Allergies

what is the definition of a hypersensitivity?

'harmful immune responses that produce tissue damage' allergies reside within hypersensitivity

Effector T cell produce distinct molecules what are the subtypes of T cells?

CD8 cytotoxic, directly kills cells, secretes IFN gamma and TNF alpha to target cell lysis CD4 Th1 secretes IFN gamma, GM-CSF and TNF alpha for macrophage activation CD4 Th2 is the main way antibodies are formed, secretes IL4 and IL5 for B cell activation

what are the features of some inhaled allergens?

Protein: only proteins induce T cell responses Enzymatically active: allergens are often proteases Low dose: favours IL4 producing CD4 T cells. Small size: allergens can diffuse out of particle Highly soluble: elutes readily from particle Stable: allergen can survive dessication.

what are common contacted allergens?

plant leaves industrial products made from plants synthetic chemicals in industrial products metals (latex sensitivity)

what are common inhaled allergens?

plant pollen dander of domesticated animals mould spores faeces of very small animals e.g house dust mites

what is desensitisation and blockade as treatment of allergies?

• Aim to shift response from IgE dominated to IgG dominated • Patients injected with escalating doses of allergen, gradual shift from Th2 to Th1 T cells. • Potential risk of inducing anaphylaxis! • Anti-histamines, H1 receptor blocking. • Topical or systemic corticosteroids to supress chronic inflammation in asthma and rhinitis

what is a skin allergy?

• Allergens entering at skin sites cause rashes. • Wheal and Flare, first appearing within a few minutes as a result of vasodilation after Mast Cell degranulation, localised redness • Around 8 hours later more diffuse oedema at site due to influx of lymphocytes (inflammatory blood cells) and other leukocytes, attracted by chemokines.

Summary of Allergies

• Allergic reactions result in IgE responses • Allergens usually small antigens that enter body at low doses, often mucosally. • Promotion of Th2 T cells favours IgE response • Mast cells strategically placed at mucosal surfaces. • Engagement of IgE on Mast cell results in degranulation, also basophil and eosinophil involvement. • Late phase of allergic response can involve tissue damage.

How does pollution affect allergies?

• Environmental pollution, does it increase allergic asthma? • East German children exposed to high levels of air pollution had lower levels of asthma than West German children. • This does not mean air pollution is good for you, the East German children had higher levels of respiratory disease, but mostly not allergic type.

what is the role of Cytokines in allergy?

• IL-4, IL-13; amplify Th2 response • IL-3, IL-5, GM-CSF; promote eosinophil activation and production • TNF-alpha; pro-inflammatory, activates endothelium Chemokine MIP-1 alpha; attracts macrophages and neutrophils

Describe the production of IgE

• IgE is produced by plasma B cells in lymph nodes, or locally at site of inflammation • IgE is located mostly in tissue (hence low serum concentration), bound to Mast Cell surface through high affinity IgE receptor FcεRI • Certain antigens and routes of delivery appear to favour IgE production. Transmucosal at low doses is often a common route. • CD4+ T cells of the Th2 phenotype that produce IL4 cytokines favour IgE responses • Th2TcellsalsoforceBcellstoswitchthe isotype of the Ig they secrete from IgM to IgE

what do you know about enzymes that are allergens?

• IgE is thought to be crucial in host defence against parasites, many of which gain access by secreting proteolytic enzymes Many allergens are enzymes. Major allergen in faeces of house dust mite is Der p 1, which can cleave tight junctions between epithelial cells in airway, thus enhancing access. Der p 1 then is taken up by Dendritic Cells, presented to T cells, which become Th2, and cause B cells to secrete IgE.

what are main symptoms of ingested allergens?

• Ingested allergens leads to two main symptoms • Activation of GI Mast cells results in transepithelial fluid loss and smooth muscle contraction: diarrhoea and vomiting • If allergen enters blood stream, generalised disseminated rash, Urticaria, (hives). • In severe cases of food allergy, e.g. nuts and shellfish, life threatening generalised anaphylaxis and cardiovascular collapse may occur

what are the chemical mediators of allergic responses

• Mast cells granules contain a wide range of inflammatory mediators • Lipids • Toxic mediators • Cytokines • enzymes

what are the enzymes involved in allergy?

• Tryptase • Chymase • Cathepsin G • Carbopeptidase • Remodel connective tissue matrix

what is type I hypersensitivity reaction?

Type I - driven by immune reactant IgE, antigen is soluble, mast cell activation is the effector mechanism and an example of type 1 is classic allergies or asthma

what is atopy?

capacity to generate allergic responses becomes mrs when you develop first allergy. Then go on to develop other closely related or not closely related allergies. Atopy refers to the genetic tendency to develop allergic diseases such as allergic rhinitis, asthma and atopic dermatitis (eczema). Atopy is typically associated with heightened immune responses to common allergens, especially inhaled allergens and food allergens.

what happens on exposure to pollen?

first exposure to pollen extraction of antigen cause its got to get access to the airway activation of antigen specific T cells production of IgE and binding to mast cells

what are common ingested allergens?

food orally administered drugs

what are common injected allergens?

insect venoms vaccines - sometimes patients aren't allergic to the vaccine but more the preservatives that are in them drugs - like penicillin is common therapeutic proteins

what is the definition of an allergy?

'an altered capacity of the body to react to a foreign substance'. 'disease following a response by the immune system to an otherwise innocuous antigen'

How does an allergy arise?

Allergy is IgE mediated, and always occurs on secondary exposure to an allergen, so an initial exposure event is always taken place. Allergies are very common in the west, often between 25 and 50% of the population have an allergy. Allergy occurs when IgE triggers mast cell granulation. Mast cells sit in peripheries jam packed with things that can dilate blood vessels and cause rhinitis (runny nose).

what is the role of Toxic mediators in allergy?

Histamine, increase vascular permeability, and promotes movement of fluid from the vasculature by constricting vascular smooth muscle. • Heparin, inhibits coagulation

what are the five immune reactants?

IgG, IgM, IgD, IgA, IgE

what is the significance of immune reactant levels in serum?

Serum IgE levels are normally very low This is due to IgE removed from plasma which sits on the surface of mast cells Theres usually about 0.003 mg/ml but IgG there is about 15mg/m. Huge difference there.

what is the common test for allergen sensitivity?

Skin prick test: pricking the skin with a needle or pin containing a small amount of the allergen. (on the arm)

Infection control of Allergy, how is that achieved?

• Allergies and asthma is lower in areas with high Helminth burdens. • IgE is a key defines in Helminth expulsion. • 300 Gabonese children treated with anti-helminth drugs, followed over 30 months; increase observed in house dust mite allergy • Is immune system diverted by presence of helminth, or does helminth actively suppress allergy? • Latest data suggest that helminth infection induces a new set of T cells, regulatory T cells (Tregs) that actively suppress Th2 cells.

what is allergic asthma?/

• Bronchial constriction • Increased secretion of fluid and mucus, trapping inhaled air • Chronic inflammation may ensue with continued presence of Th2 T cells, eosinophils, neutrophils. • Chronic asthma driven originally by specific allergen, but may then result in hyperreactive airways to other irritants such as cigarette smoke and other pollutants

what are the genetic influences on allergy?

• Over 35 genes now thought to influence allergy and asthma. • IL-4; promoter variants affect levels of IL-4 secretion • IL-4 receptor: variants have different signalling response • B2 -adrenergic receptor: variants increase bronchial hyperreactivity • 5-Lipoxygenase; variation in leukotriene levels. • Possibility of epigenetic influences; modifying gene behaviour by methylation, either in utero, or in childhood, may effect subsequent responses. Familial heredity?

How is a severe anaphylaxis treated?

• Potentially life threatening reactions should be treated with epinephrine (adrenaline) injection • Affected individuals often carry self- admin inject devices, Epi-pen or Ana-pen. • 0.15mg dose for child, 0.3mg dose for adults. Delivered in thigh. Second dose possible if no signs of improvement within 10-15 mins. Seek professional advice ASAP! • Do not inject in thumb!!! Why? Risk vs benefit? prevents smooth muscle contraction but also blood flow constriction so can lose a finger if injected there.

what are the Lipids role in allergy?

• Prostaglandins, increase vascular permeability, increase body temperature. Platelet activating Factor, increases adhesion between endothelium and neutrophils. Leukotrienes, attract and activate neutrophils, increase vascular permeability

why is route of allergen delivery crucial to symptoms?

• The location and distribution of the antigen is the most important factor in what symptoms occur • Inhaled antigens will affect nasal epithelium, causing allergic rhinitis, ie hay fever etc. due to seasonal pollens. Local edema, nasal discharge, often containing eosinophils • Allergen induced degranulation further down airway results in allergic asthma

what is the treatment of allergy

• Two main types of treatment currently used, desensitisation, and blockade of effector pathways • Future therapies may involve recombinant allergens, hypoallergenic derivatives, T cell peptides, B cell peptides, DNA vaccines.

what is the Hygiene Hypothesis and why is it linked to allergy?

• Why are economically developed societies more prone to allergies? living in too clean an environment now • Exposure to infectious diseases in childhood? Early childhood exposure to Th1 inducing pathogen (bacterial or viral) may prevent bias towards Th2 responses later. • Allergen levels? • Dietary change? • Pollution levels?