Chapter 2 Innate Immunity.pdf

Immunology & Vaccines
Chapter 2: Innate Immunity

…Definition of the innate immunity
• Innate immunity: the defense mechanisms that evolved first
are always present in the body, ready to recognize and
eliminate microbes and dead cells.
• Its also called natural immunity or native immunity.
• Innate immunity is the critical first step in host defense against
infections. It blocks microbial invasion through epithelial
barriers, destroys many microbes that do enter the body, and is
capable of controlling and even eradicating infections.
• The innate immune response is able to combat microbes
immediately upon infection.

…General Features & Specificity…
• The innate immune system performs its defensive functions
with a small set of reactions, which are more limited than the
varied and specialized responses of adaptive immunity.
• Principal types of reactions of the innate immune system:
1. Inflammation: accumulation and activation of leukocytes and
plasma proteins at sites of infection or tissue injury →
extracellular microbes and to eliminate damaged tissues.
2. Antiviral Defense: mediated by natural killer (NK) cells, which
kill virus-infected cells, and by cytokines called type I
interferons (IFNs), which block viral replication within host
cells.

• The innate immune system responds in essentially the same
way to repeat encounters with a microbe, whereas the
adaptive immune system mounts stronger, more rapid and
thus more effective responses on successive encounters with
a microbe.
• There is emerging evidence that some cells of innate
immunity (such as macrophages and natural killer cells) are
altered by encounters with microbes such that they respond
better upon repeat encounters.

• The innate immune system recognizes limited numbers of
various classes of microbes structures not present on normal
host cells.
• The microbial molecules that stimulate innate immunity are
often called pathogen-associated molecular patterns (PAMPs)
to indicate that they are present in infectious agents
(pathogens) and shared by microbes of the same type
(pattern recognition receptors).
• Examples:
• Phagocytes express receptors for bacterial endotoxin & other
receptors for peptidoglycans, each of which is present in the
outer membranes or cell walls of many bacterial species.

• Other receptors of phagocytes recognize terminal mannose
residues, which are typical of bacterial and fungal.
• Receptors in mammalian cells recognize and respond to
double-stranded ribonucleic acid (dsRNA).
• Unmethylated CG-rich (CpG) oligonucleotides, which are
common in microbial DNA but are not abundant in
mammalian DNA.
• Innate immune receptors are specific for structures of
microbes that are often essential for the survival and
infectivity of these microbes.

• The innate immune system also recognizes molecules that are
released from damaged or necrotic host cells.
• Such molecules are called damage-associated molecular
patterns (DAMPs).
• Example; HMGB1 a histone protein that is released from cells
with damaged nuclei, and extracellular ATP, which is released
from damaged mitochondria → eliminate the damaged cells
and to initiate the process of tissue repair.

• The receptors of the innate immune system are encoded by
inherited genes that are identical in all cells.
• The pattern recognition receptors of the innate immune
system are nonclonally distributed → many cells of innate
immunity may recognize and respond to the same microbe.
• 100 types of innate immune receptors that are capable of
recognizing about 1000 PAMPs and DAMPs.

General Features & Specificity…
• The innate immune system does not react against the
normal host.
1. The receptors of innate immunity have evolved to be specific
for microbial structures (and products of damaged cells) but
not for substances in healthy cells.
2. Some pattern recognition receptors can recognize substances
such as nucleic acids that are present in normal cells.
3. Normal mammalian cells express regulatory molecules that
prevent innate immune reactions.

Cellular receptors for microbes and
damaged cells…
• The pattern recognition receptors used by the innate immune
system to detect microbes and damaged cells are expressed
on phagocytes, dendritic cells, and many other cell types and
are located in different cellular compartments where
microbes or their products may be found.
• These receptors present on:
1. Cell surface: they detect extracellular microbes.
2. Vesicles (endosomes): into which microbial products are
ingested.
3. In the cytosol: where they function as sensors of cytoplasmic
microbes.

…Cellular receptors for microbes and
damaged cells…
• These receptors for PAMPs and DAMPs belong to several
protein families including:
1. Toll-like receptors (TLRs): In vertebrates, there are 10
different TLRs specific for different components of microbes
Recognition
TLRs
glycolipids and peptidoglycans of gram-positive bacteria and some parasites
TLR-2
double-stranded RNA
TLR-3
single-stranded RNA
TLR-7&8
bacterial LPS (endotoxin)
TLR-4
bacterial flagellar protein called flagellin
TLR-5
unmethylated CpG DNA (microbial genome)
TLR-9

damaged cells…
• Signals generated by TLRs activate transcription factors that
stimulate expression of cytokines and other proteins involved
in the inflammatory response and in the antimicrobial
functions of activated phagocytes and other cells.
• κB (NF-κB) family, which promote expression of various
cytokines and endothelial adhesion molecules that play
important roles in inflammation, and interferon regulatory
factors (IRFs), which stimulate production of the antiviral
cytokines, type I interferons.

damaged cells…
2. NOD-Like Receptors:
• Large family of innate receptors that sense DAMPs and PAMPs
in the cytosol of cells and initiate signaling events that
promote inflammation containing contain a nucleotide
oligomerization domain or different N-terminal domains.
• NOD1 & NOD2:
• N-terminal caspase related domains (CARDs)
• Expressed in several cell types including mucosal barrier
epithelial cells and phagocytes.
• Recognize peptides derived from bacterial cell wall
peptidoglycans.

damaged cells…
• In response, they generate signals that activate the NF-κB
transcription factor, which promotes expression of genes
encoding inflammatory proteins.
• NOD2 is highly expressed in intestinal Paneth cells in the small
bowel, where it stimulates expression of antimicrobial
substances called defensins in response to pathogens.
3. Inflammasomes:
• Multi protein complexes that assemble in the cytosol of cells
in response to microbes changes associated with cell injury.

damaged cells…
• Proteolytically generate active forms of the inflammatory
cytokines IL-1β and IL-18.
• There are many different types of inflammasomes most of
which use 1 of 10 different NLR-family proteins as sensors.
• These sensors directly recognize microbial products in the
cytosol or sense changes in the amount of endogenous
molecules or ions in the cytosol that indirectly indicate the
presence of infection or cell damage.

damaged cells…
• Example: NLRP3 (NOD-like receptor family, pyrin domain
containing 3) in innate immune cells including macrophages &
neutrophils.
• A wide variety of stimuli induce formation of the NLRP3
inflammasome, including crystalline substances such as uric
acid and cholesterol crystals, extracellular adenosine
triphosphate inflammasome reacts to injury affecting various
cellular components.

damaged cells…
4. Cytosolic RNA and DNA Sensors:
• Recognize microbial RNA or DNA and respond by generating
signals that lead to the production of inflammatory and
antiviral cytokines.
• The RIG-like receptors (RLRs) are cytosolic proteins that sense
viral RNA and induce the production of the antiviral type I IFNs.
• Cytosolic DNA sensors (CDSs) include several structurally
related proteins that recognize microbial double-stranded (ds)
DNA in the cytosol and activate signaling pathways that initiate
antimicrobial responses, including type 1 IFN production and
autophagy.

damaged cells…
5. Other Cellular Receptors of Innate Immunity:
• Some lectins (carbohydrate-recognizing proteins) in the
plasma membrane are receptors specific for fungal glucans
or for terminal mannose residues (called mannose
receptors).
• They are involved in the phagocytosis of fungi and bacteria
and in inflammatory responses to these pathogens.

damaged cells…
• Formyl peptide receptor 1, recognizes polypeptides with an N-
terminal formylmethionine, which is a specific feature of
bacterial proteins.
• Signaling by this receptor promotes the migration as well as
the antimicrobial activities of the phagocytes.

…Components of innate immunity…
• The components of the innate immune system include:
1. Epithelial Barriers:
• Physical barrier to infection formed by keratin (in the skin) or
secreted mucus.
• Killing of microbes by locally produced antibiotics e.g.
defensins and cathelicidins.
• Killing of microbes and infected cells by intraepithelial
lymphocytes by recognizing microbial lipids and other
structures.

2. Phagocytes: Neutrophils and Monocytes/ Macrophages:
• Neutrophils (dominant cells of acute inflammation):
• They are the first and most numerous cell type to respond to
most infections, particularly bacterial and fungal infections.
• They ingest and kill microbes in the circulation, in
extravascular tissues at sites of infection.
• They express receptors for products of complement
activation and for antibodies that coat microbes. Which
enhance phagocytosis of microbes and they initiate the
clearance of cell debris.

• Monocytes/Macrophage:
• They also ingest microbes in the blood and in tissues.
• During inflammatory they enter extravascular tissues and
differentiate into cells called macrophages survive in these
sites for long periods.
• Tissue resident macrophages (e.g. brain, liver, lung) are
derived from precursors in the yolk sac and liver.
• They expresses TLRs and NLRs receptor which recognize
products of microbes and damaged cells and activate the
macrophages plus mannose receptors & scavenger receptors
for phagocytosis.

• Macrophages roles in host defense: they produce cytokines
that induce and regulate inflammation, they ingest and
destroy microbes, and they clear dead tissues and initiate the
process of tissue repair.
• Macrophages may be activated by two different pathways:
i. Classical macrophage activation is induced by innate
immune signals, such as from TLRs, and by the cytokine IFN-
γ.
ii. Alternative macrophage activation occurs in the absence of
strong TLR signals and is induced by the cytokines IL-4 and
IL-13.

…Components of the innate
immunity…
• Dendritic Cells: produce numerous cytokines that serve two
main functions: they initiate inflammation and they stimulate
adaptive immune responses by interacting with T-cells so its
serves as bridge between innate and adaptive immunity.
• Mast Cells: bone marrow–derived cells with abundant
cytoplasmic granules that are present throughout the skin &
mucosal barriers.
• They are activated by microbial products binding to TLRs, as
part of innate immunity, or by a special antibody-dependent
mechanism.

• Role of mast cells:
1. Contain vasoactive amines such as histamine that cause
vasodilation and increased capillary permeability.
2. Secrete proteolytic enzymes that can kill bacteria or
inactivate microbial toxins.
3. Synthesize and secrete lipid mediators (e.g., prostaglandins)
and cytokines (e.g., tumor necrosis factor [TNF]), which
stimulate inflammation.
4. Mast cell products provide defense against helminths and
other pathogens and are responsible for symptoms of
allergic diseases.

• Innate Lymphoid Cells:
• Tissue-resident cells that produce cytokines similar to those
secreted by helper T lymphocytes but do not express T cell
antigen receptors (TCRs).
• The responses of ILCs are often stimulated by cytokines
produced by damaged epithelial and other cells at sites of
infection.
• They provide early defense against infections in tissues.

• Natural killer cells:
• They contain abundant cytoplasmic granules and express
some unique surface proteins but do not express
immunoglobulins or T cell receptors.
• Role of NK cells in innate immunity:
1. kill host cells infected by intracellular microbes by secretion
of their cytoplasmic granules into the infected cells, the
granule proteins activate enzymes that induce apoptosis.
2. NK cells respond to interleukin-12 (IL-12) produced by
macrophages and secrete interferon-γ (IFN-γ), which
activates the macrophages to kill phagocytosed microbes.

• NK cells Activation & Inhibition:
• NK cells doesn’t attack normal
host cells because they express
self class I MHC molecules.
• NK cells are activated by
infected cells in which ligands
for activating receptors are
expressed (often at high levels)
and class I MHC expression is
reduced.

• Complement System:
• Collection of circulating and membrane-associated proteins
(proteolytic enzymes) that are important in defense against
microbes and their activation happen in sequential manner.
• The complement cascade may be initiated by any of three
pathways:
1. Alternative pathway: complement proteins are activated on
microbial surfaces and cannot be controlled, because
complement regulatory proteins are not present on microbes
(but are present on host cells). The alternative pathway is a
component of innate immunity.

2. Classical pathway: triggered by antibodies that bind to
microbes or other antigens and is thus a component of the
humoral arm of adaptive immunity.
3. Lectin pathway: activated when mannose-binding lectin
(MBL) binds to its carbohydrate ligands on microbes. it is a
component of innate immunity.
• The central component of all complement pathways is C3
protein, which is cleaved by enzymes generated in the early
steps. The C3b, becomes covalently attached to microbes and
is able to recruit and activate downstream complement
proteins on the microbial surface.

• The complement system serves three main functions in host
defense:
1. Opsonization and phagocytosis: C3b coats microbes and
promotes microbes binding to C3b phagocytes receptor.
2. Inflammation: some proteolytic fragments of complement
proteins, especially C5a and C3a promote leukocyte
recruitment at the site of complement activation.
3. Cell lysis: by forming a polymeric protein complex inserted
into the microbial cell membrane, disturbing the
permeability barrier and causing either osmotic lysis or
apoptosis of the microbe.

• Other plasma proteins of innate immunity:
1. Mannose-binding lectin protein(MBL): recognizes microbial
carbohydrates and can coat microbes for phagocytosis or
activate the complement cascade.
2. Surfactant proteins: in the lung protect the airways from
infection.
3. C-reactive protein (CRP): binds to phosphorylcholine on
microbes and opsonizes the microbes for phagocytosis by
macrophages.

• Cytokines:
• Soluble proteins that mediate immune and inflammatory
reactions and are responsible for communications between
leukocytes and between leukocytes and other cells.
• In innate immunity, the principal sources of cytokines are
mast cells, dendritic cells, and macrophages activated by
recognition of microbes.
• Tumor necrosis factor (TNF), interleukin-1 (IL-1), and
chemokines (chemoattractant cytokines) are the principal
cytokines involved in recruiting blood neutrophils and
monocytes to sites of infection.

…Components of innate immunity
• TNF and IL-1 also have systemic effects, including inducing
fever by acting on the hypothalamus.
• IL-6 stimulate liver cells to produce various proteins of the
acute phase response, such as C-reactive protein and
fibrinogen, which contribute to microbial killing and walling
off infectious sites.

Innate Immune Reaction…
• The innate immune system eliminates microbes mainly by:
1. Inducing the acute inflammatory response.
2. Antiviral defense mechanisms.
• Different microbes may elicit different types of innate
immune reactions, each type of response being particularly
effective in eliminating a particular kind of microbe.
• The major protective innate immune responses to different
microbes are the following:

…Innate Immune Reaction…
1. Extracellular bacteria and fungi are combated mainly by the
acute inflammatory response, in which neutrophils and
monocytes are recruited to the site of infection, and by the
complement system.
2. Intracellular bacteria, which can survive inside phagocytes,
are eliminated by phagocytes that are activated by Toll-like
receptors and other sensors as well as by cytokines.
3. Defense against viruses is provided by type I interferons and
natural killer cells.

• Inflammation:
• Tissue reaction that delivers mediators of host defense
circulating cells and proteins to sites of infection and tissue
damage.
• Inflammation process consists of recruitment of cells and
leakage of plasma proteins through blood vessels and
activation of these cells and proteins in the extravascular
tissues.

• Recruitment of Phagocytes to Sites of Infection and Tissue
Damage
• Neutrophils and monocytes migrate to extravascular sites of
infection or tissue damage by binding to venular endothelial
adhesion molecules and in response to chemoattractants
produced by tissue cells reacting to infection or injury.
• When microbe breaches an epithelium and enters the sub
epithelial tissue, resident dendritic cells, macrophages, and
other cells recognize the microbe and respond by producing
cytokines. TNF and IL-1 initiate the sequence of events in
leukocyte migration into tissues.

• Rolling of leukocytes: in response to TNF and IL-1, leukocyte
use E-selectin to roll along the endothelial surface.
• Firm adhesion: integrin bind to proteoglycans on the luminal
surface of endothelial cells.
• Leukocyte migration: through the junctions between
endothelial cells, exiting the blood vessels. Within the tissue,
leukocytes migrate along extracellular matrix fibers, directed
by concentration gradients of chemoattractants, including
chemokines, bacterial formyl peptides, and complement
fragments C5a and C3a.

…Innate immune reaction…
• Phagocytosis and destruction of microbes:
• Phagocytosis is a process of ingestion of particles larger than
0.5 μm in diameter by Neutrophils and macrophages.
• Steps of Phagocytosis:
1. The principal phagocytic membrane receptors (e.g. mannose
receptors and other lectins, and receptors for antibodies and
complement) binding to the microbe.
2. Binding of the microbe to the cell is followed by extension of
the phagocyte plasma membrane around the particle.

3. The membrane then closes up and pinches off, and the
microbe is internalized in a membrane-bound vesicle, called
a phagosome.
4. The phagosomes fuse with lysosomes to form
phagolysosomes.
5. At the same time that the microbe is being bound by the
phagocyte’s receptors and ingested, the phagocyte receives
signals from various receptors that activate several enzymes
in the phagolysosomes which kills the microbe.

• Types of enzyme used inside phagolysosome:
1. Phagocyte oxidase: converts molecular oxygen into
superoxide anion and free radicals which known as Reactive
oxygen species (ROS).
2. Nitric oxide synthase (iNOS): catalyzes the conversion of
arginine to nitric oxide (NO), also a microbicidal substance.
3. lysosomal proteases: break down microbial proteins.

…Innate immune reaction
• Note: all of the mentioned enzymes they act on the ingested
microbes but do not damage the phagocytes.
• Neutrophils also release microbicidal granule contents into
the extracellular environment called neutrophil extracellular
traps (NETs), these NETs trap bacteria and fungi and kill the
organisms.

• Tissue Repair:
• Macrophages, especially of the alternatively activated type,
produce growth factors that stimulate the proliferation of
residual tissue cells and fibroblasts, resulting in regeneration
of the tissue and scarring of what cannot be replaced.
• Other immune cells, such as helper T cells and ILCs, may serve
similar roles.

• Antiviral Defense:
• Involves interferons, NK cells, and other mechanisms, which
may occur concomitantly with, but are distinct from,
inflammation.
• Type I interferons inhibit viral replication and induce an
antiviral state, in which cells become resistant to infection.
• Type I IFNs, which include several forms of IFN-α and one of
IFN-β, are secreted by many cell types infected by viruses. A
major source of these cytokines is a type of dendritic cell
called the plasmacytoid dendritic cell.

• When type I IFNs secreted from dendritic cells or other
infected cells bind to the type I IFN receptor on the infected or
adjacent uninfected cells, signaling pathways are activated
that inhibit viral replication and destroy viral genomes.
• Type I IFNs enhance the ability of NK cells to kill infected cells.

• Regulation of Innate Immune Responses:
• By the production of antiinflammatory cytokines by
macrophages and dendritic cells.
• Interleukin-10 (IL-10) Inhibits the microbicidal and
proinflammatory functions of macrophages.
• IL-1 receptor antagonist, which blocks the actions of IL-1.
• TLR signaling stimulates expression of proteins called
suppressors of cytokine signaling (SOCS), which block the
responses of cells to various cytokines, including IFNs.

• Role of innate immunity in adaptive immune response
activation:
• Innate immune responses generate molecules that provide
signals, in addition to antigens, that are required to activate
naive T and B lymphocytes.
• Antigen may be referred to as signal 1, and innate immune
responses to microbes and to host cells damaged by microbes
may provide signal 2.

• Microbe-dependent signal ensures that lymphocytes respond
to infectious agents and not to harmless, noninfectious
substances.
• Example: use the adjuvants in vaccines which elicit the same
innate immune reactions as microbes do.
• Second signal: In infected tissues, microbes (or IFN-γ
produced by NK cells in response to microbes) stimulate
dendritic cells and macrophages to produce two types of
second signals that can activate T lymphocytes.

• First, dendritic cells increase their expression of surface
molecules called costimulators, which bind to receptors on
naive T cells and function together with antigen recognition to
activate the T cells.
• Second, the dendritic cells and macrophages secrete
cytokines such as IL-12, IL-1, and IL-6, which stimulate the
differentiation of naive T cells into effector cells of cell-
mediated adaptive immunity.

…Innate Immune Reaction
• In complement system a fragment of C3b called C3d, becomes
covalently attached to the microbe. The B cells recognize the
C3d bound to the microbe by a receptor for C3d.
• The combination of antigen recognition and C3d recognition
initiates the process of B cell differentiation into antibody-
secreting cells.

Chapter 2 Innate Immunity.pdf

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