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Integrated Defence System
Immune responses can be subdivided into two categories – innate (natural) and
acquired (antigen-specific).
Innate immunity is present at birth and is not related to previous exposure. Innate
immunity involves non-specific defence strategies, which prevent the entry and
limit the spread foreign invaders.
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Innate (Non-specific defences)
Physical and chemical barriers make up the body’s first line of defence – if you
can keep invaders out, they cannot harm the body. Physical barriers include the
skin, mucous membranes of the conjunctiva, respiratory tract, as well as
gastrointestinal and genitourinary tracts. Chemical barriers include stomach acid,
which disables swallowed pathogens, and lysozyme, which attacks and digests
bacteria.
In addition to physical and chemical barriers, a number of other public safety
groups are involved in non-specific defence:





phagocytes (neutrophil, monocyte/macrophage, eosinophil) engulf debris
and foreign invaders (discussed earlier – link to phagocytosis)
specialized lymphocytes known as natural killer (NK) cells perform
immunological surveillance in the tissues and destroy abnormal
(cancerous) and virus infected cells (air-force surveillance or elite force of
marksmen)
interactions between specialized lymphocytes that capture foreign
antigens (T-lymphocytes or T-cells and “present” them to another
specialized type of lymphocyte (B-lymphocytes or B-cells) stimulating
antibody production
a complex chemical communication system that coordinates defence
against viral infection complement – a system of proteins that assist
antibodies the inflammatory response that restricts the spread of invasion
and is involved in emergency response – paramedics, fire-fighters and
police
fever accelerates metabolism and enhances immune response
Lymphocytes
As you will recall, there are three main types of lymphocytes – B-cells, T-cells
and NK cells.
Link to antibody production: http://www.cellsalive.com/antibody.htm
B-cells
B-cells are produced in the bone marrow (“b” for bone) and are involved in
protection conferred by antibodies (humoral immunity). In the bone marrow, Bcells mature to the point where they express antigen receptors – IgM antibodies
– on their surfaces. Once matured (trained and armed), they move out of the
bone marrow (training center) to lymphoid organs (military bases such as the
spleen and lymph nodes).
Link
to
B-cell
maturation:
http://www.bio.davidson.edu/Courses/immunology/Flash/Bcellmat.html
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The surface of each B-lymphocyte is coated with as many as 100,000 nonsensitized antibody molecules attached to the B-cell surface by their Fc ends
(base of the “Y” structure of the antibody molecule), and arms (Fab segments)
extended like antennae sniffing out foreign antigens. B-lymphocyte antibodies
bind to viruses and bacterial toxins to prevent them from affecting host cells and
begin production of antibodies specific for the antigen detected.
Link
to
Antibody
molecule:
http://www.biology.arizona.edu/immunology/tutorials/antibody/structure.html
There are millions of different populations of B-cells in the body, each population
binds to specific antigens circulating in the blood stream and becomes activated
(sensitized).
The IgM antibodies expressed on the surface of the B-cells are capable of
responding to one specific antigen or to a few closely related antigens. Once
dispatched to an alert (chemical communication forces at site of invasion –
phagocytes, memory cells) resulting from detection of foreign antigen in the
home nation, B-cells become activated by contact with the foreign antigen and
confirmation provided by T-cell binding to the target cell surface – T-cells provide
the second key or code for weapons use.
Activated B-cells (pleural) begin cloning two forms of it-self (singular) – memory
cells and plasma cells. Plasma cell production greatly outnumbers memory cell
production at this point, and following initial activation, B-cells generally change
their antibody class from IgM to IgG, IgA, and sometimes IgE (Link to page 15 –
Antibody classes and link from page 15 back to page 9). Changes in antibody
class are directed by cytokines produced by T-cells.
Memory cells do not take part in the initial direct battle – they persist, travelling
the nation after the enemy has been defeated providing rapid preliminary
defence and calling out new forces (chemical communication) if the antigen ever
attempts to re-enter.
B-cells also possess a variety of receptors on their surface including complement
receptors and glycoproteins. The structure of these glycoproteins is genetically
determined and coded by major histocompatability complex (MHC) proteins.
There are two classes of MHC protein – Class I and Class II. MHC proteins are
also known as human leukocyte antigens (HLA). MHC class I (MHC-I) proteins
are found on all nucleated cells, while MHC class II (MHC-II) proteins are found
mainly on macrophages, B-cells, and dendritic cells.
Link
to
MHC
I
antigen
http://www.bio.davidson.edu/Courses/immunology/Flash/MHCI.html
loading:
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Link
to
MHC
II
antigen
http://www.bio.davidson.edu/Courses/immunology/Flash/MHCII.html
loading:
When viruses or bacteria invade a cell, they are ingested and disassembled into
fragments inside the cell (weapon destruction program), loaded onto an MHC-I or
MHC-II platform, and delivered to the cell surface for display (through a process
known as exocytosis).
The number of B-cells is enormous – only about one in every 100,000 B-cells will
recognize a specific antigen.
T-cells
T-cells develop in the thymus gland (“t” for thymus) from immature lymphocytes
that migrate there from the bone marrow. T-cells may be found in the thymus,
lymph nodes and blood circulation.
There are three types of T-cells that vary with respect to their function:
cytotoxic T-cells (TC-cells) – responsible for cell-mediated immunity helper Tcells (TH-cells) – stimulate T-cell and B-cell response suppressor T-cells (TScells) – moderators of T- and B-cell activity
Cytotoxic T-cells (TC cells)
TC-cells contain CD8 receptors to recognize foreign antigen fragments
(remnants of invasion), displayed on MHC-I containing cells, as infected or
cancerous and kill the cells to prevent replication (doesn’t sound very fair, but I
suppose you can’t be too careful in protecting against double-agents).
Link to Cytotoxic T-cell movie: http://www.cellsalive.com/ctl.htm
Link
to
Cytotoxic
T-cell
killing
http://www.bio.davidson.edu/courses/movies.html
its
target:
Helper T-cells (TH cells)
TH-cells are also referred to as T4-cells because they present CD4 on their cell
surface. T4-cells recognize foreign antigen fragments displayed on MHC-II
containing cells and secrete cytokines to improve immune response. T4-cells are
essential for activation of B-cells, additional T-cells, natural killer cells, and
macrophages in response to bacterial, viral, parasitic or fungal invasion.
T4-cells also bind to B-cells and promote their differentiation into plasma cells
and memory cells. There are two subpopulations of TH-cells – TH1 and TH2.
CD4 is the receptor for the human immunodeficiency virus (HIV) associated with
AIDS.
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Link
to
Helper
T-cell
message
interpretation:
http://www.hhmi.org/biointeractive/animations/tcell/tcell_frames.htm
Suppressor T-cells (TS cells)
TS-cells act as moderators (United Nations) and inhibit T-cell and B-cell activity
when it is excessive.
Link
to
T-cell
http://www.bio.davidson.edu/Courses/immunology/Flash/Main.html
selection:
Immune regulation
T-cells act as regulators of the immune system attacking cells that are malignant
or defective, stimulating T-cell and B-cell activation, killing foreign pathogens or
infected cells, and even suppressing the immune response.
Inactive T-cells have receptors that recognize antigens bound to MHC proteins
on the surface of citizen cells of the homeland (remnants of infection or abnormal
processes). T-cell receptors are protein complexes that bind to MHC-antigen
complexes on citizen cells displaying abnormal antigen fragments.
T-cells are activated when antigen fragments bind to T-cell receptors. Like
antibodies, T-cell receptors are specific for only one antigen and are capable of
distinguishing self from non-self. Once antigen attachment has taken place, that
cell becomes specific for that antigen and ultimately results in production of clone
cells that are also specific for that antigen.
As mentioned previously, CD antigens (markers) are uniquely expressed on the
surface of all lymphocytes, and serve as biochemical markers characteristic for a
particular cell type indicating the lineage or stage of maturity.
All T-cells have CD3 receptor complexes and various other CD antigens. CD8
(CD+8) antigens are found on TC-cells and TS-cells. CD8-cells respond to
antigens displayed on Class I MHC proteins. CD4 (CD+4) antigens are found on
TH-cells, and respond to antigens displayed on MHC II proteins. CD4 and CD8
markers are bound to the CD3 complex on the T-cell surface. Activation does not
usually occur until the T-cell encounters and recognizes (binds) a second antigen
of the same type. The “double-signature” is a double-check before destruction.
CD8 cell activation
There are two types of CD8 cells – one type results in rapid response stimulating
large numbers of TC-cells (killer T-cells) and memory T-cells. Once activated,
TC-cells seek and destroy cells containing the antigen they are specific for. A
variety of weaponry is used by TC-cells against invaders. Chemical agents such
as perforin are released, a poisonous chemical known as lymphotoxin is
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secreted, or programmed cell death is activated – a process known as apoptosis
(cell suicide).
Memory T-cells immediately differentiate to TC-cells resulting in a swift cytotoxic
response.
The second type results in a slower response and results in production of small
numbers of suppressor T-cells (TS-cells). TS-cells produce inhibitory cytokines
for T-cells and B-cells. TS-cells are slow to respond and act only after the initial
immune response.
CD4 cell activation
CD4 cells divide to produce TH-cells and memory TH-cells. CD4 markers are
found on TH-cells. CD4 stimulates a variety of cytokines that stimulate T-cell
division to produce memory T-cells and accelerate TC-cell maturity, attracts
macrophages, attracts and stimulates NK cell activity, and promotes B-cell
activation.
Natural killer cells (NK cells)
Natural killer cells perform immunological surveillance of body tissues. NK-cells
are extremely versatile lymphocytes that can attack virus-infected cells and
cancer cells in interstitial fluids. NK cells respond immediately to contact with any
abnormal antigens. NK cells perform “silent hits” by attaching to cells containing
abnormal antigens, lining up a secretory apparatus (Golgi apparatus) in the
cytoplasm of the NK cell and releasing a chemical (perforin) that creates holes in
the membrane of the target cell.
Link to animation – NK cell bound to target cell – Be patient, it takes a few
minutes
for
the
video
to
load,
but
its
worth
the
wait!:
http://www.hybridmedicalanimation.com/pages/jjani_pc/NK_ani_pc.html
Chemical communication system
Small proteins known as interferons are released by activated lymphocytes,
activated macrophages, and virus-infected tissue. Interferons stimulate more
macrophages and NK-cells, and bind to cell surface receptors of virus-infected
cells triggering production of antiviral proteins in the cytoplasm of the target cell
that interfere with viral replication.
There are three types of interferon:



alpha-interferon (-interferon) – attracts and stimulates NK cells
beta-interferon (- interferon) – slows inflammation in damaged areas
gamma-interferon (-interferon) – secreted by T-cells and NK cells –
stimulate macrophage activity
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Most cells other than lymphocytes and macrophages secrete beta-interferon in
response to viral infection.
Complement system
The complement system consists of 11 special proteins (designated C1-C11)
that complement the action of antibodies. The complement system has two
different pathways – classical and alternative. The classical system is the more
rapid of the two pathways.
Classical pathway
Think about a team of navy seals executing manoeuvres to plant charges on the
hull of a marked enemy ship. C1 is a bit like those seals; it binds to antibody that
is bound to antigen (antigen-antibody [Ag-Ab] complex) on the target cell surface.
The Ag-Ab complex catalyzes a series of chemical reactions that ends with the
inactive C3 converting to the active form, C3b, which then binds to the surface of
the target antigen. Once bound, C3b stimulates phagocytosis and promotes
inflammation. C3b also triggers reactions that lead to the creation of a membrane
attack complex (MAC) that creates pores in the membrane of the target cell, like
holes blown in the hull of a ship.
Alternative pathway
When the target is not marked (no Ag-Ab complex), the navy divers do not know
where the enemy ship is, so other techniques (alternate pathway) are used to
detect and mark the location of enemy ships. The alternative pathway uses
communication satellites (complement proteins) suspended in the plasma that
become activated on contact with foreign materials.
The activated proteins catalyze a series of reactions that result in conversion of
C3 to C3b, stimulation of phagocytosis, and formation of membrane attack
complex (navy seals). Proteins of the alternative pathway interact in the plasma
in response to contact with bacteria, certain parasites and virus-infected cells.
However, the alternate pathway results in an overall slower response, because
the alternate pathway functions to trigger the classical pathway, which then
destroys the target.
In addition to destroying foreign invaders, complement causes degranulation of
mast cells, and formation of the membrane attack complex – a group of lipidsoluble proteins that punch holes in the cell membrane of pathogens.
Inflammation
Inflammation involves a localized heat, redness, swelling, and pain in response
to a break in one of the physical body barriers (skin, mucous membranes lining
the eyes, nose, mouth, respiratory tract, intestinal tract and genital tract).
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Inflammation results in temporary repair of the injury; prevention of additional
microorganisms and foreign substances from entering the body; inhibition of
invasion; and mobilization of body defences (emergency responders, police
forces and possibly military personnel).
Link to Splinter - http://www.cellsalive.com/ouch1.htm
Degranulation of mast cells and basophils results in the release of histamine,
which initiates the inflammatory response. Histamine is one of a number of
chemical messengers (cytokines) involved in immune response. Other cytokines
include interleukins, interferons, tumor necrosis factors, chemicals that regulate
phagocytic activity, and colony-stimulating factors that stimulate blood cell
production in bone marrow and lymph tissues.
Histamine attracts more leukocytes to the area, and opens pores in capillaries to
allow plasma proteins and fluid to pass into the interstitial space causing edema.
Histamine also dilates blood vessels increasing blood flow to the area. The result
is inflammation.
Fever
Fever results from the action of pyrogens that are stimulated by microorganisms
and bacterial toxins. Ag-Ab complexes can also act as pyrogens and can
stimulate pyrogen production by macrophages (interleukin-1). Fever increases
body metabolism resulting in increased rates of immune cell activity, and inhibits
certain viruses and bacteria.
Acquired Immunity (Specific defences)
Specific defence forms the special-forces known as acquired or adaptive
immunity. There are two types of acquired immunity – active and passive.
Specific immunity is conferred by cell-mediated forces provided by two types of
lymphocytes – cytotoxic T-cells and helper T-cells, and humoral or antigenspecific forces provided by another type of lymphocytes called B-cells (navy/airforce).
The initial immune response takes 7-10 days to develop, and typically lasts a few
weeks before taking leave following the battle. Memory T- and B-cells are left
behind – surveillance forces – trained to recognize the invader if it is encountered
again. Memory cells result in a swift strong response (within 1-2 days of antigen
re-exposure) should the invader ever attempt to penetrate “the system” again in
the future.
These cells do not respond to invasion by nations (antigens) other than the one
previously fought. Surveillance for new invaders is provided by NK- cells and
phagocytes that routinely patrol for suspicious activity and invasion by foreign
antigens.
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Active immunity
Active immunity is immunity that results from previous exposure to a microorganism or foreign antigen. There are two types of active immunity – acquired
and induced.
Active acquired immunity
Active acquired immunity results in production of antibodies in response to
foreign and abnormal antigens. Active immunity can be acquired naturally
through infection or induced.
Active acquired immunity could be compared to notoriety due to accumulated
minor infractions (invasions) that together result in strong antibody response in
the future.
Induced active acquired immunity
Induced active acquired immunity is obtained by administering vaccine – a
process known as immunization. Vaccine is a preparation containing a dead or
inactive micro-organism, or antigens from it. The body responds to the
administration of vaccine by producing antibodies against the antigens of the
micro-organism.
Passive immunity
Passive immunity is short-term immunity that is acquired from antibodies made
by another animal - transfer of antibodies from mother to fetus or immunoglobulin
shots like the ones used as prophylactic treatment following blood or body fluid
exposure
As with active immunity, there are two types of passive immunity – natural and
induced.
Natural passive immunity results from transfer of maternal antibodies across the
placenta or through breast milk.
Induced passive immunity results from administration of antibodies produced by
another individual or animal. The antibodies provide short-term assistance in
fighting infection.
Properties of immunity
 specificity – antibody production against one particular antigen –
equivalent human personality trait: attention to detail
 versatility – ability to respond effectively to different stimuli – equivalent
human personality trait: ability to adapt to change
 memory – excellent memory required to recognize and initiate a rapid,
strong and long (or prolonged) response on subsequent exposure to a
particular antigen – equivalent human personality trait: long-term memory
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Module 3: Defence – The Immune System at work
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(remembering what happened from birth when someone recalls a
situation)
tolerance – not overly sensitive to stimulants so that “self” antigens are
not attacked – equivalent human personality trait: positive self-image
Antibodies
Foreign and abnormal antigens trigger lymphocyte production and stimulate
lymphocytes to produce antibodies in response. Once an invader has been
recognized, more antibodies are made to attack and neutralize it. When
antibodies identify antigens, phagocytes engulf and neutralize or disassemble
them.
There are more than 1,000,000 different types of antibodies performing
surveillance for invading foreign antigens that enter the body.
Antibodies circulating in the bloodstream bind to antigens that they recognize and
attack it.
Antibodies are Y-shaped proteins with two arms that act as antigen-binding sites
and a base that determines the class of antibody as described below. Antibodies
are also referred to as gamma-globulins or immunoglobulins. Immunoglobulins,
and are named according to their functions – agglutinins, precipitins, hemolysins,
etc.
Animation
–
Antibody
production
from:
http://www.wellesley.edu/Biology/Concepts/ncwebpage/immunicyto.html
Created in 2003 by Giuliana Funkhouser and Cristina Greavu for CarolAnn Paul
of the Wellesley College Biology Dept., under the auspices of the Betsy Wood
Knapp Technology Intern Program at Wellesley College.
The base of the Y is made of heavy chains, while its arms are made of both light
and heavy chains. The tips of the arms contain a cavity with a shape unique for
the shape of the protein fragment (antigen) that the antibody is specific for.
Immunoglobulins
There are five general classes of immunoglobulins:
IgG
- account for 75% of plasma antibody produced in secondary immune
response
- capable of crossing the placental membrane from mother to fetus
IgA
- found in secretions such as saliva, tears, intestinal and bronchial mucus, as
well as breast milk
- disable invaders
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IgE
- allergic responses
- IgE/antigen complex stimulates mast cells to release histamine
IgM
- activates complement
- reacts to blood group antigens
IgD
- found on surface of B-lymphocytes
- role unclear
Response to invasion
Bacterial infection
When body surface barriers fail and bacteria reach the extracellular fluid, an
inflammatory response develops as immune cells defend the body against further
penetration and invasion. A series of events occurs:
1. phagocytes and NK-cells migrate to the area in response to chemical
messages (cytokines) sent by emergency responders at site of invasion,
and ingest and/or destroy bacteria
2. TC-cells appear as T-cells are activated by antigen presentation
3. plasma-cell production increases as activated B-cells differentiate
4. surge in plasma cell production is followed by gradual decrease and
sustained levels of circulating antibodies
5. complement system activated by components of bacterial cell wall complement causes degranulation of mast cells and basophils, followed
by cytokine release, which attracts more immune cells, dilates blood
vessels and increases capillary permeability – increased blood flow to the
area results in inflammation, and plasma proteins and water passing into
the interstitial spaces results in edema
6. membrane-attack-complex (MAC) molecules blow holes in the bacterial
cell wall resulting in plasma influx resulting in lysis and death (navy divers
plant charges on hull of ship ultimately sinking the ship)
7. macrophages ingest bacteria opsonization of encapsulated bacteria
acquired immune response – antibodies already present act as opsonins
and also inactivate bacterial toxins
8. memory B-cells attracted to infection site activated by antigens that they
recognize (police line-up) if blood vessels are also damaged, platelets
and coagulation proteins help reduce damage
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Viral infections
The initial steps in response to viral invasion are different from those involved in
bacterial invasion. Phagocytes digest and disassemble viruses and display viral
antigen fragments on MHC proteins on the cell surface activating TC-cells and
NK-cells. In addition to activation by antigen presenting phagocytes, TC-cells and
NK-cells are activated by contact with antigen-presenting phagocytes or virus
infected tissue cells.
Viruses bind to cell membranes in the body and cross the cell membrane by
binding to membrane receptors and triggering endocytosis, a process similar to
phagocytosis, except that the cell membrane indents rather than pushing out
around the particle to be ingested. Alternatively, the viral envelope fuses with the
cell membrane, injecting the virus core into the cytoplasm.
Once inside the cell, the virus uses the cell’s resources to replicate – create new
viral nucleic acid and viral proteins, which then assemble to new virus particles
that are released and subsequently infect new cells. In the process, host cell
function may be disrupted resulting in cell death, or may be temporarily disrupted
by viruses which reproduce only sporadically (e.g. Herpes simplex type 1). Other
viruses (e.g. HIV) incorporate viral DNA into host cell DNA and reproduce.
Viruses are released through cell rupture or they cloak themselves in a capsule
of host membrane and escape through the surface unnoticed.
Immune Response to Viral Infection
Innate immune response and antibodies are involved in defence against acute
viral infection. However, once viral particles enter host cells, TC-cells form the
main line of defence, searching for infected host cells and destroying them (hitmen locating and killing off traitors).
Antibodies play an important role in acute viral infection:
- act as opsonins and coat the viral particle to enhance their visibility to
macrophages
- bind to virus to prevent entry into cells
- macrophages ingest viruses and insert fragments in cell membrane bound to
MHC molecules and produce cytokines – cytokines initiate the inflammatory
response; one of these, interferon, causes host cells to make antiviral
proteins that prevent viral replication
- TH-cells bind to viral antigen fragments on macrophages and enhance
immune cell response
- TC-cells recognize viral antigen fragments bound to MHC complexes and
induce the cell to commit suicide (apoptosis).
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Diagnostic tests
The immune system is one of the most difficult systems to understand, because
of its complexity. The easiest way to evaluate the function of various cells of the
immune system is by drawing blood from the arm.
Other tests are also performed to observe possible complications related to the
virus and most importantly to observe possible toxicities (adverse affects) of
medications being studied. These tests, referred to as safety bloods (labs),
include a CBC/differential, full chemistries and a urinalysis. The CBC consists of
the white blood cell count, differential, hemoglobin, hematocrit and platelet count.
The differential is the percent of the various types of white cells; lymphocytes,
granulocytes, and several others. The full chemistries look at the functioning of
the liver, kidneys, heart and many other important functions of the body. The
urinalysis also helps determine the function of the kidneys. There is some
overlap of safety bloods and immune function studies as may be noted.
Immune Function Studies
White Blood Cells (WBCs):
White blood cells play a major role in defending the body against infections and
foreign invaders such as bacteria, fungi, viruses and parasites. There are five
types of white blood cells: granulocytes (also known as neutrophils), lymphocytes
(lymphs), monocytes, eosinophils and basophils.
Normal Value: 3300-9600/mm3
Polymorphonuclear granulocytes (polys):
Polymorphonuclear granulocytes are commonly referred to as polys, segs,
neutrophils or grans. Mature white blood cells are referred as polymorphonuclear
granulocytes, while bands are less mature polys. Neutrophils, both polys and
bands, are scavenger cells and are the first immune cells to arrive at a site of
infection or injury.
When the total neutrophil count (polys + bands) drops to less than 1000/mm3,
there is an increased risk for bacterial and certain fungal infections, and severe
risk when less than 500/ mm3.
Normal Value: 40-78% of WBC or 1200-7800/ mm3.
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Lymphocytes (Lymphs):
Lymphocytes specifically identify foreign substances as being "non-self" or
mutant (defective) cells and cause their destruction and elimination preventing
cell replication. There are two major classes of lymphocytes, B-lymphocytes and
T-lymphocytes, as well as the natural killer cells that fall under the classification
of lymphocytes.
Normal Value: 14-49% of WBC or 420-4900/mm3.
Cell Type
Total lymphocytes
Total T cells
CD4 cells
CD8 cells
Total B cells
NK cells
Proportion of total
~ 30% of total WBC count
~ 70% of total lymphocyte count
~ 50% of total T-cell count
~ 20% of total T-cell count
~ 10-15% of total lymphocyte count
~ 10-15% of total lymphocyte count
Reference: Hayglass, K. 2003. Immunology Notes – Medical Physiology. Retrieved from
http://www.umanitoba.ca/faculties/medicine/units/immunology/medphys.htm on August 4, 2004.
B Lymphocytes
B cells are programmed to produce immunoglobulins. Each B-cell produces a
specific antibody for a specific foreign antigen. Antigen/antibody complexes
render the antigen harmless and mark them for destruction.
Normal values: 50-250 cells/mL
T Lymphocytes
Normal values: 600-2,400 cells/mL
Normal Values of Immunoglobulins:
IgG: 650-1600 mg/dl
IgM: 50-320 mg/dl
IgA: 65-415 mg/dl