TY - JOUR
T1 - Deficiency of the oxidative damage-specific DNA glycosylase NEIL1 leads to reduced germinal center B cell expansion
AU - Mori, Hiromi
AU - Ouchida, Rika
AU - Hijikata, Atsushi
AU - Kitamura, Hiroshi
AU - Ohara, Osamu
AU - Li, Yingqian
AU - Gao, Xiang
AU - Yasui, Akira
AU - Lloyd, R. Stephen
AU - Wang, Ji Yang
N1 - Funding Information:
The authors wish to thank Akiko Ukai for excellent technical assistance, the RCAI Animal Facility for breeding and maintaining the mice and the Immunogenomics group for sequencing. This work was supported by a budget of the Research Center for Allergy and Immunology and NIH R01 DK075974 (RSL).
PY - 2009/11/2
Y1 - 2009/11/2
N2 - 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.
AB - 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.
KW - DNA glycosylase
KW - Germinal center B cells
KW - Immune response
KW - Oxidative damage
KW - Somatic hypermutation
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U2 - 10.1016/j.dnarep.2009.08.007
DO - 10.1016/j.dnarep.2009.08.007
M3 - Article
C2 - 19782007
AN - SCOPUS:70349859987
SN - 1568-7864
VL - 8
SP - 1328
EP - 1332
JO - DNA Repair
JF - DNA Repair
IS - 11
ER -