title: Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome-associated lymphoproliferation.
abstract: OBJECTIVE
  Primary Sjögren's syndrome (SS) is an autoimmune disease associated with a high risk of developing non-Hodgkin's lymphoma. This study was undertaken to determine the nature of B cells driving lymphoproliferation in primary SS.
  
  
  METHODS
  B cell subsets and function were analyzed in peripheral blood from 66 adult patients with primary SS (including 14 patients with B cell lymphoproliferative disease [LPD]) and 30 healthy donors, using flow cytometry, calcium mobilization, and gene array analysis. The reactivity of recombinant antibodies isolated from single B cells from patients with primary SS and LPD was tested using an enzyme-linked immunosorbent assay.
  
  
  RESULTS
  We observed an expansion of an unusual CD21-/low B cell population that correlated with lymphoproliferation in patients with primary SS. A majority of CD21-/low B cells from patients with primary SS expressed autoreactive antibodies, which recognized nuclear and cytoplasmic structures. These B cells belonged to the memory compartment, since their Ig genes were mutated. They were unable to induce calcium flux, become activated, or proliferate in response to B cell receptor and/or CD40 triggering, suggesting that these autoreactive B cells may be anergic. However, CD21-/low B cells from patients with primary SS remained responsive to Toll-like receptor (TLR) stimulation. Molecules specifically expressed in CD21-/low B cells that are likely to induce their unresponsive stage were detected in gene array analyses.
  
  
  CONCLUSIONS
  Patients with primary SS who display high frequencies of autoreactive and unresponsive CD21-/low B cells are susceptible to developing lymphoproliferation. These cells remain in peripheral blood controlled by functional anergy instead of being eliminated, and chronic antigenic stimulation through TLR stimulation may create a favorable environment for breaking tolerance and activating these cells.
authors.affiliation: CNRS UMR 7211, INSERM U959, Groupe Hospitalier Pitié-Salpêtrière, and Université Pierre et Marie Curie, Paris 6, Paris, France. david.saadoun@psl.aphp.fr
authors.forename: D
authors.initials: D
authors.lastname: Saadoun
authors.forename: B
authors.initials: B
authors.lastname: Terrier
authors.forename: J
authors.initials: J
authors.lastname: Bannock
authors.forename: T
authors.initials: T
authors.lastname: Vazquez
authors.forename: C
authors.initials: C
authors.lastname: Massad
authors.forename: I
authors.initials: I
authors.lastname: Kang
authors.forename: F
authors.initials: F
authors.lastname: Joly
authors.forename: M
authors.initials: M
authors.lastname: Rosenzwajg
authors.forename: D
authors.initials: D
authors.lastname: Sene
authors.forename: P
authors.initials: P
authors.lastname: Benech
authors.forename: L
authors.initials: L
authors.lastname: Musset
authors.forename: D
authors.initials: D
authors.lastname: Klatzmann
authors.forename: E
authors.initials: E
authors.lastname: Meffre
authors.forename: P
authors.initials: P
authors.lastname: Cacoub
mesh_terms: D000328:Adult; D000368:Aged; D016175:B-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D016022:Case-Control Studies; D017635:Clonal Anergy; D003449:Cryoglobulinemia / Q000150:complications / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006801:Humans; D016393:Lymphoma, B-Cell / Q000150:complications / Q000235:genetics / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D017464:Receptors, Complement 3d / Q000235:genetics / Q000378:metabolism*; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology*
chemical_list: D012333:RNA, Messenger; D017464:Receptors, Complement 3d; D002118:Calcium