Hypersensitivity Reactions Dr. Raid Jastania

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.

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

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

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

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.

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: 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

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: Complement-dependent reaction Resulting in direct lysis of cells by MAC Or by opsonization and phagocytosis by macrophages

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

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: Ag-Ab complex formation Deposition of Ag-Ab complex 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: 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.

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.

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.

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

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: 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.

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

T-Cell Mediated Cytotoxicity Examples: Graft rejection Tumor immunity