Immune system: Mechanisms of antibody variability

The heavy chain and light chain subunits of antibodies both contain three regions called complementarity determining regions (CDR1, CDR2, and CDR3). The CDRs are responsible for the high specificity of the fragment antigen binding region (Fab region) of antibodies. CDRs are hypervariable among antibodies, allowing for an extensive range of antigens with which different antibodies can interact.

During B cell maturation, the gene for CDR3 of the heavy chain is formed when a random ${\text{V}}_{\text{H}}$‍ segment, a random ${\text{D}}_{\text{H}}$‍ segment, and a random ${\text{J}}_{\text{H}}$‍ segment are joined together, as shown in Figure 1. To further randomize CDR3, DNA breaks are introduced at the junction sites, leading to nucleotide addition or subtraction before the breaks are sealed. A similar process occurs with only ${\text{V}}_{\text{L}}$‍ and ${\text{J}}_{\text{L}}$‍ segments to form CDR3 of the light chain.

Figure 1 Joining of ${\text{V}}_{\text{H}}$‍, ${\text{D}}_{\text{H}}$‍, and ${\text{J}}_{\text{H}}$‍ gene segments

Three different mechanisms cause random nucleotide alteration at the junction sites – these include P-addition, N-addition, and junctional flexibility:

These processes are summarized in Figure 2.

Figure 2 P-addition, N-addition, and junctional flexibility

In addition to these nucleotide alteration mechanisms, another mechanism that increases Fab variability is somatic hypermutation, which enhances the diversity and specificity of antibodies produced in response to antigens. During somatic hypermutation, the DNA of the B cell's antibody genes undergoes random mutations, introducing point mutations in the variable region of the antibody. In a process known as affinity maturation, B cells with mutated antibodies that exhibit higher affinity for the target antigen receive survival signals and continue to proliferate, while those with lower affinity undergo apoptosis.

If there were 44 ${\text{V}}_{\text{H}}$‍ gene segments, 27 ${\text{D}}_{\text{H}}$‍ gene segments, and 6 ${\text{J}}_{\text{H}}$‍ gene segments, how many potential SEQUENCES (x) can the antibody heavy chain have?