3 - Hypersensitivity and Allergies (19.02.2020) Flashcards
What should appropriate tolerance occur to?
Food, pollens, other plant proteins, animal proteins, commensal bacteria
What does appropriate immune tolerance involve?
- Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production
- Antigen recognition in context of “danger” signals leads to immune reactivity, absence of “danger” to tolerance
What are hypersensitivity reactions? What are the different types?
Hypersensitivity Reactions occur when immune responses are mounted against
- Harmless foreign antigens (allergy, contact hypersensitivity)
- Autoantigens (autoimmune diseases)
- Alloantigens (serum sickness, transfusion reactions, graft rejection)
What are the different types of hypersensitivity reactions?
Classified by Gell & Coombs:
Type I : Immediate Hypersensitivity
Type II : Antibody-dependent Cytotoxicity
Type III : Immune Complex Mediated
Type IV : Delayed Cell Mediated
Examples of Type 1 Hypersensitivity
=> immediate
Anaphylaxis Asthma Rhinitis - Seasonal - Perennial Food Allergy
Mechanism of Type 1 Hypersensitivity
Primary Antigen exposure
- Sensitisation not tolerance
- IgE antibody production
- IgE binds to receptors Mast Cells & Basophils
= IMMEDIATE HYPERSENSITIVITY
Secondary Antigen Exposure
- More IgE Ab produced
- Antigen cross-links IgE on Mast Cells/Basophils
- Degranulation
Mechanism of Type 2 Hypersensitivity
Clinical presentation depends on target tissue
- Organ-specific autoimmune diseases
- Myasthenia gravis (Anti-acetylcholine R Ab)
- Glomerulonephritis (Anti-glomerular basement membrane Ab)
- Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
- Pernicious anaemia (Intrinsic factor blocking Abs)
Autoimmune cytopenias (Ab mediated blood cell destruction)
- Haemolytic anaemia
- Thrombocytopenia
- Neutropenia
= ANTIBODY DEPENDANT HYPERSENSITIVITY
Test for specific autoantibodies
- Immunofluorescence
- ELISA eg anti-CCP (Cyclic Citrullinated Peptide Abs for Rheumatoid Arthritis)
Mechanism of Type 3 Hypersensitivity
- Formation of Antigen-Antibody complexes in blood
- Complex deposition in blood vessels/tissue
- Complement & cell activation
- Activation of other cascades eg clotting
- Tissue damage (vasculitis)
- Systemic lupus erythematosus (SLE)
- Vasculitides (Poly Arteritis Nodosum, many different types)
IMMUNE COMPLEX MEDIATED HYPERSENSITIVITY
Examples of Type 4 Hypersensitivity
Chronic graft rejection GVHD Coeliac disease Contact hypersensitivity (e.g. nickel) Many autoimmune diseases…. Asthma Rhinitis Eczema
Mechanism of Type 4 Hypersensitivity
Three Main Varieties
- Th1
- Cytotoxic
- Th2
Mechanisms
- Transient/Persistent Ag
- T cell activation of macrophages, CTLs
- Much of tissue damage dependent upon TNF & CTLs
=> DELAYED TYPE CELL MEDIATED HYPERSENSITIVITY
What is a common feature of hypersensitivity reactions?
Inflammation
- Immune cell
- recruitment to sites of injury and/or infection
- activation - Inflammatory mediators – complement, cytokines, etc
What are the features if hypersensitivity reactions?
- Vasodilatation, increased blood flow
- Increased vascular permeability
- Inflammatory mediators & cytokines
- Inflammatory cells & tissue damage
=> Redness, Heat, Swelling and Pain
Which molecules cause increased vascular permeability?
C3a, C5a, histamine, leukotrienes
Molecular aspects of inflammation>
Increased vascular permeability Caused by:- C3a, C5a, histamine, leukotrienes Cytokines IL-1, IL-6, IL-2, TNF, IFN-γ Chemokines IL-8/CXCL8, IP-10/CXCL10 Inflammatory cell infiltrate Cell trafficking – chemotaxis Neutrophils, macrophages, lymphocytes, mast cells Cell activation
What are the key inflammatory cytokines and chemokines?
Cytokines: IL-1, IL-6, IL-2, TNF, IFN-γ
Chemokines: IL-8/CXCL8, IP-10/CXCL10
CXCL - what do these molecules do?
recruit leukocytes usually
chemokines
Genetic risk factors for allergy
~80% of atopics have a family history
Polygenic
- 50-100 genes linked to asthma/atopy
- genes of IL-4 gene cluster (chromosome 5) linked to raised IgE, asthma, atopy
- genes on chromosome 11q (IgE receptor) linked to atopy and asthma
- genes linked to structural cells linked to eczema (filaggrin) and asthma (IL-33, ORMDL3, CDHR3)
Severity levels of allergic reactions
mild occasional symptoms
severe chronic asthma
life threatening anaphylaxis
Is allergy common?
yes
- prevalence of atopy is 50% in young adults in UK
Environmental risk factors for allergy
- Age - increases from infancy, peaks in teens, reduces in adulthood
- Gender - asthma more common in males in childhood, females in adults (sex hormones play a role but it is not yet understood)
- Family size - more common in small families (also e.g. first born is more likely to get allergy than a e.g. 6th born)
- Infections - early life infections protect
- Animals - early exposure protects
- Diet - breast feeding, anti-oxidants, fatty acids protect
What are the different types of inflammation in allergy?
Anaphylaxis, urticaria, angioedema
- type I hypersensitivity (IgE mediated)
Idiopathic/chronic urticaria
- type II hypersensitivity (IgG mediated)
Asthma, rhinitis, eczema:
- mixed inflammation
- type I hypersensitivity (IgE mediated)
- type IV hypersensitivity (chronic inflammation)
What is required to express allergy as a disease?
- Development of sensitisation to allergens instead of tolerance (primary response - usually in early life)
- Further allergen exposure to produce disease (memory response - any time after sensitisation)
What happens in sensitisation to an antigen in atopic airway disease?
- inhaled antigen
- taken up by dendritic cells lining the airway
- dendritic cells process protein into peptides and presents these to CD4+ T-cells
- T-cell can develop into
- Th1
- Th2
- Treg
- in allergy the Th2 cell is the dominant pathway (in developing sensitisation rather than tolerance)
- produce IL-4 and IL-13
- this causes B-cell proliferation and differentiation (to plasma cells)
- B-cells make IgE antibodies (due to stimulation by T-helper cells with IL-4 and IL-13
What happens during a subsequent exposure to an antigen in atopic airway disease?
- dendritic cells take up antigen and process it into peptiedes
- present peptides to memory T-cells
- these produce IL-4 and IL-13
- B-cells incl. plasma cells make antibodies (IgE)
- IL-5 also secreted by Th2 cells: causes recruitment of eosinophils
- this leads to inflammation (eosinophilic)
- there is also mast-cell and t-cell mediated inflammation
-> all this occurs as a memory response.
Neutrophils
- Important in
- virus induced asthma
- severe asthma
- atopic eczema
- 55-70% of blood leukocytes
- Polymorphonuclear cells (PMNs)
- nucleus contains several lobes
- Granules contain
- digestive enzymes
- Also synthesize
- oxidant radicals
- cytokines
- leukotrienes
- Most common Leukocytes
Immunopathogenesis of asthma
Acute inflammation of the airways
- mast cell activation & degranulation
- Pre stored mediators
- histamine
- Newly synthesised mediators
- prostaglandins, leukotrienes
- Pre stored mediators
- Acute airway narrowing
Chronic inflammation of the airways
- Cellular infiltrate
- Th2 lymphocytes, eosinophils
- Smooth muscle hypertrophy
- Mucus plugging
- Epithelial shedding
- Sub epithelial fibrosis
What is the rsponse pattern to allergens?
- there is an early response
- goes back to baseline
- there is a weaker late response some hours later.
Important clinical features of asthma
- Reversible generalised airway obstruction
- Chronic episodic wheeze
- Bronchial hyperresponsiveness
- Bronchial irritability
- Cough
- Mucus production
- Breathlessness
- Chest tightness
- Response to treatment
- Spontaneous variation
- Reduced & variable peak flow (PEF
What is allergic rhinitis?
- Seasonal - hay fever - grass, tree pollens
- Perennial - perennial allergic rhinitis
- HDM, pets
- Symptoms
- sneezing
- rhinorrhoea
- itchy nose, eyes
- nasal blockage, sinusitis, loss of smell/taste
Allergic eczema
- Chronic itchy skin rash
- Flexures of arms and legs
- HDM sensitisation and dry cracked skin
- Complicated by bacterial and (rarely) viral infections (early childhood, herpes simplex)
- 50% clears by 7 years
90% by adulthood
Food allergy
Infancy-3yrs: egg, cows milk
Children/adults: peanut, nuts, shell fish, fruits, cereals, soya
Mild
-> Itchy lips, mouth, angioedema, urticaria
Severe
-> Nausea, abdominal pain, diarrhoea, collapse, wheeze
Anaphylaxis
What is anaphylaxis?
- Anaphylaxis: severe generalised allergic reaction
- Uncommon, potentially fatal
- Generalised degranulation of IgE sensitised mast cells
What body systems are involved in anaphylaxis?
Cardiovascular - vasodilatation, cardiovascular collapse
Respiratory - bronchospasm, laryngeal oedema
Skin - vasodilatation, erythema, urticaria, angioedema
GI - vomiting, diarrhoea
Symptoms of anaphylaxis
- itchiness around mouth, pharynx, lips
- swelling of the lips, throat and other parts of the body
- wheeze, chest tightness, dyspnoea
- faintness, collapse
- diarrhoea & vomiting
- death if severe & untreated
Symptoms of anaphylaxis
- itchiness around mouth, pharynx, lips
- swelling of the lips, throat and other parts of the body
- wheeze, chest tightness, dyspnoea
- faintness, collapse
- diarrhoea & vomiting
- death if severe & untreated
Investigations and diagnosis of allergies?
- Careful history essential
- Skin prick testing
- RAST (blood specific IgE): Radioallergosorbent test
- Total IgE
- Lung function (asthma)
How do you treat anaphylaxis?
Emergency Treatment
- EpiPen & Anaphylaxis kit
- antihistamine, steroid, adrenaline
- Seek immediate medical aid!!
Prevention
- Avoidance of known allergen
- Always carry a kit & EpiPen
- Inform immediate family & caregivers
- Wear a MedicAlert® bracelet
How do you treat allergic rhinitis and eczema?
Allergic rhinitis
- anti-histamines (sneezing, itching, rhinorrhoea)
- nasal steroid spray (nasal blockage)
- cromoglycate (children, eyes)
Eczema
- emollients
- topical steroid cream
If severe
anti-IgE, anti-IL-4/-13, anti-IL-5 mAb
Steps in asthma treatment
Step 1. Use short acting b2 agonist drugs as required by inhalation -> Salbutamol
Step 2. Inhaled steroid low-moderate dose
Beclomethasone/budesonide (50-800mg per day)
Fluticasone (50-400mg per day)
Step 3. Add further therapy
Add long acting bronchodilators, leukotriene antagonist
High dose inhaled steroids - up to 2mg per day via a spacer
Step 4. Add courses of oral steroids, SLIT, azithromycin
Prednisolone 30mg daily for 7-14 days
Anti-IgE, anti-IL-5, anti-IL-4/-13 monoclonal Abs
SLIT
sublingual immunotherapy
Immunotherapy in allergies
Effective for single antigen hypersensitivities
- Venom allergy - bee or wasp stings
- Pollens
- HDM (house dust mites)
- Antigen used is purified
Subcutaneous immunotherapy (SCIT)
- 3 years needed
- Weekly/monthly 2hr clinic visits
Sublingual immunotherapy (SLIT)
- Can be taken at home
- 3yrs needed
Immunotherapy in allergies
Effective for single antigen hypersensitivities
- Venom allergy - bee or wasp stings
- Pollens
- HDM (house dust mites)
- Antigen used is purified
Subcutaneous immunotherapy (SCIT)
- 3 years needed
- Weekly/monthly 2hr clinic visits
Sublingual immunotherapy (SLIT)
- Can be taken at home
- 3yrs needed
What are the important cell types in allergy?
- eosinophils
- mast cells
- neutrophils
