chapter_4 - Chapter 4: The Generation of the Lymphocyte...

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Chapter 4: The Generation of the Lymphocyte Antigen Receptors >>million of receptors (ab and TCR) to bind >>millions of antigen Variations in the variable regions of antibodies and TCRs explains why different receptors bind different antigen. But, where do the variations come from?
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Additionally, how is it possible to have a germline encode constant region that is tandem-linked to a variable region that cannot be germline encoded? V H C H Answer: gene rearrangements and, for B cell but not T cells, somatic mutations How big is the repertoire? At this point, the book say >10 11 . That is so big that an individual may not be able to express the whole repertoire at one time. (in other places, the book say 10 9 or 10 16 ) (humans have about 10 11 B cell but mice have only 10 8 ; they have approximately the same potential repertoire size). (potential repertoire vs. functional repertoire) How is it possible to generate >>millions of receptors with thousands (or fewer) of genes? Also, how is it possible to make sure that the members of a clone have the same receptor? How can one construct such an mRNA or protein?
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Experiment showing that gene rearrangements occur in the Ig locus (somatic gene recombination) 1 . Isolate DNA 2. Cut with restriction enzyme 3. Run on gel to sort pieces by size 4. Probe with v and c fragments Cut with restriction enzyme 2 3 v c 1 germline 4 4 4 4 Radioactive probes V probe C probe V probe C probe v c rearranged Restriction site between the segment No restriction site between the segment This restriction site is missing in B cells Sothern blot
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Germline configuration of human Ig heavy and light chains loci κ , λ and the heavy chains are encoded at separate genetic loci on different chromosomes. All heavy chain constant region isotypes are encode at the heavy chain locus (downstream of C μ )
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For B cells, in the bone marrow
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L κ 1 V κ 1 L κ 2 V κ2 L κ3 V κ 3 L κ4 V κ4 L κ5 V κ5 L κ6 V κ6 L κ n V κ n J κ 1 J κ 2 J κ 3 J κ 4 J κ 5 C κ L κ3 V κ 3 J κ 3 Germline DNA
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L κ3 V κ 3 J κ 3 L κ 1 V κ 1 L κ 2 V κ2 L κ3 V κ 3 L κ4 V κ4 L κ5 V κ5 L κ6 V κ6 L κ n V κ n J κ 1 J κ 2 J κ 3 J κ 4 J κ 5 C κ Germline DNA L κ3 V κ 3 J κ 4 J κ 5 C κ Transcribe this L κ3 V κ 3 J κ 3 C κ mRNA (processed RNA) Back to slide 18
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For B cells, in the bone marrow
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D1 D2 D2 D4 J H 3 J H 4 J H 2 J H 1 D5 D6 D7 C μ DJ rearranged D4 J H 3 C μ V H 1 V H 2 V H 3 V H 4 V H 5 V H n D1 D2 D3 D4 D5 D6 D7 J H 1 J H 2 J H 3 J H 4 C μ Germline DNA Gene rearrangements at the heavy chain locus page 1 of 2 Signal joint Coding joint
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V H 1 V H 2 V H 3 D4 J H 3 J H 4 V H 4 V H 5 V H n D1 D2 D3 C μ Gene rearrangements at the heavy chain locus continued C μ V H 1 V H 2 V H 3 D4 J H 3 J H 4 Which exons have been deleted?
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This note was uploaded on 09/22/2011 for the course BIOL 6570 taught by Professor Jenniferleavey during the Spring '11 term at Georgia Institute of Technology.

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chapter_4 - Chapter 4: The Generation of the Lymphocyte...

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