Chapter 16

Innate Immunity:
Nonspecific
Defenses of the
Host
Lectures prepared by Christine L. Case

Lecturer:
Dr. Nino Janelidze
University of Georgia
© 2013 Pearson Education, Inc.

Copyright © 2013 Pearson Education, Inc.

Lectures prepared by Christine L. Case
 The Concept of Immunity
What is Immunology?
Immunology is the study of protection mechanisms of our body
from foreign macromolecules or invading organisms and our
responses to them.
What is Immunity (resistance)
The state in which a person, either naturally or by some acquired
mechanism, is protected from different diseases or infections
It can be innate (nonspecific), or it may be adaptive (acquired
or specific).

 Innate immunity: defenses against any pathogen

 Adaptive immunity: immunity or resistance to a specific
pathogen
 Vulnerability or lack of immunity is referred to as susceptibility

© 2013 Pearson Education, Inc.

 The Concept of Immunity
 Innate immunity: defenses against any pathogen
- refers to defenses that are present at birth
- always present and available to provide rapid responses
to protect against disease
- does not involve specific recognition of a microbe
- does not have a memory response
 First line of defense is
- skin and mucous membranes.
 Second line of defense
- various defensive cells (Natural killer cells and Phagocytes)
- inflammation, fever, and antimicrobial substances produced
by the body.

© 2013 Pearson Education, Inc.

The Concept of Immunity
 Adaptive immunity is based on a specific response to a
specific microbe once a microbe has breached the
innate immunity defenses.
 It adapts or adjusts to handle a particular microbe.
 Slower to respond, but it does have a memory
component
 Involves lymphocytes (a type of white blood cell) called
T cells (T lymphocytes) and B cells (B lymphocytes)

© 2013 Pearson Education, Inc.

 Adaptive (Acquired) Immunity
Humoral (formation of antibodies)
Humoral immunity is so named because it involves substances
found in the humours, or body fluids (B lymphocytes (produced
in bone marrow)- cells belong to a group of white blood cells
 known as lymphocytes, which produce the antibodies that
circulate in the body fluids.)
The function of antibodies is to bind the specific antigens (or
immunogens - the foreign substance, usually protein that are
responsible for antibodies production ) and to inactivate and
destroy them

Cell-mediated is an immune response that does not involve 

antibodies but rather involves the activation of antigen-specific 
cytotoxic T-lymphocytes (T cells-produced in thymus) or T
lymphocytes are a type of lymphocyte (itself a type of 
white blood cell) that play a central role in cell-mediated immunity)
© 2013 Pearson Education, Inc.
An overview of the body’s defenses

Innate Immunity is native or natural. It is inborn and provides the

body with the ability to resist many pathological conditions.
The mechanisms responsible for this native immunity include
natural barriers: Mechanical barriers Chemical and Molecular
Microbial bariers

First line of defense Second line of defense Third line of defense

• Phagocytes, such as neutrophils, • Specialized lymphocytes:

• Intact skin
eosinophils, dendritic cells, and T cells and B cells
• Mucous membranes
macrophages • Antibodies
and their secretions
• Inflammation
• Normal microbiota
• Fever
• Antimicrobial substances

Response is antigen-independent
There is immediate maximal response
Not antigen-specific
Exposure results in no immunologic memory
© 2013 Pearson Education, Inc.
 The Concept of Immunity
 Innate immune system responses are activated by protein receptors
in the plasma membranes of defensive cells
 Toll-like receptors (TLRs) attach to various components commonly
found on pathogens that are called pathogen associated molecular
patterns (PAMPs), including:
- lipopolysaccharide (LPS) of the outer membrane of gram-negative
bacteria
- flagellin in the flagella of motile bacteria
- peptidoglycan in the cell wall of gram-positive
bacteria
- DNA of bacteria, DNA and RNA of viruses
- components of fungi and parasites
 TLRs induce cytokines that regulate the intensity and duration of
immune responses

© 2013 Pearson Education, Inc.

© 2013 Pearson Education, Inc.
 First line defense: Physical Factors/Bariers
 Skin- human body's largest organ in
Top layers
terms of surface area and weight of epidermis
 Consists of two distinct portions: with keratin
- dermis, the skin's inner, thicker portion, is

Epidermis
composed of connective tissue.
- epidermis, the outer, thinner portion, is in
direct contact with the external environment.
 Epidermis consists of many layers of
continuous sheets of tightly packed Dermis
epithelial cells with little or no material
between the cells.
- top layer of epidermal cells is dead
and contains a protective protein called
keratin.

© 2013 Pearson Education, Inc.

 First line defense: Physical Factors
Skin
 Intact skin provides a powerful barrier to the
entrance of microorganisms
Microorganisms rarely, if ever, penetrate the
intact surface of healthy epidermis
 When the epithelial surface is broken, a
subcutaneous infection often develops
- bacteria normally inhabiting the epidermis
( e.g. staphylococci) cause infection at the hair
follicles, and sweat and oil glands of the skin.
 Skin infections and underlying tissues
frequently result from burns, cuts, stab
wounds, or other conditions that break the skin.

© 2013 Pearson Education, Inc.

 First line defense: Physical Factors
 Periodic shedding of skin’s top layer
helps remove microbes at the surface.
 Dryness of the skin-a major factor in
Dead cells filled
inhibiting microbial growth on the
with keratin
skin.
 Normal microbiota and other
microbes are present on the entire skin,
they are most numerous on moist
areas of the skin.
 When the skin is moist (in hot, humid
climates) skin infections are quite
common, especially fungal infections
(fungi hydrolyze keratin when water
is available).

© 2013 Pearson Education, Inc.

 Physical Factors Mucous membranes
 Mucous membranes - important component of the first
line of defense
- consist of an epithelial layer and an underlying connective
tissue layer
- Mucous membranes line the entire gastrointestinal,
respiratory, and genitourinary tracts
 Epithelial layer (goblet cells) secretes fluid mucus -
a viscous glycoprotein that prevents the tracts from drying out
and traps microbes out
 Some pathogens thrive on the
moist secretions of mucous
membrane and are able to
penetrate the membrane ( e.g.
Treponema pallidum) .
- penetration may be facilitated by
microbe’s toxic substances
© 2013 Pearson Education, Inc.
FIRST LINE OF DEFENSE: MUCOUS MEMBRANES
Protective mechanisms in the eye
- Eye conjuctiva: Goblet cells within the conjunctival epithelium are
specialized cells that secrete mucins onto the surface of the eye.
- lacrimal apparatus, a group of structures (lacrimal glands and
tubes) that manufactures and drains away tears
- The tears are spread over the surface of the eyeball by blinking.
Normally, the

tears evaporate or pass into the nose

as fast as they are produced.
- Continual washing action helps keep microorganisms from settling on
the surface of the eye
- If an irritating substance or large numbers of microorganisms come in
contact with the eye, the lacrimal glands start to secrete heavily, and the tears
accumulate more rapidly than they can be carried away. This excessive
production is a protective mechanism because the excess tears dilute and
wash away the irritating substance or microorganisms
© 2013 Pearson Education, Inc.
FIRST LINE OF DEFENSE:MUCOUS MEMBRANES
Respiratory and Digestive system have many physical
forms of defense
 Mucus, produced by mucous membranes, traps many of
entering microorganisms
 Saliva, produced by the salivary glands, dilutes the numbers of
microorganisms and wash them from surface of the teeth and
the mucous membrane of the mouth.
 Movement of tongue also removes microbes from the surface
of teeth. This prevents colonization by microbes.
 Nasal mucous membrane also has mucus-coated hairs that
filter inhaled air and trap microorganisms, dust, and pollutants.

© 2013 Pearson Education, Inc.

 FIRST LINE OF DEFENSE: MUCOUS MEMBRANES
 Ciliary escalator: transports microbes trapped in mucus away from
the Lower Respiratory tract ( e.g. Lungs)
- Cilia covering cells of mucous membrane are moving synchronously
(at a rate of 1 to 3 cm /hr), propel inhaled dust and microorganisms that
have become trapped in mucus upward toward the throat
- coughing and sneezing speed up the escalator.

Toxic substances in cigarette smoke can seriously

impair the functioning of the ciliary escalator
Ciliary escalator mechanism is inhibited in
mechanically ventilated patients thus this
patients are vulnerable to respiratory tract
infections
The small lid of cartilage (epiglottis) which covers
the larynx during swallowing also prevents entering
microbes in Inc.the lower respiratory tract
© 2013 Pearson Education,
Ciliary escalator:

© 2013 Pearson Education, Inc.

 Physical Factors
 The external ear canal contains hairs and earwax (cerumen),
which help prevent microbes, dust, insects, and water from
entering the ear
 Movement of tongue removes microbes from the
teeth
Urine: flows out and cleans urethra - prevents
microbial colonization in the genitourinary tract.
- urinary catheters alter urine flow - urinary tract
infections may develop.
 Vaginal secretions: flow out move microorganisms out
of the female body.
 Peristalsis, defecation, and vomiting also expel
microbes.
 In response to microbial toxins, the muscles of the
gastrointestinal tract contract vigorously, resulting in
vomiting and/or diarrhea, which may also rid the body
of microbes.
© 2013 Pearson Education, Inc.
 First line of defense: Chemical factors
 Perspiration produced by sweat glands
help
- to maintain body temperature
- eliminate certain wastes
- flush microorganisms from the skin surface
- contains enzyme lysozyme
 Lysozyme breaks down cell walls
of gram-positive bacteria and, to a
lesser extent, gram negative bacteria
- breaks chemical bonds on
peptidoglycan,
- found in tears, saliva, nasal
secretions, tissue fluids, and urine,
where it exhibits its antimicrobial activity.
© 2013 Pearson Education, Inc.
First line of defense: Chemical Factors
 Sebaceous (oil) glands of the skin produce an oily
substance - Sebum
- Forms a protective film over the skin surface
- Prevents hair from drying and becoming brittle.
- Contains Bacteristatic and Fungistatic fatty acids One
of the components of sebum is unsaturated fatty acids, which
inhibit the growth of certain pathogenic bacteria and fungi.
- Low pH (3–5) of the skin ( low pH is caused in part by the
secretion of fatty acids and lactic acid).
 Certain bacteria commonly found on the skin
metabolize sebum, and this metabolism forms free fatty
acids causing the inflammatory response associated with
acne

© 2013 Pearson Education, Inc.

 First line of defense: Chemical factors
 Earwax, besides serving as a physical barrier,
also functions as a chemical protectant.
- The secretions are rich in fatty acids, giving the ear
canal a low pH, between 3 and 5, which inhibits the
growth of many pathogenic microbes.
- Earwax also contains many dead cells from the
lining of the ear canal.
 Saliva contains not only an enzyme salivary amylase that
- digests starch, but also a number of substances that inhibit
microbial growth. These include lysozyme, urea, and uric
acid.
Saliva also contains an antibody (immunoglobulin A) that
prevents attachment of microbes so that they cannot
penetrate mucous membranes.

© 2013 Pearson Education, Inc.

 First line of defence: Chemical Factors
 Gastric juice, produced by stomach glands, is
a mixture of hydrochloric acid, enzymes, urea
and mucus.
 Very high acidity of gastric juice (pH 1.2-3.0) is
sufficient to destroy bacteria and most
bacterial toxins
- exception are toxins of Clostridillm botullinum
and Staphylococcus aureus .
.
 Many enteric pathogens are protected by food particles
and can enter the intestines via the gastrointestinal tract
 In contrast, Helicobacter pylori neutralizes stomach acid,
thereby allowing the bacterium to grow in the stomach. Its
growth initiates an immune response that results in gastritis
and ulcers.
© 2013 Pearson Education, Inc.
 Chemical Factors
 Vaginal secretions play a role in antibacterial activity in
two ways:
- Glycogen in the vaginal epithelial cells is broken
down into lactic acid by Lactobacillus acidophilils
causing reduction in pH (3-5) - inhibiting microbes
- Cervical mucus - fluid or gel-like discharge from the
cervix also has antimicrobial activity

 Urine inhibits microbes because:

- contains lysozyme
- has an acid pH
- contains urea and hippuric acid
© 2013 Pearson Education, Inc.
 Normal Microbiota and Innate Immunity
 Microbial antagonism/competitive exclusion:
Normal microbiota prevents colonization with
pathogens
- competing with them for nutrients (competitive
exclusion),
- producing harmful substances ( e.g. E.coli –
bacteriocins that inhibit the growth of Salmonella and
Shigella)
- altering conditions/environment ( e.g. pH and
oxygen availability) The presence of normal
microbiota in the vagina, for example, alters pH, thus
preventing overpopulation by Candida albicans, a
pathogenic yeast that causes vaginitis
© 2013 Pearson Education, Inc.
 SECOND LINE OF DEFENSE
When microbes penetrate the first line of
defense, they encounter a second line of
defense
- defensive cells (such as phagocytic cells)
- inflammation
- fever
- antimicrobial substances (AMP’s; INF; Iron-
binding Proteins; Complement system)

© 2013 Pearson Education, Inc.

Formed Elements in Blood
 Blood consists of fluid, called plasma, and
formed elements--cells and cell fragments
suspended in plasma

© 2013 Pearson Education, Inc.

Formed Elements in Blood
 Leukocytes (white blood cells) are divided into two main categories ( by light
microscopy)
A.Granulocytes - presence of large granules in the cytoplasm (seen after staining in the
light microscope). Differentiated into three types of cells:
1. Neutrophils, 2. Eosinophils and 3. Basophils
B. Agranulocytes also have granules in their cytoplasm, but the granules are not visible
under the light microscope
1. Monocytes, 2. Dendritic cells and
3. Lymphocytes (NK, T-cells and B-cells)

© 2013 Pearson Education, Inc.

Formed Elements in Blood
I. Erythrocytes (Red Blood Cells)
4.8–5.4 million per mm3
Function: Transport of O2 and
CO2

2. Leukocytes (white blood cells)

Neutrophils (PMNs- polymorphonuclear neutrophils,
because of the varying shapes of the nucleus)
(60–70% of leukocytes)
Function: Phagocytosis
Eosinophils (2–4%)
Functions: Production of
toxic proteins against certain
parasites;
Basophils (0.5–1%)
Function: Production
of histamine
© 2013 Pearson Education, Inc.
 Formed Elements in Blood
Granulocytes
 Neutrophils or polymorphonuclear leukocytes
(PMNs) with granules stained pale lilac with a
mixture of acidic and basic dyes. Their nuclei
contain 2-5 lobes (segments)
- highly phagocytic and motile
- active in the initial stages of an infection
- have the ability to leave the blood, enter an
infected tissue, and destroy microbes and foreign
particles
 Basophils stain blue-purple with methylene blue
- release substances ( histamine)
- important in inflammation and allergic responses.
© 2013 Pearson Education, Inc.
 Formed Elements in Blood
Granulocytes
 Eosinophils stain red or orange with eosin
(acidic dye)
- Eosinophils are somewhat phagocytic, have
the ability to leave the blood.
- major function is to produce toxic proteins
against certain parasites, such as helminths
- too small size to ingest and destroy helminths,
can attach to the outer surface of the parasites
and discharge peroxide ions to destroy them
 Number of eosinophils increases significantly
during parasitic worm infections and
hypersensitivity (allergy) reactions.
© 2013 Pearson Education, Inc.
 Formed Elements in Blood: Agranulocytes
Monocytes (3–8%)
Three different types
Macrophages
monocytes Function:
dendritic cells Phagocytosis
(when they mature
lymphocytes into macrophages)

1. Monocytes are the biggest type of white blood cell in the

immune system.
- Originally formed in the bone marrow
- are not actively phagocytic until they leave circulating
blood, enter body tissues, and mature into macrophages.
 Macrophages (the largest phagocytic cells) are
monocytes that have migrated from the bloodstream into any
tissue in the body. Here they aid in phagocytosis to eliminate
harmful materials such as foreign substances. Macrophages
also dispose of worn out (old) blood cells.
© 2013 Pearson Education, Inc.
Phagocytes
Actions of Phagocytic Cells
 Free (wandering) macrophages, which roam the tissues and
gather at sites of infection or inflammation
 Fixed macrophages, or hystiocytes are resident in
certain tissues and organs of the body, found in:
- macrophages in liver (Kupffer's cells),
- macrophages in lungs (alveolar macrophages),
- macrophages in nervous system (microglial cells),
- Bronchial tubes,
- spleen (splenic macrophages),
- lymph nodes,
- peritoneal cavity surrounding abdominal organs
(peritoneal macrophages).
© 2013 Pearson Education, Inc.
 Formed Elements in Blood: Agranulocytes
2. Dendritic cells (resemble the dendrites of
nerve cells), are believed to be derived from Dendritic cells
monocytes.
 Dendritic cells are especially abundant in
the
- epidermis of the skin
- mucous membranes
Functions:
- the thymus
Derived from
- lymph nodes monocytes;
 The function of dendritic cells: phagocytosis and
initiation of adaptive
- destroy microbes by phagocytosis immune responses
- to initiate adaptive immunity responses

© 2013 Pearson Education, Inc.

 Formed Elements in Blood: Agranulocytes
3. Lymphocytes include Natural killer cells
- natural killer cells (non phagocytic cells) (NK)
- T cells and B cells
 Natural killer (NK) cells are cytotoxic cells found in
blood and in the spleen, lymph nodes, and red bone marrow.
- have the ability to kill a wide variety of infected body cells
and certain tumor cells. Function:
- play a role in defense of against intra- and extracellular Destroy target
pathogenes cells by
- attack any body cells that display abnormal or unusual cytolysis and
plasma membrane proteins Apoptosis
-  small granules in their cytoplasm contain special proteins
such as perforin and proteases known as granzymes. https://www.
Binding of NK cells to a target cell causes release of youtube.co
vesicles containing this toxic substances m/watch?v=
W2q7WNrq
7FU
© 2013 Pearson Education, Inc.
 Formed Elements in Blood: Agranulocytes
Cytolysis: Some granules of NK contain a protein called
perforin creates channels (perforations) in the membrane of
target cell
- fluid flows into the target cell and the cell bursts (osmolyses)
Apoptpsos: Other granules of NK cells release granzymes,
which are protein-digesting enzymes-proteases that induce
the target cell to undergo apoptosis, or selfdestruction.
- Apoptosis leads to destruction of infected cells and the viruses
inside of cell, but this type of attack does not kill other microbes
inside the cells;
- the released microbes, which may or may not be intact, can be
destroyed by phagocytesc
NK cells are indirectly involved in elimination of extracellular
pathogens: secrete gama-inteferon – macrophage activation
factor (as a result macrophage becomes more activated in
phagocytosis of extracellular pathogens)
© 2013 Pearson Education, Inc.
Formed Elements in Blood: Agranulocytes
 T cells and B cells are not usually phagocytic but play a
key role in adaptive immunity
- occur in lymphoid tissues of the lymphatic system
and also circulate in blood

T cells B cells
Function: Cell-mediated Function: Descendants
immunity (discussed in of B cells (plasma cells)
Chapter 17) produce antibodies
© 2013 Pearson Education, Inc.
Formed Elements in Blood
 Leikocytosis – an increase in total number of white
blood cells during infections, especially bacterial
infections, as a protective response to combat the
microbes;
- leukocyte count might double, triple, or quadruple,
depending on the severity of the infection (e.g.
during meningitis, infectious mononucleosis, appendicitis,
pneumococcal pneumonia, gonorrhea).
 Leikopenia - a decrease in the leukocyte count, might
be caused by some bacterial (Salmonellosis and
Brucellosis), and mostly by Viral and Rickettsial
infections.

© 2013 Pearson Education, Inc.

Differential White Blood Cell Count
Differential white blood cell count: a
calculation of the percentage of each kind of
white cell in a sample of 100 white blood
cells (percentage)
Percentage of each type of white cell in a sample of 100
white blood cells

Neutrophils 60–70%
Basophils 0.5–1%

Eosinophils 2–4%

Monocytes 3–8%

Lymphocytes 20–25%
© 2013 Pearson Education, Inc.
 Lymphatic system
The lymphatic system is a network of tissues and organs that
help rid the body of toxins, waste and other unwanted
materials.
The primary function of the lymphatic system is to
transport lymph, a fluid containing white blood cells,
throughout the body
 Lymphatic system consists of :
- a fluid (lymph),
- vessels (lymphatic vessels),
- a number of structures and organs containing lymphoid
tissue
- red bone marrow ( where stem cells develop
into blood cells, including lymphocytes)
 Lymphoid tissue contains large numbers of lymphocytes,
including T cells, B cells, and phagocytic cells
© 2013 Pearson Education, Inc.
Lymphatic system
 Lymphoid tissues and organs are scattered throughout
the mucous membranes that line the gastrointestinal,
respiratory, urinary, and reproductive tracts.
- protect against microbes that are ingested or inhaled
 Multiple large aggregations of lymphoid tissues are
located in specific parts of the body (tonsils in the throat
and Peyer's patches in the small intestine)
 Spleen contains lymphocytes and macrophages
- monitor the blood for microbes and secreted toxins
 Lymph nodes monitor lymph
 Thymus - site for T cell maturation. It also contains
dendritic cells and macrophages.

© 2013 Pearson Education, Inc.

© 2013 Pearson Education, Inc.
 Phagocytes
Phago: from Greek, meaning eat; Cyte: from Greek, meaning
cell
Phagocytosis- ingestion of a microorganism or other
substances (such as debris) by a cell ( phagocyte)
Actions of Phagocytic Cells
When an infection occurs, both granulocytes
(especially neutrophils) and agranulocytes
-monocytes migrate to the infected area.

- During this migration monocytes enlarge and develop into

actively phagocytic macrophages, leave the blood and
migrate into tissues
.
© 2013 Pearson Education, Inc.
Four main Phases of Phagocytosis : chemotaxis,
adherence,ingestion, and digestion 3.Ingestion A phagocytic
macrophage uses a
pseudopod to engulf a.formation of
1. Chemotaxis is the Pseudopods nearby bacteria.

pseudopods that
chemical attraction of Phagocyte engulf the
phagocytes to
microorganism
microorganisms.
b. surrounding the
Cytoplasm 3 Formation of phagosome
1 CHEMOTAXIS (phagocytic vesicle)
2 INGESTION
microorganism
and
2. adherence is ADHERENCE
of phagocyte to
of microbe by phagocyte

the attachment
microbe
4 Fusion of phagosome with a sac called a
with a lysosome

of the
Microbe
or other
particle
Lysosome
to form a phagolysosome
phagosome, or
phagocyte’s phagocytic
plasma Details of
adherence
PAMP
(peptidoglycan
Digestive 5 DIGESTION
of ingested
vesicle
in cell wall) enzymes
microbes by
membrane to the Partially
digested
enzymes in the
phagolysosome
microbe
surface of the Indigestible
material
microorganism TLR 6 Formation of
Attachment of (Toll-like receptor)
Plasma membrane
the residual body
containing

PAMP’s of
indigestible
material 4. Digestion
microbe to TLR the phagosome
on the surface of 7 DISCHARGE of
pinches off from
phagocyte waste materials
the plasma
membrane and
enters the
© 2013 Pearson Education, Inc. cytoplasm.
Phagocytosis
 Neutrophils
 During the course of an infection,
granulocytes,especially neutrophils,
dominate in the initial phase of
bacterial infection, at which time they
are actively phagocytic; this
dominance is indicated by their
increased number

However, as the infection progresses, the

macrophages dominate; they scavenge and phagocytize
remaining living bacteria and dead or dying bacteria.
The increased number of monocytes (which develop
into macrophages) is also reflected in a differential white
blood cell count.
© 2013 Pearson Education, Inc.
 Microbial Evasion of Phagocytosis

Inhibit adherence: Streptococcus pyogenes,

M protein, capsules S. pneumoniae
Kill phagocytes: Leukocidins Staphylococcus aureus

Lyse phagocytes: Listeria monocytogenes

Membrane attack complex
(MAC)
Escape phagosome Shigella, Rickettsia

Prevent phagosome– HIV, Mycobacterium tuberculosis

lysosome fusion
Survive in phagolysosome Coxiella burnettii

© 2013 Pearson Education, Inc.

Second line of defense: Inflammation
Damage to the body’s tissues triggers a local
defensive response called inflammation
Four signs and symptoms of Inflammation
-Redness
-Swelling (edema)
-Pain
-Heat
 If the cause of an inflammation is removed in a relatively
short period of time, the inflammatory response is intense
and is referred to as an acute inflammation.
 If the cause of an inflammation is difficult or impossible to
remove, the inflammatory response is longer lasting but less
intense and is referred to as a chronic inflammation. An
example is the response to a chronic infection such as
tuberculosis, caused by M. tuberculosis.
© 2013 Pearson Education, Inc.
Second line of defense: Inflammation
Inflammation has the following functions:
(1)to destroy the injurious agent, if possible, and to
remove from the body;
(2)if destruction is not possible, to limit the effects on
the body by confining or walling off the injurious agent
(3)to repair or replace tissue damaged by the injurious
agent

During the early stages of inflammation:

- microbial structures (bacterial flagellin, LPS, DNA)
stimulate the Toll-like receptors of macrophages to
produce cytokines, such as tumor necrosis factor
alpha (TNF-α).
© 2013 Pearson Education, Inc.
Second line of defense: Inflammation
-In response to TNF-α in the blood, the liver synthesizes
a group of proteins called acute-phase proteins;

- other acute-phase proteins are in the blood in an

inactive form and are activated during inflammation.

-Acute-phase proteins induce both local and systemic

responses.
-Include proteins such as C-reactive protein, mannose-
binding lectin, fibrinogen for blood clotting and kinins,
histamine, prostaglandins, leukotrienes for
vasodilation.
*Vasodilation is the increase in the interior diameter of
blood vessels ( widening of blood vessels)
© 2013 Pearson Education, Inc.
Chemicals Released by Damaged Cells
Histamine Vasodilation*, increased permeability
of blood vessels
Kinins Vasodilation, increased permeability
of blood vessels, chemotaxis
Prostaglandins Intensify histamine and kinin effect, help
phagocytes move through capillary walls.
Leukotrienes Vasodilation*, Increased permeability of
blood vessels, help attach phagocytes to
pathogens
All of the cells involved in inflammation have receptors for
TNF-α and are activated by it to produce more of their own
TNF-α. This amplifies the inflammatory response.

excessive production of TNF-α may lead to disorders

such as rheumatoid arthritis and Crohn’s disease.
© 2013 Pearson Education, Inc.

Three stages of Inflammation
1. vasodilation and
increased permeability of
blood vessels
2. phagocyte migration
and phagocytosis
3. tissue repair
- blood vessels increase
in diameter
- Increased
permeability permits
defensive substances
to pass through the
walls of the
blood vessels and enter
the injured area
- Vasodilation and
increased
permeability of blood
vessels
are caused by a number of
chemicals released by
damaged cells in response
©to injury.
2013 Pearson Education, Inc.
The process of inflammation
Bacteria entering
on knife
Bacteria
Epidermis
Blood vessel
Dermis
Nerve
Subcutaneous
tissue
(a) Tissue damage (1) Vasodilation and increased
permeability of blood vessels
1 Chemicals such as histamine, kinins,
prostaglandins, leukotrienes, and
cytokines (represented as blue
dots) are released by
damaged cells.
2 Blood clot forms.
3 Abscess starts to form
(orange area).
Figure 16.8c The process of inflammation.
Blood vessel
endothelium
Monocyte
4 Margination—
phagocytes stick
to endothelium.

5 Diapedesis
—phagocytes Insert Fig 16.8c
squeeze
between
endothelial cells.

6 Phagocytosis of
invading bacteria occurs.
Red
Macrophage blood
cell
(2) Phagocyte migration and
phagocytosis Bacterium Neutrophil
© 2013 Pearson Education, Inc.
Figure 16.8d The process of inflammation.

Scab

Blood clot
Regenerated
epidermis
(parenchyma)

Insert Fig 16.8d

Regenerated
dermis
(stroma)

(3) Tissue repair

© 2013 Pearson Education, Inc.

Second line of defense: Fever
 Systemic response
 Abnormally high body temperature
 Hypothalamus (sometimes called the body’s thermostatis) normally
set at 37°C
 Gram-negative endotoxins cause phagocytes to release the
cytokines interleukin-1 (IL-1) along with TNF-α
 These cytokines cause the hypothalamus to release prostaglandins
that reset the hypothalamic thermostat at a higher temperature,
thereby causing fever a high temperature
 To adjust to the new thermostat setting, the body responds by
constricting blood vessels, increasing the rate of metabolism, all
of which raise body temperature.
 Even though body temperature is climbing higher than normal, the skin
remains cold, and shivering occurs. This condition, called a chill

© 2013 Pearson Education, Inc.

Second line of defense: Fever
 When body temperature reaches the setting of the
thermostat, the chill disappears.
 The body will continue to maintain its temperature at 39°C
until the cytokines are eliminated.
 Vasodilation and sweating: body temperature falls
(crisis)
Fever is considered a defense against disease.
- Interleukin-1 helps step up the production of T cells.
- High body temperature intensifies the effect of antiviral
interferons and increases production of transferrins that
decrease the iron available to microbes.
- Because the high temperature speeds up the
body’s reactions, it may help body tissues repair
themselves more quickly.
© 2013 Pearson Education, Inc.
Antimicrobila Substances: The Complement System
 The complement system is a defensive system consisting of
over 30 proteins produced by the liver and found circulating in
blood serum and within tissues throughout the body
 The complement system is so-named because it
“complements” the cells of the immune system in
destroying microbes.
 proteins of the complement system destroy microbes by
(1)cytolysis, (2) inflammation, and (3) phagocytosis
Complement proteins are usually designated by an uppercase
letter C and are inactive until they are split into fragments
(products).
 The proteins are numbered C1 through C9, named for the order
their discovery
 The fragments are activated proteins and are indicated
by the lowercase letters a and b. For example, inactive complement
protein C3 is split into two activated fragments, C3a and
C3b.
© 2013 Pearson Education, Inc.
Outcomes of Complement Activation.
C3 1. Inactivated C3 splits into activated C3a and C3b.

C3b C3a 2. C3b binds to microbe, resulting in opsonization.

C3b
proteins 5. C3a and C5a cause
mast cells to release histamine, and other
3. C3b also splits C5 chemicals that increase blood vessel permeability
into C5a and C5b resulting in inflammation; C5a also attracts
phagocytes.
opsonization C5

Enhancement of phagocytosis C5a

C5a receptor
Histamine
by coating with C3b C5b C5a

4. C5b, C6, C7, and C8 bind

together sequentially and Insert Fig 16.9
C6
Mast cell
C3a receptor C3a
insert into the microbial
plasma membrane, where
C7
C8
inflammation
they function as a receptor Increase of blood vessel
to attract a C9 fragment; permeability and chemotactic
additional C9 fragments are C9
attraction of phagocytes
added to form a channel.
Together, C5b through Microbial

C8 and the multiple C9 plasma

membrane C5a also functions
fragments form the C6
Channel
C6
C5b as a very powerful
membrane attack C7 C5b
C8 C9
C7
C8
C9 chemotactic factor
complex, (MAC) resulting
in cytolysis- the bursting of
Formation of membrane
attack complex (MAC)
Cytolysis
that attracts
the microbial cell due to the phagocytes to the
inflow of extracellular fluid
through the channels cytolysis site of an infection.
Bursting of microbe due to inflow of extracellular fluid through
© 2013 Pearson
Pearson Education,
Education,Inc.
Inc. transmembrane channel formed by membrane attack complex
Inflammation stimulated by complement.

A mast cell is a migrant cell of connective tissue that contains

many granules rich in histamine and heparin.
it is a type of granulocyte derived from the bone very similar in both
appearance and function to the basophil
Histamine increases the permeability of the capillaries to white blood cells and some proteins, to
allow them to engage pathogens in the infected tissues

C5a C5a receptor Histamine Phagocytes C5a attracts

Neutrophil phagocytes to
the site of an
Histamine- infection
containing
granule

Insert Fig 16.11

Histamine-
releasing C3a C5a Macrophage
mast cell
C3a receptor

(a) C3a and C5a bound to mast cells, basophils, and platelets trigger the release of histamine,
which increases blood vessel permeability. (b) C5a functions as a chemotactic factor that attracts
© 2013 Pearson Education, Inc.
phagocytes to the site of complement activation.
 Effects of Complement Activation
Cytolysis caused by complement
 Bacteria that are not killed
by the MAC are said to be
MAC resistant
 Gram-negative bacteria
are more susceptible to
cytolysis because they
have only few layers of
peptidoglycan
The many layers of peptidoglycan of gram-positive
bacteria limit access of complement to the plasma membrane
and thus interfere with cytolysis

The cascade of complement proteins that occurs during an

infection is called complement activation and may occur in
three pathways.
© 2013 Pearson Education, Inc.
1. Classical pathway of complement activation
Microbe
Antigen
 Antibodies attach to
C1 is activated
antigens (proteins or large by binding to
antigen–antibody
polysaccharides on the surface of a complexes.
Antibody

bacterium or other cell), forming

C1
antigen–antibody
complexes. The antigen–
antibody complexes bind Activated C1
splits
C2 C4

and activate C1. Insert

C2 into C2a
C2b, and C4
and Fig 16.12

 activated C1activates C2 and into

C4a and C4b.
C2b
C2a C4b C4a

C4 by splitting them.
 C2a and C4b combine and
C3
together they activate C3 by C2a and C4b
combine and

splitting it into C3a and C3b. activate C3,

splitting it into C3a
 The C3 fragments then initiate and C3b
Opsonization
C3b C3a
Inflammation
cytolysis, inflammation, and
opsonization Cytolysis (by MAC)
© 2013 Pearson Education, Inc.
2. Alternative pathway of complement activation.

- the alternative pathway does not

involve antibodies
- Is activated by contact between
certain complement proteins and a
pathogen
- C3 is constantly present in
the blood. It combines with complement
proteins called factor B, D, and P
(properdin) on the surface of a
pathogenic microbe. The complement
proteins are attracted to microbial cell

Opsonization
surface material (mostly lipid–
carbohydrate complexes of certain
bacteria and fungi
- Once the complement proteins combine
and interact, C3 splits into C3a and C3b. As in the classical
pathway, C3a participates in inflammation, and C3b
functions in cytolysis and opsonization
© 2013 Pearson Education, Inc.
3. The lectin pathway of complement activation.

- When macrophages ingest Microbe

pathogens by phagocytosis, they Carbohydrate
containing
release cytokines that stimulate the mannose
Lectin
liver to produce lectins, proteins that Lectin binds to
an invading cell.
bind to carbohydrates
- One such lectin, mannose-binding lectin C2 C4
Bound lectin
splits C2 into
(MBL), binds to the carbohydrate C2b and C2a
and C4 into
mannose. MBL binds to many pathogens C4b and C4a.

because the MBL molecules recognize C2b

C2a C4b
C4a

a distinctive pattern of carbohydrates that C2a and C4b

includes mannose, which is found in combine
and activate C3
bacterial cell walls and on some viruses. C3

As a result of binding, MBL functions

Inflammation
Opsonization
as an opsonin to enhance
phagocytosis and activates C2 and C4 C3b C3a

- Bound lectin splits C2 into C2b and C2a

and C4 into C4b and C4a
Cytolysis
C2 a and C 4b combine and activate C3
5 7 8 9
© 2013 Pearson Education, Inc.
 Interferons (IFNs)
Because viruses are intracellular parasites, it is difficult to inhibit
viral multiplication without affecting the host cell itself.
One way the infected host counters viral infections is with a family of
cytokines called interferons, class of antiviral proteins produced by
certain animal cells – lymphocytes and macrophages, after viral
stimulation.
Three types of Human Interferon (INF)
Are produced by fibroblasts in connective tissue and by lymphocytes and other leukocytes
Stabile at low pH and resistant to the heat
IFN- and IFN-:
-are produced by virus-infected host cells only in very small quantities and diffuse to uninfected cells causing
the cells to produce antiviral proteins that inhibit viral replication
IFN-:
- is produced by lymphocytes; it induces neutrophils and macrophages to kill (phagocytize) bacteria.

© 2013 Pearson Education, Inc.

Antiviral action of alpha and beta interferons (IFNs).
1 Viral RNA from
an infecting virus 2 The infecting virus
enters the cell. 5 New viruses released by
replicates into the virus-infected host
Viral RNA
new viruses. cell infect neighboring
host cells.

3 The infecting virus

also induces the
Infecting
host cell to produce Viral RNA
virus Antiviral
interferon mRNA
Nucleus proteins
(IFN-mRNA), which
Translation (AVPs)
is translated into
alpha and beta
interferons. Insert Fig 16.15
Transcription Transcription
6 AVPs degrade
viral mRNA and
inhibit protein
IFN-mRNA synthesis—and
Translation thus interfere
4 Interferons released by the Alpha with viral
virus-infected host cell bind and beta replication.
to plasma membrane or interferons
nuclear membrane receptors
Virus-infected Neighboring host cell
on uninfected neighboring
host cells, inducing them to host cell
synthesize antiviral proteins
(AVPs). These include
oligoadenylate synthetase
and protein kinase.

Alpha interferon is approved in the USA for treating several virus-

associated disorders (Kaposi’s sarcoma, a cancer that often occurs in
patients infected with HIV, genital herpes; hepatitis B and C; malignant
melanoma; Crohn’s disease; rheumatoid arthritis;
© 2013 Pearson Education, Inc.
 Antimicrobial Substances: Interferons (IFNs)

Because of their beneficial properties, interferons would

seem to be ideal antiviral substances, but certain problems
do exist:
-are effective for only short periods; do not remain stable for
long periods of time in the body.
-when injected, interferons have side effects, (nausea,
fatigue, headache, vomiting, weight loss, and fever).
-high concentrations of interferons are toxic to the body
-they have no effect on viral multiplication in infected cells
-some viruses, such as adenoviruses have resistance
mechanisms that inhibit anti viral proteins (AVPs).
-some viruses such as the hepatitis B virus, do not induce the
production of sufficient amounts of interferon in host cells
following viral stimulation.
© 2013 Pearson Education, Inc.
Antimicrobial Substances: Iron-binding Proteins
 Iron-binding proteins—molecules such as transferrin,
lactoferrin, ferritin, hemoglobin— whose function is to transport
and store iron
 Transferrin is found in blood and tissue fluids, binds serum iron;
Lactoferrin is found in milk, saliva, and mucus. Ferritin is located
in the liver, spleen, and red bone marrow, hemoglobin is located
within red blood cells.
 The iron-binding proteins not only transport and store iron but also,
by doing so, deprive most pathogens of the available iron.
 Many pathogenic bacteria obtain iron by secreting proteins called
siderophores which compete to take away iron from iron-binding
proteins by binding it more tightly.
A few pathogens do not use the siderophore mechanism to obtain iron

© 2013 Pearson Education, Inc.

 Antimicrobial peptides
 Short peptides consisting of a chain of 12 - 50 amino acids synthesized on
ribosomes
 First discovered in the skin of frogs and human neutrophils
- To date 600 AMPs have been discovered in nearly all plants and animals.
 AMPs have a broad spectrum of antimicrobial activity against
bacteria, viruses, fungi, parasites;
 Synthesis of AMPs is triggered by protein and sugar molecules on the surface
of microbes. Cells produce AMPs when microbial chemicals attach to TLRs
 The modes of action of AMPs: - inhibiting cell wall synthesis;-forming
pores in the plasma membrane, resulting in lysis; -destroying DNA and RNA.

 Human AMP’s:
- dermcidin, produced by sweat glands;
- defensins produced by neutrophils, macrophages, and epithelium;
thrombocidin, produced by platelets.

© 2013 Pearson Education, Inc.

Increasing interest in AMPs for a number of
reasons:
- AMPs have shown synergy (working together)
with other antimicrobial agents

- AMPs are very stable over a wide range of pH

- Resistance to AMP’s doesn’t develop even

though the microbes are exposed to them for long
periods of time.

© 2013 Pearson Education, Inc.

Summary of innate immune defenses

© 2013 Pearson Education, Inc.

Summary of innate immune defenses

© 2013 Pearson Education, Inc.