Transcript Lec 9 Innate immunity - Cal State LA

Lecture 9: Innate Immunity
Edith Porter, M.D.
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 Concept of immunity
▪ Innate immunity
▪ Adaptive immunity
 Innate immunity: first line of defense
▪ General aspects
▪ Physical factors
▪ Chemical factors
▪ Normal microbiota
▪ Cellular elements
▪ Epithelial cells
▪ Phagocytes
▪ Effector molecule
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Complement
Antimicrobial peptides
Interferons
Iron binding proteins
 Acute inflammation
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INNATE IMMUNITY
 Functional at birth
 Rapid responses:
preformed or available
within hours after
infection
 Limited specificity:
pattern recognition via
toll like receptors
 Widely present in nature
including in plants,
invertebrates and
vertebrates
ADAPTIVE IMMUNITY
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Acquired, available
within days
High specificity
Memory
In higher vertebrates
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First Line of Defense
Second Line of Defense
•NK cells
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Outer body surface
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Keratin barrier
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Epithelial cell shedding
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Dryness
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Inner body surfaces
Mucus
 Viscous
 Protects underlying cells
 Contains antimicrobial factors
▪ Lysozyme
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Constant fluid flow
 Tears
 Saliva
 Intestinal peristaltic
 Urine production and urination
 Vaginal secretions
 Mucociliary clearance
▪ 1 – 3 cm/h
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Epithelial cell shedding
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Sebum, unsaturated fatty acids
 “antimicrobial lipids”
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Low pH
 Skin (pH 3-5)
 Stomach (pH 1.5 – 3)
 Vagina (pH 3 – 5)
http://www.niams.nih.gov/Health_Inf
o/Acne/images/normal.jpg
 Urine (pH 6)
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Competes with potential pathogens for nutrients
Directly inhibits potential pathogens
 Lactobacilli: lactic acid, low pH
 Bacteriocins
Skin
Tongue
Esophagus
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Epithelial Cells
Leukocytes
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Keratinizing in skin
Non-keratinizing elsewhere
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Express toll-like receptors (TLR 1 –10)
that recognize specific pathogen
associated molecular patterns (PAMP)
 LPS
 PG
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Produce antimicrobial peptides (AMP)
 Kill microbes
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Secrete pro-inflammatory cytokines
 Alert the host
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Microbial Products
(LPS, PG, etc)
TLR
Antimicrobial
Peptides
Cytokines
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Granulocytes
neutrophil
eosinophil
Anti-bacterial
Anti-fungal
Anti-parasitic
Anti-allergic
Natural Killer Cells
basophil
Anti-parasitic
Anti-allergic
Anti-viral
Monocytes
Lymphocytes
Anti-bacterial
Anti-fungal
B-Ly : antibody production
T-Ly: orchestrate
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Mast cell
Macrophage
in bone marrow
Dendritic cell
Anti-parasitic
Allergic responses
Clears bacteria and
fungi in tissues
Communicates
with lymphocytes
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All originate from bone marrow (red bone
marrow)
Circulate in the body through vascular system
and lymphatic system
Enter tissue as needed
 Some differentiate here and remain in the tissue:
macrophages, dendritic cells
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Performed by phagocytes (professional eaters)
 Neutrophils
 Monocytes  Macrophages
Refers primarily to the uptake of bacteria and fungi
Relatively inefficient without special opsonins
Opsonins are molecules that enhance phagocytosis
 Make “food more edible”
 Host derived molecules that cover the microbe and are
recognized by phagocytes
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Chemotaxis
Opsonization
Adherence (attachment)
Ingestion (engulfment)
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Pseudopods
Phagosome
Phagolysosome
Killing and digestion
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Chemical attraction of phagocytes to
microorganisms and movement of phagocytes
towards the source of infection
 Induced by chemoattractants:
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Microbial products (formyl-methionine-peptides)
Complement
Cytokines (“Chemokines”)
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Phagocytes need their food
(microorganisms) served on silver
plates
 Opsonines significantly enhance
microbial uptake by phagocytes
 Cover microbial surfaces and are
recognized by specific receptors
on phagocyte surfaces
 Examples are:
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 Antibodies
 Complement
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Oxygen dependent
 Oxidative Burst
 Reactive oxygen and reactive nitrogen intermediates
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Oxygen-independent
 Antimicrobial peptides
 Low pH
 Enzymes (Hydrolases, proteases, phopholipases)
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Complement system
 Kills and helps in phagocytosis
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Antimicrobial Peptides:
 Kill
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Interferons
 Strengthen basic host cell defenses
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Iron binding proteins
 Expressed by both host and microbe
 Competition for iron
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System of over 30 serum proteins
Active components (C-) and inhibitors
Widely distributed in body
Many cells can synthesis complement factors
Major producers:
 Hepatocytes (liver cells)
 Monocytes/macrophages
 Fibroblasts
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Early events: proteolytic cascade generates
bioactive cleavage fragments
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C1 C4 C2 C3 C5  C6  C7 C8C9n
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Late events: Protein polymerization generate a
pore on target cell
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Classical pathway
 Antibodies bound to microbes change
conformation and open up binding sites for C1
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Lectin pathway
 Sugar-binding molecule with similar structure to
C1 binds to the microbe and activate complement
C2 and C4
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Alternative pathway
 C3 binds directly to the microbial surface aided by
factors B, D, and P and activates C5
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Always the same
Pore formation on microbe and direct killing
(C5b- C9n)
Opsonization and improved phagocytosis
(C3b)
Inflammation and recruitment of phagocytes
(C5a, C3a, C4a)
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Figure 16.9 (3 of 29
5)
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Action on blood vessels and
Mast cells
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Dilation  reddening and
heat
Leakage of blood
components  edema
Make endothelial cells and
leukocytes sticky
Transmigration of leukocytes
 pus
Chemoattractant for
leukocytes
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1) Innate immunity is
A) The body's ability to ward off
diseases.
B) The body's defenses against any kind
of pathogen.
C) The body's defense against a
particular pathogen.
D) The lack of resistance.
E) Increased susceptibility to disease.
2) The complement protein cascade is
the same for the classical pathway,
alternative pathway, and lectin pathway
beginning with the activation of
A) C1.
B) C2.
C) C3.
D) C5.
E) C6.
3) Which of the following does NOT increase
blood vessel permeability?
A) Kinins
B) Prostaglandins
C) Lysozymes
D) Histamine
E) Leukotrienes
4) Which of the following does NOT provide
protection from phagocytic digestion?
A) Preventing formation of phagolysosomes
B) Killing white blood cells
C) Causing formation of phagolysosomes
D) Ability to grow at a low pH
E) Biofilms
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Found in phagocytes and
epithelial cells
Small (< 100 amino acids)
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Cationic
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positive net charge at
physiological pH
Arginine and/or lysine rich
Amphiphilic: also hydrophobic
domains
Microbial killing through
membrane permeabilization and
other mechanisms
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Example: defensins
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Host derived proteins
 Transferrin: blood and tissue fluid
 Lactoferrin: milk, saliva, mucus
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Bind iron which is essential to microbe
 Microbes counteract with siderophores or iron
binding protein receptors
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Relatively uniform response to a variety of causes
 Infection
 Physical agents like heat, radiation etc
 Chemical agents like acids, bases etc.
Key signs are rubor (redness), dolor (pain), calor
(heat), and tumor (swelling)
 Local response includes vasodilation and increase of
permeability, phagocyte migration and phagocytosis,
tissue repair
 Systemic response mediated by TNFa and acute
phase proteins like C-reactive protein up to 1000x fold
increased) can lead to fever, shock, disseminated
coagulation
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Innate immunity is widely conserved, functional upon
birth, operates via pattern recognition and TLR, has
no memory
Key cells in innate immunity are epithelial cells and
phagocytes
Phagocytosis is enhanced by opsonins
Phagocytes kill via oxygen radicals, antimicrobial
peptides, low pH, and enzymes.
The effector molecules of innate immunity are
complement (killing, inflammation, enhanced
phagodytosis), antimicrobial peptides (killing),
interferons (activation of host antiviral defenses), and
iron binding proteins (deprive microbes of iron).
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First line defense from concept to molecules
Emphasis on primary research and hands on training in current methods in innate immunology
including flow cytometry
Lec: MW 9:50 - 10:40 am * Lab: M 10:50 – 2:20 pm * Rec: W 10:50 – 11:40 am
Prerequisites: One of the following; MICR 201+MICR 202, MICR 300,
BIOL 380, or instructor consent. Questions? email/call Dr. Edith Porter
at [email protected] , (323) 343 6353 or drop by at ASCL 355