IMM250H1 Study Guide - Midterm Guide: Innate Immune System, Adaptive Immune System, Edward Jenner

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Published on 16 Jul 2018
IMM250 Lecture 1Immune System, From Historical to Modern Perspectives
Notes under slides not talked about in class and not on slides is NOT tested; textbook information not talked about in slides/talking about NOT tested
Immune System
= system of tissues, cells, soluble products that recognize, attack & destroy foreign entities that can endanger health when they enter our bodies
Classes of pathogens (smallest to largest):
(1) virus 20-800 nanometers obligate, intracellular, host machinery to reproduce influenza
(2) bacterium 0.2-20 micrometers prokaryote (no nucleus), multiple lifestyles staphylococcus
(3) fungus 2 nano-cm eukaryotic (yes nucleus), some outside cell some inside candida
(4) protozoal parasite 10-200 nanometers single-cellular, 2+ hosts, some outside cell come inside malaria (mosquito to human)
(5) multicellular parasite 1-3 centimeters multiple life cycles in bodies, too big to be inside cells tapeworms
Stages of the immune response
(1) Entry of a pathogen
(2) Recognition of pathogen challenges: pathogens varied in structure | pathogens mutate & evolve quickly escape recognition by immune system (HIV)
(3) Response to pathogen challenges: replicate quickly, or produce toxins quickly
e.g. E.coli reaches 108 in 12-18 hours; urinary infections at 105 (100,000) bacteria/mL
e.g. bacterium that causes diphtheria makes 5000 toxin mol’c/hr
Infection can occur anywhere in the body, have to survey different areas and respond at different sites
(4) Return to resting challenges: immune-induced disease can be caused if immune response out of control (immunopathology)
Collateral damage to healthy tissues caused by immune response = symptoms like fever, response to infection
Mechanisms of defense against infection
(1) Physical barriers = epithelia of skin, lungs airways, GI tract, urogenital tract
(2) Innate cells & soluble factors (innate immunity)
(3) Adaptive cells & antibodies (adaptive immunity) ON as a result in innate immunity
(4) Host integrity & immunity (host back to baseline state, and increase immunity to subsequent infection)
Barriers (effective immediately)
Stomach: chemical barrier, highly acidic
Skin: mechanical barrier
Innate immunity (effective in min-hrs)
Cells & mol’cs recruited to site of infection
Adaptive immunity (effective in days-weeks)
Cells & mol’cs like antibodies recruited to site of infection
Delayed but confers long-lasting immunity and memory of infection (after innate immunity)
Milestones in history of immunology
Immunitas = to be exempt from, Latin
used when Roman senators exempted from public service & legal prosecution
Immunity = exempt from illness or disease
History of infection & immunity
First concept of immunity in context of disease
Peloponnesian war between Sparta and Athens
Sparta’s victory believed to be due to illness that killed Athenian army
Thucydides, a Greek historian, documented the war
and made the connection between people who recovered from the illness and their resistance to secondary infection (first documented case of immunity)
and suggested people who had recovered should be treating others being infected for the first time
but did not put name “immunity” and did not know the cause of the disease
Caused by Variola major, human virus with no animal reservoir (which is unusual, most viruses/bacteria also infect some animals, then transfer to humans)
Causes small, fluid-filled vesicles/pox on skin, people often die, people who recover have extensive scarring and blindness, kills 1/3 of people infected
Killed 1/3 of the European population in 1700’s
First recorded in India, Ancient Egypt, China
Smallpox brought to the New World by Europeans (came to Mexico)
Smallpox in Mexican population helped Europeans (Spanish) colonists conquer Mexico
Smallpox outbreak contributed to American defeat in Battle of Quebec (Brit vs. American)
Tried to control smallpox by variolation = take pustule/scab from smallpox make paste scratch into skin of someone w/o smallpox protection (worked a little)
Lady Mary Wortley brought idea back to Europe
used prisoners and orphans as guinea pigs showed although people contracted mild illness, most survived and became immune
Variolation was popular in aristocrats, then became common in all people
Problem: giving people live virus and inoculating it into their skin still hazardous and resulted in death of some individuals, and spread of disease
Edward Jenner, noticed milkmaids did not contract smallpox, used to milk cows,
cows had a disease that looked similar to smallpox (cowpox), milkmaids would contract mild form of cowpox by touching udders, get pustules on hands
Milkmaids protected from developing smallpox, cowpox less virulent
Edward Jenner hypothesized that he could inoculate people with cowpox virus to induce immunity to smallpox & cowpox
pus from pustule on hand of milkmaid and inoculated James with it got a little sick but recovered inoculated serious case of smallpox (variolation)
boy did not develop any symptom = suggesting that boy had acquired immunity to smallpox
Vacca = cow in Latin vaccination
Vaccination against smallpox has lead to eradication of the disease, WHO said vaccination eradicated smallpox from earth (no animal reservoirs of virus, only in 2 labs)
Smallpox immunization (vaccination) spread across North America and Europe, mandatory for infants
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What is the crucial point of the landmark experiment performed by Edward Jenner on a young boy?
A. He discovered how to distinguish mild smallpox from virulent smallpox
B. He performed for the first time a pioneering form of vaccination called variolation
C. He discovered a route of variolation which would not result in overt disease
D. He proved that a previous exposure to cowpox can protect from a smallpox infection
First successful immunization worldwide was in 1800s, against smallpox
Thought disease was caused by ‘bad air’ you breathe in, need better understanding of mechanisms of infectious disease to advance immunization
Did not have understanding of germs or infectious disease, immune response, how to immunize against other diseases
Antoine van Leeuwenhoek, discovered microbes with a microscope, did not know these germs caused infectious diseases
Microbe organisms too small to be seen by eye (virus, bacteria, fungi)
Pathogen microbes that are disease-causing, given pathogen causes specific illness (Koch’s Postulates)
The Germ Theory of Disease
Louis Pasteur & Robert Koch isolated and characterized bacteria and organisms in pure culture, observed under microscope, proposed Germ Theory of Disease
Discovered that anthrax caused by bacterium Bacillus anthracis, and that tuberculosis caused by Mycobacterium tuberculosis
Culture in pure form, inoculate healthy mouse, see if disease caused, see if can culture same microorganism
Spontaneous generation life-forms spontaneously arise from other lifeforms/inanimate objects, e.g. milk turns broth-y b/c micro-organisms spontaneously (i.e. maggots)
Pasteur disproved spontaneous generation by proving the Germ Theory of Disease
Pasteur’s experiment disproving spontaneous generation
Put broth inside flasks, applied heat to make sure broth was sterile (killed organisms by heat), let sit
Observed bacteria not present under microscope, could not culture bacteria, broth clear
Repeated experiment, but removed the neck, allowing air and particles to enter
Observed that bacteria were present, broth cloudy
Repeated experiment with a tilted flask, allowing air and particles to enter
Observed bacteria were present again, broth cloudy
Pasteur’s attenuated germ cultures
Extended Edward Jenner’s immunization approach using attenuated germ cultures
Found could still induce protective immunity to virulent cholera using an attenuated (dead) cholera culture
Cholera (Vibrio cholera), accidentally left culture of cholera over days
Tried to inoculate chickens but realized only had dead bacteria (did not have broth to survive)
But still induced immunity to cholera in chickens
Did same w/ anthrax bacteria, attenuated bacteria, injected cows, immune against live forms of infection
Did same w/ rabies vaccination, infection you get from rabid animal bites, 100% fatality once bitten
Use attenuated rabies virus to induce immunity after bite
Pasteur = disproved spontaneous generation of microorganisms, fermentation, pasteurization (use w/ milk to make sure no contaminating microorganisms)
Joseph Meister bit by rabid dog, knew what rabies wasbitten by animal with rabies, would die went to see Pasteur, tried to vaccinate against rabies, saved his life
Rabies caused by inoculation of virus into humans through bites from rabid animals
Causes inflammation of brain, always fatal
Can vaccinate people who have already been bitten, can protect against further symptoms and death
Why is rabies not vaccinated against?
RARE, only 4-5 cases of human rabies in the U.S./year (cost vs. risk vs. benefit)
Dogs are vaccinated against rabies since are most likely to transmit to humans
Vaccination post-exposure works, not usually the case (is because symptoms of rabies occur slowly, so after bite, infection spread to brain can be blocked)
How does immunity work to protect from infection?
Cellular immunology vs. humoral immunology
(1) Cellular immunology
Lead by Ilya Metchnikoff, thought cells within us protecting us and triggering immunity to infectious disease
Cellularists believe cells (WBCs/phagocytes) protect us from infection
Used starfish larvae to study how cells protect us from infection
Starfish larvae are transparent, can see cells circulating in microscope, see how cells react to induced injury
Skin of starfish larva poked by rose thorns
Cells normally in vessels crawled out of vessels went towards point of injury
Rose thorns put particles in tissue cells would migrate to site and engulf
Called cells phagocytes feeding cells; process = phagocytosis = engulfment/eating
Showed that cells in human blood also capable of phagocytosis
WBCs recognize microbe engulf & encase in phagosome enzymes in phagosome kill
Metchnikoff won Nobel prize WBCs phagocytosis 1st line of defense against pathogens
(2) Humoral immunology
Lead by Paul Ehrlich, soluble factors/proteins secreted to blood confer immunity; won Nobel for side-chain theory
Von Behring and Kitasato experiment
Serum (non-coagulated yellow serum after spinning down blood, no cells, all soluble factors)
Inject serum from previously exposed animal prevent disease in naïve animals
serum = anti-toxin (antibodies) (proof that something in serum confers immunity in exp)
Experiment: diphtheria toxoid (bacteria Corynebacterium diphtheriae produces toxin diphtheria
Causes Croup in kids, coughing
Injected attenuated/heated/inactive diphtheria toxin into healthy rabbit
rabbit became vaccinated against diphtheria isolated serum from vaccinated rabbit’s blood injected into other healthy rabbit
injected virulent diphtheria (high diphtheria toxin production) in vaccinated serum rabbit & non-serum rabbit serum lived, non-serum died
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Antitoxins = antibodies = central components of humoral immunity
Ehrlich came up with “side-chain theory”
Antibodies are receptors that have structural complementarity to a toxin, bind to the toxin in lock-&-key fashion
Toxin + antitoxin causes production and release of more receptors (more antibodies secreted into blood, immunity b/c will bind antigens/toxins)
Frank MacFarlane Burnet revised Paul Ehrlich’s theory Clonal Selection Hypothesis (is what happens)
Each antibody/antitoxin is specific product of one cell (unlike Ehrlich who thought cells have several kinds), on cell surface (same as Ehrlich)
Antigens react with cells that carry appropriate specific receptors (antibodies/antitoxins) induce cells to proliferate & differentiate
Some cells differentiate to form clones of same antibody-forming cells (clonal selection & clonal expansion)
Both cellular and humoral immunity involved in immune response
Cellular immunity: WBCs/leukocytes can phagocytose and kill pathogens | type of leukocytes = lymphocytes can produce antibodies
Humoral immunity : soluble serum proteins = antibodies that bind to bacterial toxins/antigens
and complement (group of enzymatic proteins that clear pathogens)
Which of the following is incorrect about Paul Ehrlich’s side-chain theory?
A. Anti-toxins bind toxin in a “lock & key” fashion
B. Each cell makes one kind of antitoxin specific for one type of toxin
(FALSE, thought they had a repertoire of antibodies,
but Frank MacFarlane Burnet showed each cell has one type of receptor
to allow for clonal expansion of cell to increase cells with that antibody receptor on them)
C. Interaction of toxin and antitoxin induces that cell to produce more antitoxin
D. The theory was the basis of his Nobel prize in 1908
Most experiments are on adaptive immunity (learned immunity)teaching immune system to respond to antigen/infection e.g, serum injection from animal w/ prior exposure
Metchnikoff’s experiments on starfish larvae showed that immunity could also be innate, without prior exposure (innate immunity)
Charles Janeway brought innate immunity back into spotlight, wondered why vaccination only works when you add adjuvants
Adjuvants inject w/ a protein antigen, but also add some kind of mineral oil or allum or PAMPs (pathogen-associated molecular patterns) which are microbial products
adjuvants recognized by innate immune system prime/activate adaptive immune system to recognize antigen you are injecting as a foreign substance
Protection against pathogens relies on LEVELS of defense
Innate immunity
1. Anatomic barriers skin, oral mucosa, respiratory epithelium, intestine
2. Complement/antimicrobial proteins C3, defensins, RegIII
3. Innate immune cells macrophages, granulocytes, natural killer cells
Adaptive immunity
4. Adaptive immunity B cells/antibodies, T cells
Innate immunity is REQUIRED to induce adaptive immunity
All immune cells (white blood cells/leukocytes) are formed from hematopoietic [of blood origin] stem cells (HPSC)
HPSC common lymphoid precursor (CLP) & HPSC T cell OR B cell OR NK cell = cells of adaptive system
HPSC common myeloid precursor (CMP)
monocyte/macrophage/dendritic cells OR granulocyte = cells of innate system (NK both)
RBCs, platelets
3 main ways immune cells eliminate infectious agents/protect agains infection
1. Direct killing
Specialized phagocytes (macrophages, neutrophils) detect & engulf phagosome (specialized organelle) kill intracellularly
2. Killing of infected cells
Lymphoid cell of adaptive system, NK cells & cytotoxic T cells
Kill infected cells by inducing apoptosis, preventing pathogen replication and release of microbes i.e. viruses
3. Expulsion or tissue repair
Larger parasites i.e. Intestinal worms
Cells of myeloid lineage, innate system cells (granulocytes, eosinophils)
recognize worms trying to get through intestinal barrier
secrete nasty chemicals to (1) kill it w/ extracellular expulsion (2) block ability to bind to epithelial cells in intestine
Innate immunity
first line of defense against infection/injury
constitutively present in all plants & animals
all blue on right = WBCs/leukocytes
T cell B cell and NK cells = lymphocytes
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Document Summary

Imm250 lecture 1 immune system, from historical to modern perspectives. Notes under slides not talked about in class and not on slides is not tested; textbook information not talked about in slides/talking about not tested. = system of tissues, cells, soluble products that recognize, attack & destroy foreign entities that can endanger health when they enter our bodies. Classes of pathogens (smallest to largest): (1) virus (2) bacterium (3) fungus (4) protozoal parasite (5) multicellular parasite. Infection can occur anywhere in the body, have to survey different areas and respond at different sites (4) return to resting challenges: immune-induced disease can be caused if immune response out of control (immunopathology) Collateral damage to healthy tissues caused by immune response = symptoms like fever, response to infection. Innate cells & soluble factors (1) physical barriers (2) (3) adaptive cells & antibodies (4) host integrity & immunity.

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