PBL 6: Dangerous Liaisons
Rachel Lim PBL Group C2
Introduction: The immune system
The immune system protects the body by identifying and eliminating pathogens and tumour cells using 2 layered defences that act independently and also cooperatively – the Innate immune system and the Adaptive immune system. The ability of each immune system to differentiate between self, the body’s own health tissues and cells and non-self molecules (foreign to the body) is paramount to their function (1)
A specific type of non-self molecules are antigens, defined as substances that bind to specific immune receptors and elicit and immune response (2)
Components of the immune system
The immune system’s defence mechanism is in layers of increasing specificity.
Fig 1 provides an overview of the layered defences of the immune system.
1. Surface Barriers
As shown, the first line of defence to stop pathogens from entering the body is the physical surface barrier – skin and mucous membranes, as well as enzymes and natural flora.
2. Innate Immune System
However, if pathogens make it through these barriers, the innate immune will be triggered to release an immediate non-specific response. Pathogens are recognised by the Pattern Recognition Receptors (PRR) which identify components that are conserved among broad groups of microorganisms. (3)
3. Adaptive Immune System
Next, if pathogens manage to evade this second layer, the third layer of the adaptive response is activated, and the immune system improves recognition of the pathogen through signature antigens. This consists of the humoural immunity, which is mediated by antibodies produced by B lymphocytes, and cellular immunity which is mediated by T lymphocytes (4)
Mechanism of Action for Allergy and Signs and Symptoms
In this case, Rachel presented with the following signs and symptoms characteristic of anaphylaxis:
– Widespread Urticaria and Angioedema
– Significant itching of vagina and vulva
– Wheezing
– Faintness
– Dyspnea
Angioedema is the swelling of deep dermis, subcutaneous, or submucosal tissue due to vascular leakage. Visible swelling is observed and this is largely associated with local burning sensation and pain. (5)
Typical signs and symptoms include
– Peripheral swelling of the skin and urogenital area (eg. Eyelids or lips, tongue, hands, feet, scrotum, etc.)
– Abdomen: Abdominal pain
– Larynx (swelling): Throat tightness, voice changes, and breathing trouble
o This could have compromised her airways and resulted in dyspnea and wheezing (6)
Urticaria is commonly called hives, and presents as raised, well-circumscribed areas of erythema and edema that affects a more superficial layer of skin – the dermis and epidermis. Urticaria is very pruritic.(6)
Mechanism of Action for Allergy
Rachel’s allergic reaction is classified as type 1 hypersensitivity, an allergic reaction triggered by reexposure to a specific type of allergen, causing an IgE-mediated release of histamine and other pro-inflammatory mediators from mast cells and basophils. (7)
Rachel’s allergic reactionto Brazil nuts first required prior sensitisation to the specific antigen on Brazil nuts, the 9kDa 2S albumin. This had occurred more than 2 years before, when she was then diagnosed with Brazil nut allergy. The Brazil nut allergen protein is resistant to digestion in the human digestive system. Thus, this allowed for the protein to enter the body’s circulatory system and reproductive system, and then transferred during sexual intercourse via seminal fluid and ultimately reach her immune system to cause re-exposure anaphylaxis.
Phase 1 Sensitisation
The 9kDa 2S albumin protein is ingested and then detected and processed by an antigen-presenting cell (APC), such as a dendritic cell, macrophage or B-cell.
Next, the antigen-presenting cells move to the lymph nodes where the naïve TH cells reside. Following that, the APC prime naïve TH cells that possess the specific antigen receptors.
After antigen priming, the naïve TH cells differentiate into TH2 cells, which go on to release IL-4, IL-5, IL-9 and IL-13. IL-5 contributes to the development of eosinophils, and their recruitment and activation. IL-9 contributes to regulating the activation of mast cells.
IL-4 and IL-13 act on B cells to stimulate the production of antigen-specific IgE antibodies. (8)(9)(11)
Action of B cells
For antigen-specific IgE antibodies to be produced, B cells will first bind to the allergen through their allergen-specific receptors. Then, they process the antigen and produce peptides that are bound to the MHC class II molecules on B-cell surfaces, and present them to the antigen receptors on TH2 cells. IL-4 and IL-13 released by the TH2 cells will subsequently act on the B cell to cause class switching from IgM production to antigen-specific IgE production. (8)(9)
Phase 2 Clinical disease
The antigen-specific IgE antibodies are now able to bind to the high-affinity receptors presented on the mast cells and basophils surface and the sensitisation process is complete. During the second exposure of the immune system to the Brazil nut antigen, the antigen binds and cross-links the bound IgE antibodies on the mast cells and basophils, triggering a mass release of chemical mediators from these 2 cell types. (9)(10)
Major Mediators released and their effects as seen
Histamine
This binds to H1 and H2 receptors in the smooth muscles of the airway and gastrointestinal tract and causes the contraction of smooth muscles, increases vasopermeability and vasodilation, and pruritus.
Thus, histamine release is responsible for her faintness, caused by hypotension due to vasodilation. Also, her dypsnea is a result of the smooth muscle contraction of the airways, and increased vasopermeability resulted in urticarial and angioedema
Leukotriene B4: Augmentation of vascular permeability
Leukotriene C4 and D4: Potent bronchoconstrictors, increase vascular permeability
Leukotriene E4: Enhances bronchial responsiveness and increases vascular permeability
Prostaglandin D2: Produced mainly by mast cells, causes bronchoconstriction, increases histamine release from basophils
Thus, these pro-inflammatory mediators contribute to the contraction of her airways and vasopermeability which resulted in her physical symptoms. (12)
4 different types of hypersensitivity
How are allergies diagnosed/tested for?
During consultation with a GP, patients should describe symptoms, frequency of occurrence, and if they suspect any triggers. For mild allergies with a clear cause, GPs can offer advice and treatment. However, if the specific cause of allergies is not apparent, or if allergic reactions are more severe, patients are referred to a specialist allergy clinic for allergy testing. (13)
These are a few tests that are vital to allergy diagnosis
Skin Prick Testing
This is one of the most common allergy tests, and is painless and very safe. A drop of liquid that contains a substance the patient is suspected to be allergic to is placed onto his forearm. Following that, a needle is used to pierce the outer layer of skin, under the drop. After 15 minutes, if there is a positive allergic reaction, the skin around the prick will quickly become itchy and a red, swollen mark called a wheal will be present. The size of wheal is measured in comparison to other tested allergens (14)
Blood test
The main blood test uses RAST testing (radioallergosorbent) or fluorescence enzyme-labelled assays.
Both of these tests identify the specific IgE immune molecule for each allergen and can also determine the amount of IgE antibodies in the patient’s blood that has been produced by his immune system in response to an allergen. For example, determining the amount of antibodies for pollen in patient’s blood.
This result shows if the immune system has been exposed to the allergic substance before, but not whether an actual allergic reaction will happen. Thus, blood tests are a good screening tool but have to be used together with skin prick testing. (14)
Patch Test
Patch testing is a specialist procedure to find out whether a patient’s skin condition is caused or aggravated by coming into contact with a specific substance. It is used to help determine the cause of skin contact allergy or contact dermatitis – delayed type hypersensitivity (Type IV, non-IgE mediated reaction). There are approximately 40 substances which are most frequently in contact with the skin such as natural rubber latex, preservatives, metals, perfumes, cosmetics, leather chemicals, lanolin and plants among others. The suspected allergen is added in a small amount to special metal discs and taped to skin for 48 hours. The skin is then examined for possible reactions after 48 hours, and after 2-3 days later. (15)
Food Challenge
The patient is given food that he may be allergic to, in gradually increasing amounts to test reaction. This is only done in a hospital under close medical supervision. Food challenges are used when the patient may have an unclear history of food allergies, if blood and skin tests are not indicative enough for a specific food allergy, or if it is suspected that the patient has outgrown a food allergy. (16)
How are allergies treated?
Anaphylaxis is broadly defined as a severe, life-threatening, generalised or systemic hypersensitivity reaction by the European Academy of Allergology and Clinical Immunology Nomenclature Committee
This figure illustrates the ABCDE assessment of anaphylaxis and treatment procedure, included the dosage of drugs
In this case, namely Epipen, anti-histamines and oxygen therapy was used for her treatment.
Epipen
For laryngeal swelling and airway obstruction: Epinephrine (1:1000) should be administered IM at a dose of 0.01mg/kg or 0.3mg. This is then repeated every 10-15 minutes if necessary. Patients should also be admitted for at least 24 hours of observation
Pharmacodynamics
Alpha/Beta-adrenergic agonists will result in vasoconstriction and bronchodilation and reduce vascular permeability. Strong beta1 and moderate beta2-adrenergic effects causes bronchial smooth muscle relaxation to open airways
This is vital to treat acute angioedema associated with an allergic reaction affecting the upper airways, as it allows clears the tightness in airways and allows normal breathing to resume.
Dosage
Autoinjector: 0.3mg (contents of 1 autoinjector) intramuscularly once in anterolateral aspect of the thigh
– May repeat dose after 5-15 minutes if symptoms persist
– Intramuscular injection in the thigh (vastus lateralis muscle) results in the fastest rise of blood levels of epinephrine
– In comparison with subcutaneous (just under skin) injections: tigh muscle is large, greater supply of blood vessels allowing for multiple points of access for injected epinephrine to enter into the blood circulation, can hold a larger volume of medication (17)
Antihistamine: Cetirizine
Mechanism of Action
– Histamine H1-receptor antagonist; competes with histamine (for receptor sites) on effector cells in the GI tract, blood vessels, respiratory tract. Hence this iinhibits physiologic effects that histamine normally induces at H1 receptor sites
– Once-daily dosing
– Cetirizine is 2nd generation anti-histamine which is produced to be less sedative as it cannot pass blood-brain barrier (18)
Oxygen Therapy
Highest concentration of oxygen possible is given using an oxygen mask supplied with an oxygen reservoir (usually more than 10 litres per min). If the patient’s trachea is intubated, lungs have to be ventilate with high concentration oxygen using a self-inflating bag. (19)
Immunotherapy
This treatment is also otherwise known as desensitisation. The patient is given small doses of the allergen between long intervals of time over an extended period of time, through an injection, or drops, or as tablets under the tongue. The goal of this treatment is for the body to gradually get acclimatised to the allergen so that it does not react in the same severity over the periods of desensitisation. It aims to cause the allergic reaction to become milder over time so that less medication can be administered. As there is a risk of severe reactions happening in immunotherapy injections, it can only be performed at specialists clinics so doctors will be present to supervise. (20)
Conclusion
Both allergic reactions and sexually transmitted diseases can be prevented through the use of barrier contraceptives like condoms. For individuals with known allergies, it is important to keep medication by their side to relieve anaphylaxis. Although allergen testing is extensive, the diagnosis of nut allergy may be complicated by the variability of crossreactivity among different species of nuts, which can result in unexpected reactions to aeroallergens not previously suspected.
References
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