title: Hyporesponsiveness following booster immunization with bacterial polysaccharides is caused by apoptosis of memory B cells.
abstract: BACKGROUND
  Repeated immunizations with polysaccharide (PS) vaccines cause hyporesponsiveness through undefined mechanisms. We assessed the effects of a PS booster on immune responses, frequency, and survival of PS-specific B-cell subpopulations in spleen and bone marrow.
  
  
  METHODS
  Neonatal mice were primed with meningococcus serotype C (MenC) conjugate MenC-CRM(197)+CpG1826, boosted with MenC-CRM(197), MenC-PS, or saline; subsequently, bromodeoxyuridine (BrdU) was injected daily intraperitoneally. MenC-PS-specific cells were labeled with fluorescent MenC-PS and phenotyped by flow cytometry.
  
  
  RESULTS
  After MenC-PS booster, proliferating (BrdU(+)) MenC-PS-specific naive B cells (CD138(-)/B220(+); P = .0003) and plasma cells (CD138(+)/B220(-); P = .0002) in spleen were fewer than after saline booster. BrdU(+) MenC-PS-specific plasma cells were also reduced in bone marrow (P = .0308). Compared to saline, MenC-PS booster reduced BrdU(+) IgG(+) MenC-PS-specific B cells in spleen (P = .0002). Twelve hours after the MenC-PS booster, an increased frequency of apoptotic (AnnexinV(+)) MenC-PS-specific B cells in spleen was observed compared with MenC-CRM(197) (P = .0286) or saline (P = .001) boosters.
  
  
  CONCLUSIONS
  We demonstrated that the MenC-PS booster significantly reduced the frequency of newly activated MenC-PS-specific B cells-mostly switched IgG(+) memory cells-by driving them into apoptosis. It shows directly that apoptosis of PS-specific memory cells is the cause of PS-induced hyporesponsiveness. These results should be taken into account prior to consideration of the use of PS vaccines.
authors.affiliation: Department of Immunology, Landspitali, The National University Hospital of Iceland, Reykjavik, Iceland.
authors.forename: Siggeir F
authors.initials: SF
authors.lastname: Brynjolfsson
authors.forename: Maren
authors.initials: M
authors.lastname: Henneken
authors.forename: Stefania P
authors.initials: SP
authors.lastname: Bjarnarson
authors.forename: Elena
authors.initials: E
authors.lastname: Mori
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Del Giudice
authors.forename: Ingileif
authors.initials: I
authors.lastname: Jonsdottir
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000831:Animals, Newborn; D017304:Annexin A5 / Q000032:analysis; D017209:Apoptosis; D001402:B-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D001853:Bone Marrow / Q000276:immunology / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000032:analysis; D022401:Meningococcal Vaccines / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D013154:Spleen / Q000276:immunology / Q000473:pathology; D053668:Syndecan-1 / Q000032:analysis; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D017304:Annexin A5; C408982:CPG-oligonucleotide; D022401:Meningococcal Vaccines; D009838:Oligodeoxyribonucleotides; D011135:Polysaccharides, Bacterial; D053668:Syndecan-1; D018074:Vaccines, Conjugate; D017493:Leukocyte Common Antigens