Hypersensitivity Flashcards
What do appropriate immune responses occur in response to?
Foreign harmful agents such as viruses, bacteria, fungi and parasites
What is a common side effect of an appropriate immune response?
Concomitant tissue damage but as long as pathogen is eliminated quickly this will be minimal and repaired easily
What does appropriate immune tolerance occur in response to?
Self and foreign harmless proteins- food, pollens, other plant proteins, animal proteins and commensal bacteria
What is involved in the process of immune tolerance?
Antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody IgG4 production
When do hypersensitivity reactions occur?
When immune responses are mounted against:
Harmless foreign antigens (allergy, contact hypersensitivity)
Autoantigens (autoimmune disease)
Alloantigens (serum sickness, transfusion reactions, graft rejection)
What is an alloantigen?
An antigen present only in some individuals (particular blood group) and capable of inducing the production of an alloantibody in people that lack it
What are the different classes of hypersensitivity?
Type I- immediate
Type II- Antibody-dependent cytotoxicity
Type III- Immune-complex mediated
Type IV- Delayed cell mediated
What does type I-III hypersensitivity depend on?
Interaction of antigen with antibody
What are common examples of type 1 hypersensitivity?
Anaphylaxis
Asthma
Rhinitis
Food allergy
What is the mechanism of type 1 hypersensitivity?
1st exposure- Sensitisation not tolerance IgE antibody production IgE binds to mast cells and basophils 2nd exposure- More IgE antibody produced Antigen cross-links IgE on mast cells and basophils This leads to degranulation and release of inflammatory mediators
What does the clinical presentation of type 2 hypersensitivity depend on?
Target tissue
Give examples of organ specific autoimmune diseases
Myasthenia gravis (anti-acetylcholine receptor antibodies) Glomerulonephritis (anti-glomerular basement membrane antibody) Pemphigus vulgaris (anti-epithelial cell cement protein antibody) Pernicious anaemia (intrinsic factor blocking antibodies)
Give some examples of autoimmune cytopenias
Haemolytic anaemia
Thrombocytopenia
Neutropenia
How can you test for specific antibodies?
Immunofluorescence
ELISA (anti-CCP antibodies in rheumatoid arthritis)
What is the mechanism of action of type 3 hypersensitivity (immune complex mediated)?
Formation of antigen-antibody complexes in the blood
They can’t get through small blood vessels very easily and these complexes become deposited in various tissues and lead to complement activation and cell recruitment/activation
This leads to activation of other cascades e.g. clotting which leads to:
Tissue damage, SLE and vasculitis
What is the most common site of vasculitis?
Renal (glomerulonephritis), skin, joints and lung
Give some examples of type 4 hypersensitivity?
Chronic graft rejection Graft-versus-host disease (GVHD) Coeliac disease Contact hypersensitivity Many others- asthma, rhinitis and eczema
What is Th1 characterised by?
Producing lots of gamma-interferon
What does Th2 release?
IL-4
IL-5
IL-13
What does Th2 mediate?
Allergic inflammation e.g. astma, rhinitis and eczema
What do T cells activate after the antigen has come into contact?
Macrophages and CTLs
What is much of tissue damage dependent upon?
TNF-alpha
What are hypersensitivity type 1-3 mediated by?
Antibodies
How do you distinguish between type 2 and type 3?
Based on antigens
Type2= cell surface or matrix bound antigens
Type3= soluble antigens
What causes asthma?
IgE binding to mast cells and by the induction of T cells producing Th2 type cytokines
What is the body’s response to tissue injury?
Inflammation
What is the reason for inflammation?
It is a rapid attempt to bring body’s defences to site of injury
What causes inflammation?
Once immune cells reach the site of damage they release cytokines that leads to the features of inflammation
What are the features of inflammation?
Vasodilation- 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 causes increased vascular permeability?
C3a, C5a, histamine and leukotrienes
Which cytokines are involved in inflammation?
IL-1 IL-2 IL-6 TNF IFN-gamma
What chemokine are involved in inflammation?
IL-8/CXCL8
IP-10/CXCL10
What is atopy?
A form of allergy in which there is a hereditary of constitutional tendency to develop hypersensitivity reactions in response to allergens/ Individuals with this predisposition and conditions provoked in them by contact with allergens are described as atopic
How common is atopy?
50% of young adults in UK
What percentage of atopics have a family history?
80%
How many genes are involved in the genetic component of atopy?
Many- it is polygenic and 50-100 genes are associated with asthma and atopy
Which gene cluster is linked to raised IgE, asthma and atopy?
IL-4 gene cluster
Genes on which chromosome are linked to atopy and asthma?
Chromosome 11q (IgE receptor)
What environmental risk factors are there for atopy?
Age- increases from infancy, peaks in teens and reduces in adulthood
Gender: more common in males in childhood but females in adults
Family size- more common in small families
Infections- early life infections protect
Animals- Early exposure protects
Diet- breast feeding, anti-oxidants and fatty acids protect
What does expression of hypersensitivity disease require?
Development of sensitisation to allergens to sensitise instead of develop tolerance
Exposure to produce disease
After naive CD4+T cells are activated by an antigen presenting cell they then become specific to the presented antigen and what can’t hey can then become?
Th1- producing IFN gamma
Th2- activation of B cells
If a T cells is presented with a harmless antigen what can they become?
Regulatory T cells
What happens in subsequent exposure when the allergens are presented by APCs to 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 becomes mobilised onto the surface of mast cells
The antigens cross link with IgE on the surface of the mast cells and causes degranulation
There is massive release of inflammatory mediators which gives rise to allergic reaction effects
Where are eosinophils most commonly found?
They are present in the blood but more reside in tissues
When are eosinophils recruited?
During allergic inflammation
What are eosinophils generated from?
Bone marrow
What is the nucleus of an eosinophil like?
Polymorphous- two lobes
How do eosinophils cause tissue damage?
They contain large granules that are full of toxic proteins
Where are mast cells found?
They are tissue resident cells
What do mast cells have on their cell surface?
IgE receptors
What does cross linking of IgE with mast cells lead to?
Mediator release Preformed: Histamine Cytokines Toxic proteins Newly synthesised: Leukotrienes Prostaglandins
What do all of the mediators released by mast cells cause?
Acute inflamation
In terms of hypersensitivity, what are neutrophils important in?
Virus induced asthma, severe asthma and atopic eczema
What percentage of blood leukocytes are neutrophils?
55-60%
What do the granules in neutrophils contain?
Digestive enzymes
What do neutrophils synthesise?
Oxidant radicals
Cytokines
Leukotrienes
What type of hypersensitivity reaction is asthma?
Type 1 and 4
What does mast cell activation and degranulation lead to?
Release of histamines (pre-stored mediators) and prostaglandins and leukotrienes (newly synthesised mediators)
What does the release of mediators due to mast cell activation and degranulation lead to?
Acute airway narrowing
What causes the airway narrowing in acute asthma?
Three processes:
Vascular leakage leading to airway wall oedema
Mucus secretion fills up the lumen
Smooth muscle contraction around the bronchi
What is the immunopathogenesis of of chronic asthma?
Chronic inflammation of airways and lumen of airway is very narrow and airway wall is grossly thickened
There will be cellular infiltration- Th2 lymphocytes and eosinophils
Smooth muscle hypertrophy
Mucus plugging
Epithelial shedding
Sub-epithelial fibrosis
What important clinical features of asthma are there?
Reversible generalised airway obstruction- causes chronic episodic wheeze Bronchial hyperresponsiveness Cough Mucus production Breathlessness Chest tightness Response to treatment Spontaneous variation Reduced and variable peak expiratory flow (PEF)
What are the two types of allergic rhinitis?
Seasonal- e.g. hay fever
Perennial- perennial allergic rhinitis (house dust mites, animal allergens)
What are the symptoms of allergic rhinitis?
Sneezing
Rhinorrhoa
Itchy nose and eyes
Nasal blockage, sinusitis and loss of smell/taste
How does allergic eczema present?
Chronic itchy skin rash
Where is allergic eczema most commonly found?
Flexures of arms and legs
What can eczema lead to?
House dust mite sensitisation- proteins can get through dry cracked skin
What can complicate allergic eczema?
Bacteria and rarely viral infections
What type of hypersensitivity reaction is a food allergy?
Type 1
What are the most common food allergies in infants (3 years)?
Eggs
Cows milk
What are the most common food allergies in children/adults?
Peanuts Shellfish Nuts Fruits Cereals Soya
What is a mild reaction to a food allergy?
Itchy lips and mouth
Angioedema
Urticaria
What is a severe reaction to a food allergy?
Nausea
Abdominal pain
Diarrhoea
Anaphylaxis
What is anaphylaxis?
Severe generalised allergic reaction
What happens to mast cells in anaphylaxis?
Generalised degranulation of IgE sensitised mast cells
What are the symptoms of anaphylaxis?
Itchiness around mouth, pharynx and lips Swelling of lips, throat and other parts of body Wheeze, chest tightness and dyspnoea Faintness, collapse Diarrhoea and vomiting Death if severe and untreated
What systems are affected in anaphylaxis?
Cardiovascular- vasodilation, cardiovascular collapse
Respiratory- bronchospasm, laryngeal oedema
Skin- vasodilation, erythema, urticaria and angioedema
GI- vomiting and diarrhoea
How are allergies diagnosed?
Careful history Skin prick testing RAST (radioallergosorbent test)- tests for amount of specific IgE antibodies in the blood Measure total IgE Lung function (in asthma)
How is anaphylaxis treated?
It is an emergency:
Epipen and anaphylaxis kit
Antihistamine if mild
Adrenaline if severe
How are anaphylaxis attacks prevented?
Avoidance of allergen
Always carry epipen and anaphylaxis kits
Inform immediate family and caregivers
Wear a MedicAlert bracelet
How do you treat allergic rhinitis?
Anti-histamines
Nasal steroid therapy
Cromoglycate
How do you treat eczema?
Emollients (maintain moisture in skin thus reinforcing its barrier function) Topical steroid cream If severe: Anti-IgE mAb Anti-IL4/13 mAb Anti-IL5 mAb
What are the 4 steps in treating asthma?
Step 1- short acting beta-2 agonist by inhalation e.g. salbutamol
Step 2- Inhaled steroid low-moderate dose e.g. beclomethasone/budesonide and fluticasone
Step 3- Further therapy- long-acting beta-2 agonist or leyukotrine antagonist. High dose inhaled steroid- up to 2mg a day via spacer
Step 4- Add course of oral steroids, prednisolone or anti-IgE, Anti-IL4 and anti-IL5 mAbs
What is immunotherapy?
Where you make people develop tolerance but exposing them to a small amount of the allergen that they are allergic to
Which hypersensitive is immunotherapy successful for?
Single antigen hypersensitivities
