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

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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

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Eosinophil

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Eosinophils

• Increase during allergic response • Release enzymes which degrade

histamine and other mediators of inflammation

• Protects the body from some protozoal and helminth infections

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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