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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