Activation-Induced Cytidine Deaminase, commonly known as AID, is an enzyme primarily found within the immune system’s B lymphocytes. This specialized protein plays a role in modifying genetic information, which is a fundamental process for the immune system to adapt and respond to various threats. AID acts as a molecular tool, orchestrating changes within the DNA of these immune cells.
How AID Modifies DNA
AID chemically alters DNA bases. The enzyme specifically targets cytidine bases (‘C’) within a DNA strand, converting them into uridine (‘U’). This deamination process occurs when the DNA is in a single-stranded configuration, often during gene transcription. The conversion of ‘C’ to ‘U’ directly within the DNA creates a mismatch, as uridine is normally found in RNA, not DNA.
This U-G mismatch is unstable and signals other DNA repair pathways. Cellular enzymes recognize this incorrect pairing and initiate further DNA processing. These repair mechanisms ultimately lead to the diverse genetic changes observed in antibody genes.
AID’s Key Role in Antibody Maturation
AID performs two distinct yet complementary functions central to the maturation of antibodies within B cells, enhancing the immune response.
Somatic Hypermutation (SHM)
Somatic hypermutation is a process initiated by AID that introduces point mutations into the variable regions of antibody genes. AID targets these DNA segments, leading to C-to-U deamination that serves as a template for error-prone DNA repair. This results in random mutations within the genetic code that dictates the antibody’s antigen-binding site. B cells producing antibodies with improved antigen binding are then preferentially selected to multiply. This iterative process of mutation and selection refines the antibody’s specificity and binding strength, leading to a more potent immune response.
Class Switch Recombination (CSR)
Class switch recombination also depends on AID, involving larger-scale DNA rearrangements. AID induces deamination within specific DNA sequences called “switch regions,” located upstream of constant region genes in antibody loci. These deaminations lead to DNA nicks and breaks in the double helix. Breaks on different switch regions are then joined, excising the intervening DNA.
This allows the B cell to change the constant region of the antibody it produces, altering its effector function while maintaining antigen-binding specificity. For example, a B cell initially producing IgM antibodies might switch to producing IgG, IgA, or IgE antibodies. Different antibody classes perform distinct roles in immunity: IgG provides long-term systemic immunity, IgA protects mucosal surfaces, and IgE is involved in allergic reactions and parasitic defense.
When AID Goes Wrong
The DNA-modifying activity of AID must be regulated to prevent harmful consequences. Both a lack of AID function and its uncontrolled activity can lead to severe health issues.
AID Deficiency
A complete lack of functional AID results in a rare inherited immunodeficiency known as Hyper-IgM Syndrome Type 2 (HIGM2). Individuals with HIGM2 are unable to perform class switch recombination effectively. Their B cells are largely restricted to producing IgM antibodies, which are the first line of defense but less versatile and efficient for long-term protection than other antibody types. This deficiency leaves patients highly susceptible to recurrent bacterial, viral, and fungal infections, often affecting the respiratory and gastrointestinal tracts.
AID Dysregulation/Misdirection
AID is important for a healthy immune system, but its capacity to modify DNA must be tightly controlled. If AID activity is misdirected to genes outside of antibody loci or prolonged beyond its normal regulatory windows, it can introduce mutations in unintended locations. Such off-target mutations can contribute to genomic instability within cells. This uncontrolled activity is implicated in the development of certain B-cell lymphomas, where AID can mutate genes involved in regulating cell growth or suppressing tumors. When these protective genes are disrupted, it can lead to uncontrolled cell proliferation and the formation of cancerous cells.