Medicine, Division of Gastroenterology, University of Illinois Chicago, 808 S Wood Street, Chicago, Illinois, 60612, USA. bjung@uic.edu.
authors.forename: Barbara
authors.initials: B
authors.lastname: Jung
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, 1 Rope Ferry Road, Hanover, NH, 03755, USA. Tammara.A.Wood@dartmouth.edu.
authors.forename: Tammara A
authors.initials: TA
authors.lastname: Wood
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, Suite M300, Chicago, IL, 60611, USA. s-bhattacharyya@northwestern.edu.
authors.forename: Swati
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, Suite M300, Chicago, IL, 60611, USA. o-almagor@northwestern.edu.
authors.forename: Orit
authors.initials: O
authors.lastname: Almagor
authors.affiliation: Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA. jungwha-lee@northwestern.edu.|Institute for Public Health and Medicine, Northwestern University, 633 N. St. Clair Street, 18th floor, Chicago, IL, 60611, USA. jungwha-lee@northwestern.edu.
authors.forename: Jungwha
authors.initials: J
authors.lastname: Lee
authors.affiliation: Department of Radiology, Northwestern University Feinberg School of Medicine, 676 N. St. Clair Street, Chicago, IL, 60611, USA. asirajud@nmff.org.
authors.forename: Arlene
authors.initials: A
authors.lastname: Sirajuddin
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, Suite M300, Chicago, IL, 60611, USA. j-varga@northwestern.edu.
authors.forename: John
authors.initials: J
authors.lastname: Varga
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, Suite M300, Chicago, IL, 60611, USA. rwchang@northwestern.edu.|Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA. rwchang@northwestern.edu.|Institute for Public Health and Medicine, Northwestern University, 633 N. St. Clair Street, 18th floor, Chicago, IL, 60611, USA. rwchang@northwestern.edu.|Department of Physical Medicine and Rehabilitation, Northwestern University Feinberg School of Medicine, 710 N. Lake Shore Drive, Chicago, IL, 60611, USA. rwchang@northwestern.edu.
authors.forename: Rowland W
authors.initials: RW
authors.lastname: Chang
authors.affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, 1 Rope Ferry Road, Hanover, NH, 03755, USA. Michael.L.Whitfield@dartmouth.edu.
authors.forename: Michael L
authors.initials: ML
authors.lastname: Whitfield
authors.affiliation: Department of Medicine, Division of Rheumatology, Northwestern University Feinberg School of Medicine, 240 E. Huron Street, Suite M300, Chicago, IL, 60611, USA. m-hinchcliff@northwestern.edu.|Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, 680 N. Lake Shore Drive, Suite 1400, Chicago, IL, 60611, USA. m-hinchcliff@northwestern.edu.|Institute for Public Health and Medicine, Northwestern University, 633 N. St. Clair Street, 18th floor, Chicago, IL, 60611, USA. m-hinchcliff@northwestern.edu.
authors.forename: Monique
authors.initials: M
authors.lastname: Hinchcliff
mesh_terms: D000328:Adult; D000368:Aged; D049109:Cell Proliferation / Q000502:physiology*; D004947:Esophagus / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D006801:Humans; D018836:Inflammation Mediators / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012595:Scleroderma, Systemic / Q000235:genetics* / Q000473:pathology*
chemical_list: D018836:Inflammation Mediators