Hypersensitivity and allergy Flashcards
What are appropriate immune reactions?
Occur to foreign harmful agents such as viruses, bacteria, fungi and parasites.
Required to eliminate pathogens.
May be concomitant tissue damage as a side effect, but as long as pathogen is eliminated quickly will be minimal and repaired easily.
Involves antigen recognition by cells of the immune system and antibody production.
What is appropriate immune tolerance?
Occurs to self, and to foreign harmless proteins: food, pollens, other plant proteins, animal proteins, commensal bacteria.
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, in absence of ‘danger’ leads to tolerance.
When do hypersensitivity reactions occur?
When immune responses are mounted against harmless foreign antigens (allergy, contact hypersensitivity), auto-antigens (autoimmune diseases), allo-antigens (serum sickness, transfusion reactions, graft rejection).
How are hypersensitivity reactions classified?
Classified by Gell and Coombs: Type I: immediate hypersensitivity Type II: antibody-dependent cytotoxicity Type III: immune complex mediated Type IV: delayed cell mediated Many diseases involve a mixture of types.
Which hypersensitivity reactions are classified as Type I (immediate hypersensitivity)?
Anaphylaxis
Asthma
Rhinitis (seasonal or perennial)
Food allergy
In a type I hypersensitivity reaction (immediate hypersensitivity), what happens upon primary antigen exposure?
Sensitisation not tolerance
IgE antibody production
IgE binds to mast cells and basophils
In a type I hypersensitivity reaction (immediate hypersensitivity), what happens upon secondary antigen exposure?
More IgE Ab produced
Antigen cross-links IgE on mast cells/basophils
Degranulation
Which hypersensitivity reactions are classified as Type II (antibody-dependent 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
What tests can be used for specific autoantibodies in a type II hypersensitivity reaction (antibody-dependent hypersensitivity)?
Immunofluorescence
ELISA, e.g. anti-CCP (cyclic citrullinated peptide Abs for rheumatoid arthritis)
What happens in a type III hypersensitivity reaction (immune complex mediated hypersensitivity) and when may it occur?
Formation of antigen-antibody complexes in blood
Complex deposition in blood vessels/tissue
Complement and cell activation
Activation of other cascades, e.g. clotting
Tissue damage (vasculitis)
Systemic lupus erythematosus (SLE)
Vasculitides (poly arteritis nodosum, many different types)
Which hypersensitivity reactions may be classified as Type IV (delayed hypersensitivity responses)?
Chronic graft rejection GVHD Coeliac disease Contact hypersensitivity Many autoimmune diseases… Asthma Rhinitis Eczema
What is the mechanism of type IV hypersensitivity reactions?
Transient or persistent antigen presence.
T cell activation of macrophages and CTLs (cytotoxic T lymphocytes).
Much of the tissue damage is dependent upon TNF-alpha, so neutralising TNF-alpha has marked clinical benefits.
What are the features of inflammation?
Vasodilatation, increased blood flow
Increased vascular permeability
Inflammatory mediators and cytokines
Inflammatory cells and tissue damage
What are the signs of inflammation?
Redness
Heat
Swelling
Pain
What is increased vascular permeability in inflammation caused by?
C3a
C5a
Histamine
Leukotrienes
What is the purpose of inflammation and when does it occur?
Body’s response to tissue injury.
Rapid attempt to bring the body’s defences to the site of injury.
Once the immune cells reach the site of damage, they release cytokines and that leads to the features of inflammation.
What are the cytokines involved in inflammation?
IL-1 IL-2 IL-6 TNF IFN-gamma
What are the chemokines involved in inflammation?
IL-8/CXCL8
IP-10/CXCL10
What happens when inflammatory cells infiltrate a tissue?
Cell trafficking is mediated by chemokines.
Neutrophils, macrophages, lymphocytes and mast cells recruited.
Cell activation.
What is the prevalence of atopy in young adults in the UK?
50%
How does the severity of allergies vary?
Mild occasional symptoms
Severe chronic asthma
Life-threatening anaphylaxis
What are the 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
Family size- more common in small families
Infections- early life infections protect
Animals- early exposure protects
Diet- breastfeeding, antioxidants, fatty acids protect
What percentage of topics have a family history?
Around 80%
How many genes are linked to asthma/atopy?
50-100
List genetic risk factors for asthma/atopy.
Polygenic:
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)
What are the 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 does expression of disease require?
Development of sensitisation to allergens instead of tolerance (primary response- usually in early life)
Exposure to produce disease (memory response- any time after sensitisation)
Describe the process of sensitisation in atopic airway disease.
T cells are naïve before they have seen the antigen
Once the CD4+ T cells are activated by an antigen presenting cell, they then become specificto the presented antigen
They could become Th1 (producing IFN-gamma)
They could become Th2 cells- leads to activation of B cells
If the T cell was presented with a harmless antigen, can become regulatory T cells
Describe what happens on subsequent exposure after sensitisation in atopic airway disease.
The allergens are presented by APCs to the memory Th2 cells
These then cause degranulation of eosinophils by releasing IL-5
Th2 cells also release IL-4 and IL-13, which stimulate the production of IgE by plasma cells
The IgE then becomes mobilised onto the surface of mast cells
The antigens then cross-link with the IgE on the surface of the mast cells and cause degranulation
There is a massive release of inflammatory mediators, which gives rise to the effects seen in an allergic reaction
Discuss eosinophils and their relevance to allergy/atopy.
2-5% of blood leukocytes
Present in the blood, but more reside in tissues
Recruited during allergic inflammation
Generated from bone marrow
Polymorphous nucleus- 2 lobes
Contain large granules full of toxic proteins
Lead to tissue damage
Discuss mast cells and their relevance to allergy/atopy.
Tissue resident cells
Have IgE receptors on their cell surface
Cross-linking of IgE leads to mediator release: preformed (histamine, cytokines, toxic proteins) and newly synthesised (leukotrienes, prostaglandins)
This all leads to acute inflammation.
Discuss neutrophils and their relevance to allergy/atopy.
Important in virus induced asthma, severe asthma and atopic eczema
55-60% of blood leukocytes
Multilobed nucleus
Granules contain digestive enzymes
Also synthesise oxidant radicals, cytokines and leukotrienes
What is the immunopathogenesis of acute asthma?
Acute inflammation of the airways- type 1 and type 4 hypersensitivity.
Mast cell activation and degranulation- release of histamine (prestored mediator) , prostaglandins and leukotrienes (newly synthesised mediators).
Acute airway narrowing, mainly caused by vascular leakage leading to airway wall oedema, mucus secretion filling up the lumen, and smooth muscle contraction around the bronchi.
What is the immunopathogenesis of chronic asthma?
Chronic inflammation of the airways.
Cellular infiltrate (Th2 lymphocytes and eosinophils).
Smooth muscle hypertrophy.
Mucus plugging.
Epithelial shedding.
Subepithelial fibrosis (if inflammation has persisted for a long time).
What are the 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 and variable peak flow (PEF)
What are the types of allergic rhinitis?
Seasonal- e.g. hay fever (grass and tree pollens).
Perennial- e.g. house dust mites, animal allergens.
What are the symptoms of allergic rhinitis?
Sneezing
Rhinorrhoea
Itchy nose and eyes
Nasal blockage, sinusitis, loss of smell/taste
What is allergic eczema?
Chronic itchy skin rash affecting flexures of arms and legs.
HDM sensitisation and dry cracked skin.
Complicated by bacterial and (rarely) viral infections (herpes simplex).
50% clears by 7 years, 90% by adulthood.
What are the common food allergies for infants up to 3 years?
Eggs
Cows milk
What are the common food allergies for children/adults?
Peanuts Nuts Shellfish Fruits Cereals Soya
What are the symptoms of a mild allergic reaction to food?
Itchy lips
Itchy mouth
Angioedema
Urticaria
What are the symptoms of a severe allergic reaction to food?
Nausea Abdominal pain Diarrhoea Collapse Wheeze Anaphylaxis
What is anaphylaxis?
Severe generalised allergic reaction.
Uncommon, potentially fatal.
Generalised degranulation of IgE sensitised mast cells.
What are the 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 and vomiting. Death if severe and untreated.
What systems does anaphylaxis affect, and how?
Cardiovascular: vasodilatation, cardiovascular collapse.
Respiratory: bronchospasm, laryngeal oedema.
Skin: vasodilatation, erythema, urticaria, angioedema.
GI: vomiting, diarrhoea.
How are allergies/atopy investigated and diagnosed?
Careful history is essential. Skin prick testing. RAST (radioallergosorbent test)- tests for the amount of specific IgE antibodies in the blood. Measure total IgE. Lung function (in asthma).
How is anaphylaxis treated?
Emergency treatment: EpiPen and anaphylaxis kit- antihistamine, steroid, adrenaline. Seek immediate medical aid.
How is anaphylaxis prevented?
Avoidance of known allergen.
Always carry a kit and EpiPen.
Inform immediate family and caregivers.
Wear a MedicAlert bracelet.
How is allergic rhinitis treated?
Antihistamines (sneezing, itching, rhinorrhoea)
Nasal steroid spray (nasal blockage)
Cromoglycate (children, eyes)
How is eczema treated?
Emollients
Topical steroid cream
How are allergic rhinitis and eczema treated if severe?
Anti-IgE
Anti-IL-4/-13
Anti-IL-5 mAb
How is asthma treated?
STEP 1: Use short acting beta-2 agonist drugs as required by inhalation- salbutamol.
STEP 2: Inhaled steroid low-moderate dose- beclomethasone/budesonide (50-800µg per day); fluticasone (50-400µg 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 course of oral steroids, SLIT (sublingual immunotherapy), azithromycin; prednisolone 30mg daily for 7-14 days; anti-IgE, anti-IL-5, anti-IL-4/-13 monoclonal Abs.
What hypersensitivity reactions may immunotherapy be effective at treating?
Single antigen hypersensitivities: -venom allergy (bee or wasp stings) -pollens -HDM Antigen used is purified.
What are the types of immunotherapy that may be used to treat hypersensitivity reactions?
Subcutaneous immunotherapy (SCIT)- 3 years needed, weekly/monthly 2 hour clinic visits. Sublingual immunotherapy (SLIT)- can be taken at home; 3 years needed.
