Lecture 8

Hypersensitivity Types II-V

 Type II: Cytotoxic (ITH)

 Type III: Toxic Complex (ITH)

 Type IV: T Cell-Mediated (DTH)

 Type 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 A
Antigens
NAG Gal NAcGA

H Fuc

NAG Gal NAG Gal A antigen

Fuc B antigen

Precursor
oligosaccharide H antigen
NAG Gal Gal

NAcGA (N-acetylgalactoseamine)
Gal (galactose) B Fuc
 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 B cell anti-RhD

red cells

RhD positive Lysis

fetus Of RhD positive
anti-RhD
RBC’s 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
 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
 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 maximal reaction time

Jones-Mote 24 hours
Contact 48-72 hours
tuberculin 48-72 hours
granulomatous at least 14 days
 Jones-Mote
Jones-Mote Hypersensitivity
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 antigen-coated
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)
 smallpox
 measles
 herpes simplex
 Fungi
 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)
 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