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The Immune System P A R T A 1. Immunity: Two Intrinsic Defense Systems Innate (nonspecific) system...
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Transcript of The Immune System P A R T A 1. Immunity: Two Intrinsic Defense Systems Innate (nonspecific) system...
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The Immune System
P A R T A
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Immunity: Two Intrinsic Defense Systems Innate (nonspecific) system responds quickly
and consists of:First line of defense – skin and mucosa
prevent entry of microorganismsSecond line of defense – antimicrobial
proteins, phagocytes, and other cells Inhibit spread of invaders throughout the
body Inflammation is its most important
mechanism
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Immunity: Two Intrinsic Defense Systems Adaptive (specific) defense system
Third line of defense – mounts attack against particular foreign substancesTakes longer to react than the innate
systemWorks in conjunction with the innate
system
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Innate and Adaptive Defenses
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Innate Defense - First Line
Surface Barriers: skin and mucosa Skin, mucous membranes, and their secretions
make up the first line of defense Keratin in the skin:
Presents a physical barrier to most microorganisms
Is resistant to weak acids and bases, bacterial enzymes, and toxins
Mucosa provide similar mechanical barriers
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Innate Defense Epithelial membranes produce protective
chemicals that destroy microorganismsSkin acidity (pH of 3 to 5) inhibits bacterial
growthSebum contains chemicals toxic to bacteriaStomach mucosa secrete concentrated HCl
and protein-digesting enzymesSaliva and lacrimal fluid contain lysozyme
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Innate Defense
Mucus traps microorganisms that enter the digestive and respiratory systems
Respiratory Tract Mucosae:Mucus-coated hairs in the nose trap inhaled
particlesMucosa of the upper respiratory tract is
ciliatedCilia sweep dust- and bacteria-laden mucus
away from lower respiratory passages
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Innate Defense - Second Line Cells Mast cells and basophils
Release histamine and heparin
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Innate Defense – Second Line
Phagocytes 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 They derive from monocytes
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Innate Defense – Second Line
Neutrophils become phagocytic when encountering infectious materialThey also release defensins that will
perforate the pathogen’s membrane Eosinophils are weakly phagocytic. They are
important against parasitic wormsThey degranulate their enzymes when
encountering the parasite
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11Figure 21.2b
(b)
Lysosome
Microbe adheres to phagocyte.
Phagocyte forms pseudopods thateventually engulf the particle.
Phagocytic vesicle isfused with a lysosome.
Microbe in fused vesicleis killed and digested bylysosomal enzymes withinthe phagolysosome, leavinga residual body.
Indigestible andresidual materialis removed byexocytosis.
Phagocytic vesiclecontaining antigen(phagosome).
Residual body
Acidhydrolaseenzymes
Phagolysosome
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Innate Defense – Second Line
Mechanism of phagocytosis: First step for phagocytosis is adherence of the
pathogen to the phagocyte. Adherence will be facilitated when the
pathogen is coated with complement or antibodies:Opsonization
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Innate Defense – Second Line
Respiratory burst It happens when the pathogen is resistant to
common digestive enzymesNeutrophils and macrophages will then
release more powerful enzymes that are lethal to most bacteria.
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Innate Defense – Second Line
Natural Killer (NK) Cells Can lyse and kill cancer cells and virus-
infected cells Are a small, distinct group of large granular
lymphocytes They lack specificity They are not phagocytes
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Innate Defense – Second Line
Kill their target cells by releasing perforins to destroy virus-infected cells
They release interferons that interfere with viral replication
Secrete chemicals that enhance the inflammatory response
They can recognize self cell receptors
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Innate Defense – Second Line Inflammation: Tissue Response to Injury The inflammatory response is triggered
whenever body tissues are injured Prevents the spread of damaging agents to
nearby tissuesDisposes of cell debris and pathogensSets the stage for repair processes
The four cardinal signs of acute inflammation are redness, heat, swelling, and pain
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Innate Defense – Second Line
Begins with a flood of inflammatory chemicals released into the extracellular fluid
Inflammatory mediators:Kinins, prostaglandins (PGs), complement,
and cytokines Released by injured tissue, phagocytes,
lymphocytes, and mast cellsCause local small blood vessels to dilate,
resulting in hyperemia
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Innate Defense – Second Line
Vasodilation and increased vascular permeability
Chemicals liberated by the inflammatory response willDilate small blood vessels
HyperemiaIncrease the permeability of local capillaries
Exsudate
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Innate Defense – Second Line
Exudate—fluid containing proteins, clotting factors, and antibodies Exudate seeps into tissue spaces causing
local edema (swelling), which contributes to the sensation of pain.
Also the bacterial toxins, prostaglandins and kinins contribute for the pain
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Innate Defense – Second Line
The surge of protein-rich fluids into tissue spaces (edema):Helps dilute harmful substancesBrings in large quantities of oxygen and
nutrients needed for repairAllows entry of clotting proteins, which
prevents the spread of bacteria by creating a gel-like fibrin mesh
Inflammation will also release β-defensins that have antimicrobial properties
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Innate Defense – Second Line Mobilization of Phagocytes:
Leukocytosis- the increase of WBC in the blood. It is caused by factors released by injured cells.
Margination – neutrophils cling to the walls of capillaries in the injured area
Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis
Chemotaxis – WBC attraction to chemicals that guide them to the site of injury or inflammation after they leave the bloodstream.
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22Figure 21.4
Neutrophils enter blood from bone marrow
EndotheliumBasement membrane
Capillary wall
Margination
Diapedesis
Positivechemotaxis
Inflammatorychemicals diffusingfrom the inflamedsite act as chemotactic agents
Innate defenses Internal defenses
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Innate Defense – Second Line
Antimicrobial Proteins Enhance the innate defenses by:
Attacking microorganisms directlyHindering microorganisms’ ability to
reproduce The most important antimicrobial proteins are:
InterferonComplement proteins
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Innate Defense – Second Line 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 healthy cells to
activate genes for an antiviral protein production
This antiviral protein nonspecifically blocks viral reproduction in the neighboring cell
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Interferon
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Innate Defense – Second Line IFNs family
Family of related proteins each with slightly different physiological effects
Lymphocytes secrete gamma () interferon, but most other WBCs secrete alpha () interferon
Fibroblasts secrete beta () interferonInterferons also activate macrophages and
mobilize NKsSome anticancer property
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Innate Defense – Second Line
Complement 20 or so proteins that circulate in the blood in
an inactive form Proteins include C1 through C9, factors B, D,
and P (properdin), and regulatory proteins Provides a major mechanism for destroying
foreign substances in the body
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Innate Defense – Second Line
Amplifies all aspects of the inflammatory response
Kills bacteria and certain other cell types (our cells innactivate complement)
Enhances the effectiveness of both nonspecific and specific defenses
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Innate Defense – Second Line Complement Pathways:
Complement can be activated by two pathways: classical and alternate (properdin)
Classical pathway is linked to the immune system Depends on the binding of antibodies to
invading organisms Subsequent binding of C1 to the antigen-
antibody complexes (complement fixation)
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Innate Defense – Second Line
Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms
Each pathway involves a cascade in which complement proteins are activated in a sequence where each step catalyzes the next
Both pathways converge on C3, which cleaves into C3a and C3b
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Innate Defense – Second Line
C3b initiates formation of a membrane attack complex (MAC)
MAC causes cell lysis by creating pores in the cell membranes
C3b also causes opsonization, and C3a causes inflammation
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Complement Pathways
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Innate Defense – Second Line
C-reactive Protein (CRP) CRP is produced by the liver in response to
inflammatory molecules CRP is a clinical marker used to assess:
The presence of an acute infectionAn inflammatory condition and its response
to treatment
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Innate Defense – Second Line
Functions of C-reactive Protein:Binds to receptor of pathogens and exposed
self-antigens of damaged body cellsTargets them for disposal by
macrophages and complements Activates complement
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Innate Defense – Second Line
Fever Abnormally high body temperature in response
to invading microorganisms The body’s thermostat is reset upwards in
response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances
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Innate Defense – Second Line
High fevers are dangerous because they can denature enzymes
Moderate fever can be beneficial, as it causes:The liver and spleen to sequester iron and
zinc (needed by microorganisms)An increase in the metabolic rate, which
speeds up tissue repair
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Adaptive Defenses – Third Line
The adaptive (specific) immune system is a functional system that:Recognizes specific foreign substancesActs to immobilize, neutralize, or destroy
foreign substancesAmplifies inflammatory response and
activates complement
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Adaptive Immune Defenses
The adaptive immune system is antigen-specific, systemic, and has memory
It has two separate but overlapping arms:Humoral, or antibody-mediated immunityCellular, or cell-mediated immunity
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Self-Antigens
Our cells are dotted with a variety of protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others
One type, MHC proteins, mark a cell as self The two classes of MHC proteins are:
Class I MHC proteins – found on virtually all body cells
Class II MHC proteins – found on certain cells in the immune response
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Nonself Antigens
Substances that can mobilize the immune system and provoke an immune response
The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself)
They can be complete or incomplete
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Complete Antigens Important functional properties:
Immunogenicity – ability to stimulate proliferation of specific lymphocytes and antibody production
Reactivity – ability to react with products of activated lymphocytes and the antibodies released in response to them
Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides
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Haptens (Incomplete Antigens)
Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers
If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy)
Haptens are found in poison ivy, dander, some detergents, and cosmetics
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Antigenic Determinants
Only certain parts of an entire antigen are immunogenic
Antibodies and activated lymphocytes bind to these antigenic determinants
Most naturally occurring antigens have numerous antigenic determinants that:Mobilize several different lymphocyte
populationsForm different kinds of antibodies against it
Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity
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Complete Antigens
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HAPTENS
Antibody molecules can bind ahapten (partial antigen) once it hasbecome a complete antigen bycombining with a carrier molecule.
Completeantigen
HaptenCarrier
molecule
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Cells of the Adaptive Immune System Two types of lymphocytes
B lymphocytes – oversee humoral immunity
T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity
Antigen-presenting cells (APCs):Do not respond to specific antigensPlay essential auxiliary roles in immunity
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Lymphocytes
Immature lymphocytes formed in the bone marrow are essentially identical
Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent (ability to recognize a specific antigen) and self-tolerantB cells mature in the bone marrowT cells mature in the thymus
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T Cells T cells mature in the thymus under negative
and positive selection pressures Positive selection – selects T cells that
recognize self-antigens, Happens in the thymic cortex
Negative selection – eliminates T cells that are strongly anti-selfHappens in the inner thymic cortex They become self-tolerant (ignore one’s self
antigens)
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T Cell Selection in the Thymus
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B Cells B cells become immunocompetent and self-
tolerant in bone marrow Some self-reactive B cells:
Are killed (clonal deletion) in the bone marrow
Other B cells undergo receptor editing in which there is a rearrangement of their receptors in the bone marrow
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Immunocompetent B or T cells
Display a unique type of receptor that responds to a distinct antigen
Become immunocompetent before they encounter antigens they may later attackIt is genes, not antigens, that determine
which foreign substances our immune system will recognize and resist
Are exported to secondary lymphoid tissue where encounters with antigens occur
Mature into fully functional antigen-activated cells upon binding with their recognized antigen
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Red bonemarrow
Bone marrowThymus
Lymph nodes, spleen, and other lymphoid tissues
ImmaturelymphocytesCirculation
in blood
Immunocompetent,but still naive,lymphocyte migratesvia blood
ActivatedImmunocompetentB and T cells recirculate in blood and lymph
= Site of lymphocyte originKey:
= Site of antigen challenge, activation, and final diff erentiation of B and T cells
= Site of development of immunocompetence as B or T cells; primary lymphoid organs
Lymphocytes destined to become T cells migrate to the thymus and develop immunocompetencethere. B cells develop immunocompetence in red bone marrow.
After leaving the thymus or bone marrow as naïveimmunocompetent cells, lymphocytes “seed” thelymph nodes, spleen, and other lymphoid tissueswhere the antigen challenge occurs.
Antigen-activated immunocompetent lymphocytes circulate continuously in thebloodstream and lymph and throughout the lymphoid organs of the body.
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Antigen-Presenting Cells (APCs)
Major rolls in immunity are:To engulf foreign particlesTo present fragments of antigens on their
own surfaces, to be recognized by T cells Major APCs are dendritic cells (DCs-in
epidermis and connective tissue), macrophages
The major initiators of adaptive immunity are DCs, which migrate to the lymph nodes and secondary lymphoid organs, and present antigens to T and B cells
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Macrophages and Dendritic Cells Secrete soluble proteins that activate T cells Activated T cells in turn release chemicals that:
Stimulate the maturation and mobilization of DCs
Cause macrophages to become activated macrophages, which are insatiable phagocytes that secrete bactericidal chemicals
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Adaptive Immunity: Summary
Two-fisted defensive system that uses lymphocytes, APCs, and specific molecules to identify and destroy nonself particles
Its response depends upon the ability of its cells to:Recognize foreign substances (antigens) by
binding to themCommunicate with one another so that the
whole system mounts a response specific to those antigens
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Humoral Immunity Response
Antigen challenge – first encounter between an antigen and a naive immunocompetent B or T cell
Takes place in the spleen or any other lymphoid organ
If the lymphocyte is a B cell:The challenging antigen provokes a humoral
immune responseAntibodies are produced against the
challenger
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Clonal Selection
Stimulated B cell growth forms clones bearing the same antigen-specific receptors
A naive, immunocompetent B cell is activated when antigens bind to its surface receptors
These, plus T cell interactions, trigger clonal selection
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Plasmacells
Secretedantibodymolecules
Clone of cellsidentical toancestral cells
Subsequent challenge by same antigen
MemoryB cell
MemoryB cells
Plasmacells
Secretedantibodymolecules
Secondary Response (can be years later)
Primary Response(initial encounterwith antigen)
Antigen
Antigen bindingto a receptor on aspecific B lymphocyte(B lymphocytes withnon-complementaryreceptors remaininactive)
Proliferation toform a cloneB lymphoblasts
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Fate of the Clones
Most clone cells become antibody-secreting plasma cells (short-lived cells)
Plasma cells secrete specific antibody at a higher rate than B cells
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Fate of the Clones
Secreted antibodies:Bind to free antigensMark the antigens for destruction by specific
or nonspecific mechanisms Clones that do not become plasma cells
become memory (long-lived) cells that can mount an immediate response to subsequent exposures of the same antigen
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Immunological Memory
Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigenLag period: 3 to 6 days after antigen
challengePeak levels of plasma antibody are
achieved in 10 daysAntibody levels then decline
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Immunological Memory
Secondary immune response – re-exposure to the same antigenSensitized memory cells respond within
hoursAntibody levels peak in 2 to 3 days at much
higher levels than in the primary response Antibodies bind with greater affinity, and
their levels in the blood can remain high for weeks to months
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Primary and Secondary Humoral Responses
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Active Humoral Immunity
B cells encounter antigens and produce antibodies against themNaturally acquired – response to a bacterial
or viral infectionArtificially acquired – response to a vaccine
of dead or attenuated pathogens Vaccines – spare us the symptoms of disease,
and their weakened antigens provide antigenic determinants that are immunogenic and reactive
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Passive Humoral Immunity Differs from active immunity in the antibody
source and the degree of protectionB cells are not challenged by antigensImmunological memory does not occurProtection ends when antigens naturally
degrade in the body Naturally acquired – from the mother to her
fetus via the placenta Artificially acquired – from the injection of
serum, such as gamma globulin
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Types of Acquired Immunity
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Antibodies
Also called immunoglobulins Constitute the gamma globulin portion of
blood proteinsAre soluble proteins secreted by activated B
cells and plasma cells in response to an antigen
Are capable of binding specifically with that antigen
There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE
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Classes of Antibodies
IgD – monomer attached to the surface of B cells, important in B cell activationFunction as antigen receptor of the B cell
IgM – pentamer released by plasma cells during the primary immune response
IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity
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Classes of Antibodies
IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces
IgE – monomer that binds to mast cells and basophils, causing histamine release when activated
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Basic Antibody Structure Consists of four looping polypeptide chains
linked together with disulfide bondsTwo identical heavy (H) chains and two
identical light (L) chains The four chains bound together form an
antibody monomer Each chain has a variable (V) region at one
end and a constant (C) region at the other Variable regions of the heavy and light chains
combine to form the antigen-binding site
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Basic Antibody Structure
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Antibody Structure
Antibodies responding to different antigens have different V regions but the C region is the same for all antibodies in a given class
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Antibody Structure
C regions form the stem of the Y-shaped antibody and:Determine the class of the antibodyDetermine how the antibody functions to
eliminate the antigensDictate the cells and chemicals that the
antibody can bind to
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Mechanisms of Antibody Diversity Plasma cells make over a billion types of
antibodies However, each cell only contains 100,000
genes that code for these polypeptides To code for this many antibodies, somatic
recombination takes place:Gene segments are shuffled and combined
in different ways by each B cell as it becomes immunocompetent
Information of the newly assembled genes is expressed as B cell receptors and as antibodies
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Antibody Diversity
Random mixing of gene segments makes unique antibody genes that: Code for H and L chains Account for part of the variability in
antibodies V gene segments, called hypervariable
regions, mutate and increase antibody variation
Plasma cells can switch H chains, making two or more classes with the same V region
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Antibody Targets
Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction
All antibodies form an antigen-antibody (immune) complex
Defensive mechanisms used by antibodies are neutralization, agglutination, precipitation, and complement fixation
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Complement Fixation and Activation Complement fixation:
Main mechanism used against cellular antigens
Antibodies bound to cells change shape and expose complement binding sites
This triggers complement fixation and cell lysis
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Complement Fixation and Activation
Stimulates inflammation (C3a)Enlists more and more defensive
elementsPromotes opsonization (C3b)
Enhancing phagocytosis
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Other Mechanisms of Antibody Action Neutralization – antibodies bind to and block
specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells
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Other Mechanisms of Antibody Action Agglutination – antibodies bind the same
determinant on more than one antigen Makes antigen-antibody complexes that are
cross-linked into large latticesCell-bound antigens are cross-linked,
causing clumping (agglutination) Precipitation – soluble molecules are cross-
linked into large insoluble complexes
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Mechanisms of Antibody Action
Figure 21.14
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Monoclonal Antibodies
Commercially prepared antibodies are used:To provide passive immunityIn research, clinical testing, and cancer
treatment Monoclonal antibodies are pure antibody
preparations Specific for a single antigenic determinantProduced from descendents of a single cell
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Cell-Mediated Immune Response
Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed
Two major populations of T cells - based on the type of glycoprotein present on the T cell membrane:CD4 cells (T4 cells) are primarily helper T
cells (TH) CD8 cells (T8 cells) are cytotoxic T cells (TC)
that destroy cells harboring foreign antigens
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Cell-Mediated Immune Response Other types of T cells are:
Regulatory T cells (Treg) Memory T cells
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Major Types of T Cells
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Importance of Humoral Response Soluble antibodies
The simplest ammunition of the immune response
Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph. Do not invade solid tissues.
Interact with free antigens or antigens in their natural state
Do not destroy the antigens but prepare them for destruction
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Importance of Cellular Response T cells recognize and respond only to
processed fragments of antigen displayed on the surface of body cells
T cells are best suited for cell-to-cell interactions, and target:Cells infected with viruses, bacteria, or
intracellular parasitesAbnormal or cancerous cellsCells of infused or transplanted foreign
tissue
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Antigen Recognition and MHC Restriction Immunocompetent T cells are activated when
the V regions of their surface receptors bind to a recognized antigen
T cells must simultaneously recognize:Nonself (the antigen)Self (a MHC protein of a body cell)
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MHC Proteins
Are coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual
Each MHC molecule has a deep groove that displays a peptide, which is a normal cellular product of protein recycling
In infected cells, MHC proteins bind to fragments of foreign antigens, which play a crucial role in mobilizing the immune system
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MHC Proteins Both types of MHC proteins are important to T cell
activation Class I MHC proteins
Present in almost all body cells (except RBCs)Bound to fragments of self proteins
Ignored by CD8 cellsBound to nonself peptides
Destroyed by CD8 cells Always recognized by CD8 T cellsDisplay peptides from endogenous antigens
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Class I MHC Proteins
Endogenous antigens are:Degraded by proteases and enter the
endoplasmic reticulum ferried from the cytosol by TAPTransporter associated with Antigen
ProcessingLoaded onto class I MHC moleculesDisplayed on the cell surface in association
with a class I MHC molecule
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Class I MHC ProteinsPlasma membraneof a tissue cell
Extracellular fluid
Class IMHC
Class IMHC
TAP
Loaded MHC protein migratesto the plasma membrane, whereit displays the antigenic peptide
Endogenous antigenpeptide loaded ontoclass I MHC
Antigenic peptide
Endogenous antigen(viral protein)
Endogenous antigenpeptides enter ER via TAP
Endogenous antigendegraded by protease
Cytoplasm ofvirus-invaded cell
Endoplasmicreticulum (ER)
(a)
4
2
3
1
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Class II MHC Proteins
Class II MHC proteins are found only on mature B cells, and antigen-presenting cells (monocyte-macrophage group and dendritic cells)
A phagosome containing pathogens (with exogenous antigens) merges with a lysosome
Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum
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Class II MHC ProteinsExtracellular antigen(bacterium) phagocytized
After synthesis at the ER,the class II MHC proteinmigrates in a vesicle, whichfuses with the phagolysosome;invariant chain removed,antigen loaded
Loaded MHC proteinmigrates to the plasma membrane
Lysosomemerges withphagosome,forming aphagolysosome;antigendegraded
Invariant chainprevents class II MHC binding topeptides in the ER
Endoplasmic reticulum (ER)
Antigenic peptide
Plasma membraneof an APC
Extracellular fluid
Cytoplasm of APC
ClassII
MHC
ClassIIMHC
ClassII
MHC
ClassIIMHC
4
3
1
2
(b)
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Antigen Recognition
Provides the key for the immune system to recognize the presence of intracellular microorganisms
MHC proteins are ignored by T cells if they are complexed with self protein fragments
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Antigen Recognition
If MHC proteins are complexed with endogenous or exogenous antigenic peptides, they:Indicate the presence of intracellular
infectious microorganismsAct as antigen holdersForm the self part of the self-antiself
complexes recognized by T cells
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T Cell Activation: Step One – Antigen Binding
Instead of MHC T cells have T cell antigen receptors (TCRs):Bind to an antigen-MHC protein complexT cells recognize only antigens they are
programmed to detect
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T Cell Activation: Step One – Antigen Binding MHC restriction – TH and TC bind to different
classes of MHC proteins TH cells bind only to antigen linked to class II
MHC proteins TC cells are activated by antigen fragments
complexed with class I MHC proteins
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T Cell Activation: Step One – Antigen Binding
Mobile APCs (dendritic cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen
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T Cell Activation: Step One – Antigen Binding
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T Cell Activation: Step Two – Co-stimulation
Before a T cell can undergo clonal expansion, it must bind to other surface receptors on the APC cells Ex: APC cells sprout B7 proteins when
nonspecific defenses are mobilized B7 binds to T cell receptors (co-stimulation)Other co-stimulatory signals include
cytokines and interleukin 1 and 2 T cell now will clone
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T Cell Activation: Step Two – Co-stimulation Depending on receptor type, co-stimulators
can cause T cells to complete their activation or abort activation
Without co-stimulation, T cells display anergy:Become tolerant to that antigenAre unable to divide Do not secrete cytokines
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T Cell Activation: Step Two – Co-stimulation
T cells that are activated:Enlarge, proliferate, and form clonesDifferentiate and perform functions
according to their T cell class
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T Cell Activation: Step Two – Co-stimulation
Primary T cell response peaks within a week after signal exposure
T cells then undergo apoptosis between days 7 and 30
Effector activity wanes as the amount of antigen declines
The disposal of activated effector cells is a protective mechanism for the body
Memory T cells remain and mediate secondary responses to the same antigen
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T Cell Activation: Step Two – Co-stimulation
Primary T cell response peaks within a week after signal exposure
T cells then undergo apoptosis between days 7 and 30 A protective mechanism for the body As T cell dies, the effectors activity wanes
as the amount of antigen declines Memory T cells remain and mediate secondary
responses to the same antigen
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Cytokines
Mediators involved in cellular immunity, including hormone-like or paracrine-like glycoproteins released by activated T cells and macrophages
Some are co-stimulators of T cells and some promote T cell proliferation
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Cytokines
Examples include:Perforin and lymphotoxin – cell toxinsGamma interferon – enhances the killing
power of macrophagesInflammatory factors
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Specific T Cells
Helper T cells (TH)
Cytotoxic T cells (TC)
Regulatory T cells (TREG)
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Specific T Cell Roles Helper T Cells (TH) Regulatory cells that play a central role in the
immune response Once primed by APC presentation of antigen,
they: Stimulate proliferation of other T cellsStimulate B cells that have already become
bound to antigen
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Helper T Cell TH cells interact directly with B cells that have
antigen fragments on their surfaces bound to MHC II receptors
TH cells stimulate B cells to divide more rapidly and begin antibody formation
B cells may be activated without TH cells by binding to T cell–independent antigens
Most antigens, however, require TH co-stimulation to activate B cells: T cell dependent antigens
Cytokines released by TH amplify nonspecific defenses
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Cytotoxic T Cell (Tc)
TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells
They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized
Their targets include:Virus-infected cellsCells with intracellular bacteria or parasitesCancer cellsForeign cells from blood transfusions or
transplants
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Mechanisms of Tc Action
In some cases, TC cells:Bind to the target cell and release perforin
into its membrane In the presence of Ca2+ perforin causes
cell lysis by creating transmembrane pores
Other TC cells induce cell death by:Secreting lymphotoxin, which fragments the
target cell’s DNASecreting gamma interferon, which
stimulates phagocytosis by macrophages
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Mechanisms of Tc Action
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Regulatory T Cells (TREG)
Regulatory T cells (TREG) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells
They act either by direct contact or by releasing cytokines
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117Figure 21.20
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Organ Transplants
The four major types of grafts are:Autografts – graft transplanted from one site
on the body to another in the same personIsografts – grafts between identical twinsAllografts – transplants between individuals
that are not identical twins, but belong to same species
Xenografts – grafts taken from another animal species
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Prevention of Rejection
Prevention of tissue rejection is accomplished by using immunosuppressive drugs
However, these drugs depress patient’s immune system so it cannot fight off foreign agents
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Immunodeficiencies
Diseases in which the function or production of immune cells, phagocytes, or complement is abnormalCongenital (genetic)
Severe Combined Immunodeficiency Syndromes (SCID)
Deficits of B and T cellsAcquired
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Acquired Immunodeficiencies
Hodgkin’s disease – cancer of the lymph nodes
Acquired immune deficiency syndrome (AIDS) – cripples the immune system by destroying helper T (CD4) cells
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Autoimmune Diseases
Loss of the immune system’s ability to distinguish self from nonself
The body produces autoantibodies and sensitized TC cells that destroy its own tissues
Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, Type I (juvenile) diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis
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Mechanisms of Autoimmune Diseases Ineffective lymphocyte programming – self-
reactive T and B cells that should have been eliminated in the thymus and bone marrow escape into the circulation
New self-antigens appear, generated by:Gene mutations that cause new proteins to
appearChanges in self-antigens by hapten
attachment or as a result of infectious damage
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Mechanisms of Autoimmune Diseases If the determinants on foreign antigens
resemble self-antigens:Antibodies made against foreign antigens
cross-react with self-antigens
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Hypersensitivity Immune responses that cause tissue damage Different types of hypersensitivity reactions are
distinguished by:Their time courseWhether antibodies or T cells are the
principle immune elements involved Antibody-mediated allergies are immediate
and subacute hypersensitivities T cell-mediated allergic condition causes
delayed hypersensitivity
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Immediate Hypersensitivity
Acute (type I) hypersensitivities begin in seconds after contact with allergen
Initial allergen contact is asymptomatic but sensitizes the person
Subsequent exposures to allergen cause: Release of histamine and inflammatory
chemicalsSystemic or local responses
Anaphylaxis
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Immediate Hypersensitivity
The mechanism involves IL-4 secreted by TH cells Increased in susceptible persons
IL-4 stimulates B cells to produce IgEIgE binds to mast cells and basophils
causing them to degranulate, resulting in a flood of histamine release and inducing the inflammatory response
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Antigen (allergen)invades body.
Mast cell withfixed IgEantibodies
Granulescontaininghistamine
IgE
More of same antigeninvades body.
Antigen combineswith IgE attachedto mast cells (andbasophils), which triggers degranulation and release of histamine(and other chemicals).
Histamine causes blood vessels to dilate and becomeleaky, which promotes edema; stimulates secretion oflarge amounts of mucus; and causes smooth musclesto contract (if respiratory system is site of antigenentry, asthma may ensue).
Outpouring of fluid from capillaries
Release of mucus
Constriction of small respiratory passages(bronchioles)
IgE antibodiesattach to mast cells in body tissues (and to circulatingbasophils).
Sensitization stage
Subsequent (secondary)responses
Antigen
Histamine
Mast cell granules release contents after antigen bindswith IgE antibodies
Plasma cellsproduce largeamounts of classIgE antibodiesagainst allergen.
1
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Anaphylaxis
Reactions include runny nose, itching reddened skin, and watery eyes
If allergen is inhaled, asthmatic symptoms appear– constriction of bronchioles and restricted airflow
If allergen is ingested, cramping, vomiting, or diarrhea occur
Antihistamines counteract these effects
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Anaphylactic Shock Response to allergen that directly enters the
blood (e.g., insect bite, injection) Basophils and mast cells are enlisted
throughout the body Systemic histamine releases may result in:
Constriction of bronchioles Sudden vasodilation and fluid loss from the
bloodstreamHypotensive shock and death
Treatment – epinephrine is the drug of choice
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Subacute Hypersensitivities
Caused by IgM and IgG, and transferred via blood plasma or serumOnset is slow (1–3 hours) after antigen
exposure Duration is long lasting (10–15 hours)
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Subacute Hypersensitivities
Cytotoxic (type II) reactionsAntibodies bind to antigens on specific body
cells, stimulating phagocytosis and complement-mediated lysis of the cellular antigens
Example: mismatched blood transfusion reaction
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Subacute Hypersensitivities
Immune complex (type III) hypersensitivityAntigens are widely distributed through the
body or bloodInsoluble antigen-antibody complexes form Complexes cannot be cleared from a
particular area of the bodyIntense inflammation, local cell lysis, and
death may result Example: systemic lupus erythematosus
(SLE)
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Delayed Hypersensitivities (Type IV) Onset is slow (1–3 days) Mediated by mechanisms involving delayed
hypersensitivity T cells and cytotoxic T cells Cytokines from activated TC are the mediators
of the inflammatory response Antihistamines are ineffective and
corticosteroid drugs are used to provide relief
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Delayed Hypersensitivities (Type IV) Example: allergic contact dermatitis (e.g.,
poison ivy) Involved in protective reactions against
viruses, bacteria, fungi, protozoa, cancer, and rejection of foreign grafts or transplants
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Developmental Aspects
Immune system stem cells develop in the liver and spleen by the ninth week
Later, bone marrow becomes the primary source of stem cells
Lymphocyte development continues in the bone marrow and thymus system begins to wane
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Developmental Aspects
The immune system is impaired by stress and depression
With age, the immune system begins to wane