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Questions and Answers
Which characteristic distinguishes antibody isotypes?
Which characteristic distinguishes antibody isotypes?
- The constant region sequence of the heavy chain. (correct)
- The variable region sequence of the heavy chain.
- The presence of either kappa or lambda light chains.
- The ability to bind to different antigens.
On which chromosome is the human kappa light chain gene located?
On which chromosome is the human kappa light chain gene located?
- Chromosome 14
- Chromosome 6
- Chromosome 22
- Chromosome 2 (correct)
What is the approximate number of different specificities for antigens that antibodies can produce?
What is the approximate number of different specificities for antigens that antibodies can produce?
- 10^15 to 10^20
- 10 to 100
- 10^7 to 10^11 (correct)
- 1000 to 10,000
What process allows B cells to create diverse antibodies from a limited amount of genetic information?
What process allows B cells to create diverse antibodies from a limited amount of genetic information?
Which of the following gene segments are used in the recombination of antibody heavy chains, but not in light chains?
Which of the following gene segments are used in the recombination of antibody heavy chains, but not in light chains?
What is the order of gene segments in the heavy chain locus?
What is the order of gene segments in the heavy chain locus?
In humans, approximately what percentage of light chains are lambda type?
In humans, approximately what percentage of light chains are lambda type?
Which of the following is the correct number of functional J segments in the kappa light chain?
Which of the following is the correct number of functional J segments in the kappa light chain?
How many $D_H$ segments are there in humans?
How many $D_H$ segments are there in humans?
What is the function of Recombination Activating Genes (RAG) 1/2?
What is the function of Recombination Activating Genes (RAG) 1/2?
Which of the following best describes the "12/23 rule" in V(D)J recombination?
Which of the following best describes the "12/23 rule" in V(D)J recombination?
What component is critical for stabilizing the complex of RAG1/2 bound to RSSs during V(D)J recombination?
What component is critical for stabilizing the complex of RAG1/2 bound to RSSs during V(D)J recombination?
Which of the following proteins adds nontemplated N nucleotides to V-D and D-J joints of Ig heavy chain and all joints of TCR chains?
Which of the following proteins adds nontemplated N nucleotides to V-D and D-J joints of Ig heavy chain and all joints of TCR chains?
What is the consequence of defects in RAG1/2?
What is the consequence of defects in RAG1/2?
If the coding joint results in loss of coding nucleotides at the joint, what is the outcome?
If the coding joint results in loss of coding nucleotides at the joint, what is the outcome?
Which mechanism generates antibody diversity by inserting nucleotides randomly into the junctions between gene segments?
Which mechanism generates antibody diversity by inserting nucleotides randomly into the junctions between gene segments?
Allelic exclusion ensures which of the following?
Allelic exclusion ensures which of the following?
What is the initial step in B-cell receptor expression after heavy-chain recombination?
What is the initial step in B-cell receptor expression after heavy-chain recombination?
What is the fate of a developing B cell if its initial heavy chain and surrogate light chain pairing is nonproductive?
What is the fate of a developing B cell if its initial heavy chain and surrogate light chain pairing is nonproductive?
What process allows B cells to modify their light chain after receptor assembly, potentially rescuing them from autoreactivity?
What process allows B cells to modify their light chain after receptor assembly, potentially rescuing them from autoreactivity?
What mechanism allows mature B cells to express both IgM and IgD antibodies?
What mechanism allows mature B cells to express both IgM and IgD antibodies?
What type of RNA sequence is removed by mRNA splicing during heavy chain transcription?
What type of RNA sequence is removed by mRNA splicing during heavy chain transcription?
How is it determined whether a B cell will produce membrane-bound or secreted IgM?
How is it determined whether a B cell will produce membrane-bound or secreted IgM?
Which type of T cell receptor (TCR) is structurally like an antibody?
Which type of T cell receptor (TCR) is structurally like an antibody?
How are T cell receptor genes like Ig genes?
How are T cell receptor genes like Ig genes?
Which chain of T cell receptors is similar in structure to the antibody light chain?
Which chain of T cell receptors is similar in structure to the antibody light chain?
With what molecule does B cell's heavy chain first pair?
With what molecule does B cell's heavy chain first pair?
Once paired with a heavy chain, how do cells avoid autoreactivity?
Once paired with a heavy chain, how do cells avoid autoreactivity?
When would cell death by apoptosis most likely occur in B cells regarding rearrangements?
When would cell death by apoptosis most likely occur in B cells regarding rearrangements?
How many mechanisms help the body create antibody diversity in naive B cells?
How many mechanisms help the body create antibody diversity in naive B cells?
With the expression of a function heavy chain, what happens to the recombination machinery in the cell?
With the expression of a function heavy chain, what happens to the recombination machinery in the cell?
If cells are oriented in opposite directions, can V(D)J recombination still occur?
If cells are oriented in opposite directions, can V(D)J recombination still occur?
Which of the following chains are structurally similar to antibodies?
Which of the following chains are structurally similar to antibodies?
Which of the gene segments below are encoded by V and J segments?
Which of the gene segments below are encoded by V and J segments?
Besides V, J, D, and C gene segments, what part of the immunoglobulin aids in the diversity of the chains?
Besides V, J, D, and C gene segments, what part of the immunoglobulin aids in the diversity of the chains?
Where V, D, and J segments recombined?
Where V, D, and J segments recombined?
Which of the following determines the function on the constant region?
Which of the following determines the function on the constant region?
During V(D)J recombination, what dictates the pairing of RSSs to ensure proper gene segment joining?
During V(D)J recombination, what dictates the pairing of RSSs to ensure proper gene segment joining?
If a developing B cell fails to produce a productive rearrangement of the heavy chain gene, what is the immediate outcome?
If a developing B cell fails to produce a productive rearrangement of the heavy chain gene, what is the immediate outcome?
Mature B cells can express both IgM and IgD due to a mechanism involving:
Mature B cells can express both IgM and IgD due to a mechanism involving:
How does the TdT enzyme contribute to antibody diversity?
How does the TdT enzyme contribute to antibody diversity?
Unlike immunoglobulin genes, T-cell receptor genes:
Unlike immunoglobulin genes, T-cell receptor genes:
Flashcards
Constant Region (Antibody)
Constant Region (Antibody)
The region of the heavy chain that determines the class (isotype) of an antibody.
Isotypes (Antibody)
Isotypes (Antibody)
Classes of antibodies defined by the constant region of the heavy chain (IgA, IgD, IgE, IgG, IgM).
Immunoglobulin Gene Structure Puzzle
Immunoglobulin Gene Structure Puzzle
The puzzle of how a limited amount of DNA can produce the vast diversity of possible antibodies.
V(D)J, and C Gene Segments
V(D)J, and C Gene Segments
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Kappa Genes
Kappa Genes
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Lambda Genes
Lambda Genes
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Heavy Chain Genes
Heavy Chain Genes
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RAG1/2 Recombinase
RAG1/2 Recombinase
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RAG Acronym
RAG Acronym
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Autoreactive Receptors
Autoreactive Receptors
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mRNA Splicing Mechanism
mRNA Splicing Mechanism
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Allelic Exclusion:
Allelic Exclusion:
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Antibody Diversity Mechanisms
Antibody Diversity Mechanisms
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Non-templated N nucleotide addition
Non-templated N nucleotide addition
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Exonuclease trimming
Exonuclease trimming
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P nucleotide addition:
P nucleotide addition:
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Study Notes
- The constant region of the heavy chain has five distinct classes of antibody called isotypes
- IgA: alpha (α) heavy chain
- IgD: delta (δ) heavy chain
- IgE: epsilon (ε) heavy chain
- IgG: gamma (γ) heavy chain
- IgM: mu (μ) heavy chain
- Light chain isotypes: Kappa (κ) and Lambda (λ)
- Antibodies can be produced for an enormous variety of different specific antigens (10^7-10^11 different specificities!)
- B cells use groups of gene parts to create different possible antibodies using recombination
- B cells use recombination of gene segments (PARTS) to create different possible antibodies
- Variable (V), diversity (D), joining (J), and constant (C) region gene segments are present
- Diversity (D) segments are used in antibody heavy chains only
- Immunoglobulin proteins consist of 2 identical heavy chains and 2 identical light chains, which can be either kappa or lambda
- Each set of gene families are encoded on separate chromosomes
- Kappa genes are on human chromosome 2, mouse chromosome 6
- Lambda genes are on human chromosome 22, mouse chromosome 16
- Heavy chain genes are on human chromosome 14, mouse chromosome 12
Kappa Light-Chain Genes
- Kappa light-chain genes include V, J, and C segments
- Mice have 18 Vk gene families
- Downstream of Vk genes are the four functional Jk segments
- Humans have a similar arrangement but with differing numbers of Vk and Jk genes
Lambda Light-Chain Genes
- Lambda light-chain genes pair each J segment with a particular C segment
- Only 5% of mouse Igs have lambda light chains due to a loss of most of the V segments
- In humans, 40% of light chains are lambda type
- About 33 V₁ genes are used
- There are a series of 7 J₁-C₁ pairs (four are functional)
- Heavy-chain gene organization includes VH, DH, JH, and CH segments
- Humans express at least 45 functional VH segments
- Mice express 101 VH segments
- Downstream of the VH segments are DH segments
- There are 14 DH segments in mice and 23 in humans
- JH segments number 4 in mice and 6 in humans
- Eight CH regions exist, encoding for different isotypes of antibodies
- Recombination is directed by signal sequences
- Recombination signal sequences (RSSs) flank each antibody gene segment
- Each RSS has a conserved nonamer and heptamer sequence
- In between the nonamer/heptamer lies either a 12 or a 23 bp spacer sequence
- The spacing and arrangement dictates that a 12 bp RSS must pair with a 23 bp RSS for recombination to occur (the "12/23 Rule")
- Gene segments are joined by the RAG1/2 recombinase
- RAG = recombination activating gene
- Both proteins are needed for recombination
- RAG1 is more important because it forms a complex with RSSs stabilized by binding RAG2
- Numerous other proteins are required for recombination, including several that are not unique to lymphocytes
- V(D)J recombination results in a functional Ig variable region gene
- Mechanisms that generate antibody diversity in naïve B cells:
- Multiple gene segments are put together
- P nucleotide addition: templated nucleotide addition between joints, resulting from asymmetrical cleaving of hairpin structures
- Exonuclease trimming: sometimes occurs at junctions, losing nucleotides and changing reading frames
- Non-templated N nucleotide addition: mediated by TdT activity, adding in random nucleotides between joints
- Combinatorial diversity: heavy chains pair with light chains
B-Cell Receptor Expression
- Allelic exclusion ensures that each B cell synthesizes only one heavy and one light chain
- Recombination is a very ordered process
- Heavy chains are recombined and expressed first
- Expression of a functional heavy chain shuts down recombination machinery temporarily
- The heavy chain is paired with a surrogate light chain (SLC) to form a pre-BCR
- If the SLC will pair with the heavy chain, the machinery is started up again
- Light-chain recombination then takes place
- Nonproductive arrangements lead to programmed cell death (apoptosis) during development
- Receptor editing of potentially autoreactive receptors occurs in light chains
- A functional antibody may bind to self molecules, so recombination machinery can be turned back on
- Mature B cells express both IgM and IgD antibodies
mRNA Splicing Mechanism
- Heavy chain transcripts have VDJ put together, but there is a spacer RNA sequence between the VDJ and C regions
- mRNA splicing removes the intervening spacer, leaving VDJC mRNA ready to be translated
- Primary transcripts for IgM heavy chains may result from RNA polymerase transcribing through both the IgM and IgD constant regions
- Depending on which C segment becomes polyadenylated, IgM or IgD could end up being produced
- mRNA splicing mechanisms also control whether the cell produces membrane-bound or secreted IgM
- T-cell receptor genes and expression
- Alpha and gamma chain are similar in structure to the antibody light chain
- Beta and delta chain are similar in structure to the antibody heavy chain
- A small subset of T cells express γδ TCR rather than an αβ TCR, but the two are structurally similar
- TCR genes undergo a process of rearrangement very similar to that of Ig genes
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