Week 4: Over Active Immune Systems Flashcards
Describe Type 1 Hypersensitivity reactions
Type 1 is an IgE mediated reaction. Mast cells have IgE specific FC region receptors on their cell membranes. Antigen binding to at least two molecules of IgE on the cell membrane of a mast cell leads to cross linking which triggers cell degranulation. Degranulation leads to the release of inflammatory mediators and cytokines. This release results in the clinical features seen in type 1 hypersensitivity. Common conditions include seasonal rhinitis (hay fever), asthma and anaphylaxis. These reactions are rapid, occurring within minutes and hence type 1 hypersensitivity is also called immediate hypersensitivity. Atopy is a term used to for IgE mediated hypersensitivity and individuals affected are described as ‘atopic’.
Describe the Sensitization Phase of Type 1 Hypersensitivity reactions
An allergic reaction first requires sensitisation to a specific allergen (antigen) and occurs in genetically predisposed individuals. The antigen is processed by an antigen – presenting cell and presented to TH2). The TH2 cells produce cytokines which promote B cell specific IgE antibody synthesis on encountering the same antigen. The IgE antibodies produced by the B cell attach to the FC receptors on mast cells.
Describe the Activation Phase of Type 1 Hypersensitivity reactions
Re exposure to the antigen can lead to antigen binding and cross linking of the IgE molecules on the mast cells. Cross linking leads to calcium influx and rapid degranulation with the release of preformed mediators.
Describe the Effector Phase of Type 1 Hypersensitivity reactions
The symptoms and signs produced are the result of inflammatory mediator release from mast cells. Histamine release causes contraction of smooth muscles of the airway (bronchospasm) and GI tract, increased vascular permeability and vasodilation (oedema and fall in blood pressure), mucus production, itching, cutaneous vasodilation, and gastric acid secretion.
Chemotactic factors released from mast cells attract eosinophils, neutrophils, basophils, macrophages, platelets and lymphocytes to the site. Eosinophils and neutrophils can cause significant tissue damage in the later phases of allergic reactions.
Describe Type 2 Hypersensitivity reactions
Type 2 hypersensitivity reactions involve binding of antibody directly to an antigen on the surface of a cell. The cell is then damaged through either:
Complement mediation leading to cell lysis or opsonisation and phagocytosis.
Antibody dependent cell mediated cytotoxicity. Antibody – mediated cellular dysfunction. Antibody binding to cell membrane antigens activates the complement cascade which leads to cell lysis (through the membrane attack complex) or opsonisation (through C3b) and phagocytosis by macrophages. An example is the transfusion of ABO – incompatible blood resulting in complement mediated lysis. In antibody-dependent cell mediated cytotoxicity (ADCC) IgG coated target cells are killed by cells with Fc receptors for IgG (NK cells). Binding to the Fc receptors releases cytoplasmic granules that lead to cell apoptosis.
When autoantibodies bind to cell surface receptors they may impair cell function. For example, antagonistic autoantibodies react with acetylcholine receptors in the motor end plates which impairs neuromuscular transmission (myasthenia gravis). In Graves’ disease, the autoantibodies stimulate TSH receptors on thyroid cells and cause hyperthyroidism.
Describe Type 3 Hypersensitivity reactions
Type 3 hypersensitivity results from the presence of immune complexes in the circulation or in the tissues. Normally, circulating immune complexes are removed by phagocytic cells. Phagocytosis is facilitated by Fc receptors for IgG on the phagocytes. Red blood cells have C3b receptors that bind the complement fixed on the immune complexes transporting them to the liver where the complexes are phagocytosed by the Kupffer cells The system may be overwhelmed leading to deposition of immune complexes in the tissues for example the kidneys, skin and joints. Tissue injury results from fixation of complement and activation of the complement cascade with the release of biologically active fragments. The activation of the classical pathway produces C3a and C5a which stimulate mast and basophil cells to release chemokines which attract basophils, eosinophils, macrophages and neutrophils to the area. Clinical examples of type 3 hypersensitivity include serum sickness, systemic lupus erythematosus, glomerulonephritis and extrinsic allergic alveolitis.
Describe Type 4 Hypersensitivity reactions
Type 4 hypersensitivity is T cell-mediated and involves the activation, proliferation and mobilisation of antigen specific T cells. Type 4 hypersensitivity is also referred to as delayed hypersensitivity. Delayed hypersensitivity reactions can result in tissue damage through the release of large quantities of cytokines by the activated T cells. Chemokines attract other non-antigen specific cells including monocytes and macrophages. It is the recruitment and activation of these cells that leads to the tissue damage seen in delayed hypersensitivity.
what is an autoimmune response
When an immune response is directed against a self-antigen it is called an autoimmune response. Antibodies raised against the self-antigen or T cells reacting with self-antigens may cause damage to the tissues. Disorders in which chronic inflammation is present are called immune mediated inflammatory diseases they may be auto immune but may be directed against commensal bacteria
The majority of autoimmune diseases are believed to be caused by inheritance of susceptible diseases or environmental triggers. However, in order to diagnose an autoimmune disease there are at least three requirements:
Presence of an immune reaction specific for a self-antigen or self- tissue.
Evidence that such a reaction is not secondary to tissue damage but is the primary pathogenic cause.
Alternative causes of the disease are absent.
What is the most significant allele associated with autoimunue disease?
The genetics behind the inheritance of autoimmune disease is often complex and associated with multiple gene loci. The most significant of which is the MHC allele. This demonstrates the importance of T cells in autoimmune diseases as MHCs present to T cells.
The strength of the association between the occurrence of an autoimmune disease and the presence of a particular HLA gene is known as the relative risk.
Not all autoimmune diseases are associated with changes in HLA genes, there are a number of autoimmune diseases caused by polymorphisms in other genes too.
Describe Hashimoto’s Thyroiditis
Autoimmune damage to the thyroid, primarily by the humoral response, results in decreased function and clinical hypothyroidism. It is characterised by the presence of circulating antibodies to thyroglobulin and thyroid peroxidase.
The aetiology of this disease is generally unclear, but may include initial damage to the organ from either a viral infection or trauma. Treatment includes hormone replacement.
Describe Grave’s disease.
Graves’ disease is characterised by hyperthyroidism. Autoantibodies are produced which are directed against the receptor for Thyroid Stimulating Hormone (TSH) which is expressed on thyroid follicular cells, and these antibodies stimulate the chronic overproduction of thyroid hormone.
The antibody acts as an agonist for its target molecules stimulating TSH activity, as opposed to an antagonist.
Treatment commonly involves reducing thyroid function by surgery or radioactive iodine.
Describe Multiple Sclerosis
Multiple sclerosis is characterised by inflammatory demyelination in the central nervous system. Its causes are unknown, although the appearance of high levels of antibodies to measles and other viruses suggests a connection with viral infection. CMI involving CD8+ T-cells specific for myelin basic protein (MBP) is responsible for the demyelination.
Describe Myasthenia gravis.
Myasthenia gravis is associated with circulating antibodies against the AcCh receptor, resulting in progressive muscle weakening. There is also a frequent presence of structures resembling germinal centres within the thymus. It can be treated with anti-cholinesterase drugs together with immunosuppressive therapy. Thymectomy is often beneficial in treating this disease for reasons which aren’t fully clear, although cells producing anti-AcCH antibodies have been found within these ectopic germinal centres.
Describe RA
During Rheumatoid Arthritis (RA) autoantibodies are directed against the Fc fragment of IgG. The anti-IgG autoantibodies are known as rheumatoid factor, and are mostly IgM (but may be IgG). The resulting immune complexes may be deposited in various sites within the vasculature and the joints. In either location, they can cause tissue damage through the fixation of complement and the attraction of PMN’s; these processes result in the synovitis and vasculitis.
Describe SLE
Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies to a wide variety of autoantigens, including DNA, RNA, histones, ribonucleoproteins and other nuclear and cellular elements. These antibodies are associated with a pattern of damage to an equally wide variety of tissues and organs including skin lesions (erythema) and damage to the vocal cords which results in a characteristic hoarseness. It is believed to arise, in part, due to a loss of the suppression mechanisms that control self- reactive cells.
Define Hypersensitivity
Hypersensitivity is an exaggeration of the normal immune processes leading to tissue damage
Which immunoglobulin mediates Type 1 Hypersensitivity reactions
IgE mediated hypersensitivity
Define atopy
immediate hypersensitivity reaction to environmental antigens mediated by IgE
Define Atopy trait
risk of reactions run in families • Asthma, hay fever, eczema
Describe the role of mast cells in type 1 hypersensitivity reactions
In tissues IgE Fc receptors Granules Proteolytic enzymes (tryptase) Increase SM contraction (bronchi) Activate complement (inflammation) Histamine SM contraction (Gut & Lungs) Vascular permeability (endothelial cell contraction) Chemotactic for white cells Itching Cytokines TNF (diapedesis) IL4 (activate TH2) IL 3 & 5 (stimulate eosinophils)
What are the physical effects of Mast cell degranulation and what symptoms/signs may this result in?
- Vasodilatation - Hypotension
- Increase vascular permeability – swelling, urticaria
- Fluid shifts from vascular to extravascular - swelling
- Fall in vascular tone – Hypotension
- Smooth muscle contraction (bronchi) - wheeze
What are the signs/symptoms of type 1 hypersensitivity reactions?
- Cutaneous/ocular - Flushing, urticaria, angioedema, cutaneous and/or conjunctival pruritus, warmth, and swelling
- Respiratory - Nasal congestion, rhinorrhoea, throat tightness, wheezing, shortness of breath, cough, hoarseness
- Cardiovascular - Dizziness, weakness, syncope, chest pain, palpitations
- Gastrointestinal - Dysphagia, nausea, vomiting, diarrhoea, bloating, cramps
- Neurologic - Headache, dizziness, blurred vision, and seizure (very rare and often associated with hypotension)
- Other - Metallic taste, feeling of impending doom
How is adrenaline used to treat type 1 hypersensitivity reactions?
Adrenaline – α and β-adrenergic decreases vascular permeability, increases blood pressure, reverses airway obstruction
Which immunoglobulin mediates Type 2 Hypersensitivity reactions
IgG or IgM binding to surface of cells
Describe farmers lung as a type 3 hypersensitivity reaction
Farmers lung
Farmer SOB cough & fever on several occasions after feeding cattle (hay).
IgG to mould extract
Challenge to mould spores - symptoms
what is SLE?
A multisystem disease characterised by the presence of autoantibodies to a many self-antigens, affecting a wide variety of tissues and organs.
• Auto immune disease mediated by immune complexes
• Antibodies against DNA and other nuclear components
• Loss of T cell tolerance to DNA
• Genes (Twins, HLA DR2, debris clearing proteins (MBL, C1q)) • Drugs (inhibit DNA clearance)
• Female 20:1
Aetiology
Most common in African-Caribbean women, ages 25-35 years
• UV light
• Joint, skin and kidney involvement
Why is type 4 hypersensitivity reactions also known as delayed?
- Slowest form of hypersensitivity mediated by T cells
- 2-3 days after exposure to antigen
- TH1 cells driving inflammatory response mediated by macrophages
list examples of type 4 hypersensitivity reactions
- Physiological response to pathogens hard to clear • Mycobacterium and Hepatitis B virus
- Response to environmental antigens • Nickel contact dermatitis
- Response to autoantigens
- Type 1 diabetes mellitus (TH1 cell response to islet cell antigens) • Rheumatoid arthritis, multiple sclerosis, coeliac disease
What is an autoimmune disease?
• Where the body reacts to a self-antigen using antibodies or T cells
• Clinical presentations can be very varied and sometimes vague • T1DM - T cells and antibodies against one organ (pancreas)
• Systemic Lupus Erythematous – antibodies against many tissues
• Important genetic link is the MHC allele
• Demonstrates the importance of T cells in autoimmune diseases
(as MHCs present to T cells)
What is the pathophysiology of Rheumatoid Arthritis
A systemic autoimmune disorder affecting the synovial joints with extra-articular manifestations
Anti-IgG autoantibodies known as Rheumatoid Factor are directed against the Fc fragment of IgG.
Aetiology
Prevalence 1-3%, F > M, peak age of onset 40 year
what investigations do you run in a suspected case of RA?
Bloods
• ESR andCRP
• Anaemia of chronic disease • Low albumin
Immunology
• Rheumatoid factor (RhF), anti-CCP Antibody
What are the classic radiological features of RA?
RA Radiology • Soft tissue swelling • Jointspacenarrowing • Peri-articularosteoporosis • Bonyerosions • Deformities • Atlanto-axialsubluxation
List some complications of RA
- Pulmonary fibrosis, pleural effusions
- Pericarditis, pericardial effusions
- Dry eye syndrome (keratoconjunctivitis sicca)
- Neuropathy
- Felty’s syndrome (splenomegaly and neutropaenia)
- Anaemia
- Orthopaedic complications: carpal tunnel syndrome, tendon rupture (particularly extensors of fingers or thumb)
- Atlantoaxial instability
What is the prognosis of RA?
• Variable
• Poor Prognostic factors include: − Systemic involvement
− Insidious onset
− Rheumatoid nodules
− High Rheumatoid Factor
− Persistent activity for >12 months − Early bone erosions
What are the signs and symptoms of SLE?
VAGUE! • Malaise • Fever • Arthralgia • Ulcers • Myalgia Signs • Malar ‘butterfly’ rash • Discoid lupus • Mucosal ulcers • Vasculitic rash • Symmetrical arthritis • Raynaud’s • Episcleritis • Retinal infarcts
ORDER HIS ANA! what does this mnemonic for SLE stand for?
Oral ulcers
Rash (malar)
Discoid rash
Exaggerated photosensitivity Renal disease
Haematological abnormality Immunological abnormality Serositis
Arthralgia Neurological disease ANA
what investigations do you run in a suspected case of SLE?
Bloods: Investigations • Haemolytic anaemia, neutropenia, lymphocytopaenia, thrombocytopaenia,ESR, CKD Antibodies: • ANA • Anti-dsDNA • Antiphospholipid Ab • Anti-Ro/La • C3 & C4
What is the treatment for SLE?
• Minor symptoms: steroids
• Major symptoms:
− Steroids and immunosuppression
What are the complications of SLE?
- Renal: 50% can develop lupus nephritis
- CNS: Psychosis, strokes, fits
- CVS: Pericarditis, myocarditis
- Respiratory: Pleural effusion, ARDS
What is the pathophysiology of Graves disease?
The commonest cause of hyperthyroidism.
Due to IgG autoantibody production against the thyroid stimulating hormone (TSH) receptor.
This stimulates the receptor and results in increased thyroxine production.
What is the aetiology of Graves disease?
Aetiology
• Affects 1-2% of females
• 5:1 Female: Male
• Strong association with HLA-DR3 in Caucasian people
What are the symptoms of Graves disease?
• Weight loss despite an increased appetite • Irritability • Weakness and fatigue • Diarrhoea • Sweating • Oligomenorrhoea or amenorrhoea • Tremor • Mental illness: range from anxiety to psychosis. • Heat intolerance • Loss of libido
What are the signs of Graves disease?
- Goitre
- Exopthalmos
- Lid retraction
- Pre-tibial myxoedema
- Palmar erythema
- Sweaty, warm palms
- Fine tremor
- Tachycardia - may be AF
What is the treatment for Graves disease?
• Carbimazole peroxidase
• Radioactive iodine
− Given as a drink. Taken up by the thyroid gland, leading to destruction of the gland.
• Surgery - thyroidectomy
What is the pathophysiology and aetiology of type 1 Diabetes Mellitus
Autoimmune destruction of the β cells in the islets of Langerhans in the pancreas leading to absolute insulin deficiency
Aetiology: HLA-DR3, DR4, peak age of onset approximately 12 years
what investigations do you run in a suspected case of T1DM?
Bloods: U&E, FBC, Glucose Immunology: Anti-islet cell Ab
(antibody), Anti-GAD Ab Urine: Glucose, Ketones, VBG
how is T1DM managed?
• Supportive: patient education
• Glycaemic control: commence insulin, aim HbA1c < 7%, dietary
advice
• Complications surveillance: Annual review (fundoscopy, feet examination – neurological and vascular), check insulin sites, BP monitoring, monitor renal and thyroid function
define Crohn’s disease
• A chronic, relapsing inflammatory bowel disease (IBD)
• Characterised by a transmural granulomatous inflammation
caused by antibody production which attacks the gut lining
• Can affect any part of the GI tract, most commonly the ileum
• Skip lesions
• Cobble stone appearance of mucosa
• Aetiology: Genetics, smoking
• Symptoms: Abdominal pain, diarrhoea, weight loss, mucus, arthritis
• Signs: Fever, malaise, anaemia, palpable inflammatory mass, fistulae, erythema nodosum, pyoderma gangrenosum
what investigations do you run in a suspected case of Crohn’s disease
- Stool microscopy/ culture
- Bloods: ↑CRP, ↑ESR, ↓Hb, ↓Albumin
- Sigmoidoscopy/colonoscopy (+ biopsy)
- Tests for malabsorption: Vitamin B12, Folate, Vitamin D, Calcium
- AXR – cobblestone appearance
what are the signs and symptoms of Crohn’s disease?
- Symptoms: Abdominal pain, diarrhoea, weight loss, mucus, arthritis
- Signs: Fever, malaise, anaemia, palpable inflammatory mass, fistulae, erythema nodosum, pyoderma gangrenosum
what is the differential diagnosis for Crohn’s disease?
- Coeliac
- Ulcerative colitis
- Gastroenteritis/ travelling bug
- Malignancy
How is Crohn’s disease managed?
• Diet advice
• Lifestyle advice
• Medications:
− 5-aminosalicyclic acid (5- ASA) eg mesalazine − Steroids
− Methotrexate
− Infliximab
• Surgery – resection of affected segment of bowel +/- stoma formation
What is anaphylaxis?
A severe, life threatening, generalised or systemic hypersensitivity reaction characterised by rapidly developing, life threatening airway and/or breathing and/or circulation problems.
What causes anaphylaxis?
Venom (bee stings), foods (nuts, fish etc), drugs (antibiotics, anaesthetics, NSAIDs, aspirin), contrast media
How do you recognise someone who is having an anaphylactic reaction? Use the ABCDE approach.
Airway swelling, e.g., throat and tongue swelling (pharyngeal/laryngeal oedema). The patient has difficulty in breathing and swallowing and feels that the throat is closing up.
Hoarse voice.
Stridor – this is a high-pitched inspiratory noise caused by upper airway obstruction.
Breathing problems
Shortness of breath – increased respiratory rate. Wheeze.
Patient becoming tired.
Confusion caused by hypoxia.
Cyanosis (appears blue) – this is usually a late sign. Respiratory arrest.
Circulation problems
Signs of shock – pale, clammy.
Increased pulse rate (tachycardia).
Low blood pressure (hypotension) – feeling faint (dizziness), collapse.
Decreased conscious level or loss of consciousness.
Anaphylaxis can cause myocardial ischaemia and electrocardiograph (ECG) changes even in individuals with normal coronary arteries.
Cardiac arrest.
Disability problems
There may be confusion, agitation and loss of consciousness because of decreased brain perfusion.
Intramuscular adrenaline is the first line drug treatment for anaphylaxis. How does adrenaline work?
Alpha-receptor agonist:
• reverses peripheral vasodilation and reduces oedema. beta-receptor activity
dilates the bronchial airways, increases the force of myocardial contraction, and suppresses histamine and leukotriene release. There are also beta-2 adrenergic receptors on mast cells that inhibit activation, and so early adrenaline attenuates the severity of IgE- mediated allergic reactions.
Why are IV fluids given in anaphalaxis?
Large volumes of fluid may leak from the patient’s circulation during an anaphylactic reaction. There will also be vasodilation, a low blood pressure and signs of shock.
After initial resuscitation chlorphenamine and hydrocortisone are given for anaphalaxis what is the rationale for their use?
Chlorphenamine
H1-antihistamine may help counter histamine-mediated vasodilation and bronchoconstriction. They may not help in reactions depending in part on other mediators but they have the virtue of safety. Used alone, they are unlikely to be lifesaving in a true anaphylactic reaction.
Hydrocortisone
Corticosteroids may help prevent or shorten protracted reactions. In asthma, early corticosteroid treatment is beneficial in adults and children.
After resuscitation a mast cell tryptase level is measured. What is mast cell tryptase and why may it be useful?
The specific test to help confirm a diagnosis of an anaphylactic reaction is measurement of mast cell tryptase. Tryptase is the major protein component of mast cell secretory granules. In anaphylaxis, mast cell degranulation leads to markedly increased blood tryptase concentrations. Tryptase levels are useful in the follow-up of suspected anaphylactic reactions, not in the initial recognition and treatment: measuring tryptase levels must not delay initial resuscitation. Usually a sample is taken as soon as possible after resuscitation, another at 1-2 hours after the start of symptoms (tryptase levels peak at about 1.5 hours) and a third sample in convalescence (provides baseline tryptase levels - some individuals have an elevated baseline level). Serial samples have better specificity and sensitivity than a single measurement in the confirmation of anaphylaxis.
A 25 year old woman was referred to the neurology clinic with a six week history of double vision, difficulty swallowing and weak upper limbs. The symptoms were mild in the morning but by the afternoon were more marked. She was seen at the end of the afternoon clinic where on examination she was found to have bilateral ptosis and dysconjugate eye movements. A differential diagnosis included myasthenia gravis.She was given an intravenous injection which completely abolished her neurological signs but her eye movements deteriorated 30 minutes later. A clinical diagnosis of myasthenia gravis was made.
4. What is likely to have been in the injection and why did it abolish her neurological signs?
Edrophonium – short acting cholinesterase inhibitor. Delays breakdown of acetylcholine end plate working as Ach around which is able to bind to reduced number of Ach receptors
What signs of thyrotoxicosis would you look for on clinical examination?
Smooth goitre, bruit, eye signs (exophthalmos, lid lag), tachycardia, AF, fine tremor, sweaty, pretibial myxoedema, anxious
Thyroid function test results T3- 5.1 nmol.l-1 (NR 0.8 – 2.4) T4 – 53nmol.l-1 (NR 9-23) TSH 0.4 mU.l-1(NR 0.4 – 5) Circulating antibodies to thyroid peroxidase detected 2. Explain these test results
High T3 and T4 high leading to negative feedback on pituitary inhibiting TSH - low normal TSH Primary thyroid disease rather than pituitary. Likely autoimmune thyrotoxicosis. Autoantibodies to thyroid peroxidase is also seen in Hahsimoto’s, primary mxyoedema and 5-10% of the normal population
What is the pathogenesis of Graves’ disease?
IgG auto-antibodies to TSH receptor that stimulate the thyroid cell. The thyroid is infiltrated with CD8 and CD4 T cells. The degree of thyrotoxicosis is not related to the size of the goitre (10% of patients have no goitre)
Bilateral exophthalmos – proptosis. What is the underlying mechanism for these appearances? What are the complications of the eye condition?
Myositis affecting eye muscles and a proliferation of retro-orbital tissue. The myositis is accompanied by infiltration of CD4 lymphocytes. Retro-orbital fibroblasts secrete hydrophilic glycosaminoglycans in response to T-cell cytokines altering the osmotic pressure and fluid accumulation. The TSH receptor is expressed in the orbital tissue suggesting an immune reponse is implicated in the eye disease.
Exposure keratopathy. Optic nerve compression
What treatment options are there for thyrotoxicosis?
Drug therapy – carbimazole Radio iodine
Surgery
A 30 year old woman presented with a three week history of an acute rash under her wrist watch. Two weeks later a further patch appeared at the umbilicus
What type of hypersensitivity is this? Explain the mechanism.
Type 4 – delayed hypersensitivity. The list of agents includes nickel (jewellery), neomycin (topical antibiotic), epoxyresins, plants (primula, geranium) and cosmetics. These agents are of relatively low molecular weight and therefore not immunogenic on their own. As small molecules they are able to penetrate the skin and act as haptens combined with host cells as carriers. In the induction phase Langerhans cells bind the hapten-carrier protein present it in association with MHC class 2 antigens to lymphocytes. Re- exposure to the antigen triggers the elicitation phase that produces the features of dermatitis. The effector T cells previously carried to the skin meet the meet the hapten-carrier complexTh1 CD4 T cells release cytokines that activate CD8 and Th17 cells that produce the inflammation.
What is nephrotic syndrome?
Low plasma levels of albumin, dependent oedema, severe proteinuria (>3.5g/day). Acute nephritis is acute onset of haematuria, proteinuria, hypertension and oliguria
An eight year old boy complained to his mother that he had a sore throat and feeling generally “under the weather”. He was kept off school, given paracetamol and he rested on the sofa. A week later he was taken to the Emergency Department with swelling around his eyes. On examination he had scrotal oedema. You think he might have nephrotic syndrome.
His urine was positive for protein, blood and red cell casts
2. Explain these results.
Glomerulus leaky for protein and blood. Red cell casts - presence of red blood cells within the cast is always pathological, and is strongly indicative of glomerular damage, which can occur in glomerulonephritis
An eight year old boy complained to his mother that he had a sore throat and feeling generally “under the weather”. He was kept off school, given paracetamol and he rested on the sofa. A week later he was taken to the Emergency Department with swelling around his eyes. On examination he had scrotal oedema. You think he might have nephrotic syndrome.His urine was positive for protein, blood and red cell casts
What do you think is the underlying problem?
What further tests should you do?
Post streptococcal glomerulonephritis. – Immune complex deposition along GBM – inflammation and leaky glomerular membrane (protein & blood)
The diagnosis rests on prior microbiological culture, increasing titres of streptococcal antibodies and a low C3 level. Antistreptococcal antibody titres – antistreptolysin (ASO), antihyaluronidase (AHase), antistreptokinase (ASKase), antiNAD and antiDNAse B
A 60 year old man was stung by a wasp whilst he was eating a sandwich. He rapidly developed a generalized, raised, itchy rash, and started to experience hoarseness of voice and difficulty in breathing. The patient lost consciousness and a paramedic ambulance was summoned. He was resuscitated and taken to hospital. In his past medical history, the patient has ischaemic heart disease, chronic obstructive airways disease, and consumed between 50-60 units of alcohol a week. He is taking β-blockers and an angiotensin converting enzyme (ACE) inhibitor for hypertension.
What is the immune mechanism driving this life threatening condition?
Anaphylaxis is a severe allergic reaction that starts suddenly and affects many body systems. It results from the release of inflammatory mediators and cytokines from mast cells and basophils. This release is typically associated with an immune system reaction
Iimmunoglobulin E (IgE) binds to the foreign material that starts the allergic reaction (the antigen). The combination of IgE bound to the antigen activates FcεRI receptors on mast cells and basophils. The mast cells and basophils react by releasing inflammatory mediators such as histamine. These mediators increase the contraction of bronchial smooth muscles, cause blood vessels to widen (vasodilation), increase the leakage of fluid from blood vessels, and depress the actions of the heart muscle. (There is also an immunologic mechanism that does not rely on IgE, but it is not known if this occurs in humans).
Note : There are some cases when anaphylaxis is not caused by an immune response, the reaction is due to an agent that directly damages mast cells and basophils, causing them to release histamine and other substances that are usually associated with an allergic reaction (degranulation). Agents that can damage these cells include contrast medium for X-rays, opioids, temperature (hot or cold), and vibration
A 60 year old man was stung by a wasp whilst he was eating a sandwich. He rapidly developed a generalized, raised, itchy rash, and started to experience hoarseness of voice and difficulty in breathing. The patient lost consciousness and a paramedic ambulance was summoned. He was resuscitated and taken to hospital. In his past medical history, the patient has ischaemic heart disease, chronic obstructive airways disease, and consumed between 50-60 units of alcohol a week. He is taking β-blockers and an angiotensin converting enzyme (ACE) inhibitor for hypertension.
Explain why as part of his condition the patient became “hoarse” and started to wheeze?
Difficulty breathing is due to swelling and/or spasm in the airways (which can include swelling of the tongue or the airways). In very rare cases, breathing can stop altogether
A 60 year old man was stung by a wasp whilst he was eating a sandwich. He rapidly developed a generalized, raised, itchy rash, and started to experience hoarseness of voice and difficulty in breathing. The patient lost consciousness and a paramedic ambulance was summoned. He was resuscitated and taken to hospital. In his past medical history, the patient has ischaemic heart disease, chronic obstructive airways disease, and consumed between 50-60 units of alcohol a week. He is taking β-blockers and an angiotensin converting enzyme (ACE) inhibitor for hypertension.
Explain why the patient was subsequently given subcutaneous adrenaline in the emergency room?
Injection of adrenaline into the blood stream will cause an increase of blood flow throughout the body. The relief is only temporary due to the short half- life of adrenaline; therefore, immediate hospitalisation is required to ensure safety to the individual
Epinephrine is a direct-acting sympathomimetic drug that acts as an agonist at alpha and beta-adrenergic receptors. It produces vasoconstriction to counteract the vasodilation and resulting hypotension associated with anaphylaxis. The bronchodilatory effects of epinephrine and its ability to reduce mucosal edema relieve bronchoconstriction and improve respiratory effort.
Adrenaline also down-regulates the release of histamine, tryptase, and other inflammatory mediators from mast cells and basophils, improving respiratory function and reducing the pruritus, urticaria, angioedema, and gastrointestinal symptoms which occur after allergen exposure
Describe the effects of adrenaline on the smooth vascular system
Relaxation and contraction of smooth muscle cells (i.e. heart, arteries, and veins) are controlled through epinephrine receptors.
Contraction occurs through binding of calmodulin to Calcium ions when the concentration is ten times larger than normal in the cell. The Calcium- Calmodulin complex then activates the myosin light chain kinase (MLCK), which in turn phosphorylates the LC2 causing contraction. Binding of adrenaline to the adrenoreceptors receptors activates adenylyl cyclase producing cyclic AMP from ATP. Cyclic AMP activates a protein kinase thereby phosphorylating the MLCK. This has a lower affinity for Calcium- Calmodulin complex and is thus inactive; thereby, relaxing the smooth muscle tissue. For this reason adrenaline is used for cardiac arrests, asthma, and anaphylactic shock patients
Describe the differences between the actions of noradrenalin and adrenaline
Adrenaline responses to stressors are more closely linked to responses of the hypothalamic-pituitary-adrenocortical system than of the sympathetic nervous system.
Adrenoceptors in the membranes of effector cells determine the physiological and metabolic effects of catecholamines.
Beta-adrenoceptors mediate stimulatory effects of catecholamines on the rate and force of the heartbeat; stimulation of vascular alpha-adrenoceptors produces vasoconstriction and increases blood pressure, and stimulation of vascular beta-adrenoceptors – especially beta-2 adrenoceptors in skeletal muscle – produces vasodilation
A 60 year old man was stung by a wasp whilst he was eating a sandwich. He rapidly developed a generalized, raised, itchy rash, and started to experience hoarseness of voice and difficulty in breathing. The patient lost consciousness and a paramedic ambulance was summoned. He was resuscitated and taken to hospital. In his past medical history, the patient has ischaemic heart disease, chronic obstructive airways disease, and consumed between 50-60 units of alcohol a week. He is taking β-blockers and an angiotensin converting enzyme (ACE) inhibitor for hypertension.
What tests could you do to confirm the diagnosis and identify the trigger?
Skin tests
Determine the presence of IgE antibodies and identify anaphylactic reactions triggered by food, medications and stinging or biting insects
9. Is there any definitive therapy/cure that can be offered to prevent this happening again?
Skin tests are performed at least 3 to 4 weeks after an anaphylactic reaction
In the case of a skin prick/puncture test, a positive result is indicated by a mean wheal diameter of 3 mm or greater7
Since this anaphylactic reaction was triggered by insect stings, a series of allergy injections (immunotherapy) can be used to reduce the body’s allergic response and prevent a severe reaction in the future. In most other cases there’s no way to treat the underlying immune system condition that can lead to anaphylaxis.
In vitro tests
Determine the presence of allergen-specific IgE levels in the serum and identify anaphylactic reactions triggered by food, biting or stinging insects, medications and latex
In vitro tests are considered less sensitive than skin tests
ImmunoCAP is an example of a quantitative in vitro test that correlates IgE levels with clinical reactivity and has predictive values for positive or negative results
Challenge tests
Physician-monitored challenge tests may be used if skin or in vitro test results are inconclusive. Challenge tests help predict the clinical reactivity to anaphylaxis triggered by food and medication. Challenge tests should not be performed in patients with a documented history of food-related anaphylaxis due to an increased risk of triggering an attack
Your patient is a 35-year-old man who noted some generalised malaise over the past few months with some weight gain and bloating. He notices his feet in particular are quite swollen. When he urinates, he has seen some “darker tinges”. He presents today as he is concerned about some red sputum he coughed up over the last 3 days. He is not, and has never been, a smoker.
He has had no recent symptoms suggestive of respiratory disease and he is currently apyrexial. His doctor ordered routine blood tests, a complete blood cell count and differential, a Mantoux test and a chest X-ray.
Although the Mantoux test was negative and chest radiography uninformative, explain the rationale for requesting these tests.
The Mantoux test is a widely used test for latent TB. It involves injecting a substance called PPD tuberculin into the skin of the forearm. If there is a latent TB infection, the skin will be sensitive to PPD tuberculin and a hard red bump will develop at the site of the injection, usually within 48 to 72 hours of having the test. If there is a very strong skin reaction, a chest X-ray to confirm an active TB infection.
BCG vaccination, may have a mild skin reaction to the Mantoux test. This does not necessarily mean latent TB.
Which type of hypersensitivity reaction is activated during the Mantoux test?
Type iv hypersensitivity
Delayed hypersensitivity reactions -e inflammatory reactions initiated by mononuclear leukocytes
Your patient is a 35-year-old man who noted some generalised malaise over the past few months with some weight gain and bloating. He notices his feet in particular are quite swollen. When he urinates, he has seen some “darker tinges”. He presents today as he is concerned about some red sputum he coughed up over the last 3 days. He is not, and has never been, a smoker.
He has had no recent symptoms suggestive of respiratory disease and he is currently apyrexial. His doctor ordered routine blood tests, a complete blood cell count and differential, a Mantoux test and a chest X-ray.
Considering the history above, which symptoms and subsequent blood test results would indicate a kidney related problem?
Haematuria, weight gain, bloating and swelling
Test for albumin levels (low levels may indicate a problem) and FBC (To test for severe anemia
Direct immunofluorescence staining (IgG) of a subsequent renal biopsy (Figure 2) reveals a smooth, diffuse, linear staining that is characteristic IgG antibody deposition on the glomerular basement membrane. Describe the principles of this test? What is the likely diagnosis?
Immunofluorescence (IF) is a common laboratory technique used in almost all aspects of biology. The antibody against the molecule of interest is chemically conjugated to a fluorescent dye. The antibody recognizes the target molecule (antigen) and binds to a specific region called the epitope. The attached fluorophore can be detected via fluorescent microscopy, which, depending on the messenger used, will emit a specific wavelength of light once excited
Goodpasture syndrome is an autoimmune disorder. It occurs when the immune system mistakenly attacks and destroys healthy body tissue. People with this syndrome develop substances that attack a protein called collagen in the tiny air sacs in the lungs and the filtering units (glomeruli) of the kidneys.
These substances are called antiglomerular basement membrane antibodies. The glomerular basement membrane is a part of the kidneys that helps filter waste and extra fluid from the blood. Antiglomerular basement membrane antibodies are antibodies against this membrane. They can damage the basement membrane, which can lead to kidney damage.
Sometimes, this disorder is triggered by a viral respiratory infection or by breathing in hydrocarbon solvents. In such cases, the immune system may attack organs or tissues because it mistakes them for these viruses or foreign chemicals
Considering of good pastures of this disease why is the patient presenting with both kidney and respiratory problems?
Anti-GBM antibodies are directed against the noncollagenous (NC-1) domain of the α3 chain of type IV collagen, which occurs in highest concentration in the basement membranes of renal and pulmonary capillaries.
Environmental exposures—cigarette smoking, viral URI, and hydrocarbon solvent inhalation most commonly and pneumonia less commonly—expose alveolar capillary antigens to circulating antibody in genetically susceptible people, most notably those with HLA-DRw15, -DR4, and -DRB1 alleles. Circulating anti-GBM antibodies bind to basement membranes, fix complement, and trigger a cell-mediated inflammatory response, causing glomerulonephritis, pulmonary capillaritis, or both.
The white blood cell count indicates an increase in neutrophils and lymphocytes suggesting of an ongoing immune response. Review the immunologic mechanism that would lead to this in the pathologic process occurring in the lung and kidney.
Under normal circumstances neutrophils follow an orderly progression from the marrow through the blood to tissue sites of utilization. Neutrophilia may occur by several mechanisms: increased cell production, accelerated release of cells from the marrow into the blood, shift within the circulation from the marginal to the circulating pool, reduced egress of neutrophils from the blood to tissues, or a combination of these mechanisms. The time required for these events varies substantially. Shifts between the marginal and circulating pools take only a few minutes. Shifts of neutrophils from the marrow to the blood occur within a few hours. Increases in the production of neutrophils, even with intense stimulation, may take at least a few days
Your patient is a 26-year-old married woman. Over the last six months she noticed increasing swelling in her fingers and legs with “frothy” dark urine. She complains of intermittent severe headaches unrelated to menses. She has been unable to conceive for the last 5 years and has had three spontaneous abortions, all in the first 8 to 12 weeks of pregnancy. Enlarged lymph nodes were felt behind her ears and the in back of her neck. A family history reveals that she was an adopted child. A detailed analysis of her serum immunoglobulin, complete blood cell count, and blood chemistry was ordered. Laboratory results indicate a mild increase in leukocytes, elevated IgG and serum creatinine levels and mild thrombocytopenia. Analysis of the urine reveals the presence of protein with red blood cells.
1. When exposed to the sun, the patient always develops a red rash on her cheeks (Figure 3). What is the rash on the face called and what is the likely diagnosis?
- Which laboratory tests will confirm the diagnosis?
The Malar (over the cheeks of the face) is sometimes called the “butterfly” rash.
Systemic lupus erythematosus (SLE). Note Skin lesions include malar butterfly erythema (flat or raised) that generally spares the nasolabial folds. The absence of papules and pustules helps distinguish SLE from rosacea
Laboratory testing differentiates SLE from other connective tissue disorders. Routine testing should include the following: Antinuclear antibodies (ANA) and anti–double-stranded (ds) DNACBC Urinalysis Chemistry profile including renal and liver enzymes
What symptoms and signs would suggest an ongoing immune response in this patient? SLE
increasing swelling in her fingers and legs, “frothy” dark urine, three spontaneous abortions, all in the first 8 to 12 weeks of pregnancy; Enlarged lymph nodes behind her ears and the in back of her neck; mild increase in leukocytes; elevated IgG and serum creatinine levels and mild thrombocytopenia; headaches
xplain why the patient should avoid direct exposure to sunlight. SLE
Abnormal light sensitivity (“photosensitivity”) is a major feature of most forms of lupus. Lupus patients are particularly susceptible to sunburn which may lead to “prolonged erythema” (redness). Sunlight may also cause the development of new lupus skin lesions (e.g. DLE and SCLE). Sunlight can also lead to flares of disease activity in SLE, including joint pains and fatigue. Finally, sunlight causes other skin diseases such as polymorphic light eruption (PLE or “prickly heat”) which is usually fairly mild but very irritating and has recently demonstrated in 50% of lupus patients, compared with 15% of the general population
Explain how the immune system attacks multiple organs/tissues in this condition. SLE
in lupus and other autoimmune diseases, the immune system begins to recognize and attack “self.” In other words, the cells of the immune system begin to injure the body’s own tissues and can cause permanent scarring that ultimately jeopardizes the function of certain organs and systems in the body. Certain cells and processes of the immune system have been identified as playing a role in lupus.
Antiphospholipid Antibodies are antibodies directed against cell membranes phospholipids, certain blood proteins that bind with phospholipids, and the complexes formed when proteins and phospholipids bind. Approximately 50% of people with lupus possesses these antibodies, and over a twenty-year period of time, one half of lupus patients with one of these antibodies—the lupus anticoagulant—will experience a blood clot.
Lupus may attack the nervous system via antibodies that bind to nerve cells or the blood vessels that feed them, or by interrupting the blood flow to nerves. Conditions associated with or sometimes seen in lupus include cognitive dysfunction, fibromyalgia, headaches, organic brain syndrome, and CNS vasculitis
In active disease, levels of complement proteins C3 and C4 are often decreased. Explain the mechanism for this. What are the clinical benefits of monitoring C3 and C4 levels?
Measurement of serum complement is useful in the monitoring of specific immune complex diseases e.g SLE and infectious diseases post streptococcal disease, subacute bacterial endocarditis. Consumption of one or both components may also be useful prognostically e.g nephritis in lupus.
Complement concentrations are acute phase proteins and may be normal, despite complement consumption, in some inflammatory and infective disorders.
C3 and C4 are measured at the same time since this gives an indication of the complement pathway (classical or alternative) which is being activated and thus the cause of this activation. C3 alone is often decreased in infectious disease (septicaemia, endocarditis), C3 and C4 are often both decreased in immune complex disease, C4 alone is characteristically decreased in angioedema, immune complex diseases particularly vasculitis and in cryoglobulinaemia and cold agglutinin disease.
Though genetic deficiencies of C3 are exceedingly rare, deficiencies in other components which are more common (though still very rare) can result in low C3
The direct and indirect coombs tests were negative. What do these results tell us in this case? (SLE)
It shows that there are no red cell antibodies in the serum or on the red cell. Direct abnormal results show a condition that causes the destruction of red blood cells by the immune system (hemolysis). The DAT is used to determine whether patients with hemolysis have an immune etiology. Indirect coombs abnormal result antibodies circulating in your bloodstream that could cause your immune system to react to any red blood cells that are considered foreign to the body, particularly regarding those that may be present during a blood transfusion. The IAT is used to identify clinically significant red cell alloantibodies that are important in choosing compatible blood products
The patient was advised to take an antimalarial agent, hydroxychloroquine sulphate (plaquenil). Discuss the benefit of this drug based in this article (Fessler BJ, Alarcon GS, McGwin G, et al. Systemic lupus erythematosus in three ethnic groups. XVI. Association of hydroxychloroquine use with reduced risk of damage accrual. Arthritis Rheum. 2005; 52:1473-1480.) You can also try to look for more recent clinical evidence supporting the use of antimalarial drugs in this diseas
Studies have shown lupus patients on anti-malarials actually live longer than those who are not, and these medications are usually prescribed when someone is first diagnosed with the disease. Anti-malarial medications help to control lupus in several ways by modulating the immune system without predisposing patient to infection. Anti-malarials can protect against UV light and sometimes even improve skin lesions that do not respond to treatment with topical therapy. Anti-malarial medications may prevent activation of plasmacytoid dendritic cells, a component of the immune system that is responsible for making interferon
The patient improved initially but after 4 weeks her joint symptoms worsened. What treatment would you recommend? SLE
Corticosteroids are first-line therapy. A combination of prednisone and immunosuppressants is recommended in active, serious CNS lupus, vasculitis especially affecting viscera or nerves, or active lupus nephritis. For most patients, the risk of flares can be decreased without prolonged high-dose corticosteroids. Chronic disease should be treated with the lowest dose of corticosteroids and other drugs that control inflammation (eg, antimalarials, low-dose immunosuppressants) to maintain remission.
How is the clinical pathology laboratory evaluation used to help diagnose HIV infection?
The ELISA HIV-1 antibody test is the first-line test to assess whether the patient has an HIV infection. The HIV-1 ELISA has excellent sensitivity and specificity (>99%); however, due to the gravity of the diagnosis, a confirmatory test is done.
The Western blot confirms the presence of the HIV antibody. In this test, HIV antigens are electrophoresed in a gel, transferred to a membrane, and overlaid with the patient’s serum. The classic pattern of HIV positivity shows 9 bands. The HIV p24 antigen test also uses an ELISA method to look for viral particles in the serum before antibodies rise.
The polymerase chain reaction (PCR) amplification for HIV-1 is used to diagnose perinatally-acquired HIV infection, because the HIV-1 antibody test in the perinatal period reflects the mother’s status instead of the infant’s; therefore, the antibody test has limited value until about 15 months of age.
Cd4+ counts determines the amount of CD4+ cells in the blood.
What is the normal role of CD4+ and CD8 + cells in cell mediated immunity?
CD4+ helper T cells secrete cytokines that recruit and activate other leukocytes to phagocytose (ingest) and destroy microbes, and CD8+ cytotoxic T lymphocytes (CTLs) kill any infected cell containing microbial proteins in the cytosol, eliminating cellular reservoirs of infection. CD4+ T cells recognize antigens of microbes in phagocytic vesicles and secrete cytokines that recruit and activate leukocytes that kill the microbes, whereas CD8+ cells recognize antigens of microbes that are present in the cytosol and destroy the infected cells.
Why does a reduced CD4+ count matter if the CD8 cell mediated immunity will kill viruses?
CD8+ T cells require activation signals before they can differentiate into effector CTLs with the full range of molecules required to kill a target cell by inducing apoptosis. The required activation signals are MHC–antigenic peptide complexes and costimulatory signals from antigen-specific CD4+ TH cells. CD4+ TH cells recognize viral antigen displayed on APCs; activation of the CD4+ TH cell causes release of IL-2, which stimulates viral antigen-specific CD8+ T cells. TCR recognition of viral antigen, plus a second signal via the IL- 2 receptor, stimulates differentiation of the CD8+ T cell into an effector CTL to induce apoptosis
For the most effective killing, CTLs need to be stimulated with IFN-γ secreted by a TH1 cell
What is the first line of defence that the human immunodeficiency virus faces in the endocervix?
Dendritic cells stretch their dendrites through epithelial tight junctions towards the laminal surface. Dendrites cut virus into epitopes to display on cell surface, travels to lymph nodes
HIV infects memory and activated T cells but is inefficient at productively infecting naive (unactivated) T cells. Why is this? How does a CD4+ T cell become activated?
Naive T cells contain an active form of an enzyme that introduces mutations in the HIV genome and stops it replicating, mature T cells don’t have the active enzyme.
T cells (produced in the thymus) circulate throughout the body until they recognise foreign particles (antigens) on the surface of antigen presenting cells (APCs). In addition to T cell receptor (TCR) binding to antigen-loaded MHC both helper T cells and cytotoxic T cells require a number of secondary signals to become activated and respond to the threat.
Reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template. What enzyme is used in the human cells during normal transcription process?
RNA polymerase
The patient is tired and short of breath on minimal exertion. A blood test shows her Hb is 70g/L. The GP prescribes Epo therapy. What is this?
Epo (epoetin alfa) is a drug developed by recombinant DNA technology. Like G-CSF it is a growth factor used to boost, this time a different subset of blood cell, erythrocytes (red blood cells). Indications include chronic kidney disease, anaemic from AIDS, multiple myeloma, myelodysplastic syndromes and some cancer patients who are anaemic following chemotherapy.
Patients with HIV infection require immunologic (CD4 count) and virologic (viral load) monitoring. What does is a viral load test and what does it measure?
Viral-load tests measure HIV viremia and reflect long-term risk for disease progression. Viral load and CD4 counts are used to determine the use of antiretroviral treatment.
Name the infectious agent responsible or the pneumocystis
Pneumocystis in humans is caused by P. jirovecii
What other types of specimens are typically collected to detect Pneumocystis?
Bronchial washings or sputum samples may be collected to diagnose Pneumocystis
What is the significance of the falling CD4+ cell counts in this patient? (HIV)
HIV infection is stratified into three clinical categories:
CD4+ cells greater than or equal to 500/μL; 200-499/μL; and <200/μL.
If the count is above 500/μL, there is a low probability of progression. If the count is below 200/μL, or is rapidly falling, the probability of progression is high.
Using the self-regulatory model, give one example of how the doctor could ensure that this patient adheres to anti-retroviral medication.
Correct inaccurate perceptions about the cause of an illness (and therefore their future risk)
Focus on controllable aspects of the illness (e.g. Symptom management) Reduce perceptions of severe consequences (e.g. education)
