Lecture 1: The Immune System From historical to modern perspectives
The Immune System
Immune system: a system of tissues, cells and soluble products that recognize, attack and destroy entities that can endanger
our health when they enter our bodies
Four major classes of pathogens:
1. Bacteria (e.g. salmonella)
2. Virus (e.g. rhinovirus)
3. Fungi
4. Parasite (e.g. malaria)
Immune Response
There are 4 stages of immune system and 3 challenges associated with each step
1. Recognition: pathogens are highly varied in structure and evolve quickly
2. Response: pathogens replicate or produce toxins quickly
3. Returning to resting: collateral damage to healthy tissue caused by immune response
Smallpox
Disease caused by virus variola major - no animal reservoir
o Causes small fluid filed vesicles on skin
Variolation: inoculation with material from small pox pustule to produce immunity
o vaccination
o Very bad because it spread disease even more
o Edward Jenner paved the road for vaccination when he realized cowpox (attenuated version of small pox) could
produce immunity
Germ Theory of Disease
Louis Pasteur & Robert Koch began isolating and characterizing organisms that could only bee see under a microscope
The germ theory proposed that microbe are organisms too small to be seen by eye, and some cause specific diseases
Koch developed techniques for cultivating pure cultures of bacteria
Louis Pasteur
Realized he could induce acquired immunity in chickens
He made two major discoveries;
1. Fermentation
2. Pasteurization
Disproved the spontaneous generation of microorganism
Cellular v Humoral Immunology; A Century-Long Dispute
Metchnikoff theorized and demonstrated that human white blood cells similarly engulf and destroy pathogens like bacteria
o Demonstrated that phagocytes represent a first line of defence
o He was a cellularity; believed that phagocytes, not antibodies, played a prominent role in immunity
Paul Ehrlich was a humoralist and believed soluble anti-toxins(antibodies) were responsible for immunity
o Anti-toxins (according to Ehrlich)
Anti-toxins were receptors with lock and key structure
Bind to infectious agent to a anti-toxin would cause release and production of more the anti-toxin receptors
He thought that cells express several different anti-toxins which is false
o MacFarlane revised Ehrlich theory with clonal selection hypothesis:
Each lymphocyte makes one kind of antibody
“Antigens” stimulate the clonal proliferation of lymphocytes that make an antibody that recognizes a
particular antigen
Lymphocytes
Two major types of lymphocytes that look the same up until they mature:
1. B cell: Produce antibodies
i. Differentiate into plasma cells
2. T cell: produce cytokines
i. Help antibody production
Strategies used by Immune Cells
There are several strategies used by immune cells to eliminate infectious agents or protect against infection
o Killer cells which induce cell death in virally-infected cells
o Pre-existing antibodies block access of the virus to its cellular receptor
Protecting target cells from infection
o Phagocytes ingest extrasellar bacteria
, o Degranulating cells (e.g. neutrophil) release granules containing toxic molecules to kill antibody coated parasites
Lecture 2: Innate Immunity: First Line of
Defense
Requirements
There are 8 requirements for infectious disease:
1. Reservoir
2. Transmission to host
3. Invasion through a portal of entry
4. Adherence to host tissue
5. Infection
6. Temporary evasion of host defenses
7. Disease: interference with normal host function
8. Exit and transmission
Clinical and subclinical infection
Most of the time our innate mechanisms of defense are sufficing to avoid the establishment of infection → sub-clinical
infection
When the immune system is defective, same microbes that are normally controlled cause opportunistic infections
Pathogens causing acute infections are cleared by innate and adaptive effectors
What is a pathogen
A bacteria, virus, or microbe that posse’s inherent ability to cross anatomical barriers and causing disease in healthy person
o Posses genes encoding virulence factors that increase their effectiveness
Flagella
Adhesion
Effector proteins: proteins from the bacteria that hijack host cell
proteins to allow bacterial entry
and survival inside the cell
toxins
Koch's Postulate
Contains 4 postulates:
1. Pathogen has to be in all diseased individuals and not healthy organisms
2. Pathogen is isolated from diseased individual and grown in culture
3. Put pathogen in healthy individual
4. Remove pathogen and see if it identical to original causing factor
Pylori
Causes ulcers - proven by Marshall
Used to be part of normal microbiota but in late 90s became eradicated through antibiotics
Microbes and Humans
Infectious disease can come about in several ways:
1. Some bacteria are entirely adapted to the pathogenic way of life in humans.
2. Some bacteria acquire extra virulence factors making them pathogenic
3. Some bacteria from the normal flora can cause disease if they gain access to deep tissues by trauma
4. In immunocompromised patients, many free-living bacteria an can cause disease
Growing recognition of the link between microbes and chronic diseases
Ulcer shows ink between pylori and stomach cancer
Cervical cancer can be caused by papilloma virus
Drug-resistant microbes
Nosocomial (hospital acquire) infections are antibiotic resistant
There are 3 factors that contribute to hospital acquired infections:
1. Surgery's
2. Immunocompromised hosts
3. Contamination (chain of transmission)
Antibiotic resistance
excessive use in farming
Excessive and unnecessary antibiotics given to patients
, Patients not completing cycle
First Line Defense Strategies
There re two types of barriers in first line of defense:
1. Chemical and biological barriers:
i. Lysozyme
a. Enzyme that breaks the cell wall of bacteria by attacking the bond that keeps together the two
sugar components of peptidoglycan
ii. Antimicrobial peptides of skin and gut kill microbes
iii. Stomach acid and enzymes inhibit bacterial growth
iv. Microbiota outcompete pathogenic microbes in body
2. Physical barriers:
i. Mucus and cilia
ii. Epithelial cells of skin and mucosal surfaces
a. Skin epithelium is also multilayered
ii. Gut mucus keeps particles and microbes at a safe distance from epithelial layer
Defensins
Natural peptide antibiotic that is cationic which disrupts pathogen membrane layer by creating a pore
Innate Immunity Receptors
Innate immune cells recognize conserved features of infectious pathogens called PAMPs & MAMPs
o PAMPs & MAMPS are recognized using PRR (PATTERN RECOGNTION RECEPTORS)
PAMPS
Components of the bacterial cell wall represent a source of pamp (e.g. LPS on gram negative bacteria)
PAMPs are conserved molecular structures present on pathogens
o On bacteria: LPS, peptidoglycan, flagellin
o On viruses: ssRNA, dsRNA
o On fungi: several glycans
o On parasites: GPI anchors
Bacteria can be differentiated into 2 groups based on the gram stain of cell wall:
o Gram +ve stain purple with crystal violet while gram +ve stain red
Gram +ve & -ve staining
Gram +ve cell walls have a single membrane enclosed by thick cross-linked sugars these sugars take up dye and make
bacteria appear purple
Gram -ve bacteria have a thin cell wall which can take up purple but easily washed out and takes up counter stain (red)
Toll
Toll-like Receptors (TLRs) were the first PPR discovered
The human toll is TLR4 and it is the receptor for LPS
Human TLRs: cellular location and ligands
TLR1/2/6/4/5 are membrane receptors
TLR3/7/8/9 are intracellular receptors
Ligand → receptor → recruits’ adaptor → kinase phosphorylates → intimidate signalling molecules → metabolic change,
cell movement, or gene transcription
Recognition of LPS and signalling through TLR-4
LPS → TLR4 → IKK(adaptor) → IkappaB degrades (kinase activity) → NFkappaB enters cytosol and will induce
transcription of pro-inflammatory cytokines
Lecture 3: The acute inflammatory response: Cellular and humoral mediators of
innate defense
Cellular and humoral mediators of innate defense
Cells of the innate system = phagocytes, mast cells, NK cells
o All use phagocytosis
Secreted mediators of the innate system = cytokines & complement system
Innate and adaptive immunity work together to clear infections;
The Immune System
Immune system: a system of tissues, cells and soluble products that recognize, attack and destroy entities that can endanger
our health when they enter our bodies
Four major classes of pathogens:
1. Bacteria (e.g. salmonella)
2. Virus (e.g. rhinovirus)
3. Fungi
4. Parasite (e.g. malaria)
Immune Response
There are 4 stages of immune system and 3 challenges associated with each step
1. Recognition: pathogens are highly varied in structure and evolve quickly
2. Response: pathogens replicate or produce toxins quickly
3. Returning to resting: collateral damage to healthy tissue caused by immune response
Smallpox
Disease caused by virus variola major - no animal reservoir
o Causes small fluid filed vesicles on skin
Variolation: inoculation with material from small pox pustule to produce immunity
o vaccination
o Very bad because it spread disease even more
o Edward Jenner paved the road for vaccination when he realized cowpox (attenuated version of small pox) could
produce immunity
Germ Theory of Disease
Louis Pasteur & Robert Koch began isolating and characterizing organisms that could only bee see under a microscope
The germ theory proposed that microbe are organisms too small to be seen by eye, and some cause specific diseases
Koch developed techniques for cultivating pure cultures of bacteria
Louis Pasteur
Realized he could induce acquired immunity in chickens
He made two major discoveries;
1. Fermentation
2. Pasteurization
Disproved the spontaneous generation of microorganism
Cellular v Humoral Immunology; A Century-Long Dispute
Metchnikoff theorized and demonstrated that human white blood cells similarly engulf and destroy pathogens like bacteria
o Demonstrated that phagocytes represent a first line of defence
o He was a cellularity; believed that phagocytes, not antibodies, played a prominent role in immunity
Paul Ehrlich was a humoralist and believed soluble anti-toxins(antibodies) were responsible for immunity
o Anti-toxins (according to Ehrlich)
Anti-toxins were receptors with lock and key structure
Bind to infectious agent to a anti-toxin would cause release and production of more the anti-toxin receptors
He thought that cells express several different anti-toxins which is false
o MacFarlane revised Ehrlich theory with clonal selection hypothesis:
Each lymphocyte makes one kind of antibody
“Antigens” stimulate the clonal proliferation of lymphocytes that make an antibody that recognizes a
particular antigen
Lymphocytes
Two major types of lymphocytes that look the same up until they mature:
1. B cell: Produce antibodies
i. Differentiate into plasma cells
2. T cell: produce cytokines
i. Help antibody production
Strategies used by Immune Cells
There are several strategies used by immune cells to eliminate infectious agents or protect against infection
o Killer cells which induce cell death in virally-infected cells
o Pre-existing antibodies block access of the virus to its cellular receptor
Protecting target cells from infection
o Phagocytes ingest extrasellar bacteria
, o Degranulating cells (e.g. neutrophil) release granules containing toxic molecules to kill antibody coated parasites
Lecture 2: Innate Immunity: First Line of
Defense
Requirements
There are 8 requirements for infectious disease:
1. Reservoir
2. Transmission to host
3. Invasion through a portal of entry
4. Adherence to host tissue
5. Infection
6. Temporary evasion of host defenses
7. Disease: interference with normal host function
8. Exit and transmission
Clinical and subclinical infection
Most of the time our innate mechanisms of defense are sufficing to avoid the establishment of infection → sub-clinical
infection
When the immune system is defective, same microbes that are normally controlled cause opportunistic infections
Pathogens causing acute infections are cleared by innate and adaptive effectors
What is a pathogen
A bacteria, virus, or microbe that posse’s inherent ability to cross anatomical barriers and causing disease in healthy person
o Posses genes encoding virulence factors that increase their effectiveness
Flagella
Adhesion
Effector proteins: proteins from the bacteria that hijack host cell
proteins to allow bacterial entry
and survival inside the cell
toxins
Koch's Postulate
Contains 4 postulates:
1. Pathogen has to be in all diseased individuals and not healthy organisms
2. Pathogen is isolated from diseased individual and grown in culture
3. Put pathogen in healthy individual
4. Remove pathogen and see if it identical to original causing factor
Pylori
Causes ulcers - proven by Marshall
Used to be part of normal microbiota but in late 90s became eradicated through antibiotics
Microbes and Humans
Infectious disease can come about in several ways:
1. Some bacteria are entirely adapted to the pathogenic way of life in humans.
2. Some bacteria acquire extra virulence factors making them pathogenic
3. Some bacteria from the normal flora can cause disease if they gain access to deep tissues by trauma
4. In immunocompromised patients, many free-living bacteria an can cause disease
Growing recognition of the link between microbes and chronic diseases
Ulcer shows ink between pylori and stomach cancer
Cervical cancer can be caused by papilloma virus
Drug-resistant microbes
Nosocomial (hospital acquire) infections are antibiotic resistant
There are 3 factors that contribute to hospital acquired infections:
1. Surgery's
2. Immunocompromised hosts
3. Contamination (chain of transmission)
Antibiotic resistance
excessive use in farming
Excessive and unnecessary antibiotics given to patients
, Patients not completing cycle
First Line Defense Strategies
There re two types of barriers in first line of defense:
1. Chemical and biological barriers:
i. Lysozyme
a. Enzyme that breaks the cell wall of bacteria by attacking the bond that keeps together the two
sugar components of peptidoglycan
ii. Antimicrobial peptides of skin and gut kill microbes
iii. Stomach acid and enzymes inhibit bacterial growth
iv. Microbiota outcompete pathogenic microbes in body
2. Physical barriers:
i. Mucus and cilia
ii. Epithelial cells of skin and mucosal surfaces
a. Skin epithelium is also multilayered
ii. Gut mucus keeps particles and microbes at a safe distance from epithelial layer
Defensins
Natural peptide antibiotic that is cationic which disrupts pathogen membrane layer by creating a pore
Innate Immunity Receptors
Innate immune cells recognize conserved features of infectious pathogens called PAMPs & MAMPs
o PAMPs & MAMPS are recognized using PRR (PATTERN RECOGNTION RECEPTORS)
PAMPS
Components of the bacterial cell wall represent a source of pamp (e.g. LPS on gram negative bacteria)
PAMPs are conserved molecular structures present on pathogens
o On bacteria: LPS, peptidoglycan, flagellin
o On viruses: ssRNA, dsRNA
o On fungi: several glycans
o On parasites: GPI anchors
Bacteria can be differentiated into 2 groups based on the gram stain of cell wall:
o Gram +ve stain purple with crystal violet while gram +ve stain red
Gram +ve & -ve staining
Gram +ve cell walls have a single membrane enclosed by thick cross-linked sugars these sugars take up dye and make
bacteria appear purple
Gram -ve bacteria have a thin cell wall which can take up purple but easily washed out and takes up counter stain (red)
Toll
Toll-like Receptors (TLRs) were the first PPR discovered
The human toll is TLR4 and it is the receptor for LPS
Human TLRs: cellular location and ligands
TLR1/2/6/4/5 are membrane receptors
TLR3/7/8/9 are intracellular receptors
Ligand → receptor → recruits’ adaptor → kinase phosphorylates → intimidate signalling molecules → metabolic change,
cell movement, or gene transcription
Recognition of LPS and signalling through TLR-4
LPS → TLR4 → IKK(adaptor) → IkappaB degrades (kinase activity) → NFkappaB enters cytosol and will induce
transcription of pro-inflammatory cytokines
Lecture 3: The acute inflammatory response: Cellular and humoral mediators of
innate defense
Cellular and humoral mediators of innate defense
Cells of the innate system = phagocytes, mast cells, NK cells
o All use phagocytosis
Secreted mediators of the innate system = cytokines & complement system
Innate and adaptive immunity work together to clear infections;
