Download Cytotoxic Hypersensitivity

Lecture 8
Hypersensitivity Types II-V
Type
 Type
 Type
 Type

II: Cytotoxic (ITH)
III: Toxic Complex (ITH)
IV: T Cell-Mediated (DTH)
V: Stimulatory
Cytotoxic Hypersensitivity (Type II)
Characteristics of Cytotoxic
Hypersensitivity


Directed against cell surface or tissue
antigen
Characterized by complement cascade
activation and various effector cells
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

Examples of Type II Hypersensitivity
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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
ABO Blood Group
Antigens
A
NAG
Gal
Precursor
oligosaccharide
NAcGA
Fuc
H
NAG
Gal
NAG
Gal
A antigen
Fuc
B antigen
H antigen
NAcGA (N-acetylgalactoseamine)
Gal (galactose)
NAG
B
Gal
Fuc
Gal
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
Hemolytic Disease of the Newborn
first birth
post partum
subsequent
RhD
negative
mother
RhD positive
red cells
RhD positive
fetus
B cell
anti-RhD
anti-RhD
Lysis
Of
RBC’s
RhD positive
fetus
Drug-Induced Reactions:
Adherence to Blood
Components
blood cell adsorbed drug
or antigen drug metabolite
antibody to drug
complement
lysis
Toxic Complex Hypersensitivity
(Type III)
Diseases associated with immune complexes

Persistent infection

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
Autoimmunity



microbial antigens
deposition of immune complexes in kidneys
self antigens
deposition of immune complexes in kidneys, joints,
arteries and skin
Extrinsic factors


environmental antigens
deposition of immune complexes in lungs
Inflammatory Mechanisms in Type III

Complement activation
anaphylatoxins
 Chemotactic factors


Neutrophils attracted
difficult to phagocytize tissue-trapped complexes
 frustrated phagocytosis leads to tissue damage

Disease Models
Serum sickness
 Arthus reaction

Serum Sickness
Arthus Reaction
T-Cell Mediated Hypersensitivity
(Type IV / Delayed-Type)
Manifestations of T-Cell Mediated
Hypersensitivity
Allergic reactions to bacteria, viruses and fungi
 Contact dermatitis due to chemicals
 Rejection of tissue transplants

General Characteristics of DTH



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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
Inducers of Type
IV Hypersensitivity
Types of Delayed Hypersensitivity
Delayed Reaction
time
Jones-Mote
Contact
tuberculin
granulomatous
maximal reaction
24 hours
48-72 hours
48-72 hours
at least 14 days
Jones-Mote Hypersensitivity
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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
Contact Hypersensitivity

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Usually maximal at 48 hours
Predominantly an epidermal reaction
Langerhans cells are the antigen presenting cells

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a dendritic antigen presenting cell
carry antigen to lymph nodes draining skin
Associated with hapten-induced eczema
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nickel salts in jewellry
picryl chloride
acrylates
p-Phenylene diamine in hair dyes
chromates
chemicals in rubber
poison ivy (urushiol)
Poison Ivy
contact
dermatitis
Tuberculin Hypersensitivity
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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

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cavitation, caseation, general toxemia seen in TB
May progress to granulomatous reaction in
unresolved infection
Granulomatous Hypersensitivity
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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)
Epitheloid Cell Granuloma Formation



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Large flattened cells with increased endoplasmic
reticulum
Multinucleate giant cells with little ER
May see necrosis
Damage due to killer T-cells recognizing antigencoated macrophages, cytokine-activated
macrophages
Attempt by the body to wall-off site of persistent
infection
Granuloma Formation
Examples of Microbial-Induced DTH

Viruses (destructive skin rashes)

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Fungi

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smallpox
measles
herpes simplex
candidiasis
dematomycosis
coccidioidomycosis
histoplasmosis
Parasites (against enzymes from the eggs lodged in liver)


leishmaniasis
schistosomiasis
Type V Stimulatory Hypersensitivity

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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
Innate Hypersensitivity Reactions

Toxic shock syndrome (S. aureus TSS toxin)
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Septicemia - Septic Shock
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primarily due to lipopolysaccharide
Adult respiratory distress syndrome
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hypotension, hypoxia, oliguria and microvascular abnormalities
excessive release of TNF, IL-1, IL-6
intravascular activation of complement
overwhelming accumulation of neutrophils in lung
Platelet aggregation/adherence to macrophages by gram-positive
bacteria
Superantigens
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Gram positive enterotoxins
react directly with T-cell receptors and induce massive cytokine release