Lecture Allergy(1).pdf

Lecture Allergy Blok 2.4 Digestion and Defense II ITM Medicine

What we are going to discuss? • • • • •

Allergy IgE in and outs Allergy diagnostics Anaphylaxis Allergy vaccination

Hayfever

Allergy • Summary: • Immunologic reaction, because of specific recognition by gammaglobulines (IgE) or (sometimes) immune cells • Antigen non-self • Related with complaints • Eg: hay fever, astma, urticaria, eczema, anafylaxis, food allergy

IgE and Allergy • Allergy is not related to high total IgE levels. • There is no relation between IgE and atopy, high IgE is not automatically atopy (genetic propensity to develop IgE mediated reactions) • IgE titer is genetically determined, oa locus on 5q31-32 • Atopy, however, ís defined as high specific IgE against allergen (except for immune responses against worms)

IgE, Allergy and Worms • In atopy there is high specfic IgE, low irrelevant IgE, whereas in parasitic infection there is high bystander (thus irrelevant IgE) and little specific IgE • Relevant, because a lot of bystander IgE “dilutes” specific IgE on mast cells and reduces IgE-crosslinking

Common allergens (geograpy!) • • • • • •

House dust mite (sept-dec) Tree pollen (dec-april) Grass pollen (mai-july) Weed pollen (june-aug Funghi (aug-sept) Animals (all year long)

• Italy: olive pollen

4 types hypersensitivity reactions, summerised

Immunologic inducers of infection: Antibodies (Type I and II), immune complexes (Type III) and effector lymphocytes (Type IV)

Common food allergens (prevall data) • • • • • • • • • • •

Egg Milk Kiwi Apple Hazelnut Peanut Soy Fish Shrimps Tomato Wheat

Immediate type hypersensitivity

Nature of humane immunoglobulines

Immunoglobuline IgG1 IgG2 IgG3 IgG4 IgM IgA1 IgA2 IgD IgE MW (kDa)

146

146

165

146

970 160

160

184 188

Serum (mg/ml)

9

3

1

0.5

1.5

3.0

0.5

0.03 5x10

T½ (dagen)

21

20

7

21

10

6

6

3

2

-5

IgE formation

IgE class switching is rare!

IgE switching • B cells leave bone marrow carrying IgM. • Under influence of Il-4 and Il-13 class switch to IgE (skipping IgG and IgA ?) • Plasma and memory cells for IgE • How about changing to IgG4?

Class switching: role of germinal center

Modified B-cell response in mature germical center

IgE class switching!

Effect of protein allergens on IgEmast cell

Role of lymf node germinal center (GC) in IgE generation (source Davies)

Diagnosis of allergy • Skin tests : SPT, ICT, epicutaneous test, patch test • Plasma analysis with either crude extracts of natural allergens (Immunocap)or with recombinants allergens(ISAC) • Basofil degranulation-assay with FACS of histamine-measurement

Skin prick testing (SPT) for immediate type hypersensitivity

Intracutaneous testing (ICT)

Hundred to thousand times more sensitive than skin prick testing, for immediate type hypersensitivity

Epicutaneous testing for type IV reactions

Positive reaction on epicutaneous testing (EPT) nickel latex Colophonium Methylisothiazoline perfum

Eczemateous reaction (eg. contact allergy after nickel)

Immunocap testing • In vitro determination of specific IgE, about 500 allergens or allergen mixes can be tested • Allergen is fixed upon paper, patient serum is added and a second antibody is used to indicate binding of patient serum • Phadiatop: specific IgE against most relevant inhalationallergens for northern Europe, house dust mite, cat, dog, tree pollen, grass pollen, weed pollen, fungi • MUMC food allergy mix (fx1 t/m 5) measures sIgE against egg white, cow’s milk, fish, wheat, peanut, nuts, soy, sea food, shrimps, sesame seed. • Phadiatop infant: determines house dust mite, cat, dog, grass pollen, egg white, milk and peanut

Phad Phadiatop positive Gx3 Grass positive >100 [kU/L] * Tx9 Tree positive 3.7 [kU/L] * Wx3 Herb positive 3.3 [kU/L] * Mx1 Fungus negative D1 House dust mite positive 3.5 [kU/L] class: 3 E1 cat hair/scall positive 2.5 [kU/L] class: 2 E5 dog hair/scall positive 10 [kU/L] class: 3 Fx5 food in general positive >100 [kU/L] * class: 6 F1 egg white positive 1.9 [kU/L] class: 2 F2 milk positive >100 [kU/L] class: 6 Fx3 awn positive 4.3 [kU/L] * F4 wheat positive 3.5 [kU/L] class: 3 F7 oat positive 1.9 [kU/L] class: 2 F8 corn positive 3.6 [kU/L] class: 3 F11 buckwheat positive 3.2 [kU/L] class: 2 F14 Soy positive 4.7 [kU/L] class: 3 F10 Sesame seed positive 4.9 [kU/L] class: 3 Fx1 nuts positive 4.2 [kU/L] * class: 3 F13 peanut positive 4.3 [kU/L] class: 3 F17 hazelnut positive 2.4 [kU/L] class: 2 F18 Para nut positive 0.54 [kU/L] class: 1 F20 almond positive 3.1 [kU/L] class: 2 F36 coconut positive 2.0 [kU/L] class: 2 F202 Cashew nut positive 1.9 [kU/L] class: 2 Fx2 seafood positive 10 [kU/L] * class: 3 F3 kabeljou positive 0.63 [kU/L] class: 1 F24 shrimp positive 13 [kU/L] class: 3 F37 shell positive 1.2 [kU/L] class: 2 F40 tuna positive 0.77 [kU/L] class: 2 F41 salmon negative 0.24 [kU/L] F27 beef meat positive 7.8 [kU/L] class: 3 F83 chicken meat positive 1.1 [kU/L] class: 2 F92 banana positive 2.7 [kU/L] class: 2

Cross reactivity

Causes cross reactivity • Shared allergens (tropomyosin in HSM and shrimps, storage proteins in nuts, serum albumen in animals and meat) • Molecular mimicry (Betv1 homology with Mal d1 apple, Gly m4 soymilk, etc) • NEW: also carbohydrate-structures on proteins: galactose-α-1,3-galactose story

Two stories 1. cetuximab • 2006 cetuximab, monoclonal against epidermal growth factor, used in bladder cancer • In USA several cases of infusion-related anaphylaxis

Two stories 1. cetuximab 2. red meat allergy • 2006 cetuximab, monoclonal against epidermal growth factor, used in bladder cancer • In USA several cases of infusion-related anaphylaxis • Same region dr. Platt Mills et all. several patients with delayed anaphylaxis on red meat

Red meat-tick- cetuximab anaphylaxis

anaphylactic reactions to cetuximab in 2006 (A) Rocky Mountain spotted fever (B). patients with delayed anaphylaxis to red meat whose serum contained IgE antibodies to alpha-gal (C).. In panel D, distribution of the tick Amblyomma americanum

Galactose-1,3-galactose • 2006 tick bites • 2009 cat IgA

• 2012 gelatin in marsh mallows

ISAC component resolved diagnosis 112 molecular allergens tested

ISAC component resolved diagnosis • • • • • • • • • • • • • •

rApi g 1 rDau c 1 rMal d 1 rPru p 1 nPru p 3 rAna o 2 nAra h 1 nAra h 2 nAra h 3 rAra h 8 rBer e 1 rCor a 1.0401 rCor a 8 nCor a 9

Celery Carrot Apple Peach Peach Cashew nut Peanut Peanut Peanut Peanut Brazil nut Hazelnut Hazelnut Hazelnut

Apium graveolens Daucus carota Malus domestica Prunus persica Prunus persica Anacardium occidentale Arachis hypogaea Arachis hypogaea Arachis hypogaea Arachis hypogaea Bertholletia excelsa Corylus avellana Corylus avellana Corylus avellana

PR-10 protein PR-10 protein PR-10 protein PR-10 protein Lipid transfer protein (nsLTP)

• • •

rGly m 4 nGly m 5 nGly m 6

Soybean Soybean Soybean

Glycine max Glycine max Glycine max

PR-10 protein Storage protein, b-conglycinin Storage protein, glycinin

• • • • • • • • •

nSes i 1 nTri a 18 nTri a gliadin rTri a 19.0101 nTri a aA_TI rHev b 1 rHev b 3 rHev b 5 rHev b 6

Sesame seed Wheat Wheat Wheat Wheat Latex Latex Latex Latex

Sesamum indicum Triticum aestivum Triticum aestivum Triticum aestivum Triticum aestivum Hevea brasiliensis Hevea brasiliensis Hevea brasiliensis Hevea brasiliensis

Storage protein, 2S albumin

Storage protein, vicilin Storage protein, Conglutin Storage protein, 11S globulin PR-10 protein Storage protein, 2S albumin PR-10 protein Lipid transfer protein (nsLTP) Storage protein, 11S globulin

Crude gliadin Omega-5 gliadin

Clinical examples of ISAC vs. ImmunoCAP | De Boer et al. | xxxx xx, xxxx

36

Comparison of ISAC vs. ImmunoCAP Gx3 Grass positive >100 [kU/L] * Tx9 Tree positive 3.7 [kU/L] * Wx3 Herb positive 3.3 [kU/L] * Mx1 Fungus negative D1 House dust mite positive 3.5 [kU/L] class: 3 E1 cat hair/scall positive 2.5 [kU/L] class: 2 E5 dog hair/scall positive 10 [kU/L] class: 3 Fx5 food in general positive >100 [kU/L] * class: 6 F1 egg white positive 1.9 [kU/L] class: 2 F2 milk positive >100 [kU/L] class: 6 Fx3 awn positive 4.3 [kU/L] * F4 wheat positive 3.5 [kU/L] class: 3 F7 oat positive 1.9 [kU/L] class: 2 F8 corn positive 3.6 [kU/L] class: 3 F11 buckwheat positive 3.2 [kU/L] class: 2 F14 Soy positive 4.7 [kU/L] class: 3 F10 Sesame seed positive 4.9 [kU/L] class: 3 Fx1 nuts positive 4.2 [kU/L] * class: 3 F13 peanut positive 4.3 [kU/L] class: 3 F17 hazelnut positive 2.4 [kU/L] class: 2 F18 Para nut positive 0.54 [kU/L] class: 1 F20 almond positive 3.1 [kU/L] class: 2

F36 coconut positive 2.0 [kU/L] class: 2 F202 Cashew nut positive 1.9 [kU/L] class: 2 Fx2 seafood positive 10 [kU/L] * class: 3 F3 kabeljou positive 0.63 [kU/L] class: 1 F24 shrimp positive 13 [kU/L] class: 3 F37 shell positive 1.2 [kU/L] class: 2 F40 tuna positive 0.77 [kU/L] class: 2 F41 salmon negative 0.24 [kU/L] F27 beef meat positive 7.8 [kU/L] class: 3 F83 chicken meat positive 1.1 [kU/L] class: 2 F92 banana positive 2.7 [kU/L] class: 2

Clinical examples of ISAC vs. ImmunoCAP | De Boer et al. | xxxx xx, xxxx

37

Comparison of ISAC vs. ImmunoCAP ISAC112 tropomyosin panel

ISAC112 storage protein panel rAna o 2

0.6 ISU

ISAC112 profilin panel

nPen m 1

11 ISU

rPhl p 12

1.7 ISU

rDer p 10

8.4 ISU

rBet v 2

3.7 ISU

nBla g 7

13 ISU

rMer a 1

7.2 ISU

16 ISU

rHev b 8

12 ISU

nOle e 2

― ISU

rBer e 1

neg

rAni s 3

nCor a 9

neg

rPen a 1

― ISU

nJug r 1

neg

nPen i 1

― ISU

nJug r 2

1.6 ISU

nSes i 1

neg

ISAC112 egg panel nGal d 1

neg

nGal d 2

neg

rAra h 1

neg

rAra h 2

neg

nGal d 3

neg

rAra h 3

neg

nGal d 5

0.6 ISU

nAra h 6

neg

nGly m 5

neg

nGly m 6

neg

nFag e 2

neg

ISAC112 serum albumin panel

ISAC112 CCD panel nAna c 2

― ISU

nMUXF3

1.6 ISU

ISAC112 milk panel nBos d 4

9.3 ISU

nBos d 5

15 ISU

nBos d 6

1.1 ISU

nBos d 6

1.1 ISU

nFel d 2

0.9 ISU

nCan f 3

0.7 ISU

nBos d 8

2.8 ISU

nEqu c 3

0.6 ISU

nBos d lactoferrin

neg

Immunocap versus ISAC • Soy immunocap contains rGly m5 and rGly m6, but no rGly m4 • ISAC soy contains all three proteins • rGly m5 and nGlym6 are storage proteins, present in fermented soy products and related to severe soy allergy. • rGly m4 is present in soy milk, not in fermented soy products and related to anaphylaxis due to soy milk

Anaphylaxis

What is anaphylaxis? • Brown FA, JACI, 2004

• 1. Acute allergic reaction: diffuse erythema, itching, rhinoconjunctivitis, urticaria, angioedema • 2a. Mild/moderate anaphylaxis; 1. plus dyspnea, wheezing, hoarseness, nausea, vomitting • 2b. Severe anaphylaxis: 2a plus collaps, dizzyness, loss of conciousness, < 90 mm Hg, GCS < 15. Or resp. symptoms with stridor, cyanosis, larynx edema (hoarseness), tachypnoe > 25.

Causes of anaphylaxis • Age dependent: • under 5 years of age frequently milk, egg, soy, wheat, nuts, peanut • Young adults nuts, peanut, sea food, milk often tolerated • Adults: NSAIDs, latex, antibiotics, contrast media, cytostatica, blood products, biologicals, insect stings, etc: (food-associated, exercise-induced anaphylaxis), idiopathic anaphylaxis .etc

Case material • Case 1. 73 year old woman, drinking coffee with her cousin, with a biscuit, within 20 minutes itching in palms of the hands, red skin, dyspnea and collaps. Specific history revealed: lots of pain in her arthrotic hip recently. • Case 2. 50 year old man, for years after a meal red skin rash and frequently palpitations with diarrhea. Eight years ago consultation of a gastroenterologist because of diarrhea, no explanation found

Case material • Case 3. 27 year old Chinese woman, medical doctor-intraining, previously, while living in China, diagnosed with asthma. Indonesion week in the hospital restaurant: almost daily nausea, vomitting, more asthma complaints and sometimes red skin rash. • Case 4. Erasmus hospital Rotterdam, after lunch thirteen health care workers reported at the first aid ward with diffuse redness, itching, nausea, diarrhea and palpitations. The menu mentioned thuna fish.

Diagnosis • Case 1 : NSAIDs-induced anaphylaxis

diagnosis • Case 1 : NSAIDs-induced anaphylaxis • Case 2 : small intestin carcinoïd (hormonally active tumor in the intestins secreting serotine-like substances)

diagnosis • Case 1 : NSAIDs-induced anaphylaxis • Case 2 : small intestin carcinoïd (hormonally active tumor in the intestins secreting serotinelike substances) • Case 3 : fish allergy in astmatic patient

diagnosis • Case 1 : NSAIDs-induced anaphylaxis • Case 2 : small intestin carcinoïd (hormonally active tumor in the intestins secreting serotinelike substances) • Case 3 : fish allergy in astmatic patient • Case 4 : scrombroidosis (food poisoning where fish contain high amounts of histamine, due to degradetion of fish proteins (histidine)

Treatment of anaphylaxis and allergy • Anaphylaxis: epinefrine (adrenalin) intramuscularly, (epipen) and AFTER adrenaline, antihistaminics and steroids • Hayfever: antihistaminics, nasal steroid spray • Asthma: inhalation steroids, beta mimetics, antileukotriens, oral, anti IgE-treatment, etc. steroids • Food allergy: ……avoidance or recently: oral desensibilisation reported in peanut, not for severe anafylaxis. • How about Allergy vaccination?

Allergy vaccination • When ?: • In proven IgE mediated hypersensitivity leading to anaphylaxis upon wasp or bee stings • In hay fever and asthma upon exposure to cat, tree pollen, grass pollen, house dust mite, alternaria alternata (fungus), ambrosia (weed pollen)

Allergy vaccination will never let you down!

How allergy vaccination? • • • •

With injections: Natural allergen extracts Recombinant allergen extracts Allergoiden

• (With droplets or) tablets • Sublingualy

Mechanism of protection by allergy vaccination • Change of immune response: • Increase of specific IgG4,interfering with crosslinking of IgE on mast cells • Increase in (inducible)T reg cells • Downregulation in APC presentation through the Fcepsilon receptor, decreasing Th2 induction of T-cells • ….?

Questions?