Lecture 10

Organized Notes: How Are Antibodies Generated In Response to Antigens?

1. Historical Background

• Louis Pasteur, Joseph Meister, Rabies Vaccine (1885)

• Paul Erlich (1891): "Anti-Body" (Antibody-Generator, Antigen)

• Paul Erlich’s Side-Chain Theory (1900)

• Macfarlane Burnet’s Clonal Selection Theory

2. Antibody Structure

• B Cell Receptors and Antibodies: Four Polypeptide Chains Linked by Disulfide Bonds

• Variable Region, Flexible Hinge, Constant Region (Figure 3.10)

• Structure of the Immunoglobulin Variable Domain (Figure 3.8)

• CDRs (Complementarity Determining Regions)

3. Clonal Selection of B Cells

• Selection of Antibodies During an Immune Response

• Mediated by Clonal Selection of B Cells

4. Immunoglobulin (Ig) Gene Rearrangement

• Discovery (Hozumi & Tonegawa, 1976; Nobel Prize 1987)

  • Antibody and BCR genes are located in different genome regions

  • Composed of V, D, and J segments

  • Gene segments recombine to create functional antibody genes

• Gene Rearrangement & Loci

  • Antibody Heavy and Light Chains: Encoded by V, D, J, and C Gene Segments

  • Three Immunoglobulin Gene Loci: IgH, Igκ, Igλ (Mouse Loci)

  • Immunoglobulin Gene Segments Are Flanked by Recombination Signal Sequences (RSSs)

  • The "12-23 Rule" for RSSs (Figure 6-8)

5. V(D)J Recombination Process

• Overview of V(D)J Recombination (Figure 6-9)

• Evolutionary Origins of Immunoglobulin Gene Rearranging Lymphocytes

• Recombination Signal Sequences (RSSs)

  • Recognized by a Recombinase (RAG-1 and RAG-2) (Figure 6-10)

6. Mechanisms of Antibody Diversity in Naïve B Cells

1. Variable region encoded by different V, D, and J segment combinations

2. Heavy chains can pair with either kappa (κ) or lambda (λ) light chains

3. P-nucleotide addition: Palindrome sequence generation during recombination

4. Exonuclease trimming: Nucleotide loss during recombination

5. N-nucleotide addition: Terminal deoxynucleotidyl transferase (TdT) adds nucleotides in heavy chain recombination