Pathophysiology

1. Hypersensitivity
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

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

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

8. Hemolytic Disease of the
Newborn
RhD positive
red cells
RhD
negative
mother
RhD positive
fetus
Lysis
Of
RBC’s
B cell
anti-RhD
first birth post partum subsequent
anti-RhD
RhD positive
fetus

9. Drug-Induced Reactions:
Adherence to Blood Components
complement
blood cell adsorbed drug
or antigen drug metabolite antibody to drug
lysis

10. Toxic Complex Hypersensitivity (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 48-72 hours
tuberculin 48-72 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)

23. Poison Ivy
contact
dermatitis

24. 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

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)

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