1. Allergy and Hypersensitivity Zahaib Quadri MD Department of physiology Dow medical college, DUHS

2. Important definitions Hypersensitivity reactions Are harmful antigen-specific immune responses, occur when an individual who has been primed by an innocuous antigen subsequently encounters the same antigen, produce tissue injury and dysfuntion. Allergen: The antigens that give rise to immediate hypersensitivity Atopy ： The genetic predisposition to synthesize inappropriate levels of IgE specific for external allergens

3. Types of Hypersensitivity 1. Type I Hypersensitivity 2. Type II Hypersensitivity 3. Type III Hypersensitivity 4. Type IV Hypersensitivity 5. Type V Hypersensitivity

4. Type I Hypersensitivity (Anaphylactic) Reactions/Allergy Occur within minutes of exposure to antigen Occur within minutes of exposure to antigen Antigens combine with IgE antibodies Antigens combine with IgE antibodies IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators: IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators: Histamine: Histamine: Prostaglandins: Prostaglandins: Leukotrienes: Leukotrienes: Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes. Anaphylactic shock: Massive drop in blood pressure. Can be fatal in minutes.

5. Type I Hypersensitivity (Anaphylactic) Reactions/Allergy Exposure to an allergen activates B cells to form IgE secreting plasma cells Secreted IgE molecules bind to Fce receptors on mast cells A subsequent exposure to the allergen results in crosslinking of the bound IgE which triggers the release of various compounds

6. Mast Cells and the Allergic Response

8. Examples of type 1 Atopy Atopy Anaphylaxis Anaphylaxis Asthma Asthma

9. Type II Hypersensitivity (Cytotoxic) Reactions/antibody-dependent Involve activation of complement by IgG or IgM binding to an antigenic cell. Involve activation of complement by IgG or IgM binding to an antigenic cell. Antigenic cell is lysed Antigenic cell is lysed Transfusion reactions: Transfusion reactions: ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. ABO Blood group system: Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells. Rh Blood Group System: 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells. Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta. Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.

10. Hemolytic disease of the newborn is caused by type II hypersensitivity reactions When an Rh- mother carries an Rh+ fetus

11. Examples of type II Autoimmune hemolytic anemia Autoimmune hemolytic anemia Thrombocytopenia Thrombocytopenia Erythroblastosis fetalis Erythroblastosis fetalis Goodpasture's syndrome Goodpasture's syndrome

12. Type III Hypersensitivity (Immune Complex) Reactions Involve reactions against soluble antigens circulating in serum. Involve reactions against soluble antigens circulating in serum. Usually involve IgA antibodies. Usually involve IgA antibodies. Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. Glomerulonephritis: Inflammatory kidney damage. Glomerulonephritis: Inflammatory kidney damage. Occurs with slightly high antigen-antibody ratio is present. Occurs with slightly high antigen-antibody ratio is present.

13. Immune Complex Mediated Hypersensitivity

14. Type III Hypersensitivity Insect bites—if an individual has been previously sensitized and has circulating antibodies, the initial reaction will be type I at the site of the bite and 4- 8 hours later a type III reaction might develop Arthus reaction: deposits of immune complexes draw neutrophils, leading to an accumulation of fluid (edema) and RBC’s (erythema) Severity of the reaction varies from mild swelling and redness to tissue necrosis Type III reactions can also be generalized (as opposed to localized to a specific tissue) Large amounts of circulating antigen can form immune complexes which are not easily cleared by phagocytic cells Example: “serum sickness” following the injection of an anti-toxin

15. Examples of type III Serum sickness Serum sickness Arthus reaction Arthus reaction Systemic lupus erythematosus (SLE) Systemic lupus erythematosus (SLE)

16. Type IV (Cell-Mediated) Reactions/Delayed-type hypersensitivity/antibody-independent Involve reactions by T D memory cells. Involve reactions by T D memory cells. First contact sensitizes person. First contact sensitizes person. Subsequent contacts elicit a reaction. Subsequent contacts elicit a reaction. Reactions are delayed by one or more days (delayed type hypersensitivity). Reactions are delayed by one or more days (delayed type hypersensitivity). Delay is due to migration of macrophages and T cells to site of foreign antigens. Delay is due to migration of macrophages and T cells to site of foreign antigens. Reactions are frequently displayed on the skin: itching, redness, swelling, pain. Reactions are frequently displayed on the skin: itching, redness, swelling, pain. Tuberculosis skin test Tuberculosis skin test Poison ivy Poison ivy Metals Metals Latex in gloves and condoms (3% of health care workers) Latex in gloves and condoms (3% of health care workers) Anaphylactic shock may occur. Anaphylactic shock may occur.

17. Type IV Mechanism APC resident in the skin process antigen and migrate to regional lymph nodes where they activate T cells Sensitised T cells migrate back to the the skin where they produce cytokines which attract macrophages which cause tissue damage

18. Type IV or delayed type hypersensitivity – cell mediated Many contact dermatitis reactions are mediated by TH1 cells The molecules (such as pentadecacatechol) complex with skin proteins and this complex is then internalized by antigen presenting cells, processed and presented with Class II MHC molecules which are recognized by appropriate TH1 cells and which are now “sensitized” to pentadecacatechol Subsequent exposure to pentadecacatechol will activate these TH1 cells and induce cytokine production; approximately 48 to 72 hours after this second exposure macrophages accumulate at the site and release lytic enzymes that cause the redness and pustule formation of poison oak exposure

19. Examples of Type IV Contact dermatitis Contact dermatitis Mantoux test Mantoux test Chronic transplant rejection Chronic transplant rejection Multiple sclerosis Multiple sclerosis

20. Type V Hypersensitivity / Auto immune This is an additional type that is sometimes (often in Britain) used as a distinction from Type 2 This is an additional type that is sometimes (often in Britain) used as a distinction from Type 2 Instead of binding to cell surface components, the antibodies recognize and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signaling Instead of binding to cell surface components, the antibodies recognize and bind to the cell surface receptors, which either prevents the intended ligand binding with the receptor or mimics the effects of the ligand, thus impairing cell signaling

21. Examples of Type V Grave's disease Grave's disease Myasthenia Gravis Myasthenia Gravis Hashimoto's thyroiditis Hashimoto's thyroiditis Systemic lupus erythematosus Systemic lupus erythematosus

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