Download Kinds of Resistance Defense Mechanisms

Lec 7 (Ch14, 15):
Nonspecific Immunity –
Host Defenses
Topics
- Defense Mechanisms (innate, acquired)
- Systems (anatomic, immunological)
- Non-specific immunity (general response)
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Kinds of Resistance
• 2 Major divisions:
– Nonspecific
– Specific
• 3 Lines of Defense
– Exterior
– General response
– Specialized response
2
Defense Mechanisms
• Innate and nonspecific
– First line of defense
(barriers)
– Second line of defense
(phagocytes, inflammation, fever, antimicrobials)
• Acquired and specific
– Third line of defense (specific resistance,
B&T lymphocytes, Abs
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Major Components of Host Defenses
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First line of defense
(mechanical, chemical, normal flora)
• Barriers
–
–
–
–
Anatomical
Chemical
Normal Flora
Genetic
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Anatomical barriers
• Skin
– Outermost layer
– Hair follicles
– Skin glands
• Mucous membrane
–
–
–
–
Digestive
Urinary
Respiratory
Eye
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2
The trachea contain cilia that entrap and propel particles out of the
respiratory tract.
F
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Chemical barriers
• Antimicrobial peptides:
– Sebaceous secretions
– Eyelid glands – meibomian gland
– Tears and saliva – lysozyme
• Acidic pH
–
–
–
–
–
Sweat
Stomach
Skin
Semen
Vagina
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1st Line Nonspecific Chemical
Defenses
• Toll-like receptors (TLRs)
– Integral membrane proteins produced by
phagocytic cells
– Bind pathogen-associated molecular patterns
(PAMPs)
– Initiate defensive responses
• Apoptosis
• Secretion of inflammatory mediators
• Production of stimulants of adaptive immune
response
• NOD proteins
– Cytosolic proteins that bind PAMPs
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3
Primary anatomical
and chemical defense
barriers
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Normal Flora as 1st Line
Microbial antagonism
Normal flora compete against potential
pathogens:
•Nutrients
•Environment
•Stimulate second line of defense
•Promote health (provide vitamins)
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Genetic barriers
• Different level of sensitivity and
resistance to infectious agents
– Malaria
– Tuberculosis
– Leprosy
– Fungal infections
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4
2nd Line of Defense
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2nd line of Defense – What is it?
• Response to pathogen penetration (skin or mucous
membranes)
• Cells, antimicrobial chemicals
• Blood Chemistry:
– Plasma
– Serum
– Erythrocytes (O2)
– Leucocytes (white cells) (5 kinds)
– Platelets (blood clotting)
• Immunology
• Protective cells
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What is Immunology?
• Study of the development of resistance to
infectious agents by the body
– Surveillance of the body
– Recognition of foreign material
– Destruction of foreign material or agent
• Involve nonspecific and specific immune
defense systems
• White blood cells (wbc) or leukocytes are
involved
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5
Non-specific Phagocytosis
• Phagocytes (white
cells)
• Migration of
roaming cells
• also histiocytes Kupffer’s cells,
alveolar,
microglial etc.
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WBC
• WBC recognize self markers on the
host cell
– Do not attack or do not respond to host cell
• WBC recognize non-self markers on the
invading microbe
– Attack or respond to microbe
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WBC must
recognize and
destroy non-self
cells
18
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Systems - connections
• All systems are integrated
–
–
–
–
Recticuloendothelial system (RES)
Extracellular fluids system (ECF)
Blood or circulatory
Lymphatic
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Reticuloendothelial (RES)
• Network of connective tissue fibers
(Reticulum)
• Interconnects cells
• Allows immune cells to bind and move
outside the blood and lymphatic system
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Extracellular fluid (ECF)
• The spaces
surrounding tissue
cells and RES
• Enable immune
cells to move
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Blood
• Stem cells precursors
• Hemopoiesis
• Components :
(Blood Chemistry)
–
–
–
–
Plasma
Serum
Erythrocytes (O2)
Leucocytes (white cells)
(5 kinds)
– Platelets (blood clotting)
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Stem cells
• From blood cells
– RBC
– platelets
• Hematopoietic stem cells
(yolk sack and liver, then bone marrow)
– Neutraphils, basophils, eosinophils, monocytes
• Lymphoid stem cells
– T cells
– B cells
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Hematopoiesis
24
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The three types
of stem cells -
differentiate into:
•Blood
•platelets
•Granulocytes
•agranulocytes
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Leucocytes
(white blood cells)
• Leukocytes
– Granulocytes (large cytoplasmic granules)
• Neutrophils  phagocytes, digestive enzyme, 1st to
arrive
• Basophils  histamine, like eosinophils, localized ones
called mast cells
• Eosinophils phagocytosis, eukaryotic pathogens,
inflammation & allergy
– Agranulocytes (very small granules)
• T cells  cell-mediated
• B cells  Ab production
• Monocytes  mature into macrophage
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Leukocytes (Blood Smear)
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Lymphocytes
• Specific immunity
– T cells (cell-mediated)
– B cells (Ab-mediated)
• Present throughout the
body:
– Phagocytes (white cells)
– Migration of roaming
cells
– also histiocytes
Kupffer’s cells, alveolar,
microglial etc.
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Phagocytosis
• Chemotaxis
• Adherence (opsins can increase this)…
• Ingestion via phagocytic vesicle
phagosome
– pH to 4.0, enzymes kick in
• Lysosomes fuse w/ phagosome
phagolysosome
• 30 minutes bacteria dead
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Phagocytosis
– the artist’s rendition
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How to evade phagocytosis!
(run away run away!)
• Adherence inhibition via M protein or
capsule
• Toxins (Staph produces leukocidins,
Streps produce streptolysin)
• Membrane attack proteins
• Special adaptive factors and tolerances
31
Non-phagocytic Killing
• Eosinophils:
– Attack parasitic helminths (surface attachment)
– Secrete toxins (weaken or kill helminths)
– Eosinophilia (elevated) often = helminthic infestation
– Eosinophil mitochondrial DNA and proteins form
structure that kills some bacteria
• Natural Killer Cells (lymphocytes):
– Secrete toxins onto surface of virally infected cells and
tumors
– Differentiate normal body cells because they have
membrane proteins similar to the NK cells
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Non-phagocytic Killing (cont.)
• Neutraphils:
– Produce chemicals that kill nearby invaders
– Generate extracellular fibers [neutrophil extracellular
traps (NETs)] that bind to and kill bacteria
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11
Lymphatic system
• Network of vessels that extend to most body
areas
• Includes nodes, spleen, thymus…
• Connected to the blood system
• Provides an auxiliary route for the return of
extracellular fluid to the circulatory system
• “Drain off” system for inflammatory response
• Contains lymphocytes, phagocytes and
antibodies
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Artist’s rendition- Lymphatic System
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Lymphatic Fluids
• Plasma-like fluid (lymph)
– Water
– Dissolved salts
– Proteins (antibodies, albumin)
– White blood cells
– No red blood cells
• Formed from blood components
– Diffuse into the lymphatic capillaries
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12
Lymphatic Vessels
(carry lymphatic fluid…)
• Parallels the blood system
• Returns lymph to the blood system
• Movement of lymph depends on muscle
contractions
• Permeates the body except the cns,
bone, placenta, and thymus.
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Lymph nodes
• Exist in clusters
• Located
– along the lymphatic
channels and blood
vessels
– in the thoracic and
abdominal cavity regions,
armpit, groin and neck
• Filter for the lymph
• Provide environment for
immune reactions
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Spleen
• Located in the upper left portion of the
abdominal cavity
• Filter for blood
– traps pathogens and phagocytizes
pathogens
• Adults can survive without spleen
• Asplenic children are severely
immunocompromised
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Thymus
• Embryo
– two lobes in the pharyngeal
region
– Differentiate immature T-cells
into mature t-cells
– High activity (releases
mature T cells) until puberty
• Adult
– Gradually shrinks
– Lymph node and spleen
supply mature T cells
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Gut-Associated Lymphoid Tissue
(GALT)
• Recognized incoming microbes from food
• Supply lymphocytes for antibody response
• Ex. Appendix, lacteals, Peyer’s patches,
isolated lymphoid follicles (ILF)
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Non-specific Immunity
•
•
•
•
Inflammation
Phagocytosis
Interferon
Complement
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Inflammation
•
•
Triggered by damage
Five (4 major) symptoms 
1.
2.
3.
4.
5.
•
Redness
Warmth
Swelling
Pain
*Loss of function
Acute vs. Chronic
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Typical symptoms that occur after injury.
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Inflammation
•
Causes:
– Trauma
– Tissue injury due to physical
or chemical agents
– Specific immune reactions
•
3 Functions:
– Destroy agent (and remove
or destroy)
– Limit wall or confine
– Repair or replace
•
Results in:
• Mobilization and attraction of
immune components to the
site of injury
• Aid in repair of tissue
damage
• Localized, remove of harmful
substances
• Destroy microbes and block
their invasion
Stages:
– vascular
– edema
– fever
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The major events in inflammation:
injury, vascular reactions, edema, resolution
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3 Stages of Inflammation
1. Vascular changes
(vasodilation = increased permeability)
2. Edema
(phagocytic migration and phagocytosis)
3. Fever
(followed by tissue repair)
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1-Vascular changes
• Blood cells, tissue cells, and platelets release
chemical mediators and cytokines
• Chemical mediators (Cause fever, stimulate
lymphocytes, prevent virus spread, cause allergic reactions)
– Vasoactive
• Affect endothelial cells, smooth muscles of blood vessels
• histamines
• permeability rise = edema  nerve damage, toxin
irritation, pressure etc.)
– Chemotactic (chemokines)
• Affect WBC
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Effects of chemical mediators during inflammation
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2 - Edema
• Leakage of vascular fluid (exudate) into
tissue
• Exudate - plasma proteins, blood cells
(wbc), debris, and pus
• Migration of wbc is called diapedesis or
transmigration
– Chemotaxis
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Transmigration (diapedesis) of WBCs
is followed by chemotaxis
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3 - Fever
• Caused by pyrogens
– reset the hypothalamic thermostat (increase
temperature)
– Vasoconstriction
•
•
•
•
Phagocytes release IL-1 increase t-cells
Increases interferon effect (Fe++)
Speeds up metabolism
Inhibits microbe and viral multiplication (
reduces nutrient availability, increases immune reactions )
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Fever (pyrexia)
•
•
•
elevation in the
thermoregulatory set-point:
release of prostaglandin E2
 hypothalamus
Caused by pyrogens
Endogenous
– (cytokines, IL-6, tumornecrosis factor)
OR
• Exogenous
– Microbes and their products
(ex. Endotoxins, LPS,
superantigens)
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Neutrophils and eosinophils
• Early responders to inflammation
• Neutrophils are primary components of
pus
• Eosinophils are primary responders to
parasitic infections
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18
Macrophages
• Monocytes transform into macrophages
• Scavengers
– Histiocytes – reside in one location (ex.
Alveolar, Kupffer, Langerhans)
– Drift throughout the RES
• Undergo phagocytosis,
• Interact with B and T cells
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Histiocytes
Macrophages can
become histiocytes
by taking up
permanent
residence in the
lung (alveolar), liver
(Kupffer) and skin
(Langerhans).
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Macrophage mechanism
•
•
•
•
Chemotaxis
Ingestion
Phagolysosome
Destruction
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Chemotaxis
• Directed by
– Pathogen-associated molecular patterns
(PAMPs)
• Peptidoglycan
• LPS
– Foreign debris
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Ingestion
• Pseudopods enclose the pathogen or
foreign material
• Form a phagosome
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Phagolysosome
• Lysosomes fuse with the phagosome
• Other antimicrobials chemicals are
released into the phagolysosome
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20
Destruction
• Within the phagolysosome
– Oxygen-dependent system
• Oxidative burst (oxidizing agents)
– Enzymes
– Nitric oxide
• Undigestible debris are released
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Phagocytosis mechanism
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2nd Line includes:
Nonspecific Chemical Defenses –
Interferons
Interferons
– Protein molecules released by host cells to
nonspecifically inhibit the spread of viral
infections
– Cause many symptoms associated with
viral infections
– Two types
• Types I (alpha and beta)
• Type II (gamma)
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21
Interferon
•Produced in response to:
•viral infections
•microbe infections
•RNA
•immune products
•antigens
•
•
Synthesis: WBCs,Tissue cells
Classes:
1. Alpha = prod of
lymphocytes and
macrophages
2. Beta = prod of fibroblasts
and epithelial cells
3. Gamma = prod of T-cells
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Interferon activity
• Ex. Virus - binds to host cell
• A signal is sent to the nucleus to synthesized
(transcription and translation) interferon
• Interferon is secreted
• Binds to other host cells
• Host cells produce antiviral proteins
– inhibit viral multiplication or translation
• Not virus-specific
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Interferon mechanism: produced, released, and taken-up by a near-by cell,
original cell is not protected but recipient cell is protected
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22
Alpha & Beta Interferons
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Other Interferon roles
• Activates and instructs T and B cell
development
• Inhibits cancer cells
• Activates macrophages
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Complement – What is it?
• Causes cell lysis
• Consist of 26 blood proteins
• Produced by liver hepatocytes,
lymphocytes, and monocytes
• 3 major Pathways
• Cascade reaction
• What are the stages?
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23
Complement pathways
• Classical
– activated by the presence of antibody bound to
microbes
• Lectin
– activated when a host serum protein binds a sugar
(mannan) in the wall of fungi and other microbes
• Alternative
– activated when complement proteins bind to cell
wall or surface components of microbes
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The complement pathways, activators, and involved
proteins
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Complement Pathwaysanother view
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24
Complement Stages
1.
2.
3.
4.
Initiation
Amplification and cascade
Polymerization
Membrane attack !!
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The Cascade
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Classical pathway
Begins when C1
components bind
to antibodies.
It completes by
puncturing small
pores through the
membrane.
This results in
lysis.
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Membrane Attack Complex=
Lysis!
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Onward!
…to Specific Immunity –
The 3rd Line of Defense
Graphic from: Oat Willie’s Logo, Austin Texas
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Some additional Info
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