Immunoglobulin Genes

Schooling, instead of encouraging the asking of questions, too often discourages it
Madeleine L’Engle

Who am I?:

I showed that B cell generate different antibody molecules by recombination bwteen multiple gene segements. I received the Noble Prize in Medicine in 1987

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Immunoglublin Genetics

Immunoglogulin genetics : organization of re arrangement of the genes that are used to make antibodies

ASSIGNED READING

Kuby's Immunology 4th Ed Chapter 5 pp 115-148
Kuby's Immunology 3rd Ed Chapter 7: pp 165-194

OUTLINE/SUMMARY

1. Genetic models
   • germ line vs somatic mutation model
   • Dryer Bennett: Two gene model
   • Verification
2. Multigene Organization of Immunoglobulin Genes
   • lambda chain multigenes
   • kappa chain multigenes
   • heavy chain multigenes
3. Variable-Region Gene Rearrangements
   • V-J rearrangements of light chains
   • V-D-J rearrangements of heavy chains
   • mechanisms
   • recombination signal sequences
   • enzymatic joining of gene segements
   • RAG-1 RAG-2
   • Defects
   • Productive vs non productive gene rearrangements
   • Allelic exclusion
4. Generation of Antibody Diversity
   • multple germ line gene segments
   • combinatorial V-J & V-D-J joining
   • junctional flexibility
   • P-nucleotide addition
   • N-nucleotide addition
   • Somatic hypermutation
   • Assocation of light & heavy chains
5. Class Switching in C Region Genes
   • Expression of Ig Genes
     • Differential processing of RNA transcipts of heavy chains
       • Membrane bound vs secreted Ig
       • Coexpression of IGM & IgD
       • Synthesis, assembly and secretion
   • Regulation of Ig-Gene Transcription
     • DNA rearrangement
     • Inhibition by T Cells

PERFORMANCE OBJECTIVES

ON COMPLETION OF THIS SECTION THE STUDENT SHOULD BE ABLE TO:

1. Describe how the number and organization of immunoglobulin gene segements or exons contribute to the generation of antibody diversity
2. Draw the organization of Kappa light chain genes.
3. Draw the organization of Lambda light chain genes.
4. Draw the organization of heavy chain genes.
5. Describe the V-J joining for light chain genes in terms of the 7-9 and the 12-23 rules
6. Describe the V-D-J joining of heavy chain genes in terms of the 7-9 and the 12-23 rules.
7. Explain how allelic exclusion leads to cells that produce immunoglobulins with a single antigen binding site.
8. Describe how transcription controls immunoglobulin gene expression
9. Describe at least four mechanisms that contribute to antibody diversity
10. Describe the coexpression of IgM and IgD in terms of RNA processsing
11. Describe the mechanisms for class switching
12. Correlate B cell differentiation with immunoglobulin gene rearrangements

SHORT ANSWER QUESTIONS

1. Why is it important to have antibody diversity?
2. Differentiate between the germline theory and the somatic theory of generation of antibody diversity.
3. How are BOTH germline and somatic mechanisms sources of antibdoy diversity?
4. Why did the amino acid sequencing of antibody light chains lead Dryer and Bennet to abandon the one gene- one polypeptide theory and propose that two genes code for a single polypeptide?
5. Describe Tonagawa's approach to answering Dreyer and Bennett's hypothesis that two genes code for a single polypeptide.
6. In addition to showing that DNA seqments come together to form a functional antidoby gene, Tonagawa's experiments showed two other things. What were they?
7. The phrases "race car", "Madam I am Adam" and "sex at noon taxes" represent pallindromes in the english language. What are pallindromes in the genetic code and what is their importance in V region construction?
8. What are the two DNA recombinational events required to assemble a functional heavy chain V region gene?
9. The two DNA recombinational events required to assemble a functional heavy chain V region gene, are governed by the 7-9 and the 12-23 rules. Explain.
10. Discuss four mechanisms that contribute to antibody diversity.
11. Describe the differential splicing of RNA that progresses from membrane bound IgM to secreted IgM.
12. Explain how a particular B cell can secrete different antibody isotypes, yet remain specific for the same epitope.
13. What are the two stages of class switching?
14. Dicuss allelic exclusion; what it is and how it is regulated.
15. List in correct chronological order the events leading to the synthesis of a Kappa light chain and its incorporation into an antibody molecule.
16. List in correct chronological order the events leading to the synthesis of a Gamma chain and its incorporation into an antibody molecule.