Aims
• Explain the mechanisms of hypersensitivity reactions.
• Define anaphylaxis
• Readings: Abbas & Lichtman, Chapter 11
Hypersensitivity
• Hypersensitivity reactions refer to adaptive immune responses that occur in exaggerated or inappropriate forms and result in disease.
• Four types of hypersensitivity reactions.
Pathologic immune Mechanism ofType of hypersensitivity mechanism tissue injury
Type I - IgE antibody mast cell immediate hypersensitivity degranulation(hay fever, asthma)
Adapted from Abbas & Lichtman’s Basic Immunology 11-1
Type I
Immediate Hypersensitivity
Pathologic immune Mechanism ofType of hypersensitivity mechanism tissue injury
Type II - IgG or IgM bound to C’ activationantibody-mediated host cells phagocyte cytotoxic or cytolytic reactions activity(HDN, transfusion reactions, abnormalities in autoimmune) membrane
receptor functions
Adapted from Abbas & Lichtman’s Basic Immunology 11-1
Type II
Antibody-mediated
Pathologic immune Mechanism ofType of hypersensitivity mechanism tissue injury
Type III - Deposition of IgG or C’ activationImmune complex-mediated IgM IC phagocyte activity(Arthus reaction, serum sickness)
Adapted from Abbas & Lichtman’s Basic Immunology 11-1
Type III
Immune complex-mediated
Pathologic immune Mechanism ofType of hypersensitivity mechanism tissue injury
Type IV - Activation of CD4+ M activation
Delayed hypersensitivity and CD8+ T cells CTL lysis of cells(PPD, contact dermatitis)
Adapted from Abbas & Lichtman’s Basic Immunology 11-1
Type IV
T cell-mediated
Type I Hypersensitivity“Immediate Hypersensitivity”
• Biologic role in the control of helminth infections (schistosomiasis).
• Reactions include:– Hay fever– Food allergies– allergic asthma– ___________________________________
Predisposing Factors to Type I Reactions
• Type of allergens
• Route of exposure
• Genetic predisposition
• Age
Airborne Allergens
• Low dose antigens.
• Can become airborne due to small size (10-40 µm in diameter).
Pollen
fecal pellets
Dust mite
Adapted from Roitt’s Immunology 15-4
Pathogenesis of Type I
• IgE- mediated– Due to low dose
antigen resulting in CD4+ T cells differentiating into IL-4 producing TH2 cells.
– IL-4 enhances the growth of B cells and induces their class switch from IgM to IgE.
Abbas & Lichtman’s Basic Immunology 11-2
Pathogenesis of Type I
• Initial Exposure• IgE binds to high-affinity Fc receptors on mast cells and
basophils. • Repeat Exposure• Allergen is multi-valent meaning it can bind multiple
IgEs at the same time.• Mast cell and basophil are activated.
Abbas & Lichtman’s Basic Immunology 11-2
Pathogenesis of Type I
• Activated cell releases:• ____________________
– constricts bronchial and intestinal smooth muscle.
– Increases vascular dilation and permeability.
– Causes sneezing, itching (pruritis), and runny nose (rhinorrhea).
Adapted from Abbas & Lichtman’s Basic Immunology 11-4
Pathogenesis of Type I
• Activated cell releases:• Leukotrienes and
Prostaglandins– generated from membrane
phospholipids.
– Prolonged bronchial constriction.
– Vasodilation.
Adapted from Abbas & Lichtman’s Basic Immunology 11-4
Pathogenesis of Type I
• Activated cell releases:• Cytokines
– IL-4
– IL-5• Eosinophil activation.
– TNF
Adapted from Abbas & Lichtman’s Basic Immunology 11-4
Clinical Manifestations of Type 1 Hypersensitivity
• Mild local – “wheal and flare”
• Mosquito bite
– nasal congestion– Pruritis (itching)– Rhinitis– Conjunctivitis– Asthma
Allergic Asthma
• Mast cell activation resulting in:– ________________________________________.– Increased inflammation and mucus.– Chronic bronchospasm.
Adapted from Roitt’s Immunology 21-22
Clinical Manifestations of Type 1 Hypersensitivity
• Mild systemic– generalized pruritis
(itching)– urticaria (hives)– Nausea– Vomiting– Diarrhea
Roitt’s Immunology 26-2
Clinical Manifestations of Type 1 Hypersensitivity
• Anaphylaxis – Extreme systemic form of Type I hypersensitivity reaction– Immediate reaction (<20 minutes).– Can be local reaction or general leading to fall in blood
pressure due to vasodilation and edema, airway obstruction and broncospasm.
Adapted from Roitt’s Immunology 21-2
Clinical Manifestations of Type 1 Hypersensitivity
• Severe anaphylaxis - laryngeal edema, hypotension, shock, bronchospasm, cardiac arrhythmia, arrest and death.
– Three possible outcomes that can lead to death:• asphyxiation from laryngeal edema.• suffocation from bronchiolar
constriction/contraction• loss of adequate blood pressure from an
overwhelming edema
Review of Normal Sequence of Events
1 Exposure to allergen2 Th2 activation and IgE production3 IgE binds to mast cell Fc receptors4 2nd exposure to allergen5 Allergen binds to mast cell-associated IgE6 Signal transduction 7 Mediator release (e.g. histamine)8 End organ effects of mediators
Sensitization phase
Activation phase
Effector phase
Management of the Allergic Patient
• Identify the allergen(s):– in vivo challenge tests
– in vitro tests
Management of the Allergic Patient
• Environmental intervention• Pharmacological intervention
– antihistamines– corticosteroids– epinephrine
• Hyposensitization therapy– blocking antibodies – Th2 to Th1 switch– specific suppressor T cells
Type II Hypersensitivity“Antibody-Mediated”
• Caused by _____________________________ antibodies against cell and tissues.
Adapted from Abbas & Lichtman’s Basic Immunology 11-7A
Effector Mechanisms of Type II Hypersensitivity
• Binding of antibody induces inflammation.– By attracting and activating leukocytes.
• Via Macrophages and neutrophils Fc receptors.
– By activating the classical pathway of the complement cascade.
Abbas & Lichtman’s Basic Immunology 11-8A
Effector Mechanisms of Type II Hypersensitivity
• Binding of antibody to cells results in opsonization and phagocytosis.– Through phagocytic cells Fc receptor.– Through phagocytic cells C3b receptor.
Abbas & Lichtman’s Basic Immunology 11-8B
Effector Mechanisms of Type II Hypersensitivity
• Binding of antibody interferes in normal cell functions.– Binding to receptors resulting in their stimulation
(Graves disease).– Binding to receptors resulting in their inhibition
(Myasthenia Gravis).
Abbas & Lichtman’s Basic Immunology 11-8C
Next Time
• Compare and contrast the ABO and Rho(D) alloantigens.
• Describe an Arthus reaction.• List the cells involved in a DTH response.• Describe ocular immune privilege• Describe the role Anterior Chamber Associated
Immune Deviation (ACAID) is believed to play in an ocular immune response.
• Readings: Abbas & Lichtman, Chapter 11