Immuno 1: Hypersensitivity and allergy Flashcards
During appropriate immune reactions, there should be no tissue damage
F. May be concomitant tissue damage as a side effect, but as long as pathogen is eliminated quickly will be minimal and repaired easily
Approrpaite immune tolerance occurs to what
Appropriate immune tolerance occurs to self, and to foreign harmless proteins:
Food, pollens, other plant proteins, animal proteins, commensal bacteria
What does development of appropriate immune tolerance involve
Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production
Antigen recognition in context of “danger” signals leads to immune reactivity, absence of “danger” to tolerance
Hypersemsitivity reactions invole immune responses against what
Harmless foreign antigens (allergy, contact hypersensitivity)
Autoantigens (autoimmune diseases)
Alloantigens (serum sickness, transfusion reactions, graft rejection)
Outline the 4 types of hypersenstivity reactions
Type I : Immediate Hypersensitivity
Type II : Antibody-dependent Cytotoxicity
Type III : Immune Complex Mediated
Type IV : Delayed Cell Mediated
t/f diseases often fit into a distinct catgory of immune hypersensitivity
F… lots are a mixture
Examples of Type 1 immediate hypersestivity
Anaphylaxis Asthma Rhinitis -Seasonal -Perennial Food Allergy
What occurs in type 1 immediate hypersenstivity
1^o Antigen exposure:
- Sensitisation not tolerance
- IgE antibody production
- IgE binds to Mast Cells & Basophils
2^o Antigen Exposure
- More IgE Ab produced
- Antigen cross-links IgE on Mast Cells/Basophils
- Degranulation
Outline the 2 categoties of type II antibody-dependent hypersenstivity
Organ-specific autoimmune diseases
Autoimmune cytopenias (Ab mediated blood cell destruction)
Give examplesof the type II organi-soecific autoimmune diseases, adnd the antibody :
Myasthaenia gravis
Glomerulonephritis
Pemphigus vulgaris
Pernicious anaemia
- Myasthenia gravis (Anti-acetylcholine R Ab)
- Glomerulonephritis (Anti-glomerular basement membrane Ab)
- Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
- Pernicious anaemia (Intrinsic factor blocking Abs)
Outline types of type II, autuimmune cytopenias
Haemolytic anaemia
Thrombocytopenia
Neutropenia
T/f.. pernicious anaemia is an example of an autoimmune cytopenia
F…. it is an organ specific aurommune disease
Give 2 examples of tests for speicifc autoanibodies
Immunofluorescence
ELISA eg anti-CCP (Cyclic Citrullinated Peptide Abs for Rheumatoid Arthritis)
Outline type III reactions
Formation of Antigen-Antibody complexes in blood
Complex deposition in blood vessels/tissue
Complement & cell activation
Activation of other cascades eg clotting
Tissue damage (vasculitis)
Outline examples of tissue damage (vasculitis) as part of type III immune complex hypersenstivity
Systemic lupus erythematosus (SLE)
Vasculitides (Poly Arteritis Nodosum, many different types)
Outline why vasculitis occurs in type III hypersensitivty
Antibodies bound to antigen then deposit in vessel walls (or tissue) and activate complement (C3) and cellular activatin (monocyte/neutrophil)
What are the most common sites of vasculitis in type III hypersensitivity
Skin
Renal (glomerulonephritis)
Joints
Lung
Give examples of type IV delayed hypersensitivty responses
Chronic graft rejection GVHD Coeliac disease Contact hypersensitivity Many autoimmune diseases….
Outline the three main varieties of type IV delayed hypersensitivity reaction
Th1
Cytotoxic
Th2
Outlne the mechanisms of type IV hypersensitivtiy
Transient/Persistent Ag
T cell activation of macrophages, CTLs
Much of tissue damage dependent upon TNF & CTLs
Give an example of how a type IV hypersensity rreaction might occur
Antigen is presented on an APC
APC presented to Th1, which releases IFN-g, FGF and IL-2
IFN-g activates macrophages which release TNF
FGF activates fibroblast which casues angiogenesis and fibrosis
IL-2 causes cytotoxic T lymphocytes to release perforin
Nickel is a type II mediated hypersensitvitiy
improve
F. Type 4… as it contact hypersenstivity (contact dermatits)
inflammation only where the nickle is present e.g. if a nickel thimble was worn
Outline the immune reactant for each hypersensitivty reaction
I- IgE
II-IgG
III- IgG
IV- Th1/Th2/CTL
t/f inflammation is part of all immune reactions
T
What is inflammation and what is a common feature of it
This is the body’s response to tissue injury
- It is a rapid attempt to bring the body’s defences to the site of injury
- A common feature of inflammation is immune cell recruitment (sites of injury/infection) and activation
- Once the immune cells reach the site, they release cytokines that leads to the features of inflammation
- Inflammatory mediators include complement, cytokines, etc.
What are the signs of inflammation
Redness
Heat
Swelling
Pain
What are the features of inflammation
Vasodilatation, increased blood flow
Increased vascular permeability
Inflammatory mediators & cytokines
Inflammatory cells & tissue damage
Increased vascular permeability is caused by which mediators
C3a, C5a, histamine, leukotrienes
Which cytokines are involved in inflammation
IL-1, IL-6, IL-2, TNF, IFN-γ
Which chemokinesa re involved in inflammation
IL-8/CXCL8, IP-10/CXCL10
What can happen to cells during inflammation
Inflammatory cell infiltrate
Cell trafficking – chemotaxis
Neutrophils, macrophages, lymphocytes, mast cells
Cell activation
Overall, which 4 things occur in infkamation
Increased vascular permeability
Cytokines
Chemokines
Inflammatory cell infiltrate
What is atopy
a form of allergy in which there is a hereditary of constitutional tendency to develop hypersensitivity reactions (e.g. hay fever, allergic asthma, atopic eczema) in response to allergens (atopens). Individuals with this predisposition - and conditions provoked in them by contact with allergens - are described as atopic.
What is the prevalence of atopy
Common - prevalence of atopy is 50% in young adults in UK
How does the severity of allergy vary
mild occasional symptoms
severe chronic asthma
life threatening anaphylaxis
T/f the genetic risk factors of atopy is usually monogenic
~80% of atopics have a family history
Polygenic
Which genes are linked to raised IgE, asthma atopy
genes of IL-4 gene cluster (chromosome 5) linked to raised IgE, asthma, atopy
Which genes are linked to atopa and asthma
genes on chromosome 11q (IgE receptor) linked to atopy and asthma
Which genes are linked to eczema
genes linked to structural cells linked to eczema (filaggrin) and asthma (IL-33, ORMDL3, CDHR3)
What are the environmental risk factors for atopy
Age - increases from infancy, peaks in teens, reduces in adulthood
Gender - asthma more common in males in childhood, females in adults
Family size - more common in small families
Infections- early life infections protect
Animals - early exposure protects
Diet - breast feeding, anti-oxidants, fatty acids protect
Give examples of type 1 hypersensitivty mediated inflammation
Anaphylaxis, urticaria, angioedema
TYPE 1- IgE
Give examples of type 2 mediated inflammation
Idiopathic/chronic urticaria
TYPE II- IgG
Give examples of confitions involving mixe inflammaiton.
Which hypersensitivt yreactions are these mediated by
Asthma, rhinitis, eczema
Mesiated by
type I hypersensitivity (IgE mediated)
type IV hypersensitivity (chronic inflammation)
What is rewquired for expression of allergic disease
Development of sensitisation to allergens instead of tolerance (primary response - usually in early life)
Further allergen exposure to produce disease (memory response - any time after sensitisation)
Outline sensitisation of atopic airway disease
Dendritic cell samples the airway
Presents antigen to naive T cell
T cell decides whether to be tolerant to the antigen (in which case it becomes Treg) or auto-immune disease (Th1) or an allergic response (Th2)
If Th2 route was chosen, then Th2 cells will then proliferate and produce IL-4 and IL-13, which makes B cell produce IgE, not IgG antibodies
IgE which is specific to the antigen will bind to plasma cells and cause IgE production
IgE bind to mast cells
Outline what happens in subsequent exposure, following sensitisation in atopic disease
Same process with dendritic cell
But the antigen will be presented to Th2 memory cells from the sensitisation stage
Which will then cause more IL4 and IL13 to make more IgE.
IL5 released by Th2 to recruit eosinophils and activate them.
Eosinophils then release inflammatory mediators
IgE bound to mast cells undergoes crosslinking with the antigen
Causes degranulation of mast cells and release of inflammatory mediators
Eosinophils make up what proportion of blood leukocytes
0-5% of blood leukocytes
T/F most eosinophils present in tissues
T…. Present in blood, most reside in tissues
What is the nucleus of an eosinophil like
Nucleus - two lobes
What is contained in the granules of eosinophils
Toxic proteins…. the grnules arfe LARGE
What is an effect of eosinophil activation
TISSUE DAMAGE
T/F mast cells are tissue resident cells
T
How are mast cells avtivated
IgE receptors on cell surface
What happens upon IgE cross linking to mast cells (what mediators are contained there)
MEDIATOR RELEASE
- Pre-formed:
- Histamines
- Cytokines
- Toxic proteins - Newly synthesised
- leukotrienes
- prostaglandings
Which disease are neutorhils important in
virus induced asthma
severe asthma
atopic eczema
What proportion of blood leukocytes are neutrophils
55-70% of blood leukocytes
Neutrophils are aka
Polymorphonuclear cells (PMNs)
What is the nucleus of a neutrophil like
Nuecleus several lobes
What is contained within the granules of neutrophils
what else do neutrophils synthesise
digestive enzymes
Also synthesize
oxidant radicals
cytokines
**leukotrienes
Outline the pathology of asthma
Acute airway inflammation
Mast cell activation and degranulation
- -> release of prestored mediators (e.g. histamine, leading to airway wall oedema)
- -> release of newly synthesised mediators (prostaglandins and leuktrienes)
LEADS TO:
Acute airway narrowing (airway smooth muscle contraction)
What are the three things in asthma that cause airway narrowing
Airway wall oedema (due to vascular leakage)
mucus secretion and
airway smooth muscle contraction
(NOTE: these are all due to the mediators released from the mast cell activation and degranulation)
What happens upon exposure to asthama causing antigen to peak flow
PEF starts at less than 100% (as asthmatic so reduced anyway)
EARLY RESPONSE:
Initially, there is a rapid and significant reduction in PEF in response to antigen exposure. This is due to the immediate hypersensitiviy (IgE mediated, mast cell activation, acute airway narrowing due to the oedema, mucus and contraction)
This recovers quickly (within an hour)
However, over 2-8hrs there is then another reduction in PEF , the
LATE RESPONSE:
There is cell-mediated delayed type hypersensitivity in which lymphocyte and eosinophil mediated infmallation occurs (Th2 cells activate eosinohils, leading to IL4 and IL5 release)
Important to remember that asthma is a mixture of type I and type IV.
This graph is on somebody who has already been sensitised to antigen and had subsequent exposures already.
So what happens when you give them allergen
You get type I reaction straight away (due to IgE cross-linking)
Then later you get cell mediated type IV reaction which is when Th2 activates eosinophils. This is not accounted for by type I, which only involves mast cell/basophil degranulation
Outline the chronic airway inflammation in asthma
So we had early and late response which are referring to acute onset inflammation
Not there is also CHRONIC INFLAMMATIONlON
- Cellular infiltrates (Th2 lymphocytes and eosinophils, from delayed type hypersensitivity)
- Smooth muscle hypertrophy
- Mucus plugging
- Epithelial shedding
- Sub-epithelial fibrosis
What are the important clinical features of asthma
REVERSIBLE generalised airway obstruction (–> chronic episodic wheeze)
Bronchial hyperresponsiveness (–>bronchial irritability)
Cough
Mucus
Breathlessness
Chest tightness
Responds to treatment (COPD doesn’t)
Spontaneous variation
Reduced and variable PEF
What are the important clinical features of allergic rhinitis
Note the mechanism is very similar to asthma in terms of type 1 and then type 4
Seasonal (hay fever, grass, tree pollens)
Perennial (house dust mites or pets)
Symptoms: sneezing, rhinorrhoea, itchy nose and eyes, nasal blockage, sinusitis, loss of smell/taste
Outline the clinical features of allergic eczema
Atopic dermatitis is allergy due to genetics, contact dermaitis is at the site of the chemical exposure=type IV)
Chronic itchy skin rash
Flexures of arms and legs
HDM sensitisation and dry cracked skin
Complicated by bacterial and (rarely) viral infections (early childhood, herpes simplex)
50% clears by 7 years
90% by adulthood
Outline the important clinical features of food allergy
Mild: itchy lips, mouth, angioedema, urticaria
Severe: nausea, abdominal pain, diarrhoea, collapse, wheeze, ANAPHYLAXIS
What are the most common food allergens in infants and adults
Infancy-3yrs
egg, cows milk
Children/adults
peanut, nuts, shell fish, fruits, cereals, soya
What is anaphylaxis
severe generalised allergic reaction
Generalised degranulation of IgE sensitised mast cells
Symptoms of anaphylaxis
itchiness around mouth, pharynx, lips
swelling of the lips, throat and other parts of the body
wheeze,
chest tightness,
dyspnoea
faintness,
collapse
diarrhoea & vomiting
death if severe & untreated
Which systems are involved in anaphylaxis
Systems:
Cardiovascular - vasodilatation, cardiovascular collapse
Respiratory - bronchospasm, laryngeal oedema
Skin - vasodilatation, erythema, urticaria, angioedema
GI - vomiting, diarrhoea
How can food allergens be tested
Careful history essential
Skin prick testing
RAST (blood specific IgE):
Total IgE
Lung function (asthma)
What is the emergency treatment of anaphylaxis
EpiPen & Anaphylaxis kit
- ->antihistamine, steroid, adrenaline
- -> Seek immediate medical aid
How is anaphylaxis prevented
Avoidance of known allergen
Always carry a kit & EpiPen
Inform immediate family & caregivers
Wear a MedicAlert® bracelet
How is allergic rhinitis treated
anti-histamines (sneezing, itching, rhinorrhoea)
nasal steroid spray (nasal blockage), if the inflammation is cell mediated (anti-histamine only helps if it’s just due to type 1)
cromoglycate (children, eyes)= a mast cell stabiliser
How is eczema treated
emollients
topical steroid cream
(as mostly cell mediated)
What drugs are now used for sever rhinitis and eczema
anti-IgE, anti-IL-4/-13, anti-IL-5 mAb
What is the treatment for asthma
- Short acting b2 agonist drugs as required by inhalation (SALBUTAMOL,)
- Inhaled steroid low-moderate dose (Beclomethasone/budesonide or flutocasone, 40-800micrograms )
- Add further therapy
- long acting bronchodilators, leukotriene antagonist
- high dose inhaled steroids via spacer (2milligrams, much higher) - Add oral steroids, SLIT (sub lingual immune therapy), azithromycin
- prednisolone (30mg)
- Anti-IgE, anti-IL-5, anti-IL-4/-13 monoclonal Abs
When is immunotherapy used
Effective for single antigen hypersensitivities
- Venom allergy - bee or wasp stings
- Pollens
- HDM
- Antigen used is purified
Why is azithromycin given for asthma treatment eventually
Asthma may be due to bacteria colonisaton of the lungs
How can immunotheray be given
Subcutaneous immunotherapy (SCIT)
3 years needed
Weekly/monthly 2hr clinic visits
Sublingual immunotherapy (SLIT)
3yrs needed
Taken at home
Can be used for anaphylaxis or severe allergic rhinitis for example
Differentiate pemphigus and pemphigoid
Pemphigus is Abs directed at intercellular cement
Pemphigpoid is Abs directed at the basement membrane
