Description

This video is part 3 of Innate Immunity – Complement System (Humoral Factors).

All information in my immunology videos is sourced from:

• Book: Immunology, Eighth Edition by David Male, Jonathan Brostoff, David Roth, and Ivan Roitt
• Additional research: PubMed
• University lecture materials

Mechanisms of the Complement System:

• Membrane Attack Complex (MAC)
• Chemotaxis
• Opsonization
• Anaphylatoxins

Classical Pathway:

Antibody-dependent (Adaptive Immune System)

1. Step 1: C1q binds to antibody-antigen complex
2. Step 2: C1r activates C1s
3. Step 3: C1s cleaves C4 and C2
4. Step 4: C4b and C2b form C3 convertase
5. Step 5: C3 convertase cleaves C3, which binds to the surface as an opsonin or binds to C3 convertase to form C5 convertase
6. Step 6: Membrane Attack Complex (MAC) forms on Gram-negative bacteria

Alternative Pathway:

Antibody-independent

1. Step 1: C3 undergoes spontaneous cleavage in the bloodstream. C3b binds to bacterial surfaces
2. Step 2: Factor B binds
3. Step 3: Factor D cleaves Factor B into Bb
4. Step 4: Properdin (Factor P) stabilizes the complex, forming C3 convertase
5. Step 5: The pathway proceeds as in the classical pathway

Mannose-Binding Lectin (MBL) Pathway:

Triggered by Acute Phase Response

1. Step 1: Active macrophages release IL-1, IL-6, and TNF-α as endogenous pyrogens
2. Step 2: Cytokines travel to the hypothalamus, triggering Prostaglandin E2 (PGE2) release and causing fever
3. Step 3: IL-6 signals the liver to release acute phase proteins, including C-reactive protein (CRP) and Mannose-Binding Lectin (MBL)

C-Reactive Protein (CRP) Functions:

• Acts as an opsonin
• Activates the classical pathway of the complement system

Mannose-Binding Lectin (MBL) Pathway:

Activation begins 1-2 days after infection

1. Step 1: MBL binds to Mannose (monosaccharide) on fungal capsules and surfaces
2. Step 2: MBL recruits MASP-1 (Mannan-binding Lectin Serine Protease 1), which functions as an enzyme
3. Step 3: The pathway proceeds as in the classical pathway

Note: The Membrane Attack Complex (MAC) does not form on capsules.

Complement System Effector Functions:

• C4a, C5a, and C3a:
  • Act as Anaphylatoxins by increasing capillary permeability and activating mast cells
  • Function in Chemotaxis by directing phagocytes to infection sites
• Complement system removes immune complexes from the bloodstream

Transcript

Introduction
0:00
the compliment system is a part of the
0:02
immune system that enhances the defense
0:04
against pathogens and there are
0:06
different mechanisms that the complement
0:08
system actually has that allows it to
0:10
help the immune system one of these ways
0:13
is that it forms this complex on the
0:15
surface of the micro organisms called
0:17
the membrane attack complex which makes
0:19
holes on the membrane of the micro
0:21
organisms and these holes going to
0:23
disturb the environment inside the cell
0:26
by water leaking in causing cell lysis
0:29
so what more can I do you know when a
0:32
macrophage is just circling around your
0:33
body the complement system acts as
0:36
something called chemotaxis where they
0:38
go tell the macrophage hey I found a
0:40
bacteria can come and kill it hence I
0:42
underlined the word taxi because it
0:44
actually works at a taxi for the
0:45
macrophages it tells them where to go
0:47
all the things we can do is work as
0:49
obstinate and optimize bacteria makes it
0:53
easier for phagocytes to come and
0:55
actually eat them other factors is that
0:57
the same chemotactic molecule can work
0:59
as what is called an affiliate auxins
1:01
which goes to the blood vessels and
1:04
causing vasodilation and increase the
1:07
permeability for water and proteins and
1:10
cells to squeeze through other futures
1:13
is that we if you add a mast cell right
1:15
here some of these molecules can cause a
1:17
massive degranulation of nearby mast
1:20
cells releasing millions like histamine
1:22
for example histamine also increases
1:25
permeability of the capillaries and
1:26
cause other things like bronchial
1:28
constriction and vasodilation other
1:31
functions the complement system has is
1:32
that it can bind and remove immune
1:35
complexes off from the bloodstream so
1:38
only by looking at this you can already
1:40
tell that the complement system has a
1:42
lot of functions hopefully at the end of
1:44
this video you will see that the
1:46
complement system really isn’t that
1:47
complicated so nearly all the proteins
Classical Pathway
1:51
for the complement system is made by the
1:53
liver and release into the bloodstream
1:55
now let’s add a bacteria and see how the
1:58
complement system functions there are
2:00
mainly three ways the complement system
2:02
works the first or the classical one can
2:05
only begin once an antibody has bound to
2:08
the micro organisms and whenever you see
2:10
antibodies are involved I want you to
2:12
immediately think hey
2:13
this body has been infected with these
2:15
microorganisms before because this body
2:18
has antibodies against it so this
2:21
pathway of complement system doesn’t
2:23
really include innate or natural immune
2:24
system it includes the adaptive immune
2:27
system all right so the first complement
2:31
system is c1 it looks like this it’s
2:34
composed of c1 Q c1 R and C 1 s so QRS
2:38
the c1 Q binds to the FC region of the
2:42
antibody it only binds to IgM and IgG
2:45
keep that in mind
2:46
and after c1 Q binds to the antibody it
2:49
triggers the activation of c1 R which
2:51
then cleaves c1 s molecule and activates
2:55
it now what happens
2:57
c4 happens c1 s is gonna cleave the c4
3:02
into c4 B and C for a the c-4 B part
3:06
binds to the microbial surface and the a
3:09
part works as anaphylaxis and chemotaxis
3:11
I’ll get more into what they do later
3:14
all right next C 2 comes along is also
3:17
cleaved 2 C 2 B and C 2 8 c for B and C
3:21
2 B now works at what is called c3
3:23
convertase so when c3 comes along is
3:27
gonna cleave it into c3a and c3b and
3:30
this time though c3b does two things
3:33
either it binds to the microbial surface
3:36
itself and work as an obstinate
3:38
so that fibrosis can come and actually
3:40
phagocyte this bacteria or it’s gonna
3:43
bind to the surface of the c3 convertase
3:46
itself and form c5 convertase now what
3:50
happens if I can come and it’s gonna get
3:53
cleaved into c5 b and c 5a now this is
3:57
my favorite part
3:58
c5 B will bind to the surface of the
4:00
cell which will bind c6 and we’ll bind
4:03
c7 it will bind c8 and you’ll bind c9 so
4:08
5 6 7 8 9
4:10
now what happens this claim is up as we
4:12
agreed on earlier c3b will act as an
4:14
option which will help nearby phagocytes
4:17
with a c3 be receptor to bind and
4:20
actually hold onto this bacteria so that
4:22
phagocytosis can happen easier now I
4:25
want to remember that
4:27
this process is happening all the time
4:28
c5 convertase will continue to cleave c5
4:32
which will form this complex called
4:34
membrane attack complex or Mac and that
4:37
will cause sodium and water to go in and
4:40
as they do it will disturb the balance
4:42
of the cell causing its death now I need
4:46
to remind you about something
4:47
we got gram-positive bacteria right will
4:49
thick peptidoglycan layer on the outside
4:51
and we’ve also got gram-negative
4:53
bacteria with a life of polysaccharides
4:55
on outside
4:55
which of these two do you think the
4:58
complement system can kill directly
5:01
that’s correct is a gram-negative the
5:04
reason is in the name Mac membrane
5:06
attack complex it attacks membranes and
5:09
won’t even be close to reach the inner
5:11
membrane of the gram-positive because of
5:13
the thick peptidoglycan layer usually
5:15
only by making pores of the membrane of
5:18
the gram-negative it’s enough to to kill
5:21
it because it destroys the the
5:23
environment inner environment of the
5:24
gram-negative bacteria the gram positive
5:26
bacteria however are killed kind of
5:29
indirectly by the complement system with
5:31
the help of phagocytosis the c3b as you
5:33
see right here this pathway is called a
5:35
classical pathway it’s one of the three
5:38
ways the complement system works so
5:40
there are three mechanisms the
5:41
complement system can work in the second
Alternative Pathway
5:43
way is called the alternative pathway so
5:47
let’s start with the bacteria again c3
5:49
can actually undergo spontaneous
5:51
cleavage in the plasma to generate c3a
5:54
and c3b c3b is then rapidly inactivated
5:58
unless it binds covalently to the cell
6:00
surface then after that in the
6:02
alternative pathway factor B will come
6:04
along and bind directly to c3 B but we
6:08
need to cleave it that’s where this
6:09
samurai comes in via Proteus or
6:11
sometimes referred to as factor D factor
6:15
D is gonna clear factor D into
6:17
BB and BA now this binding is pretty
6:20
unstable and that’s where the drop
6:22
padeen comes in or factor P it binds to
6:26
the c3 b and b be together to form a
6:29
complex this complex is called the c3
6:32
convertase some familiar now it can
6:35
follow the same steps as before so c3
6:38
comes along
6:39
and is cleaved into c3a and c3b again
6:42
c3b may either sit on the surface of the
6:45
microorganisms and act as an optimum or
6:47
it can bind to c3 convertase and become
6:50
c5 convertase
6:51
where c5 comes along together with c6 c7
6:56
c8 and c9 and form the membrane attack
7:00
complex
7:01
now remember c3 be that binds directly
7:03
to the surface of the micro organism
7:05
this one works an opsin so it attracts
7:09
phagocytes and promotes binding for
7:12
phagocytosis so this whole process with
7:15
c3 be binding factor B and property in
7:17
the protease now I want you to take a
7:20
memory screenshot of this because I’m
7:21
going to test you at the end of this
7:22
video so the third and last pathway is a
Mannose Binding Lectin Pathway
7:26
mannose binding lectin pathway and this
7:29
is a special one and it usually starts 1
7:32
to 2 days after infection
7:34
you know the classical pathway and the
7:36
alternative pathway they both help the
7:39
macrophage phagocyte and activate and
7:42
once it activates is going to release
7:44
some cytokines so the active macrophage
7:47
will release three set guns called
7:49
interleukin 1 interleukin 6 and terminal
7:51
area factor alpha locally these will
7:54
help cause inflammation but they also
7:58
act as what is called endo genic para
8:00
gene now don’t get scared by the name if
8:02
you haven’t heard this before and the
8:04
genic just means something that’s
8:06
produced within the body and pyrogen is
8:09
an agent that causes fever so endo genic
8:13
pyrogen causes fever how you know the
8:17
hypothalamus in the brain it works as a
8:19
temperature regulator in the body these
8:21
androgenic para genes will circulate in
8:24
the blood and trigger the hypothalamus
8:26
into releasing something called
8:28
prostaglandin e2 which causes fever
8:31
now why is fever a good thing one thing
8:34
is that it makes a harsher environment
8:36
for certain type of micro organisms to
8:37
survive by either denied rating the
8:40
proteins or slowing them down a fever
8:43
also increases the healing process in
8:45
your body because it increases the
8:47
temperature and many of the things fever
8:50
does a lot and what else happens you
8:52
know
8:53
Interlaken 6 will travel to the liver as
8:56
well and trigger the release of what is
8:58
called acute phase proteins those
9:00
include the mannose binding lectin and
9:02
c-reactive protein let’s just give them
9:04
faces makes it easier so first let’s
9:07
look at what c-reactive protein does and
9:09
then look at what mannose binding lectin
9:11
do all right so let’s follow it now
9:14
chances are you most probably heard
9:16
about CRP without really knowing what
9:18
does or why it’s level increases so much
9:20
during an infection
9:22
you know cells that are dying or have
9:24
already died or even bacterias it can
9:27
actually bind directly to the surface of
9:29
the cell and it can also bind directly
9:31
to the surface of bacteria and certain
9:34
type of fungus as well and then it will
9:36
work as option and so that phagocytes
9:38
combined to it just like c3b but what it
9:41
also does though is that remember this
9:43
guy the c1 protein of the classical
9:45
pathway c1 can actually bind to the C
9:49
reactive protein and now the classical
9:52
pathway of the complement system can can
9:54
start I’m gonna let you do it what comes
9:56
after c1 c4 that’s good and after c-4
10:00
comes c2 that’s for good and these two
10:04
work as c3 convertase
10:07
which cleave c3 now these 3 is called c5
10:14
convertase which cleave c file and then
10:16
c6 c7 c8 and c9 binds
10:20
so CRP promotes phagocytosis and also
10:24
activates the complement system so
10:26
that’s exactly why their number
10:29
increases so much during an infection
10:31
they help kill and abstinence bacterias
10:34
and fungi and their number really
10:36
increases drastically during an
10:38
infection and can easily be measured in
10:40
the in the blood plasma as an infection
10:42
indicator because they were initially
10:44
released as macrophages got activated to
10:47
the bacterial binding remember so that’s
10:50
CRP now let’s look at balance binding
10:53
lectin let’s follow him you see now why
10:56
the last complement pathway takes one to
10:59
two days to take action you need a
11:02
macrophage to take the bacteria release
11:04
insightiq
11:05
which can induce fever and also trigger
11:08
the liver into releasing a kid face
11:09
protein so all of that has to happen in
11:11
order for the mannose binding lectin to
11:14
take proper actions you will also find
11:17
mannose binding lectin circling around
11:19
your bloodstream as well doesn’t
11:21
necessarily have to go through
11:22
macrophages to activate the mannose
11:24
binding lectin pathway but usually it
11:26
starts 1 to 2 days after infection all
11:30
right so the mannose binding lectin has
11:33
a structure that’s very similar to c1q
11:36
except that it doesn’t really have C 1 R
11:39
and C 1 s remember C 1 q binds c1r
11:43
activates even as c 1s converts but
11:46
minus binding lectin can only bind
11:48
because it’s only similar to c 1 cube
11:50
minus binding lifting will bind to the
11:52
monosaccharides menos which is present
11:55
on the surface of capsules of
11:57
microorganisms as well as certain type
11:59
of fungi and when it binds it really
12:01
cannot do anything classic black C 1 R
12:04
and C 1 s remember and that is why
12:07
another protein comes in help this one
12:10
is called man named binding lectin
12:12
serine protease 1 or simplified to mass
12:16
1 this one will bind to the surface of
12:19
the mannose binding lectin and this one
12:21
will actually act as an enzyme now it
12:24
can follow the same steps as a classical
12:26
pathway C 4 is cleaved into C 4 and C 4
12:30
B and C 2 is cleaved into C 2 and C 2 B
12:33
leaves to act as c3 convertase which
12:35
converts C 3 into binding to it for me C
12:39
file convertase or binding directly to
12:42
the surface of the bacteria acting as an
12:44
obstinate now C 5 can be converted c 6
12:49
comes along c7 c8 and c9 and for
12:53
membrane attack complex so that’s mainly
12:56
the mannose binding lectin pathway you
12:58
see that all three pathways really have
13:01
the same mechanism the only thing that’s
13:04
different between these three pathways
13:05
are the start alright so now we’ve gone
What Does the a’s Do?
13:08
through the all the B parts what about
13:11
the a part what did they do
13:13
let’s let’s look at their mechanism a
13:15
little bit see for a c5 in seat
13:18
we a are the main ones they have two
13:20
mechanisms related to inflammation they
13:23
work as an anaphylactic sense and what
13:25
does that mean if we add the capillaries
13:27
right here these guys can cause the
13:30
blood vessels to not only dilate to get
13:31
more blood to the area of inflammation
13:33
but also cause the walls of the blood
13:35
vessels to become leaky to recruit more
13:38
cells into the area and at the same time
13:41
c3 a and C file AE can activate massive
13:45
cells into releasing a lot of mediators
13:47
which can help the NFA the toxins with
13:49
their function now keep in mind that
13:51
during allergies we get too much
13:53
histamine release and that can cause
13:55
anaphylactic shock with with bronchial
13:57
constriction and stuff another thing
14:01
these guys can do is that they act as
14:03
chemotaxis meaning that if you have
14:05
bacteria in the tissue and let us say
14:08
monocytes in the bloodstream these guys
14:10
can actually work as a taxi for these
14:12
guys recruiting them and leading the way
14:15
to do the bacteria so that they can
14:17
phagocyte them now one last thing I
14:19
won’t spend a lot of time on this but if
14:22
you have free-floating let’s say you
14:24
have three floating exotoxins for
14:25
example in the bloodstream antibodies
14:28
can actually catch that and forming an
14:30
immune complex the complement system can
14:33
actually come and help remove these guys
14:35
so that’s mainly all I had for the
14:38
complement system now let’s go over and
QUIZ
14:41
have a little quiz let’s test how much
14:43
you remember let’s start with the
14:45
classical pathway what binds first and
14:48
is it a part of your innate or adaptive
14:50
immunity that’s correct
14:53
adaptive because antibodies bind to it
14:55
and after that what binds c1 correct
15:00
which cleaves c4 into C for a and C for
15:04
B after that binds c2 good as C for B
15:10
and C – B becomes c3 convertase with
15:14
which converts c3 B into C three-bean
15:17
c3a and c3b binds either to c3 be
15:21
convert ace or to the surface of the
15:26
membrane that’s good works at obstinate
15:28
so now c4 be easy to B and C 3 B works
15:32
as c5 convertase very good and they
15:36
cleave the c5 into c5 b and c 5a and
15:40
whatsits on c5 b c6 and then c7 c8 and
15:48
c9 and they work as membrane attack
15:52
complex that’s very good that was that a
15:55
classical pathway now alternative
15:57
pathway is it adaptive or innate its
16:02
innate that’s very good
16:03
why because it doesn’t involve
16:05
antibodies now what buy it first
16:09
c3 being is good and after that factor B
16:13
that’s good factor B we need to cleave
16:15
it by protease or factor D so it Cleaves
16:21
it and becomes B a and B be the binding
16:26
between C 3 b and b b is unstable what
16:29
do they need to enhance the binding it
16:32
has character p proper dean and this
16:35
complex is called c3 convertase which
16:40
cleaves c3 into c 3 b and c 3 a and it
16:44
will either bind to the complex or to
16:48
the surface itself and I said obstinate
16:50
now the complex we have is called c5
16:55
convertase that’s good
16:56
it converts c5 and we get the same as
16:59
the classical pathway remember entire
17:01
complex
17:02
so that is alternative pathway now the
17:05
last pathway the mannose binding lectin
17:06
pathway is it innate or adaptive it’s
17:11
innate that’s good because it doesn’t
17:13
really require antibodies to get
17:16
activated it can but it not necessary
17:18
all right so let’s add a bacteria in
17:21
capitalist encapsulated bacteria because
17:23
remember it binds to my nose and my nose
17:25
is kind of a sugar that exists on
17:27
capsules and fungi for example so what
17:31
point first mannose binding lectin is
17:35
good and after that you got mass one
17:39
that’s really good and mass one acts as
17:42
an enzyme so at first
17:47
ceefor cleaves it in deceiver B and C
17:50
for a and then C 2 into C 2 B and C 2 a
17:55
these to act as c3 convertase which
18:00
comes with C 3 C 3 Cleaves into c3a and
18:05
c3b and C 3 be either binds to the
18:11
surface of the bacteria working as an
18:13
abstinent or it it becomes a c5
18:16
convertase after that comes C 5 and then
18:22
membrane attack complex happens you see
18:24
it’s not really that complicated once
18:26
you get to know the the complement
18:28
system now just a bonus what do these
18:32
guys do inflammation that’s good they
18:37
work as an after the toxins or
18:42
chemotactic agents that’s good so that
18:46
was everything I had for the complement
18:47
system I hope this was a little bit
18:50
helpful at least and see you next time
18:52
bye