Hypersensitivity Flashcards
Name the four types of hypersensitivity reactions
Type 1: IgE mediated, anaphylactic/immediate
Type 2: antibody-mediated cytotoxicity
Type 3: antibody-antigen immune complexes
Type 4: Delayed or T-cell mediated
What is the function of an IgG antibody?
Highest opsonisation and neutralisation activities
classified into four subclasses
What is the function of IgM antibody
Produced first upon antigen invasion
Increases transiently
What is the function of IgA antibodies?
Expressed in mucosal tissues, forms dimers after secretion
What is the function of IgE antibody?
Involved in allergy
What type of hypersensitivity reaction is an allergy?
What are the two phases?
Type 1 - mediated by IgE antibodies
Immediate hypersensitivity because the reaction happens within minutes
Stage 1: sensitisation
stage 2: re-exposure leading to anaphylaxis
What is a multivalent antigen?
An antigen that has multiple sites of attachment for an antibody to attach to
When do non-allergic individuals produce IgE?
in response to parasitic infections
How can you test for type 1 hypersensitivity?
Skin prick test - expose the skin to small amounts of allergen
check for wheal and flare reactions
What are some common allergens?
Foods, plants, animal dander, drugs (penicillin, sulphonamides) and insect products
What is the sensitisation phase in type 1 hypersensitivity influenced by?
Genetics, environment and age
What does the sensitisation phase result in?
Formation of CD4 t-helper (th2) cells and follicular T helper cells specific to the allergen produce IL-4 and Il-3
This leads to the specific B cells switching from IgM to IgE
Th2 also recruits eosinophils to the site due to IL-5
Once produced IgE is not found in circulation, as it is quickly taken up and bound to the surface of mast cells and basophils
These granulocytes express Fc-epsilon I receptor that binds to the Fc portion of IgE antibodies
When allergen is encountered, cross linking of two IgE bound on the cell membrane of mast cells and basophils leads degranulation of the cell and an immune reaction
Name the 4 main inflammatory mediators.
Histamine
Cytokines
Leukotrines and prostaglandins
Proteases that break down proteins in the extracellular matrix
What does histamine do?
Vascular permeability and smooth muscle constriction, can lead to oedema due to fluid leakage and also urticaria/wheals/red rash
Binds to H1 receptors in airways (bronchi) causing smooth muscle to contract
What do cytokines do?
Recruit and mediate immune response
What do leukotrienes and prostaglandins do?
Vascular permeability and smooth muscle constriction- problem in asthma
What are the three phases a type 1 reaction can be divided into?
Early phase, degranulation of mast cells, within minutes
Later response, within a few hours, recruitment of neutrophils.
A third phase, or late response, 3-4 days, eosinophils are recruited and Th2 cells are present.
How can anaphylaxis be treated?
Why does it need monitoring?
Can be treated by:
Adrenaline injection – to counteract vasodilation
Antihistamines
Putting patients feet up – maintain brain perfusion
Need careful monitoring because biphasic anaphylaxis may occur - late phase reactions
Explain type II hypersensitivity reactions
IgM or IgM mediated cytotoxicity reactions
Tissue specific as they bind to antigen found on cell surfaces not soluble antigen
can be caused by a foreign antigen bound to cell membrane or self-antigen on cell membrane
Results in IgGs or IgMs that recognise cell surface structures
Result in disease through a number of different mechanisms including
- anti-receptor activity - blocking or activating its function
- antibody dependent cell-mediated cytotoxicity (ADCC)
- classical activation of the complement cascade
What do self-antibodies produced by self-reactive B cells secrete?
Secrete self reactive IgM
IgG when they are also activated by self-reactive T cells
What are the four cytotoxic mechanisms in type II hypersensitivity
Cytotoxic mechanism 1:
Activation of complement system
Antibodies bind to specific antigens on cell membranes
Antibodies induce classical complement pathway
This attracts neutrophils that degranulate
This kills cells
Cytotoxic mechanism 2:
Antibodies bind to antigens bound to cell membrane
Antibodies induce classical complement pathway
Membrane Attack Complex is formed
Cell dies because MAC causes pores that lead to osmotic overload
Cytotoxic mechanism 3:
Antibodies bind to antigens bound to cell membrane
C3b binds to antibody Fc-portion
Cells are now opsonised by Ab and C3b
Macrophages in the spleen phagocytose opsonised blood cells
This destroys and kills the cell
Cytotoxic mechanism 4:
Antibodies bind to antigens bound to cell membrane
Natural Killer cells recognise Fc portion antibody
NK cells release toxic granules containing:
Perforin – makes pore, like MAC
Granzymes and granylysin, which induce apoptosis
What is the non-cytotoxic mechanism of type II hypersensitivity?
Give examples
Antibodies bind to antigens bound to cell membrane
This can either block the receptor, so other substances cannot bind
Or can activate the receptor itself, leading to overactivation
Examples include myasthenia gravis - antibodies bind to and block Ach receptors which leads to paralysis or weakness
Graves disease - hyperthyroidism - antibodies bind to TSH receptors
What are the three mechanisms in which type II hypersensitivity can cause tissue injury?
Local or systemic inflammation
Cell depletion leading to a loss of function or
Imbalance in organ function
What occurs in type III hypersensitivity?
Non cell bound Antibody-antigen complexes called immune complexes form
These are deposited in blood vessel walls, glomeruli and joints
these complexes can activate the complement system or activate neutrophil degranulation
This leads to inflammation and damage to vessel wall
type 3 self-antibodies bind to soluble antigen
Self-reactive B cells are switched from IgM to IgG production by specific Th2 cells
Why are small soluble antigen complexes hard to remove from the blood?
What happens to them instead?
Normally immune complexes with larger antigens are quickly removed from blood
Small soluble antigens make the immune complexes less immunogenic, not removed in the spleen
Keep circulating and some fit through small pores in vessels and deposit inside which then
-can activate the complement system
-can activate neutrophil degranulations
which leads to damage to tissue where immune complexes
What type of hypersensitivity is systemic lupus erthematosus (SLE)? What occurs in it?
Type III
Auto-antibodies against DNA and nuclear proteins
The more damage that occurs the more cells get damaged and the more DNA and nuclear proteins so more antibodies are being produced
Complement becomes activated by immune complexes and is deposited in vessel walls
This leads to damage by MAC formation
This leads to oedema by anaphylatoxins - increase vascular permeability
This leads to neutrophil recruitment due to chemokines
What are some symptoms of type III hypersensitivity?
Give some examples
○ fever, rashes, joint pain or protein in the urine
○ vasculitis if deposited in blood vessels
○ glomerulonephritis if in the kidneys or
○ arthritis if in the joints.
○ Many auto-immune diseases including rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus (SLE) involve type III reactions.
What role do neutrophils play in type III sensitivity?
Neutrophils attracted to a site by chemokines
Bind to Fc-portion of antibodies
Try to phagocytose immune complexes but often unsuccessful
If neutrophils cannot phagocytose they degranulate and release:
- lysosomal enzymes
- reactive oxygen species (ROS)
Where are immune complexes deposited mainly?
- Kidneys (blood filtration)
- Joints (synovial fluid is filtered from blood)
- Vessel walls
What are the distinctions between type 2 and type 3 hypersensitivity?
- complement used in much larger amounts in type III and amount can indicate severity (C3 and C4 used as marker)
- Damage where immune complexes are deposited, not where they are formed so not tissue specific
- bind to soluble antigen not antigen on cell structures
What is type 4 hypersensitivity how is damage caused? What is it mediated by?
Mediated by T-cells
Recruitment of T cells takes time so its a delayed-type hypersensitivity
Damage occurs by CD4+ T helper cells and CD8+ cytotoxic T cells
Two phases:
- Sensitisation phase
- Re-exposure and immune response
What is a hapten?
Small proteins that function as antigens when bound to proteins
How does sensitisation occur in type 4 hypersensitivity?
Exposure to antigen leads to dendritic cell uptake
DC presents to specific naive T cells in lymph node
T cells differentiate into mature Th1-cells
Form memory cells
What usually happens in the re-exposure phase in type 4 hypersensitivity?
Re-exposure leads to a immune response, resulting in inflammation and the secrettion of IL-2 and IFN-gamma which leads to Th1-cell expansion
Leads to activation of macrophages that secrete TNF, IlL-1 and IL-6
This increases vascular permeability and cause oedemas
What is a common example of type 4 hypersensitivity and what occurs?
Contact dermatitis - exposure to poison ivy
A small molecule called urushiol acts as a hapten and binds to proteins in the skin to become an antigen which is taken up by dendritic cells causing memory T cells to be made
What is a common example of type 4 hypersensitivity and what occurs?
Contact dermatitis - exposure to poison ivy
A small molecule called urushiol acts as a hapten and binds to proteins in the skin to become an antigen which is taken up by dendritic cells causing memory T cells to be made
What T cells beside Th1 can be involved during re-exposure in type 4 hypersensitivity?
Other types of T cells can also be involved
In asthma, allergens can cause overreaction of T helper 2 cells which produce soluble mediators that that promote bronchoconstriction.
Differentiation to Th17-cells can lead to IL-17 secretion that recruits neutrophils
CD8+ self-specific cytotoxic T cells may directly kill the cells with antigens - ie can lead to inflammation and rejection of a tissue graft by directly killing transplanted cells.
What is a mantoux test?
Used to test if someone has had tuberculosis
tuberculin (antigen found in TB) is injected into the skin and after 48-72 hours the size of induration (hardness of skin caused by swelling) is measured
If someone has been exposed to tuberculin from Mycobacterium tuberculosis before, they will have been sensitised and this leads to a delayed type hypersensitivity
What is a mantoux test?
Used to test if someone has had tuberculosis
tuberculin (antigen found in TB) is injected into the skin and after 48-72 hours the size of induration (hardness of skin caused by swelling) is measured
If someone has been exposed to tuberculin from Mycobacterium tuberculosis before, they will have been sensitised and this leads to a delayed type hypersensitivity
What is a mantoux test?
Used to test if someone has had tuberculosis
tuberculin (antigen found in TB) is injected into the skin and after 48-72 hours the size of induration (hardness of skin caused by swelling) is measured
If someone has been exposed to tuberculin from Mycobacterium tuberculosis before, they will have been sensitised and this leads to a delayed type hypersensitivity
