Hypersensitivity Diseases Flashcards
What are the consequences of immune recognition?
- Intened destruction of the antigen
* Incidental tissue damage
What are hypersensitive reactions?
Immune response that results in bystander damage to the self - usually an exaggeration of normal immune mechanisms
What diseases involve hypersensitivity?
Allergy and autoimmunity
What are classifications of hypersensitivity reactions?
- Type I - immediate hypersensitivity
- Type II - direct cell killing
- Type III - immune complex mediated
- Type IV - delayed type hypersensitivity
What type of hypersensitivity reaction is involved in allergic disease?
Type 1 hypersensitivity reaction
What is type 1 immediate hypersensitivity?
Greatly enhanced sensitivity to normally innocuous substances, leading to physiological responses and tissue damage, resulting in the signs and symptoms of allergic reactions
What is an allergy?
IgE-mediated antibody response to external antigen (allergen)
What conditions are caused by allergies?
- Asthma
- Hayfever
- Urticaria
- Angioedema
- Atopic eczema
- Food allergy
- Drug allergy
- Anaphylaxis
- Allergic rhinitis
What are common allergens?
- Dust mite faeces
- Animal dander
- Shellfish
- Pollen
- Latex
- Bee and wasp venom
What are allergens?
Many allergens are soluble proteins and function as enzymes
Why is the prevalence of allergy increasing?
The “Hygiene Hypothesis” - Improved sanitation and decreased incidence of infectious disease results in increased predisposition to allergic conditions during childhood
Why is it beneficial for a child to grow up with older siblings, daycare centre, farming environment, helminth infections, microbial exposure, or pets?
Infections or viruses contracted from these factors enhance the maturation of the immune system, resulting in protection against asthma and allergy
What is the difference in immune response to an antigen between an isolated child in a sterile environment, and a child who has been exposed to many infections wth bacteria and viruses?
- Isolated child - CD4+ cells become activated by antigens, differentiate to form TH2 cells which secrete cytokines that cause B cells to secrete IgE, activating mast cell response
- Exposed child - CD4+ T cells more likely to differentiate into TH1 cells, response is “dampened down”
What is a TH1 immune response to an antigen?
No allergies - cell mediated protective immunity
What is a TH2 immune response to an antigen?
Allergies - antibody mediated immunity
What are the general clinical features of type I allergic disease?
- Occurs quickly after exposure to antigen (minutes or 1-2 hours)
- Responses are stereotyped
- May be associated with more than one organ system
- Presentation is influenced by site of contact
- Threshold for reactions may be influenced by cofactors such as exercise, alcohol and infection
What are specific clinical features of type I allergic disease?
- Asthma
- Urticaria
- Angioedema
- Allergic rhinitis (hay fever)
- Allergic conjunctivitis
- Diarrhoea and vominting
- Anaphylaxis
What cells are involved in allergic disease?
- B lymphocytes - recognise antigen, produce antigen-specific IgE antibody
- T lymphocytes - TH2 cells provide help for B lymphocytes to make IgE antibody
- Mast cells, eosinophils and basophils - inflammatory cells that release vasoactive substances (affect diameter of blood vessels)
Describe the process of an allergic response
- Stimulation of allergen-specific cells by allergen-derived peptides after being presented by dendritic cells via class II MHC molecules
- Differentiation of CD4+ T cells into effector TH2 cells
- TH2 cells produce IL-4, IL-13 and IL-15
- These cytokines stimulate B cells to stop producing IgM antibodies and start producing IgE
- Also stimulate differentiation and movement of eosinophils from bone marrow to blood
- Also activate mast cells and eosinophils at sites of allergen exposure
When is a TH2 response useful?
Immune protection against parasitic worms (helminths) - not so good for abnormal reactions to allergens
What are mast cells?
Tissue-resident cells that produce vasoactive substances (histamine, tryptase, heparin, leukotrienes, prostaglandins, pro inflammatory cytokines like IL-4 and TNF-a)
What vasoactive substances are produced by mast cells?
- Histamine, Tryptase, Heparin
- Leukotrienes, prostaglandins,
- Proinflammatory cytokines including IL-4 and TNFalpha
How do mast cells orchestrate the inflammatory cascade?
- Increase blood blow
- Contraction of smooth muscle
- Increase vascular permeability
- Increase secretions at mucosal surfaces
What is the function of mast cells?
Important in defence against parasites and in wound healing
What is the role of mast cells in the first encounter with an antigen?
- Express receptors for Fc region of IgE antibody on their surface (FcER1 receptors)
- On first encounter with allergen, B cells produce antigen-specific IgE antibody
- Allergen is cleared
- Residual IgE antibodies bind to circulating mast cells via Fc receptors
- No great consequence
What is the role of mast cells once antigen is re-encountered?
- Allergen binds to IgE-coated mast cells and disrupts cell membrane (degranulation)
- Results in release of vasoactive mediators like tryptase and histamine
- Also increased cytokine and leukotriene transcription
What do release of vasoactive mediators cause?
Clinical manifestations like: urticaria, angioedema, asthma, allergic rhinitis, allergic conjunctivitis, anaphylaxis
What is extrinsic asthma?
- Response to external allergen
* IgE mediated
What is intrinsic asthma?
- “Non-allergic” asthma
* Not IgE mediated
What are the clinical effects when an allergic reaction occurs in the lung?
- Muscle spasm - causes bronchoconstriction, wheeze
- Mucosal inflammation - causes oedema and increases secretions (sputum)
- Inflammatory cell infiltrate - infiltration of lymphocytes and eosinophils into bronchioles
What is urticaria?
Has a number of names:
- Hives
- Wheals
- Nettle rash
- Blisters
When do urticaria lesions appear?
Lesions appear with an hour and last for 2-6 hours (in some cases, 24 hours)
What is nettle rash?
- Surface of nettles covered in fine hairs
* Base of each hair contains histamine, formic acid
What is angioedema?
Self-limited, localised swelling of subcutaneous tissues or mucous membranes
What are clinical features of angioedema?
- Non-pitting oedema
- Often without clear demarcation (boundary)
- Generally not itchy unless associated with urticaria
What are the clinical features of anaphylaxis?
- Sense of impending doom
- Low blood pressure
- Dysphagia - difficulty swallowing
- Tissue swelling
- Rash
- Vomiting
- Clammy skin
What steps are involved in diagnosing allergic disease?
- Confirm diagnosis
- Identify causative agents - pinpoint specific allergen, target measures to reduce exposure and encourage lifestyle modification
- Determine risk of future severe reaction
- Determine appropriateness of therapy
What are key features of an allergy history?
- What does the patient mean by allergy?
- Ask about generic features of IgE mediated reactions
- What allergens are involved?
- History of allergy disease?
- Previous investigations for allergy?
- Has elimination of trigger made any difference to symptoms?
Specific investigations for allergies?
Elective investigations
- Skin prick tests
- Quantitate specific IgE to allergen
- Challenge test - supervised exposure to the putative antigen
During acute anaphylactic episode
* Evidence of mast cell degranulation (by measuring serum mast cell tryptase levels)
How are IgE mediated allergic disorders managed? (6)
- Avoidance of allergen
- Drugs that block mast cell activation
- Drugs that prevent effects of mast cell activation
- Anti-inflammatory agents
- Management of anaphylaxis
- Immunotherapy
How can triggers be identified for patients with IgE mediated disorders? (3)
- Clinical history
- Specific IgE tests
- Skin prick tests
What drugs are used to block mast cell activation?
Mast cell stabilisers e.g. sodium cromoglycate
What is sodium cromoglycate used for? (2)
Mast cell stabiliser (prophylaxis)
- Stabilises mast cell membranes
- Prevents release of inflammatory mediators from mast cells e.g. histamine
How is sodium cromoglycate administered?
Topical spray
What conditions can sodium cromoglycate be used for? (3)
- Allergic rhinitis
- Exercise induced asthma
- Allergic conjunctivitis
What drugs are used to prevent the effects of mast cell activation? (2)
- Anti-histamines
* Leukotriene receptor antagonists
What are anti-histamines? What do they do? What are they used for?
- H1 receptor antagonists
- Block biological effects of histamines
- Useful prophylactically and to control symptoms
What is the mainstay treatment of allergic disease?
Anti-histamines
What are examples of anti-histamines? (2)
Ioratadine and cetirizine
What are leukotriene receptor antagonists?
Block effects of leukotrienes which are synthesised by mast cells after activation
What is an example of a leukotriene receptor antagonist?
Montelukast
What are examples of anti-inflammatory agents?
Corticosteroids
What are corticosteroids? What do they do?
- Based on naturally occurring steroids
- Have anti-inflammatory actions: inhibit formation of many different inflammatory mediators like platelet activating factor, prostaglandins, cytokines
What is the treatment for anaphylaxis?
- Self-injectable adrenalin (preloaded adrenaline syringe)
How does self-injectable adrenaline treat anaphylaxis?
Acts on B2 adrenergic receptors to constrict arterial smooth muscle - increases blood pressure limiting vascular leakage, plated bronchial smooth muscle decreasing airflow obstruction
What is immunotherapy?
Controlled exposure to increasing amounts of allergen
Explain the process of immunotherapy (2)
- Subcutaneous injection of tiny amounts of allergen followed by gradual increase in dose
- May lead to inhibition of anaphylaxis
What are the risks of immunotherapy?
Anaphylaxis - must be carried out in very controlled environment
What can mast cell degranulation be triggered by? (4)
- Binding of IgE to FcER1 receptors
- Tissue injury
- Complement activation
- Some bacteria independently of IgE
