Lec 10-Hypersensitivity I Flashcards
Undesirable effects
-Many disease and conditions are caused by inappropriate immune responses
Response to
-Innocuous Ag- Allergies
-Self- Autoimmunity
-Transplants- Rejection different Ag being present on organ
Hypersensitivity
-Increasing incidence in the developing world
Why
-Clean world (hygiene, vaccination and antibiotics)
-Poor development of immune system
-Immune system less able to deal with proper infections
-Responds to imaginary foes
What is hypersensitivity
- An over reaction of the adaptive immune system
- First exposure= sensitisation
- Repeated exposure= reaction (very strong)
- This is similar to how vaccines work
- Ag are often common e.g. pollen, dust mite poo
- 10-40% of people in developed countries are allergic to 1+ environmental Ag’s
Common sources of allergens
Inhaled materials -Plant pollen -Mold spores -Feces of dust mites Injected materials -Insect venoms -Vaccine -Drugs Ingested -Food -Oral drugs- penicillins Contacted materials -Plant leaves -Synthetic chemicals -Metals
Hypersensitivity reactions
- Grouped according to effector mechanism that generate the reactions
- Some Ag cause different types of reaction depending on how they are encountered
- 4 types: classified by Coombs and Gell
Four classes of hypersensitivity
1-3
-Allergies are type 1
-Types I-III are Ab mediated
Type I
-IgE, soluble Ag, mast cell activation
-Occurs in Allergic rhinitis, asthma and anaphylaxis
Type II
-IgG
-Cell or metric Ag or cell surface receptor
-Complement FcR cells (phagocytes, NK cells) or Ab alters signalling
-Some drug allergies or Rash
Type II
-IgG, soluble Ag, complement phagocytosis, Serum sickness, Arthus reaction
Four classes of hypersensitivity
4
Th1 cells -Soluble Ag, macrophage activation -Contact dermatitis, tuberculin Th2 cells -Soluble Ag, eosinophil activation -Chronic asthma, allergies CTL -Cell-associated Ag, cytotoxicity -Contact dermatitis
Type 1 hypersensitivity
-Immediate-type hypersensitivity
-Ab (IgE) mediated
-Soluble Ag
-Effector mechanism- mast cell degranulation
Allergy
+The symptomatic reaction to innocuous Ag
Atopy- Tendency in susceptible individuals to produce immediate hypersensitivity reactions against innocuous Ag
IgE
-Protection against parasites (in the less developed world were paracites are more common there are less allergies)
+Developed world-parasites rare; allergies common
-Present in tissue
-Sensitise mast cells
+Poor opsonising, neutralising function (cross linking)
+Binds to Fc’epsilon’R1 (Very high affinity Receptor)- also on basophils and activated eosinophils
Mast cells
-Contains preformed inflammatory mediators (granules
-Trigger miscelar contraction for physical expulsion from lungs or gut
-Carry Fc’epsilon’R1
+Rapid response (Unlike B and T cells)
-Multi-tasking-each cell can carry multiple IgE
-There is a length Ag where multiple IgE can bind to it, with multiple Ab binding to the mast cells this causes degranulation
Inappropriate response
-Primary exposure \+sensitisation \+Ab response --> \+IgE binds mast cells via Fc'epsilon'RI \+No problem... yet -Repeated exposure- Allergen cross-links Fc'E'RI -Degranulation
Mast cell activation
1) Enzyme- Tryptase; chymase; Cathepsin G; carboxypeptidase
-Remodelling of connective tissue metrix
-Activate other enzymes–> MMP (metric metallo proteases)
-Breakdown metric and cause tissue destruction
2) Toxic mediator- Histamine, heparin
-Toxic to paracites, increase vascular permeability, cause smooth muscle contraction
3) Chemokine- CCL3- chemotactic for monocytes, macrophages and neutrophils
4) Lipid mediators
-LT C4,D4,E4
-Cause smooth muscle contraction, increase vascular permeability, mucus secretion
+Platelet activating factor
+Chemotactic for leukocytes
+Amplifies production of lipid mediators
+Activates neutrophils, eosinophil, platelets
Mast cell activation-5) Cytokines
TNF-a
-Promotes inflammation, stimulates cytokine production by many cell types, activates endothelium
IL-4, 13
-Stimulates and amplify Th2 cell response
IL-3, 5, GM-CSF
-Promote eosinophil production and activation
Histamine
- Toxic mediators
- Very rapid release
- Short-lived vasoactive amine
- Increases permeability of vessels (endothelial cell) = swelling
- Smooth muscle contraction
- Mucus secretion (airway mucosa)
Cytokines and chemokine
- Range of function
- Promotes- inflammation
- IgE production
- Amplify Th2
Lipid mediators
- PGd2 and PGe2
- LTb4, LTc4
- Cause many symptoms
Eosinophils
-Granulocytes
-Few in circulation
-Activation= increase in Fc’E’RI degranulation
-Hypereosinophilia can lead to tissue damage
-Presence indicates inflammation
Mast cell, basophils and eosinophils can amplify IgE response
Basophils
-Granulocytes- similar to mast cells
-Few in circulation
-Secrete Th2 cytokines
+IL-4, 13
+Polarise T cells to Th2
-Promotes class switching to IgE
Mast cell, basophils and eosinophils can amplify IgE response
Allergic reactions mediated by IgE
1) Systemic anaphylaxis: Allergens= drugs, serum, venom, food
- Route of entry: IV (following oral)
- Response:edema, vascular permeability, laryngeal edema
2) Acute Urticaria (wheel and flare): Animal hair, insect bites
- route of entry: Skin
- Local increase in blood flow and vascular permeability
3) Hayfever: Pollens
- Inhalation
- Edema of nasal, Mucosa, sneezing
4) Asthma: Dander; pollen; mite feces
- Inhalation
- Bronchial constriction, increases mucus, airway inflammation
5) Food allergy: milk, eggs, fish
- Oral
- Vomiting, diarrhoea, pruritus (itching), anaphylaxis
Allergen characteristics
-Most allergens are small, stable, soluble, proteins, often proteases
+Pollen grains, animal dander, HDM faeces
+Drugs modify proteins
-Once inhaled/Ingested particles rehydrate in mucus, from here it can bind to receptors
-Antigens processed and presented to CD4 Th cells- stimulate Th2 response- IgE
+Driven by IL4 from basophils
->20% allergies are to the cysteine protease from HDM
What happens (sensitisation)
- 1st exposure
- Extraction of Ag
- Activation of Ag specific T cells
- Production of IgE and binding to mast cells on Fc’E’RI
Early v Late
Immediate reaction
-Effects of histamine, PG and other pre-made or rapidly synthesised mediators
Late-phase reaction
- In up to 50% of patients
- Effects of induced synthesis of mediators (cytokines) causing inflammation
Allergic reactions have 2 phases
Immediate phase- wheal and flare- mast cells degranulation; histamine
-Late phase is 6-8 hours later (this is bad because they may have recovered from immediate and may be away from help) - more widespread welling; LT and cytokines
-Asthma- allergic reaction to inhaled allergen
+Breathing tests to diagnose
+Late phase reaction is more damaging- leads to chronic inflammation
Allergic asthma
-L/min of O2
Immediate: at optimum then goes to its lowest point but after 45 minutes it is returned to normal
Late phase: At optimum then lowers (not as low as immediate about 3/4) but the level of O2 stays low for hours as oppose to minutes for immediate so late phase is more severe
Allergic reactions vary by site
- mast cell activation and granule release
1) GI tract- increased fluid secretion, increased peristalsis - Expulsion of GI tract contents (vomiting and diarrhoea)
2) Airways- decreased diameter, increased mucus secretion - Expulsion of airway contents (Phlegm, coughing)
3) Blood vessels- increased blood flow, increased permeability - Oedema, inflammation, increased lymph flow and carriage of Ag to lymph nodes
- This is systemic
Allergens in blood can cause systemic anaphylaxis
-Stings, food and drugs can call cause anaphylaxis
-Disseminated mast cell activation
-Rapid
+Systemic effects
+Increased vascular permeability –> hypotension –> Shock
+Smooth muscle contraction –> bronchiole constriction –> swelling of epiglottis –> Asphyxiation
-Rare: many may be at risk
-Treat with adrenaline
+reduces vascular permeability
+Relaxes constricted smooth muscle
+Stimulates the heart
-Penicillin allergy
+ B-lactam ring opens, modifies proteins, IgE response
Allergen in blood can cause systemic anaphylaxis
- Ag in bloodstream enters tissues and activates connective tissue mast cells throughout the body
- Mast cell degranulation and release of inflammatory mediators this effects
1) Heart and vascular system: Increased capillary, permeability and entry of fluid into tissues - Swelling of tissues including the tongue
- Loss of blood pressure
- Reduced O2 to tissue
- Irregular heartbeat
- Anaphylaxtic shock
2) Respiratory tract- contraction of smooth muscle and constriction of throat and airway - Difficulty in swallowing
- Difficulty in breathing wheezing
3) GI tract- Contraction of smooth muscle - Stomach cramps
- Vomitting and diarrhoea
- Fluid outflow into gut
Clinical effects- localised
Allergic Rhinitis
- Hayfever
- Airborne allergens
- Sensitised mast cells in nasal and conjunctival mucosal
- Sneezing, coughing, exudate
Allergic Rhinitis
- Allergens enter the respiratory tract, Ag activates mucosal mast cells
- Mast cell degranulation
- Histamine affects capillaries and epithelium
- Eosinophils are attracted and activated
- Mucus production and oedema
Clinical effects localised- asthma
- Mast cells of lower respiratory tract
- Broncho-constriction
- Airway oedema, mucus secretion, inflammation
- Mucosal mast cell captures Ag
- Inflammatory mediators contract, smooth muscle, increase mucus secretion from airway epithelium and increase blood vessel permeability
- Chronic response mediated by cytokines and eosinophil production
Asthma
- Mucus plug in bronchus
- They cannot breath
Clinical effects localised- Atopic dermatitis (allergic eczema)
- Skin inflammation
- Common presentation in families with atopy
- Subcutaneous Ag, low dose
- Mast cell activation
- Increased vascular permeability leads to localised swelling
Clinical effects localised- food allergies
- Mast cells of upper or lower GI tract
- Smooth muscle contraction
- Allergen to blood stream –> asthma; urticaria (Hives)- allergen carried elsewhere to sensitised mast cells
- Rarely anaphylaxis
- Ingestion of Ag activates mucosal mast cells
- Activated mast cells release histamine, which acts on epithelium, Blood vessels and smooth muscle
- Ag diffuses into blood vessels and is widely disseminated causing urticaria; smooth muscle concentration induces vomiting and diarrhoea
3 approaches to treating allergy
1) prevention- modify behaviour or environment to avoid contact with allergen
2) Pharmacology- Anti-inflammatory drugs
- Anti-histamine (block histamine receptors)
- Corticosteroids (suppress leukocyte function)
- Sodium cromoglycate (Mast cell stabilisers)
- Adrenaline
3) Immunology- prevent IgE production by shifting to IgA or IgG production
- Desensitisation (Controlled allergen exposure)
