title: Suppression of B-cell activation and IgE, IgA, IgG1 and IgG4 production by mammalian telomeric oligonucleotides.
abstract: BACKGROUND
  The fine balance of immunoglobulins (Ig) E, IgG1, IgG4 and IgA in healthy production is maintained by the interaction of B cells with adaptive and innate immune response. The regulation of toll-like receptors (TLRs)-driven innate and adaptive immune effector B-cell response and the role of mammalian telomeric TTAGGG repeat elements represent an important research area.
  
  
  METHODS
  Human PBMC and purified naive and memory B cells were stimulated with specific ligands for TLR2, TLR3, TLR4, TLR5, TLR7, TLR8 and TLR9 in the presence or absence of telomeric oligonucleotides. B-cell proliferation, differentiation and antibody production were determined.
  
  
  RESULTS
  TLR9 ligand directly activates naive and memory B cells, whereas TLR7 can stimulate them in the presence of plasmacytoid dendritic cells. Human B cells proliferate and turn into antibody-secreting cells in response to TLR3, TLR7 and TLR9, but not to TLR2, TLR4, TLR5 and TLR8 ligands. Stimulation of B cells with intracellular TLR3, TLR7 and TLR9 induced an activation cascade leading to memory B-cell generation and particularly IgG1, but also IgA, IgG4 and very low levels of IgE production. Mammalian telomeric oligodeoxynucleotide (ODN) significantly inhibited all features of TLR ligand-induced events in B cells including B-cell proliferation, IgE, IgG1, IgG4, IgA production, class switch recombination, plasma cell differentiation induced by TLR3, TLR7 and TLR9 ligands.
  
  
  CONCLUSIONS
  B cells require specific TLR stimulation, T-cell and plasmacytoid dendritic cell help for distinct activation and Ig production profiles. Host-derived telomeric ODN suppress B-cell activation and antibody production demonstrating a natural mechanism for the control of overexuberant B-cell activation, antibody production and generation of memory.
authors.affiliation: Swiss Institute of Allergy and Asthma Research SIAF, University of Zurich, CH 7270, Davos, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Sackesen
authors.forename: W
authors.initials: W
authors.lastname: van de Veen
authors.forename: M
authors.initials: M
authors.lastname: Akdis
authors.forename: O
authors.initials: O
authors.lastname: Soyer
authors.forename: J
authors.initials: J
authors.lastname: Zumkehr
authors.forename: B
authors.initials: B
authors.lastname: Ruckert
authors.forename: B
authors.initials: B
authors.lastname: Stanic
authors.forename: O
authors.initials: O
authors.lastname: Kalaycı
authors.forename: S S
authors.initials: SS
authors.lastname: Alkan
authors.forename: I
authors.initials: I
authors.lastname: Gursel
authors.forename: C A
authors.initials: CA
authors.lastname: Akdis
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000096:biosynthesis*; D017578:Immunoglobulin Class Switching / Q000187:drug effects; D007073:Immunoglobulin E / Q000096:biosynthesis*; D007074:Immunoglobulin G / Q000096:biosynthesis*; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D009841:Oligonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D016615:Telomere / Q000737:chemistry*; D051196:Toll-Like Receptor 3 / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000276:immunology; D060152:V(D)J Recombination / Q000187:drug effects
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D008024:Ligands; D009841:Oligonucleotides; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D007073:Immunoglobulin E