title: Iron inhibits activation-induced cytidine deaminase enzymatic activity and modulates immunoglobulin class switch DNA recombination.
abstract: Immunoglobulin (Ig) class switch DNA recombination (CSR) and somatic hypermutation (SHM) are critical for the maturation of the antibody response. Activation-induced cytidine deaminase (AID) initiates CSR and SHM by deaminating deoxycytidines (dCs) in switch (S) and V(D)J region DNA, respectively, to generate deoxyuracils (dUs). Processing of dUs by uracil DNA glycosylase (UNG) yields abasic sites, which are excised by apurinic/apyrimidinic endonucleases, eventually generating double strand DNA breaks, the obligatory intermediates of CSR. Here, we found that the bivalent iron ion (Fe(2+), ferrous) suppressed CSR, leading to decreased number of switched B cells, decreased postrecombination Iμ-C(H) transcripts, and reduced titers of secreted class-switched IgG1, IgG3, and IgA antibodies, without alterations in critical CSR factors, such as AID, 14-3-3γ, or PTIP, or in general germline I(H)-S-C(H) transcription. Fe(2+) did not affect B cell proliferation or plasmacytoid differentiation. Rather, it inhibited AID-mediated dC deamination in a dose-dependent fashion. The inhibition of intrinsic AID enzymatic activity by Fe(2+) was specific, as shown by lack of inhibition of AID-mediated dC deamination by other bivalent metal ions, such as Zn(2+), Mn(2+), Mg(2+), or Ni(2+), and the inability of Fe(2+) to inhibit UNG-mediated dU excision. Overall, our findings have outlined a novel role of iron in modulating a B cell differentiation process that is critical to the generation of effective antibody responses to microbial pathogens and tumoral cells. They also suggest a possible role of iron in dampening AID-dependent autoimmunity and neoplastic transformation.
authors.affiliation: Institute for Immunology and Department of Medicine, School of Medicine, University of California, Irvine, California 92697-4120, USA.
authors.forename: Guideng
authors.initials: G
authors.lastname: Li
authors.forename: Egest J
authors.initials: EJ
authors.lastname: Pone
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Tran
authors.forename: Pina J
authors.initials: PJ
authors.lastname: Patel
authors.forename: Lisa
authors.initials: L
authors.lastname: Dao
authors.forename: Zhenming
authors.initials: Z
authors.lastname: Xu
authors.forename: Paolo
authors.initials: P
authors.lastname: Casali
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D007070:Immunoglobulin A / Q000235:genetics / Q000378:metabolism; D017578:Immunoglobulin Class Switching / Q000502:physiology*; D007074:Immunoglobulin G / Q000235:genetics / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D051379:Mice; D010950:Plasma Cells / Q000166:cytology / Q000378:metabolism*; D011995:Recombination, Genetic / Q000502:physiology*; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007501:Iron; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase