Immune System - Week 03 - PBL Case 1 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.  3.2 Virtual Patient - Abena Naylor Process of an allergic reaction and the cells involved Acute response In the early stages of allergy, a type I hypersensitivity reaction against an allergen encountered for the first time and presented by an antigen-presenting cell causes a response in TH2 lymphocytes, which belong to a subset of T cells that produce a cytokine called interleukin-4 (IL-4). There TH2 cells interact with B cells, coupled with signals provided by IL-4, this interaction stimulates the B cell to begin production of a large amount of a particular type of antibody known as IgE. Secreted IgE circulates in the blood and binds to an IgE-specific receptor (a kind of Fc receptor called FcεRI) on the surface of mast cells and basophils, which are both involved in the acute inflammatory response. The IgE-coated cells are sensitized to the allergen. If later exposure to the same allergen occurs, the allergen can bind to the IgE molecules held on the surface of the mast cells or basophils. Cross-linking of the IgE and Fc receptors occurs when more than one IgE-receptor complex interacts with the same allergenic molecule, and activates the sensitised cell. Activated mast cells and basophils undergo a process called degranulation, during which they release histamine and other inflammatory chemical mediators (cytokines, interleukins, leukotrienes, and prostaglandins) from their granules into the surrounding tissue causing several systemic effects, such as vasodilation, mucus secretion, nerve stimulation, and smooth muscle contraction. This results in rhinorrhea (runny nose), itchiness, dyspnea, and anaphylaxis. Depending on the individual, allergen, and mode of introduction, the symptoms can be systemic, or located to particular body systems (e.g. asthma is localised to the respiratory system) Late-phase response After the chemical mediators of the acute response subside, late-phase responses can often occur. This is due to the migration of other leukocytes such as neutrophils, lymphocytes, eosinophils, and macrophages to the initial site. The reaction is usually seen 2-24 hours after the original reaction. Cytokines from mast cells may play a role in the persistence of long- term effects. Hypersensitivity A person who is overly reactive to a substance that is tolerated by most other people is said to be allergic or hypersensitive. Whether an allergic reaction takes place, some tissue injury occurs. The antigens that induce an allergic reaction are called allergens (e.g. milk, peanuts, antibiotics). There are four basic types of hypersensitivity reactions: type I (anaphylactic), type II (cytotoxic), type III (immune-complex), and type IV (cell-mediated). The first three are antibody-mediated immune responses; the last is a cell-mediated immune response. Type I (anaphylactic) Type I reactions are the most common and occur within a few minutes after a person sensitized to an allergen is re-exposed to it. In response to the first exposure to certain allergens, some people produce IgE antibodies that bind to the surface of mast cells and basophils. The next time the same allergen enters the body, it attaches to the IgE antibodies already present. In response, the mast cells and basophils release histamine, prostaglandins, leukotrienes, and kinins. Collectively, these mediators cause vasodilation, increase blood capillary permeability, increase smooth muscle contraction in the airways of the lungs, and increase mucus secretion. As a result, a person may experience inflammatory responses, difficulty in breathing through the constricted airways, and a runny nose from excess mucus secretion. In anaphylactic shock, which may occur in a susceptible individual who has just received a triggering drug or been stung by a wasp, wheezing and shortness of breath as airways constrict are usually accompanied by shock due to vasodilation and fluid loss from blood. This life threatening emergency is usually treated by injecting epinephrine to dilate the airways and strengthen the heartbeat. Type II (cytotoxic) Type II reactions are caused by antibodies (IgG or IgM) directed against antigens on a person's blood cells (RBCs, WBCs, or platelets) or tissue cells. The reaction of antibodies and antigens usually leads to activation of complement. Type II reactions, which may occur in incompatible blood transfusion reactions, damage cells by causing lysis. Type III (immune-complex) Type III reactions involve antigens, antibodies (IgA or IgM), and complement. When certain ratios of antigen to antibody occur, the immune complexes are small enough to escape phagocytosis, but they become trapped in the basement membrane under the endothelium of blood vessels, where they activate complement and cause inflammation. Glomerulonephritis and rheumatoid arthritis arise in this way. Type IV (cell-mediated) Type IV reactions or delayed hypersensitivity reactions usually appear 12-72 hours after exposure to an allergen. Type IV reactions occur when allergens are taken up by antigen-presenting cells (such as intraepidermal macrophages in the skin) that migrate to lymph nodes and present the allergen to T cells, which then proliferate. Some of the new T cells return to the site of allergen entry to the body, where they produce gamma-interferon, which activates macrophages, and tumor necrosis factor, which stimulates an inflammatory response. Intracellular bacteria such as Mycobacterium tuberculosis trigger this type of cell- mediated immune response, as do certain haptens, such as poison ivy toxin. The skin test for tuberculosis also is a delayed hypersensitive reaction. Hyposensitisation During hyposensitisation the aim is to expose a patient with sensitivity to a known allergen, to progressively larger doses of the allergen so that the severity of their hypersensitive response is reduced or even abolished. Allergen immunotherapy involves the administration of gradually increasing quantities of specific allergens to patients with IgE-mediated conditions until a dose is reached that is effective in reducing severity from natural exposure. The administration of escalating doses gradually decreases IgE-dominated response, the objective is to direct the immune response away from humoral immunity and toward cellular immunity, thereby encouraging the body to produce less IgE antibodies and more TH1 regulatory T cells, which secrete IL-10 and/or TGF-β, which skew the response away from IgE production.  Progressive exposure to the allergen leads to IgG production rather than the IgE production which occurs in type I allergic responses. The patient is observed for an hour after the injection, if the patient develops any symptoms they need to be observed until these completely resolve Self-recognition, self-tolerance and auto-immune diseases To function properly, your T cells must have two traits: They must be able to recognise your own MHC proteins, a process known as self- recognition They must lack reactivity to peptide fragments from your own proteins, a condition known as self-tolerance B cells also display self-tolerance. Loss of self tolerance leads to the development of autoimmune diseases. Pre-T cells in the thymus develop the capability for self-recognition via positive selection. In this process, some pre-T cells in the thymus express T-cell receptors that interact with self- MHC proteins on epithelial cells in the thymic cortex. Because of this interaction, the T cells can recognise the MHC part of an antigen-MHC complex - these T cells survive. Other immature T cells that fail to interact with thymic epithelial cells are not able to recognise self-MHC proteins - these cells undergo apoptosis. The development of self-tolerance occurs by negative selection in which the T cells interact with dendritic cells located at the junction of the cortex and medulla in the thymus. In this process, T cells with receptors that recognise self-peptide fragments or other self-antigens are eliminated or inactivated. The T cells selected to survive do not respond to self-antigens, the fragments of molecules that are normally present in the body. Negative selection occurs via both deletion and anergy. In deletion, self reactive T cells undergo apoptosis and die In anergy they remain alive but are unresponsive to antigenic stimulation One T cells have emerged from the thymus, they may still encounter an unfamiliar self- protein; in such cases they may also become anergic if there is no costimulator. Deletion of self-reactive T cells may also occur after they leave the thymus. B cells also develop tolerance through deletion and anergy. While B cells are developing in bone marrow, those cells exhibiting antigen receptors that recognise common self-antigens (such as MHC proteins or blood group antigens) are deleted. Once B cells are released into the blood, however, anergy appears to be the main mechanisms for preventing responses to self-proteins. When B cells encounter an antigen not associated with an antigen-presenting cell, the necessary costimulation signal often is missing. In this case, the B cell is likely to become anergic (inactivated) rather that activated. Autoimmune diseases In an autoimmune disease (autoimmunity), the immune system fails to display self- tolerance and attacks the person's own tissue. Self-reactive B cells and T cells normally are deleted or undergo anergy during negative selection. However, this process is not 100% effective. Under the influence of unknown environmental triggers and certain genes that make some people more susceptible, self-tolerance breaks down, leading to activation of self-reactive clones of T cells and B cells. These cells then generate cell-mediated or antibody-mediated immune responses against self-antigens. Types A variety of mechanisms produce different autoimmune diseases. Some involve production of autoantibodies (antibodies that bind to and stimulate or block self-antigens). Graves disease - autoantibodies mimic TSH (thyroid stimulating hormone) and stimulate secretion of thyroid hormones (thus producing hyperthyroidism),  multisystemic consequences include goiter (swelling in the front part of the neck) and protruding eyes Myasthenia gravis - autoantibodies bind to and block acetylcholine receptors causing muscle weakness, multisystemic consequences include double vision, dysphagia and facial weakness Other autoimmune diseases involve activation of cytotoxic T cells that destroy certain body cells. Type 1 diabetes mellitus - T cells attack the insulin-producing pancreatic beta cells, multisystemic consequences include abdominal pain, hyperventilation, and weight loss Multiple sclerosis - T cells attack myelin sheaths around axons of neurons Inappropriate activation of helper T cells or excessive production of gamma-interferon also occur in certain autoimmune diseases. Other autoimmune disorders include rheumatoid arthritis, systemic lupus erythematosus, rheumatic fever, hemolytic and pernicious anaemias, Addison's disease, Hashimoto's thyroiditis, and ulcerative colitis. Pharmacology of Chlorphenamine, hydrocortisone and adrenaline Chlorphenamine (antihistamine) Chlorphenamine binds to the histamine H1 receptors. This blocks the action of endogenous histamine, which subsequently leads to temporary relief of the negative symptoms brought on by histamine (sneezing, watery and itchy eyes, runny nose). Common side effects may include dizziness, drowsiness, dry mouth, nose, or throat, and constipation. Hydrocortisone (glucocorticoid) Hydrocortisone binds to the cytosolic glucocorticoid receptor. After binding, the newly formed receptor-ligand complex translocates itself into the cell nucleus, where it binds to many glucocorticoid response elements in the promoter region of the target genes. The DNA bound receptor then interacts with basic transcription factors, causing the increase in expression of specific target genes. Specifically glucocorticoids induce lipocortin-1 (annexin-1) synthesis, which then binds to cell membranes preventing the phospholipase A2 from coming into contact with its substrate arachidonic acid. This leads to diminished eicosanoid production. The cyclooxygenase (both COX-1 and COX-2) expression is also suppressed, potentiating the effect. In other words, the two main products in inflammation Prostaglandins and Leukotrienes are inhibited by the action of Glucocorticoids.  Glucocorticoids also stimulate the lipocortin-1 escaping to the extracellular space, where it binds to the leukocyte membrane receptors and inhibits various inflammatory events: epithelial adhesion, emigration, chemotaxis, phagocytosis, respiratory burst and the release of various inflammatory mediators (lysosomal enzymes, cytokines, tissue plasminogen activator, chemokines etc.) from neutrophils, macrophages and mastocytes. Additionally the immune system is suppressed by corticosteroids due to a decrease in the function of the lymphatic system, a reduction in immunoglobulin and complement concentrations, the precipitation of lymphocytopenia, and interference with antigen-antibody binding. Side effects and toxicity occur mainly with prolonged systemic use as an anti- inflammatory or immunosuppressive. Adrenaline The actions of adrenaline resemble the effects of stimulation of adrenergic nerves. To a variable degree it acts on both alpha and beta receptor sites of sympathetic effector cells. Its most prominent actions are on the beta1 receptors of the heart, vascular and other smooth muscle. When given by rapid intravenous injection, it produces a rapid rise in blood pressure, mainly systolic, by: Direct stimulation of cardiac muscle which increases the strength of ventricular contraction Increasing the heart rate Constriction of the arterioles in the skin, mucosa and splanchnic areas of the circulation. When given by slow intravenous injection, adrenaline usually produces only a moderate rise in systolic and a fall in diastolic pressure. Although some increase in pulse pressure occurs, there is usually no great elevation in mean blood pressure.