Complement System

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.

00:44 And at that time, it was thought there was just one pathway.

00:48 Things were simple.

00:49 The complement activation pathway.

00:52 But subsequently, the other two pathways were discovered.

00:55 So the first pathway was renamed the classical pathway.

00:58 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 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..

02:18 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.

02:32 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.

02:43 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 C2b.

03:08 So C4bC2b 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.

04:36 So you end up with exactly the same C3 convertase, C4bC2b.

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 compliment 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.

05:29 This particular C3 convertase is called C3bBb.

05:34 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 C4bC2b, 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.

06:27 The case of the classical and lectin pathway - C4bC2b3b, 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.

06:59 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.

08:07 And those complexes of antibody bound to antigen, they can activate complement by the classical pathway as we’ve heard, 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.

08:28 C5a, just like C3a can cause mast cells and basophils to degranulate.

08:36 But additionally, is a very potent chemotactic factor for neutrophils.

08:41 Attracting neutrophils out of the blood circulation and to the site of the infection.

08:47 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.

09:14 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.

09:33 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.

09:54 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..

10:13 finally, can also be involved in activating the B-lymphocytes of the adaptive immune response.