Immunopathology - Hypersensitivity Flashcards
What is the definition of allergy?
a reaction produced by the normal immune system in a pre-sensitized (immune) host
What type of antigens are involved in allergy?
the normal immune response is directed against innocuous antigens
these are harmless antigens
How did Coombs & Gell classify hypersensitivity?
There are 4 types of hypersensitivity reactions
What is the role of a dendritic cell?
they are APCs that process antigens and present them to T cells
they are messengers between the innate and adaptive immune systems
What characterises a Type 1 hypersensitivity reaction?
IgE antibodies initially sensitize individuals to an antigen
They provoke a quick inflammatory response upon subsequent exposures
What is meant by ‘immunopathogenesis’?
the process of disease development involving an immune response or components thereof
What are the 2 stages involved in the immunopathogenesis of Type 1 hypersensitivity reactions?
- IgE antibody mediated mast cell and basophil degranulation
- release of preformed and de novo synthesised inflammatory mediators
What are the 2 main clinical features of a Type 1 hypersensitivity reaction?
- fast onset - 15-30 mins
2. weal and flare
What types of cells are involved in the late phase response of a Type 1 hypersensitivity reaction?
- eosinophils
2. Th2 T cell
What happens in a Type 1 hypersensitivity reaction when antigen comes into contact with a mast cell?
The antigen bound to IgE cross-links with membrane-bound IgE antibodies on the mast cell membrane
What is involved in the primary response of a Type 1 hypersensitivity reaction?
The mast cell degranulates and releases
- Histamine
- proteases
- chemotactic factors
What are chemotactic factors?
Substances that stimulate cellular migration (chemotaxis)
What is involved in the secondary response of a Type 1 hypersensitivity reaction?
reaction of the antigen with IgE on mast cells causes the
synthesis and release of:
- prostaglandins
- leukotrienes
What is the role of histamine that is released in a Type 1 hypersensitivity reaction?
- blood clots
- gastric acid secretion
- dilation of blood vessels
- bronchoconstriction
- increases capillary permeability
- adrenaline release
- swelling and inflammation
- increases heart beat frequency
What is the role of Th2 cells in Type 1 hypersensitivity reactions?
- antigen is taken up by a dendritic cell and presented on a class II MHC molecule
- This is recognised by the Th2 cell
- Th2 cells produce cytokines which stimulate proliferation of IgE producing plasma cells
What is meant by the mast cell being ‘sensitised’?
It has IgE molecules, attached via their constant region, on its membrane
What happens when someone is exposed to an antigen for a second time in a T1 HS reaction?
The antigen binds to IgE attached to the mast cells and causes degranulation
2 IgE molecules must react with the specific antigen
What is the definition of anaphylaxis?
an acute, potentially life-threatening IgE mediated systemic hypersensitivity reaction
What are the symptoms of a mild Type 1 hypersensitivity reaction?
- itchy eyes or nose
- cutaneuous pruritus
- flushing
- urticaria
- oral tingling/pruritus
- abdominal pain/nausea/vomining
- runny nose and sneezing
What is cutaneous pruritius?
Itchy skin
It is an unpleasant sensation of the skin that provokes the urge to scratch
What is urticaria?
“Hives” is an outbreak of swollen, pale red bumps or plaques (wheals) that appear suddenly on the skin
What is another way of describing a moderate-severe type 1 hypersensitivity reaction?
anaphylaxis
What are the symptoms of anaphylaxis related to the skin and pain?
- diffuse urticaria
- angioedema
- severe abdominal pain and vomiting/diarrhoea
What are the symptoms of anaphylaxis relating to the lungs and breathing?
- hoarseness and cough
- shortness of breath
- wheezing and cyanosis - can lead to respiratory arrest
What are the other symptoms of anaphylaxis?
- hypotension
2. dizziness and loss of consciousness
What is the main reason why people get allergies?
components of the immune system responding to parasitic infection are also involved in allergic responses
the system has developed to produce a rapid tissue-based response to re-infection
What is another contributory factor in allergic disease?
The lack of infectious drive
What happens when an allergen binds to a dendritic/AP cell?
The antigen is presented to a naive T cell
This then differentiates into a Th2 cell
What molecules are produced by the Th2 cell and what is their role?
Cytokines IL-4 and IL-13
They signal to naive B cells which undergo class-switching to IgE
What happens to the naive B cells after exposure to IL-4 and IL-13?
They become memory B cells which have specific IgE
They will recognise the antigen on further exposure
What does the ‘dual allergen exposure’ hypothesis suggest about early cutaneous exposure to food protein?
Early cutaneous exposure to food protein through a disrupted skin barrier leads to allergic sensitsation
What does the ‘dual allergen exposure’ hypothesis suggest about early oral exposure?
early oral exposure to food allergens induces tolerance
What are the main genetic influences on the allergic immune response?
- polygenic diseases
- cytokine gene cluster IL3, 5, 9, 13
- IL12R, IL4R
- FCeRI
- IFN-gamma, TNF
What is the conclusion about genetic influences on the allergic immune response?
They are NOT sufficient for disease, only susceptibility
What is a polygenic disease?
a genetic disorder that is caused by the combined action of more than 1 gene
What is meant by the atopic (allergic) march?
the natural history or typical progression of allergic diseases that often begin in early life
How does the incidence of the following diseases change throughout life?
- eczema
- food allergy
- asthma
- rhinitis
- incidence peaks around age 2 and slowly declines
- incidence peaks around age 2 and rapidly declines to almost zero by age 5
- incidence peaks around age 7 and declines steadily to plateau around age 12
- incidence rapidly increases at age 5 to plateau around age 10
What is the first stage in diagnosing an allergy?
TAKE A HISTORY!!!
What is involved in the skin prick test for diagnosing allergy?
allergen solution is placed on skin
test is positive if the wheal is >2mm bigger than negative control
What is involved in testing for specific IgE when diagnosing allergy?
Specific IgE > 0.35 KuA/L
What are the other ways of diagnosing allergy?
- intra-dermal test
2. oral challenge test
What are the 3 components of the atopic triad?
- asthma
- rhinitis
- eczema
What are the 2 types of rhinitis?
- allergic
2. non-allergic
What is allergic rhinitis?
inflammation of the inside of the nose caused by an allergen
What is non-allergic rhinitis?
inflammation of the inside of the nose that is not caused by an allergy
What are the typical symptoms of allergic rhinitis and the allergens that can trigger it?
Symptoms are usually perennial or seasonal
Blocked nose, runny nose and eye symptoms
House dust mites, animal danders and pollen
What is the treatment for rhinitis?
nasal steroids and antihistamines
What is asthma?
disease of inflammation and hyperactivity of the small airways
What is of key pathogenic importance in childhood asthma?
aero-allergic stimuli, such as house dust mite
How are the symptoms of asthma mediated?
Immediate symptoms are IgE-mediated
Damage to the airways is due to the late phase response
What is thought to be a major trigger in atopic dermatitis?
house dust mite
What are the clinical signs of atopic dermatitis?
- intense itching
- blistering/weeping
- cracking of the skin
What is the treatment for atopic dermatitis?
topical steroids and moisturisers
What are the clinical features of a Type II (cytotoxic) hypersensitivity reaction?
- onset of minutes to hours
2. cell lysis and necrosis
What is the mechanism behind a Type II hypersensitivity reaction?
IgG and IgM antibodies bind t self/foreign antigens on cell surfaces
This leads to complement activation/phagocytosis and eventual cell death
What is a common antigen that causes a cytotoxic Type II hypersensitivity reaction?
penicillin
What are 2 diseases/conditions that result in Type 2 hypersensitivity?
- goodpasture’s nephritis
2. blood transfusion reaction
What are the first 3 stages in the blood transfusion reaction?
- blood is incorrectly matched
- dendritic cells/macrophages (APCs) detect the foreign antigen
- They present the foreign antigen to B cells, which make antibodies
What happens in the blood transfusion reaction after B cells have made antibodies?
How long is the response?
Antibodies activate classical pathway complement system through MAC
It takes hours to days
What is the role of the Membrane Attack Complex (MAC)?
C6, 7, 8 and 9 unite with C5b to produce MAC
MAC is inserted into cell membranes to cause lysis
What complement components are involved in the classical pathway?
How is it triggered?
C1, C2 and C4
It is triggered by antibody-antigen complexes binding to C1
What does the classical pathway form and what is the role of this?
C3 convertase that splits C3 into C3a and C3b
What are the roles of C3a and C3b?
C3a activates mast cells and leads to histamine release
C3b attaches to the surface of pathogens to opsonise them
What is involved in the alternative pathway?
Factors B, D, H and I interact with each other, and C3b to form a C3 convertase
This will activate more C3
What is involved in the mannose-binding lectin pathway?
MBL binds to mannose residues on the pathogen surface
This activates MASP-1 and MASP 2
These activate C4 and C2 to form a C3 convertase
What is involved in the lytic/common pathway?
C5 is split into C5a and C5b
C5b attaches to a target and unites with C6, 7, 8 and 9 to form the MAC
This is inserted into cell membranes to cause lysis
What are the clinical features of a Type III hypersensitivity reaction (immune complex)?
- onset between 3 to 8 hours
2. vasculitis
What is vasculitis?
Inflammation of the blood vessels
It can restrict blood flow leading to organ and tissue damage
What is the mechanism behind a Type III hypersensitivity reaction?
IgG and IgM antibodies against soluble antigens form an immune complex that is deposited on the surface of tissues and organs
Underlying tissue is also damaged in an attempt to remove the complexes
What is the traditional cause of Type III hypersensitivity reactions?
What are the associated diseases?
Serum sickness
Associated disease is SLE -Systemic lupus erythematosus
What is the key distinction between Type II and Type III hypersensitivity reactions?
Type III is mediated by immune complexes
IgG binds to soluble antigens
Type II does NOT involve immune complexes
IgG binds to antigens on the cell surface
What is meant by someone having tolerance?
T and B cells that recognise self-antigens should be excluded in the secondary lymphoid organs
How does SLE result as a type III hypersensitivity reaction?
DNA is damaged and cell undergoes apoptosis
This exposes parts of the nucleus - nuclear antigens
B cells attack the nuclear antigens and produce antinuclear antibodies
What happens to the nuclear antigens in SLE?
They are not as easily cleared from the system, build up and stick to blood vessel walls
What happens in SLE once the immune complexes have bound to blood vessel walls?
Antigen-antibody complexes initiate a local inflammatory reaction
C1 binds to the antibody
C1-9 follow with increased permeability of the vessels
What is a key blood test used in SLE?
C3 and C4 are produced in large amounts so can be detected
Why is there increased vascular permeability in SLE?
What does this lead to?
C5a, C4a and C3a are anaphylatoxins that increase vascular permeability
This leads to oedema as fluid leads out of the blood vessel
What is the role of the neutrophil in SLE?
There is unsuccessful phagocytosis
The neutrophil degranulates and releases lysosomal enzymes and reactive oxygen species
What are the clinical features of a Type IV hypersensitivity (delayed) reaction?
- delayed onset of 48-72 hours
2. erythema induration
What is meant by induration of the skin?
a palpable, raised, hardened area of the skin
What is erythema?
redness of the skin caused by increased blood flow in superficial capillaries
What is the mechanism behind a Type IV hypersensitivity reaction?
It is regulated by T cells
It is a delayed reaction to antigens associated with specific T cells
What are the common antigens associated with Type IV hypersensitivity reaction?
What is an associated disease?
- metals e.g. nickel
- poison ivy
- tuberculin test
associated disease is contact dermatitis
What are the 2 types of T cells that cause damage to the tissues in a Type IV hypersensitivity reaction?
- CD8+ cytotoxic T cells
2. Cd4+ helper T cells
What is the general role of a helper T cell?
It locally releases cytokines to stimulate or inhibit other cells
They coordinate other immune cells
Why do both CD4+ and CD8+ T cells start as naive cells?
The T cell receptor has not yet bound to an antigen
What happens when someone brushes up against some poison ivy?
urushiol molecules pass from the epidermis of the skin through to the dermis
they combine with small proteins and are picked up by a dendritic cell
What happens once the dendritic cell has picked up the urushiol molecule?
it transports it to the nearest lymph node and presents it on an MHC II molecule
TCR and CD4 on surface of T helper cell bind to the MHC II and antigen
What happens to the T cell once it has bound to the MHC II molecule and antigen?
It expresses CD28 that binds to B7 on the surface of the dendritic cell
The dendritic cell then releases IL-12 that causes the T cell to differentiate into a Th1 cell
What does the Th1 cell release after it has matured?
IL-2
This helps it, and other T cells in the area, to proliferate
IFN-gamma
This activates macrophages that release proinflammatory cytokines (TNF, IL-1 and IL6)
What is the result of TNF, IL-1 and IL-6 production?
The cause the endothelial barriers to become more leaky, allowing more immune cells into the area
This leads to oedema and redness and fever (dermatitis)
How is tissue damage brought about in a Type IV hypersensitivity reaction?
Macrophages release:
- lysosomal enzymes
- complement components
- reactive oxygen species
What is involved in a tuberculin skin test?
Skin is exposed to mycobacterium tuberculosis protein
If they have been exposed previously, it leads to Type IV HS reaction and induration of the skin
