# Molecular Mechanisms Regulating Immunoglobulin Diversification

> **NIH NIH SC1** · CITY COLLEGE OF NEW YORK · 2021 · $392,500

## Abstract

ABSTRACT
In mammals, the innate and adaptive immune systems are functionally coordinated to protect
them from pathogenic microbial infections. Cells of the innate immune system, such as
macrophages and natural killer cells, recognize foreign molecules non-specifically and respond
quickly to eliminate the microbe. In contrast, T and B cells of the adaptive immune system
respond more slowly but recognize a unique molecule (or antigen) on the microbe. Antigen
recognition activates and expands a T or B cell clone. The development of antigen specific T
and B cells is genetically programmed through a somatic DNA recombination process called
V(D)J recombination, which allows T cells to express antigen specific receptors and B cells to
produce plasma membrane-bound immunoglobulins, which are more commonly known as
antibodies. Antigen-activated B cells can further alter the immunoglobulin (Ig) coding genes
through class switch recombination (CSR) and somatic hypermutation (SHM). CSR alters the
isotype of the expressed Ig from the default IgM to IgG, IgE, or IgA through a DNA break and
ligation reaction. SHM introduces untemplated mutations within the Ig variable coding regions to
permit the selection of high affinity Ig. Both CSR and SHM require the activity of activation-
induced cytidine deaminase (AID), an enzyme that removes the amino group on deoxycytidine
bases in DNA. AID-deficiency leads to a primary immunodeficiency (Hyper-IgM syndrome) in
humans and a complete block in CSR and SHM. Dysregulated AID activity generates mutations
and translocations in proto-oncogenes that lead to mature B cell lymphomas. More recently, AID
has been shown to regulate autoantibody production in models of lupus. Our research has
shown that AID is phosphorylated directly by PKA (cAMP-dependent Protein Kinase A) and this
phosphorylation promotes the interaction of AID with base excision repair proteins. In addition,
our published work showed that the PKA-mediated phosphorylation of AID is dependent on the
DNA break response kinase ATM (ataxia telangiectasia mutated). However, the molecular
pathway that controls ATM-dependent PKA phosphorylation of AID and the subsequent
formation of DNA breaks within the Ig genes that are required for CSR is unknown. This
proposal seeks to identify how ATM-dependent and PKA-directed AID phosphorylation allows B
cells to generate DNA breaks only in the Ig genes to generate antibody-mediated immunity. The
results from this research will allow us to develop more effective vaccines and antibody-based
therapies to treat diseases, such as viral infections and cancer.

## Key facts

- **NIH application ID:** 10098037
- **Project number:** 5SC1GM132035-03
- **Recipient organization:** CITY COLLEGE OF NEW YORK
- **Principal Investigator:** Bao Q Vuong
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $392,500
- **Award type:** 5
- **Project period:** 2019-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10098037

## Citation

> US National Institutes of Health, RePORTER application 10098037, Molecular Mechanisms Regulating Immunoglobulin Diversification (5SC1GM132035-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10098037. Licensed CC0.

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