Hypersensitivity Reactions Flashcards
What is a hypersensitivity reaction?
An inappropriate immune response to non-infectious antigens that results in tissue damage and disease
What are the different types of hypersensitivity reactions?
Type 1: immediate hypersensitivity
Type 2: cytotoxic hypersensitivity
Type 3: serum sickness and Arthus reaction
Type 4: delayed-type hypersensitivity, contact dermatitis
What causes immediate hypersensitivity?
Immediate hypersensitivity results from exposure to allergens in the environment
Describe the immune response to immediate hypersensitivity
Host immune response is characterised by IgE antibodies bound to mast cells
What are the effects of IgE in response to immediate hypersensitivity?
IgE is specific to the allergen and cross-links to activate (mast) inflammatory cells to release mediators
Summarise the immune response to immediate hypersensitivity
Immune reactant: IgE
Antigen: soluble e.g. allergen
Effector Mechanism: Mast cell activation + degranulation
Give examples of immediate hypersensitivity
Allergic Rhinitis
Anaphylaxis
Eczema (skin)
Asthma (airways)
How can we induce a immediate hypersensitivity reaction?
A Type I hypersensitivity reaction can be induced via injection or scratching an allergen on skin
What are the effects of the immune response to an immediate hypersensitivity reaction?
Mast cells release inflammatory mediators causing leakage of plasma fluid into surrounding tissue = wheal (local oedema - bump on skin)
Vasodilatation = erythema = flare response
What is systemic anaphylaxis?
An exaggerated allergic response
How does systemic anaphylaxis occur?
Exposure to allergen causes rapid allergic reaction indicated by vasodilatation and fluid release = oedema
Why is systemic anaphylaxis dangerous?
Angioedema (face) can restrict the airways and lead to death
How is systemic anaphylaxis treated?
Require adrenaline on hand to treat reaction
What is cytotoxic hypersensitivity?
Hpersensitivity reactions in response to altered components of human cells
E.g. penicillin attaches to surface of RBCs which immune system flags as foreign
Outline a cytotoxic hypersensitivity reaction to penicillin
- Platelet / RBC covered in a drug (e.g. penicillin)
- Immune systems generates IgG response to drug
- IgG activates macrophages and complements = inflammation
What allergens cause cytotoxic hypersensitivity?
Some drug allergies
Penicillin
Describe the autoimmune cytotoxic hypersensitivity response
IgG antibodies disrupt normal functions of the receptor by either:
- uncontrollable activation
- blocking receptor function
Describe the normal release of Thyroxine and TSH
Pituitary releases TSH which acts on thyroid to release thyroxine
Thyroxine in blood causes -ve feedback = reduces TSH production
Outline how cytotoxic immune response can lead to Grave’s disease
In Thyrotoxicosis / Grave’s an immune response is generated against TSH receptors causing long term stimulation of TSHR
Release of thyroxine leads to excess levels with no -ve feedback
What are the consequences of autoimmune cytotoxic hypersensitivity reactions?
Grave’s disease
Myasthenia Gravis
Haemolytic disease (newborn)
Outline the ways Type II HS reactions cause myasthenia Gravis
Antibodies block / destroy nAchR on postsynaptic junctions
Antibodies block / destroy nAchR at junction between nerve and muscle
How does haemolytic disease of newborns occur?
Blood group antigen (Rhesus) causes immune response when:
- RhD -ve mother
- RhD +ve foetus
Occurs at time of delivery
How does baby normal dissociate from maternal circulation?
Normally embryonic chorion isolates foetus from maternal circulation
How does HDN affect maternal circulation?
During incompatibility, embryonic chorion disruption causes release of red cells in maternal circulation
Mother produces antibodies against RhD+ foetus - 1st child is safe
What are the consequences of HDN on foetus during 2nd pregnancy
During 2nd pregnancy, antibodies previously stimulated can cross placenta and attack fetal RBCs with RhD resulting in death
What causes serum sickness (Type 3 HS)?
Presence of soluble antigen e.g. tetanus / diphtheria toxoids can cause serum sickness /arthus reaction
How do toxoids cause serum sickness / arthus reaction?
Large IgG response generated at site of injection causes immune complexes
These activate cells around capillaries to produce inflammatory response with activated complement
How does arthus reaction arise?
Previous vaccination = elevated antibodies
If vaccinated again = more immune complexes form
High levels of antigens can cause localised inflammation
Outline the process of arthus reaction formation
- Activate mast cells to release inflammatory mediators.
- inflammatory cells invade site
- Blood vessel permeability + blood flow increased.
- Platelets accumulate = occlusion of small blood vessels, hemorrhage, and appearance of purpura
What causes serum sickness?
- large intravenous doses of soluble antigens (e.g. drugs)
IgG antibodies produced form small immune complexes with antigen in excess
immune complexes deposited in tissues e.g. blood vessel walls
What causes tissue damage during serum sickness?
Tissue damage is caused by complement activation and the subsequent inflammatory responses
How does antivenom cause serum sickness?
- large amounts of horse Ig
- Vasculitis rash on skin
- nephritis; immune complexes deposited in kidney ⇒ fatal
What causes farmers lung?
- hay mold inhaled into lungs
- localised inflammation; immune complexes
What are the consequences of farmer’s lung?
Antigen inhaled (mold etc.) that forms immune complexes with alveoli
Complexes stimulate an inflammatory response within lung resulting in fibrosis, granulation + inflammation
What causes hypersensitivity pneumonitis?
- Dusts, bacteria, fungi
- Farmer’s lung - thermophilic actinomycosis
- Pigeon breeder’s lung - protein derived from birds
Describe the histology of hypersensitivity pneumonitis
- Interstitial pneumonia
- Non-caseating granulomas in 2/3rd patients
- Interstitial fibrosis, honeycombing & obliterative bronchiolitis
- Intra-alveolar infiltrate
What determines Type III HS reaction pathology?
Antigen dose and route of delivery determine the pathology observed in type III hypersensitivity reactions
What are the effects of Type III HS due to a High IV dose?
- Vasculitis: Blood vessel walls
- Nephritis: renal glomeruli
- Arthritis: joint spaces
What are the consequences of Type III HS in subcutaneous tissue?
Causes arthus reaction due to immune complexes forming in perivascular areas
What is the effect of an inhaled Type III HS allergen?
Farmer’s lung leads to immune complexes forming in alveolar / capillary interfaces
What are the 2 types of delayed-type hypersensitivity?
- Th1 (intracellular bacteria)
- Th2 (worm infection / allergens)
Outline the Th1 mediated delayed-type reaction
- Antigen activates Th1 cells
- Cytokines (IFN-y + !L-12) released
- Macrophages tstimulated o release cytokines / chemokines to recruit specific cells (granuloma) to inflammation site
~2-3 days for reaction
Name an antigen that induces a Th1 mediated delayed-type hypersensitivity response
Tuberculin
Describe the Th2 mediated delayed-type HS reaction
Cells produce IL-4 + IL-5 cytokines that recruit IgE and eosinophils to site of inflammation
Why does a delayed response occur in Type IV HS reactions?
T cell mediated Macrophages recruit cytokines / chemokines that recruit further immune cells to inflammation site
- takes 24 -72 hrs
Give examples of Type IV HS disorders
Contact dermatitis
Tuberculoid Leprosy
Poison Ivy
Describe how a mantoux test is carried out
Subcutaneously inject tuberculin extract (bacilli)
Wait ~2-3 days for reaction
Ulceration shows sensitisation
What is tuberculoid leprosy?
Tuberculoid leprosy is a strong Th1 response in response to tuberculin bacilli presence resulting in typical granuloma
How does poison ivy cause a delayed-type hypersensitivity reaction?
People previously sensitised to pentadecacatechol (in poison ivy) can develop a strong contact dermatitis type reaction upon re-exposure
What is allergy?
Defined as “disease following a response by the immune system to an otherwise innocuous antigen”
What is the significance of IgE?
First line of defence against worms and allergies
How do IgE molecules create an immune response?
Binds FcεR1 receptor on mast cells
Coats mast cells to react when in the presence of antigen
Outline the simple allergy IgE reaction
- First exposure to pollen
- IL-4 drives B cells to produce IgE in response to pollen antigens
- Pollen-specific IgE binds to mast cells
What causes allergic sensitisation?
Exposure to Allergen is critical, this includes:
- Nature of the allergen
- Dosage of Allergen (high vs. low)
- Timing
- Location of Priming
Role of pro-allergic dendritic cells and cytokines
Genetic predisposition to Allergy
How does the environment affect allergy cases?
Microbiome altered due to increased cleanliness - lack of diversity (aseptic environment) may cause sensitivity to more allergens
What are some common allergens?
House dust mite, pollens, cockroach etc
How are allergens named?
Allergens are named systematically:
- After source organism and order discovered
e. g. Der p1 comes from Dermatophagoides pteronyssinus
Not all proteins are allergenic
Describe the genetics of allergy
Most allergies are polygenic - however interaction between genes and environment can determine development of allergies
What is the role of filaggrin?
Filaggrin links skin integrity and allergy
What is the consequence of defective filaggrin?
When defective atopic dermatitis is greater due to increased access for allergens
What factor determines the production of an allergic response?
Type of cell presenting the antigen initially can affect whether an allergic response is generated or not
What cells are switched to ‘pro-allergic’ due to antigen presentation?
APCs within skin called langerhan cells (epidermis) and dendritic cells (dermis)
What causes the switch of cells to pro-allergic?
Not Known but one Candidate Protein is TSLP
This may switch DC to a ‘pro-allergic’ state
(TSLP= Thymic stromal lymphopoietin)
What are the effector mechanisms of the allergic immune response?
- First exposure to pollen
- IL-4 drives B cells to produce IgE in response to pollen antigens
- Pollen-specific IgE binds to mast cells
- Second exposure to pollen
- Acute release of mast-cell content causes allergic rhinitis (hay fever)
Describe the structure of resting mast cells
Resting mast cells contain dense granules full of inflammatory mediators (histamine, leukotrienes etc.)
How do activated mast cell structures change?
Activated mast cell releases all mediators revealing a different structure
What are the 2 phases of an allergic response?
Allergic responses have an early and late phase
- Early mediated by mast cells
- Late mediated by T cells
Describe the early allergic response
Early response = typical wheal & flare response (Type 1)
What is a late allergic response charcterised by?
High allergen dose - recruitment of other immune cells to site of inflammation causes later reaction - more diffuse oedema and inflammation
Describe the allergic reaction phases of the airways
Reduced FEV1 in airway inflammation ~30 mins after allergen inhalation
Recruitment of inflammatory cells causes late response lasting longer ~24hrs
Outline primary sensitisation to allergens
> Mediated by B cells
DC activation: present antigen to T cells (Th2)
Activated Th2 produce IL-4, IL-13 which signal B cell IgE production
IgE lines mast cells ready for secondary allergen exposure
⇒ acute allergic reaction
Describe the secondary allergen exposure
> Mediated by Th2
Recruitment of other immune cells e.g. eosinophils and mast cells mediate over a prolonged period of time
⇒ Chronic allergic reaction
What effector mediators are produced by mast cells during early phase?
- histamine
- leukotrienes
- prostaglandins
What effect does histamine have during early phase?
- increase vascular permeability
- smooth muscle contraction
Describe the effects of leukotriene release during early phase allergic reactions
- increase vascular permeability
- smooth muscle contraction
- mucus secretion
What are roles of prostaglandin release in response to early phase allergic reactions?
Acts as chemoattractants for T cells, eosinophils and basophils
What cytokines are released during late phase?
- IL-4 + IL-13
- TNF-a
What are the effects of IL-4 and IL-13?
promote Th2 activity
Activate IgE
What is the effect of TNF-a during late phase allergic reaction?
promotes tissue inflammation
How does mast cell activation effect GI tract?
- inc. fluid secretion
- inc. peristalsis
Expulsion of contents (diarrhoea + vomiting)
What are the effects of mast cell activation on the airways?
- dec. diameter
- inc. mucus secretion
Congestion / blockage; wheezing, coughing, phlegm
Swelling + mucus secretion in nasal passages
Describe the effects of mast cell activation on blood vessels
- inc. blood flow
- inc. permeability
Inc. fluid in tissues = more lymph to lymph nodes = more cells + proteins in tissues
- increased effector response in tissues
Where are eosinophils found?
Located in the tissues and recruited to allergic reaction site
Express FcεRI upon activation
What are the 2 effector functions of eosinophils?
- Release toxic granule proteins + free radicals to kill microorganisms / parasites and cause tissue damage
- Synthesise + release prostaglandins, leukotrienes and cytokines to amplify inflammatory response - activate epithelial cells + recruit leukocytes
What does ate phase allergic response depend upon?
Late-phase reaction is dependent on allergen dose
Continued synthesis and release of inflammatory mediators
