Allergic Reaction

• Hypersensitivity reactions are excessive reactions to things in our environment - the basis of a hypersensitivity reaction is needed as inflammation is normal and necessary
• IgE is a problem in hypersensitivity, but important in cancer cell recognition and defends against complex parasites such as worms and ticks
• Hypersensitivity describes immune responses being damaging rather than helpful to the body - it may be an excessive response or response to harmless stimuli from the atmosphere
• the major classification system used for hypersensitivity is the Gell and Coombs classification with 4 different types of hypersensitivity
• The first three hypersensitivity reactions are mediated by antibodies and the fourth is mediated by T-cells
• Type 1 hypersensitivity reaction involves IgE.
• IgM and IgG are involved in hypersensitivity types two and three.
• there may be antibody secondary to the T cell activation, but primarily type 4 hypersensitivity is about T cells
• Patients will potentially have more than one type of disorder, so a mixed response can occur
• type 1 (immediate) hypersensitivity is also called allergy or atopy and affects 20-30% of the population
• Atopy is an allergic response in someone genetically programmed for that response
• type 1 begins with the inhalation of an allergen (likely benign) it's then recognized by an antigen-presenting cell which then digests the antigen and presents a peptide that identifies the allergen to T lymphocytes which are initially in a naive form called Th0 and in response to an allergen they then form into the subtype TH 2.
• TH 2 lymphocytes will then activate B cells and B cells form into plasma cells and plasma cells produce and release IgE
• B cells can also be directly activated by the allergen, although its more common to be activated by a TH 2 cell
• type 1 hypersensitivity causes the expression of IgE receptors - IgE binds to high-affinity receptors (Fc epsilon RI) on mast cells and basophils and low-affinity receptors on macrophages, eosinophils and platelets
• IgE needs to lock into its receptor in order to produce a type 1 hypersensitivity response
• FC Epsilon RI receptors is where IgE produced by the plasma cell is going to bind, and once that happens we have a primed system - it takes 10% occupancy to reach this state
• a primed system means that the system has now recognized the allergen
• on subsequent exposure to the allergen when two or more IgE antibodies on mast cells crosslink to the allergen leading to rapid degranulation (60-300sec) of the mast cell and release of preformed mediators
• preformed mediators released during a type 1 hypersensitivity reaction include:

  • histamine
  • 5-HT
  • proteases
  • chemotaxins
• histamine produces an immediate smooth muscle constriction but also increases vascular permeability, leading to inflammation and oedema - therefore causing swelling of the area
• 5-hydroxytryptamine (5-HT or serotonin) is released and causes smooth muscle contraction and oedema and a variety of enzymes are released
• proteases such as tryptase cause mucus secretions and connective tissue degredation
• chemotaxins such as ECF-a (eosinophils) and NCF-A (neutrophils) bring cells to the affected area bringing a more profound immune responce
• Other mediators in a type 1 hypersensitivity reaction are synthesized de novo (from scratch from a mast cell membrane) include:

  • compounds formed from the arachidonic acid cascade, such as leukotrienes and prostaglandins and leukotrienes - causing smooth muscle contraction and vascular permeability and chemotaxis of leukocytes (LTB4)
  • prostaglandin PG F 2A prostaglandin D2, prostaglandin E2 - causing smooth muscle contraction and vascular permeability but also activation of platelets.
• bradykinin can be formed very quickly from its precursor in type 1 hypersensitivity reactions and causes smooth muscle contraction, and vascular permeability
• cytokines such as TNF-alpha, IL-4, and IL-5 are involved in type 1 hypersensitivity reactions and cause the activation, recruitment and increased life span of eosinophils, increased mast cell numbers, and t-cell and macrophage recruitment
• TNF-alpha is a benchmark pro-inflammatory cytokine
• IL-5 is a target in blocking type 1 hypersensitivity responses to try and improve asthma
• ◦Nitric oxide from mast cells and immune cells releases reactive oxygen species to evoke cellular damage and vasodilatation
• reactive oxygen species are free radicals and cause cellular damage
• platelet-activating factor (PAF) is a chemotaxin and it also activates platelets, producing clotting, and it's also capable of producing oedema due to its effect on vascular permeability.
• leukotrienes cause constriction and mucus buildup in asthma responces.
• Prostaglandins produce dilation of blood vessels, causing swelling, oedema and the lungs are constricted
•  Activation of nerve cells causes headaches, and agents like histamine, serotonin, and bradykinin cause oedema giving hives or urticaria. Constricted airways, wheezing and difficulty breathing. Increased changes to the contractile arrangement within the gut diarrhoea or sickness and excess mucus tear formation, glandular secretions causing allergic rhinitis, and the associated eye problems.
• the initial release of mediators in a type 1 hypersensitivity response results in acute effects apparent within a few minutes and maximal after about 20 min. - increased vascular permeability leading to oedema, smooth muscle contraction, and extravasation leading to redness and heat etc
•  A secondary, more profound late-phase response (4-8h) occurs in a type 1 hypersensitivity reaction as chemotaxins draw in leukocytes (especially eosinophils) and further activation of Th-cells and macrophages occurs
• in the immediate response in a type 1 hypersensitivity reaction, there will be a small reddened area compared to the late-phase response which is noted as a much larger area of inflammation
• in the immediate response in a type 1 hypersensitivity reaction, there will be a sharp drop in lung function (peak flow expiratory rate) compared to the late-phase response which is a slower, later and longer more profound fall in breathing associated with the influx of immune cells
• Examples of allergic reactions;

  • urticaria (skin - hive),
  • asthma,
  • allergic rhinitis (itchy, runny nose),
  • anaphylaxis,
  • atopic eczema (skin - redness)