title: B-Cell Dysregulation in Crohn's Disease Is Partially Restored with Infliximab Therapy.
abstract: BACKGROUND
  B-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn's disease.
  
  
  OBJECTIVE
  To elucidate the involvement of B cells in Crohn's disease, we here performed an 'in depth' analysis of intestinal and blood B-cells in this chronic inflammatory disease.
  
  
  METHODS
  Patients with Crohn's disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.
  
  
  RESULTS
  Granulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.
  
  
  CONCLUSIONS
  B cells in patients with Crohn's disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn's disease, which could be targeted with new therapeutics that specifically regulate B-cell function.
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Wilhelmina M C
authors.initials: WM
authors.lastname: Timmermans
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Jan A M
authors.initials: JA
authors.lastname: van Laar
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Tim B
authors.initials: TB
authors.lastname: van der Houwen
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Lieke S J
authors.initials: LS
authors.lastname: Kamphuis
authors.affiliation: Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Sophinus J W
authors.initials: SJ
authors.lastname: Bartol
authors.affiliation: Department of Pathology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: King H
authors.initials: KH
authors.lastname: Lam
authors.affiliation: Department of Gastroenterology, Ikazia Hospital, Rotterdam, The Netherlands.
authors.forename: Rob J
authors.initials: RJ
authors.lastname: Ouwendijk
authors.affiliation: Department of Gastroenterology, Alfred Hospital, Monash University and Alfred Health, Melbourne, VIC, Australia.
authors.forename: Miles P
authors.initials: MP
authors.lastname: Sparrow
authors.affiliation: Department of Gastroenterology, Alfred Hospital, Monash University and Alfred Health, Melbourne, VIC, Australia.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Gibson
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: P Martin
authors.initials: PM
authors.lastname: van Hagen
authors.affiliation: Department of Immunology, Erasmus MC, Rotterdam, The Netherlands.|Department of Immunology and Pathology, Monash University, Melbourne, VIC, Australia.
authors.forename: Menno C
authors.identifier: http://orcid.org/0000-0003-4161-1919
authors.initials: MC
authors.lastname: van Zelm
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology*; D003424:Crohn Disease / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D000069285:Infliximab / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000069285:Infliximab