Immunology workshop Flashcards
What are the key signs and symptoms of anaphylactic shock from food?
Mouth itching
Struggling to breath/airway obstruction
Angioedema of lips and tongue
Hives
Hypotension
Arrythmia
Tachycardia
Wheeze/cough
Altered mental status/sense of doom - most concerning
Skin redness and urticaria
What are some risk factors for a food allergy?
Family history/genetic predisopitions: polymorphisms of chromosome 5,6 and 11 can increase risk, for example:
MHC2 - enhanced presentation of allergen peptides
IL-4R - increased signalling from IL-4
IL-4 - variation in IL-4 expression
Fc epsilon receptor - variation in IgE binding
Chromosome 5 - genes involved in IL3,4,5 and 13 expression
May have a medical history of eczema and asthma - atopy.
A patients has an allergic reaction to peanuts, presents to A&E. What is the immunopathological mechanism underpinning this reaction?
Type 1 hypersensitivity reaction as against a foreign but harmless antigen. No autoimmune component.
Patient would have had an initial exposure to allergen (peanuts), the antigen would been presented on MHC by Langerhans cells in the oral cavity mucosa. Langerhans cell migrates to local lymph node resulting in the subsequent activation of a T lymphocyte then B lymphocyte in the presence of all three activation signals. B cell will differentiate into a plasma cell in the germinal centre of the lymphoid follicle and undergo class switching with IL-4 promoting the change from IgM to IgE. Plasma cell will produce IgE which binds to Fc epsilon receptors on mast cells, resulting in sensitised mast cells.
On second exposure to the allergen, antigen would have bound to IgE, resulting in cross linking of receptors and clumping of signalling machinery generating a strong activation signal for the mast cell, triggering mast cell degranulation releasing inflammatory mediators such as histamine (preformed), prostaglandins and leukotrienes (synthesised de novo). This gives the classic symptoms of inflammation including tumour and rubor.
Later inflammatory phase includes a Th2 response and the recruitment of eosinophils. In particular, IL-4 and IL-13 promote the Th2 response and IL-5 promotes the eosinophil recruitment and activation. Eosinophils can accumulate in chronic disease and release MBP and ECP causing damage to epithelial cells in the airways.
Basophils can also be recruited to the site of inflammation by IgE, PAMPs, chemokines and lipid mediators (such as those released from mast cells). Basophils have Fc epsilon receptors, IgE binds to these receptors causing degranulation, releasing more histamine contributing to the cardinal signs of inflammation. Also secretes IL-4 and IL-13 reinforcing the Th2 response and class switching to IgE. Basophils have a more important role in systemic anaphylaxis.
What is meant by anaphylatic shock?
Allergic reaction where cardiac output and arterial pressure decrease drastically leading to a type of hypovolemic shock.
Primarily from an antigen-antibody reaction.
Key effectors are basophils and mast cells
Mediate histamine release - vasoidlationof veins results in increasing vascular capacity reduceding venous return decrease Co, dilation of arterioles reducing blood pressure, increased capillary permeability, rapid loss of fluid and protein into the tissue space
What are the warning signs/symptoms of a severe anaphylactic shock reaction?
Tachycardia
Hypotension
Tachypnoea
Confusion
What antigen is most often responsible for a peanut allergy?
Ara peanut allergen
What is the use of adrenaline in anaphylactic shock?
Class: sympathomimetic agent, catecholamine
Pharm: is an agonist at adrenergic receptors
Beta 2 receptors - GPCR - activate adenylyl cyclase - ATP to cAMP - activates PKA decrease Ca2+ in smooth muscle - cause bronchodilator
Alpha 1 receptors in blood vessel - GPCR - PLC - DAG and IP3 - Ca2+ inc - calcium calmodulin complex - smooth muscle contraction
Physio: increase airway diameter
prevent systemic hypotension /odema
Clinical: given in epi pens, patient carries two, can be given 5 mins apart.
What is the use of chlorophenamine in treating anaphylactic shock?
Chem: small molecule, alkylamine, anti-histamine
Pharm: H1 histamine receptor antagonist, out competes histamine for H1 receptors on effector cells including blood vessels
Physio: provides relief from swelling and itching
prevents histamine mediated vasodilation and bronchoconstriction
Clinical : administered subcutaneously, IM or IV, Used in emergency for symptomatic relief of allergy/atopy.
What are some of the potential side effects of chlorophenamine?
As a 1st gen anti-histamine can cross BBB, and act as an antagonist at cholinergic, adrenergic and serotonergic receptors causing urine retention, dry mouth, hypotension, reflex tachycardia, increase appetite
What is the use of hydrocortisone in anaphylactic reaction?
Chem: corticosteroid, has equal glucorticoid and mineral corticoid receptor activity
Pharm: Lipophilic so crosses over the cell membrane
Binds to cytoplasmic corticosteroid receptors acts as agonist, cause to dissociate from heat shock protein and heterodimerise becoming active
Migrate to nucleus, acts as transcription factor, binds to glucorticoid response element on DNA, alters gene expression.
Transactivation – active replication machinery – increase expression of anti-inflam such as INF-y, IL-10 and annexin A1 (leads to inhibition of PLA2 hence prostaglandin production)
Transrepression – deactivate replication machinery – decrease expression of pro-inflam such as TNFalpha and COX.
Physio: reduce inflammation phase, Leads to greater balance of anti-inflammatory compared to inflammatory cytokines, reduce immune cell recruitment, activation, endothelial cell permeability/adhesion molecules, vasodilation.
Why does respiratory deterioration occur in myasthenia gravis patients?
Reduced contraction of the diaphragm and accessory muscles due to anti-AChR, results in reduced respiratory effort, unable to create a volume hence pressure change is required. This can lead to respiratory failure and is termed a myasthenic crisis.
What are the risk factors for myasthenia gravis?
Autoimmune - FH or genetic polymorphisms - Ch6 (MHC class 2) or CTLA4 on Ch2.
Thymic hyperplasia and thymoma - affects central tolerance mechanisms and T cell maturation
Not sure why this specific autoimmune disease and at what specific time in life.
What is the immunopathological process underpinning myasthenia gravis?
Type 2 hypersensitivity to a self-antigen. Auto-immunity.
Failure of central and/or peripheral tolerance mechanisms, enables reaction against self antigen found at the post synaptic terminal or the neuromuscular junction.
Plasma cell secrete IgG antibodies – bind to nicotinic acetylcholine receptors.
Effect – direct blockage of ACh binding, cross linking of nicotinic receptors results in internalistation and degradation of the receptors, activation of complement causing lysis of the muscle end plate due to membrane attack complex formation.
This impairs signalling, so no muscle contraction as reduced activation of muscle fibres, results in clinical weakness.
Typically effects the upper limbs causing weakness, then develops to ptosis, then bulbar symptoms then dyspnoea as diaphragm and other respiratory muscles are effected.
Other targets for auto-antibodies include:
MuSK – anchors AChR to the postsynaptic junction – damage reduces the conc of active receptors available, anchors AChesterase to the basal lamina, helps to monitor and manage its activity.
LRP4 – role in activating MuSK
What is the use of pyridostigmine in the treatment of myasthenia gravis?
Class: anticholinesterase, small molecule
Pharm: binds to and inhibits acetylcholinesterase reversibly
Physio: prevents the break down of ACh into acetic acid and choline, in conc ACh in the neuromuscular junction,
Inc conc of ACh able to outcompete with autoimmune antibodies, increased binding to and activation of nicotinic receptors at the neuromuscular junction, increase in muscle power, prolongs the action of acetylcholine.
What is the use of intravenous immunoglobulins in the treatment of myasthenia gravis?
Antibody/ biological agent taken from purified plasma of a healthy individual. Neutralises the autoreactive antibodies, neutralises cytokines and blocks activating Fc receptors, used in the situation of a severe acute exacerbation of myasthenia gravis.
