Download Microbiology: Basic Concepts of Immunology pg. 1 Haleigh Stidham

Microbiology
08/18/2008
Basic Concepts of Immunology
Transcriber: Haleigh Stidham
58:42
Scott Barnum:
o
Recommends book
o If you have never had Immunology—buy book or borrow it from a friend
o Lecturers will use figures and information from book
o There are good diagrams/figures/text
o Best way to reach is by e-mail: [email protected]
o Encourages asking questions throughout the course. Don’t be scared.
o Material covered in immunology is rather cumulative and complex at first, and then it will pick
up and inter-relate to get the “big picture”
o If you have trouble in the beginning…it is not going to get easier
o Get help if you need it!
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Slide 1: BASIC CONCEPTS OF IMMUNOLOGY
Slide 2: Why should you care about immunology? Why is it interesting?
1. There are situations in our careers that occur because of the failure of the immune system to
cope with infections or trauma. It’s mostly due to the host’s response to the
infection/pathogen.
2. Another important feature is the immunological status of your patient will dictate how you treat
these patients
a. i.e. radiation, chemotherapy, AIDS, genetic deficiencies—all have depressed immune
systems and more susceptible to infections
b. Will encounter patients who are deficient in one component and how you treat that
patient will determine how they come out (better or worse)
3. You also have to protect yourself and your staff from patients with colds, Tb, etc.
a. You need to be able to take the appropriate precautions to prevent spreading the
disease to yourself, staff, and other patients
Slide 3: What is immunology?
1. Old study that comes from the Greek word “immunitas” which is Latin for exempt. Originally
meant exempt from being prosecuted from Roman senators.
2. What it really refers to is protection from infectious disease => “immune”
3. Hundreds of years ago when plagues would run through cities, there would always be somebody
who didn’t get sick. These people would stand out because they could help people and not get
sick. Those people were considered to be immune.
4. Or those people who got the disease, didn’t get very sick, survived it, and the next time the
disease came through they didn’t get sick at all.
5. There was this idea that in fact maybe you could become immune to everything, which of
course is not true. But that is the idea, that people were immune to disease.
6. Say you got a cold, are you immune from getting colds in the future? No.
7. Why is that? You should have made nice antibody responses.
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 2
8. Over time the organism mutates, which allows the pathogen to keep infecting us and keeps the
immune system on its toes.
a. That is why we put out a new flu vaccine every year—because it mutates.
9. Definition: Immunology is the study of the molecular and cellular events that occur when an
organism encounters a pathogen or foreign substance.
a. It doesn’t always have to be a foreign substance. Ex: autoimmunity
What are the components that make up the immune system?
1. The immune system in a broad sense is made of a number of different cell types and organs
(primarily the thymus and bone marrow—where lymphocytes are made) and a number of
humoral, or plasma/blood derived, components (these are soluble molecules that compose
important components of the immune system)
a) For the immune system in terms of cells and organs, you will hear in the next lecture the
primary and secondary organs (ex. bone marrow, thymus, spleen, lymph nodes, etc.)
b) T and B cells are critical players in the adaptive immune response
c) Macrophages and neutrophils which play a role in the innate immune response (play a role
in phagocytosis invading pathogens and clearing them out)
d) Dendritic cells and macrophages are known as Antigen Presenting Cells (APCs) because in
order for an adaptive immune response to occur, T cells have to see bits and pieces of
invading pathogens. They see these because these APCs chew up antigens and present them
in small pieces. T cell sees the bits and pieces rather than the whole organism and becomes
activated accordingly.
e) Mast cells are important for allergic responses.
f) Antibodies – key players produced by B cells that are involved in targeting antigens for their
removal.
i) Antibodies—think “humoral”
ii) Antibodies don’t actually kill anything.
iii) They bind to things and then one end of the antibody molecule has specific receptors
that determine the fate of the pathogen.
g) Lots of other molecules that are involved in regulation of the immune response:
i) Cytokines – from start to finish help drive developmental responses and help in the
development and maturation of the immune response. These cells can become effector
molecules. They are also shut the immune system down.
ii) Complement proteins, enzymes, acute phase proteins (help eliminate pathogens), a
number of anti-microbial that are produced by a number of cell types.
2. We need both the adaptive and innate pathways of the immune system in order to fight off
invading pathogens.
Slide 4: Innate versus adaptive immunity… (Memorize this slide. Hint, hint.)
1. Two types of broad categories of immune responses:
a) Innate immune response (IIR)
i) Occurs very quickly. Almost immediately.
ii) The main difference is that it is NOT specific!!
iii) NO sensitivity or specificity!
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 3
iv) NO memory….won’t recognize virus if you get it again and won’t get better any faster
v) Examples are macrophages, neutrophils, NK cells, dedritic cells
b) Adaptive immune response (AIR)
i) VERY specific
ii) HIGHLY diverse
iii) Has memory…the next time you are exposed to the virus, you can recover much more
quickly
iv) Generally pretty good at discriminating against self vs. non-self, with the exception of
autoimmune diseases
v) Examples are T cells, B cells, and APCs
2. These two immune responses overlap in their function and they can’t do without each other. They
work together to take care of invading pathogens. You need both arms of the systems to take care
of the pathogens.
a) So if you are missing one component of either response you are going to have a pretty serious
immunodeficiency
b) If you are missing B-cells, the innate immune response will be intact, but will not do as good of
job of eliminating some pathogens
c) If you are missing key component of the complement system, which is part of the innate
immune response, you are going to have lots and lots of bacterial infections throughout your life
unless there is a way they can supplement that protein
Compare/Contrast innate and adaptive
1. Response time
a) IIR is present all the time and it works immediately.
i) As soon as you encounter a pathogen various aspects of the IIR are doing their best to try to
eliminate the pathogen by preventing entrance or trying to kill it or sending signals to other
cell types.
b) AIR takes days.
i) If you get a cold it takes about 7-10 days.
ii) That is because it takes the AIR to find the appropriate T and B cells with the right specificity
in order to eliminate that virus. AIR has memory.
iii) So the next time you encounter, instead of having just a few T and B cells that are specific,
now you will have many more so that AIR can much more rapidly respond in the second
phase/encounter immune response.
2. Specificity
a) IIR is not very specific in its responses.
i) Can respond to thousands of different bacteria, viruses, pathogens of all different sorts
b) AIR is highly specific
i) Any given T cell is only going to react with one given type of bacteria or one given type of
virus/fungus
ii) Same for B cells
3. Diversity
a) IIR is not particularly diverse in its responses
b) AIR is highly diverse
i) It has been estimated the AIR can react with as many as 10 9-10 different pathogens in a very
specific fashion.
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 4
ii) Reason is that T and B cells have genes that are rearranged that allow you to mix and match
pieces of proteins so that you can get antibodies or T cell receptors with unique specificities.
iii) Basically it means you can make antibodies to almost anything you can encounter in the
world.
iv) The AIR can generate a hugely diverse repertoire of antibodies or T cells receptors to deal
with pathogens.
4. Memory
a) IIR, even though it can react very quickly to invading pathogens, has no memory
i) The next time it encounters the pathogen it is not going to respond any differently than the
first time it encountered that pathogen
b) AIR has very specific memory
i) Every time you encounter a bacterium, you clear the infection, and the immune system
cycles back to homeostasis, you are going to be left with a handful of memory cells that are
specific for that invading pathogen.
ii) Instead of the 2-5 clones initially, now you have several hundred.
iii) So the next time you encounter the pathogen, you will respond much more quickly, usually
within a few days rather than a week or two.
5. Self/Non-Self Discrimination
a) You certainly want the immune system to recognize the bacteria that has caused the infection,
but you don’t want them to activate in response to your own tissues.
b) IIR is non discriminatory in this regard.
i) IIR will attack your own tissues, just as well as it will invading pathogens because it can’t tell
the difference between you and the pathogen.
ii) It just doesn’t have that level of specificity.
iii) So part of the immune response is to generate molecules that help control the IIR, to initiate
repair, and also to generate molecules that will lessen the damage of these molecules to
your own tissue.
iv) Your body is basically willing to take a hit in order to clear an invading pathogen.
c) AIR is very good at recognizing self vs. non-self.
i) There is a whole process that occurs in the thymus early in development where your T cells
basically learn to recognize you and not to attack those tissues or molecules.
ii) Does this always work? No. We have lots of autoimmune diseases.
(1) The immune system is actually so powerful and determined to get rid of invading
pathogens, that the mechanisms it uses can damage your tissues significantly.
(2) Almost all of the autoimmune diseases we have are mediated by all different aspects of
the immune system that have come in and been inappropriately activated and damaged
tissue in response to this.
(3) The immune system uses very potent mechanisms to kill invading pathogens, but it can
damage your own tissue as well.
Slide 5: Components of IIR
1. IIR has a lot of different mechanisms to eliminate invading pathogens:
a) Anatomical Barriers – somebody who gets burns basically dies of infection. They have lost the
primary protection against invading pathogens.
i) Skin is one of the most important barriers on the outside to preventing invading pathogens.
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 5
(1) Not just the physical aspect, there are also defensins on your skin that are anti-microbial
to prevent other bacterial species from colonizing the skin.
(2) Skin also has a slightly low pH, which for some bacteria is not a hospitable environment.
ii) On the inside, you have mucosal tissue along the wall, gut, GI tract, is all mucosal tissue
covered in mucus.
(1) Without it you would be highly susceptible to infection.
(2) There are all kinds of cells lining various parts of the mucosal immune system that are
critical for developing immune responses to pathogens that you breathe and eat.
(3) It turns out that most of the time what you actually breathe and eat is what causes
infections. It is what you eat or what gets sneezed into your face is how you get colds,
sinus infections, and GI problems.
b) Physiological Barriers
i) Stomach – has a very low pH and not a hospitable environment.
ii) If they should manage to make it through the stomach into the intestines, you have bile
salts, a much higher pH (you have gone from a low pH to a very high pH)
iii) When you get into the large intestine you have a large number of bacteria that just live
there normally.
iv) Everyone in here has normal flora in their intestinal tract which is critical. When you take
antibiotics, you end up with diarrhea because you have wiped out your own bacteria.
v) You have these bacteria as a normal part of modulating an immune response.
Slide 6: Couple other aspects of the innate immune response
1. Phagocytosis
a) Couple of main cell types that are good at this, professionals
i) Neutrophils and macrophages
ii) Aka: professional phagocytic cells.
b) Other antigen presenting cells (dendritic cells) can also engulf invading pathogens and eliminate
them
c) Key thing to do – you want to take these guys in, chew them up, and kill them so that they do
not cause infection
d) Phagocytosis is an example of a bridge between IIR and AIR because some of the cells that are
going to take in bacteria/viruses are going to break them into little pieces and put them on MHC
Class II molecules and put them on the surface of their cells so that T cells can see those
molecules (usually peptides) and recruit the adaptive immunes response.
i) That’s what T cells recognize in the immune response, these little peptides and the MHC
molecules that hold them.
e) Phagocytic cells chew up these molecules in part to give you these peptides and present the
antigen to T cells.
2. Another part of the IIR is Inflammation
a) When you get a cut on your skin, you activate lots of cells types that are present there
b) Mast cells get activated that de-granulate to release histamine and other vaso-active amines
which cause the blood vessels to dilate; cytokines cause edema, inflammation, and swelling at
the site which makes it easier for blood borne components like macrophages and neutrophils to
get from the blood into the sites of infection.
c) Also makes is easier for blood borne molecules (those of the complement system/antibodies) to
get into the site of infection.
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 6
d) Inflammation is a critical part of the immune response because it gives you increased access for
the components into a site that might be somewhat difficult to get to.
Slide 7: How does the IIR recognize infection?
1.
The innate immunes system recognizes molecules called Pathogen Associated Molecular Patterns
(PAMPs) that are on invading pathogens.
a) There are specific receptors that recognize microbial components (PAMPs).
b) There are receptors that recognize LPS (component of the cell wall on bacteria), lipoproteins,
peptidoglycans, all which can be on different types of bacteria, different types of single or
double stranded RNA (components of viruses), and flagellan.
2. These are the molecules that are being recognized by the IIR and the receptors that are mediating
this recognition are Pattern Recognition Receptors (PRRs).
a) This whole concept of PAMPs and PRRs is something that has come up in the last 10-15 years
and has revolutionized how people understand innate immunity.
b) Some of the PRRs are found on T and B cells and are molecules like collectins, C-Reactive Protein
(CRP) and manos-binding proteins, which kicks off the IIR.
Slide 8: Toll-like Receptors
1. TLRs: These are the molecules that really recognize a huge array of structural features on invading
pathogens (viruses and bacteria).
2. In humans there are now about 13 different toll-like receptors.
3. This is a structurally and functionally conserved group of molecules that goes all the way back to
flies.
i) First recognized in Drosophila (fruit flies).
ii) This is something that is evolutionary—very conserved way down the line.
b) Toll-like receptors are on the surface of the cell where they are going to encounter invading
pathogens like bacteria or fungus.
c) There are also toll-like receptors inside the cell. These are very important in virus recognition
because they do their replicating inside the cell.
i) So, the toll-like receptors inside the cell send the appropriate signal to mediate the
appropriate response depending on the encountered pathogen.
d) There is a list of what these different toll-like receptors recognize. It is not very complete and is
much more complex. Don’t memorize this slide, just be familiar with TLRs.
e) They recognize things like LPS, peptidoglycan, flagellan (not a component of human tissues), etc.
(1) TLR-4 binds to LPS on bacteria
(2) TLR-3 and TLR-7 bind to RNA molecules in viruses
Slide 9: Adaptive Immune Response
1. There are a number of different terms in different textbooks to AIR
a) Active Immunity – basically means you got infected and developed an immune response. Or by
an immune response that occurs in response to vaccination (immunization) or by actually
encountering the pathogen.
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 7
b) Passive immunity – protection without actually encountering the organism. It is mediated by
antibody transfer.
There are a couple of classic examples ( 2 really good ways)
i) In utero:
(1) The mother passively transfers her own antibodies to whatever she is immune to during
pregnancy, but she only transfers IgG molecules.
(2) Also in breast milk where IgA molecules are transferred.
(3) So whatever the mother is immune to in these two different classes of antibodies, the
baby will at least be transiently immune to as well.
ii) Snake bite:
(1) If you get a nasty snake bite, they are going to give you anti-venom (antibodies that
have been raised in a horse or goat, for example, that will be directed toward all those
different toxins in the bite). Hopefully, it will neutralize it so that you will not die.
(2) The next time you get bit by that snake, are they going to give you that anti-venom
again? No. Because in that anti-venom are horse or goat antibodies. Do you have any
horse antibodies floating in you right now? Hope not.
(3) That means the immune system is going to recognize this the first time as a foreign
antigen. It is going to make antibodies to it and amount an immune response to it, and
you will develop anti-horse antibodies. Antigen/antibody complexes can lodge in your
tissues, know as “Serum Sickness.” It is not uncommon for somebody who has been
given anti-venom materials to have swelling and pain in their joints.
c) Humoral immunity - immunity mediated by antibodies produced by B cells.
i) Then B cells will differentiate into Plasma Cells and produce antibodies.
ii) Plasma cells will flood the body with antibodies specific to that invading pathogen.
iii) They will also form memory cells and continually secrete small amounts of that antibody.
d) Cell-Mediated immunity - immunity mediated by T cells.
i) T helper cells (TH cells)
(1) Antibody mediated immunity
(2) These are a subset of T cells in the immune response that produce lots of different
cytokines (the molecules that help regulate immune responses).
(3) Their function is to basically direct the immune response depending on the type of
pathogen that has been encountered.
(a) TH1 => INF-gamma and important for TC cell development
(b) TH2 => IL-4 and important for TH cells
ii) Cytotoxic T cells (TC cells)
(1) These cells can actually lyse virally infected cells or other types of infected cells that
have intracellular pathogens.
(2) Their job is to go around and identify virally infected cells and kill them. There are lots of
other different types of T cell subsets.
Slide 10: Lymphocytes
1. Schematic picture of the B cell
a) On the surface of the B cell you see antibodies. On every given B cell, there are multiple
antibodies, membrane bound antibody, which is always the exact same antibody on one given B
cell. Every antibody on the surface of that B cell is identical and has identical specificity because
B cells can only recognize one given antigen.
2. These are T helper cell and T cytotoxic cells
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 8
a) One way these molecules/cell types are distinguished from each other are these surface
molecules called CD antigens
i) CD4 in the case of T helper cells
ii) CD8 in the case of cytotoxic T cells.
b) What T cells use to recognize their specific pathogens is the T cell receptor. They have lot of
copies of the T cell receptor on their surface. But each T cell receptor on a given T cell is
identical and recognizes only one peptide that might be presenting by an antigen presenting
cell.
Slide 11: Adaptive Immunity
1. The adaptive immune response is highly specific and highly diverse in its ability to respond to
invading pathogens.
2. It has been estimated that there are approximately 109 different invading pathogens that you can
recognize. So you have 109 different antibodies too! But you don’t have 109 different antibody
genes.
3. Memory—Generation of antigen specific memory clones, memory T cells. This gives you faster and
more sensitive responses on re-exposure to that antigen.
4. Self-limiting responses—You don’t want your body to continually generate millions and millions of
these clones until your spleen and lymph nodes are all filled up with these T cells. As soon as you
eliminate the pathogen, the immune system isn’t getting the signal to respond anymore, and it
tamps itself down. One mechanism of regulation of the immune response is a response in
proportion to the amount of pathogen you are encountering. Cytokines are produced for only a very
short period of time. That is why the cytokines are released very shortly after the pathogen invades.
If not, toxic shock syndrome (TSS) can occur and your body releases too much Tumor Necrosis
Factor Alpha (TNF-a) and can become septic and die.
5. Regulatory loops— There are also signals by cytokines and other mechanisms that are responsible
for tamping this response down. Most of the cells die off pretty quickly. That is why your body
responds much more quickly when you get sick the second time around.
6. Tolerance—The recognition of self versus non-self. T cells developing in the Thymus learn to
become tolerant of self. They are eliminated in the thymus or in the periphery. These are in place
to help eliminate autoimmunity. Basically your immune response tolerates you. If we could get the
immune system to tolerate more things, we could eliminate a lot of autoimmune diseases. A lot of
work is being put into understanding this mechanism of tolerance and a therapeutic response to
autoimmune diseases.
Microbiology: Basic Concepts of Immunology
Haleigh Stidham
pg. 9