lecture 9 innate immunity edith porter m d n.
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Lecture 9: Innate Immunity Edith Porter, M.D. MICR 201 Microbiology for Health Related Sciences. Lecture outline. Concept of immunity Innate immunity Adaptive immunity Innate immunity: first line of defense General aspects Physical factors Chemical factors Normal microbiota

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lecture outline
Lecture outline
  • 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
      • Complement
      • Antimicrobial peptides
      • Interferons
      • Iron binding proteins
  • Acute inflammation
concept of immunity
Concept of immunity

Innate immunity

Adaptive immunity

Acquired, available within days

High specificity

Memory

In higher vertebrates

  • 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
overview of host defenses
Overview of host defenses

First Line of Defense

Second Line of Defense

  • NK cells
physical mechanical defense of skin
Physical (mechanical) defense of skin
  • Outer body surface
  • Keratin barrier
  • Epithelial cell shedding
  • Dryness
physical mechanical defense of mucosa
Physical (mechanical) defense of mucosa
  • Inner body surfaces
  • Mucus
    • Viscous
    • Protects underlying cells
    • Contains antimicrobial factors
      • Lysozyme
  • Constant fluid flow
    • Tears
    • Saliva
    • Intestinal peristaltic
    • Urine production and urination
    • Vaginal secretions
    • Mucociliaryclearance
      • 1 – 3 cm/h
  • Epithelial cell shedding
chemical defense
Chemical defense
  • Sebum, unsaturated fatty acids
    • “antimicrobial lipids”
  • Low pH
    • Skin (pH 3-5)
    • Stomach (pH 1.5 – 3)
    • Vagina (pH 3 – 5)
    • Urine (pH 6)

http://www.niams.nih.gov/Health_Info/Acne/images/normal.jpg

normal microbiota as part of host defense
Normal microbiota as part of host defense
  • Competes with potential pathogens for nutrients
  • Directly inhibits potential pathogens
    • Lactobacilli: lactic acid, low pH
    • Bacteriocins

Skin Tongue Esophagus

cellular elements of host defense
Cellular elements of host defense
  • Epithelial Cells
  • Leukocytes
epithelial cells
Epithelial cells

Keratinizing in skin

Non-keratinizing elsewhere

immune function of epithelial cells
Immune function of epithelial cells
  • Express toll-like receptors (TLR 1 –10) that recognize specific pathogen associated molecular patterns (PAMP)
    • LPS
    • PG
  • Produce antimicrobial peptides (AMP)
    • Kill microbes
  • Secrete pro-inflammatory cytokines
    • Alert the host
epithelial cell defense
Epithelial cell defense

Microbial Products

(LPS, PG, etc)

TLR

Antimicrobial Peptides

Cytokines

leukocytes in peripheral blood
Leukocytes in peripheral blood

Granulocytes

Natural Killer Cells

neutrophil eosinophilbasophil

Anti-parasitic

Anti-allergic

Anti-parasitic

Anti-allergic

Anti-bacterial

Anti-fungal

Anti-viral

Monocytes

Lymphocytes

Anti-bacterial

Anti-fungal

B-Ly : antibody production

T-Ly: orchestrate

leukocytes in tissue
Leukocytes in tissue

Mast cell

Macrophage

in bone marrow

Dendritic cell

Anti-parasitic

Allergic responses

Clears bacteria and fungi in tissues

Communicates with lymphocytes

origin of leukocytes
Origin of leukocytes
  • 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
phagocytosis
Phagocytosis
  • 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
key steps of opsonophagocytosis 2
Key steps of opsonophagocytosis (2)
  • Chemotaxis
  • Opsonization
  • Adherence (attachment)
  • Ingestion (engulfment)
    • Pseudopods
    • Phagosome
  • Phagolysosome
  • Killing and digestion
chemotaxis
Chemotaxis
  • Chemical attraction of phagocytes to microorganisms and movement of phagocytes towards the source of infection
  • Induced by chemoattractants:
    • Microbial products (formyl-methionine-peptides)
    • Complement
    • Cytokines (“Chemokines”)
opsonization
Opsonization
  • 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:
    • Antibodies
    • Complement
killing and digestion by phagocytes
Killing and digestion by phagocytes
  • Oxygen dependent
    • Oxidative Burst
    • Reactive oxygen and reactive nitrogen intermediates
  • Oxygen-independent
    • Antimicrobial peptides
    • Low pH
    • Enzymes (Hydrolases, proteases, phopholipases)
effector molecules of host defense
Effector molecules of host defense
  • Complement system
    • Kills and helps in phagocytosis
  • Antimicrobial Peptides:
    • Kill
  • Interferons
    • Strengthen basic host cell defenses
  • Iron binding proteins
    • Expressed by both host and microbe
    • Competition for iron
complement system
Complement system
  • 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
the complement cascade
The Complement Cascade
  • Early events: proteolytic cascade generates bioactive cleavage fragments
  • C1 C4 C2 C3 C5  C6  C7 C8C9n
  • Late events: Protein polymerization generate a pore on target cell
activation of complement system
Activation of complement system
  • Classical pathway
    • Antibodies bound to microbes change conformation and open up binding sites for C1
  • Lectin pathway
    • Sugar-binding molecule with similar structure to C1 binds to the microbe and activate complement C2 and C4
  • Alternative pathway
    • C3 binds directly to the microbial surface aided by factors B, D, and P and activates C5
outcomes of complement activation
Outcomes of Complement Activation
  • 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)
pro inflammatory action of complement
Pro-inflammatory action of complement
  • Action on blood vessels and Mast cells
    • Dilation  reddening and heat
    • Leakage of blood components  edema
    • Make endothelial cells and leukocytes sticky
    • Transmigration of leukocytes  pus
  • Chemoattractant for leukocytes
practice questions
Practice questions

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.

3) Which of the following does NOT increase blood vessel permeability?

A) Kinins

B) Prostaglandins

C) Lysozymes

D) Histamine

E) Leukotrienes

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.

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

antimicrobial peptides

+ + +

+ + +

Antimicrobial peptides
  • Found in phagocytes and epithelial cells
  • Small (< 100 amino acids)
  • Cationic
    • positive net charge at physiological pH
    • Arginine and/or lysine rich
  • Amphiphilic: also hydrophobic domains
  • Microbial killing through membrane permeabilization and other mechanisms
    • Example: defensins

+ + +

iron binding proteins
Iron binding proteins
  • Host derived proteins
    • Transferrin: blood and tissue fluid
    • Lactoferrin: milk, saliva, mucus
  • Bind iron which is essential to microbe
    • Microbes counteract with siderophores or iron binding protein receptors
acute inflammation
Acute inflammation
  • 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
important to remember
Important to remember
  • 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).
w2011 micr 450 innate immunity 4
W2011 MICR 450 Innate Immunity (4)

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 eporter@calstatela.edu , (323) 343 6353 or drop by at ASCL 355