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
Hypersensitivity• Hypersensitivity is the term used when an immune response results in exaggerated or inappropriate reaction harmful to the host.
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
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
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
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
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
Type 1 Hypersensitivity• Anaphylaxis• Atopy – Richet – Theobald smith theory
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.
Features of Anaphylaxis• Edema• Decreased coagulablity of blood• Fall in Blood Pressure• Fall in temperature• Leucopenia• Thrombocytopenia
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
• 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
Mechanism of Type 1 reaction B cell to plasma cell BindingActivation Release
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
What comes out?• Seratonin• Eosinophil chemotactic factor (ECF-A) 1• Neutrophil chemotactic factor ( NCF-A)• Platelet activating factor 2• Bradykinin
ANAPHYLACTOID REACTIONS Peptone , Trypsin etc anaphylaxis like reactions (anaphylactoid reactions) No immunological basis Non specific mechanisms involving activation of complement & release of anaphylotoxins
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
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
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
Type II hypersensitivityBLOOD TRANSFUSION REACTIONSHEMOLYTIC DISEASE OF NEWBORNDRUG INDUCED HEMOLYTIC ANAEMIAS
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
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.
Hemolytic disease of Newborn• Minor• Serious• Lethal Erythroblastosis fetalis Hemoglobin Accumulate Brain converted in brain damage to Bilirubin
• 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
Drug induced Hemolytic anaemia Antibiotics attach to RBC Drug protein complex Formation of antibody Bind to drug on RBC Activates complement Lysis of RBC
• Antigen + Antibody Immune complex Small Large Clearance of antigen Tissue damage• Tissue damage Localized Generalized
Formed in blood Blood vessel wall Synovial membraneGlomerular basement membrane Choroid plexus Initiates reaction Increase in Neutrophils Granular release Tissue damage
• 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.
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
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
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
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
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.