Complement System

by Peter Delves, PhD

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    00:01 You’ve heard me talk about complement.

    00:03 You’ve heard me mention complement.

    00:05 You may be wondering, what is this? What is complement? Well, it’s not a single molecule.

    00:11 It’s a series of molecules, it’s a complement system.

    00:15 And this system of molecules and regulators of those molecules and receptors for those molecules are incredibly important in host defense against infection.

    00:30 Complement can be activated by three different pathways.

    00:36 Firstly, the classical pathway.

    00:38 It’s called the classical pathway because this was the pathway of complement activation that was initially discovered. And at that time, it was thought there was just one pathway. Things were simple; the complement activation pathway. But subsequently, the other two pathways were discovered. So the first pathway was renamed the classical pathway. The one everybody knew about.

    01:00 And this is activated when an antibody binds to an antigen.

    01:07 In other words, antibody-antigen complexes are formed.

    01:13 There are other ways in which the classical pathway of complement can be activated.

    01:17 For example, C-reactive protein, an acute phase protein that was mentioned in the… a few slides ago.

    01:24 This C-reactive protein (CRP), can also activate the classical pathway of complement.

    01:31 So, antibody binding to antigen will activate the first component in the complement system which is called complement component C1q.

    01:45 This then helps to recruit two other components of C1 called C1r and C1s.

    01:56 These C1 components activate complement component C4, which then goes on and activates complement component C2.

    02:09 You’ll notice that the order of these doesn’t seem to go with the normal order.

    02:13 Normally we have one, two, three, four, don’t we? But these complement components were actually ordered in the… or named rather in the order they were first discovered.

    02:26 So scientists discovered complement component C2 before they discovered C4.

    02:31 But when the details of the pathways were worked out, it was found that C4 comes before C2.

    02:37 So hence the rather confusing numbering of these complement components.

    02:42 The next result of activation is that you generate a enzyme complex that is referred to as a C3 convertase.

    02:54 And the C3 convertase produced by the classical pathway of complement activation consists of a fragment of C4 called C4b, together with a fragment of C2 called C2a.

    03:08 So C4b2a is the C3 convertase of the classical pathway.

    03:15 What about the two other pathways? The lectin pathway is activated by microbial sugars.

    03:24 Perhaps you already know that a lectin is a protein that recognizes sugars.

    03:30 Hence the name of this pathway.

    03:33 In this pathway, sugars on the surface of microorganisms are recognized by a molecule called mannose-binding lectin, MBL.

    03:44 As its name suggests, it recognizes mannose, and indeed it can recognize some other sugars as well.

    03:49 But it gets its name from being able to recognize the sugar mannose.

    03:53 Mannose-binding lectin, sometimes called mannose-binding protein as an alternative name.

    03:59 When mannose-binding lectin recognizes sugars on the surface of microorganisms, it recruits two molecules that are very similar to C1r and C1s of the classical pathway.

    04:11 And those are called MASP-1 and MASP-2, stands for Mannose-binding lectin Associated Serine Protease-1 and Mannose-binding lectin Associated Serine Protease-2; MASP-1 and MASP-2.

    04:27 And they are very, very similar to C1r and C1s, and in fact they do the same thing.

    04:33 They activate C4, and then C2 joins the pathway.

    04:37 So you end up with exactly the same C3 convertase, C4b2a.

    04:43 This is in contrast to the alternative pathway of complement activation, where microbial sugars are not recognized, but other structures on the surface of the microbe are recognized.

    04:57 So various microbial surface structures are recognized that are not sugars.

    05:03 And here, complement component C3 binds to the surface of microorganisms, becomes stabilized on the surface of microorganisms and then recruits some other molecules of the complement system called Factor B and Factor D.

    05:19 And you end up with a C3 convertase that is a different structure to the C3 convertases of the classical and lectin pathways. This particular C3 convertase is called C3bBb. C3b is a fragment of C3, and Bb is a fragment of Factor B.

    05:39 So following activation by, for example a microorganism or by antibody binding to antigen, you get splitting of complement C3 by the C3 convertase; either C4b2a in the case of the classical or lectin pathways, or C3bBb in the case of the alternative pathway.

    06:04 And this complement component C3, which really lies at the heart of the complement system gets split into initially two fragments called C3a and C3b.

    06:16 And then subsequently, by addition of other molecules to the C3 convertase, you generate a C5 convertase.

    06:26 The case of the classical and lectin pathway - C4b2a3b, the case of the alternative pathway - C3bBb3b.

    06:37 And that C5 convertase, you won’t be too surprised to hear, splits C5 into two fragments, just like the C3 convertase split C3 into two fragments.

    06:49 C5 convertase split C5 into two fragments, and of course they’re called C5a and C5b.

    06:57 So that’s all very well.

    06:58 A little overview of the biochemistry if you’d like, of complement.

    07:02 But from an immunological point of view, perhaps more interesting is what does complement actually do? So let’s look at the main functional components of the complement system.

    07:14 Complement component C3a is involved in causing mast cells in the tissues and basophils in the blood circulation to degranulate, release granules that contain inflammatory mediators.

    07:29 Complement component C3b, the other fragment that is generated when complement component C3 gets split is involved in opsonization of microorganisms for phagocytosis.

    07:40 That term, opsonization, what does that mean? Well it means coating a microorganism to make it more readily detected by a phagocytic cell.

    07:50 And there are a number of substances that can do that.

    07:52 Complement component C3b is really good at doing that; also the clearance of immune complexes.

    07:59 Again another sort of slightly strange term that immunologists tend to use.

    08:03 Immune complex simply means an antibody bound to an antigen.

    08:08 And those complexes of antibody bound to antigen, they can activate complement via the classical pathway as we’ve heard.

    08:15 That can lead to the generation of C3b.

    08:18 And C3b is involved in linking immune complexes to erythrocytes, to red blood cells, which can help in them being cleared. C5a just like C3a can cause mast cells and basophils to degranulate, but additionally is a very potent chemotactic factor for neutrophils. Attracting neutrophils out of the blood circulation and to the site of the infection. And then complement component C5b, together with component C6, C7, C8 and C9 collectively form something called the Membrane Attack Complex or MAC.

    09:03 And as its name suggest, the Membrane Attack Complex attacks the membranes of microorganisms leading to their lysis. So really, at the heart of activation of the complement system, which is a key part of inflammation and immune defense, is splitting complement component C3 into C3a and C3b, and complement component C5 into C5a and C5b. Because that leads to the generation of C3a and C5a involved in mast cell degranulation, of the C5a which is also involved in neutrophil chemotaxis.

    09:45 Of complement component C3b and then a further split fragment called C3d, which is involved in opsonization of microorganisms.

    09:55 C5b to C9, as we’ve already heard, generating the Membrane Attack Complex, lysing microorganisms.

    10:02 C3b involved in immune clearance of immune complexes, by red blood cells.

    10:11 And C3d finally, can also be involved in activating the B-lymphocytes of the adaptive immune response.

    About the Lecture

    The lecture Complement System by Peter Delves, PhD is from the course Innate Immune System. It contains the following chapters:

    • The Complement System
    • Main Functional Components of the Complement System

    Included Quiz Questions

    1. MASP-1
    2. Factor B
    3. Factor D
    4. C1q
    5. C3bBb3b
    1. Alternative- microbial sugars
    2. Classical- antibody antigen complexes
    3. Classical- CRP
    4. Lectin- microbial sugars
    5. Alternative- microbial structures
    1. C3b
    2. C3a
    3. C5a
    4. C4
    5. C5b6789
    1. C3a, C5a
    2. C3a, C3b
    3. C3b, C5a
    4. C5a, C5b6789
    5. C3a, C5b6789
    1. They are responsible for the cleavage of C3 and C5, creating C3a/C3b and C5a/C5b- which are responsible for activating the bulk of the complement immune response.
    2. They are active early in the Classical Pathway of complement activation.
    3. They help activate lymphocytes that respond to antigens that activate complement
    4. They mediate complement by halting converting active complement factors back to their inactive form
    5. They stimulate degranulation of mast cells and basophils

    Author of lecture Complement System

     Peter Delves, PhD

    Peter Delves, PhD

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