Lecture 6- VDJ

Lecture 6- VDJ - Bi114 Lecture GenerationofmatureBCRandTCR

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Bi 114 Lecture t i f t BCR d TCR Generation of mature BCR and TCR V(D)J recombination, CSR and SH January 21, 2010 eading: Reading: Chapter 4 (Janeway’s Immunobiology) G Schatz Seminars in Immunology 16 (2004) 245 56 D.G. Schatz, Seminars in Immunology 16 (2004) 245–256 Cortes et al., PNAS 93 (1996) 14008 14013 Muramatsu et al., Cell 102(2000) 553 563
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otal number of antibody specificities available to Immunology Total number of antibody specificities available to an individual is at least 100,000,000,000 Health Biology Lack of antibodies or T cells One of the few examples of somatic recombination in mammals Evolution Rag genes only found in Jawed vertebrates, and ey function much like transposons ook almost a century to figure out 900 History they function much like transposons Took almost a century to figure out 1900 Paul Echrlich proposed the side chain theory
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nate vs adaptive immune Innate vs adaptive immune receptors Tailored antigen ecific response for specific response for any given pathogen t M Generates Memory
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Basic antibody structure: end protein product Each of the 5 isotypes are encoded by different genes in the constant region of the heavy chain. Class switching generates isotypes from the initial IgM (or IgD)
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How are we able to get such a large amount of diversity from such a small amount of genetic material? The diverse specificity of the immunoglobulin repertoire is a result of 4 mechanisms •Combinatorial diversity among V regions •Junctional diversity o bi ato ial di e ity ao the li ht ad hea y hai •Combinatorial diversity among the light and heavy chain •Somatic hypermutation
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Experiment from Non lymphoid cells lymphocytic leukemia 1976: Susumu Tonagawa won the 1987 Nobel rize for ʺ his Prize for his discovery of the genetic principle for generation of antibody diversity. ʺ Somatic recombination Different DNA fragment Same DNA fragment
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V segments are located far from C regions eries of C regions Se ies o C egio s corresponding to each of the isotypes 3 different genetic loci (found on different chromosomes) encode for all immuno globulins V regions are the result of gene duplications that have expanded and diversified throughout evolution (pseudogenes genes that have accumulated mutations so that they e o lo e fu tio al) are no longer functional)
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Ordering of events ombinatorial Combinatorial diversity
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Ordering of events Combinatorial Diversity For immunoglobulins, the heavy chain recombines V(D)J in a cell before the light chain Then, several rounds of cell division occur within each cell (clone for the heavy chain) During this time, the light chain is rearranging and each new light chain can pair with the existing heavy chain in that cell herefore combinatorial diversity alone can generate over Therefore, combinatorial diversity alone can generate over a million different antibodies [(200 +120 ) X 6000]
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What guides rearrangement?
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This note was uploaded on 01/03/2012 for the course BI 144 taught by Professor List during the Fall '10 term at Caltech.

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Lecture 6- VDJ - Bi114 Lecture GenerationofmatureBCRandTCR

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