We study how B cells intentionally edit antibody DNA to build better immunity—
and how the same mechanisms can misfire and contribute to genome instability and cancer.
|
How B cells modify immunoglobulin genes to generate effective immune responses. |
How the cell restricts DNA editing activity to immunoglobulin loci and avoids off-target mutations. |
How DNA repair signaling enables programmed breaks during CSR—and what happens when regulation fails. |
Innate immunity responds quickly and non-specifically (e.g., macrophages, NK cells).
Adaptive immunity responds more slowly but specifically (T and B cells), recognizing unique antigens.
Antigen specificity is genetically programmed via V(D)J recombination, enabling:
- T cells to express antigen-specific receptors (TCRs)
- B cells to produce membrane-bound immunoglobulins (antibodies)
After activation, B cells further diversify antibody genes through:
- Class Switch Recombination (CSR)
- Somatic Hypermutation (SHM)
| Process | What it changes | Mechanism (high level) |
|---|---|---|
| CSR | Antibody isotype | DNA double-strand breaks + NHEJ recombination |
| SHM | Antigen-binding variable region | Untemplated mutations that tune binding affinity |
Both CSR and SHM require AID (Activation-Induced Cytidine Deaminase), a single-stranded DNA cytidine deaminase.
- AID deficiency → complete block in CSR and SHM (humans and mice)
- Promiscuous AID activity → mutations/translocations in non-immunoglobulin genes
To minimize off-target damage, AID is regulated transcriptionally and post-transcriptionally.
A key regulatory axis involves AID phosphorylation at Ser38:
- PKA phosphorylates AID on Ser38 at recombining switch (S) regions (Vuong et al. 2009)
- AID(S38A) mice show a significant block in CSR and SHM (Cheng et al. 2009)
- pS38-AID interacts with APE1 to generate DNA breaks in S regions (Vuong et al. 2013)
- AID phosphorylation depends on DNA breaks and ATM, suggesting repair signaling feeds back into diversification
