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The Immune Response:

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Title: The Immune Response:


1
The Immune Response
  • Introduction to Immunity
  • Part I Innate Immunity Major Cells
  • Part II Innate Immunity The Inflammatory
    Response
  • Part III Treatment of Inflammation
  • Part IV Adaptive Immunity

2
  • Introduction to Immunity

3
Functions of the Immune Response
4
The Immune Response
  • The Immune Response A collective and
    coordinated response of cells of the immune
    system
  • 1. Protects host from invasion of anything
    foreign
  • Ex. foreign pathogens, bacteria, parasites,
    viruses, the environment in general
  • 2. Distinguishes self from non-self
  • Ex. cancer, autoimmune reactions
  • The immune system has a surveillance mechanism to
    identify itself
  • When it recognizes something that is nonself, the
    immune system has mechanisms to kill the cell
  • When the surveillance system breaks down or is
    over-challenged, disease occurs
  • 3. Mediates healing
  • Modulate inflammatory process and wound repair
  • Immunity and inflammation are wrapped up together
    to make healing more efficient

5
Results of Immune Dysfunction or Deficiency
6
Results of Immune Dysfunction or Deficiency
  • Immunodeficiency
  • Do not have the requisite amount of immunological
    ability
  • Cannot keep up with what is going on
  • Allergies/Hypersensitivities
  • The response to something is exaggerated
  • Transplantation pathology
  • Autoimmunity

7
Innate Immunity
8
Innate Immunity
  • Natural resistance that a person is born with
  • Do not need anything else special
  • Comprises physical, chemical, and cellular
    barriers that keep the self and the nonself apart
  • First line of defense
  • Ex. skin, mucosa
  • When radiator heat comes on, it dries out the
    mucosal membranes and makes you more susceptible
    to microorganisms
  • A person in the healthcare system needs to take
    care of the skin because dry skin makes a person
    more susceptible to invasion

9
Adaptive Immunity
10
Adaptive Immunity
  • Acquired
  • When you are born and come into contact with
    antigens in the environment, your body mounts a
    response
  • Are able to recognize the pathogen in the future
  • Specific
  • Amplified response with memory
  • Has a recognition system
  • There is a molecular memory in the body about
    what happened
  • Able to respond more quickly to the pathogen when
    interact with it in the future

11
Components of the Adaptive Immune Response
12
Components of the Adaptive Immune Response
  • Divided into two major components
  • Cell-mediated adaptive immunity
  • - T cells
  • Antibody-mediated (humoral immunity)
  • Circulating antibodies
  • B cells produce the antibodies for humoral
    immunity
  • Antibody-mediated immunity is triggered by
    encounters with Antigens (Ags)
  • b. Antibodies are also known as Immunoglobulins
    (Igs)

13
  • Part I
  • Innate Immunity

14
Primary Immune Cells of Innate Immunity
15
Primary Immune Cells of Innate Immunity
  • Monocytes, macrophages, dendritic cells
  • Neutrophils
  • Eosinophils
  • Basophils
  • Mast cells
  • Natural killer cells

16
Monocytes, Macrophages, and Dendritic cells
17
Monocytes, Macrophages, and Dendritic cells
  • Phagocytic cells that are located in different
    areas of the body
  • While macrophages are important cells of the
    innate immunity, they also play key role in
    adaptive immunity
  • Monocytes in blood ? Macrophages in tissues
  • Dendritic cells are phagocytic cells in the
    nervous system
  • Include Kupffer, Langerhans, alveolar, peritoneal
    oligodendrocytes etc
  • Phagocytize antigen ? present antigen
    (APC-antigen presenting cell)
  • Internalize and consume pathogens with lysosomes
    and peroxisomes
  • Process the antigen out of the substance that is
    foreign
  • Takes the antigen, sticks it outside of itself,
    and presents it
  • When activated, secrete cytokines (tumor necrosis
    factor, interleukin-1, and others), oxygen
    radicals, proteolytic enzymes, arachidonic acid
    metabolites, prostaglandins
  • Release molecules that are very important in
    inflammation
  • Macrophages are phagocytes

18
Neutrophils
19
Neutrophils
  • AKA Polymorphonuclear leukocytes (PMN)
  • Antigen binding and non-specific phagocytosis
  • Inflammatory response First-line defender
    against bacterial invasion, colonization, and
    infection
  • Important in innate immunity
  • Responsible for antigen binding and phagocytosis

20
Eosinophils
21
Eosinophils
  • Inflammatory response
  • Fight parasites (worms especially)
  • May release chemicals in respiratory tract during
    allergic asthma
  • Release chemical mediators

22
Basophils
23
Basophils
  • Release potent mediators during allergic
    responses (e.g. histamine)
  • Have binding sites for IgE antibodies (Type 1
    Hypersensitivity)
  • The antibody will bind to antigen, and the
    basophil will release the inflammatory substances
  • Reside in blood

24
Mast Cells
25
Mast Cells
  • Also from bone marrow and share characteristics
    with basophils
  • Located in tissues not blood
  • Releases histamine which is the hallmark of
    tissue inflammatory response.

26
Natural Killer Cells
27
Natural Killer Cells
  • Natural Killer Cells an effector cell important
    in innate immunity.
  • Small of lymphocytes
  • Part of the lymphocyte population but are a small
    amount
  • Can bind with antibody coated target cell ?
    Antibody dependent cell-mediated cytotoxicity
    (ADCC)
  • Can recognize the antibody and destroy the cell
  • Can attack virus-infected cells or cancer cells
    without help or activation first
  • Important in immunosurveillance
  • Can recognize antigen without MHC restrictions
  • Major histamine compatibility
  • NO MEMORY
  • Lives by the minute by doing what it does
  • Regulated by cytokines, prostaglandins and
    thromboxane
  • Release NK perforins, enzymes, and toxic
    cytokines to destroy target cells

28
Outline of Immunity
29
(No Transcript)
30
Cytokines and the Immune Response
31
Cytokines and the Immune Response
  • Small, low molecular weight proteins
    (hormone-like) which are produced during all
    phases of the immune response.
  • They are released form one area, move, and act on
    another area
  • Short half-life
  • Work in a parocrine system (acts locally) rather
    than an endocrine system
  • This is characteristic of many of the
    immunological cytokines
  • Primarily made by T cells and macrophages
    (lymphokines/ monokines) and act primarily on
    immune cells
  • Lymphokines a cytokine released from a
    lymphocyte (T cell)
  • Monokines a cytokine released from a macrophage

32
Processes that Cytokines are Involves in
33
Processes that Cytokines are Involves in
  • Innate immunity
  • Adaptive immunity
  • Hematopoiesis

34
Cytokines and Innate Immunity
35
Cytokines and Innate Immunity
  • IL-1, IL-6, TNF (tumor necrosis factor) are
    important in the early inflammatory response.
  • Derived mainly from macrophages,endothelial, and
    dendritic cells, and lymphocytes (T cells)
  • Processes
  • Stimulate acute phase protein production by the
    liver
  • Stimulate the hypothalamus for a fever response
  • Increase adhesion molecules on the vascular
    endothelium

36
Acute Phase Protein Production by the Liver
37
Acute Phase Protein Production by the Liver
  • Overlaps with the ESR
  • Increases cytokine release in the body-sensed by
    the liver-liver increases amount of acute-phase
    proteins (complement, clotting factors)
  • Increased cytokines due to inflammation causes
    liver to produce more proteins, which increases
    ESR

38
Stimulate Hypothalamus for Fever Response
39
Stimulate Hypothalamus for Fever Response
  • Hypothalamus in the base of the brain
    thermoregulates the body
  • One of the main reasons that you get a fever is
    because a cytokine burden increases enough to
    pass through the vasculature of the hypothalamus
    and resets the temperature of the body
  • Reason why anti-inflammatory decrease fever
    decrease the burden of the cytokine production,
    which decreases the reason that the hypothalamus
    causes fever

40
Increase in Adhesion Molecules
41
Increase in Adhesion Molecules
  • Cytokines trigger the endothelium to put out
    adhesion molecules so that when a macrophage
    comes by it sticks to it and squeezes between the
    endothelium cells out into the tissue to fight
    infection

42
Cytokines and Adaptive Immunity
43
Cytokines and Adaptive Immunity
  • Activate immune cells to proliferate and
    differentiate into effector and memory cells.

44
Cytokines and Hematopoiesis
45
Cytokines and Hematopoiesis
  • Cytokines that stimulate bone marrow pluripotent
    stem cells, progenitor cells and precursor cells
    to produce large numbers of platelets,
    erythrocytes, lymphocytes, neutrophils,
    monocytes, eosinophils, basophils and dendritic
    cells are termed Colony Stimulation Factors (CSFs)

46
  • PART II
  • Innate Immunity
  • THE INFLAMMATORY RESPONSE

47
Inflammation
48
Inflammation
  • Reaction of vascularized tissue to local injury
    (cellular) manifesting as redness, swelling,
    heat, pain, loss of function
  • Non-specific, chain of events similar regardless
    of injury type and extent
  • Stereotypic no matter the size of the injury
  • Includes vascular and cellular changes
  • Triggered when FIRST LINE OF Defense's integrity
    has been breached (skin, mucus membranes and
    damaged the endothelium or gotten to a vessel)
  • May be from the outside into the body or from the
    inside of the body out (ex. vacularitis)
  • Unpleasant and uncomfortable, but essential for
    survival
  • May lead to inflammatory diseases

49
Acute Inflammation
50
Acute Inflammation
  • 1. vascular phase
  • 2. cellular phase

51
Acute InflammationVascular Phase
52
Acute InflammationVascular Phase
  • After injury or insult, inflammation initiates a
    rapid vasoconstriction of small vessels in the
    local area
  • The same thing as the rapid vasoconstriction that
    occurs in hemostasis
  • This vasoconstriction is then followed by a rapid
    vasodilatation of arterioles and venules
    (vasoactive hyperemia) that supply the local
    area.
  • Results in the erythema (redness) and warmth in
    the area due to the increased blood flow to the
    area
  • Capillary permeability increases and fluid moves
    into the tissues (edema) causing swelling and
    pain.
  • Due to cytokines that are released
  • The capillaries become more permeable cells
    that make up the cell wall become looser,
    allowing fluids and proteins to move out of the
    capillaries and into the tissue

53
Vascular PhasePossible Scenarios
54
Vascular PhasePossible Scenarios
  • 1. Immediate transient response to minor injury
  • Ex. very small, sterile cut (ex. razor cut, paper
    cut)
  • At first you do not notice the blood because of
    the rapid vasoconstriction but then after rapid
    vasoconstriction the vasodilation occurs
  • 2. Immediate sustained response (several days
    results in damaged vessels)
  • More of a traumatic event and possibly a less
    sterile field
  • Ex. step on a garden hose
  • The issue cannot resolve quickly and due to the
    hemostasis and clotting necessary, the several
    day response results in extra damage to the skin
    and vessels
  • 3. Delayed hemodynamic response (increase in
    capillary permeability 4-24 hours after injury
    e.g., radiation burns, sun burns)
  • Have an insult but do not realize an effect until
    4-24 hours after an injury
  • Ex. sunburn cooks the cells and damages them but
    they take a while to build up the response and
    the damage so that the response takes a while to
    show
  • Redness is the vasodilation, vascular
    permeability leads to the edema

55
Acute InflammationVascular Phase
56
Acute InflammationCellular Phase
57
Acute InflammationCellular Phase
  • Ex. step on a garden rake and bacteria enters the
    site of injury
  • Characterized by the movement of phagocytic cells
    into the site of injury
  • Need to remove them by recycling them
  • Release of chemical mediators by sentinel cells
    in the tissue (mast cells, basophils,
    macrophages)
  • Sentinel cells in the tissues release cytokines,
    the endothelial cells recognize them, stick out
    adhesion molecules to allow phagocytic cells to
    stick to them
  • Chemotaxis of the phagocytic cells from the
    vessels to the tissue because the cells of moving
    to the area of high signaling
  • Increases capillary permeability and allows
    leukocytes to migrate to the local area.
  • Water wants to leave the vasculature, making it
    easier for the cells to get out of the blood and
    into the tissue where they can fight infection

58
Acute InflammationCellular Phase
59
Inflammatory Mediators
60
Inflammatory Mediators
  • Histamine
  • Plasma proteases
  • Arachidonic acid metabolites
  • Platelet aggregating factors
  • Cytokines

61
Histamine
62
Histamine
  • One of the first mediators of inflammation
    causing dilatation and increased capillary
    permeability.
  • Histamine high concentration in platelets,
    basophils, and mast cell
  • Allows there to be a cross talk between the
    clotting cascade and platelet plug
  • In mast cells histamine is released in response
    to binding of IgE Antibodies

63
Plasma Proteases
64
Plasma Proteases
  • Kinins, activated complement, clotting proteins
  • Bradykinin causes increased capillary
    permeability and pain.
  • Byproduct of plasma proteases
  • Causes pain by binding to nociceptors

65
Arachidonic Acid Metabolites
66
Arachidonic Acid Metabolites
  • Metabolism of arachidonic acid into
    prostaglandins via the cyclooxygenase pathway
  • Metabolism of arachidonic acid into leukotrienes
    via the lipoxygenase pathway

67
Metabolism of Arachidonic Acid into
Prostaglandins via the Cyclooxygenase Pathway
68
Metabolism of Arachidonic Acid into
Prostaglandins via the Cyclooxygenase Pathway
  • Arachidonic metabolics are very, very important
    inflammatory mediators
  • PGE1(prostaglandin E1) and PGE2, prostaglandin
    intermediates, are important in inducing
    inflammation
  • Promoting the inflammatory pathways
  • Induces vasodilation and bronchoconstriction
  • Inhibits inflammatory cell function
  • Prostaglandins released during the pulsatile flow
    are important in making blood not stick
  • Control of acid production in the stomach
  • Some are pro-inflammatory and some are pro-other
    things that are important and beneficial to the
    body
  • TXA2 (Thromboxane A2) promotes platelet
    aggregation and vasoconstriction
  • Promotes branchoconstriction
  • Non-steroidals (aspirin etc) inhibit the first
    enzyme in the cyclooxygenase pathway.
  • Used pharmacologically to reduce inflammation

69
Metabolism of Arachidonic Acid into Leukotrienes
via the Lipoxygenase Pathway
70
Metabolism of Arachidonic Acid into Leukotrienes
via the Lipoxygenase Pathway
  • Leukotrienes are critically important in the
    generalized response of anaphlaxis
  • C4, D4, E4 the slow releasing substances of
    anaphylaxis (SRAs). They cause slow sustained
    contraction of bronchiole smooth muscle. Are
    important in asthma and anaphylaxis.
  • Target of the newer anti-asthma drugs, e.g.,
    montelukast (Singulair), which act as leukotriene
    inhibitors

71
Arachidonic Acid Diagram
72
(No Transcript)
73
Platelet Aggregating Factor
74
Platelet Aggregating Factor
  • Induced platelet aggregation
  • Pathways that are important for hemostasis are
    also important in the immune and inflammatory
    pathways
  • Neutrophil activation
  • Eosinophil chemotaxis

75
Complement System
76
Complement System
  • Functionally analogous to the clotting cascade in
    hemostasis
  • Primary mediator of the innate and adaptive
    humoral immune response. Produce inflammatory
    response, lyse foreign cells, increase
    phagocytosis
  • About 20 plasma proteins. Circulate in inactive
    form much like clotting factors (C1, C4, C2, C3,
    C5?C9). Proteins must be activated in the proper
    sequence in order to have their end effect (as
    with the clotting factors)
  • Non-specific and no memory

77
Complement Pathways for Activation
78
Complement Pathways for Activation
  • Classical pathway depends on
  • 1. Binding of IgG or IgM to invading
    organisms
  • - antibodies bind to invading organisms
  • 2. Binding of complement to circulating
    antigen-antibody complex
  • (complement fixation)
  • - undergoes molecular change that promotes the
    activation complement
  • - complement sees this and there is a molecular
    recognition
  • Alternate pathway is triggered by interactions
    between complement and polysaccharides on
    microbes
  • Lectin pathway is activated by binding proteins
    interacting with cell surface proteins in
    bacteria and yeast
  • Lectin can be recognized by complement and
    activates it
  • Lection is located inside cells and is seen when
    cells lyse

79
Results of Complement
80
Results of Complement
  • MAC (membrane attack complex) insertion into
    target cell membrane ? holes in cell membrane
    (lysis)
  • Form a pore that sticks into a cell and causes
    the cell to die through membrane depolarization
  • Opsonization - C3b coats Ag-Ab complexes
  • Helps out neutrophils and macrophages with
    phagocytosis
  • Opsonization is when an antibody binds to
    bacteria
  • Complement binds to the antigen-antibody complex
    and opsonizes it so that the phagocytes want to
    phagocytize the complex even more
  • Chemotaxis - C3a stimulates mast cells and
    basophils to release histamine and attract
    neutrophils and others
  • C3a and C5a produce anaphylatoxin inducing
    histamine release in mast cells and basophils
  • Leads to contraction of smooth muscle, ? vascular
    permeability, edema
  • Complement, if activated, will bind to these
    cells and cause them to release histamine

81
Complement PathwaysDiagram
82
(No Transcript)
83
Chronic InflammationPersistent Irritants
84
Chronic InflammationPersistent Irritants
  • Ex. talc, silica, asbestos that are breathed
    deeply into the respiratory tract, surgical
    sutures
  • The chronic inflammation causes persistent
    problems that results in disease
  • Some bacteria (tuberculosis, syphilis)
  • Can be in the body for a long time, escape
    surveillance, and cause inflammation
  • Injured tissue surrounding healing fracture
  • Keep stressing the healing fracture, leading to
    inflammation
  • Inflammatory process lasts a prolonged amount of
    time
  • Sustained types of response

85
Chronic InflammationPatterns
86
Chronic InflammationPatterns
  • Non-specific diffuse accumulation of macrophages
    and lymphocytes leading to fibroblast
    proliferation and scar tissue formation
  • Relsease cytokines and mediators that lead to the
    fibroblast proliferation and scar tissue
    formation
  • Ex. in the respiratory tract of smokers the
    epithelium begins dying and as the body goes to
    replace it, it says that the epithelium is
    difficult to replace so it replaces it with less
    ciliated, good cells, and then a scar tissue and
    fibroblasts
  • Granulomatous lesion ? epitheloid cells form
    granuloma
  • Lesions are very discrete
  • Ex. splinters, foreign bodies
  • After a couple of days, a granulomatous lesion
    forms and encapsulates the splinter
  • Eventually fibroblasts form around it and the
    nodule stays there for a long time
  • Ex. Tuberculosis tubercle
  • Waiting for the immune system to decrease so that
    the tuberculosis can come back

87
Chronic InflammationCauses and Characteristics
88
Chronic InflammationCauses and Characteristics
  • Due to
  • Recurrent or progressive acute inflammation
    (smoking), OR
  • Low-grade responses that fail to evoke acute
    responses (talc, silica, asbestos, tb)
  • Characteristics
  • Infiltration by mononuclear cells (Macs and
    Lymphs) not Neutrophils like in acute
    inflammation.
  • Proliferation of fibroblasts (? scarring) not
    exudates

89
Manifestations of InflammationExudation
90
Manifestations of InflammationExudation
  • Local manifestation of inflammation
  • Extra vascular influx of fluid with high
    concentration of proteins, salts, cells (WBC) and
    cell debris
  • The fluid from the vessel leaves the vessel and
    enters into the tissues
  • Fluid dilutes injurious chemicals
  • Fluid brings in complement, Abs, and other
    chemotactic substances to injured areas in the
    tissues due to osmotic gradient
  • The extra vascular proteins also act to pull
    water out of plasma ? ? blood viscosity ?
    clotting because water is taken out and cells are
    left behind (increase hemotocrit) containment of
    pathogens ? cellular phase begins

91
Manifestations of InflammationTypes of Exudate
92
Manifestations of InflammationTypes of Exudate
  • Serous watery low in protein
  • Early exudate
  • Fibrinous large amounts of fibrinogen in the
    exudate
  • Membranous necrotic debris in fibrinous matrix
    on mucus membrane surfaces
  • Forms a muscosy sheen on certain membranous
    surfaces
  • Purulent degraded white cells, protein, tissue
    debris
  • Ex. white looking acne blemish
  • Hemorrhagic severe leakage of red cells from
    capillaries
  • Blood leaves the vasculature and enters the
    tissue
  • Ex. petechiae, purpura

93
Systemic Manifestations of Inflammation
94
Systemic Manifestations of Inflammation
  • Most all of the inflammatory mediators have very
    short half lives so autocrine and paracrine
    signaling predominates.
  • Mechanisms whereby cells secrete substances and
    they act very, very locally
  • Compared to endocrine systems
  • If the site of inflammation is large enough or
    robust enough of if the inflammation is in the
    circulation, systemic manifestations can be
    evident in addition to the local manifestations
  • Acute phase response
  • Lymphadenitis

95
Acute Phase Responses
96
Acute Phase Responses
  • Acute-Phase Response (hours-days after onset)
  • Increase in plasma proteins (e.g., C-reactive
    protein)
  • Increased erythrocyte sedimentation rate (ESR)
  • Fever (IL-1, IL-6 and TNF effects on
    hypothalamus)
  • Drive the hypothalamus to increase body
    temeprature
  • Leukocytosis (presence of immature neutrophils
    band cells)
  • Are consuming leukocytes to significant amounts
    and are trying to replace them
  • Similar to the reticulocytes in red blood cells
  • Band cells are indicative are immature
    neutrophils
  • Skeletal muscle catabolism (mobilize amino acids
    for protein synthesis)
  • When there is active inflammation, individuals do
    not feel well, lose the drive to eat, do not take
    in enough nutrition, ask the liver to make a
    bunch of proteins
  • Break down the skeletal muscle to increase amino
    acid pool and make more proteins
  • Negative nitrogen balance
  • Skeletal muscle is wasting

97
Lymphadenitis
98
Lymphadenitis
  • Regional swelling of lymph nodes, painful upon
    palpation
  • A swollen lymph node is indicative of an
    inflammatory event in a local area or regional
    area
  • The regional swelling is an indication of
    systemic inflammation

99
  • Part III
  • Treatment of Inflammation

100
Types of Treatment of Inflammation
101
Types of Treatment of Inflammation
  • Focus Prevent the synthesis and release of
    pro-inflammatory mediators, such as
    prostaglandins
  • NSAIDs
  • Steroids

102
Treatment of InflammationDiagram
103
Treatment of InflammationDiagram
104
Treatment of InflammationNSAIDs
105
Treatment of InflammationNSAIDs
  • NSAIDS nonsteroidal anti-inflammatory drugs
    inhibit cyclooxygenase (COX), the enzyme that
    converts arachidonic acid to prostaglandins and
    thromboxane (e.g., aspirin, et al.) through the
    cyclooxygenase pathway
  • Inhibit the enzymatic conversion

106
Treatment of InflammationSteroids
107
Treatment of InflammationSteroids
  • Steroids given systemically or topically
  • Have a multiplicity of actions, many of which
    impair immune cell proliferation or cytokine
    release.
  • Stop the metabolism of arachidonic acid from cell
    membrane phospholipids

108
COX-1 and COX-2
109
COX-1 and COX-2
  • Both produce prostaglandins and thromboxane (TXA)
    and convert arachidonic acid into prostaglandins

110
COX-1
111
COX-1
  • Found in many different tissues
  • Inhibition of COX-1 is responsible for the
    adverse effects of NSAIDs because the drug works
    on all COX-1 tissue types
  • COX-1 inhibition impairs the gastrointestinal
    mucosal barrier and gastric erosion and
    ulceration may result
  • COX-1 inhibition impairs renal function so that
    sodium and water retention can result
  • Leads to edema and hypertension
  • COX-1 inhibition decreases the creation of
    thromboxane, which prevents platelet aggregation,
    which may produce bleeding.
  • Such inhibition may also prevent myocardial
    infarction or ischemic (thrombotic) stroke in
    patients with overactive coagulation pathways.

112
COX-2
113
COX-2
  • COX-2 is predominantly in immune cells.
  • Inhibiting COX-2 results in the therapeutically
    desirable effects of NSAIDs
  • If you are targeting inflammation, you should
    really be targeting COX-2 because it is more
    specific
  • Suppression of inflammation
  • Decreasing systemic side effects
  • Alleviation of pain
  • Reduction of fever
  • However, many of the non-steroidals inhibit both
    COX-1 and COX-2

114
Contraindications
115
Contraindications
  • NSAIDs
  • Hypersensitivity syndrome

116
NSAIDs
117
NSAIDs
  • NSAIDs should be avoided in mid to late pregnancy
    since
  • They may cause premature closure of the ductus
    arteriosus.
  • A shunt in the heart in the developing fetus that
    allows proper blood flow
  • Important in maternal-fetal circulation and
    oxygenation of the fetus
  • They might also cause prolonged bleeding
    following delivery because of their effects on
    platelets.

118
Hypersensitivity Syndrome
119
Hypersensitivity Syndrome
  • Hypersensitivity syndrome caused by COX
    inhibition
  • This is not an allergic response because there
    are no antibodies to the NSAID in susceptible
    individuals, any NSAID can trigger the reaction.
  • Certain people are more sensitive to NSAIDs just
    because
  • Symptoms are similar to those of anaphylaxis.
  • Susceptible individuals should avoid all NSAIDS

120
Aspirin
121
Aspirin
  • An irreversible inhibitor of both COX-1 and COX-2
    (it is nonselective).
  • Metabolized (with a half-life of 20 minutes) to
    salicylic acid, which inhibits both COXs
    reversibly and has a longer half-life than
    aspirin
  • The anti-inflammatory activity is due to both the
    irreversible inhibition of both COXs by aspirin
    and reversible inhibition by salicylic acid.

122
Uses of Aspirin
123
Uses of Aspirin
  • Anti-inflammatory
  • Anti-pyretic (suppression of fever)
  • Analgesic
  • Dysmenorrhea
  • Menstrual cramps are due to the production of
    prostaglandins
  • Aspirin decreases smooth muscle cramping
  • Suppression of platelet aggregation

124
Uses of AspirinSuppression of Platelet
Aggregation
125
Uses of AspirinSuppression of Platelet
Aggregation
  • This use is usually accomplished by
    administration of an 81-mg enteric-coated tablet
    each morning.
  • Allows the drug to pass through the stomach and
    be absorbed in the intestine
  • Do not want aspirin to dissolve in the stomach
    because it affects gastric pH
  • The aspirin irreversibly inhibits COX-1 in
    platelets it encounters in the portal
    circulation, but in its 81 mg form it is
    completely metabolized on first pass and has no
    systemic effects.
  • When aspirin is taken, any platelets in
    circulation are irreversibly inhibited but on the
    second time, the aspirin is converted to
    salicyclic acid and reversibly inhibit platelets
  • Taking the small dose allows it to be that only
    the platelets in the circulation are irreversibly
    affected (because of the short life of the
    platelets)
  • Over time, a substantial portion of platelets are
    affected by the low dose aspirin without undue
    systemic side effects.

126
Adverse EffectsCommon to all Aspirin Formulations
127
Adverse EffectsCommon to all Aspirin Formulations
  • Salicylism tinnitus, headache and dizziness
    caused by high doses such as the doses that are
    used in rheumatoid arthritis. Respiratory
    alkalosis may also result.
  • Reyes syndrome a fatal syndrome of liver
    failure in children suffering from chickenpox or
    influenza who use aspirin. For this reason, it
    is recommended that children be only given
    acetaminophen or ibuprofen for febrile illness.
    With this recommendation, the incidence of Reyes
    syndrome has plummeted.
  • Poisoning before childproof caps were mandated
    by law, aspirin poisoning was a common cause of
    illness and death in children. This is no longer
    such a problem
  • The toxicity of aspirin in children is what
    prompted the mandation of childproof safety caps

128
Aspirin Formulation
129
Aspirin Formulation
  • Plain aspirin tablets.
  • Buffered aspirin includes sodium bicarbonate to
    neutralize stomach acid and prevent gastric
    irritation.
  • The sodium bicarbonate acts as the buffer
  • Inhibit the prostaglandins, allowing the gastric
    mucosa to temporarily go down but you are also
    buffering the aspirin so you are helping it out
  • Enteric coated aspirin remains intact in the
    stomach and dissolves in the duodenum prevents
    gastric irritation.
  • Timed released makes no sense for an
    irreversible drug that is completely metabolized
    on first pass
  • Rectal suppositories Not recommended due to
    inconsistent absorption and rectal ulceration.

130
Aspirin Dosage
131
Aspirin Dosage
  • Is commonly available in
  • regular strength (327 mg)
  • extra-strength (500 mg)
  • low-dose (81 mg) tablets
  • Used by adults for the inhibition of platelets
  • There is no evidence that taking more than 81 mg
    leads to further platelet aggregation
  • Adults 650-1000 mg in one dose can be repeated
    every 4 hours.
  • Children aspirin is not recommended unless
    specifically requested by the childs physician.
  • Inhibition of platelets 81 mg per day.

132
Other Non-Selective NSAIDs
133
Other Non-Selective NSAIDs
  • Non-specific COX-1 and COX-2 inhibitors
  • Specific COX-2 inhibitors

134
Non-specific COX-1 and COX-2 Inhibitors
135
Non-specific COX-1 and COX-2 Inhibitors
  • Nonspecific COX-1 and -2 inhibitors (aspirin,
    Ibuprofen, naproxen, etc.)
  • All have interactions with warfarin (Coumadin)
    they may potentiate bleeding tendencies produced
    by warfarin
  • Coagulation studies should be obtained frequently
    and warfarin dosage adjusted in patients who take
    both an NSAID and warfarin

136
Specific COX-2 Inhibitors
137
Specific COX-2 Inhibitors
  • Have recently been associated with increased risk
    of heart attacks.
  • A result of clinical trials but many of the
    reasons are not known
  • Could inhibit prostacycline, which is a positive
    mediator
  • Purported to produce fewer adverse effects in
    some individuals, such as GI irritation,
    bleeding, and sodium/water retention. However,
    data in the general population to support this
    contention is shaky.
  • Much more expensive than nonselective NSAIDS
  • A nonselective NSAID is equally effective as a
    COX-2 inhibitor
  • Include
  • Rofecoxib (withdrawn from the market)
  • Valdecoxib (withdrawn from the market)
  • Celecoxib (Celebrex) is still available

138
Acetaminophen
139
Acetaminophen
  • Does not inhibit COX in the periphery MOA is
    unclear
  • Is not a COX inhibitor
  • Has no anti-inflammatory activity.
  • Does not decrease inflammatory mediators
  • No side effects of gastric ulceration, sodium and
    water retention.
  • No effect on platelets or coagulation.
  • Uses
  • Antipyretic
  • Analgesic

140
AcetaminophenAdverse Effects
141
AcetaminophenAdverse Effects
  • Adverse effects Hepatoxicity
  • Usually occurs because of overdose
  • Decreases liver function and may
  • increase toxicity
  • Greatly exacerbated by concurrent alcohol use
    so, hepatoxicity may occur at therapeutic doses
    in heavy drinkers.
  • Hepatotoxicity from acetaminophen has resulted in
    deaths from liver failure.

142
AcetaminophenDrug Interactions
143
AcetaminophenDrug Interactions
  • May affect warfarin metabolism because it is
    metabolized by the liver to increase levels of
    warfarin and increase its anticoagulant effects.

144
AcetaminophenDosages
145
AcetaminophenDosages
  • Available in 327 mg and 500 mg tablets.
  • Adult dose is 650 mg to 1000 mg every 4-6 hours
    with a daily limit of 3 g (3000 mg).
  • Dosage is reduced depending on the age of the
    child

146
Formulations of NSAIDs and Acetaminophen
147
NSAIDS and acetaminophen are found in many
formulationsBe careful !
148
  • Part IV
  • Adaptive Immunity

149
Active Adaptive Immunity
150
Active Adaptive Immunity
  • Active passive immunity - Through immunizations
  • Active natural immunity - Through having the
    disease
  • Present for a life-time

151
Passive Adaptive Immunity
152
Passive Adaptive Immunity
  • Transferred from another source (in utero, breast
    milk, antibodies)
  • Short-term
  • It is only around as long as we are given the
    substances

153
Characteristics of the Adaptive Immune Response
154
Characteristics of the Adaptive Immune Response
  • Self tolerance Discrimination of self and
    non-self
  • Self-regulation the immune system can initiate,
    maintain, and down-regulate without help of the
    nervous system (NS) or other systems
  • This is one of the only body systems that can do
    this
  • Specificity Targets very specific antigens
  • Diversity Can invoke specific immune response to
    an indefinite number of different antigens
  • Memory Makes memory cells (only IS and CNS have
    memory)

155
Major Functional Cells of the Adaptive Immune
Response
156
Major Functional Cells of the Adaptive Immune
Response
  • B-Cell Lymphocytes including
  • Plasma B Cells
  • Memory B Cells
  • T-Cell Lymphocytes including
  • T-Helper Cells
  • Cytotoxic T Cells

157
Antigens
158
Antigens
  • Antigens Initiators of Immune response and
    Adaptive Immunity
  • Antigens (aka immunogens) are
  • Substances foreign to the host which stimulate an
    immune response
  • Antigens are ligands that are recognized by
    receptors on immune cells and by antibodies
    (immunoglobulin's Igs)
  • Often proteins or polysaccharides and less often
    lipids or nucleic acids.
  • Your DNA can actually act as an antigen in some
    instances, but it is not as common

159
Locations of Antigens
160
Locations of Antigens
  • Antigens are found on
  • Bacteria, fungi, protozoa, parasites or
    non-microbial agents such as pollens, plant
    resin, insect venom, transplanted organ.

161
AntigensDiagram
162
AntigensDiagram
163
Immunity Antigens
164
Immunity Antigens
  • Many antigens are large molecules.
  • The antigen may be recognized by multiple
    antibodies at a number of locations
  • Small fragments, often single sites, can be
    immunologically active. These sites are called
    epitopes.
  • Antigens or epitopes are what is recognized by a
    specific Ig receptor
  • Often a single antigen can have several antigenic
    sites. A distinct lymphocyte clonal population
    will recognize each distinct site
  • Certain small molecules are unable to stimulate
    an immune response (Haptens) .
  • Too small to stimulate a response
  • These molecules can become immunologically active
    when bound to a carrier protein (e.g., penicillin
    hypersensitivity)
  • The body is now able to recognize the body as
    foreign and can recognize the antigen as foreign

165
Major Histocompatibility Complex
166
Major Histocompatibility Complex
  • Cell surface molecules which provide a mechanism
    to differentiate self from non-self
  • The portion of your DNA that encodes for your MHC
    molecules is what makes you unique
  • This becomes important when we want to transplant
    organs because one persons MHC may not match the
    other persons MHC
  • Region of genetic information that makes each
    individual of one and the same species different
  • aka Human Leukocyte Antigens (HLA) since these
    were first identified on white blood cells.
  • Cytotoxic T cells and helper T cells both
    recognize MHC complexed with antigen
  • Because these molecules (MHC) play a big role in
    transplant rejection, they are also termed
    antigens in this instance.

167
MHC-II Complex
168
MHC-II Molecules
  • Found primarily on antigen-presenting cells
    (APCs) such as macrophages, dendritic cells, and
    B lymphocytes.
  • MHC-II molecule contains a groove in them that
    contains a recognition site which binds a peptide
    fragment of an antigen from pathogens
    engulfed/digested during phagocytosis.
  • The APC comes into contact with a virus,
    recognizes an antigen on the virus, activates
    complement, opsonizes the virus, which increases
    the phagocytic action, the phagocytic cell
    ingests the virus, takes the foreign antigen and
    then presents it on itself
  • Holds the antigens out to a T helper cell and the
    T cell agrees that it is foreign
  • The T cell then calls in other players to become
    immune to it and calls cytokines to destroy the
    cell
  • Helper T cells (Th) recognize these complexes on
    APCs and they become activated.

169
MHC-II Molecules
170
MHC-I Molecules
171
MHC-I Molecules
  • Found on cell surface glycoproteins on most
    nucleated cells of body.
  • They Interact with antigen receptor and CD8
    molecule on cytotoxic T lymphocytes (Tc)
  • Tc cells are responsible for direct cell killing
  • The virus enters a cell and the cell presents the
    virus on the outside
  • Indicates that the cell has been infected with
    the virus
  • Cytotoxic T-cells (Tc) become activated only when
    they are presented with an antigen associated
    with a Class I MHC.
  • MHC has the ability to present antigens on our
    body cells
  • Distinguishes self from non-self
  • Antigen peptides associate with MHC-I in cells
    that are infected with intracellular pathogen
  • E.g., as virus multiplies, small degraded
    peptides associate with MHC-I and are transported
    to the membrane.
  • This antigen-MHC complex communicates with the Tc
    cell and the host cell is destroyed.

172
MHC-I MoleculesDiagram
Virus particles
173
Comparison of MHC-II and MHC-I
174
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175
Humoral vs. Cell-Mediated Immunity
176
Humoral vs. Cell-Mediated Immunity
  • Lymphocyte stem cells are located in the bone
    marrow
  • Lymphocytes which migrate through lymphoid tissue
    ? B cells (make antibodies)
  • 2. Lymphocytes which migrate through the
    thymus ? T lymphocytes (cell-mediators)

177
Development of B Lymphocytes and T Lymphocytes
178
Development of B Lymphocytes and T Lymphocytes
  • If the bone marrow lymph cell matures in the
    thymus, it is called a T cell
  • T cells can become memory, cytotoxic, or helper T
    cells
  • Cell mediated immune response
  • If the cell leaves the bone marrow and goes to
    the bursal equivalent tissue (lymphoid tissue),
    it becomes a B cell
  • Can become a memory cell or antibodies (plasma
    cell)
  • Produce cells that make antibodies
  • A part of the humoral immune system

179
Development of B Lymphocytes and T
LymphocytesDiagram
180
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181
B Lymphocytes
182
B Lymphocytes
  • Responsible for antibody production (humoral
    immunity)
  • Function
  • Identified by the presence of surface
    immunoglobulin (antibody) bound to them
    permanently that functions as an antigen
    receptor, particular CD proteins and complement
    receptors
  • Plasma cells are antibody factories
  • Manufactures specific antibodies that target
    bacteria, neutralize bacterial toxins, prevent
    viral infection, and produce immediate allergic
    response
  • Formed from bone marrow stem cells
  • --Pre-maturation in the bone marrow to
    immature precursor cells
  • --Genetic rearrangement results in a unique
    receptor and type of effector antibody (IgM or
    IgD)
  • - shown an antigen by a presenting cell
  • - the plasma cell recognizes the cell with the
    antigen and inside the cell itself, a genetic
    rearrangement is made so that the antibody will
    only ever recognize the specific antigen

183
Differentiation of B Lymphocytes
184
Differentiation of B Lymphocytes
  • Mature B Lymphocytes leave the bone marrow, enter
    the blood and travel to peripheral tissues
  • B lymphocytes bind antigens with help of Th and
    then differentiate into
  • Plasma cells (large of cells which are
    responsible for antibody secretion)
  • Memory cells (small of cells pre-programmed
    to become plasma cells from that clonal line)

185
B LymphocytesDiagram
186
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187
B LymphocytesDescription
188
B LymphocytesDescription
  • Helper T cell can present cell to B cell and the
    B cell can recognize the antigen from then on
  • Later, if the B cell recognizes the antigen it
    can do something about it
  • A mature B cell produces a memory B cell and a
    plasma cell
  • A memory just remembers what antigen it should
    recognize and then goes dormant
  • Plasma cells are not dormant like memory cells
  • Produce antibodies
  • Look for the foreign antigen

189
Activation of B Lymphocytes
190
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191
AntibodiesPrimary Immune Response
192
AntibodiesPrimary Immune Response
  • Sensitization
  • Antigen is first introduced into the body
  • Antigen is processed by Antigen Presenting Cells
    (APCs)
  • Activation
  • MHC complexed Antigen is recognized by Th cells
  • Differentiation
  • Activated Th cells release cytokines and trigger
    B lymphocytes to proliferate into a clonal line
    of plasma cells and memory cells
  • Plasma cells release antibody
  • This time course has a significant lag time.

193
AntibodiesSecondary Immune Response
194
AntibodiesSecondary Immune Response
  • Once re-challenged with antigen at a later time,
    the memory cells recognize antigen and respond
    quickly to the antigen.
  • Immunization boosters (e.g., tetanus) take
    advantage of this response.

195
Primary and Secondary B Lymphocyte Immune
ResponseDiagram
196
  • Primary and Secondary B Lymphocyte Immune
    Response
  • Diagram

197
Primary and Secondary B Lymphocyte Immune
ResponseDescription
198
Primary and Secondary B Lymphocyte Immune
ResponseDescription
  • A B cell that has never been exposed to an
    antigen but is mature is naïve
  • A naïve B cell does not know what it wants to be
    yet
  • The first time that a B cell sees the antigen,
    the antigen has to be injected, complement binds
    to it, presented to helper T cells, B cell is
    sensitizes and becomes a memory B cell or a
    plasma cell
  • Takes about two weeks
  • Creates a bunch of memory B cells that remember
    the antigen and can mount a quicker response
  • The second exposure is very quick because the
    memory B cell is present
  • Secondary immune response

199
Antibody Types (Immunoglobulins)
200
Antibody Types (Immunoglobulins)
  • IgA
  • IgM
  • IgD
  • IgE
  • IgG

201
IgA Antibodies
202
IgA Antibodies
  • Secretory (saliva, colostrum, bronchial,
    pancreatic, GI,prostatic, vaginal).
  • Prevents viral and bacterial binding to
    epithelial tissues.
  • IgA is first line of defense in mucosal tissues
  • Secretions can bind the pathogen so that it does
    not enter the vasculature

203
IgM Antibodies
204
IgM Antibodies
  • Large macromolecular Ig complex.
  • First Ig made in response to an antigen.
  • First antibody type made by a newborn
  • During fetal development, the fetus is receiving
    Igs passively

205
IgD Antibodies
206
IgD Antibodies
  • Found primarily on cell membranes of B
    Lymphocytes.
  • Acts as antigen receptor.

207
IgE Antibodies
208
IgE Antibodies
  • Involved in inflammation, allergic responses and
    combating parasitic infections.
  • Antigen binding to IgE on mast cells or basophils
    causes histamine release
  • Important in inflammation and allergies.

209
IgG Antibodies
210
IgG Antibodies
  • Most abundant circulating antibody in blood
  • Only Ab that can cross the placenta.
  • Ig in fetus/newborn is passed from mother until
    new Igs are formed by newborn.
  • Targets bacteria, virus and toxins.
  • Can activate complement.

211
Maternal vs. Fetal/newborn IgG Contributions
212
  • Maternal vs. Fetal/newborn IgG Contributions

213
T Lymphocytes
214
T Lymphocytes Responsible for cell mediated
immunity
  • Formed from bone marrow stem cells which migrate
    to the thymus (T) for maturation. Mature T-cells
    then migrate to peripheral lymphoid organs
  • Genetic modification to form a unique T-cell
    antigen receptor (clonal selection)
  • Produce a specific receptor (T cell receptor)
    which recognizes the antigen
  • TCR two polypeptide grooves that recognize
    processed antigen-peptide MHC complexes.
  • -TCR is associated with CD3 cell surface
    molecules, which is a protein
  • The TCR is bound to the CD3 protein
  • Subpopulations of CD proteins offer further cell
    specificity
  • 1. CD4 T-helper cells (have CD3 and CD4)
  • 2. CD8 T-cytotoxic (have CD3 and CD8)

215
Types of T Lymphocytes
216
Types of T Lymphocytes
  • CD4 cells T helper cells
  • CD8 cells Cytotoxic T cells

217
Helper T Cell
218
Helper T Cell
  • Helper T cell (Th or CD4 cell) Regulatory cells
  • Master switch of immune system
  • Do not do direct cell killing
  • Recognizes Ag-MHC-II complex
  • Once activated by APC, they release cytokines
    that affect most other cells of immune system
  • Orchestrate the immune response by telling the B
    cells what to become and by secreting cytokines
  • Activated Th cell can differentiate into
  • distinct sub-populations based on cytokines
    secreted by the APC.

219
Cytotoxic T Cell
220
Cytotoxic T Cell
  • Cytotoxic T cell (Tc or CD8 cell) Effector
  • Get activated by Th cells
  • Recognize Ag-MHC-I complex on infected cells
  • Destroy infected cells by releasing cytolytic
    enzymes, toxic cytokines, Perforins
  • Important in controlling intracellular pathogens
    (bacteria and viruses)
  • Do a lot of self vs. nonself checking
  • Natural killer cells do not check the MHC, like
    the cytotoxic cells do
  • Tc cells are much more selective

221
Types of T LymphocytesDiagram
222
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223
Cell-mediated Immunity
224
Cell-mediated Immunity
  • Provide protection from viruses, bacteria, cancer
    cells
  • T lymphocytes and macrophages predominate
  • APC cells present MHCII-Ag to Th cells
  • Th cells become activated by antigen recognition
    and by interleukin-2.
  • Th cells then produce IL-2 and IL-4 to drive
    clonal expansion of Th cells and Interferon-gamma
    which activate Tc cells (cytotoxic T cells).
  • Tc cells and macrophages form the basis of the
    cell- mediated cell destruction in the immune
    response, while Th cells modulate the process.

225
Cell-mediated and Humoral ImmunityDiagram
226
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227
Cell-mediated and Humoral ImmunityDescription
228
Cell-mediated and Humoral ImmunityDescription
  • T helper cell recognizes the antigen that becomes
    activated, releases cytokines, sensitizes B cell,
    helper T cell recruits Tc cell, Tc cell can kill
    cells that recognize the MHC-1 antigen
  • When B cells are sensitized, they either make
    memory cells or plasma cells
  • T helper cells orchestrate virtually the entire
    process
  • Both the memory cells and the other cells all
    have specific genetic memory for the certain
    antigen

229
Natural Killer Cells
230
Natural Killer Cells
  • Natural Killer Cells an effector cell important
    in innate immunity.
  • Small of lymphocytes
  • Can bind with antibody coated target cell ?
    Antibody dependent cell-mediated cytotoxicity
    (ADCC)
  • Can attack virus-infected cells or cancer cells
    without help or activation first
  • Can recognize antigen without MHC restrictions
  • Difference between NK and T cells
  • NO MEMORY
  • Activity is regulated by cytokines,
    prostaglandins and thromboxane locally
  • Release NK perforins, enzymes, and toxic
    cytokines to destroy target cells
  • They do not phagocytize

231
Cytotoxic C vs. Natural Killer Cells
232
Cytotoxic C vs. Natural Killer Cells
  • Cytotoxic T Cells
  • Natural Killer Cells
  • T lymphocyte
  • Do phagocytize
  • Do have memory
  • Do require MHC-1 restrictions
  • Small percentage of lymphocytes
  • Do not phagocytize
  • Release NK perforins, enzymes, and toxic
    cytokines to destroy target cells
  • Do not have memory
  • Do not require MHC restrictions
  • Activity is regulated by cytokines,
    prostaglandins and thromboxane locally

233
Secondary Lymphoid Organs
234
Secondary Lymphoid Organs
  • Connected by blood and lymphatic vessels
  • The secondary lymphoid organs provide an
    environment for lymphocytes to circulate, meet
    and fight antigens, spread antigens, encounter
    information
  • Lymphocytes circulate constantly between blood ?
    tissue?lymphatic ducts ? lymph nodes ? thoracic
    duct bloodstream
  • This is a good place for immunosurveillance

235
Lymph Nodes
236
Lymph Nodes
  • Localize and prevent the spread of infection
  • Contain both B and T cells
  • Discrete locations of concentration of the
    lymphatic system
  • Good place to aggregate and look for antigens

237
Spleen
238
Spleen
  • Filters and processes antigens from blood
  • Contains both B and T cells
  • Functions as a reservoir for blood (red pulp)
  • RBC graveyard ? Hb released
  • Macrophages and other phagocytic cells in white
    pulp
  • Some parts innervated by sympathetic NS

239
MALT
240
MALT
  • MALT (Mucosa Associated Lymphoid Tissue)
  • Major po
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