title: Inhibition of the catalytic function of activation-induced cytidine deaminase promotes apoptosis of germinal center B cells in BXD2 mice.
abstract: OBJECTIVE
  To determine whether functional suppression of the catalytic domain of activation-induced cytidine deaminase (AID) can suppress the hyperreactive germinal center (GC) responses in BXD2 mice.
  
  
  METHODS
  We generated transgenic BXD2 mice expressing a dominant-negative (DN) form of Aicda at the somatic hypermutation site (BXD2-Aicda-DN-transgenic mice). Real-time quantitative reverse transcriptase-polymerase chain reaction was used to determine the expression of Aicda and DNA damage/repair genes. Enzyme-linked immunosorbent assay was used to measure serum levels of autoantibodies and immune complexes (ICs). Development of GCs and antibody-containing ICs as well as numbers of proliferative and apoptotic cells were determined using flow cytometry and/or immunohistochemical analyses. Development of arthritis and kidney disease was evaluated histologically in 6-8-month-old mice.
  
  
  RESULTS
  Suppression of the somatic hypermutation function of AID resulted in a significant decrease in autoantibody production without affecting the expression of DNA damage-related genes in GC B cells of BXD2-Aicda-DN-transgenic mice. There was decreased proliferation, increased apoptosis, increased expression of caspase 9 messenger RNA in GC B cells, and lower numbers of GCs in the spleens of BXD2-Aicda-DN-transgenic mice. Decreased GC response was associated with lower levels of IgG-containing ICs. Anti-IgM- and anti-CD40 plus anti-Ig-induced B cell proliferative responses were decreased in BXD2-Aicda-DN-transgenic mice.
  
  
  CONCLUSIONS
  Inhibition of the AID somatic hypermutation function in BXD2 mice suppressed development of spontaneous GCs, generation of autoantibody-producing B cells, and autoimmunity in BXD2 mice. Suppression of AID catalytic function to limit selection-based survival of GC B cells could become a novel therapy for the treatment of autoimmune disease.
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Hsu
authors.forename: Pingar
authors.initials: P
authors.lastname: Yang
authors.forename: Qi
authors.initials: Q
authors.lastname: Wu
authors.forename: John H
authors.initials: JH
authors.lastname: Wang
authors.forename: Godwin
authors.initials: G
authors.lastname: Job
authors.forename: Tanja
authors.initials: T
authors.lastname: Guentert
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Cecil R
authors.initials: CR
authors.lastname: Stockard
authors.forename: Thuc-Vy L
authors.initials: TV
authors.lastname: Le
authors.forename: David D
authors.initials: DD
authors.lastname: Chaplin
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: John D
authors.initials: JD
authors.lastname: Mountz
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020134:Catalytic Domain / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D018858:Germinal Center / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001323:Autoantibodies; D003564:Cytidine Deaminase