Function of Immune System

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Function of Immune System
bacteria
virus
Protection from pathogen
fungi
parasite
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Skin
Barrier
Respiratory tract
Mucous membrane
Gastrointestinal tract
Urogenital tract
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Skin
Physical barrier epidermis (epithelial cells
with keratin, waterproof)
Epithelial cells anti-microbial peptide
Chemical barrier
Sweat glands sweat (salt)
Sebaceous gland Sebum (lipids)
fatty acids
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Mucous membrane
Physical barrier epithelia cells (single layer,
more vulnerable).
Anti-microbial peptide
Iron-binding protein (lactoferrin)
Enzymes lysozyme (tear, saliva), protease
Chemical barrier
Mucus / cilia (respiratory system)
Low pH (stomach)
antibodies
Competition (attachment site, nutrient)
Microbiological barrier normal flora (intestine)
Anti-bacterial proteins (colicin)
lumen
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Anti-Microbial Peptides
More than 500 anti-microbial peptides are found
in many species.
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Many anti-microbial peptides have clustering of
positively charged and hydrophobic amino
acids (amphipathic).
Red positively charged amino acids
Green hydrophobic amino acids
Anti-microbial peptides bind tighter to bacterial
membranes than eukaryotic cell membranes.
The outer leaflet of bacterial membrane
contains more negatively charged phospholipids.
Discrimination between Self and foreign
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Anti-microbial peptides disrupt bacterial
membranes.
Red positively charged
Greenhydrophobic
Amphipathic conformation
Anti-microbial peptides bind to Negatively
charged phospholipid
The hydrophobic part of anti-microbial peptides
interact with hydrophobic part of membrane
phospholipids and disrupt the membrane.
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Impaired ?-defensin Function in Cystic Fibrosis
Symptoms
Cystic fibrosis occurs 1/2000 among Caucasian
Children.
Abnormally thick mucus in the airway of lung.
High levels of bacteria in mucus.
Most patients die from severe lung infection.
Cause
Caused by mutation in CFTR gene (cystic fibrosis
transmembrane conductance regulator).
CFTR functions as Cl- channel in the plasma
membrane of epithelial cells.
Cystic Fibrosis patients show defects in ion
transport. Salt accumulates in the fluid lining
the airways.
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High Salt Concentration in the Airway Fluid of CF
Patient Interfere with Defensin Function.
Culture of epithelial cells from airways
Infect with bacteria (P. aeruginosa)
(S. aureus)
Determine the number of bacteria 24 hours later
CF epithelial cells
Expression of functional CFTR (Ad/CFTR) Expression
of irrelevant protein (Ad/?Gal)
Epithelial cells from CF patients fail to kill
Bacteria.
The defect can be corrected by expressing CFTR in
the epithelial cells of CF patients.
Bacterial infection
Determine the number of bacteria
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Epithelial cells
Cover epithelial cells with solution
containing high or low salt
Airway fluid of CF patients contains higher
levels of Cl-.
Infect with bacteria
Determine the number of bacteria
182mM Cl-
92mM Cl-
High salt concentration inhibits bacteria killing
by epithelial cells.
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Human ?-defensin-1 (HBD-1) is salt-sensitive Bacte
rial killing activity in airway.
Epithelial cells of lung airway
HBD-1 is a 36 amino-acid peptide expressed
in airway epithelial cells.
Bactericidal activity of HBD-1 is inhibited by
high salt.
Bacteria HBD-1
Incubate for 20 minutes
Count bacteria
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Mice deficient in cathelicidin are susceptible to
bacterial infection.
mice
Infection with bacteria
Wild-type mice
Cathelicidin deficient mice (-/-)
Measure lesion size
Normal amount of cathelicidin
Culture bacteria from lesion
Half the amount of cathelicidin
No cathelicidin
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Psoriasin (11 kDa protein) kills E.coli.
Psoriasin is expressed in the skin epidermis
(E), hair follicles (HF), Sebaceous gland (SG)
Toxicity specific for E.coli
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The barrier can be breached by pathogens.
Tetnus wound infections (Staphylococcus aureus)
Injury
wound
West Nile fever, Yellow fever, Malaria
Mosquito
Typhus, Lyme disease
Ticks
Insect or animal bite
Skin
Flea
Plague
Infected dogs
Rabies
Blood transfusion
Hepatitis B, AIDS
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Infection of Mucous membrane
Adherence to cells of the mucosal tissues through
adhesins on fimbriae (pili).
Fimbriae (pili)
E.coli adhere to surface of urinary tract.
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Pathogens can break epithelial barrier.
lumen
pathogen
Degradation enzyme
Internal tissue
Tight junction
P. gingivalis causes periodontal disease.
Epithelial cells are held together through cell
adhesion molecules (E-cadherin), which form tight
junctions.
Intact epithelial layer
P. gingivalis produces an enzyme that degrade the
cell adhesion molecules to break the epithelial
barrier.
epithelial layer exposed to P. gingivalis
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Pathogens can cross epithelial layer through
transcytosis.
M cells in intestine mediate transcytosis.
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Shigella invade intestines through M cells.
Arrow points to rod-shaped Shigella bacteria
within M cells.
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Pneumococci use IgA transport system to cross
bronchial epithelial cells.
pneumococci
IgA
IgA
Pneumococci internalized by epithelial cells
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Virus enter host cells through endocytosis.
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Summary
skin
Barrier
Mucosal surface
Block entry of pathogen
Function
Anti-microbial peptides damage bacterial membrane.
Kill pathogen
Pathogens may break the barrier.
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Questions
How do skin and mucosal surface prevent pathogen
entry?
How do anti-microbial peptides function?
Where are anti-microbial peptides produced?
How do anti-microbial peptides kill bacteria?
How do anti-microbial peptides distinguish host
cells from bacteria?
List a few other mechanisms.
Relevant part in textbook
p53-55, p59-61