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The Innate Immune
Response
Chapter 15
Overview of Innate Defenses
 First line of defense are
barriers that shield interior of
body from external
surroundings
 Anatomical barriers include
skin and mucous membranes


Provide physical separation
Membranes bathed in
antimicrobial secretions
Overview of Innate Defenses
 Sensor system signals when first line barriers
have been breached

Two important groups of receptors

Toll-like receptors and NOD proteins
 Cell membrane proteins that recognize and bind to
families of compounds unique to microbes
 nucleotide-oligomerization domains

Complement System
Overview of Innate Defenses
 Toll-like receptors and
NOD proteins



Found on variety of
cells
Recognize families of
compounds
Enables cells to sense
invasion
 Sends signal to body
to respond
Overview of Innate Defenses
 Complement System
 Acts in response to
stimuli
 Activation sets off
chain reaction that
results in destruction
or removal of
invader
Overview of Innate Defenses
 Phagocytes are specialized
cells that engulf and digest
microbes and cellular debris
 Act as sentries


Alerted to signs of invasion
Release cytokine chemicals
 More phagocytes can be
recruited from bloodstream

Attracted by chemical gradient
of the released cytokines

Phagocytosis movie
Overview of Innate Defenses
 Cells of the immune system have an elaborate
communication system
 Communication achieved through productions
of proteins

Proteins act as chemical messengers


Called cytokines
Cytokines from one cell diffuse to another

Bind to cytokine receptor on cell
 Receptor transmits signal to cell interior
 Induces changes in cellular activities
Overview of Innate Defenses
 Inflammation is initiated by microbial invasion
or tissue damage
 During inflammation cells in blood vessels
undergo changes that allow certain immune
particles to leak out of the blood
First Line of Defense
 Physical barriers
 Skin is most visible barrier
 Covers majority of surfaces
in obvious contact with
environment
 Mucous membranes
barrier that lines digestive
tract, respiratory tract and
genitourinary tract
 Mucous protects these
surfaces from infections
First Line of Defense
 Skin
 Provides the most difficult barrier to penetrate
 Composed of two main layers

Dermis
 Contains tightly woven fibrous connective tissues
 Makes extremely tough

Epidermis
 Composed of many layers of epithelial cells
 As cells reach surface become increasingly flat
 Outermost sheets of cells embedded with keratin
 Makes skin water repellent
 Outer layers slough off taking microbes with it
First Line of Defense
 Mucous membranes

Constantly bathed with mucus


Helps wash surfaces
Some mucous membranes have mechanisms
to propel microorganisms and viruses to areas
where they can be eliminated
First Line of Defense
 Antimicrobial substances
 Both skin and mucous membranes are protected by
variety of antimicrobial substances including
 Lysozyme
 Enzymes that degrades peptioglycan
 Found in tears, saliva, blood and phagocytes

Peroxidase
 Found in saliva, body tissues and phagocytes
 Breaks down hydrogen peroxide to produces reactive oxygen

Lactoferrin
 Sequesters iron from microorganisms
 Iron essential for microbial growth
 Found in saliva, some phagocytes, blood and tissue fluids

Defensins (Antibiotics)
 Antimicrobial peptides inserted into microbial membrane
 Found on mucous membranes and in phagocytes
First Line of Defense
 Normal flora
 Defined as microorganisms found growing on
body surfaces of healthy individuals
 Not technically part of immune system


However, provides significant protection
Protects through competitive exclusion

Covers binding sites
 Pathogens can’t bind

Completes for nutrients
 Nutrients unavailable for pathogens
Cells of the Immune System
 Always found in normal blood
 Numbers increase during infection
 Some cells play dual roles in both innate and
adaptive immunity
 Blood cell formation called hematopoiesis


Blood cells including immune cells originate
from hematopoietic stem cells in bone marrow
Blood cells stimulated to differentiate by
colony-stimulating factor
Cells of the Immune System
 General categories of blood cells
 Red blood cells (RBC)
 A.k.a erythrocytes
 Carry oxygen in blood
 Platelets
 Fragments of megakaryocytes
 Important component in blood clotting
 White blood cells (WBC)
 A.k.a leukocytes
 Important in host defenses
 Divided into four categories
 Granulocytes
 Dendritic cells
- Mononuclear phagocytes
- Lymphocytes
Cells of the Immune System
 Granulocytes
 Contain cytoplasmic
granuals
 Divided into three types
 Neutrophils
 Basophils
 Eosinophils
Cells of the Immune System
 Neutrophils
Most abundant and important
in innate response
 Sometimes called
polymorphonuclear
neutrophilic leukocytes
(PMNs)
 Basophils
 Involved in allergic reaction
 Eosinophils
 Important in expelling
parasitic worms
 Active in allergic reactions

Cells of the Immune System
 Mononuclear phagocytes


Constitutes collection of
phagocytic cells called
mononuclear phagocyte
system
Includes monocytes


Circulates in blood
Macrophages
differentiate from
monocytes
 Present in most
tissues
 Abundant in liver,
spleen, lymph
nodes, lungs and
peritoneal cavity
Cells of the Immune System
 Dendritic cells
 Branched cells
involved in adaptive
immunity
 Functions as scout in
tissues
 Engulf materials in
tissue and bring it to
cells of adaptive
immunity
Cells of the Immune System
 Lymphocytes
 Involved in adaptive
immunity
 Two major groups
 B lymphocytes
 B cells

T lymphocytes
 T cells

Another type
 Natural killer
 Lacks specificity of
B and T cells
Cell Communication
 In order for immune system to respond cells
must communicate with environment and with
each other
 Cell surface receptors are the “eyes” and
“ears” of the cell
 Cytokines are the “voice”
 Adhesion molecules act as the “hands”
Cell Communication
 Surface receptors


Membrane proteins to which signal molecules
bind
Receptors specific to molecule to which it
bonds


Binding molecules called ligands
When ligand binds, receptor becomes
modified and send signal to cell

Cell responds by initiating some action
Cell Communication
 Cytokines
 Cytokines bind to surface receptors regulate cell function
 Numerous cytokine classes
 Chemokines = important in chemotaxis
 Enhance ability of cells to migrate to appropriate site in body

Colony stimulating factors = important in multiplication and
differentiation of leukocytes
 During immune response directs immature leukocytes to correct
maturation pathway

Interferons = important in control of viral infections
 Also associated with inflammatory response

Interleukins = produced by leukocytes
 Important in innate and adaptive immunity

Tumor necrosis factor = kill tumor cells
 Instrumental in initiation of inflammation
Cell Communication
 Adhesion molecules


Allows cells to adhere to each other
Responsible for the recruitment of phagocytes
to area of injury

Endothelial cells lining blood vessels produce
adhesion molecules that catch phagocytes as
they pass by
 Causes phagocytes to slow and leak out of vessels
to area of injury
Sensor Systems
 System within blood and tissue detect signs
of tissue damage or microbial invasion
 Responds to patterns associated with danger
by


Directly destroy invading microbe
Recruiting other host defenses
Sensor Systems
 Toll-like receptors (TLR) and NOD
proteins
 Pattern recognition receptors
 TLR allow cells to “see”
molecules signifying presence
of microbes outside the cell
 TLR found in variety of cell
types

Recognize distinct “danger”
compounds
 Signal is transmitted
 Results in change of
gene expression of cell

NOD proteins do same for
inside cell
Sensor Systems
 Complement system
 Series of proteins circulating in blood and fluids



Augment activities of adaptive immune response
Stimulation of inactive proteins initiates cascade of
reactions


Circulate in inactive form
Results in rapid activation of components
Three pathways of activation



Alternative pathway
Lectin pathway
Classical pathway
Sensor Systems
 Alternative pathway
 Quickly and easily initiated
 Relies on binding of
complement protein C3b to
cell surface
 Initiates activation of
other compliment
proteins
 Allows formation of
complement complex

C3b always circulating in
blood
Sensor Systems
 Lectin pathway
 Activation requires
mannan-binding lectins
(MBL)
 Pattern recognition
molecules
 Detect mannan
 Polymer of mannose
 Found in microbial
cells

MBL attaches to surface
 Activates complement
proteins
Sensor Systems
 Classical pathway
 Activation requires
antibodies
 Antibodies interact
with complement C1
 Activates protein
 Leads to
activation of all
complex
proteins
Sensor Systems
 Complement
 Complement system composed of nine proteins
 C1 – C9
 Numbered as discovered not order of activation

Certain proteins split into “a” and “b” fragments after
activation
 C3 can spontaneously split to C3a and C3b
 Insures enough C3b for activation of alternative pathway

Activation of complement leads to major protective
outcomes
 Inflammation
 Opsonization
 Lysis of foreign cells
Sensor Systems
 Inflammation

Complement components C3a and C5a
induce changes in endothelial cells

Effects vascular permeability associated with
inflammation
 Opsonization

C3b binds foreign material

Allows phagocytes to easily “grab” particles
Sensor Systems
 Lysis of foreign cells
 Complexes of C5b, C6, C7,
C8 and multiple C9
spontaneously assemble
 Forms donut shaped
structure called
membrane attack
complex (MAC)
 Creates pores in
membrane
 Most effective on Gramnegative cells
 Little effect on Grampositive cells
Phagocytosis
 Process of phagocytosis

Chemotaxis


Recognition/attachment


Use receptors to bind
invading microbes
Engulfment


Cells recruited to
infection
Phagocyte engulfs
invader forming
phagosome
Phagosome lysosome
fusion

Phagosome binds
lysosome forming
phagolysosome

Destruction and digestion


Organism killed due to
lack of oxygen and
decreased pH
Exocytosis

Phagocyte expels
material to external
environment
Inflammation
 Inflammation occurs in
response to tissue damage
 Four cardinal signs




Heat
Pain
Redness
Swelling
 Loss of function
 Fifth sign that can also be
present
Inflammation
 Factors that initiate inflammatory response

Microbial products trigger toll-like receptors of
macrophages


Microbial cell surface can trigger complement


Causing release of pro-inflammatory cytokines
Leads to the production of C3a and C5a
Tissue damage results in enzymatic cascade

Cascades initiate inflammation
Inflammation
 The inflammatory process

Initiation leads to a cascade of
events

Results in dilation of blood
vessels, leakage of fluid from
vessels and migration of
leukocytes and phagocytes
 Leakage of phagocytes from
blood vessels called diapedesis

Certain pro-inflammatory
mediators cause the diameter of
blood vessels to increase

Resulting in increased blood
flow
 Increased blood flow
responsible for cardinal signs of
inflammation
Inflammation
 Outcomes of inflammation
 Intent is to limit damage and restore function

Inflammation itself can cause considerable damage
 Release of toxic products and enzymes from phagocytic
cell responsible for tissue damage


If inflammation is limited to area of injury damage
is usually nominal
If inflammation results in delicate systems
consequences are more sever

Inflammation around brain and spinal cord can lead
to meningitis
Inflammation
 Apoptosis

Programmed cell death


Destroys cell without eliciting inflammatory
response
During apoptosis cells undergo changes to
signal macrophages

Cells are engulfed without triggering inflammatory
cascade
Fever
 One of the strongest indicators of infection
 Especially of bacterial infection
 Important host defense mechanism
 Temperature regulation center of body responds to
fever-inducing substances called pyrogens


Fever-inducing cytokines termed endogenous pyrogens
Microbial products termed exogenous pyrogens
 Resulting fever inhibits growth of pathogens by
 Elevating temperature above maximum growth
temperature
 Activating and speeding up other body defenses