Hypersensitivity1. Describe the mechanisms by which IgE, antibodies, immune complexes and T-cells can cause tissue damage and inflammation – the 4 types of hypersensitivity

o “Appropriate” immune responses to viruses, bacteria, fungi, parasiteso Required to eliminate pathogenso May be concomitant tissue damage as a side effect, but as long as pathogen is

eliminated quickly will be minimal and repaired easilyo Involve antigen recognition by antibodies and cells of the immune system.

o Hypersensitivity reactions occur when immune responses mounted against:o Harmless foreign antigens (allergy, contact hypersensitivity)o Autoantigens (autoimmune diseases)o Alloantigens (serum sickness, transfusion reactions, graft rejection)o Infectious agents (that are not cleared and lead to chronic immune mediated damage)

There are 4 types of hypersensitivity reaction: Type 1 - Immediate hypersensitivity Type 2 - Anti-body-dependant Cytotoxic Hypersensitivity Type 3 – Immune Complex Mediated Hypersensitivity Type 4 – Delayed Cell Mediated Hypersensitivity

Hypersensitivity is an incidental response, usually an over-response with harmful consequences for the patient

Review of Inflammation : The body’s rapid response Immune molecules involved – antibodies, compement, cytokines etc Occurs at site of injury or infection Signs – Heat, pain, redness, swelling Features – Local dilation, increased blood flow, increased vascular permeability, inflammatory mediators and cytokines

o Increased vascular permeabilityo Caused by C3a, C5a, histamine, leukotrienes.

o Cytokines IL-1, IL-6, IL-8, IL-2, TNF, chemokines.o Inflammatory cell infiltrate

o Cell trafficking – chemotaxiso Neutrophils, macrophages, lymphocytes, mast cellso Cell activation

Type 1 Immediate Hypersensitivity: Dependent upon the production of IgE to specific allergens e.g. pollen, animal proteins IgE binds to receptors on mast cells and basophils Further contact with the allergen leads to IgE cross-linking on the surface of mast cells and basophils causing them to de-granulate De-granulation releases histamine, tryptase and kininogenase and produces prostaglandins and leukotrienes Release of mediators causes increased vascular permeability, smooth muscle constriction and hyper-motility of the GI tract Reactions can be life threatening

1° exposure → IgE production and binding to mast cells and basophils 2° exposure → IgE cross-bridges leading to immune reaction Tested for by:

Skin prick tests – immediate skin test Serum total IgE Serum specific IgE Serum/urine tryptase – repeat samples over 36hrs

Is seen in food intolerance, drug intolerance, asthma eczema, anaphylaxis Treatment – Antigen avoidance, anti-histamines, corticosteroids

Type 2 Antibody Dependant Hypersensitivity Dependant on production of IgG and IgM against cell surface antigens Leading to either self leading autoimmunity or transfused cells leading to alloimmunity Ab interaction with cell surface Ag leads to complement activation leading to cell lysis and mast cell activation which promotes inflammation:

Attraction of cytotoxic cells – neutrophils, eosinophils, monocytes, killer cells

Clinical presentation depends on target tissue affected: Organ specific auto-immunity – e.g. myasthenia gravis (ACh Ab), glomerulonephritis (anti-GBM) Autoimmune-cytopenias (blood cell destruction) e.g. thrombocytopenia, haemolytic anaemia) Haemolytic disease of the newborn – Rh Ab

Treatment – Immunosuppressants – steroids/cyclophosphamide Plasma exchange Splenectomy IV globulin

Tested for by: Specific anti-body detection Immunofluroescene ELISA (for identified antigens)

Type 3 Immune Complex Mediated Hypersensitivity: Dependent upon the formation of antigen-antibody complexes and deposition in tissues or the circulation Deposition results in activation of complement, inflammatory cells and the clotting cascade leading to severe local damage Particularly serious when complexes are stuck to the walls of vital blood vessels – vasculitis, renal glomerulus, skin, joints, lung, heart Size and degree of complex formation depends on Antigen and Antibody concentrations When in Antibody excess there is less likely to be deposition Antibody isotype dictates ability to fix complement Immune complexes are normally cleared from the blood by macrophages – an immune response occurs when the complexes are not cleared – i.e. due to formation outstripping clearance Examples include – Serum sickness (when in blood vessels), allergic alveolitis, SLE, Arthus reactions (outside vessels), cutaneous vasculitis Tested for by:

1. Looking for complement activation C3 and C4; 2. Looking for complex formation

Treatment - Ag removal/avoidance NSAID’s, corticosteroids, plasma exchange

Type III Immune ComplexMediated Hypersensitivity

Type III Immune ComplexMediated Hypersensitivity

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Mo

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PMN

Immune ComplexImmune Complex NORMALNORMALclearanceclearance

PMN

C3C3NecrosisNecrosis

Outside blood vesselsOutside blood vessels•• ArthusArthus Type ReactionType Reaction

VasculitisVasculitis ::Renal Renal glomerulusglomerulusSkinSkinJointsJointsLungLung

Inside blood vesselsInside blood vessels•• Serum sicknessSerum sickness

C3

MCD: Immunology - Hypersensitivity

Type 4 Delayed Hypersensitivity: Dependant upon macrophage activation as a result of prolonged T-cell response Dependant upon TNF 3 Varieties:

Type III Immune ComplexMediated Hypersensitivity

Type III Immune ComplexMediated Hypersensitivity

Antigen Antibody

Optimal Proportions of Ag / Optimal Proportions of Ag / AbAb to Precipitate Complexesto Precipitate Complexes

Large complexes

SmallcomplexesSmall

complexes

1. Th12. Cytotoxic3. Th2

IL-2 on T cells augments IFN-γ, TNF-α, TNF-β IFN-γ up-regulates MHC Class II which activates macrophages and promotes antibody switching to IgG TNF activates the vascular endothelium which promotes inflammation and activates macrophages Treatment – block cytokine release from T-cells, corticosteroids remove antigen Examples – chronic graft rejection, GVHD, Coeliac disease, Contact hypersensitivity, TB, Tuberculoid lebrosy. Tested for by contact sensitivity test

b. Give examples of the clinical syndromes associated with each type of immune mediated inflammation

2. Outline the factors underlying the development of atopic and allergic diseases

Atopy = the tendency to produce abnormally high IgE responses to otherwise harmless environmental substances Allergy = the expression of the disease due to atopy

Most allergy is produced by a combination of Type 1 immediate hypersensivity (IgE) and Type 4 cell mediated chronic inflammation

Allergic Disease: Common – 50% of the young adult population is atopic and prevalence is increasing Several varieties:

Mild occasional symptoms Severe chronic illness Fatal anaphylactic shock

Genetic Risk Factors : 80% have a family history of allergy = 20% of general population Polygenic in nature

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.

Environmental Risk Factors : Age – increases in children, peaks in teens then reduces in adulthood Gender – commoner in boys in children, girls in adults Family Size – less in large families Dietary factors – anti-oxidants, breast feeding and fatty acids protect Infections – early life infections protect from allergy Animals – early exposure to animals protects from allergy

Types of Inflammation in allergy Anaphylaxis, urticaria, angioedema

type I hypersensitivity (IgE mediated) Chronic urticaria

type II hypersensitivity (IgG mediated) Asthma, rhinitis, eczema:

mixed inflammation type I hypersensitivity (IgE mediated) type IV hypersensitivity (chronic inflammation)

Expression of disease requires: Sensitisation to allergens (usually during childhood) followed by later Exposure to allergen (memory response)

Clinical manifestation: Relates to the target organ exposed to the allergen:

Nose – allergic rhinitis via inhaled allergen Bronchi – allergic astham via inhaled allergen Blood circulation – anaphylactic shock – via oral/mucosal or contact/inhalation exposure Skin – allergic eczema – from skin contact with allergen

Cellular Components:

Eosinophils : 2-5% of blood leukocytes Present in blood, most reside in tissues Recruited during allergic inflammation Generated from bone marrow in 2-6 days Polymorphous nucleus – two lobes Contain large granules – toxic proteins which lead to tissue damage

Mast Cells: Tissue resident cell IgE receptors on cell surface Cross-linking of IgE causes pre-formed histamine release and release of newly synthesised prostaglandins and leukotrienes (i.e. mediator release) Contain histamine granules – histamine release and toxic proteins Leads to smooth muscle contraction, vascular leakage, mucus secretion and tissue damage

Neutrophils : Important in virus induced, severe and atopic asthma 55%-70% of leukocytes Nucleus contains several lobules Granules contain digestive enzymes Also synthesis – oxidant radicals, cytokines, leukotrienes

3. Describe the important clinical features of asthma, hay fever, allergic eczema and anaphylaxis

Asthma : Common in the UK – 4-20% of the population and rising Characterised by:

Reversible generalised airway obstruction Bronchial hyper-responsiveness Airway inflammation

Asthma can be: Perennial (e.g. from house dust mite, cat or dog) Seasonal – e.g. pollens Occupational

Onset often in childhood and is usually associated with other atopic disorder and a family history of allergy

Immunopathogenesis : Acute mast cell activation :

Activation and degranulation leads to pre-formed histamine release and synthesis and release of prostaglandins and leukotrienes Mucosal oedema Mucus secretion Smooth muscle contraction Leads to acute, rapidly reversibly narrowing of the airways

Chronic Th2 lymphocyte and eosinophils activation: Leads to chronic inflammation of the airways Inflammatory cellular infiltration Tissue damage Epithelial cell shredding Sub-epithelial fibrosis Smooth muscle hypertrophy

Triggers of Asthma Attacks: Colds and influenza infection Allergen exposure Cold air Exercise Irritants Emotional stress Medication – β-blockers

Diagnosis : Chronic wheeze followed by episodes of wheeze within minutes or hours of allergen exposure Response to treatment Reduced and variable peak flow (PEF)

Therefore Asthma: Reversible generalised airway obstruction

o Chronic episodic wheeze Bronchial hyperresponsiveness

o Bronchial irritability Cough Mucus production Breathlessness Chest tightness

Response to treatment Spontaneous variation Reduced & variable peak flow (PEF)

Allergic Rhinitis: Hay fever Can be seasonal (hay fever) or perennial (house dust mite, animals etc) Symptoms:

Sneezing Rhinorrhoea Itchy nose, eyes Nasal blockage, sinusitis, loss of smell/taste

Allergic Eczema: Chronic itchy skin rash in atopic people Flexures of arms and legs HDM sensitivity and dry cracked skin 50% clears by 7yrs, 90% by adulthood Can be complicated by bacterial infection or viral (severe herpes simplex) 90% have high serum IgE House dust mite allergy may be important, food allergy’s impact is controversial

Food Allergy: Infancy-3yrs

o egg, cows milk Children/adults

o peanut, shell fish, nuts, fruits, cereals, soya

Mildo Itchy lips, mouth, angioedema, urticaria

Severeo Nausea, abdominal pain, diarrhoeao Anaphylaxis

Anaphylaxis : Anaphylactic shock is a severe generalised allergic reaction Uncommon but potentially fatal Death may occur within minutes – first sign usually itchiness The most severe and dramatic form of allergy

Generalised degranulation of IgE sensitised mast cells.

Cardiovascular - vasodilatation, cardiovascular collapse Respiratory - bronchospasm, laryngeal oedema Skin - vasodilatation, erythema, urticaria, angioedema GI - vomiting, diarrhoea

Symptoms : - due to affects on the cardiovascular, respiratory and GI systems and on the skin:

Itchiness around mouth, lips and pharynx Swelling of the mouth, lips and other body parts Wheeze, chest tightness, dyspnoea Erythema Faintness Feeling of apprehension Diarrhoea and vomiting Collapse Death is untreated

Investigation and Diagnosis Careful history essential Skin prick testing RAST (blood specific IgE): Total IgE Lung function (asthma)

Common Causes: Bee and wasp stings Food allergy – e.g. peanuts Drug allergy – e.g. penicillin

When the allergen is introduced directly into the blood the reaction is almost instantaneous and CVS collapse the predominant feature When the allergen is absorbed through the skin the reaction may develop more slowly

4. Briefly describe the approach to investigation and management of patients with these disorders

Investigation and diagnosis of allergy: Careful history is essential Immediate hypersensivity (type1) skin prick tests very useful to confirm presence of atopy and identify possible cause

Specific IgE measurement is only used if: Taking anti-histamines Extensive skin disease Presence of dermatographism In very young babies Previous anaphylaxis Food allergy – e.g. peanut

Other tests include total IgE, and lung function tests for asthma and allergen challenges

Treatment of anaphylaxis Emergency Treatment

EpiPen & Anaphylaxis kit – adrenaline, antihistamine, steroid. Seek immediate medical aid

Prevention Avoidance of known allergy

Always carry a kit & EpiPen Inform immediate family & caregivers Wear a MedicAlert bracelet

Asthma Treatment: Step 1 – inhaled β-agonists e.g. salbutamol Step 2 – inhaled low dose steroids – e.g. fluticasone, budesonide Step 3 – add further therapy e.g. long acting β-agonists, high dose inhaled steroids, leukotrienes antagonists Step 4 – oral steroids – e.g. prednisolone

Other Allergic Disease Treatment: Allergic Rhinitis:

Anti-histamines (sneezing, itching, rhinorrhoea) Nasal steroids (nasal blockage) Cromoglycate (children to relieve eye symptoms)

Eczema: Emollients Topical steroid cream

Immunotherapy : Effective for venom allergies such as bee or wasp stings

o single antigeno antigen used is purified

Effective with pollen induced allergieso Sublingual immunotherpay (SLIT)