11/5/2014

ObservationExperimentInference

Hypersensitivity Reactions
Dr Debasis Biswas

Nobel Prize in Physiology/Medicine ...Richet1913

Bathers in Mediterranean Sea.
Sting of Portuguese Man of War jellyfish..
Violent local reaction
Paul Portier & Charles Richet Toxins
Purified Toxins
Dogs .
f/u: Booster dose of toxins
Protection
XXX
Vomiting, Diarrhea, Asphyxia, Death

Anaphylaxis(Antonym. Prophylaxis)

Hypersensitivity Reactions

Gell & Coombs Classification

Hypersensitivity Reactions

Harmful/ Tissue- damaging

Exaggerated
Immune Response
Innocuous/ Harmless antigen

Immediate

Delayed
> 48 hours after
Antigen exposure

Minutes or hours after

Antigen exposure

Antibody/ Immune Complex

mediated

Sensitized T cell
mediated

IgE- mediated:Type I
Cell- mediated:Type IV
IgG- mediated cytotoxic:Type II
Immune Complex- mediated:Type III

Type I Hypersensitivity Reaction

Type I Hypersensitivity Reaction

Exposure to an allergen
activates specific B cells

Secreted IgE molecules bind to

IgE- specific Fc receptors on
mast cells & blood basophils
Fc recetors
for IgE

Sensitized Mast Cell

Activated B cells form
IgE- secreting plasma cells

Sensitizing Dose

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Type I Hypersensitivity Reaction

Electron- dense granules

in a mast cell

Repeat exposure to
same allergen
Cross- linking of IgE
molecules on mast cells

Release of

mast cell mediators

Mast Cell

Degranulation

Shocking Dose

Mast Cell Mediators

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:
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); eosinoph
activn (IL-5); shock (TNF-)

Bronchial Asthma: Early Response

Time course:
Minutes of exposure
Mediators involved:
Histamine
PGs (PGD2)
LTs (LTC4)
Manifestations:
Bronchoconstriction
Mucosal edema
Mucus secretion

Diseases associated with Type I

Hypersensitivity Reaction
Systemic
Exptal. model: Guinea pig

Local (Atopy)

(Shocking dose .
Massive vasodiln. Edema, BP, Shock
Sm. m. contraction Dyspnea, Asphyxia)

(Airborne allergens +
Mast cells in conjunctiva
& nasal mucosa)

Allergic Rhinitis

Anaphylaxis
Venom from bee, wasp, ant stings
Drugs like Penicillin, Insulin & Antitoxins
Seafoods
Nuts

Food allergies
(Food allergens +
Mast cells in GI mucosa,
May be systemic spread)

Atopic Dermatitis
Bronchial asthma

Bronchial Asthma: Late Response

Time course:
Hours of exposure
Mediators involved:
ECF
NCF
PAF
Cytokines: (IL-4, IL-5,
IL-16, TNF-)
Manifestations:
Increased endoth. cell adhesion
Influx of eosinophils & neutrophils
Tissue damage: ROIs, Enzymes
from eosinophils & neutrophils
Bronchial occlusion: Cellular debris,
mucus, thickening of
basement memb, edema,
sm m hypertrophy

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Bronchial Asthma: Pathogenesis

Assessing Type I Hypersensitivity

Response: In vivo
Skin testing:
Intradermal injection
of allergens
In forearm/ back
Looking for wheal &
flare reaction within
30 minutes

Assessing Type I Hypersensitivity

Response: In vitro

Radioimmunosorbent Test (RIST):

Nanogram quantitites of Total serum IgE

Type II Hypersensitivity: Antibodymediated Cytotoxic Hypersensitivity

Antibody- mediated effector functions:
Complement Activation
Opsonization
ADCC (Antibody- depdt cell- mediated
cytotoxicity)
Transcytosis

Assessing Type I Hypersensitivity

Response: In vitro

Radioallergosorbent Test (RAST):

Nanogram quantitites of Allergen- specific serum IgE

ADCC
Fc Receptors
bind C region of Ig

Release of cytotoxic substances

like perforins & granzymes

Target cell
(virus- infected
cell)

Antibodies

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Diseases associated with Type II

Hypersensitivity Reaction
Transfusion Reaction

Antibodies to ABO Ags

(Isohemagglutinins)
IgM class
A ag Anti B ab
B ag Anti A ab
O ag .. Anti A + Anti B
AB ag. None

Diseases associated with Type II

Hypersensitivity Reaction
Erythroblastosis fetalis

Incompatible Transfusion
ABO Blood Group Antigens

Ag- Ab Reaction between

Donor ags and Recipient Abs
Immune Complex formation

Intravascular Hemolysis

Classical Pathway of Compl Activation

Effect of treatment with Anti- Rh antibody

Diseases associated with Type II

Hypersensitivity Reaction
Drug- Induced Hemolytic Anemia

Anti- Rh antibody

Certain Antibiotics
(Penicillins, Cephalosporins, Streptomycin)
bind to proteins on RBCs
Antibodies produced
against the drug- protein
complex
Immune Complex formation on RBCs
Classical Pathway of Compl Activation

Type III Hypersensitivity: Immune

Complex mediated Hypersensitivity
Localised

Hemolytic Anemia

Type III Hypersensitivity: Pathogenesis

Systemic

Immune complex deposition Immune complex formation

near the site of antigen
in blood and deposition in
entry.
distant tissues
-- Skin (injected antigens)
-- Blood Vessel walls
-- Lungs (inhaled antigens)
-- Glomerulus
-- Synovial memb of jts.
-- Choroid plexus of brain
Arthus reaction
Serum Sickness
Infiltration of neutrophils at the site of IC deposition
Tissue damage from granules released from neutrophils

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Diseases associated with Type III

Hypersensitivity Reaction
Localised

Insect 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

Type IV Hypersensitivity Reaction

Sensitization phase
Antigens derived from
intracellular bacteria in
APCs ....

Systemic

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

Effector phase

APC
Langerhans cells;
Macrophages

Presented by APCs
to CD4+ Th cells ..
Cytokines

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

Hallmark of Type IV Hypersensitivity

Repeat exposure of antigen

to sensitized Th1 cells ...
ActivatedTh1 cells ..
Secretion of a range of cytokines
(IFN, TNF, TNF, IL-2, GM-CSF)
& chemokines (IL-8, MCAF, MIF).
Localized inflammation with
Recruitment and activation of
macrophages ( ed expression
of MHC Class II molecules;
TNF Receptors; Oxygen radicals;
Nitric Oxide)

GRANULOMA formation

Macrophages differentiate into

Epithelioid cells & Giant cells

Diseases associated with Type IV

Hypersensitivity Reaction

Pathological Hallmark: Granuloma

(lytic enzymes from Mes leading to tissue necrosis)
Clinical correlate: Induration

Diseases associated with Type IV

Hypersensitivity Reaction
Contact Dermatitis

Tuberculin Reaction
Intradermal Injection in forearm
Tubercular antigens (M tb culture filtrate,
Old Tuberculin, PPD) .

48 hours later
Localized inflammation with Induration