Download Innate Immune Response

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
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


Antimicrobial substances
and Normal Flora
pH changes

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, they become increasingly flat
 Outermost sheets of cells embedded with keratin
 Makes skin water-repellent
 Outer layers slough off, taking microbes with it

Mucous membranes
› Constantly bathed with mucus
 Help wash surfaces
› Some mucous membranes have
mechanisms (cilia)to propel microorganisms
and viruses to areas where they can be
eliminated

Antimicrobial substances
› Both skin and mucous membranes are
protected by variety of antimicrobial substances
including
 Lysozyme
 Enzymes that degrade peptioglycan
 Found in tears, saliva, blood and phagocytes
 Peroxidase
 Found in saliva, body tissues and phagocytes
 Breaks down hydrogen peroxide to produce reactive
oxygen
 Lactoferrin
 Sequesters iron from microorganisms
 Iron essential for microbial growth
 Found in saliva, some phagocytes, blood and tissue fluids
 Defensins
 Antimicrobial peptides inserted into microbial membrane
 Found on mucous membranes and in phagocytes

Normal Microbiota (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
 Competes for nutrients
 Nutrients unavailable for pathogens

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

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

Granulocytes
› Contain
cytoplasmic
graduals
› Divided into three
types
 Neutrophils
 Basophils
 Eosinophils

Granulocytes
› Contain cytoplasmic graduals
 Neutrophils
› Most abundant and important in innate
response
› Granules contain chemicals which kill
microbes
› Sometimes called polymorphonuclear
neutrophilic leukocytes (PMNs)
 Basophils
› Granules contain
histamine and other
chemicals which
increase capillary
permeability.
› Similar to mast cells
› Involved in allergic
reaction
 Eosinophils
› Important in
expelling parasitic
worms
› Active in allergic
reactions
› Granules contain
histamase and
antimicrobial
chemicals

Mononulcear phagocytes
› Constitute collection of phagocytic cells called
mononuclear phagocyte system
› Include monocytes
 Circulate in blood
 Macrophages differentiate from monocytes
 Present in most tissues
 Abundant in liver, spleen, lymph nodes, lungs and
peritoneal cavity

Dendritic cells
› Branched cells involved in adaptive immunity
› Function as scout in tissues
 Engulf material in tissue and bring it to cells of
adaptive immunity

Lymphocytes
› Involved in adaptive immunity
› Two major groups
 B lymphocytes
 B cells-mature in bone marrow
 T lymphocytes
 T cells-mature in the thymus
› Another type
 Natural killer
 Lacks specificity of B and T cells

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 sends signal to cell
 Cell responds by initiating some action

Cytokines
› Cytokines bind to surface receptors and regulate cell
function
› Numerous cytokine classes
 Chemokines – important in chemotaxis
 Colony stimulating factors – Important in multiplication
and differentiation of leukocytes
 Interferons – important in control of viral infections
 Interleukins – produced by leukocytes
 Tumor necrosis factor – kill tumor cells

Adhesion molecules
› Allow cells to adhere to each other
› Responsible for the recruitment of
phagocytes to area of injury
 Epithelia cells lining blood vessels produce
adhesion molecules that catch phagocytes as
they pass by
 Cause phagocytes to slow and leak out of vessels to
area of injury
Systems within blood detect signs of
tissue damage or microbial invasion
 Respond to patterns associated with
danger by

› Directly destroying invading microbe
› Recruiting other host defenses

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

Complement system
› Series of proteins circulating in blood and
fluids
 Circulate in inactive form
› Augment activities of adaptive immune
response
› Stimulation of inactive proteins initiates
cascade of reactions
 Results in rapid activation of components
› Three pathways of activation
 Alternative pathway
 Lectin pathway
 Classical pathway
Figure 15.7

Classical pathway
› Activation requires antibodies
 Antibodies interact complement C1
 Activates protein
 Leads to activation of all complex proteins

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

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

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 Gram-negative cells
 Little effect on Gram-positive cells
Figure 15.8
Long DoubleStranded RNA
(dsRNA)
 Induction of
alpha and beta
interferons

› Cells express iAVPs
› Leads to apoptosis

Process of phagocytosis
› Chemotaxis
 Cells recruited to infection
› Recognition/attachment
 Use receptors to bind
invading microbes
› Engulfment
 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

Role of Neutrophiles
› First responders
› Granules contain antimicrobial chemicals
› NETs-neutrophile extracellular traps
 Contain DNA and anti microbial chemicals
 Trap bacteria and destroy them with
chemicals
› Short lived but lots in reserve
Inflammation occurs in response to tissue
damage
 Four cardinal signs

› Heat
› Pain
› Redness
› Swelling
› Loss of function
 Fifth sign that can also be present

Factors that initiate inflammatory
response
› Microbial products trigger toll-like receptors
of macrophages
 Causes release of pro-inflammatory cytokines
› Microbial cell surface can trigger
complement
› Tissue damage results in enzymatic cascade
 Cascades initiate inflammation
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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
 Results in increased blood
flow
 Increased blood flow
responsible for cardinal signs of
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 cells is 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 severe
 Inflammation around brain and spinal cord
can lead to meningitis

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

One of the strongest indicators of infection
› Especially of bacterial infection
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
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