Hypersensitivity reactions lecture notes

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Hypersensitivity reactions lecture notes

  1. 1. Hypersensitivity Reactions A state of altered reactivity in which the body reacts with an exaggerated immune response to a foreign agent.
  2. 2. <ul><li>Four Types of Hypersensitivity Reactions: </li></ul><ul><li>Type I (Anaphylactic) Reactions </li></ul><ul><li>Type II (Cytotoxic) Reactions </li></ul><ul><li>Type III (Immune Complex) Reactions </li></ul><ul><li>Type IV (Cell-Mediated) Reactions </li></ul>
  3. 3. Hypersensitivity <ul><li>4 types of HS (Gell & Coombs) </li></ul><ul><ul><li>Type I : IgE-mediated degranulation of mast cells -> acute anaphylactic response </li></ul></ul><ul><ul><li>Type II : IgG / IgM on cells -> c’ lysis or ADCC </li></ul></ul><ul><ul><li>Type III: Immune complexes -> c’ activation, inflammation </li></ul></ul><ul><ul><li>Type IV : T DTH activate macs -> chronic inflammation </li></ul></ul><ul><li>Types I – III involve Abs, Type IV is CMIR </li></ul>
  4. 4. Hypersensitivity Reactions
  5. 5. <ul><li>Type I (Anaphylactic) Reactions </li></ul><ul><ul><li>Occur within minutes of exposure to antigen </li></ul></ul><ul><ul><li>Antigens combine with IgE antibodies </li></ul></ul><ul><ul><li>IgE binds to mast cells and basophils, causing them to undergo degranulation and release several mediators: </li></ul></ul><ul><ul><ul><li>Histamine: Dilates and increases permeability of blood vessels (swelling and redness), increases mucus secretion (runny nose), smooth muscle contraction (bronchi). </li></ul></ul></ul><ul><ul><ul><li>Prostaglandins: Contraction of smooth muscle of respiratory system and increased mucus secretion. </li></ul></ul></ul><ul><ul><ul><li>Leukotrienes: Bronchial spasms. </li></ul></ul></ul><ul><ul><li>Anaphylactic shock : Massive drop in blood pressure. Can be fatal in minutes. </li></ul></ul>
  6. 6. Figure 10-1
  7. 7. Type I Hypersensitivity <ul><li>classic allergic reactions </li></ul><ul><ul><li>allergens – Ags that trigger HS-I reactions </li></ul></ul><ul><ul><li>atopic people tend to mount IgE responses </li></ul></ul><ul><ul><ul><li>get hay fever, asthma, etc. </li></ul></ul></ul><ul><li>mast cells / basophils are major effectors </li></ul><ul><ul><li>have high-affinity Fc receptors for IgE </li></ul></ul><ul><ul><li>granules contain mediators of HS-I reaction </li></ul></ul>
  8. 8. Type I Hypersensitivity <ul><li>primary mediators in mast / baso granules </li></ul><ul><ul><li>histamine </li></ul></ul><ul><ul><li>serotonin ~ effects to histamine </li></ul></ul><ul><ul><li>heparin – anticoagulant </li></ul></ul><ul><ul><li>chemotactic factors recruit eos, neutrophils </li></ul></ul><ul><li>secondary mediators made later </li></ul><ul><ul><li>arachadonic acid metabolites (PG, LT) </li></ul></ul><ul><ul><li>platelet activ. factors (PAF) </li></ul></ul><ul><ul><li>bradykinins </li></ul></ul>
  9. 9. Type I Hypersensitivity <ul><li>Cytokines contribute to HS-I response </li></ul><ul><ul><li>mast cells secrete IL-4, IL-5, IL-6, TNF- α </li></ul></ul><ul><ul><ul><li>IL-4 helps activate B cells; increases IgE prod </li></ul></ul></ul><ul><ul><ul><li>IL-5 recruits eosinophils </li></ul></ul></ul><ul><ul><ul><li>IL-6, TNF contribute to inflamm. (fever, etc.) </li></ul></ul></ul><ul><li>Eosinophils increased in atopic individuals </li></ul><ul><ul><li>have low-affinity FcR for IgE </li></ul></ul><ul><ul><li>degranulation -> PAF, PG, LT </li></ul></ul><ul><ul><li>important in late-phase asthma </li></ul></ul>
  10. 10. Type I Hypersensitivity <ul><li>Sensitization phase: IgE produced in response to allergen </li></ul><ul><ul><li>IgE binds to FcR on mast cells / basophils </li></ul></ul><ul><ul><li>mast cells sensitized </li></ul></ul><ul><li>Activation phase: on next encounter with allergen </li></ul><ul><ul><li>allergen cross-links IgE receptors on mast cell -> immediate degranulation </li></ul></ul><ul><ul><li>(mast cell degran. can also occur w. anti-IgE Abs, some chemicals, or c’ anaphylatoxins C3a, C5a) </li></ul></ul><ul><li>Effector phase: tissue Rx to degranulation </li></ul><ul><ul><li>vasc. perm. , mucous secretions, influx of eos, neuts, etc. </li></ul></ul>
  11. 11. Biologic effects of mediators
  12. 12. Biological effects of Eosinophil mediators Late stage of an allergic response includes the recruitment of eosinophils and Th2 cells contrast with a DTH (type IV) response which includes infiltration of macrophages and Th1 cells
  13. 13. Type I HS Reactions <ul><li>Localized anaphylaxis (atopy) </li></ul><ul><ul><li>cutaneous anaphylaxis – wheal & flare </li></ul></ul><ul><ul><ul><li>(P-K Rx) </li></ul></ul></ul><ul><ul><li>urticaria </li></ul></ul><ul><ul><li>allergic rhinitis (hay fever) </li></ul></ul><ul><ul><li>food allergies </li></ul></ul><ul><ul><li>atopic dermatitis (allergic eczema) </li></ul></ul><ul><ul><li>asthma (lower resp. tract) </li></ul></ul>
  14. 14. Type I HS Reactions <ul><li>systemic anaphylaxis worst case </li></ul><ul><ul><li>anaphylactic shock </li></ul></ul><ul><ul><li>mast cells degran. all over body </li></ul></ul><ul><ul><li>3 potentially fatal Rx </li></ul></ul><ul><ul><ul><li>laryngeal edema – fluid leaking out -> swelling </li></ul></ul></ul><ul><ul><ul><li>bronchiole constriction -> suffocation </li></ul></ul></ul><ul><ul><ul><li>peripheral edema -> shock from fluid loss </li></ul></ul></ul><ul><ul><li>2° mediators cause prolonged effects later </li></ul></ul><ul><ul><ul><li>late phase reaction </li></ul></ul></ul>
  15. 15. Figure 10-12
  16. 16. Identifying HS-I: Allergy Testing <ul><li>skin test: small doses of allergen </li></ul><ul><ul><li>look for wheal & flare </li></ul></ul><ul><li>measure IgE levels </li></ul>
  17. 17. Treatment for HS-I Disorders <ul><li>avoid allergen (Rx can get worse each time </li></ul><ul><li>drugs </li></ul><ul><ul><li>anti-histamines (not Abs) compete w. histamine for receptors </li></ul></ul><ul><ul><li>epinephrine – best immediate trt for anaphyl. shock </li></ul></ul><ul><ul><ul><li>reverses effects of granules (vasoconstriction, relaxes muscles) </li></ul></ul></ul><ul><ul><ul><li>quick acting, but short duration </li></ul></ul></ul><ul><ul><li>cortisone blocks histamine synthesis </li></ul></ul>
  18. 18. Treatment for HS-I Disorders <ul><li>immunological treatment </li></ul><ul><ul><li>hyposensitization – rpt injections of allergen </li></ul></ul><ul><ul><ul><li>may work by shifting from IgE to IgG production </li></ul></ul></ul><ul><ul><li>MAb anti-IgE that binds mIgE on B cells </li></ul></ul><ul><ul><ul><li>(if binds IgE on mast cells -> degranulation) </li></ul></ul></ul>
  19. 19. <ul><li>Type II (Cytotoxic) Reactions </li></ul><ul><ul><li>Involve activation of complement by IgG or IgM binding to an antigenic cell. </li></ul></ul><ul><ul><li>Antigenic cell is lysed. </li></ul></ul><ul><ul><li>Transfusion reactions: </li></ul></ul><ul><ul><ul><li>ABO Blood group system : Type O is universal donor. Incompatible donor cells are lysed as they enter bloodstream. </li></ul></ul></ul><ul><ul><ul><li>Rh Blood Group System : 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells. </li></ul></ul></ul><ul><ul><ul><ul><li>Hemolytic disease of newborn : Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta. </li></ul></ul></ul></ul>
  20. 20. Type II Hypersensitivity <ul><li>Ab-mediated cytotoxicity </li></ul><ul><li>Abs vs. cell surface Ags -> C’ lysis or ADCC </li></ul><ul><li>most common HS-II Rx involve rbc </li></ul><ul><ul><li>transfusion Rx </li></ul></ul><ul><ul><li>hemolytic disease of the newborn ( HDN ) </li></ul></ul><ul><ul><li>autoimmune hemolytic anemic ( AIHA ) </li></ul></ul>
  21. 21. TYPE II HYPERSENSITIVITY B. TYPE II CYTOTOXIC REACTIONS - IgG OR IgM MEDIATED, COMPLEMENT INVOLVED, REACTIONS MOST OFTEN EFFECT CELLULAR ELEMENTS IN INTIMATE CONTACT WITH CIRCULATING PLASMA EXAMPLES: HEMOLYTIC ANEMIA, TRANSFUSION REACTIONS
  22. 23. Type II Hypersensitivity <ul><li>ABO system unique; -> “naturally-occurring Abs </li></ul><ul><ul><li>IgM Abs vs Ag A or B Ags (aka isohemagglutinins) </li></ul></ul><ul><ul><li>formed in response to similar (T-indep.) Ags on bact. </li></ul></ul><ul><li>People with type A rbc make Abs vs B Ag, etc. </li></ul><ul><li>Type O rbc lack both A and B Ags (have H only) </li></ul><ul><li>blood typing = hemagglutination (cross-linking of rbc by IgM Abs </li></ul>
  23. 24. Human ABO Blood Types anti-A anti-B H O OOH none A, B, H AB ABH anti-A B, H B BBH or BOH anti-B A, H A AAH or AOH serum Abs ABO Ags on rbc rbc phenotype Genotype
  24. 25. Type II Hypersensitivity Rx <ul><li>Hemolytic Transfusion Rx </li></ul><ul><ul><li>ABO incompatible transfusion can -> immediate disaster </li></ul></ul><ul><ul><ul><li>IgM isohemagglutinins bind rbc -> activate C’ </li></ul></ul></ul><ul><ul><ul><li>rapid intravascular lysis, agglut. </li></ul></ul></ul><ul><ul><ul><li>renal failure, death </li></ul></ul></ul><ul><ul><li>Dx: clinical SS, hemoglobinuria , hemolysis </li></ul></ul><ul><ul><li>Trt: stop TF ; diuretics </li></ul></ul><ul><ul><li>Prevent by crossmatch : </li></ul></ul><ul><ul><ul><li>patient serum (Abs) + donor rbc (Ags) </li></ul></ul></ul>
  25. 26. Hemolytic Disease of Newborn (HDN ) <ul><li>involves Rh blood group system </li></ul><ul><ul><li>3 genes C, D, E: D most immunogenic </li></ul></ul><ul><ul><li>get Rh Abs only by exposure to Ags </li></ul></ul><ul><ul><li>Abs mostly IgG </li></ul></ul><ul><li>HDN ( erythroblastosis fetalis ) </li></ul><ul><ul><li>Rh(D) negative mom with Rh+ fetus makes Abs vs baby rbc that enter mom circ. at birth </li></ul></ul><ul><ul><li>next pregnancy: IgG Abs cross placenta, destroy fetal rbc -> jaundice, brain damage </li></ul></ul>
  26. 27. HDN <ul><li>Prevent HDN by giving mom RhoGAM after birth </li></ul><ul><ul><li>anti-Rh Abs that lyse baby rbc in mom circ. </li></ul></ul><ul><ul><li>Abs also prevent sensitization (activ. of B cells) </li></ul></ul><ul><li>Dx HDN in baby with Coombs test </li></ul><ul><ul><li>detects Abs already on baby rbc </li></ul></ul><ul><ul><li>add Coombs rgt (anti-IgG) to baby / cord blood </li></ul></ul><ul><ul><ul><li>look for clumping </li></ul></ul></ul>
  27. 29. Type II Hypersensitivity <ul><li>Other HS-II Rx = autoimmune hemolytic anemia (AIHA) </li></ul><ul><ul><li>autoAbs can result from drugs (e.g., penicillin) that stick to rbc -> Abs -> C’ activation </li></ul></ul>
  28. 30. <ul><li>Type III (Immune Complex) Reactions </li></ul><ul><ul><li>Involve reactions against soluble antigens circulating in serum. </li></ul></ul><ul><ul><li>Usually involve IgA antibodies. </li></ul></ul><ul><ul><li>Antibody-Antigen immune complexes are deposited in organs, activate complement, and cause inflammatory damage. </li></ul></ul><ul><ul><ul><li>Glomerulonephritis : Inflammatory kidney damage. </li></ul></ul></ul><ul><ul><li>Occurs with slightly high antigen-antibody ratio is present. </li></ul></ul>
  29. 31. TYPE III HYPERSENSITIVITY <ul><li>C. TYPE III IMMUNE COMPLEX REACTIONS – </li></ul><ul><li>IgG OR IgM MEDIATED, COMPLEMENT INVOLVED, </li></ul><ul><li>CHARACTERIZED BY FORMATION OF IMMUNE </li></ul><ul><li>COMPLEXES, TISSUE DAMAGE </li></ul><ul><li>EXAMPLES: </li></ul><ul><li>SERUM SICKNESS - DISEASE CAUSED BY ANTIBODY </li></ul><ul><li>PRODUCED TO HORSE OR BOVINE SERUM USED IN </li></ul><ul><li>ANTITOXINS. AGGREGATES OF IgG ACTIVATE </li></ul><ul><li>COMPLEMENT </li></ul><ul><li>2) ARTHUS REACTION - DERMAL INFLAMMATORY </li></ul><ul><li>RESPONSE, CAUSED BY REACTION OF ANTIBODY </li></ul><ul><li>TO ANTIGEN IN SKIN. </li></ul>
  30. 34. Type III Hypersensitivity <ul><li>immune complex reactions </li></ul><ul><li>2 types of harmful Rx </li></ul><ul><ul><li>Arthus Rx from localized immune complexes </li></ul></ul><ul><ul><li>serum sickness from circulating complexes </li></ul></ul>
  31. 35. Arthus Rx <ul><li>intradermal injection of Ag </li></ul><ul><li>complexes deposit on blood vessel walls, kidney, etc </li></ul><ul><li>damage mech: C’ activ. -> inflammation </li></ul><ul><ul><li>C3a / C5a chemotactic for neutrophils, cause degranulation of mast cells </li></ul></ul><ul><ul><li>“ frustrated phagocytes ” – neuts. bind C3b on complexes - can’t phago -> dump granules in tissues -> damage </li></ul></ul><ul><li>examples of Arthus-type Rx </li></ul><ul><ul><li>insect bite </li></ul></ul><ul><ul><li>pneumonitis / farmer’s lung </li></ul></ul>
  32. 36. Arthus Reaction
  33. 37. Serum Sickness <ul><li>generalized HS-III – circulating immune complexes </li></ul><ul><li>induced by injection of foreign proteins (antitoxin) </li></ul><ul><li>complex deposit in capillary beds </li></ul><ul><li>SS: vasculitis – rash, fever, joint pain, etc. </li></ul><ul><li>damage mech. same as Arthus: C’ and neutrophils </li></ul><ul><li>diseases characterized by circulating complexes </li></ul><ul><ul><li>glomerulonephritis </li></ul></ul><ul><ul><li>lupus (SLE), rheumatoid arthritis, chronic infections </li></ul></ul>
  34. 38. <ul><li>Type IV (Cell-Mediated) Reactions </li></ul><ul><ul><li>Involve reactions by T D memory cells. </li></ul></ul><ul><ul><ul><li>First contact sensitizes person. </li></ul></ul></ul><ul><ul><ul><li>Subsequent contacts elicit a reaction. </li></ul></ul></ul><ul><ul><li>Reactions are delayed by one or more days (delayed type hypersensitivity). </li></ul></ul><ul><ul><ul><li>Delay is due to migration of macrophages and T cells to site of foreign antigens. </li></ul></ul></ul><ul><ul><li>Reactions are frequently displayed on the skin: itching, redness, swelling, pain. </li></ul></ul><ul><ul><ul><ul><li>Tuberculosis skin test </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Metals </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Latex in gloves and condoms (3% of health care workers) </li></ul></ul></ul></ul><ul><ul><li>Anaphylactic shock may occur. </li></ul></ul>
  35. 39. TYPE IV HYPERSENSITIVITY D. TYPE IV - CELL MEDIATED OR DELAYED HYPERSENSITIVITY T-CELL MEDIATED, SENSITIZED TO LOCALLY DEPOSITED ANTIGEN. REACTION MEDIATED BY RELEASE OF LYMPHOKINE AND/OR DIRECT CYTOTOXICITY EXAMPLES: CONTACT SENSITIVITY (POISON IVY)
  36. 40. Type IV Hypersensitivity (DTH) <ul><li>delayed vs. immediate Rx </li></ul><ul><li>cell-mediated IR; NO Abs involved </li></ul><ul><li>localized Rx at site of Ag encounter </li></ul>
  37. 42. Type IV hypersensitivity - Delayed-type hypersensitivity
  38. 43. Figure 10-34
  39. 44. Figure 10-35
  40. 45. DTH <ul><li>sensitization phase = activation of T H cells </li></ul><ul><ul><li>activated T H -> T DTH (subset of T H 1 that activates macs) -> memory & effector cells </li></ul></ul>
  41. 46. DTH <ul><li>effector phase: activated T DTH secrete CK, esp. IFN- γ </li></ul><ul><ul><li>IFN- γ activates macs </li></ul></ul><ul><ul><li>activated macs secrete IL-1, IL-6, TNF- α </li></ul></ul><ul><li>chronic inflammation, granulomas (lump of T H and macs) </li></ul>
  42. 47. TYPE IV DELAYED HYPERSENSITIVITY
  43. 49. DTH <ul><li>DTH Ags are intracellular pathogens or contact Ags ( TB, leprosy, poison ivy) </li></ul><ul><ul><li>contact dermatitis </li></ul></ul>
  44. 50. DTH <ul><li>detect DTH with skin test </li></ul><ul><ul><li>TB skin test: inject PPD -> 48 hr -> lump </li></ul></ul><ul><ul><li>patch test for poison ivy / oak sensitivity </li></ul></ul><ul><ul><li>lepromin Ag for leprosy </li></ul></ul><ul><li>DTH is an important CMIR defense vs intracellular pathogens </li></ul>
  45. 51. (hives) Allergies 4 types of hypersensitivity reactions
  46. 52. Delayed-type hypersensitivity Immune complex disease
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