Hypersensitivity Reactions Flashcards
define hypersensitivity
inappropriate immune response to non-infectious/otherwise benign antigens, resulting in tissue damage and disease
4 types of hypersensitivity - name them
type 1 - immediate hypersensitivity
type 2 - cytotoxic hypersensitivity
type 3 - serum sickness and Arthus reaction
type 4 - delayed type hypersensitivity, contact dermatitis
Type I : Immediate hypersensitivity (allergy)
This type results from being exposed to allergens in the environment, and the host generates an immune response characterised by IgE antibody production
The IgE antibodies attach to mast cells, and when an antigen is present, the IgE will cross link the antigen, activating the mast cell and causing it to release mediators - cause inflammation
an example is asthma or system anaphylaxis
-system anaphylaxis is a more exaggurated allergic response, fluid leaks into tissues causing oedema - this can restrict the airways and lead to death
how can you induce an immediate hypersensitivity reaction (type 1)?
- injecting allergens into the skin
- scratching the surface of the skin with an allergen
If you have mast cells in your tissue carrying that specific IgE, the IgE will be cross linked, the mast cells will be activated and will release lots of inflammatory mediators
Results in plasma leakage into surrounding tissues causing a wheal, and vasodilation causing a flare response
this forms the basis of an allergen test:
scratch the surface of the skin with an allergen, wait 10 mins
– a wheal formation is indication you have IgE’s made against that allergen
Type II: cytotoxic hypersensitivity
respond to altered components of human cells, not something from the environment
IgG binds to “foreign antigen” on RBC or platelets - this antigen is a drug (eg. penicillin) and the immune system recognises it as a new allergen
drug now coated in IgG, activates cell containing the IgG receptor - mast cell and complement activation, resulting in inflammation. Antibody-bound cells are cleared by macrophages and complement.
Special case: slightly different in the sense that you stimulate antibodies that stimulate or block receptors
Eg. myasthesia gravis, graves disease (thyroxin release, HDN)
example of type II: Grave’s disease
thyroxin usually binds to TSH receptors on the pit gland - negative feedback mechanism
here, an immune response is made against the TSH receptors, blocking them and causing excess thyroxin levels in the blood with no negative feedback - thryotoxicosis
example of type II: Myasthenia gravis
NMJ with a synapse, Nerve is activated and releases Ach which stimulates post synaptic receptors on the muscle cell causing muscle contraction
here an immune response is made against post synaptic receptors - receptors blocked by antibodies causing nerve paralysis.
example of Type II: Hemolytic disease of the newborn
RhD is a blood group antigen on the surface of red cells
RhD negative mother has a RhD positive foetus - rupture of the embryonic chorion during delivery releases red cells into maternal circulation, and immune response (antibodies) made against the RhD antigen
The first child is ok, but the second pregnancy is the issue.
The antibodies that were stimulated in the first pregnancy can cross the placenta and attack the red cells causing anaemia and death in the child.
Type III: Serum sickness/Arthus reaction
IgG and precense of a soluble antigen, e.g. diphtheria toxoid
IgG and soluble antigen form immune complexes which are cleared by phagocytes.
serum sickness, arthus reaction, farmers lung
Arthus reaction (type III)
Mast cell activation means inflammatory mediator release - inflammatory cells invade the site of infection, and blood vessel permeability and blood flow are increased.
Platelets accumulate, leading to occlusion of the small blood vessels, hemorrhage, and purpura.
Serum sickness (type III)
- caused by large intravenous doses of soluble antigens (e.g. drugs) or following antivenom (serum from horse to treat snakebite)
- IgG antibodies produced form small immune complexes with the antigen in excess, and these complexes are deposited in tissues e.g. blood vessel walls.
- tissue damage due to complement activation and inflammatory responses
what determines type III hypersensitivity reaction pathology?
Antigen dose and route of delivery
Type IV: Delayed-type hypersensitivity
2 scenarios: TH1 and TH2 specific
- Mantoux test
- poison ivy
- antigen stimulates TH1 to produce IFN gamma and IL-12, stimulating macrophages to release chemokines/cytotoxins/cytokines which recruit immune cells to the site of infection, granuloma occurs - 2-3 days to form
- Tuberculin reaction
- Tuberculoid leprosy, strong TH1 immune response to the presence of TB - TH2 produces IL-4, IL-5, important in IgE production and activating eosinophils and recruiting them to the site of infection
- Allergic contact dermatitis (eg Nickel)
What is IgE?
First line of defence against worms
Binds FcεR1 receptor on mast cells, coating them and pre-arming them to react in the presence of antigen
diff in structure compared to IgG because it has 1 extra domain in the heavy chain
Allergen-specific IgE Production
First exposure to pollen activates immune response
APC (DC’s) pick up the pollen and take it to local lymph nodes to activate immune cells
Th2 cells release IL4 which induces B cells to produce IgE. IGE is released into circulation and binds to mast cells, ready for the next exposure to the allergen - when we are exposed to the same allergen again, we get activation of mast cells and hay fever
Filaggrin and Atopic Dermatitis
People who lack the fillaggrin gene - their skin is far less of an effective barrier to the environment and things can cross the skin more easily, so the allergic immune response is more likely to be stimulated.
What Makes Dendritic Cell Pro-Allergic?
One Candidate Protein is TSLP, may switch DC to a ‘pro-allergic’ state
(TSLP= Thymic stromal lymphopoietin)
Mast cell activation
A resting mast cell is full of dense granules which contain inflammatory mediators eg. histamine
IgE cross links and actviates the mast cell, which then releases all its mediators, and it has a different structure
2 phases to the allergic response?
early and late
Early is mediated by mast cells
Late is mediated by T cells
Early and late phase allergic response
Exposure to the allergen causes activation of mast cells and release of mediators - immediate response, lasts a few years
When the allergen dose and level of activation is quite high, we can get a late phase response due to recruitment of other immune cells such as T cells to the site, causing a later allergic response
- associated with more diffuse inflammation and oedema
The immune response to allergens
allergen exposure, DC presents APC to T cells - TH2 cells
TH2 cells release IL-4 and IL-13, which activate B cells to produce IgE which binds to mast cells producing ACUTE allergic reactions (wheezing, sneezing, conjunctivitis)
IL-4 also activates mast cells to produce histamines and cytokines which cause chronic allergic reactions (further wheezing, sustaining nose blockage, eczema)
IL-5 activates eosinophils which reduce cytokines that contribute to chronic allergic reactions
chronic means they release mediators over a longer period of time
Effector mediators produced by mast cells
EARLY PHASE
- histamine and leukotrienes to cause SM contraction and increase vascular permeability
- prostaglandins are chemoattractants for T cells
LATE PHASE
-cytokines, IL-4, IL-13 (promote TH2 and IgE) and TNF-alpha (tissue inflammation)
mast cells cause wheezing due to increased mucus secretion and decreased airway diameter
diarrhoea and vomiittng due to increased peristalsis and fluid secretion
Eosinophils
located in the tissues, recruited to the sites of allergic reactions and express FcεRI upon activation
The two effector functions of eosinophils:
1. Release highly toxic granule proteins and free radicals when activated, killing microbes and causing tissue damage in allergic reactions.
- Synthesis and release of prostaglandins, leukotrienes and cytokines to amplify the inflammatory response by activating epithelial cells and recruiting leukocytes.
what is a late phase response dependent on?
allergen dose
-more allergen you are exposed to, the more likely it is that you will have a late phase response
Mostly consisting of allergen specific Th2 cells which recruit other cells via cytokines
before individuals can react to an antigen what has to happen?
must be sensitised to an allergen before they can react
- sensitisation requires presentation of allergen to Th2 CD4 T cells by DC and the priming of Cognate B cells to produce IgE
- reaction – IgE on mast cells cross-linked by cognate antigen leading to inflammation
Asthma
reversible bronchial hyper-reactivity resulting from a persistent inflammatory process
Atopic (allergic) and Non-Atopic Non Atopic includes Occupational Exercise induced Nocturnal Asthma Post-bronchiolitic Wheeze
characteristics of Allergic Asthma
- episodes of wheezy breathing
- narrowing of the airways
- rapid changes in airway obstruction
- severity varies - slight wheeziness to asthma attack
common allergens causing asthma include:
pollen, plants, some foods
allergic asthma - acute and chronic response
Acute response:
- occurs within seconds of allergen exposure, inflammatory mediators cause increase mucus secretion and SM contraction, leading to airway obstruction and breathing difficulties
- recruitment of cells from circulation
- caused by allergen-induced mast cell degranulation in the submucosa of the airways
Chronic:
- chronic inflammation of the
airways cause by eosinophils, neutrophils and T cells activation
- mediators released by these cells cause fibrosis and airway remodelling, permanent airway narrowing and further tissue damage
Treatment of allergy in the clinic
Blockage of effector pathways:
inhibit effects of mediators on specific receptors
anti-histamine (block the histamine H1 receptor)
inhibit mast cell degranulation
mast cell stabilizer (e.g. chromoglycate)
inhibit synthesis of specific mediators lipoxygenase inhibitors (e.g montelukast)
Steroids – Act directly on DNA to increase transcription of anti-inflammatory mediators (e.g. IL-10) and decrease transcription of pro-inflammatory mediators (e.g prednisolone)
Bronchodilators – Reverse acute effect of allergy on airways (e.g B2 agonist salbutamol)
Immunotherapy – Reverses the sensitisation to allergen by means of tolerising exposure
