Immunology 3 Hypersensitivity Flashcards
Hypersensitivity reactions = __________ immune responses that cause damage
Excessive
Response to different types of antigens such as what?
- Infectious agents
- Environmental substances
- Self antigens
are all infections are capable of causing hypersensitivity reactions?
no
Do infections that elicit hypersensitivity do so in every case?
no
How does Influenza viruses can cause hypersensitivity?
- Influenza virus damages epithelial cells in the respiratory tract
- Can sometimes elicit an exaggerated immune response
- Can trigger high levels of cytokine secretion (cytokine storm)
- The cytokines attract leukocytes to the lungs and trigger vascular changes that lead to hypotension and coagulation
- In severe influenza, inflammatory cytokines also spill out into the systemic circulation, causing ill effects in remote parts of the body, such as the brain
Hypersensitivity to Environmental Substances - how can dust trigger a response?
- Dust triggers responses because it is able to enter the lower extremities of the respiratory tract, an area rich in adaptive immune response cells
- Dust can mimic parasites and may stimulate an antibody response
- If the dominant antibody is IgE, it may subsequently trigger immediate hypersensitivity, which manifests as allergy symptoms such as asthma or rhinitis
- If the dust stimulates IgG antibodies, it may trigger a different kind of hypersensitivity, such as farmer’s lung
Hypersensitivity to Environmental Substances:
- Smaller molecules sometimes diffuse into the skin and may act as ________, triggering a delayed hypersensitivity reaction
- _______ are small molecule irritants that bind to proteins and elicit an immune response
haptens
Haptens
Types of Hypersensitivity Reactions
Different type of hypersensitivity reactions - 4 different types
Main difference is the immune mechanism involved and because of this there is a difference in onset
Type 1 and 2 are very quick - Type 1 almost immediate
Type 3 caused by immune complexes
Type 4 is delayed, cell mediated, T cells and macrophages are involved, some type 4 are autoimmune diseases
Type I hypersensitivity is mediated through degranulation of what cells?
•Mediated through the degranulation of mast cells and eosinophils
how quick are the effects of Type I hypersensitivity felt after exposure?
- The effects are felt within minutes of exposure.
- Immediate hypersensitivity, allergy (or atopy)
Tend to have some genetic traits and once exposed environmentally the have IgE against certain antigens
what is atopy?
- Immediate hypersensitivity reaction to environmental antigens mediated by IgE
- Develops within minutes of exposure
- Family history with atopy traits.
- Atopy = allergy:
- Anaphylaxis, Angioedema, Urticaria, Rhinitis, Asthma and Dermatitis, eczema
Allergic march
how is atopy familial?
Doesn’t mean they have same allergy as family but increased risk of having an allergy in general
- Antigens that trigger allergic reactions are called _________
- They gain access to the ____ through inhalation, ingestion, contact or administered as drugs
allergens
body
•IgE is required for type I hypersensitivity:
what produces it?
•B cells produce it when co-stimulated with IL-4 (secreted by TH2 cells)
IgE made by B cells like any antibody
In people with allergies they produce more Th2 than Th1 whereas they should be equal
IL-4 suppresses Th1
IL-4 induces production of IgE by B cells
what causes the allergic symptoms?
Degranulating cells
Release of mediators that cause allergic symptoms
what cells degranulate causing allergic symptoms?
- Mast cells are resident in many tissues.
- Eosinophils migrate to tissues where type I hypersensitivity reaction is. (attracted to site of inflammation)
what is the process of mast cells degraulating and causing an immune repsonse?
- Mast cells initiate allergic symptoms after allergen and IgE interact
- Mast cells have receptors for IgE and FcεRI (high affinity IgE receptor)
Mast cells already attached to IgE so as soon as exposed to antigen then degranulate their components and cause an immune response
what are the different symptoms of an allergy?
Depends on system effected
anaphylaxis most serious
what is the Epidemiology of Allergies?
- Very common, up to 40% of the population affected
- Runs in families
- Prevalence on the rise globally
Inheritance is of the risk of allergies, not of the actual allergy
Genetic predisposition is multifactorial and doesn’t depend on a single gene
This is one example – genes relating to filaggrin
Filaggrin important for maintain skin
Genetics of Allergies:
- Filaggrin is expressed by keratinocytes and involved in maintaining epithelial barriers and moisturizing surfaces and controlling pH
- Polymorphisms in the gene encoding is established as a cause of allergy and implicated in 50% of severe eczema
- Exposure to environmental factors adds the risk of developing allergies
- Timing is important
Role of Environmental Factors:
•Effect of urbanization
what is the hygiene hypothesis
- Effect of urbanization
- Hygiene hypothesis: increase in allergies in the developed world is caused by reduced exposure to microorganisms in early life
- However, infections can either increase or decrease the risk of allergies depending on the timing of exposure and the genetic makeup
what envornmental factors play a role in allergy?
Many of the risk factors for allergic disease affect the microbiome of the skin, nasopharynx, lung and gut, particularly in a critical window in the early postnatal period when these organs, as well as the immune system, are still developing. Infections can have both protective and detrimental effects on allergy. Often these factors occur together, so the absence of one protective factor does not necessarily mean that allergic disease will ensue.
Also, many risk factors are associated. Antibiotic use is hard to disentangle from infection history.
(examples of antigens a baby can be exposed to)
•Anaphylaxis is the most serious type of allergy - what is the process and the effects of anaphylaxis?
- Mast cells produce prostaglandins and leukotrienes through the cyclooxygenase and lipoxygenase pathways
- The result is vasodilation and increased vascular permeability
- Shift of fluids from the vascular to the extra-vascular space resulting in a fall in vascular tone
- Severe drop in blood pressure
- IN the skin, mast cells release histamine further contributing to welling and fluid shift
what happens in allergic rhinitis?
- inhaled allergens stimulate mast cells in the nasal mucosa
- Subsequent vasodilation and oedema in the nose causes nasal stuffiness and sneezing
- Leukotrienes increase mucus secretion, which causes the discharge characteristic of allergic rhinitis
- Increased _____ secretion in asthma and contributes to the airflow obstruction
- In the lungs, _________ cause smooth muscle __________, which has the most dramatic effects on airflow reduction
mucus
leukotrienes
contraction
Upon exposure to an allergen, a patient with asthma will develop what?
- airway obstruction characterized by wheezing seconds after exposure
- The symptoms improve after an hour or so as the immediate response dies down
- Several hours after the acute episode, the airflow in the bronchi may deteriorate again, reflecting the migration of leukocytes into the bronchi in response to chemokines. The late phase may last several hours
what is the best treatment?
prevention
is treatment the same for every case?
no tailored for each case
one form of treatment is Desensitisation (allergen immunotherapy), what is it?
expose patient to allergen in small doses until they develop tolerance for these antigens, danger of may induce allergic reaction so needs to be in controlled
what different drug treamtent are there avalible for type 1 hypersensitivity reactions?
- β2-adrenergic agonists, such as salbutamol, mimic the effects of the sympathetic nervous system and work mainly by preventing smooth bronchial muscle contraction in asthma
- Epinephrine (adrenaline) can be lifesaving in anaphylaxis, where blood pressure falls dramatically. Epinephrine stimulates both α- and β- adrenergic receptors, decreases vascular permeability, increases blood pressure, and reverses airway obstruction
- Antihistamines block specific histamine receptors and have an important role in allergies that affect the skin, nose, and mucus membranes - good for mild reactions that are caused by histamine, wont work for asthma
- Specific receptor antagonists block the effects of leukotrienes. Montelukast, for example, reduces the amount of airway inflammation in asthma
- Corticosteroids can prevent the immediate hypersensitivity reaction, the late phase, and chronic allergic inflammation
what test is used to identify what they are allergic too as sometimes it is hard too know?
Skin-prick testing
To provide a control, a histamine solution is applied at position 1, and saline is applied at position 2
In skin resident mast cells and have ___ and specific to certain antigens and if inject ______ that IgE is specific for then antigen will bind to IgE and the mast cells will _________ and if mast cells degranulate this causes histamine to be released, prostaglandins and leukotriene, causing __________ and _______
IgE
antigen
degranulate
vasodilation
swelling
what is type 2 hypersensitivity?
- Antibody mediated hypersensitivity
- IgG or IgM reacting with antigen present on the surface of cells
- The bound Ig interacts with complement or with Fc receptor on macrophages.
- Opsonisation of target cells
- Immune mediated haemolysis.
- Drug-induced haemolysis.
how long does a type 2 hypersensitivity reaction take?
•Takes several hours
Can also be very quick depending on amount of immunoglobulins available to that antigen
Pre exposure to that antigen is important for type 2 hypersensitivity
One of the most important examples in relation to type 2 hypersensitivity is blood groups
how is it important in relation to blood groups?
If R negative then produces anti-D if exposed to antigen
If I negative then produces anti-I if they are exposed
If patient has blood group A then they have naturally occurring antibodies against B and vice versa
If O then antibodies against A and B
During blood transfusion you don’t want to cause haemolysis of the blood between different blood _______ between the donor and the recipient
Normally little _______ and mainly blood cells
Normally little antibodies from the _____ so normally haemolysis of the donor blood cells by the ________ antibodies
groups
plasma
donor
recipient
- A and B blood group antigens are ____________ on the surface of RBCs
- Similar to molecules expressed by ________
- ________ recognize A and B
oligosaccharides
bacteria
Antibodies
•Anti-A and Anti-B are ___ antibodies naturally occurring
We have naturally occurring antibodies that recognise them unless we have the ____ blood group
IgM - IgM antibodies are multi-polar and multi-valent, they can bind to multiple antigens
same
Individuals with O group have what antibodies?
Individuals with O group have both antibodies from birth regardless of exposure.
People with blood group AB _____ have antibodies against any of them
don’t
Antibodies produced against these antigens (of blood cells) can cause type II hypersensitivity. (and can cause lysis)
In IgG they don’t damage circulating blood cells but takes them to macrophages and attaches to FC receptor, weather is it in spleen or liver and this causes destruction of RBCs
Immune Mediated Haemolysis - what is alloimmune haemolysis?
•Rhesus antigen (IgG develops during pregnancy and crosses the placenta and causes haemolytic disease).
Incompatibility in the ABO system
When patient gets blood cells or antibodies from different source, e.g. through incompatible blood transfusion or through rhesus antigen in pregnancy
what is the process of Alloimmune Haemolysis in pregnancy?
Women is R- and baby is R+
Cells from baby passed to mother, especially during pregnancy
Mother forms IgG antibodies
And then if mother is pregnant again with another baby that is R+ blood group then already antibodies against it and it can cause haemolysis of blood cells
If you have a women with R- then need to check blood group of the baby and give an injection with anti-D so that the antibodies are inhibited and don’t cause haemolysis in the baby
Autoimmune Haemolysis:
- Autoimmune haemolytic anaemia could be induced by __________ or _______
- Part of a ________ autoimmune disease (SLE)
- Autoantibodies produces by malignant _ cells
infections or drugs
systematic
B
Do you get Type II Autoimmune Hypersensitivity Against Solid Tissue?
yes
example showing drug induced haemolysis
Is it a hapten and can bind to protein on the surface of RBCs
Can act as a hapten and induce antibody production
RBCs will be marked for destruction through the opsonisation either by complement system or FC receptor on macrophages
Type 2 can also affect the function of cells
antibodies can also affect cell function, what is an example of this?
Graves disease:
- Most common cause of hyperthyroidism
- Mainly young women
- Family history
- HLA allele DR3
- Thyroid is stimulated with an autoantibody that binds into the THS receptor (leading to constant activation and contrast production of thyroxines)
what is type 3 hypersensitivity?
- Immune complex disease
- IgG is also responsible for type III hypersensitivity
- Immune complexes of antigen and antibody form and cause damage at the site of production or circulate and cause damage elsewhere
- Immune complexes take some time to form and to initiate tissue damage
They should be cleared by complement system but if it fails to clear them e.g. to much load of the immune complex, then the immune complex will be precipitated and cause disease, either localised or systematic
what is reuqired for a type 3 hypersensitivity reaction?
- Antigens that form complexes must by polyvalent (antigen can bind to more than one antibody)
- Present long enough to start an antibody response
in typ 3 reactions, Similar to allergies, antigens can be what?
- Infectious antigens
- Innocuous environmental antigens
- Autoantigens
Clearance of complexes:
- _________ breaks down large complexes
- Complement Receptor 1 (CR1) transfers Complexes to _________
Complement
Phagocytes
- Failure of clearance leads to immune ________ disease
- Activation of the ______ immune system
complex
innate
Immune complex Disease in the Kidney:
- Common cause of renal failure
- Glomerulonephritis - what are the 2 kinds?
- Nephrotic syndrome (protein leaks into urine) with gradual development of renal failure
- Nephritis with rapid onset renal failure, blood and protein in the urine and hypertension
Depending on the rate of formation of immune complexes this could lead to nephritis or nephrotic syndrome and both lead to renal failure eventually but with different traits
what causes farmers lung?
Hypersensitivity reaction to fungus spores when inhaled and if patient has IgG antibodies against it
That’s type 3 hypersensitivity reaction
what is a Type IV Hypersensitivity?
- The slowest form of hypersensitivity is that mediated by T cells
- This can take 2 to 3 days to develop (or more)
- Delayed hypersensitivity
2 main diseases are rheumatoid arthritis and MS (but there is more)
- Delayed hypersensitivity reactions are initiated when tissue __________ recognize danger signals and initiate an inflammatory response
- Dendritic cells loaded with antigen migrate to local lymph nodes, where they present antigen to _ cells
- Specific T-cell clones proliferate in response to antigens, which migrate to the site of __________
- ____________________ (TNF) is secreted by both macrophages and T cells and stimulates much of the damage in delayed hypersensitivity
macrophages
T
inflammation
Tumour necrosis factor
Rheumatoid arthritis:
- Chronic disabling condition that affects up to 1% of the population
- Most symptoms arise in the joints and tendons. Also affects the skin, lungs, and eyes
what causes RA?
- Many features of delayed hypersensitivity with persistent TH1 and TH17 reactions and TNF secretion
- Autoantibodies (so its an autoimmune disease)
- The antigens that drive RA appear to be citrullinated proteins. Citrullination is the conversion of the amino acid arginine to the amino acid citrulline
- Autoreactive T cells and B cells can recognize citrullinated proteins. The result is production of antibodies against citrullinated protein. These are referred to as anti–cyclic citrullinated peptide (CCP) antibodies
Rheumatoid arthritis:
- The synovium becomes infiltrated by T cells (TH_ and TH__) and ____________
- TNF and IL-17 attract and activate __________ that cause damage to the synovium
- __________ are activated and destroy bone at the joint margins, creating erosions
- Persistent IL-6 secretion triggers an acute-phase response
1
17
macrophages
neutrophils
Osteoclasts
what things causes RA?
- Family history
- Association with HLA-DR4
- More common in smokers and those infected with Porphyromonas
Multiple Sclerosis:
- Chronic, disabling neurologic disease
- Initially in MS, acute attacks occur during which inflammatory lesions consisting of ___ and ____ cells and macrophages develop in the affected nervous tissue
- The ___________ lesions cause the reversible, relapsing disability typical of early MS
- Although active inflammation is present in the vicinity, myelin loss impairs the ability of neurons to conduct impulses, resulting in neurologic symptoms
TH1
TH17
inflammatory
Multiple Sclerosis:
- Once the inflammation settles, the disability _________
- Between attacks, there is usually ____ recovery of function, at least early in the disease
- The chronic disability that usually occurs later results from ______ ____
improves
good
axonal loss
what is the Treatment of delayed hypersensitivity?
- Prevention through avoiding antigens
- Anti-inflammatory drugs (When autoimmune antigens it cant be avoided and use anti-inflammatory drugs):
- NSAID
- Corticosteroids
- Drugs that block TNF and IL-6
- Antibodies against B cells
•Immunosuppressive drugs
summary:
TH2 produces IL-4 that enhances IgE
Type 4 are basically autoimmune diseases
