title: Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment.
abstract: Behçet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy.
  
  
  
  B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied.
  
  
  
  Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+IgA+B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+IgM+IgD+B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls.
  
  
  
  We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.
authors.affiliation: Department of Internal Medicine.|Department of Immunology.
authors.forename: Tim B
authors.initials: TB
authors.lastname: van der Houwen
authors.affiliation: Department of Internal Medicine.|Department of Immunology.
authors.forename: P Martin
authors.initials: PM
authors.lastname: van Hagen
authors.affiliation: Department of Internal Medicine.|Department of Immunology.
authors.forename: Wilhemina M C
authors.initials: WM
authors.lastname: Timmermans
authors.affiliation: Department of Immunology.
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 Internal Medicine.|Department of Immunology.
authors.forename: Jasper H
authors.initials: JH
authors.lastname: Kappen
authors.affiliation: Department of Immunology.|Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia.
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.affiliation: Department of Internal Medicine j.vanlaar@erasmusmc.nl.|Department of Immunology.
authors.forename: Jan A M
authors.initials: JA
authors.lastname: van Laar
mesh_terms: D000068879:Adalimumab / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D016175:B-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D001528:Behcet Syndrome / Q000150:complications / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology; D017578:Immunoglobulin Class Switching; D007072:Immunoglobulin D / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D007150:Immunohistochemistry; D007156:Immunologic Memory / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D027041:Somatic Hypermutation, Immunoglobulin; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014456:Ulcer / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D018501:Antirheumatic Agents; D007070:Immunoglobulin A; D007072:Immunoglobulin D; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D014409:Tumor Necrosis Factor-alpha; D000068879:Adalimumab
keywords: B cells; Behçet’s disease; TNF blockers; memory B cell formation