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

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

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
RBCs

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

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

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

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

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)

Poison Ivy
contact
dermatitis

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

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)

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 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)

Fungi

smallpox
measles
herpes simplex

candidiasis
dematomycosis
coccidioidomycosis
histoplasmosis

Parasites (against enzymes from the eggs lodged in liver)

leishmaniasis
schistosomiasis

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

Innate Hypersensitivity Reactions

Toxic shock syndrome (S. aureus TSS toxin)

Septicemia - Septic Shock

primarily due to lipopolysaccharide

Adult respiratory distress syndrome

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

Gram positive enterotoxins

react directly with T-cell receptors and induce massive cytokine release