The Immune System

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The Immune System
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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

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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
  animals external defenses encounters several
  innate cellular and chemical mechanisms that
  impede its attack on the body

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Innate Immunity

• Non-selective
• No lag time immediate response No previous
  exposure required
• Protects against infections, toxins
• Works with specific (acquired) immune response

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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 B cells
• Cell-mediated T cells

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Types of Immunity
Figure 22.14
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Body Defenses
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Innate Immunity

• Physical barriers, secretion, 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, inflamation
• Interferon - proteins that non-specifically
  defend against viral infection

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Innate Immunity / External Defenses

• Physical barriers prevent entry of microorganisms
  and viruses
• Epidermis
• Mucous Membranes
• Hair, Cilia
• Excretions - lacrimal, saliva
• Chemical
• 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

10?m

• In the trachea, ciliated epithelial cells sweep
  mucus and any entrapped microbes upward,
  preventing the microbes from entering the lungs

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Innate Immunity - Phagocytosis

• Scavenge dead, dying body cells, remove cellular
  debris
• Destroy abnormal (cancerous)
• Protect from pathogens foreign molecules
  parasites, bacteria, viruses
• Monocyte - macrophage system free and fixed
• Margination stick to the inner endothelial
  lining of capillaries of affected tissue
• Move by diapedesis move thru capillary walls
• Microphages Neutrophils and eosinophils
• Exhibit chemotaxis

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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

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Innate Immunity - Phagocytosis

• Monocytes
• Take longer to get to site of infection, but
  arrive in larger numbers
• Become free (roaming) macrophages, once they
  leave the capillaries
• Destroy microbes and clean up dead tissue
  following an infection

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Phagocytic Cells

• Phagocytes attach to their prey via surface
  receptors and engulf them, forming a vacuole that
  fuses with a lysosome

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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
• Most important opsonins
• Toll-like receptors (TLRs)
• Phagocytic cells studded with plasma membrane
  receptor proteins
• Bind with pathogen markers
• Recognition - Allow phagocytes to see and
  distinguish from self-cells

Figure 24-6 Phagocytosis
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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

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Inflammatory Response

• Macrophages, 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 signalss)
• 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

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How Natural Killer Cells Kill Cellular Targets
Figure 22.11
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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 (C)
  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

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Complement Activation
Figure 22.12
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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
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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

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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

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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 cells originate and mature in bone marrow
• T cells originate in bone marrow, migrate then
  mature in thymus

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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- binding sites
Epitopes (antigenic determinants)
Antigen
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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

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Lymphocyte Communication

• Over 18 different types of interleukins are
  known designated IL-1, IL-2IL-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

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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

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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
  histocompatability 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 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

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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.

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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

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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
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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 Lymphoctyes
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Antibody-Mediated (Humoral) Immunity

• Involves production of antibodies against foreign
  antigens
• Antibodies are produced B cells
• B cells that are stimulated will actively secrete
  antibodies and are called plasma cells
• Antibodies (immunoglobulins, Ig) are 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

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Antibody-Mediated (Humoral) Immunity

• 1000s of different B cells, each recognizes a
  different antigen on the surface of a macrophage.
  
• 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 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

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Consequences of Antigen-Antibody Binding

• Agglutination - antibodies cause antigens
  (microbes) to clump together
• Opsonization and Phagocytosis
• Activates Complement System / Inflammatory
  Response
• Neutralization
• Antibody dependent NK / eosinophil cell response

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Antigen-Antibody Complex On B Cell

• Activate B lymphocyte production of
• Memory cells for secondary immune response to
  that antigen
• Plasma cells that secrete antibodies

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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.
• 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
• 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

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Immunoglobulin Classes

• 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

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B Cell Sensitization And Activation

• Sensitization the binding of antigens to the B
  cell membrane antibodies
• Helper T cells present same same antigen to
  stimulate B cell
• Stimulated B cells divide into many clones called
  plasma cells, which actively secrete antibodies
• Each B cell produces antibodies that will
  recognize only one antigenic determinant
• 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

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Clonal Selection

• Clonal Selection B cells (and T cells) that
  encounter stimulating antigen will proliferate
  into a large group of cells.
• Why dont 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

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Apoptosis

• Programmed cell death (Falling away).
• Human body makes 100 million lymphocytes every
  day. If an equivalent number doesnt 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.

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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 Ts
• Intensified
• Inflammation

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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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Hemagglutination

• Agglutination of red blood cells used to
  determine ABO blood types and to detect influenza
  and measles viruses

Figure 24-20a ABO blood groups