hypersensitivity_ppt.ppt final (2).ppt
- 1. HYPERSENSITIVITY REACTIONS By- Swastika Singh Chandel Assistant Professor
- 2. Hypersensitivity Reactions Outline • Introduction • Type I Hypersensitivity • Type II Hypersensitivity • Type III Hypersensitivity • Type IV Hypersensitivity
- 3. Hypersensitivity Reactions Outline • Introduction
- 4. Introduction • Normal immune reactions do their job without hu rting the host. • Sometimes, immune reactions can be excessive , resulting in disease. • People who mount normal immune responses ar e sensitized to that antigen. • People who have excessive responses are hype rsensitive.
- 5. Introduction • Bugs • Environmental antigens • Self antigens What antigens initiate these “hypersensitivity reactions”?
- 6. Introduction • The immune response is triggered and m aintained inappropriately. • Hard to eliminate stimulus! • Hard to stop response once it starts! • …so hypersensitivity diseases are often c hronic, debilitating, hard to treat.
- 7. Introduction • Type I: allergy • Type II: antibodies • Type III: immune complex • Type IV: T-cells Four types of hypersensitivity reactions:
- 8. Hypersensitivity Reactions Outline • Introduction • Type I Hypersensitivity
- 9. Type I Hypersensitivity • ALLERGY • “Immediate” hypersensitivity • Antigen (allergen) binds to IgE antibodies on surface of mast cell • Mast cell releases nasty mediators • End result: vessels dilate, smooth muscle contracts, inflammation persists
- 10. Type I Hypersensitivity • Allergen is inhaled/eaten/injected • Allergen stimulates TH2 production • TH2 cell secretes cytokines: • IL-4 stimulates B cells to make IgE • IL-5 recruits eosinophils • IL-13 stimulates mucous secretion • Mast cell binds IgE • Allergen bridges IgE on mast cell • Mast cell degranulates Sequence of events
- 13. Mast cells intact (left) and degranulated (right)
- 14. Type I Hypersensitivity • Granule contents • histamine • some chemotactic factors • Membrane phospholipid metabolites • prostaglandin D2 • leukotrienes • Cytokines • TNF • interleukins • IL-13 What nasty stuff does the mast cell release?
- 15. Reminder: Where do inflammatory mediators come from? Complement proteins Coagulation factors Factors XII, XI, X, etc.
- 17. Type I Hypersensitivity • Act on blood vessels, smooth muscle, and WBCs. • Immediate response (minutes) • vasodilation, vascular leakage, smooth muscle spas m • granule contents, prostaglandin, leukotrienes • Late phase reaction (hours) • inflammation, tissue destruction • cytokines What do these nasty substances do?
- 18. Type I Hypersensitivity • Local reactions • skin: itching, hives • GI: diarrhea • lung: bronchoconstriction • Anaphylaxis • itching, hives, erythema • constriction of bronchioles, wheezing • laryngeal edema, hoarseness • vomiting, cramps, diarrhea • laryngeal obstruction • shock • DEATH What happens to the patient?
- 22. Type I Hypersensitivity • “Atopy” – predisposition to react to allergens • Atopic patients: higher IgE levels, more TH2 cells • Candidate genes: • 5q31 (bunch of cytokine genes here) • 6p (close to HLA complex) Why do some people have allergies, while others don’t?
- 23. Hypersensitivity Reactions Outline • Introduction • Type I Hypersensitivity • Type II Hypersensitivity
- 24. Type II Hypersensitivity • ANTIBODIES • “Antibody-mediated” hypersensitivity • Antibodies bind to antigens on cell surface • Macrophages eat up cells, complement gets act ivated, inflammation comes in • End result: cells die, inflammation harms tissue
- 25. Type II Hypersensitivity What kinds of diseases involve type II hypersensitivity? Disease Antigen Symptoms Autoimmune hemolytic anemia RBC antigens, drugs Hemolysis Pemphigus vulgaris Proteins between epithelial cells Bullae Goodpasture syndrome Proteins in glomeruli and alveoli Nephritis, lung hemorrhage Myasthenia gravis Acetylcholine receptor Muscle weakness Graves disease TSH receptor Hyperthyroidism
- 26. Type II Hypersensitivity • Antibodies bind to cell-surface antigens • One of three things happens: • Opsonization and phagocytosis • Inflammation • Cellular dysfunction Sequence of events
- 28. Inflammation
- 29. Cellular dysfunction Graves disease Myasthenia gravis
- 30. Hypersensitivity Reactions Outline • Introduction • Type I Hypersensitivity • Type II Hypersensitivity • Type III Hypersensitivity
- 31. Type III Hypersensitivity • IMMUNE COMPLEXES • “Immune complex-mediated” hypersensitivity • Antibodies bind to antigens, forming complexes • Complexes circulate, get stuck in vessels, stimu late inflammation • End result: bad inflammation, necrotizing vascul itis
- 32. Type III Hypersensitivity What kinds of diseases involve type III hypersensitivity? Disease Antigen Symptoms Systemic lupus erythematosus Nuclear antigens Nephritis, skin lesions, arthritis… Post-streptococcal glomerulonephritis Streptococcal antigen Nephritis Polyarteritis nodosa Hepatitis B antigen Systemic vasculitis Serum sickness Foreign proteins Arthritis, vasculitis, nephritis Arthus reaction Foreign proteins Cutaneous vasculitis
- 33. Type III Hypersensitivity • Systemic immune complex disease • complexes formed in circulation • deposited in several organs • example: serum sickness • Local immune complex disease • complexes formed at site of antigen injection • precipitated at injection site • example: Arthus reaction Two kinds of type III hypersensitivity reactions
- 37. Type III Hypersensitivity • In olden days: used horse serum for immunization • Inject foreign protein (antigen) • Antibodies are made; they form complexes with antigens • Complexes lodge in kidney, joints, small vessels • Inflammation causes fever, joint pain, proteinuria Serum sickness
- 38. Type III Hypersensitivity • C3b: promotes phagocytosis of complexes (and bugs!) • C3a, C5a (anaphylatoxins): increase permeability • C5a: chemotactic for neutrophils, monocytes • C5-9: membrane damage or cytolysis What are the important complement fractions to know?
- 39. Type III Hypersensitivity • “Arthus reaction” = localized area of skin necrosis resulti ng from immune complex vasculitis • Inject antigen into skin of previously-immunized person • Pre-existing antibodies form complexes with antigen • Complexes precipitate at site of infection • Inflammation causes edema, hemorrhage, ulceration Arthus reaction
- 40. Type III Hypersensitivity • Immune complexes activate complement, which: • attracts and activates neutrophils and monocytes • makes vessels leaky • Neutrophils and monocytes release bad stuff (PG, tissue-dissolv ing enzymes, etc.) • Immune complexes also activate clotting, causing microthrombi • Outcomes: vasculitis, glomerulonephritis, arthritis, other -itises How do the complexes cause inflammation?
- 42. Hypersensitivity Reactions Outline • Introduction • Type I Hypersensitivity • Type II Hypersensitivity • Type III Hypersensitivity • Type IV Hypersensitivity
- 43. Type IV Hypersensitivity • T CELLS • “T-cell-mediated” hypersensitivity • Activated T cells do one of two things: • release cytokines that activate macrophages, or • kill cells directly • This process is normally useful against intracellula r organisms (viruses, fungi, parasites) • Here, it causes bad stuff: inflammation, cell destru ction, granuloma formation
- 44. Type IV Hypersensitivity • Delayed-type hypersensitivity (DTH) • CD4+ T cells secrete cytokines • macrophages come and kill cells • Direct cell cytotoxicity • CD8+ T cells kill targeted cells Two kinds of type IV hypersensitivity
- 45. Type IV Hypersensitivity • Patient exposed to antigen • APC presents antigen to CD4+ T cell • T cells differentiate into effector and memory TH1 cells • Patient exposed to antigen again • TH1 cells come to site of antigen exposure • Release cytokines that activate macrophages, increase inflammation • Results • Macrophages eat antigen (good) • Lots of inflammation and tissue damage (bad) Delayed-type hypersensitivity (DTH)
- 48. Perivascular cuffing by CD4+ cells
- 49. Type IV Hypersensitivity • Good example of DTH: positive Mantoux test • Patient previously exposed to TB • Inject (inactive) TB antigen into skin • See reddening, induration. Peaks in 1-3 days Delayed-type hypersensitivity (DTH)
- 50. Type IV Hypersensitivity • Prolonged DTH can lead to granulomatous inflammation • Perivascular CD4+ T cells replaced by macrophages • Macrophages are activated, look “epithelioid” • Macrophages sometimes fuse into “giant cells” • Granuloma = collection of epithelioid macrophages Delayed-type hypersensitivity (DTH)
- 52. Granuloma
- 53. Type IV Hypersensitivity • Why, yes it does. The same mechanisms underlie both. • Cell-mediated immunity is the major defense we have again st intracellular bugs (like TB and fungi). • Cell-mediated immunity (good) can coexist with DTH (bad)! • Patients with AIDS: • Lack CD4+ cells • So have poor cell-mediated immune response! • Macrophages sit there unactivated; can’t kill bugs. DTH sounds a lot like cell-mediated immunity!
- 54. Type IV Hypersensitivity • CD8+ T cell recognize antigens on the surface of cells • T cells differentiate into cytotoxic T lymphocytes (CTLs) w hich kill antigen-bearing cells • CTLs normally kill viruses and tumor cells • In T-cell mediated cytotoxicity, CTLs kill other things: • Transplanted organ cells • Pancreatic islet cells (Type I diabetes) T-cell-mediated cytotoxicity
- 56. Summary • Type I • Allergy • TH2 cells, IgE on mast cells, nasty mediators • Type II • Antibodies • Opsonization, complement activation, or cell dysfunction • Type III • Immune complexes • Lodge, cause inflammation, tissue injury • Type IV • CD4+ or CD8+ T cells • DTH or T-cell-mediated cytotoxicity