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24 Cards in this Set
- Front
- Back
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How can we produce millions of different Abs with limited genes?
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Ig gene rearrangement
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Discovery of gene rearrangement
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Susumu Tonegawa – 1976 (won Nobel in 1987)
showed that DNA segments containing the Ig genes differed in size when comparing the germ-line (sperm) and in mature myeloma cells |
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gene segments of the Heavy Chain in Germ line DNA of B cells (immature B cells)
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V(ariable), D(iverse), J(joining) and C(constant) region genes
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gene segments of the Light Chain in Germ line DNA of B cells (immature B cells)
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V, J, and C region genes
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_______ make up the variable region of the antibody
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V,D& J
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Genes must be ________ in order to be functional genes that can code for an Ab. This is a _____ of the genes used is______ AND occurs before Ag stimulation
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rearranged, Selection, random
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Class switching
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After Ag stimulation, a mature B cell can change it’s isotype
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Location of genes for lambda and kappa light chain and heavy chain are all on different chromosomes for the purpose of __________
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regulation
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To achieve Ig specificity,_______ can be expressed at once
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only one allele
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Allelic exclusion
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during the process of Ig gene rearrangement, if the first allele is successful, then the process stops
if the first allele is non-productive, then the other allele will be re-arranged |
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The process of gene rearrangement is “tightly” controlled and occurs in a very specific order
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H-chain first, the k light chain, then l light chain (if needed)
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Overview of B cell development in bone marrow
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Start with a hematopoetic stem cel l(pluripotent) which based on colony stimulating factors differentiates into a lymphoid cell, specifically a B cell, you rearrange heavy chain first, once that is complete you rearrange light chain, once that is completed you have an immature B cell that can first express membrane IgM. Soon after that the mature B cell will coexpress membrane IgM & IgD. This cell is called a MATURE B CELL & a NAÏVE B CELL (because it’s never seen Ag before).
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Overview of B cell development in the peripheral lymphoid organs upon Ag Stimulation
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Mature B cell gets stimulated by Antigen, a lot of things can happen at this point depending on cytokines in the environment. B cell becomes activated to become a plasma cell if it is a primary immune response it secretes IgM. Depending on cytokines you can get memory cells that are able to class switch and produce IgG, IgA, IgE, depending on on enviornment.
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Describe heavy chain Ig rearrangement
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-DH and JH join, then V with DHJH yielding a VDJ DNA sequence
-Then C region selection occurs IgM is first, followed by co-expression of IgD, only “normal” time B cell expresses two isotypes |
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How to select ONE V,D,J region and not two or more?
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recombination signal sequences (RSS)
-12/23 bp rule – a 12 bp sequence can join with a 23 bp sequence |
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12/23 bp rule
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7-23-9-9-12-7
V—23; D-12 |
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Enzyme responsible for 12-23 BP rule
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RAG =recombination activating genes
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V(D)J recombinase
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the complex of enzymes important in recognizing and excising the intervening sequences (looping out)
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Allelic exclusion
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A given B cell will express ONE heavy chain Ag specificity and ONE light chain Ag specificity
Humans have two IgH alleles and four IgL chain alleles (2 for k and 2 for l) -Can express maternal/maternal; maternal/paternal; or paternal/paternal combinations. |
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How many shots do you have to get a successful heavy chain
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2 (1 for each parental allel)
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How many shots do you have to get a successful heavy chain
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4 (1 for each parental K & L allele )
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Generation of Diversity - Ig
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-Multiple germ-line gene segments (V, D, J)
e.g. 65 VH, 27 DH, 6 JH -Combinatorial V-(D)-J joining Joining of a V region to a particular D and then to a J e.g. VH32 with DH15 with JH2 OR VH32 with DH8 with JH2 -some examples of VDDJ and VDDDJ in H-chains (rare) Combinatorial association of light and heavy chain an Ag can interact with either the L-chain, the H-chain or the combination of the two Therefore, joining a particular H-chain with a L-chain = diversity Junctional flexibility imprecise joining together of the V-D-J or V-J regions |
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Somatic hypermutation is localized to which area of the the CDRs in heavy and light chains
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CDR3 for IgH
CDR1 for IgL |
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Affinity maturation
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Because a B cell that binds it’s Ag is most likely to be selected (= proliferation); it will also have the most variability (highest chance for somatic hypermutation)
Igs with highest affinity for Ag will be selected immunodominance these Ag specific B cells will then mutate and potentially generate higher and higher affinities |
