health & disease series: set 4 copyright © 2005version: 2.0
TRANSCRIPT
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Health & Disease Series: Set 4Health & Disease Series: Set 4Copyright © 2005 Version: 2.0
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Targets for DefenseTo defend itself against invading pathogens, the body must:
first be able to recognize its own tissues(self recognition)
ignore its normal microflora
deal with any abnormal cells which, if not eliminated, may develop into cancer
Self recognition has implications for medical procedures such as tissue grafts, tissue and organ transplants, and blood transfusions.
Failure of self/non-self recognition can lead to autoimmune disorders, in which the immune system mistakenly destroys its own tissues.
The human oral cavity has its own microflora
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The Body’s Natural Microbiota
A typical human body contains: 1 X 1013 body cells yet harbors:
1 X 1014 bacterial cells.
These microorganisms establish more or less permanent residence. Under normal conditions they do not cause disease.
The body’s normal microflora,e.g. Staphyloccus epidermidis and Propionibacterium acnes, benefits the host. It maintains the low pH of the skin, which prevents the overgrowth of harmful pathogens.
SEM showing S. epidermidis on the surface of the skin
CD
C J
anic
e C
arr
P. acnes normally resides in the sebaceous glands of the skin but it also causes pimples.
CDC
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The Body’s Natural Microbiota
Eyes: The conjunctiva, a continuation of the skin or mucous membrane, contains a similar microbiota to the skin.
Nose and throat: Harbor a variety of microorganisms e.g. Staphylococcus spp.
Large intestine: Contains the body’s largest resident population of microbes because of the available moisture and nutrients.
Skin: Skin secretions prevent most of the microbes becoming residents.
Urinary and genital systems: The lower urethra in both sexes has a resident population; the vagina has a particular acid-tolerant population of microbes.
Mouth: Supports a large and diverse microbiota. It is an ideal microbial environment; warm, and high in moisture and nutrients.
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Distinguishing Self The human immune system achievesself-recognition through the majorhistocompatibility complex (MHC).
The MHC is a cluster of tightly linked genes on chromosome 6 in humans.
These genes code for protein molecules (MHC antigens) which are attached to the surface of body cells – they show SELF.
The MHC antigens are used by the immune system to recognize its own and foreign material.
Class I MHC antigens are located onthe surface of virtually all human cells.
Class II MHC antigens are restricted tomacrophages and B-lymphocytes. HLA surface proteins (antigens)
provide a chemical signature that
allows the immune system to
recognize the body’s own cells
Location of genes
on chromosome 6
for producing the
HLA antigens
Class II HLA
Class I HLA
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Human Blood GroupsBlood groups are classifications of blood according to the marker proteins on the surface of red blood cells.
These marker proteins (antigens) determine the ability of red blood cells to provoke an immune response.
Human red blood cells have more than 500 known antigens, but fewer than 30 antigens (in 9 blood groups) are regularly tested for when blood is donated for transfusion.
Regularly tested antigens include:
ABO Lutheran
Rhesus (Rh) Kell
MNS Duffy
P Kidd
Lewis (those in red are most commonly tested)
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Blood Group AntigensBlood group Antigens present on the red blood cells Antibodies present in the plasma
A Contains anti-B antibodies,
but no antibodies that would
attack its own antigen A
B Contains anti-A antibodies,but no antibodies that would
attack its own antigen B
ABContains neither anti-A
or anti-B antibodies
O Contains both anti-A
and anti-B antibodies
antigen A
antigen B
antigensA and B
NeitherantigenA nor B
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Rh Incompatibility
If the father of a baby is Rh-positive and the mother is Rh-negative, their second baby, if Rh-positive, will suffer from hemolytic disease of the newborn.
Hemolytic disease of the newborn is a severe immune reaction caused by the mother’s newly acquired antibodies, which attack the unborn baby’s blood cells.
Rh-positive baby
Rh-negative mother
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Rh Incompatibility
Second Pregnancy
Mother’s anti-Rh antibodies cross the placenta into the fetal blood. If the baby is Rh+, HDN results.
First Pregnancy
Mother is Rh– but is
pregnant with an Rh+ fetus. Antigens pass into
the mother at birth.
Baby’s red blood cells may enter the mother’s circulation via the placenta during delivery.
Exposed to the fetal
Rh+ antigens, the mother makes anti-Rh
antibodies.
Father’s Rh+ gene passed
to baby
Father is
Rh+
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The First Line of DefensePhysical and chemical barriers form a first line of non-specific defense.
The skin provides a physical
barrier to the entry of pathogens
and is rarely penetrated by
microorganisms.
The skin produces chemical
secretions that inhibit the
growth of bacteria and fungi.
Low pH deters colonization by
pathogenic microbes.
Tears, mucus, and saliva help
to wash microbes away.
Photo: EII
Undamaged skin on the surface of the hand. Note the
thick keratin layer (arrow).
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The Second Line of Defense
A range of non-specific defenses inside the body inhibit or destroy pathogens.
These non-specific defenses react to the presence of any pathogen, regardless of which species it is.
White blood cells are involved in most of these responses.
The 1st line of defense
The 2nd line of defense
The 3rd line of defense
Eosinophils:Produce toxic proteins against certain parasites, some phagocytosis
Antimicrobial substances
Basophils:Release heparin and histamine which promote inflammation
Inflammation and fever
Neutrophils, monocytes:These cells engulf and destroy foreign material(e.g. bacteria)
Phagocytic white blood cells
40°C
37°C
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The Third Line of Defense
Specific resistance is a third line of defense. It forms the immune response and targets specific pathogens.
Specialized cells of the immune system, called lymphocytes are:
B-cells: produce specific proteins called antibodies, which are produced against specific antigens.
T-cells: target pathogens directly.
The 2nd line of defense
The 3rd line of defense
B cell:Antibody production
T cell:Cell-mediated immunity
Lymphocytes
Lymphocyte (SEM)
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The Action of PhagocytesPhagocytes are white blood cells that ingest microbes and digest them by phagocytosis.
Lysosome
Phagosome
Nucleus
MicrobesDetectionPhagocyte detects microbes by the chemicals they give off (chemotaxis), and the microbes stick to its surface.
IngestionThe phagocyte wraps pseudopodia around it the microbe, engulfing it and forming a vesicle.
Phagosome formsA phagosome (phagocytic vesicle) is formed, enclosing the microbes in a membrane.
Fusion with lysosomePhagosome fuses with a lysosome (containing powerful enzymes that can digest the microbe).
DigestionThe microbes are broken down by enzymes into their chemical constituents.
DischargeIndigestible material is discharged from the phagocyte.
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Microbial Abuse of Phagocytes
Some microbes kill phagocytes
Some microbes produce toxins that kill phagocytes.
e.g. toxin-producing staphylococci and the dental plaque-forming bacteria Actinobacillus.
Dormant microbes hide inside cells
Some microbes can remain dormant inside the phagocyte for months or years at a time.
e.g. the microbes that cause brucellosis and tularemia.
Microbes evade immune system
Some microbes evade the immune system by entering phagocytes. The microbes prevent fusion of the lysosome with the phagosome. They multiply inside the phagocyte, almost filling it.
e.g. Chlamydia, Shigella, Mycobacterium tuberculosis, and malarial parasites.
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Inflammation
Damage to the body’s tissues caused by physical agents (e.g. sharp objects), microbial infection, or chemical agents triggers a defensive response called inflammation.
Inflammation is usually characterized by four symptoms: pain, redness, heat, and swelling.
The inflammatory response is beneficialand has the following functions:
To destroy the cause of the infection andremove it and its products from the body.
If this fails, to limit the effects on the bodyby confining the infection to a small area.
To replace or repair tissue damaged bythe infection by improving blood flow.
Inflamed ulcer
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The Process of Inflammation
Epiderm
isD
ermis
Subcutaneous
tissue
Bacteria entering on knife
or other sharp object. Blood clot forms
Chemicals released by
damaged cells (e.g. histamines
and prostaglandins) attract
phagocytes to the infection.
Blood vessels increase in
diameter and permeability in the
area of damage. This increases
blood flow to the area and
allows defensive substances to
leak into tissue spaces.
Phagocytes reach the damaged area within
one hour of injury. They squeeze between
cells of blood vessel walls to enter the region
and destroy invading microbes.
An abscess starts to form after a
few days. This collection of dead
phagocytes, damaged tissue and
various body fluids is called pus.
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Fever
A fever (pyrexia) is defined as a body temperature above 37°C (98.6°F) measured in the mouth.
Normal body temperature range is:
36 to 37°C
96.8 to 98.6°F
Fevers are usually caused bybacterial or viral infections.
Fevers of less than 40°C (104°F) do not need treatment.
Excessive fever requires prompt attention as death usually results if body temperature rises above 44.4°C to 45.5°C (112°F to 114°F).
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Hypothalamus
The Cause of Fever
Bacterial toxins
Bacterium
Temperature increases
beyond the normal range of
36.2–37.2 °C (96.8–98.6 °F)
Infection by pathogen or toxinInfection from viruses and bacteria (or their toxins) is the most frequent cause of fever. A macrophage ingesting a pathogen begins the processes leading to fever.
Macrophages respondA macrophage ingests a bacterium, destroying it in a vacuole and releasing endotoxins. The presence of endotoxins induces the macrophage to produce a small protein called interleukin-1.
Thermostat is resetInterleukin-1 induces the hypothalamus to increase production of prostaglandins. This resets the body's 'thermostat' to a higher temperature, producing fever.
Macrophage releases interleukin-1 into the blood stream.
Macrophage
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Naturally Acquired Immunity
Naturally Acquired
Active
Antigens enter the bodynaturally, as when:
• Microbes cause the personto catch the disease.
• There is a sub-clinical infection(one that produces no evident
symptoms).
The body produces specialized lymphocytes and antibodies.
Passive
Antibodies pass from the motherto the fetus via the placenta
during pregnancy or to her infant through her milk.
The infant's body does not produce any antibodies of its own.
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Artificially Acquired Immunity
Active
Antigens (weakened or dead microbes or their fragments) are
introduced in vaccines.
The body produces and specialized lymphocytes and
antibodies.
Passive
Preformed antibodies in an immune serum are introduced
into the body by injection(e.g. anti-venom used to
treat snake bites).
The body does not produceany antibodies.
Artificially Acquired
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Lymph and theImmune System
Apart from its circulatory role, the lymphatic system has an important function in the immune response.
Mixed up with the lymph are pathogens and other foreign substances that must be destroyed.
Lymph nodes are the primary sites where this occurs.
A lymph node that is actively fighting an infection becomes swollen and hard as the lymph cells reproduce rapidly to increase their numbers.
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The Immune System
There are two main components of the vertebrate immune system:
The humoral immune system involves the action of B-cells, which produce antibodies. The humoral system is associated with serum, the non-cellular part of the blood.
The cell-mediated immune system is associated with the production of specialized lymphocytes called T-cells.
The humoral and cell-mediated systems work separately and together to protect us from disease. E
duca
tion
Inte
ract
ive
Imag
ing
LymphocyteRed blood cells
(erythrocytes)
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B–Cells
B-cells (also called B-lymphocytes) originate and mature in the bone marrow of the long bones (e.g. the femur).
They migrate from the bone marrow to the lymphatic organs.
B-cells defend against:Bacteria and viruses outside the cell
Toxins produced by bacteria (free antigens)
Each B-cell can produce antibodies against only one specific antigen.
A mature B-cell may carry as many as 100 000 antibody molecules embedded in its surface membrane.
B-cell
(B-lymphocyte)
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B-cells differentiate into two kinds of cells:Memory cellsWhen these cells encounter the same antigen again (even years or decades after the initial infection), they rapidly differentiate into antibody-producing plasma cells.
Plasma cellsThese cells secrete antibodies against antigens. Each plasma cell lives for only a few days, but can produce about 2000 antibody molecules per second.
Memory cell
Plasma cell
B–Cell Differentiation
Antibody
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T-CellsT-cells originate from stem cells and mature after passing through the thymus gland (located above the heart over the trachea).
They respond only to antigenic fragments that have been processed and presented bound to the MHC by infected cells or macrophages (phagocytic cells).
T-cells defend against:
Intracellular bacteria and viruses.
Protozoa, fungi, flatworms, and roundworms.
Cancerous cells and transplanted foreign tissue.
T-cells attacking a cancer cell
Mo
lecu
lar
Imm
un
olo
gy
Fou
nd
atio
n,
ww
w.m
ifou
nda
tion
.org
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T-cells can differentiate into four specialized types of cell:
Helper T-cell
Activates cytotoxic T cells andother helper T cells.
Necessary for B-cell activation.
Suppressor T-cell
Regulates immune response by turning itoff when no more antigen is present.
T-cell for delayed hypersensitivity
Causes inflammation in allergic reactions and rejection of tissue transplants.
Cytotoxic (Killer) T-cell
Destroys target cells on contact.
T-Cell Differentiation
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Antibodies (immunoglobulins) are proteins made in response to antigens.
Antibodies recognize and bind to antigens.
Antibodies are highly specific and can help destroy antigens.
Each antibody has at least two sites that can bind to an antigen.
Antigens and Antibodies 2
Antibody
Antigen
One of the two binding sites on the antibody
Molecular model
Symbolic model
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Antibody Structure
Variable regions form the antigen-binding sites. Each antibody can bind two antigen molecules.
Antibody
Light chain (short)
Hinge region connecting the light and heavy chains. This allows the two chains to open and close (like a clothes peg).
Heavy chain (long)Most of an antibody molecule is made up of constant regions which are the same for all antibodies of the same class.
The antigen-binding sites between antibodies of different types.
Antigen: Most antigens are proteins or large polysaccharides and are often parts of invading microbes.
Examples: cell walls, flagella, bacterial toxins, viral proteins and other microbial surfaces.
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Inactivation of AntigensClumping
particulate antigens
Solid antigens such as bacteria
are stuck together in clumps.
Bacterial cell
Neutralization
Antibodies bind to viral binding
sites and coat bacterial toxins.
VirusToxin
Antibody
Enhances Phagocytosis
Macrophage
Bacteria
Soluble antigens are stuck together to form precipitates.
Precipitation of soluble antigens
Soluble antigens
Antibodies
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Monoclonal AntibodiesA monoclonal antibody is an artificially produced antibody that neutralizes only one specific protein (antigen).
Monoclonal antibodies are produced by stimulating the production of B-cells in mice injected with the antigen.
These B-cells produce an antibody against the antigen.
B-cells can be isolated and made to fuse with immortal tumor cells.They can then be cultured indefinitely in a suitable growing medium.
Monoclonal antibodies are useful for 3 reasons:
They are totally uniform (i.e. clones).
They can be produced in large quantities.
They are highly specific.Monoclonal antibodies chemically
linked to a fluorescent dye to
detect the presence of gonorrhea
Pho
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Diagnostic Uses ofMonoclonal Antibodies
Monoclonal antibodies have many diagnostic uses:Detecting the presence of pathogens such as Chlamidia and streptococcal bacteria, distinguishing between Herpesvirus I and II, and diagnosing AIDS.
Measuring protein, toxin,or drug levels in serum.
Blood and tissue typing.
Detection of antibioticresidues in milk.
Detecting pregnancy.
Monoclonal antibody
technology is used in
pregnancy test kits
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Pregnancy TestingHuman chorionic gonadotropin (HCG) is released from the placenta of pregnant women.
HCG accumulates in the bloodstream and is excreted in the urine.
HCG is a glycoprotein. Antibodies against it can be used insimple test kits (below) to determine if a woman is pregnant.
A blue colored band above the dipstick indicates a positive test.
Colored band appears in the result window only if HCG is present.
Dipstick held in the urine.
Colored band appears in control window to show the test has run correctly.
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Dipstick
Antibody moves
by capillary action
Antibodies
tagged with
blue latex
HCG bound to
free antibody
HCG in the urine of a pregnant women binds to the color-labeled antibodies. The antibodies then travel up the dipstick by capillary action.
How Pregnancy Tests WorkHow home pregnancy detection kits work
The test area of the dipstick (below) contains two types of antibodies: free monoclonal antibodies and capture monoclonal antibodies, bound to the substrate in the test window (arrowed).
Immobilized capture
antibodies
Colored latex in
test window
The HCG-antibody complexes are bound by capture antibodies. The labeled antibodies create a coloured line in the test window.
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Monoclonal Antibody Therapy
Monoclonal antibodies have many therapeutic uses:Neutralizing endotoxins produced by bacteria inblood infections.
Preventing organ rejection, e.g. in kidneytransplants, by interfering with T cell activity.
Treatment of some autoimmune disorders suchas rheumatoid arthritis and allergic asthma.The monoclonal antibodies bind to and inactivatefactors involved in the inflammatory response.
Immunodetection and immunotherapy of cancer.Newer methods specifically target tumor cells,shrinking solid tumors without harmful side effects.
Inhibition of platelet clumping to preventreclogging of coronary arteries after angioplasty.The monoclonal antibodies bind to the receptorson the platelet surface, interfering with clotting. Hypersensitivity
reaction on an arm
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Immune System DisordersOccasionally the reactions of the immune system are harmful:
Instead of producing a desirable result, suchas immunity to disease, the immunesystem may over-react, react to the wrongsubstances, or not react when it should.
The immune system may fail to detectan infectious agent that has penetrated thefirst and second lines of defense.
Some immune system disorders cause onlydiscomfort, as in the case of hayfever.
Immune system failure may lead to life-threatening conditions, such as anaphylaxis,AIDS and cancer (when the abnormal tumorcells escape immune system detection).
Kaposi’s sarcoma in the foot area of
an immune supressed AIDS patient
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Autoimmune Diseases
Some people have an immune system that fails to appropriately recognize substances from their own body and attacks them.
Autoimmune diseases are the result of the damage caused by the immune system responding to self antigens.
Rheumatoid arthritisInflammation of joints leading to destruction of cartilage.
Hemolytic anemiaA disorder in which the red blood cells rupture or are destroyed at an excessive rate. Caused by a variety of factors including excessively fragile red blood cells, hereditary, and autoimmune disorders.
Multiple sclerosisA progressive inflammatory disease causing paralysis. Caused by the myelin layers around nerve axons being destroyed.
Axon
Myelin layer
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Hypersensitivity
Hypersensitivity refers to an immune system response to an antigen beyond what is considered normal.
The immunological response to the antigen (or allergen) leads to tissue damage rather than immunity.
Hypersensitivity reactions occur when a person has been sensitized to an antigen.
Allergic reactions (e.g. hayfever, asthma, and anaphylaxis from insect venom or drug injections) are rapid. They occur when antibodies respond to an allergen by causing the release of histamine from mast cells.
An SEM photo showing a pollen grain Photo: EII
Pho
to: E
yew
ire
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The mast cell binds the allergen when it encounters it again. The mast cell releases histamine and other chemicals, which together cause the symptoms of an allergic reaction.
Vesicles with histamine
Antibodies bind to specific receptors on the surface of the mast cells.
Mast cell
The Basis of Hypersensitivity
The plasma cell produces antibodies.
Plasma cellB cell encounters the allergen and differentiates into numerous plasma cells.
B cell
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Hayfever
Hayfever (allergic rhinitis) is an allergic reaction to airborne substances such as:dust, moulds, pollens, and animal fur or feathers.
Allergy to wind-borne pollen is the most common. Certain plants (e.g. ragweed and privet) are highly allergenic.
There appears to be a genetic susceptibility to hayfever, as it is common in people with a family history of eczema, hives, and/or asthma.
Those with hayfever are best to avoid the allergen, although anti-histamines, decongestants, and steroid nasal sprays will assist in alleviating symptoms.
A privet plant in flower
Pho
to: J
ames
H. M
iller
, US
DA
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est S
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An SEM photo showing a pollen grain
Pho
to: E
II