Complement System – Protein Effector Cascades

00:01 Welcome.

00:02 Previously, in this series about acute inflammation, we've talked about the vascular changes that occur.

00:08 We've talked about the cellular recruitment.

00:11 And we've talked a little bit about eicosanoids, arachidonic acid metabolites, that mediate some of the inflammatory effects.

00:19 We're going to conclude this part of our discussion of acute inflammation, looking at effector cascades.

00:27 Inflammatory cells, neutrophils don't just do their job by eating and killing, they also elaborate a variety of molecules that will drive very important downstream effects.

00:41 So acute inflammation is also about the effectors.

00:45 And that's where we're going.

00:48 There are effector cascades.

00:49 Remember that we talked about one of the truisms in biology is that you start with a little spark, and you get a cascade of ever expanding and ever increasing response.

01:03 And that's very true, the various protein effector cascades.

01:07 The proteins that we're going to be talking about come from two major sources, one is preformed and circulating in the blood.

01:14 Those are generally synthesized by the liver and excrete it into the plasma.

01:19 So there are a lot of acute phase reactants that we will revisit in other talks that are elaborated by the liver.

01:30 Then there are things that are also synthesized de novo just at the site of action.

01:36 So many of the cells directly in the line of fire, at a site of injury will elaborate proteins that also have an effector cascade.

01:49 The major cell that's synthesizing them, yet that site are going to be the macrophages.

01:54 So we have preformed circulating mediators from the liver macrophages synthesizing things as we need them, where we need them.

02:03 These proteins from both sources include complement, coagulation factors, and kinins.

02:11 And those are the three cascades that we're going to be talking about now.

02:16 Notably, they're synthesized by the liver, and by macrophages.

02:21 So we're talking about the same thing in different places.

02:26 Let's talk first about complement-activation.

02:28 There are many different ways to activate the complement cascade.

02:33 In the next few slides, we'll talk about how we do that and then exactly what that cascade involves.

02:38 There is a classical pathway, where antibody indicated here is the orange bivalent molecules binding to an antigen on the surface of the microbe will undergo a conformational change that will allow the activation of complement will start that cascade.

02:57 And complement activation is basically a variety, a sequence of proteases proteolytic cleavages to give us activated fragments.

03:06 The key linchpin is going to be C3 fragmentation C3 proteolysis, to give a C3a and C3b.

03:17 And we'll come back to that.

03:18 So the classical pathway involves antibody binding, and then complement being activated because of an antibody binding.

03:25 There's another pathway called the alternative pathway to be compared with the classical pathway.

03:31 And this involves additional proteins called factor B, factor D, and properdin.

03:39 That will also get us to that C3b proteolysis, but by a slightly different set of factors.

03:46 And then there's the lectin pathway.

03:48 And this has to do with mannose-binding lectin.

03:52 So recall that many of the proteins, glycoproteins on the surface of pathogens, and in a terminal mannose.

04:01 We know that, and our liver and macrophages synthesize a mannose-binding protein or mannose-binding lectin that will then act as a trigger once it's bound to a pathogen to activate the complement.

04:14 Again, a proteolytic cleavage from C3 to C3b and C3a.

04:19 C3a and C3b are just fragments of the original C3 molecule.

04:25 Okay, that's the way that we got it activated.

04:27 Now what happens? Well, so C3a and C3b so that activated C3b on the surface will drive the subsequent breakdown proteolysis, and a cascade of additional complement fragments including C5.

04:45 C3a and C5a are very potent chemotactic agents.

04:51 They will recruit and activate neutrophils, leukocytes that will lead to the destruction by those leukocyte destruction of the microbes by those leukocytes.

05:01 So it's pro inflammatory C3a and C5a.

05:05 C3b, once it gets generated is very sticky, and on the surface of a microbe acts as an obstinate, it makes it tasty.

05:17 So now, cells that have receptors for C3b such as neutrophils, and macrophages can bind, and will ingest will phagocytize the microbe and kill it.

05:29 And finally, starting with C3b cleavage of C3, to C3a and b.

05:35 Starting with that, we will then cleave C5, and C6, and C7, and C8 and that will form a membrane attack complex.

05:44 So we get a pore and that MAC or Membrane Attack Complex will lead to lysis of microbes.

05:50 So complement does a variety of things.

05:52 It's pro inflammatory by recruiting inflammatory cells.

05:55 It makes microbes tasty, so that we can ingest them.

05:59 And it will also directly lyse microbes.

06:04 So very important.

06:07 So complement.

06:08 Promised that we will give an overview of this.

06:10 It's a collection of circulating and macrophage-synthesize proteins.

06:15 It's a cascade of activation triggered by Antigen-antibody complexes, bacterial polysaccharides.

06:22 that's that mannose-binding protein, and aggregated IGA.

06:26 A form of immunoglobulin.

06:28 So that involves the properdin alternate pathway.

06:32 Okay.

06:33 Once they're activated, they have a variety of effects.

06:36 They will cause vasodilation increased permeability.

06:40 They will increase leukocyte adhesion.

06:42 Promote chemotaxis and activation of leukocytes.

06:45 And they will induce opsonization.

06:49 Okay, so complement does a lot of stuff.