Antibody Variable Region Diversity – Lymphocyte Development

by Peter Delves, PhD

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    00:01 So, why don’t we look at the numbers that are involved here; give us an idea about how incredible this mechanism is. There are less than 200 genes involved, yet those genes can encode millions of different antibodies. So we’ve already heard that around about 40 Variable gene segments for the immunoglobulin heavy chain, 27 Diversity gene segments and half a dozen or so Joining gene segments. And we’ve heard that this recombination is a random process. So a given B-cell can pick any one out of the 40, any one out of the 27, any one out of the six for the V, D and J. So because any of those can be picked, you can multiply those three numbers by each other. 40 x 27 x 6.

    00:58 So that gives us nearly six and a half thousand different possible sequences, protein sequences.

    01:06 From, what have we got there? 40 plus 27, that’s 67, plus 6. 73 if my maths is right.

    01:15 Okay, so a very small number of genes producing thousands of different protein sequences.

    01:23 And for the kappa (k) light chain, 40 Variable gene segments, any of which, any one of which can be chosen.

    01:31 No D remember, in the light chain.

    01:34 But five J.

    01:35 So we can multiply 40 by 5, that gives us 200.

    01:39 That’s quite a simple sum to do, and in a given B-cell, it may make exactly the same heavy chain rearrangement as another B-cell, but a different light chain.

    01:48 So we can actually take those two numbers and multiply them together.

    01:51 6480 x 200, as I’m sure you all already worked out by mental arithmetic is 1.3 x 10^6; 1.3 million different protein sequences from that, way under 200 different gene segments. And of course there’s also the lambda (λ) light chain, 30 Variable gene segments, 5 Joining gene segments, gives us 150.

    02:19 That gives us a figure of nearly a million different sequences.

    02:22 You can add those two together, so over 2 million different protein sequences from less than 200 genes.

    02:29 That’s only the start of it.

    02:31 The antibodies can have much more variability than that.

    02:35 There are a variety of mechanisms that create additional variability.

    02:41 Maybe you’re wondering where this additional variability comes from.

    02:44 Essentially there are three mechanisms that create variability that goes way beyond what occurs due to the recombination of V, D and J in the heavy chain, and V and J in the light chain.

    03:00 First of all, when that recombination process occurs, there’s not an absolutely set point at which the splicing of D to J, and then V to DJ in the heavy chain, and V to J in the light chain occurs.

    03:17 In other words, there are recombinatorial inaccuracies.

    03:20 Now this isn’t always a good thing.

    03:22 This is one of the ways in which for example a stop codon might be inserted, and you make… you’re not able to make an antibody molecule.

    03:30 But it does greatly increase the diversity.

    03:35 And that’s beneficial because there are lots and lots of different pathogens out there, and they’re mutating all the time. So we need to have an enormous diversity of antibody molecules and T-cell receptor molecules. Secondly, there is a process referred to as N-nucleotide addition; now the N stands for Non-templated. And this is a mechanism that as we’ll see is mediated by an enzyme Terminal deoxynucleotidyl Transferase. I’ve already mentioned that enzyme a little bit earlier in this lecture. Terminal deoxynucleotidyl Transferase or TdT, mediates this N-nucleotide addition.

    04:17 And then finally, somatic hypermutation.

    04:20 Now all genes mutate, but in the immunoglobulin genes, one observes a much higher rate of mutation than in other genes.

    04:28 About a thousand times more mutations are permitted within the immunoglobulin genes by a variety of mechanisms.

    04:37 And this means that the diversity of antibodies can be increased enormously.

    About the Lecture

    The lecture Antibody Variable Region Diversity – Lymphocyte Development by Peter Delves, PhD is from the course Adaptive Immune System. It contains the following chapters:

    • Allelic Exclusion
    • How Many Different Antibodies are Possible?
    • Overview of the Additional Variability of Immunoglobulin Genes

    Included Quiz Questions

    1. 200
    2. 6,480
    3. 150
    4. 40
    5. 1,000
    1. Splice site mismatching
    2. Recombination
    3. Somatic hypermutation
    4. N-nucleotide addition
    5. Diversity in both the heavy and light chains
    1. TdT
    2. IgH
    3. Kappa light chain segments
    4. Lamda light chain segments
    5. Recombinatorial inaccuracies

    Author of lecture Antibody Variable Region Diversity – Lymphocyte Development

     Peter Delves, PhD

    Peter Delves, PhD

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    Many of the questions in my mind were definitely answered.
    By James T. on 04. July 2017 for Antibody Variable Region Diversity – Lymphocyte Development

    Reading a textbook could be boring. The lecture nailed what I need to know.