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Hypersensitivity reactions are exaggerations of normal

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2 Hypersensitivity reactions are exaggerations of normal
defence mechanisms

3 Il termine allergia è stato originariamente
coniato da Clemens Von Pirquet come una “capacità alterata del corpo di reagire ad una sostanza estranea”

4 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

5 L’allergia è tipicamente l’ipersensibilità di tipo I
Le reazioni di ipersensibilità sono classificate in quatto tipi da I a IV L’allergia è tipicamente l’ipersensibilità di tipo I

6 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)

7 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)

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9 Allergy Hay fever, asthma, eczema. Atopy (Greek: ‘out of place’)
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

10 Epidemiology of Allergy
50 Million Americans Affected 10-22% Adults 10-42% Children Peak Incidence Late Childhood Early Adolescence

11 Genetics and Development of Allergies
Risk of developing allergies: No parents have allergies- 10% risk One parent has allergies % risk Both parents have allergies % risk Children with one allergic component (rhinitis, asthma, or eczema) have a 3-fold increased risk of developing others

12 Type I hypersensitivity
IgE-mediated mast cell degranulation

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14 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

15 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

16 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.

17 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

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21 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

22 PRE-FORMED MEDIATORS HISTAMINE KALLIKREIN TRYPTASE - role unclear
Stimulation of irritant nerve receptors Smooth muscle contraction Increase in vascular permeability KALLIKREIN Activates bradykinin - similar actions to histamine TRYPTASE - role unclear

23 LIPID MEDIATORS ARACHIDONIC ACID DERIVATIVES LEUKOTRIENES
Phospholipase A2 Arachidonic acid 5-Lipoxygenase Cyclo-oxygenase Molti anti-infiammatori inibiscono il metabolismo dell’acido arachidonico. Aspirina: inibitore dell’enzima cicloossigenasi, blocca la produzione delle prostaglandine LEUKOTRIENES PROSTAGLANDINS LTA4 LTB4 LTC4 LTD4 LTE4 PROSTACYLINE THROMBOXANE A2 PROSTAGLANDINS D2, E2, F2a

24 Y Y Y Y Y Newly generated:
leukotrienes, prostaglandins cytokines (IL4, IL13) Pre-formed chemicals: histamine, tryptase, heparin

25 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

26 IgE production: Induction of Th2 responses and CD40-CD40L interaction

27 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

28 Cellular distribution
FceR 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

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32 Pollution Acts as a non-specific trigger factor
Acts as a non-specific trigger factor Sulphur dioxide, nitrogen oxides, diesel exhaust particles (DEP) May increase mucosal permeability and thereby enhance antigen entry

33 Allergy Incidence DEP 2000 1960 Year

34 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 dust animal dander cockroach

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36 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)

37 LATE-PHASE RESPONSE - 1 BASOPHILS EOSINOPHILS T CELLS
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

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41 Local effects: The effects of allergen reexposure are limited to the site at which mast cells degranulation occurs

42 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

43 ALLERGIC CONJUNCTIVITIS
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

44 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

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46 Local effects or more general effects Food Allergies

47 FOOD ALLERGY MAJOR FOOD ALLERGENS COW’S MILK CHICKEN EGG
Water soluble glycoproteins kd Heat, acid & protease stable COW’S MILK CHICKEN EGG LEGUMES - PEANUT; SOYBEAN; TREE NUTS FISH CRUSTACEANS / MOLLUSCS CEREAL GRAINS

48 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

49 FOOD ALLERGY - CLINICAL
RESPIRATORY Upper and lower respiratory tract symptoms Food allergens can provoke airway hyper-reactivity Studies suggest % 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

50 Allergen introduced in the bloodstream or adsorbed from the gut
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

51 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

52 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

53 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

54 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

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56 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

57 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

58 Type II hypersensitivity
Antibody against cell surface antigens

59 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).

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62 Examples of Type II Hypersensitivity
Drug Induced Hemolytic Anemia Rh Disease of the Newborn Autoimmune hyperthyroidsim Myasthenia gravis Blood Transfusion Reactions

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64 Haemolytic disease of the newborn due
to rhesus incompatibility

65 Rhesus prophylaxis

66 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

67 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

68 Type III hypersensitivity
Immune complex mediated

69 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 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.

70 Small complexes that form at antigen excess deposit in blood vessels walls, ligate FcR on leukocytes leading to leukocyte activation and tissue damage

71 Three categories of immune-complex
disease

72 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.

73 Systemic lupus erythematosis (SLE)

74 Type IV hypersensitivity
Delayed type (DTH) T-cell mediated

75 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 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

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77 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

78 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

79 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

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