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21

The Immune System: �Innate and Adaptive �Body Defenses

Part A

Human Anatomy & Physiology, Sixth Edition

Elaine N. Marieb

PowerPoint^® Lecture Slides prepared by Vince Austin, University of Kentucky

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Primary and Secondary Humoral Responses

Figure 21.10

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Immunity: Two Intrinsic Defense Systems

Innate (nonspecific) system responds quickly and consists of:

First line of defense – intact skin and mucosae prevent entry of microorganisms
Second line of defense – antimicrobial proteins, phagocytes, and other cells

Inhibit spread of invaders throughout the body
Inflammation is its hallmark and 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 substances

Takes longer to react than the innate system
Works in conjunction with the innate system

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Surface Barriers

Skin, mucous membranes, and their secretions make up the first line of defense
Keratin in the skin:

Presents a formidable physical barrier to most microorganisms
Is resistant to weak acids and bases, bacterial enzymes, and toxins

Mucosae provide similar mechanical barriers

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Epithelial Chemical Barriers

Epithelial membranes produce protective chemicals that destroy microorganisms

Skin acidity (pH of 3 to 5) inhibits bacterial growth
Sebum contains chemicals toxic to bacteria
Stomach mucosae secrete concentrated HCl and protein-digesting enzymes
Saliva and lacrimal fluid contain lysozyme
Mucus traps microorganisms that enter the digestive and respiratory systems

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Respiratory Tract Mucosae

Mucus-coated hairs in the nose trap inhaled particles
Mucosa of the upper respiratory tract is ciliated

Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages

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Internal Defenses: Cells and Chemicals

The body uses nonspecific cellular and chemical devices to protect itself

Phagocytes and natural killer (NK) cells
Antimicrobial proteins in blood and tissue fluid
Inflammatory response enlists macrophages, mast cells, WBCs, and chemicals

Harmful substances are identified by surface carbohydrates unique to infectious organisms

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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
Neutrophils become phagocytic when encountering infectious material
Eosinophils are weakly phagocytic against parasitic worms

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Mechanism of Phagocytosis

Microbes adhere to the phagocyte
Pseudopods engulf the particle into a phagosome
Phagosomes fuse with a lysosome to form a phagolysosome
Invaders in the phagolysosome are digested by proteolytic enzymes
Indigestible and residual material is removed by exocytosis

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Mechanism of Phagocytosis

Figure 21.1a, b

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Natural Killer (NK) Cells

Cells that can lyse and kill cancer cells and virus-infected cells
Natural killer cells:

Are a small, distinct group of large granular lymphocytes
React nonspecifically and eliminate cancerous and virus-infected cells
Kill their target cells by releasing perforins and other cytolytic chemicals
Secrete potent chemicals that enhance the inflammatory response

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Inflammation: Tissue Response to Injury

The inflammatory response is triggered whenever body tissues are injured

Prevents the spread of damaging agents to nearby tissues
Disposes of cell debris and pathogens
Sets the stage for repair processes

The four cardinal signs of acute inflammation are redness, heat, swelling, and pain

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Inflammation Response

Begins with a flood of inflammatory chemicals released into the extracellular fluid
Inflammatory mediators:

Include kinins, prostaglandins (PGs), complement, and cytokines
Are released by injured tissue, phagocytes, lymphocytes, and mast cells
Cause local small blood vessels to dilate, resulting in hyperemia

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Inflammatory Response: Vascular Permeability

Chemicals liberated by the inflammatory response increase the permeability of local capillaries
Exudate (fluid containing proteins, clotting factors, and antibodies):

Seeps into tissue spaces causing local edema (swelling), which contributes to the sensation of pain

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Inflammatory Response: Edema

The surge of protein-rich fluids into tissue spaces (edema):

Helps to dilute harmful substances
Brings in large quantities of oxygen and nutrients needed for repair
Allows entry of clotting proteins, which prevents the spread of bacteria

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Inflammatory Response: Phagocytic Mobilization

Occurs in four main phases:

Leukocytosis – neutrophils are released from the bone marrow in response to leukocytosis-inducing 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 – inflammatory chemicals attract neutrophils to the injury site

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Inflammatory Response: Phagocytic Mobilization

Neutrophils enter blood from bone marrow

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Margination

Diapedesis

Positive�chemotaxis

Capillary wall

Endothelium

Basal lamina

Inflammatory chemicals diffusing from the inflamed site act as chemotactic agents

Figure 21.3

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Antimicrobial Proteins

Enhance the innate defenses by:

Attacking microorganisms directly
Hindering microorganisms’ ability to reproduce

The most important antimicrobial proteins are:

Interferon
Complement proteins

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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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Fever

High fevers are dangerous as 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 (Specific) Defenses

The adaptive immune system is a functional system that:

Recognizes specific foreign substances
Acts to immobilize, neutralize, or destroy foreign substances
Amplifies 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 immunity
Cellular, or cell-mediated immunity

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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)

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Antigenic Determinants

Figure 21.6

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Lymphocytes

Immature lymphocytes released from 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

B cells mature in the bone marrow
T cells mature in the thymus

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T Cells

T cells mature in the thymus under negative and positive selection pressures

Negative selection – eliminates (downgrades) T cells that are strongly anti-self
Positive selection – selects T cells with a weak response to self-antigens, which thus become both immunocompetent and self-tolerant

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B Cells

B cells become immunocompetent and self-tolerant in bone marrow
Some self-reactive B cells are inactivated (anergy) while others are killed
Other B cells undergo receptor editing in which there is a rearrangement of their receptors

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Adaptive Immunity: Summary

Two-fisted defensive system that uses lymphocytes, APCs (antigen presenting cells), 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 them
Communicate 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 cell
Takes place in the spleen or other lymphoid organ
If the lymphocyte is a B cell:

The challenging antigen provokes a humoral immune response

Antibodies are produced against the challenger

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Immunological Memory

Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen

Lag period: 3 to 6 days after antigen challenge
Peak levels of plasma antibody are achieved in 10 days
Antibody levels then decline

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Immunological Memory

Secondary immune response – re-exposure to the same antigen

Sensitized memory cells respond within hours
Antibody 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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Active Humoral Immunity

B cells encounter antigens and produce antibodies against them

Naturally acquired – response to a bacterial or viral infection
Artificially 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 protection

B cells are not challenged by antigens
Immunological memory does not occur
Protection 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

Figure 21.11

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Antibodies

Also called immunoglobulins

Constitute the gamma globulin portion of blood proteins
Are 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 activation
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
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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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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The complement refers to a group of at least 20 plasma proteins
When activated, virtually all aspects of the inflammatory process is amplified
Although the complement is nonspecific, it “complements” or enhances the effectiveness of both nonspecific and specific defenses

Complement Fixation and Activation

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Complement Fixation and Activation

Complement fixation is the main mechanism used against cellular antigens
Antibodies bound to cells change shape and expose complement binding sites
This triggers complement fixation and cell lysis
Complement activation:

Enhances the inflammatory response
Uses a positive feedback cycle to promote phagocytosis
Enlists more and more defensive elements

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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 lattices
Cell-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 21.13

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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 mediate cellular immunity

CD4 cells (T4 cells) are primarily helper T cells (T_H) and are attacked by the HIV virus
CD8 cells (T8 cells) are cytotoxic T cells (T_C) that destroy cells harboring foreign antigens

Other types of T cells are:

Suppressor T cells (T_S)
Memory 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

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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 parasites
Abnormal or cancerous cells
Cells of infused or transplanted foreign tissue

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Mechanisms of T_c Action

Figure 21.18a, b

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Other T Cells

Suppressor (regulatory) T cells (T_S) – cells that release cytokines, which suppress the activity of both T cells and B cells

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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 person
Isografts – grafts between identical twins
Allografts – 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

Congenital and acquired conditions in which the function or production of immune cells, phagocytes, or complement is abnormal

SCID “bubble boy” disease – severe combined immunodeficiency (SCID) syndromes; genetic defects that produce:

A marked deficit in B and T cells
Abnormalities in interleukin receptors
Defective adenosine deaminase (ADA) enzyme

Metabolites lethal to T cells accumulate

SCID is fatal if untreated; treatment is with bone marrow transplants

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Acquired Immunodeficiencies

Hodgkin’s disease – cancer of the lymph nodes leads to immunodeficiency by depressing lymph node cells
Acquired immune deficiency syndrome (AIDS) – cripples the immune system by interfering with the activity of helper T (CD4) cells

Characterized by severe weight loss, night sweats, and swollen lymph nodes
Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s sarcoma

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Autoimmune Diseases

Loss of the immune system’s ability to distinguish self from nonself
The body produces autoantibodies and sensitized T_C 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 appear
Changes in self-antigens 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 course
Whether antibodies or T cells are the principle immune elements involved

Antibody-mediated allergies are immediate and subacute hypersensitivities
The most important cell-mediated allergic condition is delayed hypersensitivity

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Immediate Hypersensitivity

Acute (type I) hypersensitivities begin in seconds after contact with allergen
Anaphylaxis – initial allergen contact is asymptomatic but sensitizes the person

Subsequent exposures to allergen cause:

Release of histamine and inflammatory chemicals
Systemic or local responses

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Immediate Hypersensitivity

The mechanism involves interleukin IL-4 secreted by T cells
IL-4 stimulates B cells to produce IgE
IgE 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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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 bloodstream
Hypotensive 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 serum

Onset is slow (1–3 hours) after antigen exposure
Duration is long lasting (10–15 hours)

Cytotoxic (type II) reactions

Antibodies 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) hypersensitivity

Antigens are widely distributed through the body or blood
Insoluble antigen-antibody complexes form
Complexes cannot be cleared from a particular area of the body
Intense 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 T_Care 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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Acute Allergic Response

Figure 21.20