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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 3-fold 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
AllergensProteins found in natureTreesGrassesWeedsMolesDust mite fecesCockroachesAnimal 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 T-helper 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
18
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
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
Arachidonic acid5-Lipoxygenase Cyclo-oxygenase
LEUKOTRIENES PROSTAGLANDINS
LTA4
LTB4
LTC4
LTD4
LTE4
PROSTACYLINETHROMBOXANE A2
PROSTAGLANDINSD2, E2, F2a
Molti anti-infiammatori inibiscono il metabolismo dell’acido arachidonico.
Aspirina: inibitore dell’enzima cicloossigenasi, blocca la produzione delle prostaglandine
Pre-formed chemicals:
histamine, tryptase, heparin
Newly generated:
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
IgESerum 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
Receptor Affinity Cellular distribution
FceRI 1010 Mast cells, basophils, eosinophils, Langerhans cells, activated monocytes FceRII 107 B cells, T cells, platelets, macrophages, NK cells, follicular dendritic cells, eosinophils, epithelial cells
FceR
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
1960 2000
Allergy
DEP
Year
Inci
den
ce
Seasonal vs Perennial Allergic Rhinitis
• Seasonal - Symptoms recur each year during the same season
• Antigens include: – 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
38
Eosinophil
39
Eosinophils
• Increase during allergic response • Release enzymes which degrade
histamine and other mediators of inflammation
• Protects the body from some protozoal and helminth infections
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 airwayEarly/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 typeBlocked nose, often with eye symptomsMajor aero-allergens include House dust mite, pollens
Early/late phase responses are involved
ALLERGIC CONJUNCTIVITIS
Skin allergy: urticaria, chronic eczema
Early/late responses are involvedLocal 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 AllergiesLocal effects or more general effects
FOOD ALLERGY
MAJOR FOOD ALLERGENS • Water soluble glycoproteins 10 -60 kd• Heat, acid & protease stable
• COW’S MILK• CHICKEN EGG• LEGUMES - PEANUT; SOYBEAN; TREE NUTS• FISH CRUSTACEANS / MOLLUSCS CEREAL GRAINS
FOOD ALLERGY - CLINICAL
GASTROINTESTINALANAPHYLAXIS - • 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 anaphylaxisDisseminated mast cells activationGeneral increase in vascular permeability:
loss of blood pressureairways constrict-respiratory difficultiesswelling in the epiglottis (suffocation)
anaphylactic shock can occur:Drug administered to people with high specific IgE levelsInsect venomSome 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 conjugatesPenicillin-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 IgEQuesto 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 GENETICHEStudi 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 IgECromosoma 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 – 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 IgGI 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