Transcript 16-Immune
Lecture 16
Immune System
The Price of Affluence
Our bodies provide our cells with a:
Safe
Nutrient-rich
Temperature & pH optimized
environment.
This is quite attractive to other
organisms that do not belong to
our body
Many of these provide value and
help maintain the environment by:
Breaking down macromolecules we
can’t
Synthesizing needed nutrients
Keeping harmful organisms in check
There Are Some Bad Apples
They destroy or degrade
the environment by:
Competing for nutrients
Overloading the system
with toxins
Taking over and destroying
cell machinery
Killing body cells
These are the disease
causing organisms our
body must defend against
What Does the Enemy Look Like?
A wide range of organisms try to exploit our bodies:
How would you approach this problem?
First line of defense: Secure the Borders
Prevent a problem from occurring in the first place
Skin and mucosae prevent entry of microorganisms
Second line of defense: Mobilize Quickly to Block a Breach
Antimicrobial proteins, phagocytes, and other cells localize the
invasion
Inflammation is the hallmark and most important mechanism
Repair of the border is the ultimate solution
Third line of defense: Hunt Down Successful Invaders
Profile the enemy (this takes time)
Catch, immobilize, & destroy invaders in the body fluids
Identify, destroy, & remove body cells already infected
The Players & Their Tools:
1st Line of Defense: Secure the Borders
Skin, mucous membranes, and their secretions create a barrier
Keratin in the skin:
Presents a formidable physical barrier to most microorganisms
Is resistant to weak acids and bases, bacterial enzymes, and toxins
Mucosae provide similar mechanical barriers
Mucus-coated hairs in the nose trap inhaled particles
Mucosa of the upper respiratory tract is ciliated
Cilia sweep dust- and bacteria-laden mucus away from lower respiratory
passages
Epithelial membranes produce protective chemicals that destroy
microorganisms
Skin acidity (pH of 3 to 5) inhibits bacterial growth
Sebum (ear wax) contains chemicals toxic to bacteria
Stomach mucosae secrete concentrated HCl and protein-digesting
enzymes
Saliva and lacrimal fluid contain lysozyme
Mucus traps microorganisms that enter the digestive and respiratory
systems
2nd Line of Defense: Mobilize Quickly
The body uses nonspecific cellular and chemical devices
to protect itself
Phagocytes and natural killer (NK) cells
Antimicrobial proteins in blood and tissue fluid
Inflammatory response enlists macrophages, mast cells, WBCs,
and chemicals
Harmful substances are identified by surface
carbohydrates unique to infectious organisms
Phagocytes: Police the Fluid Areas
Macrophages are the chief
phagocytic cells
Free macrophages wander
throughout a region in search of
cellular debris
Kupffer cells (liver) and microglia
(brain) are fixed macrophages
Neutrophils become phagocytic
when encountering infectious
material
Eosinophils are weakly phagocytic
against parasitic worms
Mast cells bind and ingest a wide
range of bacteria
Natural Killer (NK) Cells: Look for Infected Cells
NK cells can lyse and kill cancer
cells and virus-infected cells
Natural killer cells:
React nonspecifically and eliminate
cancerous and virus-infected cells
Kill their target cells by releasing
perforins and other cytolytic
chemicals
Secrete potent chemicals that
enhance the inflammatory response
Proteins Used To Kill Invading Microbes:
Complement
Complement system
~ 20 different proteins that
separately are inactive
Aggregate to form a Membrane
Attack Complex (MAC)
Kills invading microbes by
forming holes in the cell
membrane
Amplifies all aspects of the
inflammatory response
Our cells are immune to
complement
Is a major mechanism for destroying
foreign substances in the body
Proteins That Warn Neighbors of Invading Microbes:
Interferon (IFN)
Genes that synthesize IFN are
activated when a host cell is invaded
by a virus
Interferon molecules leave the
infected cell and enter neighboring
cells
Interferon stimulates the neighboring
cells to activate genes for an antiviral
protein (PKR)
PKR nonspecifically blocks viral
reproduction in the neighboring cell
FDA-approved alpha IFN is used:
As an antiviral drug against hepatitis
C virus
To treat genital warts caused by the
herpes virus
The Inflammatory Response
The inflammatory response is
triggered whenever body tissues
are injured
Prevents the spread of damaging
agents to nearby tissues
Disposes of cell debris and
pathogens
Sets the stage for repair
processes
Can be broken down into three
stages
1.
2.
3.
Injured tissue, phagocytes,
lymphocytes, and mast cells
release histamine and
prostaglandins
The four cardinal signs of acute
inflammation are:
These chemicals cause blood
vessels to expand and become
more permeable causing redness
and swelling
1. Redness
Neutrophils, then monocytes &
macrophages migrate to the site of
infection or injury
4. Pain
2. Heat
3. Swelling
Fever
Abnormally high body temperature in response
to invading microorganisms
The body’s thermostat is reset upwards in
response to pyrogens
These are chemicals secreted by leukocytes
and macrophages when exposed to bacteria
and other foreign substances
High fevers are dangerous as they can
denature our own enzymes
Fevers are not used to directly kill invaders
Fevers greater than 40.6oC (105oC) are often
fatal
Moderate fever can be beneficial:
The primary benefit is an increase in the
metabolic rate, which speeds up tissue repair
(1o in temperature = 10 X metabolic increase)
It also causes the liver and spleen to sequester
iron and zinc (needed by microorganisms),
which may help slow infectious growth
3rd Line of Defense: Attack Invaders
Acquired (or adaptive) immunity is a functional system that:
Recognizes specific foreign substances
Acts to immobilize, neutralize, or destroy them
Amplifies inflammatory response and activates complement
The adaptive immune system:
Is antigen-specific
An antigen is a molecule that provokes a specific immune response
Is systemic
It is not restricted to any region of the body
Has memory
Some “educated” cells remain after the invader is gone
It has two separate but overlapping arms
B cells: humoral immunity (body fluid)
T cells: cellular immunity
It is the most complex and slowest to respond
It has to activate cells for each new invader (antigen)
On first exposure it takes ~ 10 days to reach peak levels
B cells: Catching Invaders in the Body Fluids
Originate and mature in the
bone marrow
To help you remember the
name, you can think of the
“B” as standing for where
they mature in humans:
Bone marrow
Circulate in blood and lymph
Proliferate upon antigen exposure into:
Plasma cells
That produce antibodies
Memory cells
That provide a quick response on re-exposure
T cells: Destroying Infected Cells
Originate in bone marrow and mature in the Thymus
Develop ability to identify foreign agents by antigens present on cell surfaces
Four main types of T cells
Helper (TH) – Initiate the immune response (authorize the attack)
Cytotoxic (TC) – Lyse virus-infected cells (licensed to kill)
Memory (TM) – Provide a quick response on re-exposure (keep watch)
Suppressor (TS) – Terminate the immune response (declare victory)
What is the 1st Step in Identifying the Enemy?
Know Thy Self!
Every cell in the body carries surface markers called Major
HistoCompatibility (MHC) proteins
MHC proteins are different for each individual
So they act as “self” markers
Antigen-presenting cells
Ingest foreign particles and partially digest them
They combine pieces of the foreign particle with MHC proteins & move
them to the surface of their cell membrane
T cell receptors can only interact with cells that have this combination of
MHC and antigen
Initiating the Immune Response
Macrophages inspect the surface of cells looking for “self” MHC proteins
If a cell displays MHC protein-antigen (“self”/“nonself”) combinations the
macrophage will secrete the protein interleukin-1 as an alarm signal,
The CD4 protein is required to “authenticate” the transaction
Interleukin-1 stimulates helper T-cells to initiate:
Cellular immune response by T cells
Humoral immune response by B cells
T-cells: The Cellular Response
Once activated, the helper T cells secrete interleukin-2 which:
Activates cytotoxic T cells (TC cells) to recognize and destroy cells with the
specific antigen found on the antigen-presenting cell
Stimulates proliferation of these activated TC cells
Cytotoxic T cells will also attack transplanted tissue and cause graft
rejection
The drug cyclosporin inactivates TC cells
B-cells: The Humoral Response
B cells recognize invading microbes, but do not go on the attack themselves
They produce antibodies that inactivate and mark the pathogen for destruction
by non-specific immune defenses
B cells can bind to free and unprocessed antigens
Antigens are endocytosed, processed and presented on the surface with an
MHC protein
Helper T cells recognize this complex and stimulate B cells to proliferate into
memory cells and plasma cells, which produce antibodies
Mechanisms of Antibody Action
All antibodies form
an antigenantibody (immune)
complex
Antibodies
themselves do not
destroy antigen;
they inactivate and
tag it for
destruction
Antibody Diversity
Immune receptor genes are
assembled by a process called
somatic rearrangement
DNA segments that code for
different parts of the receptor
molecule are stitched together
Further antibody diversity is
generated by:
Imprecise DNA rearrangements
Random mutations
Plasma cells
Produce large amounts of the
same antibody that initiated the
immune response
B cells can make between one
million and one billion different
antibody molecules
Antibodies in Blood Transfusions
Blood typing
Rh factor
ABO system is the major group of RBC antigens
The immune system is tolerant to its own antigens
People who are Type A, make antibodies against
the B antigen
People who are Type B, make antibodies against
the A antigen
People who are Type AB, do not make either anti-A
or anti-B antibodies
People who are Type O, make both anti-A and antiB antibodies
Another group of antigens found on RBCs
Rh-positive people have them; Rh-negative people
don’t
Of particular significance when Rh-negative mothers
give birth to Rh-positive babies
Mother may be exposed to fetal blood and thus
produce anti-Rh antibodies
A subsequent Rh-positive pregnancy leads to
erythroblastosis fetalis
Can be prevented by injecting the mother with
anti-Rh antibodies
Primary & Secondary Immune Responses
The primary immune response is
the first encounter with a foreign
antigen
Only a few B cells or T cells can
recognize the antigen
Binding of an antigen to its
receptor on the lymphocyte
stimulates cell division
A clone is produced
This process is called Clonal
selection
Memory B cells Circulate blood
and lymph, waiting for future
exposure
Secondary immune response is
faster and amplified about a
millionfold
Types of Acquired Immunity
Immunity comes in two forms
Active: where the organism
has their own “educated” cells
Passive: where the organism
acquires only the antibodies
from another source
Summary of How the Immune Response Works
Play
Immune Response
Supporting Infrastructure
Lymphatic system
Central location for storage and
distribution of immune cells and
proteins
A network of capillaries, ducts,
nodes and organs
Some Invaders Trick the Immune System
Mycobacterium tuberculosis
Resists the cell destroying
enzymes and replicates in the
macrophages of the lungs
When the immune system finally
does respond, the bacterium is
protected by a thick waxy wall
HIV (human immunodeficiency
virus)
Mimics an antigen presenting cell by
activating the macrophage & helper T
cells CD4 receptors
Instead of an antigen it injects its own
RNA and 3 enzymes
The immune cells surround the
bacterium, walling it off (creating a
tubercle) but not killing it
The RNA is transformed into DNA and
incorporates with the macrophage or
TH cell’s DNA
The bacterium becomes dormant
until something acts to weaken the
immune system
At that time it begins to replicate
again, causing a new outbreak
Play
How HIV Infection Works
In TH cells, replication destroys the
cell and leaves the immune system
unable to mount a response to any
foreign antigen (AIDS)
A variety of otherwise
commonplace infections prove
fatal
Death by cancer becomes far
more likely
When Profiling Becomes Harassment
Allergies
Body mounts a major defense against a harmless substance
Hay fever
House dust mite
Mast cells initiate the inflammatory response
Release histamine
Capillaries swell mucus production increases
Asthma, histamine causes the narrowing of air passages in the lungs
When the Immune System Makes a Mistake
Autoimmune Diseases
Cytotoxic T cells and B cells lose their ability to distinguish “self”
cells from “nonself” cells
The body attacks its own tissues
Examples:
Multiple sclerosis
Type I diabetes
Rheumatoid arthritis
Lupus
Graves’ disease