BIO2305
Immune System
Body Defenses
Reconnaissance, Recognition, and Response
Must defend from the many dangerous pathogens it may encounter in the environment
Detect invader/foreign cells
Communicate alarm & recruit immune cells
Suppress or destroy invader
Two major kinds of defense have evolved that counter these threats
Innate immunity and acquired immunity
Innate Immunity
Innate immunity provides broad defenses against infection
Present before any exposure to pathogens and is effective from the time of birth
Involves nonspecific responses to pathogens
A pathogen that successfully breaks through an animal’s external defenses encounters several innate
cellular and chemical mechanisms that impede its attack on the body
Innate Immunity
Non-selective
No lag time – immediate response
No previous exposure required
Protects against infections, toxins
Works with specific (acquired) immune response
Acquired (Adaptive) Immune Response
Depends on B and T lymphocytes
Specific immune response directed attack against pathogens (antigen)
Lag time
Previous Antigen exposure required
Protects against pathogens and cancer cells
Types:
Antibody-mediated Immunity (aka Humoral Immunity)
B Lymphocytes (B cells)
Cell-mediated immunity
T Lymphocytes (T cells)
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Types of Immunity
Types of Immune Cells
Body Defenses
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Innate Immunity
Physical barriers, secretions, chemical toxins
Phagocytosis – macrophages, neutrophils engulf and digest recognized "foreign" cells, molecules
Inflammatory response – localized tissue response to injury producing swelling, redness, heat, pain
Natural Killer cells – special class of lymphocyte-like cells that destroy virus infected cells and cancer
cells
Complements system – activated proteins that destroy pathogen plasma membranes and enhance
phagocytosis, inflammation
Interferon – proteins that non-specifically defend against viral infection
Innate Immunity/External Defenses
Barriers - prevent entry of microorganisms and viruses
Physical barriers
Epidermis
Mucous Membranes
Hair, Cilia
Excretions - lacrimal, saliva
Chemical barriers
Skin acidity between 3 and 5, which is acidic enough
to prevent colonization
Sebum toxic to microbes
Lysozymes digests the cell walls of many bacteria
Innate Immunity – Phagocytosis
Functions:
Scavenge dead and dying body cells, remove cellular debris
Destroy abnormal cells (cancerous and virus-infected cells)
Protect from pathogens & foreign molecules: parasites, bacteria, viruses
Exhibit Margination – leukocyte adhesion to the inner endothelial lining of capillaries of affected tissue
Move via Diapedesis – movement across capillary walls
Exhibit Chemotaxis – concentration-dependent movement of a cell in response to the detection of
chemokines
Innate Immunity – Phagocytosis
Monocyte - Macrophage System:
vessel-bound, free, and fixed
monocytes and macrophage that accumulate in lymph nodes, spleen, and lungs
Monocytes:
Macrophage-precursors that remain within vessels
Macrophages:
Monocytes that have left the body’s vessels
Take longer to get to site of infection, but arrive in larger numbers
Monocytes become free (roaming) macrophages, once they leave the capillaries
Destroy microbes and clean up dead tissue following an infection
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Innate Immunity – Phagocytosis
Neutrophils
Fastest response of all WBC to bacteria and parasites
Direct actions against bacteria
Release lysozymes which destroy/digest bacteria
Release defensive proteins that act like antibiotics
Release strong oxidants (bleach-like, strong chemicals) that destroy bacteria
Eosinophils
Leave capillaries to enter tissue fluid
Attack parasitic worms
Phagocytize antibody-antigen complexes
Dendritic Cells
a type of antigen presenting cells (with the broadest range)
present in tissues in contact with the external environment
Examples: Langerhans cells of the skin and follicular dendritic cells in the lymph nodes
Phagocytic Cells
Phagocytes attach to their prey via surface receptors and engulf them, forming a vacuole that fuses
with a lysosome
Phagocytosis Mechanisms
Chemotaxis
Attraction to certain chemical mediators
Released at the site of damage
Chemotaxins induce phagocytes to injury
Opsonization
Identify (mark) pathogen
Coated with chemical mediators (antibodies, compliment proteins)
Marked for death, and phagocytized by phagocyte
Toll-like receptors (TLR’s)
Phagocytic cells studded with plasma membrane receptor proteins
Bind with pathogen markers
Recognition - Allow phagocytes to “see” and distinguish from self-cells
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Inflammatory Response
Inflammation – histamine release from mast cells and other chemicals released from injured cells
promote changes in blood vessels
Changes allow more fluid, phagocytes, and antimicrobial proteins to enter tissues
Effects of inflammation include
Mobilization of local, regional, and systemic defenses
Slow the spread of pathogens
Temporary repair of injury
Inflammatory Response
Macrophages and Mast cells release histamine
Localized vasodilation
Capillary permeability - increased gaps in capillaries bring more WBC's & plasma proteins
Swelling, redness, heat and pain are incidental
Injured cells and phagocytes release cytokines (chemical signals)
Kinins - stimulate complement system (plasma proteins)
Chemotaxins – attract more phagocytes
Clotting factors – walling off invasion
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Natural Killer Cells
Patrol the body and attack virus-infected body cells and cancer cells
Recognize cell surface markers on foreign cells
Destroy cells with foreign antigens
Rotation of the Golgi toward the target cell and production of perforins
Release of perforins by exocytosis
Interaction of perforins causing cell lysis
Natural Killer Cells Kill Cellular Targets
Antimicrobial Proteins
Proteins function in innate defense by attacking microbes directly or impeding their reproduction
Complement System - About 30 proteins involved in the lysis of invading cells and helps
trigger inflammation
Interferons – small proteins provide innate defense against viruses and help activate
macrophages
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Complement System
System of inactive proteins produced by liver circulating in
blood and on cell membranes
Cascade of plasma complement proteins activated by
antibodies or antigens causing cascade of chemical reactions
Direct effect is lysis of microorganisms by destroying target
cell membranes
Indirect effects include:
Chemotaxis
Opsonization
Inflammation
Recruit phagocytes, B & T lymphocytes
Complement Activation
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Innate Cytokines – Interferons
Small antiviral proteins released by lymphocytes, macrophages,
virally infected cells
Type I interferons – Alpha and Beta
Induced during many virus infections
IFN- a: Mainly by leukocytes
IFN- b: Mainly by fibroblast cells
Binds to membranes of adjacent, uninfected cells
Triggers production of proteins that interfere with viral
replication
Enhances macrophage, natural killer, and cytotoxic T cell
& B cell activity
Slows cell division and suppresses tumor growth
Type II Interferon - gamma
Activates macrophages and other immune cells
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Integrated Defense
Acquired Immunity
In acquired immunity, lymphocytes provide specific defenses against infection
Involves
Cell mediated immunity
Antibody mediated immunity
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Acquired Immunity
Antigen triggers an immune response
Activates T cells and B cells
T cells are activated after phagocytes exposed to antigen
T cells attack the antigen and stimulate B cells
Activated B cells mature and produce antibody
Antibody attacks antigen
Properties of Acquired Immunity
Specificity – activated by and responds to a specific antigen
Versatility – is ready to confront any antigen at any time
Memory – “remembers” any antigen it has encountered
Tolerance – responds to foreign substances but ignores normal tissues
Lymphatic System
Primary lymphatic organs – Bone marrow and Thymus
Secondary lymphatic organs - Lymph nodes, Spleen
Lymph nodes – Exchange Lymphocyte w/ lymph (remove, store, produce, add)
Resident macrophages remove microbes and debris from lymph
Lymphocytes produce antibodies and sensitized T cells released in lymph
Spleen – Exchange Lymphocytes with blood, residents produce antibodies and sensitized T
cells released in blood
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Lymphocytes
B and T cells originate in bone marrow
B cells remain in bone marrow for maturation
T cells leave bone marrow, and migrate to thymus
gland for maturation
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Lymphocytes – B and T cells
B cells – Antibody-mediated immunity (grenade launchers)
T cells – Cell-mediated immunity (hand-to-hand combat)
Antigens
An antigen is any foreign molecule that is specifically
recognized by lymphocytes and elicits a response
from them
A lymphocyte actually recognizes and binds to just a
small, accessible portion of the antigen called an
epitope or antigenic determinant
Antigenic determinants - Specific regions of
a given antigen recognized by a lymphocyte
Antigenic receptors -Surface of lymphocyte
that combines with antigenic determinant
Antigen Recognition by Lymphocytes
A single B cell or T cell has about 100,000 identical antigen receptors
All antigen receptors on a single cell recognize the same epitope
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Cell-Mediated Immunity – T Cells
Antigens that stimulate this response are mainly intracellular (cell to cell).
Requires constant presence of antigen to remain effective
Involves numerous cytokines, over 100 have been identified
Stimulate and/or regulate immune responses
Interleukins: Communication between WBCs
Interferons: Protect against viral infections
Chemotaxins: Attract WBCs to infected areas
Lymphocyte Communication
Over 18 different types of interleukins are known; designated IL-1, IL-2…IL-18, etc.
IL-1 and IL-2 are primarily responsible for activating T and B lymphocytes, with IL-2 being a stimulant of
T- and B-cell growth and maturation
IL-1, along with IL-6, is also a mediator of inflammation.
IL-4 often leads to an increase in antibody secretion by B lymphocytes
IL-12 causes a greater number of the leukocytes cytotoxic T cells and natural killer cells to be made
The set of interleukins produced by the presence of a specific infectious agent determines which cells
will respond to the infection
Types of T cells
Cytotoxic T cells – attack foreign cells
Helper T cells - activate other T cells and B cells
Suppressor T cells– inhibit the activation of T and B cells
Memory T cells – function during a second exposure to antigen
T cell membranes contain CD markers:
CD3 markers present on all T cells
CD8 markers on cytotoxic and suppressor T cells
CD4 markers on helper T cells
T Cell Activation
T cells are activated when they detect and bind to small fragments of antigens that are combined with
to cell-surface glycoproteins called major histocompatibility complex (MHC) molecules
Lymphocytes respond to antigens bound to either class I or class II MHC proteins depending on the
source of the MHC molecule and the antigen presenting cell
Class I MHC molecules are displayed on the surface of infected nucleated cells
Class II MHC molecules are displayed on the surface of phagocytes
Class I MHC molecules
Infected cells produce Class I MHC molecules which bind to antigen fragments and then are
transported to the cell surface in a process called antigen presentation
Binds and activates with Cytotoxic T cell receptor
Cytotoxic T cell response:
Clonal production of cytotoxic T cells and memory cells
Destruction of virus-infected cells, tumor cells, and tissue transplants
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Cytotoxic T (TC) Cells – CD8
Recognize and destroy host cells that are infected with viruses or bacteria, cancer cells, transplanted
tissue
Release protein called perforin which forms a pore in target cell, causing lysis of infected cells.
Produce cytokines, which promote phagocytosis and inflammation
Undergo apoptosis when stimulating antigen is gone.
Class II MHC molecules
Produced by dendritic cells, macrophages, and B cells
Macrophages & dendritic cells phagocytize antigens, proteins broken down into antigen fragments
(peptides) and combined with Class II MHC molecules
Binds and activates Helper T cells
Clonal production of Helper T cells
Activation of Cytotoxic T cells
Activation of B cells
T Helper (TH) Cells – CD4
T Helper (TH) Cells: main role in immune response
Recognize antigen on the surface of antigen presenting cells
Secrete Interleukin II (T-cell growth factor), interferon and cytokines which stimulate lymphocyte activity
Production and activation of Cytotoxic T cells and more Helper T cells
Stimulate B cells to produce antibodies
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T Cell Overview
Memory T-Cells
Can survive a long time and give lifelong immunity from infection
Can stimulate memory B-cells to produce antibodies
Can trigger production of killer T cells
Thymosin - hormone important in T cell lineage, enhances capabilities of existing T cells and the
proliferation of new T cells in lymphoid tissues - decreases after age 30-40
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Proliferation of Lymphocytes
Antibody-Mediated (Humoral) Immunity
Involves production of antibodies against foreign antigens
Plasma cells - B cells that are stimulated and begin actively secrete antibodies
Antibodies (immunoglobulins, Ig) are Y-shaped proteins found in extracellular fluids (blood plasma,
lymph, mucus, etc.) and the surface of B cells
Defend against bacteria, bacterial toxins, and viruses that circulate freely in body fluids, before they
enter cells
Also cause certain reactions against transplanted tissue
Antibody-Mediated (Humoral) Immunity
1000s of different B cells, each recognizes a different antigen on the surface of a macrophage
(specificity)
Each antigen stimulates production of a single specific antibody that the B cells (along with T cells)
come in contact with
They are stimulated (by TH cells) to produce many clones, plasma cells, which make antibodies.
Memory B cells provide secondary response (faster, more sensitive)
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Antibody Structure
Antibodies or Immunoglobulins (Ig)
Classes: IgG, IgM, IgA, IgE, IgD
Structure
Variable region - combines with anitgenic determinant of antigen
Constant region - responsible for other binding activities
Consequences of Antigen-Antibody Binding
Agglutination - antibodies cause antigens (microbes) to clump together
Opsonization and Phagocytosis – coating foreign substance with antibodies, allowing Phagocytes to
grip and engulf the invader
Complement System / Inflammatory Response – lyse the invader and attract other immune cells
(chemotaxis)
Neutralization – coat foreign substance, rendering it harmless
Antibody dependent NK/eosinophil cell response – Directly attack and lyse the cell using perforins
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Consequences of Antigen-Antibody Binding
Antigen-Antibody Complex On B Cell
Activate B lymphocyte production of:
Memory B cells for secondary immune response to that antigen
Active Plasma Cells that secrete antibodiess
Immunoglobulin Classes
IgG
Percentage serum antibodies: 80%
Location: Blood, lymph, intestine, Only lg that crosses placenta, thus
conferring passive immunity on fetus
Promotes opsonization, neutralization, and agglutination of antigens, protects
fetus and newborn.
IgA
Percentage serum antibodies: 10-15%
Location: Secretions (tears, saliva, intestine, breast milk), blood and lymph
Provides localized defense of mucous membranes by agglutination and
neutralization of antigens
Localized protection of mucosal surfaces. Presence in breast milk confers
passive immunity on nursing infant
IgM
Percentage serum antibodies: 5-10%
Location: Blood, lymph, B cell surface (monomer)
First antibodies produced during an infection. Effective against microbes,
complement activation and agglutinating antigens
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IgD
Percentage serum antibodies: 0.2%
Location: Found primarily on surface of naive B cells that have not been
exposed to antigens
Acts as antigen receptor in antigen-stimulated proliferation and differentiation
of B cells (clonal selection)
IgE
Percentage serum antibodies: 0.002%
Location: Bound to mast cells and basophils throughout body
Triggers release of histamine and other chemicals that cause allergic
reactions
B Cell Sensitization And Activation
Sensitization – the binding of antigens to the B cell membrane antibodies
Activation - Helper T cells present same antigen to stimulate B cell
Division - Stimulated B cells divide into many clones called plasma cells, which actively secrete
antibodies
Secretion - Each B cell secrete antibodies that will recognize only one antigenic determinant
Differentiation - Active B cells also differentiate into Memory B Cells
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Immunological Memory
Primary Response:
After initial exposure to antigen, no antibodies are found in serum for several days. A gradual
increase number of Abs, first of IgM and then of IgG is observed.
Most B cells become plasma cells, but some B cells become long living memory cells. Gradual
decline of antibodies follows.
Secondary Response:
Subsequent exposure to the same antigen displays a faster/more intense response due to the
existence of memory cells, which rapidly produce plasma cells upon antigen stimulation
Clonal Selection
Clonal Selection: B cells (and T cells) that encounter stimulating antigen will proliferate into a large
group of cells.
Why don’t we produce antibodies against our own antigens? We have developed tolerance to them.
Tolerance: To prevent the immune system from responding to self-antigens
Clonal Deletion: B and T cells that react against self antigens are normally destroyed during
fetal development
Preventing activation of lymphocytes – activate Suppressor T cells, control the immune system
when the antigen / pathogen has been destroyed
Apoptosis
Apoptosis - Programmed cell death (“Falling away”)
Human body makes 100 million lymphocytes every day. If an equivalent number doesn’t die, will
develop leukemia
B cells that do not encounter stimulating antigen will self-destruct and send signals to phagocytes to
dispose of their remains
Many virus infected cells will undergo apoptosis, to help prevent spread of the infection
Autoimmune Diseases: Failure of “Self-Tolerance”
Some diabetes mellitus – attack - cells
Multiple sclerosis – attack on myelin nerve sheath
Rheumatoid arthritis – attack joint cartilage
Myasthenia gravis – ACh-receptors at endplate attacked
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Allergic Response: Inflammation Reaction to Non-pathogen
First exposure: sensitization
Activation
Clone B cells
Form antibodies
Memory cells
Re-exposure
Many antibodies
Activated T cells
Intensified
Inflammation
Hemagglutination
Agglutination of red blood cells used to determine ABO blood types and to detect influenza and
measles viruses
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Summary
Body defends itself with barriers, chemicals & immune responses
WBCs and relatives conduct direct cellular attack: phagocytosis, activated NK & cytotoxic T cells and
produce attack proteins (i.e. antibodies, complement, & membrane attack complex)
Cytokines, communicate cell activation, recruitment, swelling, pain, & fever in the inflammation
response
Defense against bacteria is mostly innate while viral defense relies more on acquired immune
responses
Autoimmune diseases are a failure of self-tolerance
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