title: Increased IgG4 responses to multiple food and animal antigens indicate a polyclonal expansion and differentiation of pre-existing B cells in IgG4-related disease.
abstract: BACKGROUND
  IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition, characterised by an elevated serum IgG4 concentration and abundant IgG4-positive plasma cells in the involved organs. An important question is whether the elevated IgG4 response is causal or a reflection of immune-regulatory mechanisms of the disease.
  
  
  OBJECTIVE
  To investigate if the IgG4 response in IgG4-RD represents a generalised polyclonal amplification by examining the response to common environmental antigens.
  
  
  METHODS
  Serum from 24 patients with IgG4-RD (14 treatment-naive, 10 treatment-experienced), 9 patients with primary sclerosing cholangitis and an elevated serum IgG4 (PSC-high IgG4), and 18 healthy controls were tested against egg white and yolk, milk, banana, cat, peanut, rice and wheat antigens by radioimmunoassay.
  
  
  RESULTS
  We demonstrated an elevated polyclonal IgG4 response to multiple antigens in patients with IgG4-RD and in PSC-high IgG4, compared with healthy controls. There was a strong correlation between serum IgG4 and antigen-specific responses. Responses to antigens were higher in treatment-naive compared with treatment-experienced patients with IgG4-RD. Serum electrophoresis and immunofixation demonstrated polyclonality.
  
  
  CONCLUSIONS
  This is the first study to show enhanced levels of polyclonal IgG4 to multiple antigens in IgG4-RD. This supports that elevated IgG4 levels reflect an aberrant immunological regulation of the overall IgG4 response, but does not exclude that causality of disease could be antigen-driven.
authors: Nuffield Department of Medicine, Oxford University, Oxford, UK Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK.
authors: Emma L
authors: EL
authors: Culver
authors: Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Ellen
authors: E
authors: Vermeulen
authors: Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Mateusz
authors: M
authors: Makuch
authors: Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Astrid
authors: A
authors: van Leeuwen
authors: Department of Immunology, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
authors: Ross
authors: R
authors: Sadler
authors: Department of Immunology, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK.
authors: Tamsin
authors: T
authors: Cargill
authors: Nuffield Department of Medicine, Oxford University, Oxford, UK.
authors: Paul
authors: P
authors: Klenerman
authors: Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Rob C
authors: RC
authors: Aalberse
authors: Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: S Marieke
authors: SM
authors: van Ham
authors: Nuffield Department of Medicine, Oxford University, Oxford, UK Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK Oxford NIHR BRC, Oxford University, Oxford, UK.
authors: Eleanor
authors: E
authors: Barnes
authors: Sanquin Blood Supply, Division Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
authors: Theo
authors: T
authors: Rispens
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000941:Antigens / Q000276:immunology*; D010367:Arachis; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002415:Cats; D015209:Cholangitis, Sclerosing / Q000276:immunology; D004531:Eggs; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008892:Milk; D028521:Musa; D012275:Oryza; D014908:Triticum; D055815:Young Adult
chemical_list: D000941:Antigens; D007074:Immunoglobulin G
keywords: Autoimmunity; B cells; Corticosteroids; Inflammation
references: Hepatology. 2013 Jun;57(6):2390-8
references: 23300096
references: J Allergy Clin Immunol. 2014 Sep;134(3):679-87
references: 24815737
references: Int J Rheumatol. 2012;2012:789164
references: 22701488
references: J Immunol. 2007 Nov 1;179(9):5886-96
references: 17947662
references: N Engl J Med. 2009 Nov 26;361(22):2135-42
references: 19940298
references: Ann Rheum Dis. 2015 Jan;74(1):14-8
references: 24651618
references: Clin Exp Allergy. 1991 Jan;21(1):99-107
references: 2021885
references: J Immunol. 1998 Apr 1;160(7):3555-61
references: 9531318
references: Pancreas. 2006 Jul;33(1):20-6
references: 16804408
references: N Engl J Med. 2012 Feb 9;366(6):539-51
references: 22316447
references: Ann Rheum Dis. 2015 Jan;74(1):190-5
references: 24817416
references: Arthritis Res Ther. 2012 Jul 23;14(4):R171
references: 22824292
references: N Engl J Med. 2001 Mar 8;344(10):732-8
references: 11236777
references: Am J Gastroenterol. 2010 Sep;105(9):2060-71
references: 20407433
references: Allergy. 2014 Feb;69(2):269-272
references: 24266692
references: Clin Gastroenterol Hepatol. 2006 Aug;4(8):1010-6; quiz 934
references: 16843735
references: J Allergy Clin Immunol. 2013 Apr;131(4):1204-12
references: 23453135
references: Pancreas. 2008 Mar;36(2):133-40
references: 18376303
references: J Allergy Clin Immunol. 2014 Jan;133(1):267-70.e1-6
references: 24074895
references: Nat Biotechnol. 2009 Aug;27(8):767-71
references: 19620983