Lecture 25. Allergy, hypersensitivity, review Flashcards
Major types of Type 1 allergies
- Asthma (1 in 6 New Zealanders)
- Allergic rhinitis (seasonal hay fever)
- Skin (dermatitis) Eczema, Urticaria (hives)
- Insect allergies (House dust mite, bee stings)
- Animal dander( allergy to pets)
- Drugs (penicillin)
- Large food proteins (gluten, peanut protein)
- Nickel (Metal induced contact dermatitis)
- Anaphylaxis – a serious complication
caused by inappropriate allergic response
4 classifications of hypersensitivity
Type 1, 2, 3, 4
type 1 hypersensitivity
- immediate
- atopic allergy
- mediated by IgE subclass of antibodies- unique at recognising large parasitic type pathogens that cannot be phagocytosed.
The FcεR receptor ( FC receptor for IgE) on mast cells has very high affinity
towards IgE:antigen complexes. When IgE binds large
complex antigens (like pollen), it triggers local mast cells to
rupture and empty their granules.
Powerful inflammatory mediators are released causing an
allergic reaction. This causes immediate type (Type I)
hypersensitivity
type 2
- allergy
- mediated by complement and phagocytes
- inappropriate phagocytic mechanism against our own cells( rhesus baby)
- medically significant- Rhresus baby
- cause “frustrated phagocytes”
- some cells express an antigen that stimulates phagocytosis (of your own cells)
- phagocytes become frustrated and lyse and release enzymes that digest the cell membrane
type 4
- delayed type hypersensitivity( DTH)
- slow response
- eg. response to antigens with microbacterial proteins( eg TB)
where are mast cells mostly found
-subcutanial tissue on mucosal surfaces( nose, throat, lungs) parts of the bpdy that are exposed to the environment
how does Type 1 hypersensitivity occurs?
- early in life inhaled a pathogen( pollen)
- IgM on naive B-cells revognises the pathogen
- some of the allergen has been broken down and expressed (inappropriately) on MHC and then recognised by helper CD4 T-cells
- CD4 signals the B-cells to start producing IgE( ε gene)
- This produces memory and plasma cells and produce IgE
- Mast cells have FcεR that binds the IgE very tightly, and can presensitise the mast cells, which now are precoated with IgE antibody.
- These presensitised mast cells will sit in the mucosal layer, and as soon as the allergen is presented they will release vasoactive compounds
B-CELLS HAS MADE THE INAPPROPRIATE RESPONSE TO MAKING IgE INSTEAD OF IgG
What are some of the effects in the body of the mast cell degranulation?
- smooth muscle contraction
- blood vessels constrict
- mucous secretion by the mucous glands
- sensory nerve endings- pain
- attraction of eisinophils
What is the main response of degranulation in asthma
- attraction of eisinophils
- eosinophilia in the lung is the main cause of asthma
Rhesus baby
- RBC express antigen(RhD) that stmulate phagocytes to digest the membrane of the RBC
- causes haemolytic anaemia
Rhesus +ve- have the antigen
Rhesus -ve- do not
-mother has to be rhesus -ve and the father is +ve
the baby is born Rh +ve
-if some of the babies RBC cross placenta, the mothers immune system will recognise them as foreign and will rapidly start killing them
-the response is mild in the first baby, but in the second baby the mother has developed strong antibodies that reacts with the rhesus antigen
- mothers IgG move across the placenta and will react with the foetal RBC–> haemolytic anemia
- mother needs to be treated to remove the ability of the foetal RBC to stimulate the response. Injection of short term IgM, without stimulating the long term imune response
desensitization
- sratch test identifies the allergens
- antigens are injected into the patient at low doses, increasing the dose over time. A series of injections.
- Because it is injected in the muscle, and not in the mucousal areas, insted of stimulating IgE, it stimulates IgG
- IgG them competed for the allergen and stops the Ige from binding
What was the experiment to produce Monoclonal antibodies
-work done in 1970s
- wanted to understand the mechanism of affinity maturation
- “How would the immunoglobulin genes change over time after the injection of antigen?” Would they see the mutations?
- first evidence that the affinity maturation was produced through the mutations in the immunoglobulin genes
-they wanted to isolate individual B-cell clones:
fused B-cells from the mouse with another immortalised B-cell, called a myeloma line.( cancerous cell that has the ability to reproduce but does not produce antibodies)
Result is a single lymphocyte fusing with a single myeloma cell to produce what’s called a hybridoma. It is really easy to grow, last virtually to ever forever, and it’s producing a single antibody.
Monoclonal antibodies
A type of protein that is made in the laboratory and can bind to certain targets in the body, such as antigens on the surface of cancer cells. There are many kinds of monoclonal antibodies, and each monoclonal antibody is made so that it binds to only one antigen. Monoclonal antibodies are being used in the diagnosis and treatment of many diseases, including some types of cancer. They can be used alone or to carry drugs, toxins, or radioactive substances directly to cancer cells.
Making monoclonal antibodies in mice
- a mouse is immunized with an antigen, and boost it
-mouse is killed and the spleen is taken out
-some B-cells will be making those antibodies
-fuse the B-cells with myeloma line, add polyethylene glycol to cause the hybrid cells to form
-culture, selects the hybridomas, and eliminated the myeloma cells
-plate out in the screen, where the surfsce has been coated with the antigen–> wash and see if any antibodies haves stuck to it.
The antibodies have different specificities and we can isolate the ones that we want.
-have to use hummanised mice
What is the problem with growing monoclonal antibodies from mice?
injecting mice antobodies into humans–> human immune system will see it as foreign and destroy the antibodies
need to humanise the antobodies
can also use bacteria
Pros and Cons of MAB
PROS
-can be used in diagnostics( determining cell counts)
• Highly specific for the intended target so no “off target” effects.
• Can be tailor-made with just the right affinity
• Humanised so they stay in the blood stream for months
• No adverse reactions or toxicity to the antibody
• Can be modified to be “bi-specific” for even greater potency.
CONS
• Expensive to develop and make commercially
• Side effects of their function can be serious
