Allergy, Hypersensitivity and monoclonal antibodies Flashcards
What percentage of people having some kind of allergy?
30%
What ethnicity primarily has allergies?
Caucasian/western countries
What is the most common allergy among caucasians?
Hay fever/Seasonal rhinitis
What causes hay fever?
Pollen that gets onto mucosal surfaces (e.g. eyes, nose, throat and upper respiratory tract)
What are FcR? What do they allow?
Receptors on myeloid cells that bind fragment crystalline region (FC) from antibodies/immunoglobulin
Allow the myeloid cells to grab the bacteria that have bound antibody and engulf via phagocytosis
What antibody is involved in the allergic response?
IgE
Why does IgE stimulate the immune response?
It has a very high affinity for mast cells which triggers them to rupture and empty the cytotoxic contents of their cells
What is the main cytotoxic chemical released by mast cells during an allergic reaction? What symptoms does it cause?
Histamine
Causes the itching, swelling, mucosal excretions, smooth muscle and blood vessel constriction, platelet clot
What kind of sensitivity is an allergic reaction considered?
Immediate type (Type I) hypersensitivity
What are some common substance which cause an allergic reaction?
Pollen, dust, peanuts, bee venom
What is it about dust that causes an allergic reaction?
Dust mites live on your skin and eat dead skin cells (e.g. dust), however it is their faecal matter that causes the allergic reaction
What are two substances that are most commonly associated with anaphylaxis?
Peanuts and bee venom
What do mast cells normally do? What causes them to stimulate negative allergic reactions?
Protect against bacteria and parasites
Abnormal IgE responses
What kind are the cytotoxic substances that are contained within the mast cells?
Histamine, leukotrienes, prostaglandins, free radicals, substance P
What is the second most common site for allergic responses?
the skin
What are two common allergic response that occur onto skin? What causes them?
Urticaria/hives - release of histamine into the tissue from the mast cells in the skin
Oedema (swelling) - caused by leakage of fluid into the space between cells
What is an asthmatic allergic response? What can cause it?
Bronchial tubes thicken and inflame
Allergens or environmental triggers
What is the most serious consequence of allergy?
Anaphylaxis and anaphylactic shock
What is anaphylactic shock? What makes it so severe?
It is when the oedema and swelling occurs a multiple anatomical sites that have not been exposed to the allergen
Swelling of internal organs such as guts and airways makes it life threatening
What is the treatment of anaphylaxis and anaphylactic shock?
Immediate injection of epinephrine/adrenalin
What is the pathway for developing an allergic reaction?
1 - B cells respond to a foreign body (e.g. allergen such as pollen) and take them to a lymph node
2 - CD4 helper T cells and cytokine interleukin 4 (IL4) drive a response which causes a B cell to develop into a plasma cell which produces IgE instead of IgG
How does IgE influence mast cells to create an allergic response?
Receptors on mast cells have very high affinity for IgE so they are coated with them and last the lifetime of the cell so next time the allergen the IgE are responsive to gets into the body, the mast cells are activated and release their cytotoxic contents causing an allergic response
What are the two types of CD4 cells that are involved in allergic response?
Th1 and Th2
What are the four classifications of hypersensitive? What are they caused by? What are their characteristics?
Type I - atopic allergy which is IgE mediated, immediate
Type II - Complement mediated, medium speed
Type III - Serum sickness caused by immune complexes, medium speed
type IV - CD4 T cells, Delayed type (DTH) slow response
What parts of the immunes system does Type II hypersensitivity involve?
Neutrophils, complements and Fc receptors
How does normal phagocytosis occur?
1 - A complements and antibody that is bound onto a microbe is detected by a neutrophil
2 - the Fc receptor binds to the antibody and the C3 receptor on the neutrophil binds the complement on the bacteria creating cross links and initiating phagocytosis
3 - Neutrophil engulfs the microbe and lysosome fusion digests the bacteria
What kind of phagocytosis occurs when there is type II hypersensitivity?
Auto phagocytosis
How does auto-phagocytosis work?
1 - A complement (‘‘check @1309 for where the complement comes from) and antibody that is bound onto a normal cell is detected by a neutrophil
2 - the Fc receptor binds to the antibody and the C3 receptor on the neutrophil binds the complement on the normal cell creating cross links and initiating ‘frustrated phagocytosis’
3 - Neutrophil engulfs the normal and lysosome fusion digests the the cellular components, destroying the normal cell
What is the time take for type II hypersensitivity to occur?
12-24 hours
What is an example of type II hypersensitivity?
Rhesus haemolytic anaemia
What is rhesus?
A red blood cell antigen
Who gets Rhesus haemolytic anaemia? What does it do? What does it cause?
Babies get it
Causes lysis of the red blood cells
It is fatal
Explain how a baby gets Rhesus haemolytic anaemia and how it can affect the child
If mother does not have the rhesus antibody on her blood but the father does
1 - When the baby develops its own blood cells, if any gets into the maternal blood supply the mother (no usually FYI) develops antibodies for the rhesus antigens on the foetal blood as it is seen as a foreign substance
2 - if these antibodies get into the placenta (not usually FYI) the baby is born with these antibodies which attach to the child’s blood
3 - these antibodies activate the complement system and neutrophil phagocytosis resulting in lysis of the blood
What can be done if the mother is RhD- (doesn’t have Rh antigen) and the father has RhD+ (has the Rh antigen)?
At 28 weeks the mother can be injected with a dose of anti RhD antibodies
What kind of inheritance is RhD?
It is dominant inheritance
What do anti RhD antibodies do?
Stimulate the passive immunity (‘‘@1312 find out what passive immunity is’’) and kill of any foetal red blood cells in the mothers blood that stimulate the maternal anti-RhD response
How are the first and second born child impacted if the mother is RhD- and the father RhD+?
The first child is okay because the mother hasn’t developed the antibodies properly to mount an effective immune response
The second child however is a risk because the immune response will be stronger
What is a method for identifying an allergen? Explain what is done
The skin scratch test where little scratches in the skin are made and the potential allergens are put onto cuts
How can someone be made immune to their allergen? How does this work?
Increasing does of allergen injected every week for 12-24 weeks
It makes high affinity IgG bind to the allergen instead of IgE which means the mast cells are not activated
What are Th1 and Th2 apart of?
Part of the CD4 helper T cell population that regulate the immune response
What does Th1 do? When is this response most appropriated
Induces a predominantly cell mediated response
Appropriate for a viral response
What does Th2 do? When is this response most appropriated
Induces a predominantly B cell antibody response
Appropriate for parasitic and bacterial response
What helper T cell is being overstimulated in someone with an allergy? Why is this?
Th2 because they have an excess of IgE produced
What is the hygiene hypothesis?
Allergy is much more prevalent in developed countries with good hygiene because individuals are less exposed to pathogens when they are younger resulting in an unbalanced immune system
What is a balanced immune system?
An immunes system which contains Treg (immune suppressor) and Th17 (inflammatory response)
Children who live in a clean world develop what kind of immune response?
A Th2 mediated antibody immune response with no Treg
What are Crohn’s disease and Ulcerative colitis?
Chronic autoimmune gut diseases
What is being used to treat these autoimmune gut diseases?
Human parasitic worms, Tricuris Suis Ova (TSO)
How does using TSO alleviate autoimmune gut diseases?
Stimulates a Th2 and Treg response that counters the excessive Th1 and Th17 response responsible for the excessive autoimmune response
What are monoclonal antibodies?
Antibodies that are made by identical immune cells that are all clones of a unique parent cell
How were monoclonal cells discovered?
B cells from the spleen of vaccinated mice were fused with a B cell myeloma cell line, glycol PEG (antifreeze FYI) is used to gently fuse their membranes together. Then only the fused hybridomas were selected to grow in the culture and put into individual wells
What are the advantages of monoclonal antibodies?
- They are highly specific as they are made from cloned cells
- Can be tailored made
- Can be humanised so they stay in the blood for months
- No adverse reaction or toxicity to the antibody
- Can be modified to be bi-specific (e.g. have two binding sites for two different antigens) for greater potency
What are the cons of monoclonal antibodies?
- It is expensive to produce as a large dose of antibodies is needed
- Side effects of their function can be serious
What is an example of of a monoclonal drug for cancer treatment?
Pembrolizumab
What is Pembrolizumab used for? Give an example of its use
Used in cancer immunotherapy
Can treat stage IV melanoma with 20% success rate
How does Pembrolizumab work?
It stimulates the PD1 receptor on CTL
What does Pembrolizumab do to reduce cancer?
1 - It Blocks the PD1 receptor on CTL (Cytotoxic T lymphocyte) allowing the CTL to become recharged/reactivated
2 - CTL inside of them are reactivated by the inhibitor and they then become reactive to the tumour and it kills them
Where are PD1 found? What does it do?
PD1 ligand is found on the tumour cell and it reacts with the PD1 receptor on the cytotoxic T cell (CTL)
PD1 receptor is a check point inhibitor stopping T cells being activated and its activation causes programmed cell death
Does Pembrolizumab work for all cancers? How successful is it on melanoma?
No, only some tumour cells have PD1 ligand that interacts with receptor on the cytotoxic T cell
20%
What causes the low success rate on melanoma?
There is a requirement for the right MHC (major histocompatibility complex) class I peptide antigen to stimulate the T cell
