The proposed research continues to focus on the mechanisms that regulate development of the high affinity antibody responses which are essential to vaccine development. There are several critical aspects to these responses that are entirely B cell specific. First, clonal expansion which occurs in special microanatomic structures called germinal centers (GC). Second, diversification of antibody genes by somatic mutation (SHM) and class switch recombination (CSR), both of which are initiated by activation induced cytidine deaminase (AID). Although AID prefers antibody genes, it is not entirely lg specific and off target activity is the primary cause of B cell cancers in humans. The third B cell specific aspect of high affinity antibody development is selection for clones of B cells that express high affinity receptors. In the first 4 years of the funding period, as part of the original Aims 1 and 2, we examined the mechanisms by which AID targets lg genes and misstargets cancer genes in the germinal center. Moreover, we documented the cellular and cell biological regulation of B cell clonal expansion in the germinal center. We have initiated research on Aim 3 and have made significant progress in understanding how Rif-1 mediates its effects on CSR by studying its interaction partner ZYMD8 which has an important role in AID targeting.

Public Health Relevance

High affinity, AID dependent, antibody responses are essential to nearly all vaccines. The proposed research aims to develop an understanding of how antibodies are modified and repaired after AID mediated DNA damage with the long-term goal of being able to impact vaccine development and prevent the off target effects of AID that are associated with malignancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI037526-27
Application #
10103752
Study Section
Special Emphasis Panel (NSS)
Program Officer
Liu, Qian
Project Start
2019-02-01
Project End
2024-01-31
Budget Start
2021-02-01
Budget End
2022-01-31
Support Year
27
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Graduate Schools
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Delgado-Benito, VerĂ³nica; Rosen, Daniel B; Wang, Qiao et al. (2018) The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination. Mol Cell 72:636-649.e8
Keeffe, Jennifer R; Van Rompay, Koen K A; Olsen, Priscilla C et al. (2018) A Combination of Two Human Monoclonal Antibodies Prevents Zika Virus Escape Mutations in Non-human Primates. Cell Rep 25:1385-1394.e7
Dosenovic, Pia; Kara, Ervin E; Pettersson, Anna-Klara et al. (2018) Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen-binding affinity. Proc Natl Acad Sci U S A 115:4743-4748
Robbiani, Davide F; Bozzacco, Leonia; Keeffe, Jennifer R et al. (2017) Recurrent Potent Human Neutralizing Antibodies to Zika Virus in Brazil and Mexico. Cell 169:597-609.e11
Rommel, Philipp C; Oliveira, Thiago Y; Nussenzweig, Michel C et al. (2017) RAG1/2 induces genomic insertions by mobilizing DNA into RAG1/2-independent breaks. J Exp Med 214:815-831
Wang, Qiao; Kieffer-Kwon, Kyong-Rim; Oliveira, Thiago Y et al. (2017) The cell cycle restricts activation-induced cytidine deaminase activity to early G1. J Exp Med 214:49-58
Gitlin, Alexander D; von Boehmer, Lotta; Gazumyan, Anna et al. (2016) Independent Roles of Switching and Hypermutation in the Development and Persistence of B Lymphocyte Memory. Immunity 44:769-81
Dong, Junchao; Panchakshari, Rohit A; Zhang, Tingting et al. (2015) Orientation-specific joining of AID-initiated DNA breaks promotes antibody class switching. Nature 525:134-139
Kracker, Sven; Di Virgilio, Michela; Schwartzentruber, Jeremy et al. (2015) An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex. J Allergy Clin Immunol 135:998-1007.e6
Robbiani, Davide F; Deroubaix, Stephanie; Feldhahn, Niklas et al. (2015) Plasmodium Infection Promotes Genomic Instability and AID-Dependent B Cell Lymphoma. Cell 162:727-37

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