Week 7 S - Generation of Diversity

Introduction to Immunogenetics

• Study focus: generation of antibody and T-cell receptor diversity.

• Essential readings include chapters from:

  • Wood P. 2011, Understanding Immunology.

  • Murphy, Travers, and Walport (9th Ed.), Janeway’s Immunobiology.

  • Lydyard, Whelan, and Fanger (2nd Ed.), Instant Notes in Immunology.

Generation of Diversity

• Major challenge: estimating antibody specificities to be at least 2.5 imes 10^7.

• Central dogma states: one gene = one protein.

• Almost 3 imes 10^4 human genes; only 3 immunoglobulin loci available.

Antibody Domain Structure

• Antibody Components:

  • Variable Heavy chain (VH)

  • Variable Light chain (VL)

  • Constant regions (CH1, CH2, CH3, CL)

Immunoglobulin Diversity

• Types of diversity include:

  • Isotype: Immunoglobulin classes (IgG, IgM, etc.)

  • Allotype: Genetic variations between individuals of a species.

  • Idiotype: Unique antigen-binding sites.

• Key characteristics of the antibody response:

  • Heavy chains are produced first.

  • Isotype switching occurs throughout the response.

  • Affinity maturation increases specificity.

  • Hypervariability regions specialize in binding.

Structural Insights into Immunoglobulin

• Components:

  • Heavy Chain (μ, γ, α, δ, ε)

  • Light Chain (κ, λ)

• Biological activity parameters:

  • Antigen binding based on variable regions.

Theories of Immunoglobulin Diversity

• Germ Line Theory: genome contains a vast number of immunoglobulin genes.

• Somatic Variation Theory: involves mutations and recombination of a small set of genes.

• Each antibody consists of both constant and variable regions.

Rearrangement and Diversity Accumulation

• Immunoglobulin loci:

  • 3 major loci: kappa, lambda, and heavy chain.

  • Each locus features repeated gene segments: V, (D), J, C.

  • D-J joining happens early during B cell development.

Functional Consequences of Diversity

• Diversity is beneficial but costly:

  • High rates of lymphocyte death due to unsuccessful rearrangements.

  • Possible pathogenic changes in antibodies.

  • Successful rearrangements lead to clone proliferation and gene expression.

T-cell Receptor Diversity

• Similar repertoire size: 2.5 imes 10^7.

• Combinatorial diversity in T-cells as well.

• Receptors consist of multiple gene segments: V, (D), J, C, and vary between development stages.

Summary of Diversity Generation Mechanisms

• Multiple pathways lead to diversity in immunoglobulins and TCRs:

  • Combinatorial joining, mutations, and junctional flexibility play significant roles.

  • Specific number of combinations is calculated to assess potential diversity.

  • The complex variability in antibodies and T-cell receptors is essential for adaptive immunity.

Conclusion

• Immunogenetics shows profound diversity in antibody and T-cell receptor generation, fundamental for effective immune responses. The interplay of diverse genetic mechanisms contributes to the vast specificity required for pathogen identification and neutralization.