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
