innate immune response

Lec.1 : Innate immunity
By
Dr/ Eman Ahmed AbdAlrahman
Lecturer of Medical Microbiology and
Immunology

1) Components of Innate Immunity
a) First Line of Natural defense: Mechanical Barriers,
Chemical barrier and Biological barrier
b) 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
b) Phagocytosis and Destruction of Microbes.
c) Tissue Repair
d) Antiviral Defense
e) Regulation of Innate Immune Responses
f) Microbial Evasion of Innate Immunity
g) Role of Innate Immunity in Stimulating Adaptive
Lec.1 : Innate immunity
Agenda

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.

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.
1) Components of Innate Immunity

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.

 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.
a- First 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
b- Second Line of Natural defense.

1)Cells of innate immunity
• 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.

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.

Innate (Natural/Native) immunity
Acute phase proteins
Synthesized in the liver in response to certain
cytokines namely, IL-1, IL-6 and TNF- α 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

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
C1q, the first component of the classical pathway of
complement activation.

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
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.

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.

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”

 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.

 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.
Pathways of Complement Activation

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
• C1 is a large, multimeric protein
complex composed of C1q, C1r, and
C1s subunits;
• C1r and C1s form a tetramer
composed of two C1r and two C1s
molecules.
• C1q binds to the antibody, and C1r
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

• The reason for this is that each C1q
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).

• 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 C1q
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

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
C1r 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 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 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.

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.

 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).

Difference between innate and acquired
immune response
Classic Alternate Lectin
Type of immunity Acquired Innate Innate
Initiated by Antigen-antibody
complex
Microbial cell
surface products.
Mannose-binding
lectin (MBL) binds to
mannose residues
on surface of
microbe
Activation of All components
starting with C1, C4,
C2.
Starts with
activation of C3 by-
pass C1, C4, C2
All components
starting C1*, C4, C2,
C3
Properdin system*
involved
No Yes No
Complement
mediated defense
mechanisms
Specific after
antibody appears
Non-specific before
antibody appears
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.

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.

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.

4)Antibody production.
• C3d (a break down product of
C3b), is recognized by
complement receptor type 2
(CR2) on B lymphocytes.
• 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

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).

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.

• 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

innate immune response

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