Antigen Receptor Diversity

Learning Objectives

  • Define essential terms related to antigen receptor genetics.

  • Describe the organization of antigen receptor genes:

    • Immunoglobulin (Ig) heavy (H) and light (L) chain genes.

    • T-cell receptor (TCR) alpha (a) and beta (b) chain genes.

  • Explain gene rearrangement processes that generate receptor diversity.

  • Describe how antigen receptors recognize numerous antigens.

Key Terminology

  • Germline DNA: The hereditary material passed to offspring, not altered by somatic mutation.

  • Genomic DNA: The complete DNA sequence of an organism.

  • Locus (plural: loci): The specific physical location of a gene on a chromosome.

  • Gene recombination: The rearrangement of DNA sequences to create new gene combinations.

  • Junctional diversity: The genetic variability introduced at the junctions of gene segments during recombination.

  • Somatic hypermutation: The process that leads to mutations in B cells after antigen exposure, enhancing antibody affinity.

  • Allelic exclusion: The mechanism whereby only one allele of a gene is expressed while the other is silenced.

  • Receptor editing: A process by which B cells can modify their receptors to alter binding specificity.

Antibodies Formed by Immunisation

A 14-month-old girl was immunized with the first dose of the MMR vaccine (measles, mumps, and rubella). How can she produce antibodies against these various immunogens?

Generation of Diversity

Each person can generate between 1015 to 1018 distinct Immunoglobulin (Ig) or T Cell Receptor (TCR) molecules. This astonishing diversity is attributed to several biological processes:

  • Lymphocyte Clones: Each B cell is specific to a diverse array of antigens through a process known as gene rearrangement.

  • Gene Rearrangement:

    • Occurs during the development of B and T cells, crucial for receptor diversification.

  • Mechanisms of Receptor Diversification:

    • Somatic recombination

    • Junctional diversity

    • Random heavy (H) and light (L) chain combination

    • Somatic hypermutation

Somatic Recombination of Heavy Chain Genes

The location of Immunoglobulin heavy chain genes in humans is on chromosome 14. The process includes:

  • V(D)J recombination: Initial rearrangement stages involve

    • D-J rearrangement.

    • V-DJ rearrangement.

  • Involvement of RAG-1 and RAG-2 proteins that facilitate DNA cutting at specific signal sequences.

  • Structures:

  • Variable Region: Includes Complementarity Determining Regions (CDR1, CDR2, CDR3)

  • Constant Region: Defines the antibody class.

Light Chain Gene Rearrangement

Light chains are located on chromosomes 2 (kappa) and 22 (lambda). The rearrangement involves:

  • VJ recombination: Selection of one V gene combined with one J gene, driven by RAG protein products.

  • Similar processes of double-stranded DNA repair as in heavy chain gene rearrangement.

Random Combination of Heavy and Light Chains

The combinations can lead to diverse antibody specificities:

  • B cell clones exhibit unique V-D-J combinations leading to different binding specificities.

  • Examples include combinations of m and k chains or m and l chains.

Junctional Diversity

Junctional diversity arises from random addition of nucleotides at the recombination sites:

  • Involves terminal deoxynucleotidyl transferase (TdT) which adds nucleotides at the junctions of rearranged segments.

  • Expressed through various B cell clones leading to an array of specificity.

Receptor Editing

Occurs in response to autoreactivity in immature B cells:

  • Reactivation of RAG-1 and RAG-2 allows for additional rearrangements to refine receptor specificity.

  • If no alteration occurs to correct autoreactivity, the cell undergoes apoptosis.

Somatic Hypermutation

This process occurs following antigen exposure primarily in secondary responses:

  • Leads to point mutations in CDR regions, enhancing the affinity for antigens.

  • Activation-Induced Deaminase (AID) plays a crucial role in the introduction of mutations.

  • B cells with reduced affinity or altered specificity typically do not survive.

T Cell Receptor (TCR) Diversity

Similar mechanisms contribute to TCR diversity:

  • TCR gene rearrangement operates through V(D)J recombination, similar to Ig gene rearrangement.

  • Combinatorial diversity results from random gene rearrangements and combinations of TCR alpha and beta chains.

Conclusion

The complex interplay of genetic processes enables the immune system to generate a highly diverse repertoire of receptors, essential for effective immune responses against numerous pathogens.