Allergy and Hypersensitivity

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Allergy and Hypersensitivity
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I. Introduction
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A. Definitions

• Allergy
• Immune-mediated response to innocuous
  environmental antigen
• Can be humoral or cell-mediated reaction
• Usually involves prior exposure to antigen
  resulting in sensitization of individual
• Allergen
• Innocuous antigen
• Universal
• Non-reactiving to most people

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• Hypersensitivity reactions
• Harmful IRs that cause tissue injury and may
  cause serious pathologies
• Atopy
• State of increased susceptibility to immediate
  hypersensitivity usually mediated by IgE Abs
• Over-react to common environmental Ags

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B. Four types of immune-mediated
hypersensitivity reactions causing tissue damage

• Type I Anaphylaxis hypersensitivity (TH2 IgE)
• Type II Cytotoxic hypersensitivity (IgG)
• Type III Immune complex hypersensitivity (IgG)
• Type IV Cell-mediated hypersensitivity (TH1,
  TH2, CTL)

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II. Type I (Anaphylaxis) Hypersensitivity
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A. Pathway

• IgE made during primary response to soluble Ag ?
  Binds to high affinity FceRI on mast cells,
  basophils and activated eosinophils
• Sensitizes individual (become allergic)
• IgE aka reagin
• Secondary exposure ? allergen binds to IgE on
  sensitized mast cells, basophils or eosinophils
• IgE Ab crosslinking on leads to rapid release of
  preformed inflammatory mediators

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High affinity FceRI is functional on mast cells,
basophils, and activated eosinophils. It is
composed of a,b and two g chains. Crosslinking
of FceRI on cells by Ag and IgE induces
degranulation.
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• Induces degranulation ? Release of inflammatory
  mediators pre-formed substances including
  histamine, slow reacting substance of anaphylaxis
  (SRS-A), heparin, prostaglandins,
  platelet-activating factor (PAF), eosinophil
  chemotactic factor of anaphylaxis (ECF-A), and
  various proteolytic enzymes
• Eosinophils release major basic protein which
  induces degranulation of mast cells and basophils

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• Tachyphylaxis
• Depletion of mast cell granules
• Accounts for unresponsiveness of a patient to a
  skin test following an anaphylactic reaction
  (lasts 72-96 hours after a reaction)

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B. Ig-E mediated reactions differ depending on
route of administration and dose

• Connective tissue mast cells
• Associated with blood vessels
• IV-high dose ? Activated by allergen in the
  bloodstream ? systemic
• Systemic release of histamine
• Systemic anaphylaxis

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• SC-low dose ? subcutaneous injection ? local
  release of histamine
• Wheal and flare reaction

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• Mucosal mast cells
• Inhalation low dose ? Activated by inhaled
  allergen
• Smooth muscle contraction of lower airways
• Bronchoconstriction
• Asthma
• Allergic rhinitis (hay fever)
• Increased mucosal secretions
• Irritations

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Fig. 10.24 Allergen-induced release of
histamine by mast cells in skin causes localized
swelling. Swellings (wheals) appear 20 min.
after intradermal injection of ragweed pollen
(R), histamine (H). Saline bleb (S) is due to
volume of fluid.
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Fig. 10.14 Properties of inhaled allergens that
favor TH2 priming that promotes IgE isotype
switching.
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Fig. 10.15 Sensitization to an inhaled
allergen. Soluble allergen is processed by APC
and displayed to TH2 T cells. T cells help B
cells to produce IgE which then binds to mast
cells. IL-4 promotes isotype switching to IgE.
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Fig. 10.21 Allergic rhinitis (hay fever) is
caused by inhaled allergen entering the
respiratory tract. Sneezing, runny nose nasal
discharge is full of eosinophils. Allergic
conjunctivitis results if the conjunctiva of the
eye is affected (itchy, watery, and swelling of
eyes).
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• Ingestion Activated by ingested allergen
• Food allergy
• Gut epithelial cells are involved
• Intestinal smooth muscle contraction
• Vomiting
• Diarrhea
• Dissemination through bloodstream causes
  urticaria (hives) or anaphylaxis (rare)

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Fig. 10.25 Ingested allergen can cause vomiting,
diarrhea and urticaria.
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Summary of Type I Hypersensitivity Reactions
Fig 10.12
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C. Hereditary predisposition for IgE synthesis

• FceR genes
• Cytokine genes involved in
• Isotype switching
• Eosinophil survival
• Mast cell proliferation
• Example IL-4 promoter mutation which leads to
  elevated IL-4 can favor IgE
• MHC class II
• MHCpeptide combinations may favor TH2 response
• Example ragweed pollen associates with
  HLA-DRB11501

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D. Type I hypersensitivity reactions can be
divided into immediate and late stages

• Acute (minutes) versus Chronic (5-12 hours)
  Reactions
• Immediate allergic reactions is then followed by
  a late-phase response

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• Acute Immediate
• Peaks within minutes after allergen injection or
  inhalation and then subsides
• Wheal and flare
• Bronchial constriction in asthma
• IgE crosslinking ? rapid degranulation
• Release of preformed inflammatory mediators
• Histamine, serotonin
• Mast cell chymase, tryptase, carboxypeptidase and
  cathepsin G ? breaks down tissue matrix proteins
  (remodeling of connective tissue matrix)
• TNF-a

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Mast cell stained for protease chymase
demonstrating abundant granules residing in the
cytoplasm.
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• Chronic Late
• Caused by influx of inflammatory leukocytes
  (including eosinophils)
• Chronic allergic inflammation
• Tissue damage
• Edema, long-lasting

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• Chemokines
• Heparin
• Lipid mediators derived from membrane
  phospholipids
• Form a precursor called arachidonic acid
• Many anti-inflammatory agents inhibit arachidonic
  acid metabolism (e.g. aspirin)
• Arachidonic acid forms
• Leukotrienes
• Prostaglandins
• Thromboxanes
• Platelet activating factor

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Fig. 10.5 Mast cell products involved in
allergic reactions.
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Fig. 10.7 Mast cell production of
prostaglandins and leukotrienes by different
enzyme pathways starting with arachidonic acid.
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Fig. 10.8 Eosinophils display a unique staining
pattern with bilobed nuclei and stain pink with
eosin. Eosinophils are specialized granulocytes
that release toxic mediators in IgE-mediated
responses.
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Fig. 10.9 Products of activated eosinophils.
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Fig 10.16 Immediate and late-phase reactions to
house dust mite allergen (HDM) injected
intradermally. Saline injection control. Wheal
raised area of skin around injection site
flare redness (erythema) spreading out from
the wheal.
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Two types of anaphylaxis

• 1. Systemic anaphylaxis
• Generalized response to systemically administered
  Ag (e.g. IV) or rapidly absorbed from gut
• Immediate a lot of mast cell products released
  quickly
• Smooth muscle constriction of bronchioles ?
  breathing difficulties
• Epiglottal swelling ? Asphyxiation
• Can be fatal

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• Arterioles dilate
• Arterial blood pressure decreases
• Capillary permeability increases (increases
  vascular permeability
• Fluid loss into tissue spaces
• Edema
• Late phase reaction sustained edema
• Circulatory shock
• Can be fatal

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• Examples of allergens
• Penicillin (or cephalosporins)
• Penicillin hapten ? beta lactam ring reacts
  with amino groups on host proteins ? conjugates
  form
• Bee, wasp or hornet venom
• Peanuts or brazil nuts
• Anti-sera

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• 2. Localized anaphylaxis
• Atopic (out of place) allergy
• Examples
• Allergic rhinitis (hay fever) URT
• Airborne allergens pollen, spores, animal
  dander, house dust mite feces
• Allergens diffuse across the mucus membranes of
  nasal passages
• Mast cells sensitized in mucus membrane upon
  primary exposure
• Upon secondary exposure itchy, runny eyes and
  nose, sneezing coughing

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• Bronchial asthma allergic asthma LRT
• Air sacs (alveoli) fill with fluid and mucus
• Wall of bronchi constricted
• Bronchodilators relax muscles, making breathing
  easier (inhalers)
• Anticollinergic
• Sympathetic activators
• Metaproterenol
• Albuterol
• Hives (food allergy)
• Vomiting and diarrhea local response
• Urticaria systemic response

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Fig. 10.23 Inflammation of the airways in
chronic asthma restrict breathing A section
through bronchus of individual who died from
asthma. MP mucus plug restricts airway.
White plug depicts remaining passageway in
bronchial lumen. B Bronchial wall at higher
magnification demonstrating presence of
inflammatory infiltrate consisting of
eosinophils, neutrophils, and lymphocytes. L
lumen of bronchus.
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• In vivo skin testing can help to identify
  responsible allergens ? rapid inflammation
• Diameter of swelling measured
• Wheal-and-flare reactions
• Cutaneous allergic response
• Develops within 1-2 minutes ? lasts 30 minutes

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F. Desensitization

• Subcutaneous injections of Ag ? to produce IgG
  Abs ? can compete with IgE Ab, and neutralize
  allergens before they reach mast cells
• Tiny amounts injected initially, then dose is
  increased ? Diverts IR from TH2 to TH1 ?
  Decreases IgE production
• 65-75 effective treatment of inhaled allergens

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G. Treatment

• Inhibit allergic reactions Examples
• Desensitization (described above)
• Experimental
• Inhibit IL-4, IL-5 and/or IL-13 or CD40L to
  reduce IgE responses
• Use cytokines that enhance TH1 responses
• gIFN, aIFN, IL-10, IL-12, and TGF-b
• Block FceR (e.g. with modified Fc components that
  lack variable domains)

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• Block allergic response effector pathways
• Epinephrine
• Endothelial tight junctions reform
• Relaxation of smooth muscle
• Stimulation of heart (increase BP)
• Anti-histamines
• Block histamine receptors
• Decrease urticaria (hives)
• Corticosteroids
• Reduce inflammation

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Figure 10.20 Effect of epinephrine on blood
pressure Time 0 point at which anaphylactic
response began. Arrows times when epinephrine
was administered.
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III. Type II (Cytotoxic) Hypersensitivity
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• A. Host cells are killed or lysed
• Cell surface antigens
• B. IgG (mainly) or IgM Abs react with cell
  surface receptors, matrix associated Ag or
  modified cell membranes
• Complement is activated
• C binds Ig (C1q)
• C cascade results in formation of membrane
  attack complex (MAC)
• Holes are punched in target cells ? Death

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• FcR bind IgAg complexes
• FCR-bearing accessory cells are activated (e.g.
  macrophages, neutrophils and NK cells)
• Especially important mechanism used by splenic
  macrophages ? clearance of cells
• Opsonization induced via FcR CR1

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• Antibody-dependent cell-mediated cytotoxicity
  (ADCC) is induced in NK cells
• NK cells secrete preformed perforin and granzyme
  from cytoplasmic granules
• Perforin forms a pore in target cell
  transmembrane polymerization
• Granzyyme (aka fragmentin) 3 serine proteases
  digest host proteins and activate endonucleases ?
  DNA is degraded into 200 by multimers
  (subunits) APOPTOSIS

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• Examples
• Hemolytic disease of the newborn
  (Erythroblastosis fetalis) (Abs to Rh Ags)

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Hemolytic Disease of the Newborn
(Erythroblastosis fetalis) Type II
hypersensitivity Alloantibodies resulting from
Rh incompatibilities between mother and
father Spacing of Rh antigen is too far to
activate C or cause agglutination. Fetal RBC
destroyed by macro- phages causing edema. This
may in turn lead to heart failure, edema and
fetal death (hydrops fetalis).
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More examples

• Mismatched blood transfusion (Abs to A/B Ags)
• Autoimmune hemolytic anemia (Abs to self Ag on
  RBC)
• Autoimmune thrombocytopenia purpura (Abs to
  platelet integrin ? abnormal bleeding/hemorrhagin
  g)
• Goodpastuers Syndrome (renal failure due to
  anti-basement membrane collagen Abs)

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• Pemphigus vulgaris (skin blisters
  anti-epidermal cadherin Abs)
• Acute rheumatic fever (cross-reactive Abs to
  cardiac muscle generated following Streptococcus
  group A infection ? myocarditis, arthritis,
  heart valve scarring)
• Drug allergies (e.g. penicillin) (drug combines
  with cell proteins)

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Penicillin may also bind to surface proteins on
human cells (RBC most common). This creates
a new epitope that can act like a foreign Ag.
Penicillin interferes with the bacterial enzyme
transpeptidase after binding to the active site
in the enzyme.
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Fig. 10.27 Penicillin-protein conjugates
stimulate the production of anti-penicillin
antibodies. Penicillin-modified RBC get coated
with C3b as a bystander effect of C activation
by bacterial activating surfaces for which the
penicillin was administered. This initiates the
process by inducing opsonization by macrophages.
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• RBC and platelets are especially susceptible to
  lytic effects of Type II hypersensitivity, owing
  to reduced levels of C regulatory proteins than
  other cells have.

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• Ab can alter signaling properties of cells in
  autoimmunity
• Graves Disease
• Agonist Ab ? Hyperthyroidism
• Ab anti TSH receptor specific ? overproduction
  of thyroid hormone
• Myasthenia Gravis (MG)
• Antagonist Ab ? Blocks neuromuscular transmission
• Anti-acetylcholine receptor specific ?
  progressive weakness
• MORE LATER - AUTOIMMUNITY

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IV. Type III (Immune complex) Hypersensitivity
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A. Description of immune complexes

• Form through association of Ab with multivalent
  soluble Ag
• Complexes become deposited on blood vessel walls
  or tissue sites and activate C ? Inflammation
  induced (C5a)
• Pathogenicity depends on size of complex
• Large cleared by C fixation (Ab excess)
• Small deposited (Ag excess)

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B. Damage to host tissue

• Blood vessels ? Vasculitis
• Kidney glomerular basement membrane ?
  Glomerulonephritis
• Synovial tissue of joints ? Arthritis or
  Arthralgia
• Skin ? Butterfly rash in SLE

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The pathology of type III hypersensitivity
reactions is determined by the sites of
immune-complex deposition.
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• Mechanism
• C is activated
• Basophils and platelets degranulate
• Histamine and other inflammatory mediators are
  released
• Vascular permeability increases
• Platelets aggregate and form microthrombi (blood
  clots) on vessel walls
• Burst, hemorrhaging of skin
• Recruitment of PMNL by chemotaxis
• Further degranulation, enzyme release and host
  damage ? vasculitis

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C. Five types of disease

• Arthus reaction
• Serum sickness
• Persistent viral, bacterial or protozoan
  infection in face of weak Ig response
• Continuous autoantibody production
• Immune complexes formed at body surfaces

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D. Examples

• Arthus Reaction
• A skin reaction occuring in sensitized (already
  immune) individuals where Ag is injected into the
  dermis and reacts with IgG in extracellular
  spaces
• This in turn leads to C fixation/activation
  (mast cell degranulation) and recruitment of
  phagocytic cells leading to inflammation
• Increased fluid and protein release
• Increased phagocytosis
• Blood vessel occlusion by platelets
• Experimental model for I.C. disease

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Localized deposition of immune complexes within a
tissue causes a type III hypersensitivity
reaction.
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• Serum Sickness
• Systemic reaction to a large dose of Ag (7-10
  days after injection)
• Ag is poorly catabolized and remains in
  circulation long enough to be available following
  primary immune response
• Chills, fever, urticaria, arthritis and
  glomerulonephritis

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• Examples
• Horse serum used to treat pneumococcal pneumonia
  prior to antibiotics usage
• Anti-venin horse anti snake venom
• Mouse anti-lymphocyte globulin used for
  immunosuppression of transplantation (mouse MoAb)
• Streptokinase (bacterial enzyme) to treat heart
  attack victims
• Antibiotics (penicillin or cephalosporin)

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• Serum sickness is usually a self-limited disease
• Symptoms improve as host Abs increase to zone of
  Ab excess
• Can be fatal if kidneys shut down or hemorrhaging
  occurs in brain
• Treatment
• Prednisone (anti-inflammatory corticosteroid)
  and Benadryl (anti-histamine)
• Prior sensitization is NOT prerequisite ?
  Reaction can occur on first encounter if Ag isnt
  readily cleared from circulation and is present
  at high concentration

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Serum sickness is a classic example of a
transient immune-complex mediated syndrome.
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• Persistent viral, bacterial or protozoan
  infections
• Results in chronic immune complex formation (IC)
• Examples
• Subacute bacterial endocarditis
• Acute glomerulonephritis
• Chronic viral hepatitis

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• Autoantibody produced continuously
• Prolonged IC formation
• Systemic lupus erythematosus (SLE)
• Glomerulonephritis, arthritis, vasculitis
• AutoAbs to DNA, RNA and proteins associated with
  nucleic acids

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• Immune complex formed at body surfaces (lungs)
  (IgG not IgE)
• Exposure to very large doses of inhaled allergens
  ? Inflammation of alveolar wall of lung
• Farmers lung ? Inhalation of hay dust or mold
  spores ? Gas exchange compromised

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V. Type IV Hypersensitivity
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A. Features

• T-cell mediated immune responses
• Includes
• Delayed-type hypersensitivity
• Contact hypersensitivity
• Gluten-sensitive enteropathy (Celiac disease)

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B. Mechanism

• Delayed-type hypersensitivity DTH
• TDTH recruited
• Soluble Ag ? macrophages, TH1 activation
• Cell-associated Ag ? TH1 activation ? Tcyt
  cytotoxicity
• Cytokines and chemokines produced
• IL-2, gIFN, IL-3, TNFa, TNFb and GM-CSF
• Other cells recruited
• Macrophages, basophils, other lymphocytes
• Tissue can be severely damaged

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• Cytokines, chemokines and cytotoxins made by TH1
  during Type IV Hypersensitivity Reactions
• Chemokines
• Recruitment of macrophages to the site of Ag
  deposition
• Cytokine
• gIFN
• Macrophage activation, release of inflammatory
  mediators
• IL-3/GM-CSF
• Increased monocyte synthesis in bone marrow

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• Cytotoxins TNFa and TNFb
• TNFa activates macrophage
• TNFa and TNFb ? blood vessel adhesion molecules
  expressed (activation of endothelial cells) ?
  cells infiltrate, edema
• TNFb ? cytotoxic to macrophages and other cells

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• Tcyt may also be involved in Type IV
  hypersensitivity reactions
• Cell-mediated cytotoxicity and gIFN production
• Modified peptides associate with class I (e.g.
  pentadecacatechol of poison ivy lipid
  soluble)

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• The time course of a delayed type
  hypersensitivity reaction
• Acquired IR
• 1st phase
• Uptake, processing and presentation of Ag
• 2nd phase
• Previously primed TH1 cells migrate to site of
  infection and become activated
• T cells secrete mediators that result in
  recruitment of macrophages ? Inflammation ensues
  fluid and protein accumulate ? Lesion ?
  Induration

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C. Examples

• Tuberculin hypersensitivity
• Tuberculosis skin test (Mantoux test, Heath test
  multipronged skin prick)
• Purified protein derivative (PPD) from
  Mycobacterium tuberculosis
• Injected intradermally
• After 48 hours, induration (swelling/lesion)
  indicates positive reaction
• Related to degree of sensitivity
• Indicates prior exposure to M. tuberculosis

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• Other microbial products used in Type IV skin
  testing include
• Histoplasmic (for histoplasmosis Histoplasma
  capsulatum fungus)
• Coccidiodin (for coccidiodomycosis fungus)
• Lepromin (for Hansens disease Mycobacterium
  leprae)
• Brucellergen (for brucellosis bacteria
  Brucella spp.)

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• Allergic contact dermatitis
• Haptens combine with skin proteins
• Pentadecacatechol (poison ivy)
• Cosmetics
• Metals (jewelry)
• Nickel
• Gold
• Transplantation (Graft) Rejection

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• Autoimmune diseases
• Rheumatoid arthritis (joint inflammation)
• Multiple sclerosis and Experimental allergic
  encephalomyelitis (EAE) (demyelination)
• Diabetes mellitus (IDDM) (pancreatic beta cell
  destruction)
• Gluten-sensitive enteropathy Celiac disease
• Ag Gliadin
• Malabsorption results from villous atrophy in
  small intestine

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Fig. 10.33 Summary