Download Immunology

Public Health MP 3304
The Innate Immune Response
Chapters 15 and 19
Nester 4th. Ed.
Anjum Odhwani, MD MPH
Definition of Immunology

The branch of science that is devoted to
the study of many mechanisms the
body uses to defend itself against
invading organisms or microbes.
Types of Defense Mechanisms
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Non-specific (Innate immunity)
Specific (adaptive immunity)- Immune
Response
One branch of immunity

Non-specific immunity
– found in most of the humans and animals
– inborn, innate, natural
– already in place before the organism
enters the host
– directed against any organism that tries to
invade a host
Mechanisms involved in Nonspecific immunity
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Tissue barriers
– Mechanical
– Chemical
Non-specific antimicrobial substances
Acute inflammation
Phagocytosis
Fever
Changes in iron metabolism
First – line defense
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Physical barriers
Normal flora
Antimicrobial substances
Innate Immunity

Mechanical Barriers that prevent entry of
microorganisms (Fig 15.1-15.3)
– Skin
• Most difficult barrier
• Physically prevents microbes from
accessing the tissues
• Skin is tough and durable
• Outer layer Keratin constantly slough
off
• Arid environment
• Sweat high in salt and lysozyme
• Sebum (fatty acid)
Epithelial barriers
Innate Immunity
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Mechanical Barriers that prevent entry
of microorganisms (Fig 15.1-15.3)
Mucous membranes
– Constantly bathed with mucus and other
secretions
– Propel microbes
• Ciliated epithelium
• Peristalsis
• Urine flushes organisms
Anatomical barriers
Figure 15.1
Innate Immunity
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Chemical Barriers (Figure 15.3)
– Acid mantle
• urine, stomach acid and vaginal pH
First-line defense mechanisms in humans
Innate Immunity

Normal flora (resident flora)
– Covers binding sites
– Compete
– Consume resources
– Produce toxins e.g. Propionibacterium,
Lactobacillus species in vagina
– Stimulate host defense mechanism
Normal flora

Establishment
– fetus has no normal flora
– acquire some at birth
– acquire some in food
– acquire some from other people
– colonization
Normal flora
Importance of Normal Flora

Prevent growth of other organisms
– by taking up space - commensals
– by competing for nutrients
– by preventing attachment
Importance of Normal Flora

Prevent growth of other organisms
– by making products that are toxic to other
organisms
• lipid catabolic by-products e. g.
Propionibacterium (sebaceous
secretion to fatty acid)
• Colicins (E. coli synthesis protein toxic to
other organisms)
• Lactic acids (lactobacillus in vagina
acidic environment)
Importance of Normal Flora

Prevent the growth of other organisms
– by stimulating immunity
• an immune response to one organism may help
against a similar organism
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Providing a useful function
– degrading cellulose for nutrients
– making vitamins (biotin, panthothenic acid (B5),
folic acid and Vitamin K)
Normal flora
– Types of symbiotic relationships
• Mutualism
– An association in which both partners
benefit e.g. intestinal bacteria synthesize vit
K and vit B
• Commensalism
– An association in which one partner benefits
but other remains unharm
• Parasitism
– An association in which one organism, the
parasite derives benefit at the expense of
the other organism, the host
Normal Flora Can Change

How?
– increased perspiration
– acidity of the stomach (Alteration of the acid barrier
of the stomach by disease, surgery, drugs or antacids)
– ingestion of antibiotics
– meat diet vs. vegetarian diet (People living on
the high carbohydrate diet have significantly fewer
Bacteroides and more Enterococci in their faeces)
– changes in peristalsis (e.g. diarrhea)
Innate Immunity
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Non-specific antimicrobial factors
Antimicrobial substances found in
saliva, tears, mucus and skin
– Lysozyme
– Peroxidase
– Lactoferrin
– Interferons
Innate Immunity
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Non-specific antimicrobial factors
– Lysozyme
• Found in tears, saliva, mucus, in
phagocytic cells, blood and fluid that
bathes tissues
• Enzyme that degrades peptidoglycan
• Gram-positive bacteria peptidoglycan is
exposed
• Gram-negative peptidoglycan not
exposed
Innate Immunity
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Non-specific antimicrobial factors
– Lactoferrin and transferrin
• Found in saliva, mucus, milk, blood and
tissue fluids
• Iron binding protein
• Major element for growth of the
organism
• Sequester iron from the organisms
Innate Immunity
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Non-specific antimicrobial factors
Peroxidase
• Found in saliva, milk, body tissues and
phagocytes
• Peroxidases are a group of enzymes that
catalyze oxidation-reduction reactions
• H2O2 + peroxidase + Cl = yields chlorine and
hypochlorite (bleach)
• H2O2 + catalase yields H2O and O2
• Catalase (+) organisms are more resistant to
peroxidase
• Catalase –negative organisms are sensitive to
perxidase killing
Innate Immunity
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Non-specific antimicrobial factors
– Defensins
• Short antimicrobial peptides
• Found on mucus membranes and
within phagocytic cells (macrophages
and neutrophils)
• Insert themselves into bacterial
membranes and form pores
• Distrupt the integrity of bacterial
membrane
Interferon
Innate Immunity
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Non-specific antimicrobial factors
– Interferons
• Group of glycoproteins (control viral
infection) See Figure 15.11
• Inhibits protein synthesis in cells near
virally infected cells
• Prevent viral replication
• Are species specific with regards to host
Cells and Tissues Involved in Defense
Mechanisms

Cells are mainly the leukocytes
– Figure 15.4
– Table 15.2
– Non-specific are the granulocytes,
monocyte/macrophages and null cells
(natural killer cells)
– Specific are the lymphocytes
Cells and Tissues Involved in Defense
Mechanisms

Tissues
– lymphoid tissues (dense accumulation of
lymphocytes e.g. Peyer’s
patches)
– Lymphoid organ (spleen, lymph nodes, tonsils,
bone marrow, adenoids and appendix)
Professional
phagocytes
Professional phagocytes
Cells and Tissues Involved in
Defense Mechanisms
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Acute bacterial infection
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Neutrophils ↑
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Inflammation and allergic reaction
Basophils ↑
Eosinophils ↑
Allergic reaction and parasitic
infestation
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Eosinophils ↑
Cell Communication
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Trauma or invasion
Communicate to immediate
environment and to other cells
How do they communicate?
– Surface Receptors (eyes and ears)
– Cytokines (Voice)
– Adhesion molecules (hands)
Cell Communication

Surface receptors
– Are integral membrane proteins
– Bind specific compound or compounds
– Molecule binds to a particular receptor is
called a ligand for that receptor
– Internal portion of the receptor becomes
modified
– Elicit response (chemotaxis)
Cell Communication
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Cytokines
– Low molecular weight proteins
– Made by certain cells
• lymphokine (cytokines made by
lymphocytes)
• monokine (cytokines made by
monocytes)
• chemokine (cytokines with chemotactic
activities)
• interleukin (cytokines made by one
leukocyte and acting on other
leukocytes).
Cell Communication
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Cytokines
– Communicate with other cells (chemical
messengers)
– Short-lived
– Very powerful
– Act at extremely low concentration
– Act locally, regionally or systemically
Cell Communication
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Cytokines
– Cytokines binds to cytokine receptors
• Induce a change such as growth
(different kind of leukocytes, precursors
of blood cell and mast cells)
• Differentiation (different leukocytes)
• Movement
• Cell death
Cell Communication
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Cytokines
• See Table 15.3
• Chemokines
• Colony stimulating factors
• Interferons
• Interleukins
• Tumor necrosis factor
Direct immature leukocytes into the appropriate maturation
pathway
Cell Communication
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Cytokines: Groups of cytokines work
together
– Chemokines
• 50 different varieties
• Chemotaxis of immune cells
– Colony-stimulating factors (CSFs)
• multiplication and differentiation of
leukocytes
Cell Communication
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Cytokines
– Interferons (IFNs)
• Glycoproteins
• Control viral infections
• Gamma-interferon helps regulate the
function of the cells involved in
inflammatory response (phagocytes)
• Modulates certain responses of adaptive
immunity
Cell Communication
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Cytokines
– Interleukins (ILs)
• Produced by leukocytes
• At least 18 interleukins been studied
• Innate and adaptive immunity
– Tumor necrosis factors (TNFs)
• TNF- alpha produced by macrophages
plays an instrumental role in initiating the
inflammatory response
• Programmed cell death or appoptosis
(destroy self-cells without eliciting
inflammation)
Cell Communication
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Cytokines
– Groups of cytokines work together
• Pro-inflammatory cytokines contributes to
inflammation (TNF-alpha, IL-1, IL-6)
• Promotion of antibody responses (IL-4, IL5, IL-10 and IL-14)
• Promotion of T cell activity (IL-2, and INFgamma)
Cell Communication
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Adhesion molecules
– Allow cells to adhere to other cells
– Ex. Endothelial cells bind to phagocytic
cells grab cells
– Slow down phagocytic cell movement
– Allow cells to adhere to other cells and
deliver cytokines or other compounds
Cell Communication
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Sensor Systems
– Present within blood and tissues
– Senses tissue damage and microbial
invasion
– Either directly destroy the microbes
– Or recruit other components of the host
defenses
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E.g.
Toll-like receptors
Complement system
Sensor systems
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Toll-like Receptors (TLRs)
Figure 15-6
At least 10 TLRs identified
Each recognizes a distinct compound or
groups of compounds
E.g.
TLR-2 recognizes peptidoglycan
TLR-4 is triggered by lipopolysacchride
Sensor systems
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Toll-like Receptors (TLRs)
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Other bacterial structures or compounds that
activate these receptor
Flagellin
Bacterial nucleotides
What do they do?
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Sensor systems
 Toll-like
Receptors (TLRs)
– What do they do?
– Transmit signals to the nucleus of the host
cells to alter the expression of certain
genes
– E.g.
– Lipopolysaccharide → triggers a TLRs of
monocytes and macrophages →
chemokines
attracts additional
phagocytes
Sensor Systems
•
The Complement System (Figure 15.7 and
15.8)
– Series of about 20 proteins
• Circulate in the blood and tissue fluids
• C1 through C9 are the major components of
this system
• Routinely circulate in an inactive form
• once activated a cascade of events occurs
• one event triggers the next event
• Activated forms have specialized functions to
quickly remove and destroy the offending
material
Compliment system
C3b binds to foreign material
called opsonized, C3b called
opsonins
C3a and C5a→induce
changes in endothelial cells
and mast cells →↑ vascular
permeability
Regulatory proteins halt the
process inactivate C3b
Regulatory proteins are not
associated with microbial
surfaces
C5a attracts phagocytes
Membrane attack complex
Sensor Systems
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Complement (continued)
– Two pathways of activation
• Classical pathway part of specific immunity
• Alternate pathway part of innate immunity
– Final common pathway
• Ultimate function is lysis of a bacteria by the
membrane attack complex
• C3a and C5a are the anaphylatoxins
Sensor Systems
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Complement System
– Classical pathway
inflammation
• Antigen-antibody complexes
red
flag portion of the antibody
interact
with complement component
in turn
C3a and C5a induce changes in
endothelial cells
increase permeability
associated with inflammation
• C5a is a potent chemoattractant
Sensor Systems
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Complement System
– Alternative pathway
• C3b binds to foreign material is said opsonized
(prepared for eating)
• Phagocytes more easily destroy C3b coated
cells as they have C3b receptors
• C3a and C3b cause phagocytes to produce
more receptors for C3b
Sensor Systems
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Complement System
– Lactin pathway
cells
Lysis of foreign
• Mannan-binding lectins (MBLs), a polymer of
mannose found on microbial cells
MBL
binds to a surface and interact with compliment
component initiating classical pathway
C5b, C6, C7, C8 and C9 forms doughnut
shaped structure called membrane attack
complex (MAC)
creates pores in
membrane, disrupting the integrity of the cell
Complement System
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C3a and C5a→induce changes in endothelial
cells and mast cells →↑ vascular permeability
C5a attracts phagocytes
C3b binds to foreign material called
opsonized
C3b called opsonins
Regulatory proteins halt the process
inactivate C3b
Regulatory proteins are not associated with
microbial surfaces
Phagocytosis
Innate Immunity
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Phagocytosis (Figure 15.9)
– Chemotaxis- phagocytic cells are
recruited
– Recognition and adhesion
Direct: mannose sugar found on the surface
of certain bacteria and yeast
• Indirect: binding opsonized (C3b)
•
– Engulfment
• phagocyte engulf the invader forming a
membrane-bound vacuole called
phagosome
Innate Immunity
• Phagocytosis
• Fusion of the phagosome with lysosome
• Phagosome transported towards lysosome
forming phagolysosome
• Lysosome a membrane bound body filled with
various digestive enzymes
Innate Immunity
• Phagocytosis
• Destruction and digestion
• Oxygen dependent mechanisms oxidized
sugars via TCA cycle
• Highly toxic oxygen by-products such as
superoxide, hydrogen peroxide and hydroxyl
radicals are produced
• Once oxygen is depleted fermentation
anaerobic metabolism starts
• Metabolic pathway switches to lactic acid
production lowering pH
• Enzymes degrade bacterial cell wall and other
components of cells
Innate Immunity
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Phagocytosis
Exocytosis
– Digested material is expelled to external
environment
Innate Immunity
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Neutrophils
– First to arrive during an immune response
– Involved in inflammation
– Inherently have more killing power than
macrophages
Innate Immunity
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Macrophages
– Located throughout the body (Kupffer
cells, alveolar macrophages, etc.)
– Produce cytokines
– Interact with T helper cells – activated
macrophages
– Help form granulomas (Macrophages, Giant
cells and T-helper cells)
Innate Immunity
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Inflammation-A coordinated response
to invasion or damage
– Types of inflammation
– Cardinal signs of acute inflammation
– Factors that initiate the inflammatory
response
– Process of acute inflammation
– Outcomes of inflammation
Innate Immunity
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Inflammation
– Definition
• When a tissue have been damaged, such as when an
object penetrates the skin or when microbes produce
toxic compound, a coordinated response called the
inflammatory response, or inflammation occurs
– Types of inflammation
• Acute
– Immediate and short lived response (neutrophils)
• Chronic
– Delayed and long lived response (macrophages,
giant cells, T cells forms granulomas)
Innate Immunity
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Signs of inflammation
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–
–
–
–
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Swelling
Redness
Heat
Pain
Loss of function (sometimes present)
Intension of the inflammatory process
– limit damage and restore function
Innate immunity
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Inflammation
– Factors that initiate the inflammatory
response
• Microbial products
– Lipopolysaccharide, flagellin, bacterial
DNA trigger toll-like receptors
Innate immunity
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Factors that initiate the inflammatory
• Microbial cell surface
– Trigger complement cascasde
» leading to production of C3a and C5a
» Stimulate changes associated with
inflammation
– Complement component also induces
mast cells to release various
proinflammatory cytokines
Innate immunity
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Factors that initiate the
inflammatory
• Tissue damage
– Activate two enzymatic cascades
»Coagulation cascade results in
blood clotting and catch microbe
in a clot too
»Bradykinin increases vascular
permeability, dilates blood
vessels, contracts non-vascular
smooth muscle, and causes pain
The inflammatory process
The inflammatory process
Innate Immunity
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The acute inflammatory response
(Figure 15.10)
– Two components
• Vascular component
–Vasodilation- produces redness and
heat
–Increased vascular permeability produces swelling
Innate Immunity
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The acute inflammatory response
(Figure 15.10)
– Two components
• Cellular component
–Cell recruitment
–Phagocytosis
Innate immunity
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Inflammation
– Outcomes of acute inflammation
•
•
•
•
Resolution
Abscess formation
Scarring
Chronic inflammation
Innate immunity
 Inflammation
– Systemic response is life threatening
– Enzymes and toxic products within
phagocytic cells can damage healthy
tissues
– Inflammation in brain and spinal cord can
be life threatening
Innate immunity
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Septic shock:
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Gram-negative bacteria → endotoxins→
proinflammatory cytokines →activate
complement cascade and clotting cascade
→results in rapid decrease in blood pressure
→ shock
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Clot plugs the capillaries of vital organs e.g.
liver, lung, brain etc cutting blood supply
Innate immunity
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Apoptosis
– Mechanism of eliminating dead self-cells
without evoking an inflammatory response
– Cell suicide
– Dying cells undergo changes
•
•
•
•
Shape changes
Enzyme cut the DNA
Portions of the cells bud off
Cell shrink
Innate Immunity
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Fever
– one of the strongest indications of
infectious disease
– the hypothalamus regulates our normal
body temperature in a narrow range
• 98.6ºF or 37 ºC
– central temperature receptors and
peripheral temperature receptors
Innate Immunity
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Fever
– Cytokines and other fever-inducing
substances are called pyrogens
– Fever-inducing cytokines body makes it
e.g. IL-1 and TNF (endogenous pyrogens)
– Bacterial endotoxins, cell wall
Lipoplysaccharide are (exogenous
pyrogens)
Innate Immunity
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Fever
– microorganisms can cause the body to
respond by changing the “set point”
• components of microorganism attach to
phagocytic cells
• phagocytic cells release interleukin-1
• interleukin-1 travels via the blood to the
hypothalamus
• the hypothalamus responds by raising
body temperature
Innate Immunity
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Fever
– inhibits pathogens by:
• increasing body temperature above the
optimal temperature for growth of
microorganisms
–enzymes are inactivated
• activating and speeding a number of
body defenses
–there are many examples
Innate Immunity
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Fever
– Examples of beneficial effects of fever
• enhance inflammation
• increase killing by phagocytes
• release of chemo-attractants of
neutrophils
• activation and replication of lymphocytes
• increase production of antibody and
interferon
• decrease host’s ability to absorb iron