Lecture 8 Hypersensitivity Types II-V

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Lecture 8Hypersensitivity Types II-V

• Type II Cytotoxic (ITH)
• Type III Toxic Complex (ITH)
• Type IV T Cell-Mediated (DTH)
• Type V Stimulatory

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Cytotoxic Hypersensitivity (Type II)
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Characteristics of Cytotoxic Hypersensitivity

• Directed against cell surface or tissue antigen
• Characterized by complement cascade activation
  and various effector cells

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Complement

• Formation of membrane attack complex (lytic
  enzymes)
• Activated C3 forms opsonin recognized by
  phagocytes
• Formation of chemotactic factors
• Effector cells possess Fc and complement
  receptors
• macrophages/monocytes
• neutrophils
• NK cells

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Examples of Type II Hypersensitivity

• Blood transfusion reactions
• Hemolytic disease of the newborn (Rh disease)
• Autoimmune hemolytic anemias
• Drug reactions
• Drug-induced loss of self-tolerance
• Hyperacute graft rejection
• Myasthenia gravis (acetylcholine receptor)
• Sensitivity to tissue antigens

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ABO Blood Group Antigens
A
NAcGA
Gal
NAG
Fuc
H
A antigen
NAG
Gal
NAG
Gal
B antigen
Fuc
Precursor oligosaccharide
H antigen
Gal
Gal
NAG
NAcGA (N-acetylgalactoseamine) Gal (galactose)
B
Fuc
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ABO Blood Group Reactivity

• blood group genotypes antigens antibodies to
• (phenotype) ABO in serum
• A AA, AO A anti-B
• B BB, BO B anti-A
• AB AB A and B none
• O OO H anti-A/B

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Hemolytic Disease of the Newborn
first birth
post partum
subsequent
RhD negative mother
anti-RhD
RhD positive red cells
B cell
Lysis Of RBCs
RhD positive fetus
RhD positive fetus
anti-RhD
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Drug-Induced ReactionsAdherence to Blood
Components
blood cell adsorbed drug or antigen drug
metabolite

antibody to drug
complement
lysis
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Toxic Complex Hypersensitivity (Type III)
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Diseases associated with immune complexes

• Persistent infection
• microbial antigens
• deposition of immune complexes in kidneys
• Autoimmunity
• self antigens
• deposition of immune complexes in kidneys,
  joints, arteries and skin
• Extrinsic factors
• environmental antigens
• deposition of immune complexes in lungs

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Inflammatory Mechanisms in Type III

• Complement activation
• anaphylatoxins
• Chemotactic factors
• Neutrophils attracted
• difficult to phagocytize tissue-trapped complexes
• frustrated phagocytosis leads to tissue damage

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Disease Models

• Serum sickness
• Arthus reaction

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Serum Sickness
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Arthus Reaction
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T-Cell Mediated Hypersensitivity(Type IV /
Delayed-Type)
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Manifestations of T-Cell Mediated Hypersensitivity

• Allergic reactions to bacteria, viruses and fungi
• Contact dermatitis due to chemicals
• Rejection of tissue transplants

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General Characteristics of DTH

• An exaggerated interaction between antigen and
  normal CMI-mechanisms
• Requires prior priming to antigen
• Memory T-cells recognize antigen together with
  class II MHC molecules on antigen-presenting
  cells
• Blast transformation and proliferation
• Stimulated T-cells release soluble factors
  (cytokines)
• Cytokines
• attract and activate macrophages and/or
  eosinophils
• help cytotoxic T-cells become killer cells, which
  cause tissue damage

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Inducers of Type IV Hypersensitivity
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Types of Delayed Hypersensitivity

• Delayed Reaction maximal reaction time
• Jones-Mote 24 hours
• Contact 48-72 hours
• tuberculin 48-72 hours
• granulomatous at least 14 days

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Jones-Mote Hypersensitivity

• Now referred to as cutaneous basophil
  hypersensitivity
• Basophils are prominent as secondary
  infiltrating cells.
• Basophilic infiltration of area under epidermis
• Induced by soluble (weak) antigens
• Transient dermal response
• Prominent in reactions to viral antigens, in
  contact reactions, skin allograft rejections,
  reactions to tumor cells and in some cases of
  hypersensitivity pneumonitis (allergic
  alveolitis)
• May be important in rejection of blood-feeding
  ticks on the skin surface

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Contact Hypersensitivity

• Usually maximal at 48 hours
• Predominantly an epidermal reaction
• Langerhans cells are the antigen presenting cells
• a dendritic antigen presenting cell
• carry antigen to lymph nodes draining skin
• Associated with hapten-induced eczema
• nickel salts in jewellry
• picryl chloride
• acrylates
• p-Phenylene diamine in hair dyes
• chromates
• chemicals in rubber
• poison ivy (urushiol)

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Poison Ivy contact dermatitis
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Tuberculin Hypersensitivity

• Maximum at 48-72 hours
• Inflitration of lesion with mononuclear cells
• First described as a reaction to the lipoprotein
  antigen of tubercle bacillus
• Responsible for lesions associated with bacterial
  allergy
• cavitation, caseation, general toxemia seen in TB
• May progress to granulomatous reaction in
  unresolved infection

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Granulomatous Hypersensitivity

• Clinically, the most important form of DTH, since
  it causes many of the pathological effects in
  diseases which involve T cell-mediated immunity
• Maximal at 14 days
• Continual release of cytokines
• Leads to accumulation of large numbers of
  macrophages
• Granulomas can also arise from persistence of
  indigestible antigen such as talc (absence of
  lymphocytes in lesion)

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Epitheloid Cell Granuloma Formation

• Large flattened cells with increased endoplasmic
  reticulum
• Multinucleate giant cells with little ER
• May see necrosis
• Damage due to killer T-cells recognizing
  antigen-coated macrophages, cytokine-activated
  macrophages
• Attempt by the body to wall-off site of
  persistent infection

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Granuloma Formation
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Examples of Microbial-Induced DTH

• Viruses (destructive skin rashes)
• smallpox
• measles
• herpes simplex
• Fungi
• candidiasis
• dematomycosis
• coccidioidomycosis
• histoplasmosis
• Parasites (against enzymes from the eggs lodged
  in liver)
• leishmaniasis
• schistosomiasis

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Type V Stimulatory Hypersensitivity

• Interaction of autoantibodies with cellular
  receptors
• Antibody binding mimics receptor-ligand
  interaction
• Examples
• thyroid stimulating antibody (mimics thyroid
  stimulating hormone TSH of pituitary binds to
  thyroid cell receptor
• activation of B-cell by anti-immunoglobulin

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Innate Hypersensitivity Reactions

• Toxic shock syndrome (S. aureus TSS toxin)
• hypotension, hypoxia, oliguria and microvascular
  abnormalities
• excessive release of TNF, IL-1, IL-6
• intravascular activation of complement
• Septicemia - Septic Shock
• primarily due to lipopolysaccharide
• Adult respiratory distress syndrome
• overwhelming accumulation of neutrophils in lung
• Platelet aggregation/adherence to macrophages by
  gram-positive bacteria
• Superantigens
• Gram positive enterotoxins
• react directly with T-cell receptors and induce
  massive cytokine release