- Outline 5 examples of type I hypersensitivity related conditions
- Allergic rhinitis/sinusitis
- Allergic urticaria
- Non-complement related Angioedema (Allergic angioedema)
- Food Allergy
- Bronchial Asthma
- Insect Bites
- Anaphylaxis
- Describe in details the mechanism of Hypersensitivity Type I reaction
- Sensitization
- APC (Macrophage, DC) present allergen
- Activated Th2 secretes IL-4, IL-5, IL-13
- B-cells Class switching to IgE
- IgE binds to high affinity Fc receptors on Mast cells
- Re-exposure
- Re-exposure to antigen causes cross-linking of IgE on mast cells
- Release of mast cell mediators
- Immediate phase
- Release of vasoactive amines (preformed mediators) and metabolites of arachidonic acid, vasodilation, vascular permeability and transient contraction of smooth muscles
- Histamine (and vasoactive amines): vasodilation, increased vascular permeability, transient contraction of smooth muscles
- Prostaglandins: Vasodilation
- Leukotrienes: Prolonged smooth muscle contraction
- Proteases: damage to local tissues
- Late phase
- Recruitment of neutrophils and eosinophils to the site over many hours, tissue damage
- Mast cell derived TNF, IL-4, Il-5: promote neutrophil and eosinophil rich inflammation
- Mast cell and epithelial cell derived chemokines: leukocyte recruitment
- Th2 derived IL-5: activates eosinophils
- Proteases: liberated by eosinophils and neutrophils, cause tissue damage
- Sensitization
- Write short notes on the clinical presentation and pathogenesis of extrinsic asthma
- Clinical presentation
- Acute attacks: Cough, dyspnea, and wheezing
- Resolves with bronchodilator therapy
- Sensitization
- Antigen presentation to CD4+ T-cell
- Activation, proliferation and differentiation to Th2 cells
- Th2 cells secretes IL-4, IL-5 and IL-13
- Class switching to allergen specific IgE by plasma cells
- Allergen specific IgE binds to high-affinity receptors on mast cells (and basophils)
- Second exposure
- Inhalation of antigen
- Cross linking of allergen specific IgE molecules on mucosal mast cells
- Rapid degranulation and release of mediators
- Early phase reaction
- Bronchoconstriction within several minutes
- Histamine, PGD2, LTCD, LTD4, LTE4: contract airway smooth muscle directly or via reflex neural pathways
- Late phase reaction
- Occurs several hours later, influx of Monocytes, neutrophils, eosinophils, basophils
- Mechanisms of airflow limitation
- Contraction of airway smooth muscle due to direct effects of contractile mediators (LTC4, D4, E4, Histamine) release from inflammatory cells or reflex neural mechanisms
- Thickening of airway wall due to edema or cellular components
- Plugging of airways with mucus or cellular debris
- Airway remodelling
- Bronchial Hyperresponsiveness (BHR)
- Represents an exaggerated constrictor response to a variety of physical, chemical, or environmental stimuli
- Enhanced sensitivity by smooth muscle cells to chemical mediators and neural pathways leading to bronchoconstriction
- Airway remodelling
- Structural changes in airways that may cause irreversible airflow limitation
- Epithelial damage: loss of the normal pseudostratified structure of airway epithelium
- Fibrotic thickening of the sub-epithelial basement membrane
- Increased numbers of myofibroblasts
- Increased vascularity
- Increased airway smooth muscle mass
- Increased extracellular matrix
- Structural changes in airways that may cause irreversible airflow limitation
- Clinical presentation
- Outline the cells involved and their role in Hypersensitivity type I reactions
- Eosinophils
- (Lipid mediators) LTC4, LT4D, LTE4 and Platelet activating factor: Mediate smooth muscle contraction, neutrophil chemotaxis
- (Toxic granule products) Major basic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, eosinophil carionic protein: damage airway epithelium
- (Cytokines) GM-CSF, TGF-a, TGF-b, ILs: airway remodelling and fibrosis
- Mast cells
- Histamine, Prostaglandin, Leukotrienes: Bronchoconstriction
- TNF-a: important in the recruitment and activation of inflammatory cells, and in altered function and growth of ASM
- Th2 lymphocytes
- IL-3: survival factor for eosinophils and basophils
- IL-4: helps in differentiation of uncommitted T cells into Th2 cells, B-cell class switch to IgE
- IL-5: major hematopoietic cytokine regulating eosinophil production and survival
- IL-13:Simulates mucous gland hyperplasia, airway fibrosis, and remodelling
- GM-CSF: Survival factor for eosinophils
- Epithelial-mesenchymal contribution
- FGF-2, IGF-1, PDGF, ET-1, TGF-B2: acts on smooth muscle cells and fibroblasts to enhance matrix deposition
- Eosinophils
- Describe in details, the role of mast cells in Hypersensitivity type I reaction
- Binds to IgE via High affinity Fc receptors (Sensitization)
- Re-exposure to antigen causes cross-linking of antigen specific IgE molecules on the surface and degranulation
- Contribute towards the early phase and late phase reactions
- Mediators produced
- Histamine (and vasoactive amines): vasodilation, increased vascular permeability, transient contraction of smooth muscles
- Prostaglandins: Vasodilation
- Leukotrienes: Prolonged smooth muscle contraction
- Proteases (Tryptase, Chymase): damage local tissue
- Describe the process of recruitment, activation and role of eosinophils in the pathophysiology of atopic asthma
- Recruitement and activation
- Recruitement and activation of eosinophils occurs during the late phase response of atopic asthma
- IL-5: recruites eosinophils
- Lipid mediators
- LTC4, D4, E4: smooth muscle contraction
- Platelet activating factor: smooth muscle contraction
- Toxic granule products – damages airway epithelium
- Major basic protein
- Eosinophil-derived neurotoxin
- Eosinophil peroxidase
- Eosinophil cationic protein
- Cytokines – stimulate airway remodelling and fibrosis
- GM-CSF, TGF-a, TGF-b, ILs
- Recruitement and activation
- What is the treatment of immediate hypersensitivity
- Aim is to inhibit mast cell degranulation, antagonize the effects of mast cell mediators, and reduce inflammation
- Antihistamine, Leukotriene inhibitors
- Epinephrine (anaphylaxis)
- Corticosteroids: inhibits inflamamtions
- Allergen-specific immunotherapy (desensitization): repeated administration of small doses of allergens, reduces Th2 dominance and antibdy response away from IgE by inducing tolerance in allergen-specific T-cells, or by stimulating Treg
- Briefly describe Allergic rhinitis and sinusitis
- Common in hay fever (pollen induced rhino-conjunctivitis),
- reaction to inhaled allergens (protein of ragweed pollen)
- Histamine: from mast cells, increase mucus production
- IL-13: from mast cells, increase mucus production
- Late-phase reaction: may lead to more prolonged inflammations
- Briefly describe Allergic urticaria and angioedema
- Urticaria is characterized by itchy wheals, angioedema or both
- aka IgE mediated or allergic urticaria
- Wheals: urticarial lesions resulting from localized edema of the upper dermis
- Angioedema: pronounced swelling of deeper dermal layers and Subcutaneous and submucosal tissue
- Examples
- Food and drug induced urticaria
- Latex induced urticaria
- Generalized allergic urticaria (progress to anaphylaxis)
- Role of skin mast cells
- Predominantly located around small blood vessels and lymphatics, as well as around or within peripheral nerves
- Preformed mediators: Histamine, proteases (tryprase, chymase), and heparin
- Express high-affinity Ige receptors (FceRI)
- What is the differential diagnosis of Allergic urticaria and angioedema
- Urticarial vasculitis
- Hereditary angioedema (HAE)
- Autoinflammatory syndromes presenting with urticarial rash
- Briefly describe Food allergy
- Common allergens
- Cow’s milk
- Hen’s egg
- Peanut
- Tree nuts (cashew and wall nuts)
- Wheat
- Soy, Fish and crustacean shellfish
- Signs of acute
- Common allergens
- Briefly describe Anaphylaxis
- Anaphylaxis is a severe, life-threatening, systemic reaction of sudden onset and involves
- Respiratory compromise
- Cardiovascular collapse
- OR BOTH
- It is caused by widespread mast cell degranulation in response to systemic distribution of the antigen.
- Predisposition: Upto 20% of patients with systemic mastocytosis present with anaphylaxis during their lifetime
- Anaphylaxis is a severe, life-threatening, systemic reaction of sudden onset and involves
- List common allergens known to cause anaphylaxis
- bee sting
- drugs
- ingested nuts or shellfish
- food
- latex
- Rare causes: vaccines, semen, aeroallergen inhalation, exercise-induced anaphylaxis
- What are the clinical features of anaphylaxis
- Skin and mucous membranes: Generalized urticaria and angioedema
- Respiratory: Rhinitis, laryngeal edema, airway obstruction, dyspnea
- Cardiovascular**: Hypotension, Cardiac arrhythmias, tachychardia** (increased cardiac sympathetic drive secondary to a decrease in effective vascular volume), bradychardia may occur
- Describe the laboratory management of anaphylaxis
- Measurement of plasma tryptase
- Beta tryptase: released from mast cells, diffuses more slowly compare to histamine, conc peaks 1-2H post onset, half-life of 1.5 to 2.5 hours
- How is anaphylaxis managed
- Epinephrine: a and b adrenergic agonist
- a1: vasconstriction- increasing Peripheral Vascular Resistance
- B1: positive ionotropy and chronotropy
- B2: bronchodilation and decreased release of inflammatory mediators from mast cells and basophils
- Epinephrine: a and b adrenergic agonist
- Briefly describe the In-Vivo tests used to diagnose Type I Hypersensitivity reactions
- Provocation Tests: Gold standard, usually follow negative skin tests, oral, intravenous, nasal, bronchial or conjunctival, expensive, risk anaphylaxis, can only perform one allergen at a time
- Allergy Skin Tests: Risk systemic reaction, associated with discomfort, inhibited if on antihistamines, cannot be used in patients that cannot discontinue antihistamines, rapid, sensitive and specific, safe and relatively inexpensive
- Skin prick test (SPT): Prick the skin in the presence of a dilute solution of the egg allergen, compared to positive control of saline
- Intradermal test (IDT): Inject a tiny quantity of allergen into the dermis with a hypodermic needle (Actually CONTRAINDICATED IN FOOD TESTS)
- Skin Patch test (PT)
- Briefly describe the In-Vitro tests used to diagnose Type I Hypersensitivity reactions
- Require single venipuncture, staff do not need to be trained to perform them, no risk of anaphylaxis, not affected if patient takes antihistamine, enzyme immunoassays are sensitive and specific, more expensive than sin tests on a per test basis, result turn around time is prolonged relative to skin test
- Serum Allergen-specific IgE: Allergen specific-IgE bind to allergen on solid phase and are detected using an enzyme-conjugated anti-IgE
- Basophil Activation test: quantifies the expression of activation markers (CD36) on basophil surface in whole blood by flow cytometry on allergen stimulation
- Serum (Plasma) Tryptase: Elevated tryptase occurs in anaphylaxis ad in systemic mastocytosis, reflects increased burden of mast cells in patients with all forms of systemic mastocytosis
- Require single venipuncture, staff do not need to be trained to perform them, no risk of anaphylaxis, not affected if patient takes antihistamine, enzyme immunoassays are sensitive and specific, more expensive than sin tests on a per test basis, result turn around time is prolonged relative to skin test
A 14 year old male presented at Thika Level 5 Outpatient Department with a history of an insect bite earlier during the day. The mother suspects it was a bee sting. He has left upper eyelid swelling (which is the suspected foci of the insect bite) and generalized pruritus with wheals. The reason for rushing him to hospital was that he suddenly developed difficulty in breathing. His blood pressure at casualty was 71/46mmHg
- What is the Diagnosis? (3)
- Anaphylaxis secondary to bee sting.
- Manifests as respiratory compromise (dyspnea) and hypotension
- What is the possible mechanism of the condition listed in part 1 above (10)
- Sensitization
- APC (Macrophage DC) present mellitin (allergen)
- Activated Th2 secretes IL-4, IL-5, IL-13
- B-cells Class switching to IgE
- IgE binds to high affinity Fc receptors on Mast cellls
- Re-exposure
- Re-expoure to antigen causes cross-linking of IgE on mast cells
- Release of mast cell mediators
- Immediate phase
- Release of vasoactive amines (preformed mediators) and metabolites of arachidonic acid, vasodilation, vascular permeability and transient contraction of smooth muscles
- Histamine (and vasoactive amines): vasodilation, increased vascular permeability, transient contraction of smooth muscles
- Prostaglandins: Vasodilation
- Leukotrienes: Prolonged smooth muscle contraction
- Proteases: damage to local tissues
- Late phase
- Recruitment of neutrophils and eosinophils to the site over many hours, tissue damage
- Mast cell derived TNF, IL-4, Il-5: promote neutrophil and eosinophil rich inflammation
- Mast cell and epithelial cell derived chemokines: leukocyte recruitment
- Th2 derived IL-5: activates eosinophils
- Proteases: liberated by eosinophils and neutrophils, cause tissue damage
- Sensitization
