Hypersensitivity reactions
are exaggerations of normal
defence mechanisms
Il termine allergia è stato originariamente
coniato da Clemens Von Pirquet come una
“capacità alterata del corpo di reagire ad
una sostanza estranea”
ALLERGIA:
Malattia che deriva da una risposta
del sistema immunitario ad un
antigene innocuo
L’allergia è un tipo di reazione del
sistema immunitario classificata
come ipersensibilità
Le reazioni di ipersensibilità sono
classificate in quatto tipi da I a IV
L’allergia è tipicamente
l’ipersensibilità di tipo I
HYPERSENSITIVITY
• TYPES I - IV
I - IgE MEDIATED REACTION • Binding of antigen to IgE on the surface of mast cells
causes release of inflammatory mediators
II - CYTOTOXIC REACTION • Binding of antibody to cell surface leads to activation
of complement and damage to host cell eg. blood
cells (penicillin, methyldopa, quinidine)
HYPERSENSITIVITY
III - IMMUNE COMPLEX REACTION (Arthus) • Formation of complexes between antigen & antibody
leads to tissue damage as a result of deposition in
blood vessels (vasculitis) and activation of
inflammatory pathways (serum sickness, farmers
lung)
IV - CELL MEDIATED REACTION (DTH) • Activation of T cells around site of antigen leads to T
cell cytotoxicity & activation of macrophages, causing
tissue damage (contact sensitivity)
Allergy
Hay fever, asthma, eczema.
Atopy (Greek: ‘out of place’)
10-15% individuals clinically allergic
30% individuals show wheal and flare to skin tests for
common allergens
Asthma is the most common chronic disease of children in
Western countries. Causes 2,000 deaths/year in UK
Epidemiology of Allergy
•
•
•
•
•
•
50 Million Americans Affected
10-22% Adults
10-42% Children
Peak Incidence
Late Childhood
Early Adolescence
Genetics and Development of
Allergies
• Risk of developing allergies:
– No parents have allergies- 10% risk
– One parent has allergies- 40-50% risk
– Both parents have allergies- 70-80% risk
• Children with one allergic component
(rhinitis, asthma, or eczema) have a 3fold increased risk of developing others
Type I hypersensitivity
IgE-mediated
mast cell degranulation
Le IgE sono prodotte dalle Plasma
cellule che si trovano nei linfonodi
drenanti il sito di ingresso
dell’antigene o localmente nel sito
dove avviene la reazione allergica.
Le IgE prodotte nei centri germinativi
diversamente dagli altri anticorpi
sono presenti a livello tissutale
fortemente legate alla superficie
delle mast cells attraverso i recettori
FceRI
Sebbene non sia nota la ragione per cui
alcuni Ag sono allergeni, sono emersi
dei principi generali:
La maggior parte degli allergeni sono
proteine piccole altamente solubili
portate da particelle essiccate come il
polline o le feci degli acari
Allergens
Proteins found in nature
Trees
Grasses
Weeds
Moles
Dust mite feces
Cockroaches
Animal danders
Enter the body by ingestion or inhalation, injection
(insect venom, antibiotics)
Al contatto con le mucose, ad esempio quelle del tratto
respiratorio, gli allergeni solubili vengono eluiti dalle
particelle e diffondono nelle mucose.
Tipicamente sono presentati a dosi bassissime.
ALLERGENS
• Antigens that initiate an IgE-mediated response
• Contain B cell epitopes & T cell epitopes
• Allergen requires processing by dendritic
cells/macrophages
• Presentation to T cells results in delineation of Thelper subsets into TH1 and TH2 types
• TH2 responses lead towards IgE production
Ag presentation at very low doses at the mucosal level favor the
activation of Th2 responses.
At the mucosal level the APCs are myeloid DC that present low
antigen doses very efficiently, migrate to draining LN and activate
Th2 responses
Immediate Hypersensitivity - Type I
Hypersensitivity
• Examples: Hay Fever type allergies, anaphylactic reactions
• Reactions usually occur within minutes of exposure.
• Develops when antigen combined with IgE attached to mast
cells. Large amounts of mast cells in skin and mucous
membranes of respiratory tract
• IgE antibodies bind mast cells, basophils, cross link IgE
receptors causing degranulation
–
–
–
–
–
Release of various mediators including histamine
Histamine causes hives, itching, stridor, laryngeal edema and wheezing
Leads to vascular leakage, especially venules
The arteriolar dilation leads to hypotension
Allergen immunotherapy can reduce specific IgE levels
18
EARLY PHASE RESPONSE
MAST CELL
• GM-CSF & IL-3 important for development
• FceR1 present at high density
• Cross-linking of FceR1 by allergen leads to activation
of mast cell, resulting in :-
• DEGRANULATION - Release of pre-formed
mediators
• SYNTHESIS OF LIPID MEDIATORS
PRE-FORMED MEDIATORS
HISTAMINE
• Stimulation of irritant nerve receptors
• Smooth muscle contraction
• Increase in vascular permeability
KALLIKREIN
• Activates bradykinin - similar actions to histamine
TRYPTASE - role unclear
LIPID MEDIATORS
• ARACHIDONIC ACID DERIVATIVES
Phospholipase A2
5-Lipoxygenase
Arachidonic acid
LEUKOTRIENES
LTA4
LTB4
LTC4
LTD4
LTE4
Cyclo-oxygenase
PROSTAGLANDINS
PROSTACYLINE
THROMBOXANE A2
PROSTAGLANDINS
D2, E2, F2a
Molti antiinfiammatori
inibiscono il
metabolismo
dell’acido
arachidonico.
Aspirina: inibitore
dell’enzima
cicloossigenasi,
blocca la produzione
delle prostaglandine
Newly generated:
Pre-formed chemicals:
histamine, tryptase, heparin
leukotrienes,
prostaglandins
cytokines (IL4, IL13)
Molti allergeni sono enzimi.
Ad esempio un allergene noto è il
Der p-1 che si trova nelle feci degli
acari. E’ simile alla papaina, taglia
l’occludina e si guadagna l’accesso
alle APC subepiteliali.
Non tutti gli allergeni sono enzimi
alcuni sono inibitori di enzimi e molti
sono a funzione ignota
IgE production:
Induction of Th2 responses and
CD40-CD40L interaction
IgE
Serum concentration 100 ng/ml (IgG 15 mg/ml)
Destroyed by heating at 56o for 30 minutes
Half life: 2.5 days in serum, 12 weeks if bound to
mast cells
Elevated in:

Certain parasitic diseases (e.g. schistosomiasis)

Hyper-IgE syndrome

Allergy
Class switching to IgE promoted by IL-4 and IL-13,
inhibited by g-interferon
FceR
Receptor
Affinity
Cellular distribution
FceRI
1010
FceRII
107
Mast cells, basophils,
eosinophils,
Langerhans cells,
activated monocytes
B cells, T cells, platelets,
macrophages, NK cells,
follicular dendritic cells,
eosinophils,
epithelial
cells
Pollution
Acts as a non-specific trigger factor
Sulphur dioxide, nitrogen oxides, diesel
exhaust particles (DEP)
May increase mucosal permeability and
thereby enhance antigen entry
Incidence
1960
Allergy
DEP
2000 Year
Seasonal vs Perennial Allergic
Rhinitis
• Seasonal - Symptoms recur each year during the
same season
• Antigens include:
–
–
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tree pollen
grass pollen
weed pollen
molds
• Perennial - Symptoms are persistent year-round
resulting from constant challenge
• Antigens include:
–
–
–
–
dust
animal dander
molds
cockroach
Early phase:
Cross-linking of FceRI by allergen (immediate reaction starting
within seconds)
Late phase response:
Caused by the release of leukotrienes
chemokines and cytokines from mast
cells. These products recruit other
leukocytes including eosinophils, Th2
(this phase can easily convert into a chronic inflammatory response if
the Ag persists and stimulate Th2 cells which recruit eosinophils and
induce further IgE production, chronic asthma)
LATE-PHASE RESPONSE - 1
BASOPHILS
• Similar properties to mast cells over longer time scale
EOSINOPHILS
• GRANULES contain cytotoxic proteins (ECP, EDN, MBP, EPO)
• In tissues, RELEASE CONTENTS OF GRANULES - major
source of tissue damage in allergic response
T CELLS
• CYTOKINE-DRIVEN ACTIVITY is the major source of
PATHOGENESIS in allergic responses
Eosinophil
38
Eosinophils
• Increase during allergic response
• Release enzymes which degrade
histamine and other mediators of
inflammation
• Protects the body from some protozoal
and helminth infections
39
40
Local effects:
The effects of allergen reexposure
are limited to the site at which
mast cells degranulation occurs
Allergen inhalation
Allergic Asthma
Allergen-induced activation of submucosal mast cells in the
lower airway
Early/late phase response involved
early: bronchial constriction and secretion of fluid
and mucus
chronic: continued presence of increased number of
Th2 cells, eosinophils, neutrophils and other
leukocytes
Allergen inhalation
RHINITIS
Allergic/non-allergic
Allergic: perennial or seasonal type
Blocked nose, often with eye symptoms
Major aero-allergens include House dust mite, pollens
Early/late phase responses are involved
ALLERGIC CONJUNCTIVITIS
Skin allergy: urticaria, chronic eczema
Early/late responses are involved
Local injection of small amounts of allergen (stinging insect)
Localized allergic reaction: local mast cells activation, local
increased of vascular permeability (fluid extravasation and
swelling)
8 hours later: more spread and sustained edematous
response urticaria
Food
Local effects
Allergies or more general effects
FOOD ALLERGY
MAJOR FOOD ALLERGENS
• Water soluble glycoproteins 10 -60 kd
• Heat, acid & protease stable
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•
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•
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COW’S MILK
CHICKEN EGG
LEGUMES - PEANUT; SOYBEAN; TREE NUTS
FISH
CRUSTACEANS / MOLLUSCS
CEREAL GRAINS
FOOD ALLERGY - CLINICAL
GASTROINTESTINAL
ANAPHYLAXIS • Within 2 hours of ingestion
• Nausea , pain , cramps , vomiting , diarrhoea
ALLERGIC EOSINOPHILIC GASTROENTERITIS • Nausea & vomiting; diarrhoea , steatorrhoea
• Peripheral eosinophilia in 50% of patients
• Elevated serum IgE with positive RASTs
FOOD ALLERGY - CLINICAL
RESPIRATORY
• Upper and lower respiratory tract symptoms
• Food allergens can provoke airway hyper-reactivity
• Studies suggest 35 - 40% of children assessed for food allergy
develop respiratory symptoms
• 2 - 10% of asthmatic children have symptoms induced by food
CUTANEOUS
• Acute urticaria / angioedema said to be common
• ‘Cause - and - effect’ usually obvious to patient
• Eggs , milk , peanuts , other nuts in children - >90% of reactions
Systemic reactions
Allergen introduced in the bloodstream or
adsorbed from the gut
Systemic anaphylaxis
Disseminated mast cells activation
General increase in vascular permeability:
loss of blood pressure
airways constrict-respiratory difficulties
swelling in the epiglottis (suffocation)
anaphylactic shock can occur:
Drug administered to people with high specific IgE levels
Insect venom
Some food
Frequent allergic reaction to penicillin
When high anti-penicillin IgE levels are
present administration of the drug can
cause anaphylaxis
Penicillin acts as an hapten: b-lactamic ring react with host proteins
and form covalent conjugates
Penicillin-modifies self-peptide can induce Th2 response that activate
B cells to produce IgE
BASI GENETICHE
40% degli individui hanno una tendenza esagerata a produrre IgE
Questo fenomeno è stato chiamato ATOPIA
Gli individui atopici hanno livelli di IgE totali più alti e livelli di
eaosinofili più alti
Sono più suscettibili alla febbre da fieno e all’asma
BASI GENETICHE
Studi fatti su famiglie con individui atopici hanno identificato regioni
sui cromosomi 11q e 5q che sembrano importanti.
Cromosoma 11: b-subunità del recettore ad alta affinità delle IgE
Cromosoma 5: cluster di geni che includono IL3, IL4, IL5, IL9, IL12,
IL13, GMCSF, importanti per IgE switching, sopravvivenza degli
eosinofili, proliferazione delle mast cells.
Associazioni con particolari MHC che favoriscono risposte Th2
Skin Testing
•
•
•
•
Select antigens to be tested by history
Prick test done to minimize adverse reactions
Intradermal test most sensitive
Advantages
– rapid and inexpensive
– wide range of antigens
– very sensitive
• Disadvantage
– Some risk of acute allergic reactions
– If patient is on antihistamines, need to take them off for a
period of time before skin testing
In Vitro Testing for Specific
IgE
• Advantages
– No risk to patient
– No interference by drugs
• Disadvantages
– Expensive
– Limit on antigens available
– Less sensitive than skin tests
– Necessitates delay in obtaining results
Recommendations for Objective Allergy Testing
• Skin Test Preferred
– lower cost
– readily available
– greater sensitivity
• RAST/ELISA useful in selected cases
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–
–
–
infants, uncooperative patients
dermatographism or extensive skin disease
patients requiring antihistamines
severe risk of anaphylaxis
Type II hypersensitivity
Antibody against cell
surface antigens
Type II Antibody Mediated or Cytotoxic
Hypersensitivity
• IgG and IgM binding to fixed (not soluble)
target antigens
• Initial sensitization, or cross reaction with
infectious agent leading to Ab production
• Antibody binds to fixed antigen, attracts
complement and Ig-Fc receptor bearing cells
• Reactions Occur in hours to one day (with the
exception of blood transfusion reactions, which
can occur within minutes).
Examples of Type II
Hypersensitivity
•
•
•
•
•
Drug Induced Hemolytic Anemia
Rh Disease of the Newborn
Autoimmune hyperthyroidsim
Myasthenia gravis
Blood Transfusion Reactions
Haemolytic disease of the newborn due
to rhesus incompatibility
Rhesus prophylaxis
Incompatible Blood
Transfusion Reactions
• Type II Hypersensitivity
• Antigen-antibody complex attack blood cells
and destroy them
• Signs
– H/A, back pain, chest pain, Nausea and vomiting,
tachycardia and hypotension, hematuria
• Treatment
– Stop the transfusion save blood and tubing to
send to lab later IV fluids
– O2 and epinephrine for dyspnea and wheezing
– Mannitol to draw fluids back into vascular system
– Vasopressor drugs if needed
DRUG ALLERGY
ANAESTHETIC AGENTS
• Increasing problem
• 0.09% of operations complicated by reactions to agents
• Estimated 70% of cases due to allergy to QUATERNARY
AMMONIUM MUSCLE RELAXANTS
• (Suxamethonium; Vecuronium; Pancurounium; Atracurium)
• Diagnosis from HISTORY
Type III hypersensitivity
Immune complex
mediated
Type III - Immune Complex Hypersensitivity
– Small immune complexes are missed by phagocytic cells.
These immune complexes are then deposited in body
organs causing inflammation
– Reactions take hours to days to occur
• Rheumatoid Arthritis
– Inflammation of joint spaces
• Serum Sickness - 6-14 days after exposed to foreign serum.
– Similar reaction is also seen in some reactions to penicillin,
sulfonamide, and dilantin.
– Signs - fever, joint pain, enlarged lymph nodes, and rash
– Usually self-limiting.
– Treat with rest, and antihistamines.
Small complexes that
form at antigen
excess deposit in
blood vessels walls,
ligate FcR on
leukocytes leading to
leukocyte activation
and tissue damage
Three categories of immune-complex
disease
Systemic Lupus Erythematosis (SLE)
• Example of Type III/Type IV Hypersensitivity
Disease
• Peak incidence of SLE is in women between the
ages of 20 and 40
• Typical malar rash (butterfly rash),
lymphoadenopathy, arthralgias, fever, fatigue and
will often complain of recurrent flu-like illness.
• As the disease advances, increased evidence of
target organ damage (kidney and other organs)
can be found with protein and red cells in the
urine, pleurisy, pericarditis, hair loss, associated
with the appearance of circulating auto-antibodies,
especially antinuclear.
Systemic lupus erythematosis (SLE)
Type IV hypersensitivity
Delayed type (DTH)
T-cell mediated
Type IV Cell-mediated
delayed hypersensitivity
reactions
• Sensitized T cells (Th1, Th2 or CTLs) react with antigens
and produce lymphokines (IFNg and inflammatory mediators such
as eotaxin that recruits eosinophils).
• Reaction occurs 24-72 hours after exposure to
antigen
• Caused by chronic infections (like TB) or by contact
sensitivities as in contact dermatitis
• GVHD (graft vs host disease) and transplant
rejections are also type IV
ALLERGY - DIAGNOSIS
HISTORY


Apparently clear in many cases BUT...
<50% confirmed by double-blind challenge


Need to know: Substance involved (if known)
 Quantity ingested
 Time interval to onset
 Similarity of symptoms on each occasion
 Other factors e.g. drugs
EXAMINATION - OFTEN NOT SPECIFICALLY HELPFUL
Trattamento delle allergie
Desensitizzazione: shiftare la risposta anticorpale da IgE a IgG
I pazienti vengono iniettati con dosi sempre maggiori di allergene a partire
da dosi molto basse; questo tipo di trattamento gradualmente trasforma
una risposta Th2 in una risposta Th1
Vaccinazione: iniezione di peptidi derivanti da allergeni comuni,
procedura che induce T cell anergy. La vaccinazione è tuttavia legata al
tipo di MHC
Future Allergy Treatments
• Monoclonal Antibody to IgE (called Zolare)
– IgE binds to mast cell FceRI
– IgE triggers release of inflammatory mediators
– FDA approval pending
• Soluble IL-4 Receptors (benefit in asthma)
– IL-4 necessary for IgE synthesis by B cells
– IL-4 involved in eosinophil recruitment to airways
etc
– Studies show some clinical benefit in asthma
• Monoclonal Antibody to IL-5
– IL-5 essential for eosinophil maturationI
– IL-5 activates eosinophils, prolongs eosinophil
survival
– Clinical effect not striking