1. Hypersensitivity Reactions
Dr. Raid Jastania

2. Hypersensitivity Reactions
Normal immune reactions
Can be harmful
Examples of these diseases: bronchial asthma, allergic reactions, immune-mediated hemolysis, immune-mediated arthritis, transplant rejection.

3. Antigen
antigen is any molecule (proteins or others) that trigger the immune response and activates humoral or cellular immunity.
exogenous like bacteria, viruses, fungi, parasites, or allergen
indogenous from the cells or the extracellular matrix, like DNA, nuclear molecules, surface receptors, or desmosomes.
intracellular or extracellular.
single exposure or continuous over long period.

4. Immune system
When the immune system is activated against an antigen, there is activation of either cellular immunity or humoral immunity.
Why some antigens trigger cellular immunity and others trigger humoral immunity is not well understood.
extracellular antigens (bacteria) activate the humoral immunity
intracellular antigens (viruses) activate the cellular immunity.

5. Immune System Ag-Ab complex normally removed by phagocytic cells
if it persists it may activate the complement system and initiates inflammation.
IgG and IgM are the complement-fixing
IgA can activate the alternative complement pathway.
IgE mediates the response to parasites and mediate allergic responses.

6. Immune System
Cellular immunity:
CD4+ T-cell
CD8+ T-cell

7. Type I Hypersensitivity (Allergy and Anaphylaxis)
Events:
Exposure to antigen (allergen)
Antigen is processed and presented by APC on MHC-II
Stimulate T-cell response, Th2 (IL4, IL5)
Induce B-cell to mature and produce IgE
IgE is bound to Fc receptor on mast cells and basophils
Those mast cells are armed by IgE and ready to react

8. This result in release of primary and secondary mediators
When re-exposure to antigen (allergen) occurs it binds to IgE and activates the mast cells and degranulation
This result in release of primary and secondary mediators
Primary mediators including:
Histamine causing vasodilatation, bronchospasm and increase mucus secretion
Adenosine causing bronchospasm
Heparin

9. Secondary mediators including:
Arachidonic acid (AA) metabolites: leukotrienes and prostaglandins (PG)
LTC4, LTD4 very potent spasmogenic, and chemotactic agents attracting eosinophils and monocytes
PGD2 resulting in bronchospasm and increase mucus secretion
Cytokines: TNF, IL-1, IL-4, IL-5, IL-6.

10. Mast cells
Found near blood vessels, nerves, and in subepithelial region
Contain secretory granules
IgE bound to surface and activate them
Can be activated by drugs (codeine, morphine), physical heat and cold and sunlight

11. Localized type
Examples: hay fever, allergic rhinitis, bronchial asthma, food allergy
Familial suseptability
Exposure by skin contact, inhalation or ingestion.
2 phases:
Initial phase: (5-30 minutes) mast cell degranulation and release of primary mediators resulting in vasodilatation, vascular leakage, smooth muscle spasm.
Late phase reaction: (2-8 hours) and last for days. It is mediated by secondary mediators and recruitment of eosinophils and other inflammatory cells

12. Systemic Anaphylaxis
Pareneral administration of allergen, eg. Drugs like penicillin
Urticaria, skin erythema occurs in minutes of exposure
Pulmonary bronchospasm and increase secretion of mucus
Laryngeal edema, Vomiting and diarrhea
Vasodilatation (anaphylactic shock)

13. Type II Hypersensitivity
Events:
Antigen is present of the surface of cells or extracellular in tissues
Can be intrinsic or extrinsic antigen
Antibody binds to antigen and followed by one of the following:
Complement-dependent reaction
Resulting in direct lysis of cells by MAC
Or by opsonization and phagocytosis by macrophages

14. Type II Hypersensitivity
Events:
2. Antibody-dependent Cell-mediated cytotoxicity (ADCC):
Target cells are coated with Ab (commonly IgG)
Cells are lysed by neutrophils, eosinophils, macrophages, or NK cells.
3. Antibody-mediated cellular dysfunction
Example: Myasthenia gravis, Graves disease of thyroid

15. Type II Hypersensitivity
Examples:
Transfusion reactions (incompatible RBC from donor)
Erythroblastosis fetalis: incompatible Rh antigen
Autoimmune hemolysis and autoimmune thrombocytopenia
Drug reactions to penicillin
Pemphigus vulgaris: antibody to desmosome
Good pasture syndrome

16. Type III Hypersensitivity (Immune Complex Disease)
Events:
There are 3 phases:
Ag-Ab complex formation
Deposition of Ag-Ab complex
Injury by acute inflammation

17. Acute Serum Sickness:
It is a typical example of immune complex disease. It occurs when horse anitetanus serum is administered, or when horse antithymocyte globulin is administered for the treatment of apalstic anemia.
After 5 days, Ab is formed and Ag-Ab complex is formed
Ag-Ab complexes are deposited in tissue. Deposition is dependent on several factors

18. Acute Serum Sickness:
Deposition of complexes depends on:
Size of complexes
Status of mononuclear phagocytic system
charge of complexes, affinity of Ag to tissues, and the structure of the complexes and the hemodynamics at the site of deposition.
Favored site of deposition are: Kidneys, joints, skin, heart, serosal surfaces and small blood vessels in any tissue.

19. Acute Serum Sickness:
After deposition (10 days) there is activation of the complement system and acute inflammation resulting in tissue injury.
Immune complexes activates Hageman factor, as well, and result in thrombosis.

20. The reaction can be localized or systemic
Examples:
The reaction can be localized or systemic
Exposure to Ag can be single event or continuous chronic diseasea.
Acute serum sickness is systemic.
SLE is typical example of immune complex disease.
Arthus reaction
Glomerulonephritis, Arthritis, carditis, Serositis, vasculitis.

21. Type IV Hypersensitivity
It is cell-mediated reaction occurring in response to:
intracellular organisms (virus, TB)
Extracellular fugi or parasite.
It includes 2 types of sensitized T-cells:
CD4+ T helper cells mediate delayed-type hypersensitivity
CD8+ cytotoxic T-cell mediate Cell-mediated cytotoxicity

22. Delayed-type Hypersensitivity
Events:
Ag processed and presented by APC to CD4+ Th1 cells (IL-2, IFN-gamma)
T-cell is sensitized and stay as memory cells.
When re-exposure to Ag occurs, sensitized T-cell is activated, proliferate and secrete mediators
The result is erythema and induration, Activation of macrophages.
IL-12, IFN-gamma, IL-2, TNF

23. Delayed-type Hypersensitivity
Examples:
Tuberculin skin test in a sensitized person
Contact dermatitis
Granulomatous inflammation is a special type of delayed hypersensitivity.
It results from non-degradable antigen with T-cell reaction. After 2-3 weeks there is aggregates of macrophages that become epithelioid and form giant cells.

24. T-Cell Mediated Cytotoxicity
Mediated by sensitized CD8+ cytotoxic cells
The aim is killing of cells bearing the Ag by:
Perforin-granzyme
Fas-Fas ligand killing

25. T-Cell Mediated Cytotoxicity
Examples:
Graft rejection
Tumor immunity