Activation-induced deaminase (AID) is a B-cell specific enzyme required for initiating the mechanisms of affinity maturation and isotype switching of antibodies. AID functions by deaminating cytosine to uracil in DNA, which initiates a cascade of events resulting in mutations and strand breaks in the immunoglobulin loci. There is an intricate interplay between faithful DNA repair and mutagenic DNA repair during somatic hypermutation, in that some proteins from accurate repair pathways are also involved in mutagenesis. We have found that one protein, XRCC1, is necessary for faithful repair, and in its absence, the mutation frequency goes up. In addition, after immunization, IgM memory cells outnumber and outlive their traditional IgG counterparts, indicating that these cells should be targeted for vaccination efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000732-16
Application #
8335908
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
16
Fiscal Year
2011
Total Cost
$460,022
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Pape, Kathryn A; Maul, Robert W; Dileepan, Thamotharampillai et al. (2018) Naive B Cells with High-Avidity Germline-Encoded Antigen Receptors Produce Persistent IgM+ and Transient IgG+ Memory B Cells. Immunity 48:1135-1143.e4
Gearhart, Patricia J; Mock, Beverly A; Casellas, Rafael et al. (2018) The Reign of Antibodies: A Celebration of and Tribute to Michael Potter and His Homogeneous Immunoglobulin Workshops. J Immunol 200:23-26
Castiblanco, Diana P; Maul, Robert W; Russell Knode, Lisa M et al. (2017) Co-Stimulation of BCR and Toll-Like Receptor 7 Increases Somatic Hypermutation, Memory B Cell Formation, and Secondary Antibody Response to Protein Antigen. Front Immunol 8:1833
Zanotti, Kimberly J; Gearhart, Patricia J (2016) Antibody diversification caused by disrupted mismatch repair and promiscuous DNA polymerases. DNA Repair (Amst) 38:110-6
Maul, Robert W; MacCarthy, Thomas; Frank, Ekaterina G et al. (2016) DNA polymerase ? functions in the generation of tandem mutations during somatic hypermutation of antibody genes. J Exp Med 213:1675-83
Zanotti, Kimberly J; Maul, Robert W; Castiblanco, Diana P et al. (2015) ATAD5 deficiency decreases B cell division and Igh recombination. J Immunol 194:35-42
Maul, Robert W; Gearhart, Patricia J (2014) Refining the Neuberger model: Uracil processing by activated B cells. Eur J Immunol 44:1913-6
Saribasak, Huseyin; Maul, Robert W; Cao, Zheng et al. (2012) DNA polymerase ? generates tandem mutations in immunoglobulin variable regions. J Exp Med 209:1075-81
Pape, Kathryn A; Taylor, Justin J; Maul, Robert W et al. (2011) Different B cell populations mediate early and late memory during an endogenous immune response. Science 331:1203-7
Maul, Robert W; Gearhart, Patricia J (2010) AID and somatic hypermutation. Adv Immunol 105:159-91

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