Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion.
Mammalian cells possess multiple DNA glycosylases, including OGG1, NTH1, NEIL1, NEIL2 and NEIL3, for the repair of oxidative DNA damage. Among these, NEIL1 and NEIL2 are able to excise oxidized bases on single stranded or bubble-structured DNA and has been implicated in repair of oxidative damage associated with DNA replication or transcription. We found that Neil1 was highly constitutively expressed in the germinal center (GC) B cells, a rapidly dividing cell population that is undergoing immunoglobulin (Ig) gene hypermutation and isotype switching. While Neil1(-/-) mice exhibited normal B and T cell development and maturation, these mice contained a significantly lower frequency of GC B cells than did WT mice after immunization with a T-dependent antigen. Consistent with the reduced expansion of GC B cells, Neil1(-/-) mice had a decreased frequency of Ig gene hypermutation and produced less antibody against a T-dependent antigen during both primary and secondary immune responses. These results suggest that repair of endogenous oxidative DNA damage by NEIL1 is important for the rapid expansion of GC B cells and efficient induction of humoral immune responses.
Mori
Hiromi
H
Laboratory for Immune Diversity, Research Center for Allergy and Immunology, RIKEN Yokohama Institute, 1-7-22 Suehiro-cho, Tsurumi, Yokohama 230-0045, Japan.
Ouchida
Rika
R
Hijikata
Atsushi
A
Kitamura
Hiroshi
H
Ohara
Osamu
O
Li
Yingqian
Y
Gao
Xiang
X
Yasui
Akira
A
Lloyd
R Stephen
RS
Wang
Ji-Yang
JY
D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology; D002454:Cell Differentiation; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D018858:Germinal Center / Q000201:enzymology / Q000276:immunology; D006861:Hydrogen Peroxide / Q000494:pharmacology; D056724:Immunity, Humoral; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D027041:Somatic Hypermutation, Immunoglobulin
D006861:Hydrogen Peroxide; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse