innate immune response
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About This Presentation
innate immune response
Slide Content
Lec.1: Innate immunity
By
Dr/ Eman Ahmed AbdAlrahman
Lecturer of Medical Microbiology and
Immunology
By
Dr/ Eman Ahmed AbdAlrahman
Lecturer of Medical Microbiology and
Immunology
Lec.1: Innate
immunity
Agenda
1) Components of Innate Immunity
a)
First Line of Natural defense: Mechanical Barriers,
Chemical barrier and Biological barrier
Second Line of Natural defense
Cells of innate immunity
Complement System
Other Plasma Proteins of Innate Immunity.
Cytokines of Innate Immunity.
2) Innate Immune Reactions
a)
)
)
)
)
Inflammation
Phagocytosis and Destruction of Microbes.
Tissue Repair
Antiviral Defense
Regulation of Innate Immune Responses
Microbial Evasion of Innate Immunity
immunity
Agenda
1) Components of Innate Immunity
a)
First Line of Natural defense: Mechanical Barriers,
Chemical barrier and Biological barrier
Second Line of Natural defense
Cells of innate immunity
Complement System
Other Plasma Proteins of Innate Immunity.
Cytokines of Innate Immunity.
2) Innate Immune Reactions
a)
)
)
)
)
Inflammation
Phagocytosis and Destruction of Microbes.
Tissue Repair
Antiviral Defense
Regulation of Innate Immune Responses
Microbial Evasion of Innate Immunity
Innate (Natural/Native) immunity
¢ Innate immunity is the natural inborn barrier
against invasion by microorganisms.
» It is non-specific, acting against any foreign
invader e.g. microorganisms.
* It is not acquired through previous exposure
to the infectious agents.
¢ Innate immunity is the natural inborn barrier
against invasion by microorganisms.
» It is non-specific, acting against any foreign
invader e.g. microorganisms.
* It is not acquired through previous exposure
to the infectious agents.
1) Components of Innate Immunity
a- First Line of Natural defense: which prevent the
entry of the microorganisms:
> Mechanical Barriers
° The intact skin and mucous membranes are
effective barriers against most microorganisms.
+ The hair at the nares, coughing and sneezing help
to expel foreign particles.
* Mucous secretions trap many organisms.
* The blinking reflex and tears expel foreign
particles or bacteria entering the conjunctiva.
a- First Line of Natural defense: which prevent the
entry of the microorganisms:
> Mechanical Barriers
° The intact skin and mucous membranes are
effective barriers against most microorganisms.
+ The hair at the nares, coughing and sneezing help
to expel foreign particles.
* Mucous secretions trap many organisms.
* The blinking reflex and tears expel foreign
particles or bacteria entering the conjunctiva.
a- First Line of Natural defense.
> Chemical Barriers :
« Sweat and sebaceous secretions have antimicrobial
actions by acidic pH and high fatty acids content.
+ Hydrolytic enzymes in the saliva, HCl of the stomach,
proteolytic enzymes in the small intestine are
bactericidal.
+ Lysozyme, an enzyme that dissolves bacterial cell walls
(by breaking down peptidoglycan). It is present on the
skin, in tears and cervical secretions.
+ Acidic pH in the adult vagina is protective.
> Chemical Barriers :
« Sweat and sebaceous secretions have antimicrobial
actions by acidic pH and high fatty acids content.
+ Hydrolytic enzymes in the saliva, HCl of the stomach,
proteolytic enzymes in the small intestine are
bactericidal.
+ Lysozyme, an enzyme that dissolves bacterial cell walls
(by breaking down peptidoglycan). It is present on the
skin, in tears and cervical secretions.
+ Acidic pH in the adult vagina is protective.
a- First Line of Natural defense.
> Biological barrier
e.g microbiota that suppresses the growth of
many pathogenic bacteria and fungi by
competition for essential nutrients or by
production of inhibitory substances such as
colicins or acids.
> Biological barrier
e.g microbiota that suppresses the growth of
many pathogenic bacteria and fungi by
competition for essential nutrients or by
production of inhibitory substances such as
colicins or acids.
b- Second Line of Natural defense.
If the invading organism gets through the first line of
defense and enters the tissues, other non-specific host
defenses operate. These include:
1) Cells of innate immunity
2) Circulating effector proteins in serum and body
fluids suppress the growth and promote killing of
microbes:
+ Complement
» Acute phase proteins
If the invading organism gets through the first line of
defense and enters the tissues, other non-specific host
defenses operate. These include:
1) Cells of innate immunity
2) Circulating effector proteins in serum and body
fluids suppress the growth and promote killing of
microbes:
+ Complement
» Acute phase proteins
1)Cells of innate immunity
Phagocytes: Neutrophils and Monocytes/
Macrophages
Dendritic Cells
Mast Cells
Innate Lymphoid Cells
Natural Killer Cells
Lymphocytes with Limited Diversity
Phagocytes: Neutrophils and Monocytes/
Macrophages
Dendritic Cells
Mast Cells
Innate Lymphoid Cells
Natural Killer Cells
Lymphocytes with Limited Diversity
A) Phagocytes:
If a microorganism crosses an epithelial barrier and begins
to replicate in the tissues of the host, in most cases, it is
immediately recognized by resident phagocytic cells.
The main classes of phagocytic cells in the innate
immune system are : macrophages
* monocytes
* Granulocytes
+ dendritic cells.
Macrophages are the major phagocyte population
resident in most normal tissues at homeostasis.
If a microorganism crosses an epithelial barrier and begins
to replicate in the tissues of the host, in most cases, it is
immediately recognized by resident phagocytic cells.
The main classes of phagocytic cells in the innate
immune system are : macrophages
* monocytes
* Granulocytes
+ dendritic cells.
Macrophages are the major phagocyte population
resident in most normal tissues at homeostasis.
Origin of macrophage:
a) Progenitor cells that enter the tissues during
embryonic development(arise from either
the fetal liver, the yolk sac), and then self-
renew at steady state during life
b) Circulating monocytes.
a) Progenitor cells that enter the tissues during
embryonic development(arise from either
the fetal liver, the yolk sac), and then self-
renew at steady state during life
b) Circulating monocytes.
Innate (Natural/Native) immunity
Acute phase proteins
> Synthesized in the liver in response to certain
cytokines namely, IL-1, IL-6 and TNF- a which
are produced by macrophages when
stimulated by microbial products.
> Present at low levels in the blood of healthy
individuals, but it is produced in increased
amounts during the acute-phase response
Acute phase proteins
> Synthesized in the liver in response to certain
cytokines namely, IL-1, IL-6 and TNF- a which
are produced by macrophages when
stimulated by microbial products.
> Present at low levels in the blood of healthy
individuals, but it is produced in increased
amounts during the acute-phase response
Acute phase proteins
Examples
1) Pentraxins :
> These proteins are formed from five identical subunits.
> Prominent members of this family include :C-reactive
protein (CRP) and serum amyloid P (SAP).
The C-reactive protein:it binds to the phosphocholine portion
of certain bacterial and fungal cell-wall lipopolysaccharides.
= C-reactive protein binds to and opsonize the bacterium
= It can also activate the complement cascade by binding to
Ciq, the first component of the classical pathway of
complement activation.
Examples
1) Pentraxins :
> These proteins are formed from five identical subunits.
> Prominent members of this family include :C-reactive
protein (CRP) and serum amyloid P (SAP).
The C-reactive protein:it binds to the phosphocholine portion
of certain bacterial and fungal cell-wall lipopolysaccharides.
= C-reactive protein binds to and opsonize the bacterium
= It can also activate the complement cascade by binding to
Ciq, the first component of the classical pathway of
complement activation.
Acute phase proteins
2)Collectins
+ Three members of this family serve as soluble effector
molecules in the innate immune system; these are:
+ Mannose-binding lectin (MBL) and surfactant proteins
SP-A and SP-D.
a) Mannose-binding lectin (MBL), which is a soluble
pattern recognition receptor that binds carbohydrates
with terminal mannose
+ It can activate the lectin pathway of complement by
recognizing mannose residues on microbial surfaces
+ MBL can also function as an opsonin by binding to and
enhancing phagocytosis of microbes.
2)Collectins
+ Three members of this family serve as soluble effector
molecules in the innate immune system; these are:
+ Mannose-binding lectin (MBL) and surfactant proteins
SP-A and SP-D.
a) Mannose-binding lectin (MBL), which is a soluble
pattern recognition receptor that binds carbohydrates
with terminal mannose
+ It can activate the lectin pathway of complement by
recognizing mannose residues on microbial surfaces
+ MBL can also function as an opsonin by binding to and
enhancing phagocytosis of microbes.
Acute phase proteins
2)Collectins
b) Surfactant protein A (SP-A) and surfactant
protein D (SP-D) are collectins with lipophilic
properties shared by other surfactants.
¢ They are found in the alveoli of the lungs, and
their major functions are to maintain the ability
of lungs to expand and as mediators of innate
immune responses in the lung.
+ They bind to various microorganisms and act as
opsonins, facilitating ingestion by alveolar
macrophages.
2)Collectins
b) Surfactant protein A (SP-A) and surfactant
protein D (SP-D) are collectins with lipophilic
properties shared by other surfactants.
¢ They are found in the alveoli of the lungs, and
their major functions are to maintain the ability
of lungs to expand and as mediators of innate
immune responses in the lung.
+ They bind to various microorganisms and act as
opsonins, facilitating ingestion by alveolar
macrophages.
Acute phase proteins
3)Ficolins
« Ficolins are plasma proteins that are structurally
similar to collectins. but instead of a C-type lectin
domain, they have a fibrinogenntype
carbohydrate recognition domain (see Fig. 4-11).
« Ficolins bind to several species of bacteria,
opsonizing them and activating complement in a
manner similar to that of MBL.
+ The molecular ligands of the ficolins include :
1) N-acetylglucosamine
2) The lipoteichoic acid
Both of them are components of the cell walls of
gram-positive bacteria
3)Ficolins
« Ficolins are plasma proteins that are structurally
similar to collectins. but instead of a C-type lectin
domain, they have a fibrinogenntype
carbohydrate recognition domain (see Fig. 4-11).
« Ficolins bind to several species of bacteria,
opsonizing them and activating complement in a
manner similar to that of MBL.
+ The molecular ligands of the ficolins include :
1) N-acetylglucosamine
2) The lipoteichoic acid
Both of them are components of the cell walls of
gram-positive bacteria
The Complement System
> The complement system is one of the major effector
mechanism of innate and humoral immunity .
> The name complement is derived from experiments
performed by Jules Bordet shortly after the discovery of
antibodies.
> He demonstrated that if fresh serum containing an
antibacterial antibody is added to the bacteria at
physiologic temperature (37°C), the bacteria are lysed. If,
however, the serum is heated to 56°C or more, it loses its
lytic capacity. This loss of lytic capacity is not due to decay
of antibody activity because antibodies are relatively heat
stable, and even heated Serum is capable of agglutinating
the bacteria.
> The complement system is one of the major effector
mechanism of innate and humoral immunity .
> The name complement is derived from experiments
performed by Jules Bordet shortly after the discovery of
antibodies.
> He demonstrated that if fresh serum containing an
antibacterial antibody is added to the bacteria at
physiologic temperature (37°C), the bacteria are lysed. If,
however, the serum is heated to 56°C or more, it loses its
lytic capacity. This loss of lytic capacity is not due to decay
of antibody activity because antibodies are relatively heat
stable, and even heated Serum is capable of agglutinating
the bacteria.
The Complement System
>Bordet concluded that the serum must
contain another heat-labile component that
assists, or complements, the lytic function of
antibodies, and this component was later
given the name “COMPLEMENT”
>Bordet concluded that the serum must
contain another heat-labile component that
assists, or complements, the lytic function of
antibodies, and this component was later
given the name “COMPLEMENT”
The Complement System
> They are set of group of plasma proteins
> Made constrictively by liver
> Present in blood, lymph and extracellular fluid
> They are proteolytic enzymes
> Circulate in inactive form
> They are set of group of plasma proteins
> Made constrictively by liver
> Present in blood, lymph and extracellular fluid
> They are proteolytic enzymes
> Circulate in inactive form
Pathways of Complement Activation
There are three major pathways of complement
activation:
“The classical pathway
“ The alternative pathway
+ The lectin pathway
Although the pathways of complement activation differ
in how they are initiated, all of them result in the
generation of enzyme complexes that are able to cleave
the most abundant complement protein, C3.
There are three major pathways of complement
activation:
“The classical pathway
“ The alternative pathway
+ The lectin pathway
Although the pathways of complement activation differ
in how they are initiated, all of them result in the
generation of enzyme complexes that are able to cleave
the most abundant complement protein, C3.
Pathways of Complement Activation
> The alternative and lectin pathways are effector
mechanisms of innate immunity, whereas the
classical pathway is a major mechanism of adaptive
humoral immunity.
> Complement activation depends on the generation
of two proteolytic complexes:
a) C3 convertase, which cleaves C3 into two proteolytic
fragments called C3a and C3b;
b)C5 convertase, which cleaves C5 into C5a and C5b.
> The alternative and lectin pathways are effector
mechanisms of innate immunity, whereas the
classical pathway is a major mechanism of adaptive
humoral immunity.
> Complement activation depends on the generation
of two proteolytic complexes:
a) C3 convertase, which cleaves C3 into two proteolytic
fragments called C3a and C3b;
b)C5 convertase, which cleaves C5 into C5a and C5b.
1) The Classical Pathway
The classical pathway is initiated by
binding of the complement protein C1
to the fc portion of IgG or IgM
molecules that have bound antigen
Ci is a large, multimeric protein
complex composed of Cig, Cir, and
Cis subunits;
Cir and Cis form a tetramer
composed of two Cir and two Cis
molecules.
C1q binds to the antibody, and Cir
and C1s are proteases.
The classical pathway is initiated by
binding of the complement protein C1
to the fc portion of IgG or IgM
molecules that have bound antigen
Ci is a large, multimeric protein
complex composed of Cig, Cir, and
Cis subunits;
Cir and Cis form a tetramer
composed of two Cir and two Cis
molecules.
C1q binds to the antibody, and Cir
and C1s are proteases.
> Among IgG antibodies, IgG3 and IgG1 (in humans) are
more efficient activators of complement than are
other subclasses.
> Only antibodies bound to antigens, and not free
circulating antibodies, can initiate classical pathway
activation
more efficient activators of complement than are
other subclasses.
> Only antibodies bound to antigens, and not free
circulating antibodies, can initiate classical pathway
activation
+ The reason for this is that each Clq
molecule must bind to at least two
Ig Fc region to be activated .
« Because each IgG molecule has only
one Fc region, multiple IgG
molecules must be brought close
together before C1q can bind, and
multiple IgG antibodies are brought !
together only when they bind to a
multivalent antigen( an antigen molecule .
that carries a number of different epitopes
some times may reach hundreds epitope).
8 Soluble IgM (planar form)
6 Soluble IgG (Fe portions
not adjacent)
ARA
0 Antigen-bound IgG
U
EE
Complement
activation
No
Yes
No
Yes
molecule must bind to at least two
Ig Fc region to be activated .
« Because each IgG molecule has only
one Fc region, multiple IgG
molecules must be brought close
together before C1q can bind, and
multiple IgG antibodies are brought !
together only when they bind to a
multivalent antigen( an antigen molecule .
that carries a number of different epitopes
some times may reach hundreds epitope).
8 Soluble IgM (planar form)
6 Soluble IgG (Fe portions
not adjacent)
ARA
0 Antigen-bound IgG
U
EE
Complement
activation
No
Yes
No
Yes
C1
complex
complex
* Even though free (circulating) IgM is
pentameric, it does not bind C1q because the Fc
regions of free IgM are in a configuration that is
inaccessible to C1q.
Binding of the IgM to an antigen induces a
conformational change that exposes the Clq
binding sites in the Fc regions and allows C1q to
bind.
Because of its pentameric structure, a single
molecule of IgM can bind two C1q molecules,
and this is one reason that IgM is a more
efficient complement-binding (also called
complement fixing) antibody than IgG is.
pentameric, it does not bind C1q because the Fc
regions of free IgM are in a configuration that is
inaccessible to C1q.
Binding of the IgM to an antigen induces a
conformational change that exposes the Clq
binding sites in the Fc regions and allows C1q to
bind.
Because of its pentameric structure, a single
molecule of IgM can bind two C1q molecules,
and this is one reason that IgM is a more
efficient complement-binding (also called
complement fixing) antibody than IgG is.
Binding of C1q to the Fc regions of IgG or IgM leads
to enzymatic activation of the associated C1r, which
cleaves and activates C1sActivated
C1s cleaves C4, to generate C4b and C4a (C4a small
fragment which is released and has some biologic
activities).While C4b bind to the cell surface.
The next complement protein, C2, then complexes
with the cell surface-bound C4b and is cleaved by a
nearby C1s molecule
to generate a soluble C2b fragment of unknown
to enzymatic activation of the associated C1r, which
cleaves and activates C1sActivated
C1s cleaves C4, to generate C4b and C4a (C4a small
fragment which is released and has some biologic
activities).While C4b bind to the cell surface.
The next complement protein, C2, then complexes
with the cell surface-bound C4b and is cleaved by a
nearby C1s molecule
to generate a soluble C2b fragment of unknown
The Lectin Pathway
The lectin pathway of complement activation is
triggered by the binding of microbial polysaccharides
to circulating lectins, such as plasma mannose binding
lectin (MBL), or to ficolins
MBL and ficolins associate with MBL-associated serine
proteases (MASPs) including MASP1, MASP2, and
MASP3.
The MASP proteins are structurally homologous to the
Cir and C1s proteases.
MASP2 is the protease that cleaves C4 and C2.
Subsequent events in this pathway are identical to
those that occur in the classical pathway
The lectin pathway of complement activation is
triggered by the binding of microbial polysaccharides
to circulating lectins, such as plasma mannose binding
lectin (MBL), or to ficolins
MBL and ficolins associate with MBL-associated serine
proteases (MASPs) including MASP1, MASP2, and
MASP3.
The MASP proteins are structurally homologous to the
Cir and C1s proteases.
MASP2 is the protease that cleaves C4 and C2.
Subsequent events in this pathway are identical to
those that occur in the classical pathway
LS, Sugar moieties
on pathogen
Cleavage
a a
—
c4 ud C4b C4b2a
nl (C3 convertase)
—
=— *¢.
on pathogen
Cleavage
a a
—
c4 ud C4b C4b2a
nl (C3 convertase)
—
=— *¢.
The Alternative Pathway
The alternative pathway of complement activation is
triggered by spontaneous hydrolysis of C3 in plasma at a low
level.
The breakdown products of C3 are unstable, and, in the
absence of infection, are rapidly degraded and lost.
However, when a breakdown product of C3 hydrolysis, called
C3b, is deposited on the surface of a microbe, it forms stable
covalent bonds with microbial proteins or polysaccharides.
The microbe-bound C3b binds another protein called Factor B,
which is then cleaved by a plasma protease called Factor D to
generate the Bb fragment. This fragment remains attached to
C3b, and the C3bBb complex functions as a proteolytic
enzyme, called the alternative pathway C3 convertase.
The alternative pathway of complement activation is
triggered by spontaneous hydrolysis of C3 in plasma at a low
level.
The breakdown products of C3 are unstable, and, in the
absence of infection, are rapidly degraded and lost.
However, when a breakdown product of C3 hydrolysis, called
C3b, is deposited on the surface of a microbe, it forms stable
covalent bonds with microbial proteins or polysaccharides.
The microbe-bound C3b binds another protein called Factor B,
which is then cleaved by a plasma protease called Factor D to
generate the Bb fragment. This fragment remains attached to
C3b, and the C3bBb complex functions as a proteolytic
enzyme, called the alternative pathway C3 convertase.
The alternative pathway C3 convertase, that breaks
down more C3. The C3 convertase is stabilized by
properdin, a positive regulator of the complement
system.
As a result of this enzymatic activity, many more
C3b and C3bBb molecules are produced and
become attached to the microbe. Some of the
C3bBb molecules bind an additional C3b molecule,
and the resulting C3bBb3b complexes function as
C5 convertases, to cleave the complement protein
C5 and initiate the late steps of complement
activation.
down more C3. The C3 convertase is stabilized by
properdin, a positive regulator of the complement
system.
As a result of this enzymatic activity, many more
C3b and C3bBb molecules are produced and
become attached to the microbe. Some of the
C3bBb molecules bind an additional C3b molecule,
and the resulting C3bBb3b complexes function as
C5 convertases, to cleave the complement protein
C5 and initiate the late steps of complement
activation.
pathogen surface
Figure 2.8 The immune System, 3ed. [© Garland Science 2009)
Figure 2.8 The immune System, 3ed. [© Garland Science 2009)
Spontaneous
cleavage of C3 Fluid phase
hydrolysis
Hydrolysis and
inactivation of
C3b in fluid phase
Inactive
C3b
_C3b binds covalently to
microbial surfaces,
binds Factor B
(re > ||
Cleavage of Factor B
by Factor D; stabilization
by properdin
C3 convertase
Stabilized by Y
properdin @Ba
acsa
Cleavage of additional
C3 molecules by >
cell-associated
C3 convertase
‘3b covalently binds to
cell surface, binds to
C3bBb to form
C5 convertase
Cleavage of C5;
initiation of late steps GP a
al C5a
of complement activation
cleavage of C3 Fluid phase
hydrolysis
Hydrolysis and
inactivation of
C3b in fluid phase
Inactive
C3b
_C3b binds covalently to
microbial surfaces,
binds Factor B
(re > ||
Cleavage of Factor B
by Factor D; stabilization
by properdin
C3 convertase
Stabilized by Y
properdin @Ba
acsa
Cleavage of additional
C3 molecules by >
cell-associated
C3 convertase
‘3b covalently binds to
cell surface, binds to
C3bBb to form
C5 convertase
Cleavage of C5;
initiation of late steps GP a
al C5a
of complement activation
The terminal phase of complement
activation
The products of either pathways (C4b2a3b
and C3bBbC3b act as C5 convertase leading to
of cleavage C5. C5b activates and complexes
with factors C6, C7, C8 and C9 to form
membrane attack unit C5b6789. A potent cell
membrane disrupter is the factor C9.
activation
The products of either pathways (C4b2a3b
and C3bBbC3b act as C5 convertase leading to
of cleavage C5. C5b activates and complexes
with factors C6, C7, C8 and C9 to form
membrane attack unit C5b6789. A potent cell
membrane disrupter is the factor C9.
® “Sree Classical
Pathway Pathway
[ose ee | oe
ns Fa Te ne
Late steps of complement activation
Pathway Pathway
[ose ee | oe
ns Fa Te ne
Late steps of complement activation
> The late steps of complement activation are initiated by the
binding of C5 to the C5 convertase and subsequent proteolysis of
C5, generating C5b.
> The remaining components, C6, C7, C8, and C9, bind sequentially
to a complex nucleated by C5b. The final protein in the pathway,
C9, polymerizes to form a pore
> in the cell membrane through which water and ions can enter,
causing death of the microbe. The C5-9 complex is called the
membrane attack complex (MAC).
binding of C5 to the C5 convertase and subsequent proteolysis of
C5, generating C5b.
> The remaining components, C6, C7, C8, and C9, bind sequentially
to a complex nucleated by C5b. The final protein in the pathway,
C9, polymerizes to form a pore
> in the cell membrane through which water and ions can enter,
causing death of the microbe. The C5-9 complex is called the
membrane attack complex (MAC).
Difference between innate and acquired
Type of immunity
Initiated by
Activation of
Properdin system*
involved
Complement
mediated defense
mechanisms
immune response
Classic
Acquired
Antigen-antibody
complex
All components
starting with C1, C4,
C2
No
Specific after
antibody appears
Alternate
Innate
Microbial cell
surface products.
Starts with
activation of C3 by-
pass C1, C4, C2
Yes
Non-specific before
antibody appears
Lectin
Innate
Mannose-binding
lectin (MBL) binds to
mannose residues
on surface of
microbe
All components
starting C1*, C4, C2,
C3
No
Non-specific before
antibody appears
Type of immunity
Initiated by
Activation of
Properdin system*
involved
Complement
mediated defense
mechanisms
immune response
Classic
Acquired
Antigen-antibody
complex
All components
starting with C1, C4,
C2
No
Specific after
antibody appears
Alternate
Innate
Microbial cell
surface products.
Starts with
activation of C3 by-
pass C1, C4, C2
Yes
Non-specific before
antibody appears
Lectin
Innate
Mannose-binding
lectin (MBL) binds to
mannose residues
on surface of
microbe
All components
starting C1*, C4, C2,
C3
No
Non-specific before
antibody appears
Functions of the Complement System
1) Opsonization.
Microbes coated with C3b are phagocytosed by
phagocytes (which express complement receptor type
1 (CR1, or CD35). Thus, C3b functions as an opsonin.
“a Opsonization and phagocytosis
—— Microbe
= of Recognition of e
C3b to microbe bound C3b by emi ed
(opsonization) phagocyte C3b ehr oF microbe
1) Opsonization.
Microbes coated with C3b are phagocytosed by
phagocytes (which express complement receptor type
1 (CR1, or CD35). Thus, C3b functions as an opsonin.
“a Opsonization and phagocytosis
—— Microbe
= of Recognition of e
C3b to microbe bound C3b by emi ed
(opsonization) phagocyte C3b ehr oF microbe
2) Cell lysis. The MAC can induce osmotic lysis of
cells, including microbes. MAC-induced lysis is
effective only against microbes that have thin
cell walls and little or no glycocalyx, such as the
Neisseria species of bacteria.
(B) Complement-mediated cytolysis =
ant
ae) Microbe à ; ES
Ce — Mi
C
en Formation of the Osmotic lysis
Activation of membrane attack of microbe
C5 convertase complex (MAC)
cells, including microbes. MAC-induced lysis is
effective only against microbes that have thin
cell walls and little or no glycocalyx, such as the
Neisseria species of bacteria.
(B) Complement-mediated cytolysis =
ant
ae) Microbe à ; ES
Ce — Mi
C
en Formation of the Osmotic lysis
Activation of membrane attack of microbe
C5 convertase complex (MAC)
3) Inflammation :
The small peptide fragments C3a and C5a, which are
produced by proteolysis of C3 and C5, are chemotactic
for neutrophils, stimulate the release of inflammatory
mediators from various leukocytes, and _ stimulate
movement of leukocytes and plasma proteins across the
endothelium into tissues to eliminate microbes.
(C)Stimulation of inflammatory reactions
Recruitment and Destruction
Proteolysis of C3 activation of of microbes
and C5 to release leukocytes by by leukocytes
C3a and C5a C5a and C3a
The small peptide fragments C3a and C5a, which are
produced by proteolysis of C3 and C5, are chemotactic
for neutrophils, stimulate the release of inflammatory
mediators from various leukocytes, and _ stimulate
movement of leukocytes and plasma proteins across the
endothelium into tissues to eliminate microbes.
(C)Stimulation of inflammatory reactions
Recruitment and Destruction
Proteolysis of C3 activation of of microbes
and C5 to release leukocytes by by leukocytes
C3a and C5a C5a and C3a
4)Antibody production. ne
« C3d (a break down product of
C3b), is recognized by
complement receptor type 2
(CR2) on B lymphocytes.
Microbial Microbial
gen antigen
« Signals delivered by this
receptor enhance B cell
responses against the
microbe.
« C3d (a break down product of
C3b), is recognized by
complement receptor type 2
(CR2) on B lymphocytes.
Microbial Microbial
gen antigen
« Signals delivered by this
receptor enhance B cell
responses against the
microbe.
5-Immune complex clearance: Immune
complexes with C3b on their surfaces become
bound to C3b receptors (CR1) on erythrocytes
and are carried through the circulation to the
liver and spleen to be taken into phagocytes and
destroyed. C3 deficiency is associated with
immune-complex disease and susceptibility to
recurrent bacterial infections
complexes with C3b on their surfaces become
bound to C3b receptors (CR1) on erythrocytes
and are carried through the circulation to the
liver and spleen to be taken into phagocytes and
destroyed. C3 deficiency is associated with
immune-complex disease and susceptibility to
recurrent bacterial infections
Regulation of complement
activation.
A) C1 inhibitor (C1 INH) prevents the
assembly of the C1 complex, which
consists of C1q, C1r, and C1s proteins,
thereby blocking complement activation
by the classical pathway.
B) The lipid-linked cell surface protein
decay-accelerating factor (DAF) and the
type 1 complement
receptor (CR1) interfere with the
formation of the C3 convertase by
blocking the binding of Bb (in the
alternative pathway) or C2a (in the
classical pathway). Membrane cofactor
protein (or CD46) and CR1 serve
as cofactors for cleavage of C3b by a
plasma enzyme called factor I, thus
destroying any C3b that may be
formed (not shown).
antigen-complexed
antibodies, resulting
Antibody
C1q binds to C1 INH
prevents C1r2s2
from becoming
in activation proteolytically active
of Cirasa
Ciq C1 INH
Cirasa
Dissociation of C3
convertases by DAF
Formation of
C3 convertases
activation.
A) C1 inhibitor (C1 INH) prevents the
assembly of the C1 complex, which
consists of C1q, C1r, and C1s proteins,
thereby blocking complement activation
by the classical pathway.
B) The lipid-linked cell surface protein
decay-accelerating factor (DAF) and the
type 1 complement
receptor (CR1) interfere with the
formation of the C3 convertase by
blocking the binding of Bb (in the
alternative pathway) or C2a (in the
classical pathway). Membrane cofactor
protein (or CD46) and CR1 serve
as cofactors for cleavage of C3b by a
plasma enzyme called factor I, thus
destroying any C3b that may be
formed (not shown).
antigen-complexed
antibodies, resulting
Antibody
C1q binds to C1 INH
prevents C1r2s2
from becoming
in activation proteolytically active
of Cirasa
Ciq C1 INH
Cirasa
Dissociation of C3
convertases by DAF
Formation of
C3 convertases
Os proteins
Protein Eisen
ncentration
C1 inhibitor
(C1 INH)
Factor |
Factor H
C4 binding
protein (C4BP)
| 200 pg/ml
35 pg/ml
480 ug/ml
Inhibits Cir and C1s serine
protease activity
Proteolytically cleaves
C3b and C4b
Causes dissociation of
alternative pathway
C3 convertase subunits
Co-factor for
Factor I-mediated
cleavage of C3b
Causes dissociation of
classical pathway
C3 convertase
Co-factor for
Factor I-mediated
cleavage of C4b
Protein Eisen
ncentration
C1 inhibitor
(C1 INH)
Factor |
Factor H
C4 binding
protein (C4BP)
| 200 pg/ml
35 pg/ml
480 ug/ml
Inhibits Cir and C1s serine
protease activity
Proteolytically cleaves
C3b and C4b
Causes dissociation of
alternative pathway
C3 convertase subunits
Co-factor for
Factor I-mediated
cleavage of C3b
Causes dissociation of
classical pathway
C3 convertase
Co-factor for
Factor I-mediated
cleavage of C4b
Membrane proteins
Protein Distribution [Function]
Membrane \Leukocytes, | Co-factor for i)
co-factor coll epithelial cells, | Factor I-mediated
(MCP, Cl endothelial cells | cleavage of C3b and C4b
a cl | Blocks formation of
acceleratin | endothelial cells, | C3 convertase
| factor (DA | epithelial cells
CD59 | Blood cells Blocks C9 binding and
endothelial cells, | prevents formation
epithelial cells of the MAC
Type 1 | Mononuclear | Le dissociation El
complement phagocytes, convertase subu!
tor | Lot Show Co-factor for
(CR1,CD35) | * | Factor I-mediated
| = be ei cleavage of Cab and C4b
__ JFDCs
Protein Distribution [Function]
Membrane \Leukocytes, | Co-factor for i)
co-factor coll epithelial cells, | Factor I-mediated
(MCP, Cl endothelial cells | cleavage of C3b and C4b
a cl | Blocks formation of
acceleratin | endothelial cells, | C3 convertase
| factor (DA | epithelial cells
CD59 | Blood cells Blocks C9 binding and
endothelial cells, | prevents formation
epithelial cells of the MAC
Type 1 | Mononuclear | Le dissociation El
complement phagocytes, convertase subu!
tor | Lot Show Co-factor for
(CR1,CD35) | * | Factor I-mediated
| = be ei cleavage of Cab and C4b
__ JFDCs
Inherited deficiencies of complement
proteins
+ Inherited deficiencies of complement proteins result in
immune deficiencies and, in some cases, increased
incidence of autoimmune disease. Deficiency of C3
results in increased susceptibility to bacterial infections
that may be fatal early in life.
« Deficiencies of the early proteins of the classical
pathway, C2 and C4, may have no clinical consequence,
may result in increased susceptibility to infections, or
are associated with an increased incidence of systemic
lupus erythematosus, an immune complex-mediated
autoimmune disease.
proteins
+ Inherited deficiencies of complement proteins result in
immune deficiencies and, in some cases, increased
incidence of autoimmune disease. Deficiency of C3
results in increased susceptibility to bacterial infections
that may be fatal early in life.
« Deficiencies of the early proteins of the classical
pathway, C2 and C4, may have no clinical consequence,
may result in increased susceptibility to infections, or
are associated with an increased incidence of systemic
lupus erythematosus, an immune complex-mediated
autoimmune disease.
The increased incidence of lupus may be because the classical
pathway functions to eliminate immune complexes from the
circulation, and these complexes accumulate in individuals lacking
C2 and C4.
In addition, complement deficiencies may lead to defective
signaling in B cells and a failure of B cell tolerance (see Chapter 9).
Deficiencies of C9 and MAC formation result in increased
susceptibility to Neisseria infections. Some individuals inherit
polymorphisms in the gene encoding MBL, leading to production of
a protein that is functionally defective; such defects are associated
with increased susceptibility to infections. Inherited deficiency of
the alternative pathway protein properdin also causes increased
susceptibility to bacterial infection. Regulation of Complement
Activation Mammalian cells
pathway functions to eliminate immune complexes from the
circulation, and these complexes accumulate in individuals lacking
C2 and C4.
In addition, complement deficiencies may lead to defective
signaling in B cells and a failure of B cell tolerance (see Chapter 9).
Deficiencies of C9 and MAC formation result in increased
susceptibility to Neisseria infections. Some individuals inherit
polymorphisms in the gene encoding MBL, leading to production of
a protein that is functionally defective; such defects are associated
with increased susceptibility to infections. Inherited deficiency of
the alternative pathway protein properdin also causes increased
susceptibility to bacterial infection. Regulation of Complement
Activation Mammalian cells
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