Description

This video is part 2 of Innate Immunity – Cellular Factors (Toll-like Receptors, Phagocytosis, and Inflammation).

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

TLR dimerization: Link

Toll-like Receptors (TLRs):

Location:

• Epithelial Cells of the mucous membrane
• Endothelial Cells
• Macrophages
• Dendritic Cells
• Neutrophils

Membrane-bound TLRs:

• TLR 1/2 and TLR 2/6: Recognize Peptidoglycan/Lipoteichoic acid, Lipoproteins
• TLR 4: Recognizes Lipopolysaccharides, Fungal Mannan, Viral Envelope Proteins
• TLR 5: Recognizes Bacterial Flagellin

Intracellular Receptors:

• TLR 3: Recognizes Double-stranded RNA from viruses
• TLR 7: Recognizes Single-stranded RNA
• TLR 8: Recognizes Double-stranded RNA from viruses
• TLR 9: Recognizes Unmethylated CpG islands

Toll-like Receptors trigger:

1. Release of cytokines (TNF, IL-1, IL-12)
2. Release of chemokines (IL-8)
3. Release of antiviral cytokines (IFN α/β)

Phagocytosis:

Professional Phagocytes:

• Neutrophils
• Macrophages/Monocytes
• Mast Cells
• Dendritic Cells

Steps in Phagocytosis:

1. Binding: Non-specific surface receptors (Mannose Receptor, Toll-like Receptor, CD14), Indirect Opsonization (C3b), Direct Opsonization (Fc receptor to antibody)
2. Engulfment: Pseudopods wrap around the bacteria
3. Phagosome Formation: Enclosure of the pathogen within a vesicle
4. Digestion:
   • Oxygen-dependent digestion (Reactive Oxygen Species)
   • Oxygen-independent digestion
   • Lysosome: Breaks down bacterial cell walls
   • Enzymes: Proteolytic and hydrolytic enzymes
   • Antimicrobial peptides (Defensins)
   • Acidic reactions (low pH)
   • Lactoferrin (in neutrophils)
5. Antigen Presentation: Presented on MHC class I or II, or released into interstitial fluid to be absorbed by lymph vessels

Macrophage Cytokine Release:

• Interleukin 8: Chemotaxis for Leukocytes
• Interleukin 1: Activates T-Lymphocytes and Macrophages
• Interleukin 6: Activates T- and B-Lymphocytes
• TNF-α: Activates Endothelium
• Interleukin 12: Activates Natural Killer Cells

Endogenic Pyrogens (Fever Induction):

• IL-1, IL-6, TNF-α stimulate the hypothalamus to release Prostaglandins E2
• IL-6 stimulates the liver to release acute phase proteins

Incomplete Phagocytosis:

Some bacteria evade digestion:

• Listeria: Releases Listeriolysin to escape phagosomes
• Mycobacterium tuberculosis: Produces catalase to resist degradation

Immune System in Inflammation:

• Swelling: Due to increased permeability of blood vessels
• Pain: Due to diapedesis and edema pressing on pain receptors
• Heat: Due to increased blood flow
• Redness: Caused by vasodilation

Transcript

Introduction
0:00
and the last video we looked at the
0:01
general factors in the innate immune
0:03
system now we’re going to look at the
0:05
cellular factors in the immune system
0:07
which generally includes the taluk
0:09
receptors the phagocytosis and
0:10
inflammation natural killer cells and
0:13
the microbiota also a part of the
0:15
cellular factors keep that in mind so
0:18
we’ll start with Tullock receptors
Toll-Like Receptors
0:20
toddler preceptors are receptors you
0:22
don’t really hear about so much but
0:25
they’re actually a really important part
0:27
of the body’s nonspecific resistance and
0:29
they’re really good at activating both
0:31
innate and adaptive immunity you will
0:34
find these receptors on specific areas
0:36
in your body you will find them lining
0:38
the epithelial cells of the mucous
0:40
membranes at portland’s of entry this
0:43
includes the MCOs of the nasal cavity
0:44
the mouth esophagus lungs and many more
0:47
you will also find them lining in detail
0:50
yourselves of the blood vessels this is
0:52
very very crucial because it helps the
0:54
body detect microorganisms very fast and
0:57
you won’t just find them on tissue
0:58
you’ll also find them in cells of the
1:01
first line of defense like the
1:03
macrophages and dendritic cells and the
1:05
neutrophils I’ll get more in details
1:08
into these cells in my future video so
1:10
don’t worry if you don’t know the
1:11
characteristics of these cells yet all
1:13
right so imagine this is one of the
1:15
cells you have in your body that has two
1:17
like receptors let’s say it’s an N to
1:19
tell you site or for example or or a
1:21
macrophage keep in mind that different
1:23
cells can have different told up
1:25
receptors that other cells don’t have an
1:28
advice versa but we will simplify it and
1:31
put everything together so let’s say
1:33
this is a macrophage because most
1:34
toll-like receptors actually going to be
1:36
found on cells that can’t phagocyte all
1:39
right now
1:40
tall dark receptors are very specific to
1:42
what they bind to we first had to lock
1:45
receptor 1 and 2 which worked together
1:46
and told that receptor 2 and 6 I just
1:49
remember the number 12 26 released they
1:52
dimerize together and there’s actually a
1:54
whole mechanism of how this works if you
1:56
if you curious I can put a link in the
1:58
description if you want you don’t
2:01
gram-positive bacteria these cells are
2:03
actually able to recognize the
2:04
gram-positive peptidoglycan and the leak
2:07
will take away acid they have in the
2:09
surface and they’re also able to
2:10
recognize instructor’s in case of a
2:12
parasite and be
2:13
now these receptors are also able to
2:15
catch lipoproteins on several things
2:18
like the one you see on the mycoplasma
2:20
for example all the perceptive tools are
2:22
very good at recognizing a structure
2:24
called design machine of fungi Tolec
2:27
receptor 4 however dimerized with itself
2:29
and it’s very good at binding
2:31
lipopolysaccharide on gram-negative
2:32
bacteria what’s interesting though is
2:35
that many bacteria can escape this
2:37
mechanism by producing proteins or what
2:40
we call lipopolysaccharide mutants that
2:42
interfere with toad-like receptor
2:44
signaling likea Shinya pest is for
2:46
example this bacteria is responsible for
2:48
the plague
2:49
tolik receptor for can also bind fungal
2:52
mannose and to viral envelope proteins
2:55
tolik receptor 5 also dimerizes with
2:58
itself and this one’s very good at
2:59
detecting bacterial flagellum the rest
3:02
of the toll like receptors are found
3:04
inside the cell on surface of an
3:05
endosome and this one is just a vesicle
3:08
economic compartment and the cell that
3:10
transports lipid products so here we’re
3:13
gonna have told like receptor 3 to lock
3:15
reserves were seven eight and nine these
3:18
are very good at detecting internal
3:20
change like for example
3:21
tolik receptor 3 and 8 they’re able to
3:25
recognize double-stranded RNA from virus
3:27
for example taluk receptor 7 are able to
3:31
recognize single-stranded RNA and tall
3:33
dark receptor 9 is able to recognize
3:35
unmethylated cpg islands which is a very
3:38
important mechanism and activating
3:40
deactivating genes now what’s really
3:42
important is that all of these activate
3:44
different signaling molecules in the
3:46
cell and release depending on a signal
3:49
inflammatory cytokine like tumor
3:51
necrosis factor-alpha interlocking one
3:53
in plugin 12 these can do several things
3:55
like activating other leukocytes
3:57
maybe activate a polygenic effect by
4:00
traveling to the hypothalamus causing
4:01
fever and then we go to the liver and
4:03
produce at could face proteins right
4:05
I’ll show you later and talk about the
4:07
macrophages because they’re really good
4:09
at releasing inflammatory cytokines
4:11
another thing once they activated they
4:13
can also release chemicals like
4:15
interleukin 8 which attracts neutrophils
4:17
and basophils and maybe even t-cells and
4:20
can also secrete anti virus cytokines
4:22
like interferon alpha and beta which
4:24
can actually turn off its own DNA
4:28
replication and other cells DNA
4:30
replication in case of viral infection I
4:32
can also activate natural killer cells
4:34
to kill the infected cell and and also
4:37
the pathogen so I hope we now kind of
4:40
get an idea of what toll-like receptors
4:41
are so now let’s continue and look
4:44
detailed into these different steps of
Phagocytosis
4:46
phagocytosis so imagine we have a
4:49
bacteria right and then we add a cell
4:51
that can actually phagocyte and we
4:53
actually got cells in your body called
4:55
professional phagocytes
4:57
these include neutrophils macrophages or
5:00
monocytes if they’re in the blood mass
5:02
cells can also phagocyte and also
5:04
dendritic cells now these are
5:06
professional phagocytes but two of them
5:08
are what we call professional antigen
5:10
presenting cells I’m not going to get
5:12
into that too much yet because that has
5:15
something to do with the adaptive
5:16
immunity and we’re still in the innate
5:19
immunity but just in case to not confuse
5:22
you b-cells are also what we call
5:24
professional antigen presenting cells
5:25
but b-cells don’t actually phagocyte
5:28
they do receptor mediated endocytosis
5:30
since they have receptors on their
5:32
surface so these right here in front of
5:35
you these are professional phagocytes
5:37
alright so let’s get back to
5:38
phagocytosis the first step of
5:40
phagocytosis is binding we need to bind
5:42
to cell and there are three ways we can
5:45
do that it combine directly to the cell
5:47
using non specific cell surface
5:49
receptors right could be mannose
5:51
receptors which bind to sugar monomer
5:54
Munoz found on cell walls microorganisms
5:57
and fungi it can also bind through a
5:59
variety of toll like receptors on the
6:02
surface of the phagocytes or it can bind
6:04
through cd14 cd14 is more or less a co
6:08
receptors with the total receptor it
6:11
binds lipopolysaccharide of
6:12
gram-negative bacteria so a factor I can
6:16
bind to an antigen directly the second
6:19
way is by indirect opsonization with the
6:21
help of complement system optimization
6:24
means when the plasma proteins promote
6:26
binding meaning when the plasma protein
6:28
sits on the microorganisms and it helps
6:30
kind of the phagocyte bind so that eco
6:33
phagocyte now why is it called indirect
6:35
optimization because
6:36
somehow everything that does not include
6:39
binding of antibodies are indirect now I
6:42
haven’t gotten into what a compliment
6:44
system is yet but in case you’re not
6:46
familiar with it yet I’ll give you a
6:47
quick overview what the compliment
6:49
system is so you kind of understand the
6:51
mechanism but there are three ways the
6:53
compliment system work either
6:54
classical alternative or Manos and all
6:57
of these three pathways leads to a c3b
7:00
opsonization where it promotes
7:02
phagocytosis because the phagocytose
7:04
actually has receptors for c3b call c3b
7:08
receptors the third way is by direct
7:12
optimization or where an antibody
7:14
actually binds directly to the bacteria
7:16
promoting phagocytosis because the
7:19
phagocyte actually has receptors for the
7:22
FC region of the antibody called FC
7:24
receptor and remember this only happens
7:26
due to the adaptive immune response
7:28
because everything that includes
7:29
antibodies are the adaptive immune
7:31
response not the innate alright
7:35
step two is engulfment through forming
7:38
soda pods around the bacteria and then
7:41
step three is actually forming a
7:44
phagosome a vesicle inside the phagocyte
7:47
to to kill the bacteria kind of like a
7:50
prison know when a phagocyte engulfs a
7:53
bacteria the phagocytes oxygen
7:55
consumption increases because it needs
7:57
more energy and this increase in oxygen
7:59
consumption produce reactive oxygen
8:03
containing molecules that are
8:04
antimicrobial how does it do that
8:07
another going to much detail into this
8:09
because it’s a whole process but oxygen
8:12
gets converted into superoxide hydroxyl
8:16
radicals hydrogen peroxide or even
8:18
neutral oxide now in case the phagocyte
8:21
is having trouble killing this bacteria
8:23
it will use this mechanism called oxygen
8:26
independent phagocytosis now keep in
8:28
mind that these things are also toxic
8:30
for the cell itself and that’s why it
8:32
makes them one is having trouble with
8:33
digestion so these products are
8:35
generally called reactive oxygen species
8:38
and we secrete these into the phagosome
8:41
in case the bacteria is stubborn and
8:43
just won’t die and then the next step is
8:46
actually the same step is called lysis
8:48
of fusion where we have
8:50
in a vesicle and it goes next to the
8:53
phagosome and then it fuses becomes a
8:56
lysosome and then breaks it down
8:58
into small peptides this is called
9:01
oxygen independent mechanism I use the
9:05
example of a lysosome which breaks down
9:07
cell wall it can also release a
9:10
proteolytic or hydrolytic enzymes or
9:12
even antimicrobial peptides like defin
9:15
sins or even lower the pH or release
9:18
lactoferrin in case of in case it’s a
9:21
neutral field for example different
9:23
phagocytes can release different things
9:25
and now step 5 if it’s an
9:27
antigen-presenting cell it’s going to
9:30
present it on an MHC class 2 molecule
9:32
macrophages and dendritic cells do this
9:34
neutrophils and mast cells for example
9:36
which are not antigen presenting cells
9:38
just release their content into the
9:40
lymph vessel so that B cells or other
9:44
phagocytes in that area can catch the
9:46
peptides and then further reactions can
9:49
happen from there now these are the
9:51
steps in phagocytosis but there one more
9:54
thing happens also inflammation as this
9:56
macrophage for example gets activated by
9:59
binding its receptors to the
10:00
microorganism it releases inflammatory
10:03
cytokines to include other cells into
10:05
battle now quickly what happens the
10:07
cytokines released are pro-inflammatory
10:09
cytokines interleukin 8 works as a
10:12
chemotaxis it has the award taxi in it
10:15
so it recruits other leukocytes in
10:17
talking one activates T lymphocytes and
10:20
macrophages to come help interleukin 6
10:23
activates t and b lymphocytes for
10:25
adaptive immunity and tyranny crota
10:28
factor alpha can activate endothelium
10:31
meaning that local release makes
10:33
endothelial cells in the walls of blood
10:35
vessels Express receptors to bind
10:38
leukocytes and help them to get into the
10:40
area of infection activated and the
10:43
thulium can also release and T microbial
10:46
proteins like defenses for example to
10:48
bind and optimize the bacteria and then
10:51
interlocking 12 will activate natural
10:53
killer cells to come and help these
10:55
three however has a systemic role also
10:58
not just local they act as what we call
11:01
ended
11:02
pyrogen causing fever you know the
11:04
hypothalamus you hypothalamus senses the
11:07
body temperature and are able to
11:08
regulate it as well and these three can
11:11
actually travel to the hypothalamus and
11:13
cause it to release per sec letting e to
11:16
prospect out the e to initiate fever and
11:19
what’s going to be fever it actually
11:22
makes it a harsher environment for
11:23
certain type of microorganisms to
11:25
survive it can denature their proteins
11:28
and also slow down their their
11:30
replication fever can also for example
11:32
speed up your metabolism for a quicker
11:35
healing process fever does a lot of
11:37
things
11:37
another systemic response is you know
11:40
the liver interleukin 6 can actually
11:42
travel to the liver also and trigger the
11:44
release of acute phase proteins like
11:46
mannose binding lectin for example
11:48
c-reactive protein I’ll talk more about
11:50
these in detail when I talk about the
11:52
complement system because these are very
11:54
related to the complement system and
11:56
they assist in opsonization and also
11:59
killing of bacteria so that was that now
12:04
this is what we call complete hyper
12:06
psychosis where marker organisms are
12:08
killed but sometimes the bacteria has
12:10
mechanisms that helps it escape the
12:13
killing process this is what we call
12:15
incomplete phagocytosis take the
12:17
bacteria Listeria for example during
12:19
formation of the phagosome and it can
12:22
release enzymes called the stereo lesion
12:24
that can actually break the endosomal
12:26
membrane so that it survives the
12:28
phagocytosis
12:29
other examples are mycobacteria which
12:31
can release catalase which neutralizes
12:34
hydrogen peroxide so also keep that in
12:37
mind tricky bacterias resulting in
12:39
complete shock cytosis now the last
Immune System’s Role in Inflammation
12:42
thing or what I’ve mentioned is
12:43
inflammation now I’m not gonna go in too
12:46
much details yet just just a basic so
12:48
that you understand what’s going on so
12:50
let’s say this is your skin right with
12:52
some blood vessels down there and you
12:55
step on a pin for example it prefers
12:57
your skin and causes not only bleeding
12:59
but a bacterial infections as well i’ll
13:02
only focus on the immunity part not the
13:04
hemostasis all right
13:05
in your skin you have different white
13:07
blood cells like mast cells macrophages
13:10
dendritic cells or laga down cells in
13:13
the skin even circulating around you
13:15
you can have the monocytes or even new
13:17
chivos for example and of course you can
13:19
have red blood cells as well what can
13:21
happen is that mast cells can actually
13:22
react to it releasing different granules
13:25
like histamine for example or
13:27
macrophages can go on and react to it
13:29
flag beside it and really releasing his
13:31
cytokines or this dendritic cells can
13:34
even engulf and travel to a lymph node
13:37
and present them many things can happen
13:39
histamines I will call vasodilators
13:42
because they dilate the blood vessels
13:44
but it also increases the permeability
13:46
of local blood vessels for other cells
13:49
to come in and help this though causes
13:52
water to flow in causing swelling
13:54
swelling is one of the four
13:56
characteristics of inflammation also
13:58
keep in mind the complement system can
14:01
activate releasing their chemicals like
14:03
Kim taxis and for the toxins causing
14:05
more leakage through the blood vessels
14:07
if you haven’t yet started the
14:08
complement system please do you will
14:10
understand much more of the immunology
14:12
once you understand the competent system
14:14
so swelling the chemokines released by
14:17
the macrophages remember I said that
14:19
they activate in the tilly sites they
14:21
make them Express receptors which white
14:24
blood cells that pass through can bind
14:26
to it so that they can squeeze through
14:28
by it stretching their side paths out
14:30
this process of cells going through the
14:33
blood vessel is called diabetes and it’s
14:36
the main reason for pain pains another
14:39
characteristic of inflammation now as a
14:41
blood vessels dilating more cells more
14:43
red blood cells flow in and blood is
14:46
warm at 37 degrees right our skin is not
14:49
and so heat happens and that causes
14:52
redness due to color of blood these four
14:55
are the main characteristics of
14:57
inflammation swelling pain heat and
15:00
redness now I want to remind you again
15:03
that we can have systemic response not
15:05
just locally by the chemicals traveling
15:08
to the hypothalamus of the brain causing
15:10
fever and interleukin 6 going to liver
15:13
releasing acute phase proteins like CRP
15:15
for example so that was mainly
15:18
everything I had here next in the innate
15:20
immune realist look at the complement
15:22
system