1. Immunologic Disorders Chapter 18

2. Type I Hypersensitivities: Immediate IgE-Mediated IgE causes immediate (type I) hypersensitivities Characterized by reaction the sensitized individual immediately Generally within minutes of exposure Tendencies to have type I hypersensitivities is inherited Reactions occur in at least 20% to 30% of population Type I reactions can be classified as local anaphylaxis or generalized anaphylaxis Anaphylaxis name given for IgE mediated allergic reaction

3. Sensitization occurs when antigen makes contact with some part of body and induces response IgE antibodies bind to receptors on mast cells and basophils Antigen readily binds to cells fixed with IgE antibodies Within seconds mast cells degranulate releasing mediators that initiate immune reaction including, hives, hay fever and anaphylaxis Type I Hypersensitivities: Immediate IgE-Mediated

4. Localized anaphylaxis Most allergic reactions are local anaphylaxis Hives  Allergic skin condition characterized by formation of wheal and flare rash Hay fever  Allergic condition caused by inhaled antigen  Condition marked by itching teary eyes, sneezing and runny nose Asthma  Respiratory allergy  Allergic mediators attracted to inflamed respiratory tract  Results in increased mucous secretion and bronchi spasm

5. Generalized anaphylaxis Rare but more serious Antigen enters bloodstream and becomes widespread Reactions affects almost entire body Can induce shock  Shock is state in which blood pressure too low to supply required blood flow Massive release of mediators causes extensive blood vessel dilation and fluid loss Causes fall in pressure leading to flow insufficiency Type I Hypersensitivities: Immediate IgE-Mediated

6. Immunotherapy General term for techniques used to modify immune system for favorable effect Procedure is to inject individual with extremely dilute suspension of allergen Called desensitization or hyposensitization Concentration of allergen gradually increased over time Individual gradually becomes less sensitive

7. Immunotherapy Second therapeutic procedure is injection of antibodies to bound IgE Essentially anti-IgE antibodies Most IgE are bound to mast cells and basophils Binding of anti-IgE would cause massive release of allergic mediators that could be detrimental to patient  Engineered anti-IgE created  rhuMab = recombinant human Monoclonal antibody Type I Hypersensitivities: Immediate IgE-Mediated

8. Type II Hypersensitivities: Cytotoxic Complement-fixing antibodies react with cell surface antigens causing cell injury or death Cells can be destroyed in type II reactions through complement fixation and antibody- dependent cellular cytotoxicity (ADCC) Examples of Type II hypersensitivities are Transfusion reactions Hemolytic disease of the newborn

9. Type II Hypersensitivities: Cytotoxic Transfusion reactions Normal red blood cells have different surface antigens Antigens differ from person to person  People are designated type A, B, AB or O Transfused blood that is antigenically different can be lysed by recipient immune cells Cross-matching blood is used to ensure compatibility between donor and recipient IgM antibodies cause type II reactions Symptoms include low blood pressure, pain, nausea and vomiting

10. Type II Hypersensitivities: Cytotoxic Hemolytic disease of the newborn Basis of disease is incompatibility of Rh factor between mother and child Rh factor RBC cell surface antigen  Rh positive = Rh antigen present  Rh negative = Rh antigen missing Anti-Rh antibodies form in Rh negative mother pregnant with Rh positive fetus  First Rh positive fetus unharmed  Second Rh positive fetus provokes strong secondary immune response  IgG antibodies of secondary response cross placenta causing extensive damage to fetal red blood cells

11. Type III Hypersensitivities: Immune Complex-Mediated Immune complexes consist of antigen and antibody bound together Usually adhere to Fc receptors on cells Complexes are destroyed and removed Certain instances complexes persist in circulation or at sites of formation Initiate blood clotting mechanism Activate complement contributing to inflammation Complexes commonly deposited in skin, joints and kidney Complexes also cause disseminated intravascular coagulation (DIC) Clots in small vessels Leads to system failure

12. Type IV Hypersensitivities: Delayed Cell-Mediated Delayed hypersensitivities caused by cell-mediated immunity Slowly developing response to antigen Reactions peak in 2 to 3 days instead of minutes T cells are responsible for reactions Reactions can occur nearly anywhere in the body Delayed hypersensitivity reactions responsible for contact dermatitis, tissue damage, rejection of tissue grafts and some autoimmune disease

13. Type IV Hypersensitivities: Delayed Cell-Mediated Tuberculin skin test Test involves introduction of small quantities of protein antigens from tubercle bacillus into skin In positive skin test injection site reddens and gradually thickens Reaction reaches peak in 2 to 3 days Reactions result from sensitized T cells, release of cytokines and influx of macrophages

14. Type IV Hypersensitivities: Delayed Cell-Mediated Contact Hypersensitivities Mediated by the T cells T cells release cytokines  Cytokines initiate inflammation that attracts macrophages  Macrophages release mediators to add to inflammation Common examples of contact allergies include Poison ivy and poison oak Nickel in metal jewelry Chromium salts in leather Latex products

15. Transplant Immunity Major drawback to graft transplantation is possible immunological rejection Differences between donor and recipient tissues basis for rejection Rejection is predominantly type IV reaction Killing of graft cells occurs through complex combination of mechanisms Contact with sensitized cytotoxic T cells and natural killer cells Combination of agents commonly used to prevent graft rejection Cyclosporin A Steroids Basiliximab Monoclonal antibody preparation  Blocks binding of immune mediators Blocks binding sites of T cells  Prevents formation of antibodies

16. Autoimmune Diseases Body usually recognizes self antigens Destroys cells that would destroy self Malfunction in immune recognition basis for autoimmunity Autoimmune diseases may result from reaction to antigen that are similar to MHC self antigens Autoimmunity may occur after tissue injury Self antigens released from injured organ Autoantibodies form and interact with injured tissues

17. Spectrum of autoimmune diseases Reactions occur over spectrum Organ-specific to widespread responses Organ-specific Thyroid disease  Only thyroid is affected Widespread response Lupus  Autoantibodies made against nuclear constituents of all body cells Rheumatoid arthritis  Immune response made against collagen in connective tissue Myasthenia gravis  Autoantibody-mediated disease  Autoantibody to acetylcholine receptor proteins Autoimmune Diseases

18. Treatment of autoimmune diseases Treatment aimed at: Kill dividing cells  Immunosuppressant Controlling T cell signaling  cyclosporin Anti-inflammatory medications  Cortico steroids Replacement therapy  insulin Autoimmune Diseases

19. Immunodeficiency Disorders Immunodeficiency disorders are marked by the body’s inability to make and sustain an adequate immune response Two basic types of disorders Primary or congenital Inborn as a result of genetic defect or developmental abnormality Secondary or acquired Can be acquired as result of infection or other stressor

20. Primary immunodeficiencies Generally rare Examples Agammaglobulinemia  Few or no antibodies produces  Occurs in 1 in 50,00 people Sever combined immunodeficiency disorder (SCID)  Neither B nor T lymphocytes are functional  Occurs in 1 in 500,000 live births Selective IgA deficiency  Little or no IgA produced  Most common disorder  One in 333 to 700 Immunodeficiency Disorders

21. Secondary immunodeficiencies Result from environmental rather than genetic factors Malignancies, advanced age certain infections, immunosuppressive drugs and malnutrition are just a few Often results from depletion of certain cells of the immune system Syphilis, leprosy and malaria effect T cell population and macrophage function Malignancies of lymphoid system decrease antibody- mediated immunity Most serious widespread immunodeficiency is AIDS Destroys helper T cells  Inhibits initiation of cellular and humoral immunity Immunodeficiency Disorders