Week 03 - PBL Case 01 - Abena Naylor PDF

THE IMMUNE SYSTEM – WEEK 03 – PBL CASE 01: ABENA NAYLOR Summary: 31 Y/0 female with a wasp sting causing periorbital and lip oedema. She also has an elevated BP and heart rate. After being injected with IM drugs, her BP was back to normal however the oedema remained. She is concerned that this episo...

THE IMMUNE SYSTEM – WEEK 03 – PBL CASE 01: ABENA NAYLOR Summary: 31 Y/0 female with a wasp sting causing periorbital and lip oedema. She also has an elevated BP and heart rate. After being injected with IM drugs, her BP was back to normal however the oedema remained. She is concerned that this episode would result in rheumatoid arthritis. Terms and definitions Periorbital: Oedema around the eyes Chlorpheniramine: A H1 histamine reverse agonist Hydrocortisone: A glucocorticoid nuclear receptor agonist Epipen: Auto-injector of adrenaline Hypersensitisation: Allergen immunosuppression therapy aimed at decreasing or eliminating the body’s immune response to a certain allergen by exposure to it. L.O.1 – Typical reaction to a wasp sting and the consequences in an individual with an allergy to wasp venom Hyper-sensitivity It occurs when the immune system responds abnormally, causing potential harm to the body. A symptomatic reaction only occurs in sensitised individuals. It can be categorised into 4 types of reactions; - Type I: These are immediate allergic reactions – Food, asthma, anaphylaxis, pollen allergies - Type II: These are cytotoxic as they involve antibodies that are specific to particular tissues within the body and cause destruction of cells within these tissues – Autoimmune haemolytic anaemia - Type III: These are immune complex-mediated. Tissue damage is caused by antigen-antibody complex deposition - Type IV: These are delayed. They are cell-mediated and are the only hyper-sensitized reactions that involve T-cells rather than antibodies Hyper sensitivity can be caused by; - Infection - Environmental substances - Self-antigens In a wasp bite Allergen: Antigens that cause allergy (abnormal immune response to a harmless stimulus). They are small proteins but often contain protease. They usually mediate a TH2 immune response. TH2 cells are a distinct lineage of CD4+ cells and are involved in the secretion of several interleukins. They help regulate the humoral immune response to extracellular parasites and bacterial infections. The TH2 immune response is characterised by the presence of eosinophils and basophils and mast cell degranulation due to cross linking of surface bound IgE. Atopy is a term used to describe a predisposition for an IgE-mediated response This is a type I hyper-sensitivity reaction. Sensitisation The body’s immune system comes into contact with the allergen. The allergen is binds to receptors on APCs. Part of the antigen is transferred to the MHC molecule and is presented on the APC. When the receptor of the naive T-helper cell binds to the complex, it differentiates into a TH2 cell. This is due to the effect if certain cytokines like IL4 which is found locally. The activated TH2 cell releases cytokines like IL5, IL4 and IL13. - IL4 activates more TH2 cells. It also causes the class switching of B cells. That is, instead of antibodies forming IgM antibodies, produce antigen specific IgE antibodies. - IL5 activates and recruits eosinophils. - IL13 also enhances IgE production, as well as stimulates epithelial cells to produce mucous. These antibodies have 2 variable regions which can be used to bind to the specific antigen, in this case, the allergen. The constant region (FC portion) docks to a surface receptor on a mast cell/basophil. Mast cells and basophils have high affinity receptors called FcεR1. Mast cells are now able to respond when exposed to the same allergen. The half-life of the IgE is now increased. Re-exposure – Immediate reaction This occurs 5-30 minutes after exposure and may subside within an hour. Upon exposure, the allergen binds to the IgE receptors, cross linking the adjacent receptors. This activates the mast cell/basophil inducing the release of vesicles filled with inflammatory mediators. This is known as degranulation. There are preformed mediators and newly synthesised mediators. The preformed mediators include; - Histamine - Enzymes like tryptase and chymase: Activates the complement system - Eosinophil chemotactic factors Newly synthesised mediators are usually arachidonic acid derivatives like; - Cytokines (i.e. TNF-alpha): Induces inflammation. IL4 activates TH2 cells and IL5 recruits eosinophils. - Leukotrienes: C4 and D4 causes much stronger smooth muscle contraction than histamines and increases vascular permeability. Leukotriene B4 causes chemotaxis of neutrophils, monocytes and eosinophils. - Prostaglandin: PDG2 causes bronchospasms, increased vascular permeability and vasodilation. Histamine Causes smooth muscle contraction of airways causing breathing difficulties, vasodilation causing an increased blood flow locally and increased vascular permeability promoting oedema. It acts as a chemo attractant to other WBC like eosinophils and neutrophils. Also causes pain and pruritus (itch) by stimulating peripheral nociceptive receptors Re-exposure – Late response This occurs 2-24 hours after exposure. It is caused by the effects of leukotrienes and cytokines from the early phase. There is migration of leukocytes, mainly eosinophils. Eosinophils release substances like peroxidases that cause further tissue damage. L.O.2 – Role of histamine antagonists and glucocorticoids in treatment of allergic reactions Antihistamines There are 2 main groups of antihistamines; - H1 antihistamines - H2 antihistamines H1 antihistamines are of 2 generations. The 1st generation has more of central effect and are more often used as sedatives. The 2nd generation have less central effect and are used more often as anti- allergy drugs. H2 antihistamines primarily target gastric reflux disease as they reduce the production of gastric acid by blocking the H2 receptors in the parietal cells of gastric mucosa. Most H1 and H2 antagonists are contraindicated during childhood and pregnancy. H1 antagonists There is competitive, reversible antagonism of the H1 receptors. They target the H1 receptors found on smooth muscle (especially bronchial and nasopharyngeal lining), vascular endothelial cell surfaces, the heart and the CNS. Their effects include; - Reduces hypotension and oedema by preventing vasodilation and reducing the effects of increased vascular permeability. - Reduces bronchoconstriction by preventing smooth muscle contraction - Reduces mucous production is nose and bronchi as histamines produce more and thinner mucous - Reduces pain and pruritus (itch) caused by activation of peripheral nociceptive receptors - Decreases conduction in AV node 1st generation antihistamines Used as a sedative and antiemetic. Used in treatment of; - Motion sickness - Anaphylactic shock - Anti-allergic agent, pruritus Drugs in this category include Chlorpheniramine, Promethazine 2nd generation antihistamines Used to treat; - Anaphylactic shock - Pruritus - Anti-allergic agent: Rhinitis, urticaria, hypersensitivity to drugs Drugs in this category include Fexofenadine, Cetirizine and Loratadine  H2 antagonists include Ranitidine, Cimetidine. Glucocorticoids These drugs have anti-inflammatory, immunosuppressive, endocrine and metabolic effects. They have structural and pharmacological similarities to the endogenous hormone cortisol. They have immediate effects that don’t depend on DNA interaction (i.e. vasodilation), however they exert their main anti-inflammatory and immunosuppressive actions by binding to glucocorticoid receptors which in turn cause complex changes in gene transcription. Systemic glucocorticoids are used for hormone replacement therapy (i.e. in Addison’s disease), for acute and chronic inflammatory diseases (i.e. rheumatoid arthritis) and immunosuppression. Local glucocorticoids are used to treat conditions like dermatoses (any disease of the skin, particularly those unaccompanied by inflammation) and asthma. They can be administered topically, via local injections, by inhalation, orally or by parenteral means (IM, SC, IV). Their effects are; Anti-inflammatory and immunosuppressive  Acute effects (within minutes) - Decreased vasodilation and decreased capillary permeability - Decreased leukocyte migration to inflammatory foci (points)  Long-term effects (within hours) Is caused by the binding of glucocorticoids to cytoplasmic glucocorticoid receptors - Inhibits neutrophil apoptosis and demargination (loss of neutrophil binding to adhesive endothelial integrin molecules); neutrophilic leucocytosis - Promotion of apoptosis in eosinophils, monocytes and lymphocytes - Inhibition of phospholipase A2 which decreases the production of arachidonic acid derivatives (synthesized mediators for hypersensitivity reactions) - Inhibition of transcription factors causing the decrease of pro-inflammatory genes It translocates to the cell nucleus and binds to glucocorticoid responsive elements within the promoters of anti-inflammatory genes (I.e. IL10) - Increases expression of anti-inflammatory genes Mineralocorticoid properties Reduced Na+ excretion and increased K+ excretion Anti-proliferative effects Triggers cell apoptosis and inhibits fibroblast (involved in wound healing) proliferation Anabolic-androgenic effects with steroid abuse Increased muscle mass and strength Drugs include Beclomethasone (local), Prednisolone, and Hydrocortisone (medication form of cortisol) L.O.3 – Summarise the approaches taken for a patient with an anaphylactic reaction Anaphylactic reaction? Assess: Airway, Breathing, Circulation, Disability, Exposure Diagnosis- Look for: 1 Acute onset of illness Life-threatening features And usually skin changes +/- Exposure to known allergen +/- Gastrointestinal symptoms Call for help Lie patient flat and raise legs if breathing is not impaired Adrenaline When skills and equipment available: A. Establish airway B. High flow oxygen Monitor: 3 C. IV fluid challenge Pulse oximetry 4 Chlorphenamine ECG 5 Hydrocortisone Blood pressure Airway – Airway swelling, breathing and swallowing difficulties, hoarse voice, stridor (high pitched wheezing sound), and feeling of throat closing (Stridor: large airways, wheeze: smaller airways) Breathing: Shortness of breath, increased RR, wheezing, tiredness, hypoxia-induced confusion, cyanosis, respiratory arrest Circulation – Signs of shock (pale, clammy), tachycardia, hypotension, decreased level of consciousness, angina and cardiac arrest (Bradycardia) (DONT LET PATIENT STAND) Disability: Sense of impending doom, anxiety, panic, decreased consciousness level Exposure: Look for skin changes; Often the first feature present in >80% of anaphylactic reactions. Can be either/both skin and mucosal. Includes; - Erythema: Patchy or generalised red rash - Urticaria: Raised, red and itchy bumps or wheals - Angioedema: Swelling of deeper tissue (i.e. eyelids, lips and sometimes mouth and throat) L.O.4 – Explain why individuals don’t normally produce immune responses to self-antigens T-cells mature in the thymus. Approximately 98% of the precursors of T-cells (thymocytes) die before the completion of the maturation process. Thymocytes produced n bone marrow don’t express the T-cell receptor complexes (CD4+/CD8+). Once in the thymus, they are matured to form these complexes. Initially the cells are subjected to positive selection (cortex of the thymus). The cells that have T-cell receptors that can bind to class I or class II MHC molecules survive this selection while those that don’t undergo apoptosis and die. The cell population that survives is subjected to negative selection (medulla of the thymus). Here, the T cells that bind with high affinity to MHC complexes that are bound to self-peptides expressed on the surface of APCs in the thymus undergo apoptosis or are otherwise suppressed. Those that do not bind too avidly to any such MHC complexes complete maturation to form cytotoxic T cells or T helper cells. This negative selection step leads to self-tolerance. The HLA system is important in this as each individual has 6 HLA antigens in a combination unique to themselves. Similar mechanisms apply to B cells, suppressing B cells that express antibodies that interact strongly with self-antigens. T regulatory cells also function to control the effects of the TK cells and limit the damage it might inflict on tissues. L.O.5 – Nature of auto-antibodies and the way they may cause disease Autoantibodies They are antibodies that react with self-antigens. These may be found in all cell types (chromatin, centromeres) or be highly specific for a special cell type in one organ of the body (i.e. thyroglobulin cells of the thyroid gland). They made me made of proteins, nucleic acids, carbohydrates, lipids or various combinations of these. They are usually IgM antibodies. In disease Auto-antibodies can destroy healthy cells in auto-immune disorders. The causes are for this are mainly idiopathic. Other reasons include; - Previous infection (Guillain-Barre syndrome, rheumatic fever) - Genetic predisposition (Myasthenia gravis, Rheumatoid arthritis) Mechanisms leading to autoimmunity A) Molecular mimicry: Infectious agents have similar amino acid sequences or structure to the host’s self-antigens. The immune response eventually turns against self-antigens on host cells as a result of cross reactivity, leading to activation of naïve, auto-reactive T cells specific to the particular self-molecule B) Protein changes, cryptic antigens: Following tissue injury, cell death, oxidative stress, free radical production and reparative changes that occurs in several infections, proteins that are normally identified as self can become non-self. Also, proteins that are normally shielded/sequestered from immune recognition can be exposed to the immune system. Hence cryptic antigens become accessible to self-reacting T lymphocytes that escape central and peripheral tolerance. C) Super-antigens: These are proteins produced by a variety of microorganisms, especially bacteria or mycoplasma or virus infected cells that can bind to T cell receptors irrespective of antigen specificity. This activates a large number of T lymphocytes of different antigenic specificity, thus acting as a potent immune-stimulating molecule D) Bystander action: The enhanced processing and presentation of self-antigens induce the expansion of the immune response towards different self-antigens. This is known as epitope spreading. It is widely involved in the pathogenesis of many systemic autoimmune diseases as well as determining the expression of such diseases. Prebiotic and probiotic??? L.O.6 – Examples of diseases resulting from auto-immunity and explain the multi-system consequences Auto-immune diseases The reasons that autoimmune diseases develop are not completely understood, but are thought to involve a genetic predisposition combined with an environmental trigger, such as a viral illness or a prolonged exposure to certain toxic chemicals. There may also be a hormonal component, as many autoimmune conditions are more common in women of childbearing age. The type of autoimmune disorder or disease that occurs and the amount of destruction done to the body depends on which systems or organs are targeted by the immune system. Disorders that primarily affect a single organ, such as the thyroid in Graves’ disease or Hashimoto thyroiditis, are often easier to diagnose as they frequently present with organ- related symptoms. Autoimmune diseases that affect multiple organs or systems, called systemic autoimmune disease, can be much more difficult to diagnose and hence there can sometimes be delays in diagnosis. The signs and symptoms they cause can be multi-fold and non-specific e.g. arthritis-type joint pain, fatigue, fever, rashes, cold or allergy-type symptoms, weight loss, and muscle pain or weakness. Additional complications may include vasculitis and anaemia. Signs and symptoms will vary from person to person and they can vary over time, tapering off and then flaring up unexpectedly. To complicate the situation, some people may have more than one autoantibody or even more than one autoimmune disorder. There are also people who have an autoimmune disorder without a detectable autoantibody. These circumstances can make it difficult to identify the prime cause and arrive at a diagnosis.