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Chapter 21: The Immune System

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Immune system has two intrinsic systems
Innate (nonspecific) defense system
Adaptive (specific) defense system
Innate defense system has two lines of defense
First line of defense - skin and mucosa
Second line of defense - antimicrobial proteins, phagocytes, and other cells
inhibit spread of invaders
Inflammation is immunity's
most important mechanism
Adaptive defense system
Third line of defense attacks particular foreign substances
Surface barriers
skin, mucous membranes, and their secretions
Protective chemicals
inhibit or destroy microorganisms
Skin acidity
pH 3-5 inhibits bacterial growth
Lipids in
sebum and dermicidin in sweat are toxic to bacteria
HCl and protein-digesting
enzymes of stomach mucosae are protective chemicals
Lysozyme of
saliva and lacrimal fluid are protective barriers
Mucus traps
microorganisms in digestive and respiratory passageways
Respiratory system modifications
mucus-coated hairs in nose
cilia of upper respiratory tract
Internal defenses
phagocytes
NK cells
Inflammatory response
antimicrobial proteins (interferons and complement)
fever
Macrophages develop from
monocytes to become the chief phagocytic cells
Free macrophages
wander through tissue spaces in search of debris and invaders (alveolar macrophages)
Fixed macrophages
are permanent residents of some organs (Kupffer cells in liver and micrglia in brain)
Neutrophils (most abundant WBC)
become phagocytic on encountering infectious material on tissues
Adherence of phagocyte to pathogen
is facilitated by opsonization coating of pathogen by complement proteins or antibodies
Opsonization
"to make tasty"
so phagocytic receptors can bind
Destruction of pathogens
respiratory burst - release of cell killing free radicals
Natural Killer cells are
large granular lymphocytes
NK cells target
cells that lack "self" cell-surface receptors
NK cells induce
apoptosis in cancer cells and virus-infected cells
NK cells secrete
potent chemicals that enhance the inflammatory response
Inflammatory response is triggered
whenever body tissues are injured or infected
Inflammatory response prevents
the spread of damaging agents
Inflammatory response disposes of
cell debris and pathogens
Inflammatory response sets
the stage for repair
Cardinal signs of acute inflammation
redness
heat
swelling
pain
impairment of funciton
Inflammatory mediators
histamine
blood proteins
kinins, prostaglandins, leukotrienes, and complement
Inflammatory mediators released by
injured tissue, phagocytes, lymphocytes, basophils, and mast cells
Order of sequence of phagocytosis
C - A - I - D - K
Chemotaxis
Adherance
Ingestion
Digestion
Killing
Inflammatory chemicals cause dilation
of arterioles, resulting in hyperemia (redness and heat)
Inflammatory chemicals cause increased
permeability of local capillaries and edema (leakage of exudate)
Exudate contains
proteins, clotting factors, and antibodies, fluid that causes swelling
Surge of exudate moves
foreign material into lymphatic vessels
Surge of exudate delivers
clotting proteins to form a scaffold for repair and to isolate the area
Edema presses on
nerve endings causing pain
Leukocytes in phagocyte mobilization
release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells
Margination
neutrophils cling to the walls of capillaries in the inflamed area
Diapedisis
of neutrophils (flatten and squeeze through capillary walls)
Chemotaxis
inflammatory chemicals (chemotactic agent) promote positive chemotaxis of neutrophils
Ultimate goal of inflammation
is to clear pathogens, dead tissue cells, and debris so tissue can be repaired
Interferons (IFNs) and complement proteins
attack microorganisms directly
Interferons (IFNs) and complement proteins hinder
microorganisms' ability to reproduce
Interferons
neighboring cells produce antiviral proteins that block viral reproduction by blocking protein synthesis and degrading viral RNA
Interferons also activate
macrophages and mobilize NK cells
Functions of interferons
anti-viral
reduce inflammation
activate macrophages
mobilize NK cells
Genetically engineered IFNs for
antiviral agents against hepatitus and genital warts
MS treatment
Complement
20 blood proteins that circulate in an inactive form
Complement is a major mechanism for
destroying foreign substances
Complement amplifies
all aspects of the inflammatory response
Complement kills
bacteria and certain other cell types by cell lysis
Complement enhances
both nonspecific (innate) and specific (adaptive) defenses
Activated complement
enhances inflammation
promotes phagocytosis
causes cell lysis
C3b initiates formation
of a membrane attack complex (MAC)
C3b also causes
opsonization
C3a causes
inflammation
Fever
systemic response to invading microorganisms
Leukocytes and macrophages exposed to
foreign substances secrete pyrogens
Pyrogens reset
the body's thermostat upward
High fevers are dangerous because
heat denatures enzymes
Benefits of moderate fever
liver and spleen sequester iron and zinc (needed by microorganisms)
Increases metabolic rate (speeds repair)
Adaptive immune system
specific defense system
Adaptive immune response
is specific
is systemic
has memory
Adaptive defenses have two separate overlapping arms
Humoral (antibody-mediated) immunity
Cellular (cell-mediated) immunity
Antigens are ultimate targets
of all adaptive immune responses
Antigens are substances that can
mobilize the adaptive defenses and provoke an immune response
Most antigens are
large, complex molecules not normally found in the body (nonself)
Complete antigens have
immunogenicity
reactivity
Immunogenicity
ability to stimulate proliferation of specific lymphocytes and antibodies
Reactivity
ability to react with products of activated lymphocytes and antibodies released
Examples: foreign protein, polysaccharides, lipids, and nucleic acids
Haptens
allergic reaction
poison ivy, animal dander, detergents, and cosmetics
MHC proteins
helpers to make things compatible
Two types of lymphocytes
B cells
T cells
B cells
humoral immunity (blood and lymph)
T cells
cell-mediated immunity
Antigen presenting cells (APCs)
do not respond to specific antigens
play essential auxillary roles in immunity
Lymphocytes originate
in red bone marrow
B cells mature
in red bone marrow
T cells mature
in the thymus
Immunocompetence
mature lymphocytes are able to recongnize and bind to a specific antigen
Self-tolerance
mature lymphocytes are unresponsive to self antigens (does not attack body's own cells)
T cells mature in the thymus under
negative and positive selection pressures
Genes determine
which foreign substances the immune system will recognize and resist (it is not antigens)
Antigen presenting cells engulf
antigens
APCs present
fragments of antigens to be recognized by T cells
Major types of APCs
dendritic cells
macrophages
B cells
Macrophages and dendritic cells
present antigens and activate T cells
Activated T cells release chemicals that
prod macrophages to become insatiable phagocytes and to secrete bactericidal chemicals
Adaptive immunity uses
lymphocytes, APCs, and specific molecules to identify and destroy nonself substances
Adaptive immunity depends upon the ability of its cells to recognize (bind tightly)
antigens by binding to them
Adaptive immunity depends upon the ability of its cells to communicate
with one another so that the whole system mounts a specific response
Humoral immunity response
antigen challenge - first encounter between an antigen and a naive immunocompetent lymphocyte
If the lymphocyte is a B cell
the antigen provokes a humoral immune response
antibodies are produced
Clonal selection - B cell is activated when
antigens bind to its surface receptors and cross-link them
Stimulated B cell grows to form
a clone of identical cells bearing the same antigen-specific receptors
T cells are usually required to help
B cells achieve full activation
Most clone cellse become plasma cells and
secrete specific antibodies at the rate of 2,000 molecules per second for four to five days
Secreted antibodies circulate
in blood or lymph
Secreted antibodies bind
to free antigens
Secreted antigens mark
the antigens for destruction
Clone cells that do not become plasma cells becom memory cells
that provide immunological memory
mount an immediate response to future exposures of the same antigen
Primary immune response occurs
on the first exposure to a specific antigen
Primary immune response lag period
3 to 6 days
Primary immune response peak levels
of plasma antibody are reached in 10 days then decline
Secondary immune response occurs
on re-exposure to the same antigen
Secondary immune response causes sensitized
memory cells to respond within hours
Secondary immune response antibody levels
peak in 2-3 days at much higher levels
Secondary immune response antibodies bind
with greater affinity
Secondary immune response antibody level can remain
high for weeks to months
Active humoral immunity occurs when
B cells encounter antigens and produce specific antibodies against them
Two types of active humoral immunity
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 the primary response
Vaccines provide
antigenic determinants that are immunogenic and reactive
Vaccines target only one type of helper T cell,
so fail to fully establish cellular immunological memory
Passive humoral immunity B cells
are not challenged by antigens
Immunological memory does not occur in
passive humoral immunity
Two types of passive humoral immuntiy
Naturally acquired - antibodies delivered to a fetus via the placenta or to infant through milk
Artificially acquired - injection of serum, such as gamma globulin (protection immediate but ends when antibodies naturally degrade in body)
Artifically acquired passive humoral immunity examples
snakebites, hepatitis exposure, botulism, rabies, tetanus
Immunoglobulins are antibodies
gamma globulin portion of blood (IGSs)
Antibodies are proteins
secreted by plasma cells (effector B cells)
Antibodies are capable of binding
specifically with antigen detected by B cells
Antibodies are T or Y shaped
monomer of four looping polypeptide chains
Antibodies have two identical
heavy (H) chains and two identical light (L) chains
Antibodies have variable (V) regions
of each arm that combine to form two identical antigen-binding sites
Constant (C) region of stem determines
antibody class
cells and chemicals that antibody can bind to
how antibody class functions in antigen elimination
Classes of antibodies
IgM
IgA
IgD
IgG
IgE
IgM
pentamer
1st antibody released
IgA
secretory IgA
helps prevent entry of pathogens into body
IgD
functions as a B cell receptor
IgG
crosses the placental barrier
IgE
monomer active in some allergens and parasitic infections
causes mast cells and basophils to release histamine
Antibodies inactivate and tag antigens
form antigen-antibody (immune) complexes
Defensive mechanisms used by antibodies
neutralization and agglutination (most important)
precipitation and complement fixation
Neutralization
antibodies block specific sites on viruses or bacterial exotoxins
Neutralization prevents these antigens
from binding to receptors on tissue cells
In neutralization antigen-antibody complexes
undergo phagocytosis
In agglutination antibodies bind the same
determinant on more than one cell-bound antigen
Cross-linked
antigen-antibody complexes agglutinate (clumping of mismatched blood cells)
Complement fixation and activation is the main antibody defense
against cellular antigens
Several antibodies bind
close together on a cellular antigen
Their complement-binding sites trigger
complement fixation into the cell's surface
Complement triggers
cell lysis
T cells provide defense against
intracellular antigens
Two types of surface receptors of T cells
T cell antigen receptors
cell differentiation glycoproteins - CD4 or CD8
play a role in T cell interactions with other cells
Major types of T cells
CD4 - helper T cells when activated
CD8 - cytotoxic T cells that destroy cells harboring foreign antigens
Other types of T cells
Regulatory T cells
Memory T cells
Antibodies of the humoral response
the simplest ammunition of the immune response
Targets of antibodies of the humoral response
bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph)
T cells of cell-mediated response recognize and respond only to
processed fragments of antigen displayed on the surface of body cells
T cells of cell-mediated response target
body cells infected by viruses or bacteria
abnormal and cancer cells
cells of infused or transplanted foreign tissue
APCs (most often dendritic cells) migrate
to lymph nodes and other lymphoid tissues to present their antigens to T cells
T cell activation is a two step process
antigen binding
co-stimulation
Antigen binding stimulates
the T cell, but co-stimulation is required before proliferation can occur
Cytokines mediate
cell development, differentiation, and responses in the immune system
Cytokines include
interleukens and interferons
Interleukin 1 (IL-1) released by macrophages co stimulates bound T cells to
release interleukin 2 (IL-2)
synthesize more IL-2 receptors
IL-2 is a key growth factor
acting on cells that release it and other T cells
IL-2 encourages
activated T cells to divide rapidly
IL-2 used therapeutically to treat
melanoma and kidney cancers
Other cytokines amplify and regulate
innate and adaptive responses
Helper T cells play a
central role in the adaptive immune response
ONce a helpter T cell is primed by APC presentation of an antigen they help
activate T and B cells
Helper T cells induce
T and B cell proliferation
Helper T cells activate
macrophages and recruit other immune cells
Without Th cells
there is no immune response
Helper T cells stimulate
B cells to divide more rapidly and begin antibody formation
Most antigens require Th
co-stimulation to activate B cells
Cytotoxic (Tc) cells directly
attack and kill other cells
Th direct or help complete the activation of
both B cells and T cells
NK cells recognize
other signs of abnormality
Natural killer cells use the same key mechanisms
as Tc cells for killing their target cells
Treg cells are important
in preventing autoimmune reactions
There are four varieties of organ transplants
autografts
isografts
allografts
xenografts
Autografts
from one body site to another in the same person
Isografts
between identical twins
Allografts
between individuals who are not identical twins
Xenografts
from another animal species
Prevention of rejection depends on
similarity of the tissues
Patient is treated with immunosuppressive therapy to prevent rejection
many of these have severe side effects
Immunodeficiencies
congenital and acquired conditions that cause immune cells, phagocytes, or complement to behave normally
Severe Combined Immunodeficiency Syndrome SCID
genetic defect
marked deficit in B and T cells
abnormalities in interleukin receptors
defective adenosine deaminase (ADA) enzyme
SCID is fatal
if untreated, treatment is with bone marrow transplants
Hodgkin's disease
an acquired immunodeficiency
cancer of the B cells
leads to immunodeficiency by depressing lymph node cells
Acquired Immune Deficiency Syndrome (AIDS)
opportunistic infections occur, including pneumocystis pneumonia and Karposi's sarcoma
AIDS is caused by
human immunodeficiency virus (HIV) transmitted via body fluid; blood, semen, vaginal secretions, and breast milk
HIV multiplies
in lymph nodes throughout the asymptomatic period
HIV coated glycoprotein complex attaches
to the CD4 receptor
Autoimmune diseases cause the immune system
to turn against itself
loses the ability to distinguish self from foreign
Autoimmune diseases cause production of
autoantibodies and sensitized Tc cells that destroy body tissues
Examples of autoimmune disease
MS, myasthenia gravis, Grave's disease, type 1 diabetes mellitus, systemic lupus erythematosus (SLE), glumerolonephritis and rheumatoid arthritis
Hypersensitivites
immune responses to a perceived (otherwise harmless) threat
causes tissue damage
Anaphylactic shock is a systemic response
to an allergen that directly enters the blood
Systemic histamine releases may cause
comstriction of bronchioles
sudden vasodilation and fluid loss from bloodstream
hypotensive shock and death
Treatment of anaphylactic shock
epinephrine
Innate defense system
Like a lowly foot soldier, is always prepared, responding within minutes to protect the body from all foreign substances
Adaptive defense system
More like an elite fighting force equipped with high-tech weapons to attack particular foreign substances
First line of defense for innate defense system
The external body membranes-intact skin and mucosae
Second line of defense for innate defense system
Called into action when the first line has been penetrated, relies on internal defenses such as antimicrobial proteins, phagocytes, and other cells to inhibit the invaders' spread throughout the body (inflammation)
Immune system
Functional system rather than an organ system in an anatomical sense
Third line of defense for adaptive defense system
Attacks particular foreign substances, takes longer to react than innate system
Skin and mucous membranes produce a variety of protective chemicals
Acid, enzymes, mucin, defensins, other chemicals (sebum, dermcidin, and eccrine sweat)
Neutrophils
Most abundant but die fighting. Become phagocytic on exposure to infectious material
Macrophages
Develop from monocytes, chief phagocytic cells-robust cells, can go on to kill another day
Opsonins
Complement proteins or antibodies that provide "handles" to which phagocyte receptors can bind
Opsonization
"To make tasty". Any pathogen coated with opsonins which greatly accelerates phagocytosis of that pathogen
Respiratory burst
Helper T cells cause release of enzymes which kill pathogens resistant to lysosomal enzymes
Phagosome
Vesicle that cytoplasmic extensions bind to and engulf particle
Natural killer cells
"Police" the body in blood and lymph, are a unique group of defensive cells that can lyse and kill cancer cells and virus-infected body cells before the adaptive immune system is activated
NK cells are not
Phagocytic; they kill by directly contacting the target cell, inducing it to undergo apoptosis (programmed cell death), they also secrete potent chemicals that enhance inflammatory response
Inflammatory response
Triggered whenever body tissues are injured by physical trauma (a blow), intense heat, irritating chemicals, or infection by viruses, fungi, or bacteria
Benefits of inflammatory response
Prevents spread of damaging agents, dispose of cell debris and pathogens, alerts adaptive immune system, sets the stage for repair
Cardinal signs of inflammation
Redness, heat, swelling, and pain. Fifth one is said to be impaired function
Inflammatory chemicals are released by
Injured or stressed tissue cells and immune cells or formed from proteins circulating in the blood
Mast cells
A key component of the inflammatory response, release the potent inflammatory chemical histamine
Toll-like receptors
Play a central role in triggering immune responses
Activated toll-like receptors trigger release of
Cytokines that promote inflammation
Inflammatory mediators
Kinins, prostaglandins, and complement
All inflammatory chemicals
Dilate local arterioles and make local capillaries leakier
Hyperemia
Dilate local arterioles; redness and heat of an inflamed region are both due to this
Exudate
Fluid containing clotting factors and antibodies-seeps from the blood into the tissue spaces
Exudate causes
The local swelling, also called edema, that presses on adjacent nerve endings, contributing to a sensation of pain
Swelling of inflammation
Pushes on nerve endings which cause pain
Pain from inflammation also results from the release of
Bacterial toxins, and the sensitizing effects of released prostaglandins and kinins
Exudate moves
Foreign material into lymphatic vessels and delivers clotting proteins and complement
Clotting factors form a
Gel-like fibrin mesh (a clot) that acts as a scaffold for permanent repair and isolates the injured area and prevents bacteria and other harmful agents from spreading
Phagocyte mobilization
Phagocytes flood the damaged area, neutrophils lead; macrophages follow
Steps in which phagocytes are mobilized to infiltrate the injured site
-Leukocytosis
-Margination
-Diapedesis
-Chemotaxis
Leukocytosis
Release of neutrophils from bone marrow in response to leukocytosis-inducing factor from injured cells
Margination
Neurtophils cling to walls of capillaries in inflamed area in response to CAMs (cell adhesion molecules)
Diapedesis
Chemical signaling prompts the neutrophils to flatten and squeeze between the endothelial cells of the capillary walls
Chemotaxis
Inflammatory chemicals (chemotactic agent) promote positive chemotaxis of neutrophils
Monocytes arrive within
Twelve hours of leaving the blood and entering the tissues; they replace the neutrophils and remain for clean up prior to repair
Antimicrobial proteins
Enhance our innate defenses by attacking microorganisms directly or by hindering their ability to reproduce
Interferons
Infected cells can secrete these small proteins to help protect cells that have not yet been infected
Interferons alpha and beta have the
Antiviral effects and also activate NK cells; to warn neighboring cells
Interferons enter neighboring cells
Produce proteins that block viral reproduction and degrade viral RNA
Interferons gamma
Immune interferon; secreted by lymphocytes and has widespread immune mobilizing effects, such as activating macrophages
Interferons activate
NK cells and macrophages, indirectly fight cancer
Artificial interferons used to treat
Hepatitis C, genital warts, multiple sclerosis, hairy cell leukemia
Complement system
Twenty plasma proteins that normally circulate in the blood in an inactive state
Complement provides a major mechanism for
Destroying foreign substances in the body
Our cells are equipped with
Proteins that normally inhibit complement activation
Three pathways to which complement can be activated
1. Classical pathway
2. Lectin pathway
3. Alternative pathway
Classical pathway
Antibodies bind to invading organisms and to complement components, called complement fixation,
Lectin pathway
Produced by innate system to recognize foreign invaders; when bound to foreign invaders can also bind and activate complement
Alternative pathway
Triggered when activated C3, B, D, and P interact on surface of microorganisms
Membrane attack complex
Complement proteins insertion into cell's membrane when C3b binds to target cell; forms and stabilizes a hold in the membrane that allows a massive influx of water, lysing the target cell
C3b causes
Opsonization-process whereby opsonins make an invading microorganism more susceptible to phagocytosis
C3a and other cleavage products
Amplify inflammatory response by stimulating mast cells and basophils to release histamine and by attracting neutrophils and other inflammatory cells to the area
Pyrogens
Chemicals released by leukocytes and macrophages when exposed to foreign substances in the body, act on body's thermostat in hypothalamus
Adaptive immune system protects against
Infectious agents and abnormal body cells, amplifies inflammatory response, activates complement, must be primed by initial exposure to specific foreign substance (takes time)
Three important aspects of the adaptive immune response
Specific, systemic, and has memory
Specific
Recognizing and targets specific antigens
Systemic
Not restricted to initial site
Memory
Stronger attacks to "known" antigens
Humoral immunity
Antibodies produced by lymphocytes, circulating freely in body fluids, bind temporarily to target cell; temporarily inactivate; mark for destruction by phagocytes or complement
Cellular immunity
Lymphocytes act against target cell; directly by killing infected cells; indirectly by releasing chemicals that enhance inflammatory response; or activating other lymphocytes or macrophages
Antigens
Substances that can mobilize the adaptive defenses and provoke an immune response; ultimate targets of adaptive immune response
Complete antigens have two important functional properties
Immunogenicity and reactivity
Immunogenicity
Ability to stimulate proliferation of specific lymphocytes
Reactivity
Ability to react with activated lymphocytes and antibodies released by immunogenic reactions
Hapten
Incomplete antigen; small molecules not immunogenic by themselves