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Hypersensitivity

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  • 1. HYPERSENSITIVITY
  • 2. I intend to cover in next 30 mins!  Hypersensitivity overview  Classification of hypersensitivity  Type I Hypersensitivity  Anaphylaxis  Atopy  Type II Hypersensitivity  Blood transfusion reactions  Hemolytic disease of newborn  Drug induced hemolysis  Type III Hypersensitivity  Localized  Generalized  Type IV Hypersensitivity  Tuberculin reaction  Contact dermatitis
  • 3. Hypersensitivity• Hypersensitivity is the term used when an immune response results in exaggerated or inappropriate reaction harmful to the host.
  • 4. Hypersensitivity Antigen Immunity• Hypersensitivity is the term used when an Antigen Antigen immune response results in exaggerated killed Host or inappropriate reaction harmful to the host. Antigen ? Hypersensitivity
  • 5. Common terms• Allergen Antigen ( bland substance like serum protein or pollen)• Sensitizing / Priming dose  initial contact with allergen• Shocking dose  2nd contact with same allergen  Manifestations of Hypersensitivity• Haptens  Incomplete antigen
  • 6. ClassificationBased on time required Based on Pathogenesis• Immediate – Anaphylaxis – Atopy I – Antibody mediated cell damage II – Arthus phenomenon – Serum sickness III• Delayed – Infection – Contact IV
  • 7. Distinguishing featuresImmediate Delayed• Appears and recedes rapidly • Appears slowly and lasts longer• Induced by antigens / • Antigen /Hapten intradermally haptens by any route or skin contact• Circulating antibodies may • Circulating antibodies need be present not be present• Passive transfer possible • Transfer not possible with serum but possible with T cells with serum or transfer factor• Desensitization easy but • Desensitization is difficult but short lived long lasting
  • 8. Classification Based on Pathogenesis (CoombsBased on time required & Gell)• Immediate • Type I  anaphylactic, IgE – Anaphylaxis or reagin dependent – Atopy I • Type II  IgG mediated, – Antibody mediated cell damage rarely IgM II • Type III  immune – Arthus phenomenon complex/ toxic complex – Serum sickness III disease• Delayed • Type IV  delayed or cell – Infection mediated immunity – Contact IV
  • 9. Type 1 Hypersensitivity• Anaphylaxis• Atopy – Richet – Theobald smith theory
  • 10. Sensitization• Most effective parentrally but can occur via any route – Antigens & Haptens can induce anaphylaxis. – Interval of 2-3 weeks is required between priming & shocking dose – Once sensitized person remains so for a long period – Shocking dose is more effective • Intravenous • Intraperitoneally • Subcutaneous • Intradermal – Shocking antigen must be identical or immunologically identical to sensitizing antigen.
  • 11. Features of Anaphylaxis• Edema• Decreased coagulablity of blood• Fall in Blood Pressure• Fall in temperature• Leucopenia• Thrombocytopenia
  • 12. Susceptibility to Anaphylaxis
  • 13. Anaphylaxis reaction in Humans• Itching of scalp and tongue• Flushing of skin all over the body• Bronchospasm• Nausea, vomiting, Abdominal pain, Diarrhoea & Malena• A/c Hypotension, loss of consciousness  Death• Cutaneous Anaphylaxis – Small shocking dose  local wheal & flare reaction – Used for allergen testing in atopic diseases
  • 14. • Passive Cutaneous Anaphylaxis in vivo method of detection of antibodies Intradermal antibody injection to Normal animal 4-24 hours Antigen + Evan’s Blue Immediate blueing at the intradermal site Use To detect human IgG Cannot detect IgE
  • 15. Mechanism of Type 1 reaction B cell to plasma cell BindingActivation Release
  • 16. What comes out??Vasoactive amines Histamine Dilatation of blood vessels Transient contraction of smooth musclesProteases Local tissue damageProstaglandins Vascular dilatationLeukotrienes Prolonged smooth muscle contractionCytokines IL2, IL3, IL4, IL6, TGF-ß, Local inflammation GM-CSF, IL1 & TNF-α
  • 17. What comes out?• Seratonin• Eosinophil chemotactic factor (ECF-A) 1• Neutrophil chemotactic factor ( NCF-A)• Platelet activating factor 2• Bradykinin
  • 18. ANAPHYLACTOID REACTIONS Peptone , Trypsin etc  anaphylaxis like reactions (anaphylactoid reactions) No immunological basis Non specific mechanisms involving activation of complement & release of anaphylotoxins
  • 19. ATOPY• Naturally occurring familial hypersensitivities• Inhalants  Pollens, House dust• Ingestants  Eggs, Milk• Contact allergens  antigens not effective parenterally but induce IgE formation• Predisposition to atopy is genetically determined• Atopy runs in families• Bottle fed infants tend to develop atopy in later life
  • 20. IgE• Intially demonstrated by Radioallergo sorbent test (RAST)• Now ELISA and Passive agglutination is used• Prausnitz – kutsner (PK reaction) Kustner  atopic to cooked fish serum from Kustner injected s/c to Prausnitz 24hrs s/c injection of cooked fish antigen at same site wheal & flare reactions in few mins
  • 21. IgE• Heat sensitive• Do not cross placenta• IgE overproduction  deficiency of IgA  Atopy• IgE &IgA lymphocytes reside in submucosa• Antigens are dealt by IgA so IgE never comes into contact• When IgA is deficient IgE producing cells are exposed  IgE overproduction• Clinically – Eye  conjunctivitis – Respiratory system  Rhinitis – Intestine  G.I Symptoms – Skin  Dermatitis
  • 22. TYPE II HYPERSENSITIVITY
  • 23. Type II hypersensitivityBLOOD TRANSFUSION REACTIONSHEMOLYTIC DISEASE OF NEWBORNDRUG INDUCED HEMOLYTIC ANAEMIAS
  • 24. Blood transfusion reactions• RBC has a large number Mismatched transfusion of proteins & glycoproteins Complement mediated lysis• Antibodies formed are of IgM class Free Hb in plasma (Isohemagglutinins)• Clinically Filtered through kidneys – Immediate • Fever, Chills, Nausea, DIC, Low back pain & Hemoglobinuria Hemoglobin in urine. – Delayed Hemoglobin Bilirubin
  • 25. Delayed reactions !• Seen in people with repeated blood transfusions ( Rh, Kidd, Kell & Duffy)• Predominant isotype involved is IgG  incomplete lysis  RBC destroyed in extravascular sites ( Agglutination, Opsonization & Subsequent phagocytosis by macrophages)• Clinically – Fever, Low Hb%, Increased Bilirubin, Mild Jaundice. Free Hb absent in urine.
  • 26. Hemolytic disease of Newborn• Minor• Serious• Lethal  Erythroblastosis fetalis Hemoglobin Accumulate Brain converted in brain damage to Bilirubin
  • 27. Hemolytic disease of Newborn
  • 28. • Prevention – Rhogam  antibodies against Rh antigen within 24-48 hours of delivery – Binds to fetal blood cells and clears them before B-cell activation and memory cell production.• Diagnosis – Testing of maternal serum for antibodies to Rh antigen. Rise in titre is Diagnostic. – Presence of maternal IgG on surface of fetal RBC detected by coombs test• Treatment – Intrauterine blood exchange transfusion – Exposure to U-V light – Plasmapheresis to mother
  • 29. Drug induced Hemolytic anaemia Antibiotics attach to RBC Drug protein complex Formation of antibody Bind to drug on RBC Activates complement Lysis of RBC
  • 30. Type III Hypersensitivity
  • 31. • Antigen + Antibody  Immune complex Small Large Clearance of antigen Tissue damage• Tissue damage Localized Generalized
  • 32. Formed in blood Blood vessel wall Synovial membraneGlomerular basement membrane Choroid plexus Initiates reaction Increase in Neutrophils Granular release Tissue damage
  • 33. • C3a, C4a & C5a  Anaphylotoxins Local mast cell degranulation Increase in local vascular permeability• C3a, C5a & C5b67  Chemotactic  Attract Neutrophils• Tissue damage is as a result of lytic enzymes by neutrophils• C3b  Opsonin• Large complexes deposited in basement membrane• Small complexes deposited in subepithelium• Phagocytosis unsuccessful as complexes are attached to basement membrane  more lytic enzymes poured in  membrane attack mechanism of complement  destruction of tissue• Microthrombi formed due to complement induced aggregation of platelets & release of clotting factors.
  • 34. Localized hypersensitivity Increase in Formation of local Mediate arthus Antigen entry circulating immune complexes reaction antibodyNeutrophils adhere Localized tissue & Accumulation of to vascular Reach target site vascular damage fluid & RBC endothelium Pronouncededema & erythema Sensitized individual at a faster rateIntrapulmonary arthus type reactions induced by bacterial spores, Fungi ordried fecal proteins  Pneumonitis, AlveolitisEg- Farmer’s lung Pigeon farmer’s disease
  • 35. Generalized hypersensitivity• Large amount of uncleared complexes cause reactions at various sites – Horse anti tetanus – Anti diptheria serum• Combination of symptoms in patient who has received foreign antiserum  Serum sickness• Clinically  fever, weakness, rash,edema, erythema, lymphadenopathy, arthritis, Glomerulonephritis
  • 36. Circulating immune complexes• Autoimmune – Systemic Lupus Erythmatosis – Rheumatoid Arthritis – Good pastuer’s syndrome• Drug – Penicillins – Sulfonamides• Infections – Post streptococcal glomerulonephritis – Meningitis – Hepatitis – Mononucleosis – Malaria – Trypanosomiasis
  • 37. Type IV• Activation of sensitized TDTH Cells  Secretion of cytokines  Draws macrophages & activate them  Promote phagocytosis  Lytic enzymes into surrounding tissue  Localized tissue damage.• Hallmark of type IV – Delay in time required for reaction – Recruitment of macrophages• Important defense mechanism against intracellular pathogens
  • 38. Clinical applications• PPD antigen for detecting previous exposure to M.TB• Lepromin test for leprosy• Coccidiodin test for coccidiomycosis• Depletion of CD4+ T cells associated with AIDS  repeated skin test with various antigens or haptens
  • 39. Contact dermatitis• Common allergens  Hairdyes, Cosmetics, Nickel, Turpentine, Formaldehyde, Trinitriophenol,Poison oak, Poison Ivy.• These complex with skin proteins and internalized into APC in skin. These are processed and presented to class II MHC  activation of TDTH  Release of lymphokines• Detected by PATCH TEST sensitivity is indicated by itching in 4-5hours, Local reactions varying from erythema to vesicles to blisters in 24-48 hours.
  • 40. CONCLUSION!
  • 41. References Kuby immunology Basic immunology – Abbas
  • 42. DiagnosisType 1 Provocation test Skin test IgE RadioAllergo Sorbent Test (RAST) Leukocyte histamine release assay Surface markers for basophil activation Leukotriene release testType 2 IgG Serum test (Anti- GBM, Anti Neutrophil cytoplasmic IgG Antibody)Type 3 IgGType 4 Skin test Lymphocyte transformation test MELISA - Memory Lymphocyte Immuno Stimulation Assay