51. Genetic basis of antibodies and T-cell receptors.
Covers how antibody and T-cell receptor diversity is generated genetically, starting from the historical theories of antibody formation (side chain, template and clonal selection) and Tonegawa's discovery of gene rearrangement in B cells. It then takes V(D)J recombination, junctional diversity, somatic hypermutation and class-switch recombination in turn, followed by how TCR diversity compares, and the RAG1/RAG2 mutations behind SCID. A summary table compares the mechanisms for antibodies and TCRs, and several mnemonics are included.
Topic 52 of 105 in the MU Sofia syllabus for Biology (Medicine, Year 1). The free AceMed note covers it in 2 sections, about 1,016 words (8 min of reading), with 20 flashcards.
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Genetic basis of antibodies and T-cell receptors.
Genetic Basis of Antibodies and T-Cell Receptors
Genetic Basis of Antibodies and T-Cell Receptors
1. Introduction to Antibody Diversity
The immune system must generate highly specific antibodies capable of recognizing an enormous variety of antigens.
Antibodies are proteins encoded by genes, but their diversity exceeds the number of genes in the human genome.
The key question: how can the genome provide instructions for such an immense antibody repertoire?
Historically, scientists debated two major theories:
Instructive Theories: Antigens instruct the immune system on how to make antibodies.
Selective Theories: A pre-existing pool of antibodies exists, and antigens simply select the best match.
Eventually, selective theories were supported by experimental evidence, though their mechanisms were initially unclear.
2. Historical Theories of Immunity
a. Side Chain Theory (Paul Ehrlich, 1900)
Suggested cells have many side chains (potential antibodies) on their surface.
An antigen binds to a matching side chain, prompting the cell to produce that specific antibody in large quantities.
It was largely accurate but couldn’t explain how cells could carry such a vast array of side chains on a single membrane.
b. Template Theory (Instructive Theory by Haurowitz, 1931)
Proposed that all antibodies start with the same structure.
Upon antigen contact, the antibody would mold itself around the antigen, using it as a physical template.
This theory gained support temporarily (even from Linus Pauling), especially to explain antibody flexibility.
c. Clonal Selection Theory (Talmage and Burnet, 1957)
The currently accepted model.
Each lymphocyte produces a unique antibody even before antigen exposure.
The antigen selects the cell with the best-matching antibody.
The selected cell is activated, clones itself, and secretes large amounts of the antibody.
3. Genetic Basis of Antibody Diversity
a. Discovery of Gene Rearrangement
Susumu Tonegawa showed that in B cells, the DNA encoding antibody genes is rearranged, a phenomenon not observed in other cells.
In embryos, the variable (V) and constant (C) regions of antibody genes are far apart, but in mature B cells, they are located adjacent due to rearrangement.
This was the first evidence of somatic DNA rearrangement in vertebrates.
4. Mechanisms Creating Antibody Diversity
a. Combinatorial Diversity (V(D)J Recombination)
Immunoglobulin genes are made of several gene segments:
V (Variable) segments
D (Diversity) segments (heavy chain only)
J (Joining) segments
C (Constant) segments
During B cell development, these segments are randomly selected and joined to form a complete gene for the antibody's variable region.
Light chains use V and J segments (VJ recombination).
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