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