Download Basic Concepts of Immunology

CLASS: Fundamentals I: 10-11
DATE: 9/23
PROFESSOR: Barnum
I.
Basic Concepts of Immunology
Scribe: Jordan Ridgeway
Proof: Heather Thigpen
Page 1 of 5
Immunology is Important to You as a future Clinician Because [S2]
a. Why do you care about immunology?
b. Failure of the immune system to cope with infection/trauma is the reason for many patient visits
i. Swelling and inflammation is caused by the immune system in an effort to remove infection
1. Cavities, gingivitis, eye infections cause pain – patients come to see you
c. Many people are more susceptible to infection and must be treated appropriately
i. Do they have allergies? Are they immune deficient?
1. You need to understand these mechanisms to understand how to treat patients safely
d. Immunological status of your patients dictates treatment decisions
e. Need to protect yourself and your staff from infection
II. Adaptive Immunity [S3]
a. There are certain classic “organs” of immune system
i. One is the thymus, behind the thyroid
1. This is where T-cells, a form of adaptive immunity, are formed
2. (B cells develop in bone marrow)
ii. The spleen – where many cells of immune system which handle blood-borne infections
iii. Lymph Nodes – scattered throughout the body
1. Small collections of lymphoid tissues/cells that clear infections locally
a. Handle cuts and local infections
b. All cells involved in immune system come from stem cells and series of precursors
i. Stem cells are given to cancer patients whose immune cells have been damaged by cancer treatment
c. Two of important parts of adaptive immune system are T and B cells
d. Macrophages and Neutrophils are part of Innate Immune System
i. Cells that encounter pathogens, eat them and kill them
e. Dendritic cells are “antigen presenting cells”
i. B cells and Macrophages can also be “antigen-presenting”
ii. These cells take pieces of pathogens that they’ve chewed up and put on surface so T cells can recognize
the specific pathogen
f. Mast Cells and Basophils are involved in allergy responses
g. Humoral (Soluble)
i. Most important are antibodies, aka Immunoglobin (Ig)
1. Several different types of Ig’s with different functions
ii. Cytokines are small chemical messengers which control the immune response
1. Development of immune cells from stem cells
2. Trafficking and movement to and from immune organs
3. Activation and differentiation of cells
4. Development of memory responses
5. Turning the immune response down
6. Control almost all aspects
iii. Complement
1. Proteins that kill invading pathogens, mark them for phagocytosis, or physically kill them through
pore-forming mechanism
iv. Acute phase proteins
1. Involved in handling infections and inflammation
2. Kick the immune response off quickly
v. Many different Enzymes and Antimicrobials that body produces to destroy pathogens
1. Humans make their own antibiotics in your skin, in the gut, in the lungs
III. Innate Vs Adaptive Immunity [S4]
a. Innate and Adaptive Immunity are systems working together
i. Innate is first line of defense to kick off immune response – can trigger adaptive immune response
ii. Sometimes adaptive system is not necessary – depends on nature and amount of pathogen
iii. If you are deficient in any of these, will cause problems because they work together
b. Response Time:
i. Innate Immune system is always there almost immediately
ii. Adaptive system can take days to a week
CLASS: Fundamentals I: 10-11
Scribe: Jordan Ridgeway
DATE: 9/23
Proof: Heather Thigpen
PROFESSOR: Barnum
Basic Concepts of Immunology
Page 2 of 5
1. Adaptive response has T cells and B cells that are specific to the pathogen
2. It takes time to activate these
c. Specificity: we don’t want to immune system to attack us – this is what happens with autoimmune diseases
i. The Innate immune system is specific for certain molecular patterns on pathogens only
1. Ex: Lipopolysaccharide found only on gram negative bacteria – humans don’t make that
2. In order to mediate this specificity, innate system doesn’t need a lot of diversity - Has handful of
germ line encoded receptors and molecules
ii. Adaptive system is extremely specific – even subtle changes in structure and antibody won’t be able to
recognize pathogen
1. When pathogens (viruses) mutate, this causes a problem – we have to create a new vaccine
2. Adaptive Immune system, b/c it’s so specific and changing - get a very large number of receptors
located on B cells and T cells
3. Receptors are generated by a process that occurs only in those types of cells where they rearrange
their genes
a. Cut their own DNA – dangerous in some ways but big payoff in terms of specificity
d. Memory:
i. Innate system has no memory
ii. Adaptive system has memory
1. When you find T and B cell that reacts to that pathogen, it expands many thousand fold
2. Some of these cells become memory cells and “hide” throughout the body
3. When you encounter pathogen again, instead of one or two B or T cells you have several thousand
that respond specifically to that pathogen
e. Discriminating Self vs Non-Self:
1. Innate system is very good at discriminating host from pathogen
2. Adaptive system has some failure in discriminating b/w the two – can have autoimmune disease.
a. We all have cells that are reactive to self
b. Process is under control by process called “tolerance” where system has learned not to
recognize self
c. Tolerance is a growing focus of research to eliminate autoimmune responses – we won’t get
into this much
d. There are mechanisms in development of T and B cells to prevent autoimmune responses
f. Soluble Components:
i. Innate: Lots of soluble components for innate system
1. Antimicrobial peptides, complement system
ii. Adaptive: Primary soluble protein for adaptive response are antibodies
1. Antibodies are everywhere – blood, tears, saliva, IgA in gut, there are antibodies in all of your tissues
g. Major Cell types
i. Innate response
1. Phagocytic cells: Macrophages, Neutrophils
2. Natural killer cells – good at eliminating virally infected cells
ii. Adaptive response: T cells, B cells, and antigen presenting cells are major cells
IV. Innate Immune Mechanisms of Protecting the Host [S5]
a. Most important component of Innate immune system is your skin
i. Reason burn patients die is because they get infections
ii. Skin has fatty acids produced in sebum that are bacteriostatic
iii. Have antimicrobials on skin to prevent bacterial infection
iv. pH of skin is slightly lower than neutral – prevents some growth
v. we have 100-200 normal types of bacteria on our skin
1. we have more bacteria in our body than our own cells
vi. Skin is first line of defense
b. Most infections are not through skin – usually through mucosal route – because you breathed it in or ate it
c. In mucosa in upper oral cavity, there are all kinds of antimicrobials, enzymes, antibodies
i. You swallow into stomach – low pH, digestive enzymes
ii. Intestine pH is high, has additional enzymes and microbial peptides
iii. Large Intestine - hard for pathogen to survive – compete with normal flora
1. Why you have diarrhea with antibiotics – because you kill off some of normal flora which allows
pathogens to find a niche
CLASS: Fundamentals I: 10-11
Scribe: Jordan Ridgeway
DATE: 9/23
Proof: Heather Thigpen
PROFESSOR: Barnum
Basic Concepts of Immunology
Page 3 of 5
2. Eventually pathogens are expelled from body through large intestine
d. Airway:
i. Lungs have cilia which constantly sweep things up out of lungs into the back of the throat so they can be
swallowed
ii. There are macrophages in the lungs that eat invading pathogens
iii. Lungs are basically sterile
e. Those are the common mechanisms of the innate immune system
i. Major pathways of getting infections is eating, drinking, or breathing in
V. Innate Immune Mechanisms of Protecting the Host [S6]
a. Phagocytosis – where invading pathogen is actively taken up by phagocytic cell
i. Macrophage or Neutrophil
1. Recognized by antibodies and complement proteins bound to the pathogen which the phagocytic cell
recognizes through receptors
2. Helps envelope pathogen
3. Then it sits in vacuole
a. Some bacteria will live there and adapt mechanisms to survive there
b. Can prevent subsequent steps from occurring and can invade the cytoplasm and sometimes
other cells
c. Most of the time the vacuole is joined with other vacuoles called lysosomes
i. Lysosomes have granules that have enzymes that chew up anything: protein,
carbohydrates, lipids, anything
ii. pH is low
iii. Have enzymes that produce free radicals that will damage pathogen
iv. Pathogens are chewed up into pieces and recycled or in the case of antigen presenting
cells, the pieces are sent to the cell surface and presented to T cells to proliferate the
response
b. Inflammation is a very beneficial process
i. This illustration shows if you get a small cut/sliver, it has bacteria
ii. Those bacteria will encounter phagocytic cells (macrophages and mast cells in skin)
1. They are activated by bacterial molecular pattern molecules which triggers inflammation
2. Inflammation is important because it enable blood cells to pass through the vessel and into the tissue
3. Vessels become leaky – plasma leaks into tissue, causes swelling or edema
a. That’s important b/c blood-born components (other phagocytic cells, complement proteins,
antibodies) can leave the vessel and kill bacteria before they can cause infection
VI. How Does the Innate Immune System Recognize Infection [S7]
a. Innate immune system is recognizing Pathogen Associated Molecular Patterns (PAMPs)
i. Examples: Lipopolysaccharides, lipoproteins, peptidoglycan, viral components like ssRNA
ii. PAMPs are recognized by Pattern Recognition Receptors (PRRs)
1. Collectin molecules: one is called mannose binding protein which binds cells with mannose on
surface – not many human cells have terminal mannose residues
2. C Reactive Protein (CRP) – molecule that recognizes phosphocholine which is common in bacteria,
but not in human cells
VII. Toll-Like Receptors (TLRs) [S8]
1. The most important group is the Toll-Like Receptors (TLRs) – molecules that recognize pathogens
extracellularly and intracellularly.
a. Important b/c there are intracellular pathogens like viruses that prefer to live inside cells as
opposed to outside
b. Don’t need to memorize these, just know that there are many kinds
c. TLRs don’t recognize only one specific pathogen, they recognize a certain structure of a
class of pathogen
i. Peptidoglycan is recognized by a certain TLR
ii. LPS is recognized by TLR type IV
iii. Specific TLRs for different types of viruses
iv. This method is much more efficient than adaptive response
v. This triggers an immune response – inside structure engages with intracellular
components, leading to production of cytokines specific to these pathogens which will
turn on the specific cell types to fight the particular pathogen
CLASS: Fundamentals I: 10-11
DATE: 9/23
PROFESSOR: Barnum
Basic Concepts of Immunology
Scribe: Jordan Ridgeway
Proof: Heather Thigpen
Page 4 of 5
VIII. Adaptive Immunity [S9]
a. Active Immunity: Encountering a pathogen, probably getting sick, then clearing the infection and developing
a memory response
i. Or, another way is to be vaccinated – take a part of the pathogen that creates a good immune response
and inject it to patient to create a memory response
b. Passive Immunity: you have protection without having encountered the pathogen before
i. You give antibodies – through breast milk (IgA) – whatever mother has developed IgA antibodies for, the
child will be protected from
1. Gives protection from local environment
ii. Also give antibodies via placenta (intrauterine) – IgG antibodies
1. After a few months, antibodies wane away – child’s immune system has to kick in
iii. Also give antibodies prophylactically
1. Example: If you get a snake bite – will give antivenom – antibodies for a specific snake
2. If you are exposed to Hepatitis C - give a gamma globulin shot
c. Humoral Immunity: Talking just about antibodies (immunoglobulins)
i. Specific Ig’s produced by B cells that have differentiated into Plasma Cells
1. Can be triggered to produce 10,000/s
d. Cell-Mediated Immunity: see next slide
IX. Adaptive Immunity [S10]
a. Cell-Mediated Immunity – T and B cells (T cells primarily)
i. T cells also known as lymphocytes
ii. T helper (Th cells) produce cytokines that direct and regulate immune response
1. There are subsets of Th cells based on cytokines they produce
a. Th1 cells – involved in cell-mediated immunity
i. Cytokines turn on Cytotoxic T cells (Tc cells)
1. Tc cells directly kill infected cells in your body
2. Punch holes in infected cell and deliver contents that will trigger
apoptosis
3. Sacrifice some cells to limit the infection
b. Th2 cells – produce cytokines related to generation of antibody
Question from class: You’re saying Th1 cells help Tc cells develop?
- Yes, Th1 cells produce cytokines which will trigger Tc cells to mature to become active Tc cells.
- Likewise Th2 cells produce cytokines which help B cells mature and that helps determine which antibody those B
cells will produce
X. Adaptive Immunity [S11] - Some important points
a. Specificity
i. Innate Immune System just recognizes pattern type molecules, but the adaptive response recognizes
almost anything with exquisite specificity
1. For example, if you took one (recognized) molecule and injected it into a rabbit, you could make
specific antibodies very quickly and nicely
2. But if you subtly change that molecule and inject it into the same rabbit, the system will not recognize
it initially, just because of that small change
3. You can make antibodies specific to both of those
4. The response is extremely specific and diverse
b. Diversity – there are lots of different T and B cells, each with an antigen receptor – they only recognize one
specific antigen at a given time
i. They do this through gene rearrangements
ii. Estimates that we can recognize 10^9 different antigens
1. How? We would have to create 10^9 different antibodies
a. Total DNA code is 3x10^9 bp – Germ line is not large enough to encode all the different
possible receptors – why gene rearrangement is necessary
c. Memory
CLASS: Fundamentals I: 10-11
Scribe: Jordan Ridgeway
DATE: 9/23
Proof: Heather Thigpen
PROFESSOR: Barnum
Basic Concepts of Immunology
Page 5 of 5
i. When a B cell encounters an antigen that will cause it to expand – B cell undergoes clonal expansion
ii. If you have 100 B cells lined up and only 1 is responsive to that pathogen, that one is the only one that is
going to develop into an antibody producing cell and the other 99 will wait around
1. You only turn on the cells that you need, then they clonally expand – then you have thousands of
those cells which can become effector cells (in the case of B cells to produce antibody) then some of
those cells can become memory B cells which can expand much more quickly the next time you
encounter that pathogen
d. Self-Limiting Response – if you don’t turn these cells off, you’ll have tons of them
i. Lots of mechanisms to turn these cells down:
1. Cytokines – certain anti-inflammatory cytokines such as TGF Beta for example that helps tamp down
immune responses
2. T Regulatory cells – help tamp T cell responses back down
3. These processes are turned on really at start of immune response so that as the immune response
expands, they develop at the same time so they can turn the response down based on the specific
circumstances
4. Short-Lived – production of different cytokines are turned on only for a short time unless they are
triggered by a signal that continually pushes them up
5. Part of this is driven by how much pathogen is present
e. Recognition of Self vs Non-Self
i. This is largely what immune system is about – ability to recognize pathogen, but not your own tissue
ii. Tricky because you make many T and B cells in bone marrow and thymus and lots of those cells are selfreactive
1. Estimated that 99% of T cells never leave the Thymus – they die b/c they couldn’t make a good
receptor or because they reacted to self
2. So most do not make it out – there is always some escape though – probably a major cause of
autoimmune disease
a. Many of these cells are controlled by process called “tolerance”
[End 48:05 mins]