title: Perigranuloma localization and abnormal maturation of B cells: emerging key players in sarcoidosis?
abstract: BACKGROUND
  Recent observations of abnormal immunoglobulin responses and case reports describing successful B-cell ablative therapy suggest involvement of B cells in the pathogenesis of sarcoidosis.
  
  
  OBJECTIVE
  To investigate how abnormal B-cell maturation and function in patients with sarcoidosis contribute to disease.
  
  
  METHODS
  Patients with sarcoidosis (n = 32) were included for detailed analysis by immunohistochemistry of tissue, flow cytometry of blood B-cell subsets, and serum immunoglobulin levels. Vaccination responses in patients with sarcoidosis to influenza virus and encapsulated bacteria and molecular analysis of immunoglobulin heavy chain transcripts were studied for functional analysis of immunoglobulin responses.
  
  
  RESULTS
  Perigranuloma localization of IgA-producing plasma cells and numerous B cells were found in affected tissues. Total blood B-cell numbers were normal, CD27(+) memory B cells were significantly reduced, and CD27(-)IgA(+) B cells were significantly increased; the results are normalized in patients treated with TNF-α blockers. Despite this, patients had normal serum immunoglobulin levels and normal antigen-specific immunoglobulin responses. IgA and IgG transcripts, however, showed high frequencies of somatic hypermutations and increased usage of downstream IgG subclasses, suggestive for prolonged or repetitive responses.
  
  
  CONCLUSIONS
  The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.
authors.affiliation: Department of Immunology, University Medical Center, Rotterdam, The Netherlands.
authors.forename: Lieke S
authors.initials: LS
authors.lastname: Kamphuis
authors.forename: Menno C
authors.initials: MC
authors.lastname: van Zelm
authors.forename: King H
authors.initials: KH
authors.lastname: Lam
authors.forename: Guus F
authors.initials: GF
authors.lastname: Rimmelzwaan
authors.forename: G Seerp
authors.initials: GS
authors.lastname: Baarsma
authors.forename: Willem A
authors.initials: WA
authors.lastname: Dik
authors.forename: H Bing
authors.initials: HB
authors.lastname: Thio
authors.forename: Paul L
authors.initials: PL
authors.lastname: van Daele
authors.forename: Mirjam E
authors.initials: ME
authors.lastname: van Velthoven
authors.forename: Manou R
authors.initials: MR
authors.lastname: Batstra
authors.forename: P Martin
authors.initials: PM
authors.lastname: van Hagen
authors.forename: Jan A
authors.initials: JA
authors.lastname: van Laar
mesh_terms: D000328:Adult; D000368:Aged; D001402:B-Lymphocytes / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006099:Granuloma / Q000097:blood / Q000276:immunology*; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009975:Orthomyxoviridae / Q000276:immunology; D012507:Sarcoidosis / Q000097:blood / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000097:blood / Q000276:immunology; D055815:Young Adult
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7