1. Lecture 8 Hypersensitivity Types II-V
Type II: Cytotoxic (ITH)
Type III: Toxic Complex (ITH)
Type IV: T Cell-Mediated (DTH)
Type V: Stimulatory

2. Cytotoxic Hypersensitivity (Type II)

3. Characteristics of Cytotoxic Hypersensitivity
Directed against cell surface or tissue antigen
Characterized by complement cascade activation and various effector cells

4. 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

5. 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
Study Guide
If all of these reactions require "prior sensitization" before the destructive phase can begin, where is the "prior sensitization"?

6. ABO Blood Group Antigens
NAG
Gal
NAcGA H
Fuc
NAG
Gal
NAG
Gal
A antigen
Fuc
B antigen
Study Guide
What is the hapten? What is the carrier?
Precursor
oligosaccharide
H antigen
NAG
Gal
Gal
NAcGA (N-acetylgalactoseamine)
Gal (galactose) B
Fuc

7. 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
Study Guide
What immunoglobulin class(es) are the blood group antibodies?
Why are they called "naturally-occurring isohemagglutinins"?

8. Hemolytic Disease of the Newborn
first birth
post partum
subsequent
RhD
negative
mother
RhD positive
red cells
anti-RhD
B cell
Study Guide
What immunoglobulin class(es)?
Why is the second pregnancy at greater risk?
Is there a problem in the second pregnancy is the fetus is Rh negative? Why?
Lysis Of
RBC’s
RhD positive
fetus
RhD positive
fetus
anti-RhD

9. Drug-Induced Reactions: Adherence to Blood Components
blood cell adsorbed drug
or antigen drug metabolite
antibody to drug
complement
Study Guide
What is the hapten? What is the carrier?
lysis

10. Toxic Complex Hypersensitivity (Type III)
Study Guide
What is the difference between Type II and Type III?

11. 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

12. Inflammatory Mechanisms in Type III
Complement activation
anaphylatoxins
Chemotactic factors
Neutrophils attracted
difficult to phagocytize tissue-trapped complexes
frustrated phagocytosis leads to tissue damage

13. Disease Models
Serum sickness
Arthus reaction

14. Serum Sickness

15. Arthus Reaction

16. T-Cell Mediated Hypersensitivity (Type IV / Delayed-Type)

17. Manifestations of T-Cell Mediated Hypersensitivity
Allergic reactions to bacteria, viruses and fungi
Contact dermatitis due to chemicals
Rejection of tissue transplants

18. 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

19. Inducers of Type IV Hypersensitivity

20. Types of Delayed Hypersensitivity
Delayed Reaction maximal reaction time
Jones-Mote 24 hours
Contact hours
tuberculin hours
granulomatous at least 14 days

21. 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

22. 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)
Study Guide
What is the circulating equivalent of the Langerhans cell?
What is the carrier in hapten-induced eczema?

23. Poison Ivy contact dermatitis

24. Tuberculin Hypersensitivity
Maximum at 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
Study Guide
What are the infiltrating mononuclear cells?
When does this progress to a granulomatous reaction?
How have you heard of tubercule bacillus being used during immunizations?

25. 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)
Study Guide
Are you familiar with tuberculosis?

26. 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

27. Granuloma Formation

28. 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

29. 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

30. 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