title: Mast-cell interleukin-1β, neutrophil interleukin-17 and epidermal antimicrobial proteins in the neutrophilic urticarial dermatosis in Schnitzler's syndrome.
abstract: BACKGROUND
  Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin (IL)-1β is pivotal in the pathophysiology.
  
  
  OBJECTIVE
  Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS.
  
  
  METHODS
  Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome (CAPS), delayed-pressure urticaria (DPU) and cold-contact urticaria (CCU) were studied. We studied in vivoIL-1β, IL-17 and antimicrobial protein (AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly:IC) stimulation on cultured epidermal keratinocytes.
  
  
  RESULTS
  Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly:IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts.
  
  
  CONCLUSIONS
  Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis.
authors.affiliation: Department of Dermatology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.|Department of Internal Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, the Netherlands.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, the Netherlands.
authors.forename: H D
authors.initials: HD
authors.lastname: de Koning
authors.affiliation: Department of Dermatology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.
authors.forename: I M J J
authors.initials: IM
authors.lastname: van Vlijmen-Willems
authors.affiliation: Department of Dermatology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Rodijk-Olthuis
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, the Netherlands.
authors.forename: J W M
authors.initials: JW
authors.lastname: van der Meer
authors.affiliation: Department of Dermatology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, the Netherlands.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, the Netherlands.
authors.forename: P L J M
authors.initials: PL
authors.lastname: Zeeuwen
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, the Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Simon
authors.affiliation: Department of Dermatology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.|Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen, the Netherlands.|Nijmegen Center for Immunodeficiency and Autoinflammation, Nijmegen, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Schalkwijk
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D016022:Case-Control Studies; D002478:Cells, Cultured; D056587:Cryopyrin-Associated Periodic Syndromes / Q000378:metabolism; D005260:Female; D006801:Humans; D007369:Interferon Inducers / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins / Q000378:metabolism; D019873:Schnitzler Syndrome / Q000378:metabolism*; D014581:Urticaria / Q000378:metabolism; D023083:beta-Defensins / Q000378:metabolism
chemical_list: D023181:Antimicrobial Cationic Peptides; C106641:DEFB4A protein, human; C508717:IL17A protein, human; D007369:Interferon Inducers; D020381:Interleukin-17; D053583:Interleukin-1beta; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; C089242:S100A7 protein, human; D023083:beta-Defensins; D011070:Poly I-C