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IMMUNOLOGICAL DISEASES
AN INTRODUCTION TO HYPERSENSITIVITY
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Allergy & hypersensitivity
HYPERSENSITIVITY= harmful immune responses
autoimmunity(self antigen)
allergy( foreign antigen)
Distinct from:•pharmacological intolerance / hypersensitivity•toxicity
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Classification of Hypersensitivity
Type Mechanism Example
I IgE mediated Systemic anaphylaxis eg peanut allergyAsthma
II Antibody mediated Haemolytic disease of the newborn
III Immune complex mediated
Arthus reactionGlomerular nephritis
IV Cell mediated (delayed)
Contact dermatitis
Anaphylactichypersensitivity
Cytotoxichypersensitivity
Immune complexhypersensitivity
Cell-mediatedhypersensitivity
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Type I hypersensitivity reaction
• Dependant on IgE and Mast cells.
• Requires prior sensitisation to antigen.
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Mast cell degranulation
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Key Event. Mast cell activation (elicitation phase)
HistamineProstaglandin D2Leukotriene C4Cytokines (TNF-a)
Y Y Y Y Y IgE
antigen
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Scanning electron micrographs of RBL-2H3 (rat basophilic leukemia) cells (A) before and (B) after crosslinking IgE-primed FceRI with polyvalent antigen
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Effector mechanisms
• Mast cell activation:– preformed mediators
• histamine• enzymes (e.g. tryptase)• TNF-α
– synthesis• leukotrienes C4, D4• IL-4, IL-5
• Results:– vasodilation and increased permeability– increased mucus secretion– bronchoconstriction– Cough– chemotaxis of other inflammatory cells
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HYPERSENSITIVITY TYPE II
• Caused by IgM or IgG antibodies to cell surface and
extracellular matrix proteins.
• Abs interact with complement components and
effector cells such as macrophages and neutrophils.
• This results in tissue damage via mechanisms
normally active against foreign antigens.
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EXAMPLES
1. Reactions against incompatible blood transfusions.
2. Autoimmune haemolytic anaemia. Sensitised to patients’ own RBCs. Often drug induced.
3. Goodpastures Syndrome. Ab against basement membrane proteins produce nephritis.
4. Myasthenia Gravis. Muscular weakness associated with Abs to acetylcholine receptors.
5. Haemolytic disease of the newborn. Pregnant woman is sensitised to the fetal erythrocytes.
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HAEMOLYTIC DISEASE OF THE NEWBORN
• Occurs when mother has become sensitised to Ag on the infant’s erythrocytes. Rhesus D commonly.
• Often Rh –ve mother carrying a second or subsequent rhesus +ve infant.
• Sensitisation of the mother during the birth of the first Rh +ve baby.
• Subsequent children have an increased risk of being affected.
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HAEMOLYTIC DISEASE OF THE NEWBORN
First birth Postpartum Subsequent pregnancy
RhD+ foetus
RhD- mother
Exposure sensitisation disease
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Exposure no sensitisation no disease
RhD+ foetus
Ag removed prevents sensitisation
Anti D Abs given immediately after birth
First birth PostpartumSubsequent pregnancy
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Muscle fibres
Acetyl choline from nerve impulse
Acetyl choline receptors
Normal nerve signal
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MYASTHENIA GRAVIS
Ab against the receptor is only part of the disease process
Muscle weakness from reduced signal transmission
Antibodies to the receptor block acetylcholine binding
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HYPERSENSITIVITY TYPE III
• Caused by IgM or IgG Abs against soluble antigens.
• Ab/Ag immune complexes normally removed effectively.
• In these reactions complexes that persist are deposited in the circulation or tissue and cause inflammation.
• Frequent complication in autoimmune disease.
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Type III Hypersensitivity results from immune complex formation
Can accumulate in tissues leading to increased local concentrations
which may be pathogenic
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3 basic categories
Cause Persistent Infection
Autoimmunity Inhaled Antigen
Antigen Microbial Self-antigen Mould plant or animal antigen
Site Kidney and infected organs
Kidney, joints and skin
Lung
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MECHANISMS IN TYPE III HYPERSENSITIVITY
• Complexes interact with basophils and platelets to
induce release of vasoactive amines.
• Macrophage stimulation results in cytokine
release (TNFα IL-1).
• Complement activation and inflammation.
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MECHANISMS IN TYPE III HYPERSENSITIVITY
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Experimentally induced Type III hypersensitivity
Immune complex deposition in the skin and resultant pathology is known as the Arthus reaction
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TYPE IV HYPERSENSITIVITY
• Delayed type hypersensitivity.
• Typically mediated by TH1 cells and/or
macrophages which produce and respond to
cytokines including TNFα and IFNγ
• Can be shown experimentally by transferring T
cells between animals.
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3 BASIC TYPES
Contact hypersensitivity 48-72 hours
Tuberculin reaction 48-72 hours
Granulomatous reaction 21 days
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ANAPHYLAXIS
An immediate, severe, systemic hypersensitivity or allergic
reaction, sometimes fatal, usually characterised by at least one
or other of the following symptoms, respiratory difficulty,
hypotension or circulatory failure. Generalised urticaria and
tissue swelling also common.
Mediated by IgE antibodies and Mast cells Immunologically
disease.
‘Type One hypersensitivity’
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Common causes of anaphylaxis
• Foods• Serum/vaccines• Bee and wasp stings• Drugs• Latex rubber - gloves
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Foods commonly causing anaphylaxis
• Peanuts• Tree nuts (eg. brazil nut, almond, hazlenut)• Fish• Shellfish• Egg• Milk• Sesame
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Drugs causing anaphylaxis
• Antibiotics (especially penicillin)• Intravenous anaesthetic drugs• Aspirin• Non-steroidal anti-inflammatory drugs
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Features of Anaphylaxis• Erythema• itching• Urticaria• Asthma• Rhinitis• Conjunctivitis• Nausea, vomiting, abdominal pain• Fainting, lightheadedness• Collapse• Lose of consciousness• Hypotension/reduced blood pressure• Circulatory/heart failure
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UrticariaRaised, erythematous intensely itchy skin eruption caused by IgE-mediated histamine release from mast cells.
Causes: Drugs Food allergens
penicillinEnvironmental allergens
cephalosporins Insect bites
latex
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Is this allergy?
“Please see this patient who is:obviously allergic to something......clearly having allergy-like episodes......presumably to something he/she is eating......
......but can’t tell what he/she is allergic to.”
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Case 1
Clinical diagnosis• “oral allergy syndrome”• allergy to birch pollen causing symptoms on exposure to cross-reacting
allergens in a variety of fruits (particularly peach, pear, apple and plum)• other plant-derived foods are sometimes involved, as in this case
Tests• skin prick testing showed a very strong response to birch pollen. Strong responses were also
obtained to hazel nut, almond, carrot and celery. Extracts of the relevant fruits gave negative results. IgE results were:
– total 52.4– birch pollen 22.3– apple 1.01– carrot 1.3– celery 0.8 (peach, pear and plum were negative)
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The End