Hypersensitivity Reactions

• Gell and Coombs classification:– Type I – IgE mediated (allergy)– Type II – Antibody-mediated cytotoxic– Type III – Immune Complex mediated– Type IV – Delayed-Type Hypersensitivity

(DTH)• Types I, II and III are “immediate”• Type IV is delayed

Type I Hypersensitivity

• Antigens are called “allergens”• Unknown why people get allergies, but there is a

strong genetic predisposition (called atopy)• Hallmark is inappropriate production of IgE

against allergens that cause mast cell degranulation (see fig 15-2)

• Normally IgE/mast cell activity should be directed against parasitic infections

Type I Hypersensitivity

• Mediators of Type I hypersensitivites– Mast cell granule contents (early effects)

• Histamine and Heparin - ↑ vascular permeability, smooth muscle contraction (intestines, bronchi), mucus secretion

• Chemotactic factors – attract eosinophils and neutrophils• Proteases – mucus secretion, complement activation,

degradation of blood vessel basement membrane

– Later Effects• Leukotrienes and prostaglandins – secreted after tissue

disruption caused by mast cell degranulation, effects are similar to histamine

• Arrival of proinflammatory eosinophils and neutrophils

Clinical Manifestations of Type I• Systemic anaphylaxis

– Allergen gets into the blood stream– Dyspnea, ↓BP, bronchole constriction, GI and bladder

smooth muscle contration, shock, death within minutes if untreated

– Treatment - epinephrine• Allergic rhinitis (hay fever)

– Inhaled allergen triggers reaction in nasal mucosa– Watery exudate from nose, eyes, upper respiratory

tract, sneeezing and coughing

Clinical Manifestations of Type I• Asthma

– Allergic asthma – due to inhaled airborne allergens (pollens, dust, fumes, etc)

– Intrinsic asthma – triggered by cold, exercise– Reaction develops in lower respiratory tract– Bronchoconstriction, airway edema, mucus secretion,

inflammation• Food allergies

– Ingestion of allergen– Vomiting and diarrhea– If allergens are absorbed into bloodstream, reactions can occur

where allergen deposits• asthma-like symptoms• Urticaria (hives, wheal & flare response)

Clinical Manifestations of Type I

• Atopic Dermatitis (allergic eczema)– Often occurs in young children– Red skin rash– Strong hereditary predisposition

Type I Hypersensitivity• Skin testing

– Potential allergens are injected or scratched into the skin

– If the patient is allergic a wheal & flare response occurs

• RIST –radioimmunosorbent test – similar to RIA, non-invasive way to identify allergies

Type I Hypersensitivity

• Treatment– Avoid allergen if possible– Antihistamines, or anti-prostaglandins– Hyposensitization – injections of low doses of

allergen may cause a shift from IgE to IgG as the dominant antibody formed.

Type II Hypersensitivity

• Antibody-mediated Cytotoxic HS– Antibodies (IgM or IgG) bind to cell surface

antigens. Antigen/antibody complex may lead to:

• Complement activation lysis• ADCC• Opsonization phagocytosis

– These are normal reactions, but when they cause unwarranted tissue damage, they are considered a hypersensitivity.

Type II Hypersensitivity

• Examples of Type II HS:– Transfusion reactions

• To ABO blood groups• To other RBC blood groups

– Hemolytic disease of the newborn (erythroblastosis fetalis)

– Drug-induced hemolytic anemia (penicillin)

Type III Hypersensitivity

• Immune Complex Disease– Antibody (IgG) / attaching to soluble antigen

leads to complex formation– Immune complexes may deposit in:

• Blood vessel walls (vasculitis)• Synovial joints (arthritis)• Glomerular basement membrane

(glomerulonephritis)• Choroid plexus

Type III Hypersensitivity• Damage occurs due to:

– Anaphylatoxin release due to complement activation (C3a, C5a) which then attracts neutrophils, and causes mast cell degranulation

– Neutrophils have trouble phagocytosing “stuck” immune complexes so they release their granule contents leading to more inflammation

– Platelet aggregation also results from complement activation

• These effects are also known as the Arthus reaction

Type III Hypersensitivity

• Localized reactions– edema and redness (erythema) and tissue

necrosis of the affected tissue– Can occur in the skin following insect bites– Can occur in the lungs

• E.g. “farmer’s lung” from inhaling particles from moldy hay

Type III Hypersenstivity

• Generalized reactions:– Serum sickness (following treatment with

antiserum to a toxin)– Autoimmune diseases

• SLE• Rheumatoid arthritis

– Drug reactions (penicillin)– Infectious diseases

• Meningitis, hepatitis, malaria, mono etc.

Type IV Hypersensitivity

• Delayed type hypersensitivity (DTH)– TH cells that have been “sensitized” by an antigen

develop a TH1 and (sometimes a TC response) leading to macrophage recruitment and activation.

– First noticed with reaction to tuberculosis bacteria (tuberculin reaction)

– Hallmarks of type IV is the large number of macrophages at the reaction site, and that it takes an average of 24 hrs to manifest after repeat exposure.

Hypersensitivity ReactionsType I HypersensitivityType I HypersensitivitySlide Number 4Clinical Manifestations of Type IClinical Manifestations of Type IClinical Manifestations of Type IType I HypersensitivityType I HypersensitivityType II HypersensitivityType II HypersensitivityType III HypersensitivityType III HypersensitivityType III HypersensitivityType III HypersenstivityType IV HypersensitivitySlide Number 17