Download Immunogenetics

Organization & Expression of
Immunoglobulin Genes
Hugh B. Fackrell
5/23/2017
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Organization & Expression of
Immunoglobulin Genes
Assigned Reading
Content Outline
Performance Objectives
Key terms
Key Concepts
Short Answer Questions
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Assigned Reading
Chapter: 7 pp 165-194
 Janis Kuby’s Immunology 3rd Ed
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Content Outline
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Genetic models
Multigene
Organization of
Immunoglobulin Genes
Variable-Region Gene
Rearrangements
Generation of
Antibody Diversity
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Class Switching in C
region genes
Expression of Ig Genes
Regulation of Ig-Gene
Transcription
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Genetic models
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Germ line vs somatic mutation model
Dryer Bennett: Two gene model
Verification
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Multigene Organization of
Immunoglobulin Genes
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lambda chain multigenes
kappa chain multigenes
heavy chain multigenes
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Variable-Region Gene
Rearrangements
V-J rearrangements of light chains
 V-D-J rearrangements of heavy chains
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Mechanisms
recombination signal sequences
 enzymatic joining of gene segements
 RAG-1 RAG-2
 Defects
 Productive vs non productive gene
rearrangements
 Allelic exclusion
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Generation of Antibody
Diversity
multiple germ line gene segments
 combinatorial V-J & V-D-J joining
 junctional flexibility
 P-nucleotide addition
 N-nucleotide addition
 Somatic hypermutation
 Association of light & heavy chains
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Class Switching in C Region
Genes
Expression of Ig Genes
 Differential processing of RNA
transcripts of heavy chains
 Membrane bound vs secreted Ig
 Coexpression of IgM & IgD
 Synthesis, assembly and secretion
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Regulation of Ig-Gene
Transcription
DNA rearrangement
 Inhibition by T Cells
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DONE!!!
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Performance Objectives
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Key Terms
allelic exclusion, class switching,
 combinatorial freedom of chain
association,comibinatorial association
of
 gene segments, Constant (c) gene
segments, Diversity (D) gene segemtns,
 Palindromes, acceptor junctions, donor
junctions, enhancers, exons,
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7-9 rule, 12-23 rule, Germline theory,
somatic theory, imprecise DNA
rerangement,
 Insertion of random N regions, introns,
Joining (J) gene segments,
 junctional diversity, leader sequence,
Membrane (M) exons), n regions
 promotors, recognition sequences, spacer
sequences, somatic hypermutation,
 switch recombination. switch (S) regions,
variable(V) gene segments
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Key Concepts
Describe how the number and organization
of immunoglobulin gene segements or exons
contribute to the generation of antibody
diversity
 Draw the organization of Kappa light chain
genes.
 Draw the organization of Lambda light chain
genes.
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Draw the organization of heavy chain
genes.
 Describe the V-J joining for light chain
genes in terms of the 7-9 and the 12-23
rules
 Describe the V-D-J joining of heavy chain
genes in terms of the 7-9 and the 12-23
rules.
 Explain how allelic exclusion leads to cells
that produce immunoglobulins with a
single antigen binding site.
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Describe how transcription controls
immunoglobulin gene expression
 Describe at least four mechanisms that
contribute to antibody diversity
 Describe the coexpression of IgM and
IdD in terms of RNA processsing
 Describe the mechanisms for class
switching
 Correlate B cell differentiation with
immunoglobulin gene rearrangements
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Short Answer Questions
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Why is it important to have antibody
diversity?
 Differentiate between the germline theory
and the somatic theory of generation of
antibody diversity.
 How are BOTH germline and somatic
mechanisms sources of antibdoy diversity?
 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?
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Describe Tonagawa's approach to
answering Dreyer and Bennett's
hypothesis that two genes code for a
single polypeptide.
 In addition to showing that DNA
seqments come together to form a
functional antibody gene, Tonagawa's
experiments showed two other things.
What were they?
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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?
 What are the two DNA recombinational
events required to assemble a functional
heavy chain V region gene?
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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.
 Discuss four mechanisms that contribute to
antibody diversity.
 Describe the differential splicing of RNA
that progresses from membrane bound IgM
to secreted IgM.
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Explain how a particular B cell can secrete
different antibody isotypes, yet remain
specific for the same epitope.
 What are the two stages of class switching?
 Dicuss allelic exclusion; what it is and how
it is regulated.
 List in correct chronological order the
events leading to the synthesis of a Kappa
light chain and its incorporation into an
antibody molecule.
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List in correct chronological order the
events leading to the synthesis of a
Gamma chain and its incorporation into
an antibody molecule.
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