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Hypersensitivity Reactions
• Normal immune reactions
• Can be harmful
• Examples of these diseases: bronchial asthma, allergic reactions, immune-mediated hemolysis, immune-mediated arthritis, transplant rejection.
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.
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.
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.
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
• 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:1.Histamine causing vasodilatation,
bronchospasm and increase mucus secretion
2.Adenosine causing bronchospasm
3.Heparin
• Secondary mediators including:
1.Arachidonic acid (AA) metabolites: leukotrienes and prostaglandins (PG)
1.LTC4, LTD4 very potent spasmogenic, and chemotactic agents attracting eosinophils and monocytes
2.PGD2 resulting in bronchospasm and increase mucus secretion
2.Cytokines: TNF, IL-1, IL-4, IL-5, IL-6.
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
Localized type• Examples: hay fever, allergic rhinitis, bronchial
asthma, food allergy– Familial suseptability– Exposure by skin contact, inhalation or ingestion.
• 2 phases:1. Initial phase: (5-30 minutes) mast cell
degranulation and release of primary mediators resulting in vasodilatation, vascular leakage, smooth muscle spasm.
2. Late phase reaction: (2-8 hours) and last for days. It is mediated by secondary mediators and recruitment of eosinophils and other inflammatory cells
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)
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:
1. Complement-dependent reaction1. Resulting in direct lysis of cells by MAC
2. Or by opsonization and phagocytosis by macrophages
Type II Hypersensitivity
• Events:2. Antibody-dependent Cell-mediated
cytotoxicity (ADCC):a. Target cells are coated with Ab (commonly IgG)b. Cells are lysed by neutrophils, eosinophils,
macrophages, or NK cells.
3. Antibody-mediated cellular dysfunctionExample: Myasthenia gravis, Graves disease of
thyroid
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
Type III Hypersensitivity (Immune Complex Disease)• Events:• There are 3 phases:
1.Ag-Ab complex formation
2.Deposition of Ag-Ab complex
3.Injury by acute inflammation
• 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
• Acute Serum Sickness:• Deposition of complexes depends on:1. Size of complexes2. Status of mononuclear phagocytic system3. charge of complexes, affinity of Ag to
tissues, and the structure of the complexes and the hemodynamics at the site of deposition.
4. Favored site of deposition are: Kidneys, joints, skin, heart, serosal surfaces and small blood vessels in any tissue.
• 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.
• 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.
Type IV Hypersensitivity
• It is cell-mediated reaction occurring in response to:
1. intracellular organisms (virus, TB)2.Extracellular fugi or parasite.• It includes 2 types of sensitized T-cells:1.CD4+ T helper cells mediate delayed-type
hypersensitivity2.CD8+ cytotoxic T-cell mediate Cell-
mediated cytotoxicity
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
Delayed-type Hypersensitivity
• Examples:
1.Tuberculin skin test in a sensitized person
2.Contact dermatitis
3.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.
T-Cell Mediated Cytotoxicity
• Mediated by sensitized CD8+ cytotoxic cells
• The aim is killing of cells bearing the Ag by:
1.Perforin-granzyme
2.Fas-Fas ligand killing