Chapter 15

Innate Immunity

The Three Lines of Defense

Figure 15.1

First Line of Defense

Structures, chemicals, processes that

work to prevent pathogens entering
the body
Nonspecific defenses
Includes the skin and mucous
membranes of the respiratory,
digestive, urinary, and reproductive
systems

The Role of Skin

Two major layers
Epidermis
Outer layer composed of multiple layers of tightly packed cells
Few pathogens can penetrate these layers
Shedding of dead skin cells (1010 per day) removes attached
microorganisms

Epidermal dendritic cells

Also termed Langerhans cells (found in skin and mucous membranes)

Long, slender, multi-branched cells
Phagocytize pathogens
Not WBCs
Involved with innate and adaptive immunity

Dermis
Contains protein fibers called collagen
Give skin strength and pliability to resist abrasions that could introduce
microorganisms

EM of Skin Surface

Dust Mite

The Role of Skin

Perspiration secreted by sweat glands
Salt- inhibits growth of pathogen by
drawing water from their cells
Lysozyme- destroys cell wall of bacteria

Sebum secreted by sebaceous (oil)

glands
Helps keep skin pliable and less likely to
break or tear
Lowers the pH of the skin to a level
inhibitory to many bacteria
Many are also directly toxic to bacteria

Mucous Membranes

Line all body cavities open to the outside

environment
Comprises over 200 times more surface
area than the skin
Two distinct layers
Epithelium
Deeper connective layer that supports the
epithelium

Epithelium

Thin, outer covering of the mucous

membranes
Unlike skin surface epidermal cells,
these epithelial cells are living
Tightly packed to prevent entry of
pathogens
Continual shedding of cells carries
attached microorganisms away

The Ciliary Escalator

Microbial Antagonism
Normal microbiota help protect the body
by competing with potential pathogens
Various activities of the normal
microbiota make it hard for pathogens
to compete
Secrete antimicrobial substances that limit
pathogen growth
Consumption of nutrients makes them unavailable
to pathogens
Create an environment unfavorable to other
microorganisms by changing pH
Helps stimulate the bodys second line of defense

Other First-Line Defenses

Many body organs secrete chemicals with
antimicrobial properties
Lacrimal glands of the eye
Tears wash the eye and keep it moist
Lysozyme destroys bacteria

Saliva
Contains antibodies and lysozyme
Urine flow
Keeps bacteria out of the ureter
Stomach acid
Acidity kills most pathogens

Second Line of Defenses

Operates when pathogens succeed in

penetrating the skin or mucous membranes
Nonspecific defense
Composed of cells, antimicrobial chemicals,
and processes, but no physical barriers
Many of these components are contained
in or originate in the blood

Blood
Composed of cells and portions of cells within
a fluid called plasma
Plasma is mostly water containing
electrolytes, dissolved gases, nutrients, and
proteins
When the clotting factors (a group of plasma
proteins) are removed from plasma, the
remaining fluid is called serum
Other plasma proteins include complement
proteins and antibodies
The cells and cell fragments in plasma are
called formed elements

Plasma vs Serum:

Formed Elements
Three types of formed elements:
Erythrocytes- carry oxygen and carbon
dioxide in the blood (4.2-6.2x109/ml)
Platelets- involved in blood clotting and
inflammation (1.3-4x108/ml)
Leukocytes- involved in defending the body
against invaders (4.5-11x106/ml)
2 groups of leukocytes:
Granulocytes
Agranulocytes

Human Leukocytes
Granulocytes:
Neutrophils: 60-70% of circulating WBC
Multi-lobed nucleus
>1010 neutrophils made every day
Major phagocytes; cells of acute
inflammation
Eosinophils: 1-3% of circulating WBC
Bilobed nucleus; parasite defense; red
granules
Basophils: 0.5-1% of circulating WBC
Bilobed nucleus; contain histamine; blue
granules

Granulocytes

Neutrophil

Basophil

Eosinophil

Diapedesis

Figure 15.7

Agranulocytes
Cytoplasm appears uniform under a light
microscope
2 types
Lymphocytes: 20-40% of circulating WBC;
most involved in specific immunity
Monocytes: 1-6% of circulating WBC; leave
the blood and mature into macrophages

Lymphocyte

Monocyte

Macrophages
Phagocytic cells of the second line of defense
Monocytes leave the blood (via diapedesis),
enter tissue, and differentiate into
macrophages
Some become fixed in a particular tissue,
some remain free to wander and phagocytize
throughout the body
Fixed macrophages include microglial cells
(central nervous system), mesangial cells
(Kidney) and Kpffer cells (liver)
Wandering macrophages include alveolar
macs

Lab Analysis of Leukocytes

The differential white blood cell count test

can signal signs of disease
Increased eosinophils can indicate
allergies or parasitic worm infection
Bacterial diseases often show increase in
leukocytes, mostly neutrophils
Viral infections show increase in
lymphocytes

Components of the Second Line of

Defense

Phagocytosis
Extracellular (nonphagocytic) killing by
leukocytes
Nonspecific chemical defenses
Inflammation
Fever

Phagocytosis
Cells capable of phagocytosis (certain
leukocytes or their derivatives) are called
phagocytes
Phagocytosis is performed chiefly by
neutrophils (microphages) and
macrophages.
Can be divided into 5 stages

Fig.
Fig. 15-06
15-06

The Steps of
Phagocytosis:

Chemotaxis of
phagocyte
to microbes
Microbes

Adherence

Pseudopodia move
(chemotaxis)

Ingestion of microbes
by phagocytes

Fusion of a
series of vessicles,
including lysosomes

Phagosome

Killing of
microbes
by enzymes
and other
chemicals

Golgi body
Lysosome
Nucleus
Phagolysosome

Residual
body

Pseudopod

Phagocyte

Elimination
(exocytosis)

Host Cell Protection

The hosts cells are protected from
destruction by the phagocytes
Some phagocytes have receptors for
bacterial surface components, such as
flagellar proteins or cell wall components,
that are lacking on the bodys cells
Opsonins such as certain complement split
products and antibody provide a handle
for the phagocyte. Opsonins are
substances that enhance phagocytosis.

Extracellular (Nonphagocytic) Killing by

Leukocytes

3 Cell types that kill extracellularly:

Eosinophils
Mainly attack parasitic helminths (worms) by
attaching to their surface
Secrete protein toxins that weaken or kill helminth

Natural killer lymphocytes (NK cells)

Secrete toxic substances onto the surface of
virally-infected cells and tumor cells
Differentiate normal body cells by recognizing
type and no. of membrane proteins (MHC class I)

Neutrophils
Leak antimicrobials and trapping webs (NET for
neutrophil extracellular traps)
A form of apoptosis to kill microbes caught in NET

Nonspecific
Chemical Defenses
TLRs bind to
pathogenassociated
molecular
patterns (PAMPs).
NOD proteins are
intracellular
receptors for subcomponents of
bacterial
peptidoglycan.

Interferons
Protein molecules released by host cells
to nonspecifically inhibit the spread of
viral infections
Particularly effective against viruses with
RNA genomes
Cause many symptoms typically
associated with viral infections
3 Classes
Alpha
Beta
Gamma (also an important immune cytokine
in activating macrophages =MAF)

Interferons
Alpha and beta interferons are called type
1 interferons and are produced early in
the infection
Dendritic cells produce the most type 1
interferons
Gamma interferon appears later in the
course of infection

Table 15.3

Fig.
Fig. 15-07
15-07

Virus infects cell.

Virus

The Actions of Interferon

Doublestranded
RNA

IFN
gene
Nucleus
mRNA

Viral replication
in cell triggers
transcription
and translation
of or
interferon (IFN)
depending on
type of host
cell.

Meanwhile, the
infected cell dies
and releases
the virus.

IFN

Infected cell

Interferon receptor

Interferon is released,
diffuses to neighboring
uninfected cells, and
binds to receptors.

Infected cell
at a later time

When the second

cell becomes infected
with viruses, doublestranded RNA of the
virus activates AVP.

Inactive AVP
Binding triggers
transcription
and translation of
inactive antiviral
proteins (AVPs).

AVP
gene

Doublestranded
viral RNA
Active AVPs

Ribosome
mRNA

Uninfected
neighboring cell

mRNA
Inactive
AVPs

Same
neighboring
cell now protected
at the later time

Active AVPs degrade mRNA

and bind to ribosomes,
which stops protein
synthesis and viral
replication.

Interferon Therapy
It was thought that this might be a
good antiviral treatment
Many viral infections dont respond to
interferon therapy at all
Only a slight effect is seen with those
viral infections that do respond

Complement System
Set of serum proteins designated
numerically according to the order of their
discovery
Complement activation results in lysis of the
foreign cell
Complement can be activated in several
ways:
Classical Pathway
Alternate Pathway
Lectin Pathway

Fig.
Fig. 15-08
15-08

Classical pathway

Alternative pathway

Antigen

Mannose

C3b
Endotoxin and
glycoproteins

Antibody

C3b

Lectin pathway

Factors B,
D, and P

Complement
proteins
1, 2, 4
Complement cascade
Activation
Opsonization
(C3 C3a + C3b) Inflammation

C5 convertases
Inflammation
(C5 C5a + C5b)

Membrane attack
complex and cell lysis

Lectins

Figure 15.9 The classical pathway and complement cascade.

H2O
Membrane
attack
complex

H2O

Cytoplasmic
membrane

C9
C9

C9
C9

C9

H2O

C9
C9

C9
C9

C9
C8
Pathogen

Antigen
Antibody
1

C1 becomes
an active enzyme
when it binds to
antibody-antigen
complexes.

Enzymatic C1

C5a

C4
a

2 Enzyme C1
splits molecules
of C2 and of C4.
C2

C2a

C5
C2b

C4b
3 Fragments of C2
and C4 combine
to form a second
enzyme that
splits C3 into
C2a C4b
C3a and C3b.
Enzyme

4 C3b combines
with the remaining
fragments of C2
and C4 to form a
third enzyme.

C3a

C3
C3

2014 Pearson Education,

Inc.

5 This enzyme cleaves

C5 into C5a and C5b.

Enzyme

C4a
C4

C5b

C4b C2b C3b

C2b

C2

6 C5b combines with C6, C7, C8,

and several molecules of C9
to form a membrane attack
complex (MAC). A MAC drills a
circular hole in the pathogens
cytoplasmic membrane,
leading to lysis of the cell.

Causes
inflammation

C4b

C4

C7
C5b C6

Causes chemotaxis
of phagocytes
and triggers
inammation

C1

H2O

Causes chemotaxis
of phagocytes
and triggers
inammation

C3a

C3b

C3b

Acts as
opsonin

TEM of a Cell Damaged by Complement

Membrane Attack Complexes

The Classical Pathway

Various complement proteins act
nonspecifically to complement the action of
antibodies
Functions:
Induce inflammation (C3a, C5a)
Opsonization (C3b)
Chemotaxis of phagocytes (C3a, C5a)
Lysis of foreign cells (MAC mostly C9)

The Alternate (Properdin) Pathway

Activation independent of antibodies
Less efficient than the classical pathway
Useful in early stages of infection before
antibodies have been made
Initiated by interaction between properdin
factors B, D, and P and the endotoxins
and LPS from bacteria and fungi
Stabilizes molecules of C3b that are
normally in the blood in small quantities

The Lectin Pathway

Mannose-binding lectin (MBL) and other
serum proteins bind microbial surfaces
that contain mannose sugars
Mannose is found in fungi, bacteria, and
viruses
Rarely found in mammals
Lectins bound to mannose act to trigger
a complement cascade by cleaving C2
and C4 just like the classical pathway

Inflammation
Nonspecific response to tissue damage
resulting from various causes
Characterized by redness (rubor), heat (calor),
swelling (tumor), and pain (dolor)
Two types
Acute
Chronic

Acute Versus Chronic Inflammation

Acute inflammation
Develops quickly and is short lived
Is usually beneficial
Important in the second line of defense
Dilation and increased permeability of the
blood vessels
Migration of phagocytes
Tissue repair

Chronic inflammation
Develops slowly and lasts a long time
Can cause damage to tissues

Stimulation of Inflammation by C3a & C5a

The Events of Inflammation

Figure 15.19

The Events of Inflammation

Figure 15.19

Chemical Mediators of Inflammation

Fever
A body temperature over 37C
Results when chemicals called
pyrogens trigger the hypothalamus to
increase the bodys core temperature
Various types of pyrogens
Bacterial endotoxins
Cytoplasmic contents of bacteria released
by lysis
Antibody-antigen complexes
Interleukin-1 (IL-1)

Fever Production
IL-1 production causes the hypothalamus
to secrete prostaglandin which resets the
hypothalamic thermostat
Communication with the brain initiates
muscle contractions, increased metabolic
activity, and constriction of blood vessels
which raises the bodys temperature
Chills associated with fever are due to the
reduced blood flow of constricted vessels
Decrease in IL-1 production results in the
bodys temperature returning to normal

Fever in
Response to
Infection

Benefits of Fever
Enhances the effects of interferons
Inhibits growth of some
microorganisms
May enhance the performance of
phagocytes, cells of specific immunity,
and the process of tissue repair