Hypersensitivity Reactions
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11/5/2014
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Hypersensitivity Reactions
Dr Debasis Biswas
ObservationExperimentInference
Bathers in Mediterranean Sea.
Sting of Portuguese Man of War jellyfish..
Violent local reaction
Paul Portier & Charles Richet Toxins
Dogs .
Protection
Purified Toxinsf/u: Booster dose of toxins
X X XVomiting, Diarrhea, Asphyxia, Death
Anaphylaxis(Antonym. Prophylaxis)
Nobel Prize in Physiology/Medicine ...Richet1913
Harmful/ Tissue- damaging
Exaggerated
Immune Response
Innocuous/ Harmless antigen
Hypersensitivity ReactionsHypersensitivity Reactions
Immediate Delayed
Minutes or hours afterAntigen exposure
> 48 hours afterAntigen exposure
Antibody/ Immune Complexmediated
Sensitized T cellmediated
IgE- mediated:Type IIgG- mediated cytotoxic:Type IIImmune Complex- mediated:Type III
Cell- mediated:Type IV
Gell & Coombs Classification
Type I Hypersensitivity Reaction
Exposure to an allergen activates specific B cells
Activated B cells formIgE- secreting plasma cells
Type I Hypersensitivity Reaction
Secreted IgE molecules bind to IgE- specific Fc receptors on mast cells & blood basophils
Sensitized Mast Cell
Fc recetorsfor IgE
Sensitizing Dose
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Type I Hypersensitivity Reaction
Shocking Dose
Repeat exposure to same allergen
Cross- linking of IgEmolecules on mast cells
Release of
mast cell mediators
Electron- dense granules
in a mast cell
Mast Cell Degranulation
Primary: Synthesized prior to
activation of mast cells &
stored in granules
Histamine; Heparin; 5HT:
ed vascular permeability &
smooth muscle contraction
ECF- A; NCF- A
Secondary: Synthesized after
activation of mast cells or
released by breakdown of
memb. phospholipids during
degranulation
PGs; LTs; Bradykinin:
Mast Cell Mediators
ed vascular permeability;
bronchoconstriction & mucus production
Platelet Activating Factor:Cytokines: IL-1, TNF-;
IL-4; IL-5; IL-6
Inflammation; ed CAMs (IL-1, TNF-
); ed IgE prodn (IL-4); eosinophactivn (IL-5); shock (TNF-)
Diseases associated with Type I Hypersensitivity Reaction
Systemic
Exptal. model: Guinea pig
(Shocking dose .
Massive vasodiln. Edema, BP, Shock
Sm. m. contraction Dyspnea, Asphyxia)
Anaphylaxis
Venom from bee, wasp, ant stings
Drugs like Penicillin, Insulin & Antitoxins
Seafoods
Nuts
Local (Atopy)
Allergic Rhinitis(Airborne allergens +
Mast cells in conjunctiva
& nasal mucosa)
Food allergies(Food allergens +
Mast cells in GI mucosa,
May be systemic spread)
Atopic Dermatitis
Bronchial asthma
Time course:Minutes of exposure
Mediators involved:HistaminePGs (PGD2)LTs (LTC4)
Manifestations:BronchoconstrictionMucosal edemaMucus secretion
Bronchial Asthma: Early ResponseTime course:
Hours of exposureMediators involved:
ECFNCFPAFCytokines: (IL-4, IL-5,
IL-16, TNF-)
Manifestations:Increased endoth. cell adhesionInflux of eosinophils & neutrophilsTissue damage: ROIs, Enzymes
from eosinophils & neutrophilsBronchial occlusion: Cellular debris,
mucus, thickening of basement memb, edema, sm m hypertrophy
Bronchial Asthma: Late Response
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Bronchial Asthma: Pathogenesis
Skin testing:Intradermal injectionof allergensIn forearm/ back
Looking for wheal & flare reaction within 30 minutes
Assessing Type I Hypersensitivity Response: In vivo
Assessing Type I Hypersensitivity Response: In vitro
Radioimmunosorbent Test (RIST):
Nanogram quantitites of Total serum IgE
Assessing Type I Hypersensitivity Response: In vitro
Radioallergosorbent Test (RAST):
Nanogram quantitites of Allergen- specific serum IgE
Type II Hypersensitivity: Antibody-mediated Cytotoxic Hypersensitivity
Antibody- mediated effector functions:
Complement Activation
Opsonization
ADCC (Antibody- depdt cell- mediated cytotoxicity)
Transcytosis
ADCC
Fc Receptorsbind C region of Ig
Antibodies
Target cell (virus- infected
cell)Release of cytotoxic substances like perforins & granzymes
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Diseases associated with Type II Hypersensitivity Reaction
Transfusion Reaction
ABO Blood Group Antigens
Antibodies to ABO Ags(Isohemagglutinins)
IgM classA ag Anti B abB ag Anti A ab
O ag .. Anti A + Anti BAB ag. None
Incompatible Transfusion
Ag- Ab Reaction betweenDonor ags and Recipient Abs
Immune Complex formation
Classical Pathway of Compl ActivationIntravascular Hemolysis
Diseases associated with Type II Hypersensitivity Reaction
Erythroblastosis fetalis
Effect of treatment with Anti- Rh antibody
Anti- Rh antibody
Diseases associated with Type II Hypersensitivity Reaction
Drug- Induced Hemolytic Anemia
Certain Antibiotics (Penicillins, Cephalosporins, Streptomycin)
bind to proteins on RBCs
Immune Complex formation on RBCs
Classical Pathway of Compl Activation Hemolytic Anemia
Antibodies producedagainst the drug- protein
complex
Type III Hypersensitivity: Immune Complex mediated Hypersensitivity
LocalisedImmune complex deposition
near the site of antigen
entry.
-- Skin (injected antigens)
-- Lungs (inhaled antigens)
Arthus reaction
SystemicImmune complex formation
in blood and deposition in
distant tissues
-- Blood Vessel walls
-- Glomerulus
-- Synovial memb of jts.
-- Choroid plexus of brain
Serum Sickness
Infiltration of neutrophils at the site of IC deposition
Tissue damage from granules released from neutrophils
Type III Hypersensitivity: Pathogenesis
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LocalisedInsect bite in a sensitized
individual:
--Type I (minutes)
--Type III (4-8 hrs):
Erythema+++
Edema +++
Farmers lung
Pigeon Fanciers Disease
Pneumonitis & Alveolitis, following inhalation of ags
Systemic
Diseases associated with Type III Hypersensitivity Reaction
Horse Antitetanus serum
Horse Antidiphtheria serum
--Fever, rash, arthritis, GNitis
Autoimmune diseases
-- SLE, Rheumatoid Arthritis,
Goodpasture Syndrome
Infectious Diseases
-- Post-streptococcal GNitis,
Meningitis, Hepatitis
Type IV Hypersensitivity Reaction
APCLangerhans cells;Macrophages Cytokines
Sensitization phaseAntigens derived fromintracellular bacteria inAPCs ....
Presented by APCs to CD4+ Th cells ..
CD4+ Th cells proliferate and differentiate into Th1 cells..
Th1 cells secrete cytokines(IFN, TNF, TNF)
DTH is generally mediated by CD4+ Th1 cells & occasionally by CD8 T cells
Type IV Hypersensitivity ReactionEffector phase
Repeat exposure of antigento sensitized Th1 cells ...
ActivatedTh1 cells ..
GRANULOMA formation
Secretion of a range of cytokines(IFN, TNF, TNF, IL-2, GM-CSF)& chemokines (IL-8, MCAF, MIF).
Localized inflammation withRecruitment and activation of
macrophages ( ed expression of MHC Class II molecules; TNF Receptors; Oxygen radicals; Nitric Oxide)
Macrophages differentiate into Epithelioid cells & Giant cells
Hallmark of Type IV Hypersensitivity
Pathological Hallmark: Granuloma(lytic enzymes from Mes leading to tissue necrosis)
Clinical correlate: Induration
Tuberculin Reaction
Diseases associated with Type IV Hypersensitivity Reaction
Intradermal Injection in forearm Tubercular antigens (M tb culture filtrate,
Old Tuberculin, PPD) .
48 hours laterLocalized inflammation with Induration
Diseases associated with Type IV Hypersensitivity ReactionContact Dermatitis
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