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Course: MCAT > Unit 2

Lesson 3: Foundation 3: Organ Systems

Immune system: Mechanisms of antibody variability

Problem

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 VH segment, a random DH segment, and a random JH 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 VL and JL segments to form CDR3 of the light chain.
Figure 1 Joining of VH, DH, and JH gene segments
Three different mechanisms cause random nucleotide alteration at the junction sites – these include P-addition, N-addition, and junctional flexibility:
  1. P-addition (palindromic-sequence addition) involves the creation of a DNA hairpin at the ends of gene segments; these hairpins are enzymatically cleaved, causing the unpairing of nucleotides to form a single strand. Repair enzymes then add complementary nucleotides, generating a new palindromic sequence.
  2. N-addition entails the insertion of a random number of nucleotides (“N” number of random nucleotides, up to 15) between two gene fragments.
  3. Lastly, in the phenomenon known as junctional flexibility, a random number of nucleotides may be lost on the adjoining end of either gene fragment. These random nucleotide alterations come with the risk of non-productive rearrangements, which occur when the altered nucleotide sequence disrupts the reading frame of the heavy chain or light chain gene, resulting in a non-functional antibody. Non-productive rearrangements cause the B cell to initiate cell death.
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 VH gene segments, 27 DH gene segments, and 6 JH gene segments, how many potential SEQUENCES (x) can the antibody heavy chain have?
Choose 1 answer:
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