lecture 514.094 the pathophysiologyof allergy chapter 12 ... · isabella pali-schöll ipa...

Lecture 514.094 of the Medical University Vienna

The Pathophysiology of Allergy

Pregnancy and allergies

Isabella Pali-Schöll

IPA

Lecture 514.094 The Pathophysiology of Allergy

Chapter 12: Allergies in pregnancy, lactation and early

childhood


Institute of Pathophysiology and Allergy Research (IPA)

Medical University Vienna

[email protected]





IPA

Topics

� Immunology of pregnancy

� Influence factors on allergy development during pregnancy

� Influence factors on allergy development around birth

� Influence factors on allergy development during lactation

� Influence factors on allergy development during babyhood� Influence factors on allergy development during babyhood

� Management of allergy of mother during pregnancy





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Pali-Schöll et al. JACI 123:1012-21 (2009)





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Why is this a topic at all???

� The baby/fetus bears molecules

which are foreign to the mother!

www.fertilityc.com





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Only in the 1950s, Sir Peter Brian Medawar

(Nobel laureate 1960) pointed out that the fetus

contains maternal as well as paternal antigens

� should be rejected by mother’s immune system

Medawar PB. Symp Soc Exp Biol 7:320-338 (1953)





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Hypotheses for survival of the “allogenic transplant” embryo

i. Anatomical barrier between mother and fetus � immunological,

physical or physiological barrier blocks maternal immune competent or

cytotoxic molecules and cells

ii. Fetus immunologically undeveloped � expresses no paternal antigens

iii. Maternal immune system inactive during pregnancy iii. Maternal immune system inactive during pregnancy

� no immune reactions

Desoye et al. Arch Gyn Obst 245:146-148 (1989)





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ad iii. Immune system suppression mechanisms

3.a cytokines and Th1/Th2 environment

3.b LIF (leukaemia inhibitory factor)

3.c natural killer cells and macrophages

3.d HLA-G





3.b LIF (leukaemia inhibitory factor)

3.c natural killer cells and macrophages

3.d HLA-G3.d HLA-G

3.e progesterone

3.f apoptosis

3.g complement

3.h blocking antibodies

3.i tolerance

http://homepages.uel.ac.uk/u9400777/

Erlebacher A. Curr Opin Immunol 13:590-593 (2001)Le Bouteiller P. Nature Medicine 12:991 - 992 (2006)

3.d HLA-G

3.e progesterone

3.f apoptosis

3.g complement

3.h blocking antibodies

3.i tolerance





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� cytokines act locally

� early stages of pregnancy: conceptus and placental tissue provide:

IFN, IL, TNF, GM-CSF � mechanism of action unclear IFN, IL, TNF, GM-CSF � mechanism of action unclear Schäfer-Somi S, Animal Repr Sci 75:73-94 (2003)

Lippert H. Anatomie. 6. Auflage (1995)





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� Th2-cytokine environment essential for successful pregnancy:

IL-4, IL-5, IL-6, IL-10, IL-13

Saito S. J Repr Immunol 47: 87-103 (2000) Saito S. J Repr Immunol 47: 87-103 (2000)

� shift but no complete suppression of Th1, as mother and fetus need

to be protected from pathogens

Guilbert LJ. J Repr Immunol 32:105-110 (1996)

� not only Th2-cytokines essential, as interleukins 11-18 have been

found during different stages of pregnancy

Chaouat G et al. J Repr Immunol 53:241-256 (2002)

www.shinesa.org.au/go/information-and-resources/choose-

a-topic/pregnancy/stages-of-pregnancy-and-birth





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� decidual leukocytes and pre-implantation embryo secrete IL-10Schäfer-Somi S. Animal Repr Sci 75:73-94 (2003)

� during implantation blastocyst suppresses inflammatory response � during implantation blastocyst suppresses inflammatory response

of maternal endometrium by IL-6Vince GS et al. J Repr Immunol 32:101-104 (1996)

� IL-4 for maintenance of pregnancy, suppresses Th1 by inhibiting

IL-12 production by MΦ and DC; constitutively expressed in

amniotic and decidual tissue; critical necessity discussedBonney EA. Immunol 103:382-389 (2001)

www.tutorvista.com/content/biology/biology-

iv/reproduction-in-animals/segmentation.php





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Mechanisms involved in

maternal tolerance to the

fetal semi-allograft

Weetman AP. Nature Reviews Endocrinology 6:311-318 (2010)

en.wikipedia.org/wiki/File:Gray36.png





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� Influence factors on allergy development in mother during pregnancy

Reviewed in Pali-Schöll et al. JACI 123:1012-21 (2009)





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� Influence factors on allergy development in mother during pregnancy

Smoking

� Exposure to tobacco smoke is risk factor for sensitization in all

population and age groups (significant relationship between number of

cigarettes smoked and IgE level in active smokers)Gerrard JW et al. Ann Allergy 44:261-262 (1980)

Sherill DL et al. JACI 94:954-962 (1994)

Strachan DP et al. Thorax 53:117-123 (1998)

� Smoking (previous, current light, current heavy) assoc. with

sensitization to nickel Thyssen JP et al. Acta Derm Venereol 90:27-33 (2010)

� Human patients: smoking independent risk factor for sensitization

against respiratory allergens Bakos et al. Immunol Letters 107:15-21 (2007)

� no explicit figures for smoking in pregnancy and

allergy development in mother available

www.smokingstories.wordpress.com/page/2/





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� Influence factors on allergy development of mother during pregnancy

Alcohol

� Alcohol increased specific IgE against food antigens and aeroallergens

in adults Bakos et al. Immunol Letters 107:15-21 (2007)

Gonzalez-Quintela A. Front Biosci 7:234-244 (2002)

Linneberg A. Clin Exp Allergy 36:714-721 (2006)

� Mouse model: liquid alcohol diet � high total IgE and Th2 cytokines,

suppressed IgG2a Linneberg A. Alcohol Clin Exp Res 32:553-556 (2008)suppressed IgG2a Linneberg A. Alcohol Clin Exp Res 32:553-556 (2008)

� Controversy: no enhanced SPT in students of high social class (18-35a)

Assing K. Ann Allergy Asthma Immunol 98:70-74 (2007)

� no explicit figures for alcohol consumption

in pregnancy and allergy development available

www.topnews.in/health/effect-alcohol-foetus-

development-not-clear-say-researchers-27782





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Diet of the mother

� Japanese diet during pregnancy (vegetables, seaweed, fruit,

antioxidants, fiber, minerals)

� seaweed (28g/day) decreased allergic rhinitis in women by 49%

� calcium, phosphorus and magnesium decreased allergic rhinitis

(relax airways)(relax airways)

� β-carotene increased allergic rhinitis

Miyake Y et al. Ann Epidem 16:614-621 (2006)

www.dineouthere.com/restaurants/ebi-ten-japanese-fast-food-downtownwww.cybercolloids.net/sites/default/files/healthy%20hyd

rocolloids%20colour.pdf





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Diet of the mother

� Vitamin D: two hypotheses:

1) increase in VitD via supplementation � increase of allergic rhinitis

Wjst M et al. Allergy 54:757-759 (1999)

2) deficiency of VitD due to reduced sunlight exposure � increase

asthma and allergy (northern states of America needed 4x more asthma and allergy (northern states of America needed 4x more

epinephrine) Camargo CA et al. JACI 120:131-136 (2007)

� asthma and eczema higher in children close to equator

(melanoma protection recommendations?

Sole D et al. J Pediatr 82:341-346 (2006)

www.dreamstime.com/stock-image-sun-

nature-and-pregnancy-image5755281





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Anti-acid medication

� Gastric complaints during pregnancy in 70% of pregnant women

� 30-50% take acid-suppressing drugs � reduce pH in the stomach

� digestion incomplete Diesner SC et al. Immunol Lett 21:45-51 (2008)

Untersmayr E et al. JACI 121:1301-1308 (2008)

Untersmayr E et al. FASEB J 19:656-658 (2005)

Schöll I et al. Am J Clin Nutr 81:154-160 (2005)Schöll I et al. Am J Clin Nutr 81:154-160 (2005)


Hazelnut proteins

pH 5.0 pH 1.2

Codfish proteins

pH 1.2 pH 2.75





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� higher risk for sensitization against food allergens in human and

murine studies (adult non-pregnant patients)Diesner SC et al. Immunol Lett 21:45-51 (2008)



Schöll I et al. Am J Clin Nutr 81:154-160 (2005)


Human patients before and after

acid-suppressing therapy (3 mo)







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� this sensitization status can also be induced in pregnant mother

animals Schöll I et al. FASEB J 21:1264-1270 (2007)

� human study envisaged

Antibody-response in mother mice Skin tests in mother mice





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� Influence factors on allergy development of child during pregnancy






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� this sensitization status is conferred from mother to offspring

in a murine model Schöll I et al. FASEB J 21:1264-1270 (2007)

Antibody-response in mother mice Antibody-response in offspring





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� this sensitization status is conferred from mother to offspring

in a murine model Schöll I et al. FASEB J 21:1264-1270 (2007)

pregnancy lactation

mother p.o.

Th2-biased cytokine pattern in offspring

offspring i.p.





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Genetics

� risk for atopy seems to be directly related to the family

history of allergy

� especially to maternal atopy: only maternal total IgE levels correlated

with CB and infant IgE levels and the development of infant eczemaLiu CA et al. JACI 112:899-904 (2003)

� neither parent is allergic, the chance for allergies in child = 15%� neither parent is allergic, the chance for allergies in child = 15%

� 1 parent is allergic � risk = 30%

� both are allergic � risk > 60%Litonjua AA et al. Am J Respir Crit Care Med 158:176–181 (1998)

0

10

20

30

40

50

60

70

neither parent 1 parent both parents

risk

fo

r a

top

y/a

lle

rgy [

%]





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Smoking

� Mouse model: in utero exposure induced higher risk for sensitization

against allergens in adulthood Penn AL, Environ Health Perspect 115:548-555 (2007)

� CBMC-proliferative responses to allergens (timothy grass, house dust

mite) increased significantly in association with maternal smoking

Devereux et al. Clin Exp Allergy 32:43–50 (2002)

� Th2 cytokines higher in serum samples of neonates with smoking

mothers Noakes PS et al. Allergy 58:1053-1058 (2003)

http://www.hollybaby.com/2010/11/17/study-pregnant-

mother-heavily-smoke-cigarettes-birth-repeat-criminal-children/





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Smoking

� In later life of children:

enhanced total and specific IgE, eosinophil counts, airway disease,

positive SPT, wheezing episodes/asthma

Kulig M et al. Hum Exp Toxicol 18:241-244 (1999)

El-Nawawy A et al. J Trop Pediatr 42:166-169 (1996)

Ronchetti R et al. JACI 86:400-4´07 (1990)Ronchetti R et al. JACI 86:400-4´07 (1990)

Horak E et al. Swiss Med Wkly 137:608-613 (2007)

Sharma SK et al. Allergy Asthma Proc 28:647-653 (2007)

Palvo F et al. J Trop Pediatr 54:253-257 (2008)

www.hertels-atem-praxis.de/14-0-

Asthma-ist-keine-Krankheit.html





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Smoking

Alarmingly :

� 20% of children exposed in utero!

Raherison C et al. Ann Allergy Asthma Immunol 100:351-357 (2008)

� 43% of children exposed to environmental tobacco smoke

during first year of life

Venter C et al. JACI 117:1118-1124 (2006)

Contrasting: pre- or postnatal exposure more associated with sensitization risk

http://www.hollybaby.com/2010/11/17/study-pregnant-

mother-heavily-smoke-cigarettes-birth-repeat-criminal-children/

www.bild.de/BILD/ratgeber/gesund-fit/2010/11/26/todesrate-

passiv-rauchen-kinder/weltweit-sterben-165000.html





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Alcohol

� alcohol consumption of mother

� higher IgE levels in children and

� higher risk for atopic dermatitis in high-risk children

Linneberg A et al. Clin Exp Allergy 34:1678-1683 (2004)

www.topnews.in/frogs-provide-clues-about-

alcohol-s-effects-during-pregnancy-2147849

www.apotheken-umschau.de/Neurodermitis/Neurodermitis-

atopische-Dermatitis-Symptome-11922_3.html





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Diet of the mother

Devereux G. Nat Rev Immunol 6:869-874 (2006)





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Diet of the mother

Vitamin A: possible association between reduced vitamin A and childhood

asthma, not between maternal vitamin A intake during

pregnancy and childhood wheeze

Vitamin C: methodologically weak and unsupportive of the possible

effectiveness of vitamin C to prevent atopic outcomes

Vitamin D: high intake during pregnancy in northeastern US may

decrease risk for recurrent wheeze at 3 yrs

Camargo CA, Am J Clin Nutr 85:788-795 (2007)

Vitamin E: high maternal intake decreases CBMC proliferation to grass

and dust mite allergens Devereux G et al. Clin Exp Allergy 32:43–50 (2002)

All reviewed by Nurmatov U et al. JACI, in press (2011)





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Diet of the mother

Studied/discussed:

Selenium,

Zinc,

Sodium,

Calcium…Calcium…

Fruits,

vegetables

Reviewed by Nurmatov U et al. JACI, in press (2011)





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Diet of the mother

Reviewed in:

Nurmatov U et al. JACI, in press (2011)

West CE et al. Curr Opin Pediatr 22:635-641 (2010)





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Diet of the mother

� Antioxidant hypothesis:

� Westernized diet deficient in antioxidants

� increases susceptibility of population to allergy and asthma:

crystallizeyourlightbodynow.wordpress.com/2010/04/18/

33-healthy-foods-33-healthy-foods-33-healthy-foods/

� increases susceptibility of population to allergy and asthma:

� reduced AO-defense in lungs

� increased oxidant damage

� increased permeability of allergens & increased

inflammation of airways Seaton A et al. Thorax 49:171-174 (1994)

Devereux G. Nat Rev Imm 6:869-874 (2006)

� beneficial associations between maternal intake of some

antioxidants during pregnancy and childhood asthma

� but: limited data on maternal AO intake and childhood AD and ARAllan K. et al. Clin Exp Allergy 40:370-380 (2010)





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Diet of the mother

Ratio n-3/n-6 FA: n-6 biased diet (vegetable oil, margarine)

� more eczema in contrast to n-3 (fish)Sausenthaler S et al. Am J Clin Nutr 85:530-537 (2007)

Devereux G et al. JACI 115:1109-1118 (2005)

Devereux G. Nat Rev Immunol 6:869-874 (2006)

West CE et al. Clin Exp Allergy 40:1113-1115 (2010)

Conjugated Linoleic Acid (CLA): -CH=CH-CH=CH-

Conjugated Linoleic Acid (CLA): -CH=CH-CH=CH-

in milk, cream, butter, meat of ruminants (beef, lamb…)

� anti-inflammatory properties

www.nugowiki.org/index.php/Trans-10_Cis-12_Conjugated_Linoleic_Acid

www.kiri.at/rindfleisch.pdf

www.marsvenus-

forum.de/viewtopic.php?t

=3007&sid=12ed78855ac3

79749d8267e9128ebbf8





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Diet of the mother

� Lipid hypothesis:

� changes in dietary fats:

� increased intake of n-6 PUFA

www.kuechengoetter.de/rezepte/

warenkunde/329047/Margarine.html

� increased intake of n-6 PUFA

� decreased n-3 PUFA and SFA

� altered lipid composition of inflammatory cells (increased

AA molecules)

� PGE2 produced � suppressed diff. to Th1, reduces IFN-γ,

promotes Th2

� increased asthma and allergy

Black PN et al. Eur Respir J 10:6-12 (1997)

Devereux G. Nat Rev Imm 6:869-874 (2006)

www.liveingoodhealth.info/article/how-

eating-fat-could-make-you-lose-fat-quickly/





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Diet of the mother

Probiotics

� Germ-free animals � no tolerance in absence of gut microbiota

� Aberrant intestinal flora may cause or worsen allergic diseases

� Probiotics were recommended during pregnancy as well as for

neonates neonates

� role for certain probiotics (alone or with prebiotics) in the prevention

of atopic eczema Tang ML et al. Curr Opin Pediatr 22:626-634 (2010)

� insufficient evidence to recommend probiotics for prevention or as part of

therapy of allergic diseases Review: Yao TC et al. Ped Allergy Immunol 21:900-919 (2010)

www.natural-weightloss-energy.com/2010/10/14/

Probiotcs_fight_colds_and_flues_according_to_new_study/ www.drnatura.com/flora_protect.php





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Diet of the mother

� Overall dietary pattern (e.g. Mediterranean, healthy, western or prudent

pattern) during pregnancy is not associated with recurrent wheeze

� Maternal intake of individual nutrients may be more important

Lange NE et al. JACI 126:250-255 (2010)

www.ehow.com/how_4735599_maintain-proper-diet-

during-pregnancy.html

West CE et al. Curr Opin Pediatr 22:635-641 (2010)





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Season

� first trimester of pregnancy predicts sensitization to food

allergens

� positive in any food allergy test during first 4 years of life

(IgE or SPT or OPT):

� children born in June-July 5% � children born in June-July 5%

� children born in Oct-Nov 10%

Pyrhönen K et al. J Epidem Comm Health doi:10.1136/jech.2009.105411 (2010)

any FA test sIgE





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Antibodies via placenta

� allergen-specific IgG1 and IgG4 found in human cord blood, no IgE

transferred (case study, n=1) Flicker S et al. JACI 124:1358-1360 (2009)

� oral tolerance-induction of mouse mother to OVA

� OVA-specific IgG transferred to offspring (not in FcRn-KO mice) �

asthma-prevention even if sensitized after 8 mo (dependency on asthma-prevention even if sensitized after 8 mo (dependency on

IFN-γ shown) Polte T et al. JACI 122:1022-1030 (2008)





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Antibodies via placenta

� most murine studies show protective potential of maternal allergen-

specific antibodies against allergen-specific IgE-induction in offspring

Victor JR et al JACI 111:269-277 (2003)

Jarrett EE et al. Immunology 48:49-58 (1983)

OVA-model codfish-model

Uthoff H et al. J Immunol 171:3485–3492 (2003)

OVA-model codfish-model

Schöll I et al. FASEB 21:1264–1270 (2007)





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IgE in placenta

� IgE in human placenta bound to Hofbauer cells (Mф) in villous tissue

� irrespective of maternal allergy status

Rindsjö E et al. Allergy 65:554-560 (2010)

Joernik M et al. Allergy 64:905-912 (2009)

Immunohistochemical staining of IgE in a

second trimester human placenta.





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IgE in placenta

� IgE in placenta is of maternal origin, has to be transported over TB

� neither bound to FcεRI nor to FcεRII, stains with FcγRI

Sverremark EE et al. Clin Exp Immunol 127:274-282 (2002)

� can be allergen-specific

� correlation of total and allergen-specific IgE in placenta with � correlation of total and allergen-specific IgE in placenta with

maternal plasma, no allergen-specific IgE in cord blood � IgE most

probably of maternal origin

Joernik M et al. Allergy 64:905-912 (2009)





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Antigens via placenta

� Der p 1 found in fetal circulation or amniotic fluid

� the amniotic fluid at 16 weeks and fetal circulation at term

two routes of allergen transfer to the conceptus: transamniotic and

transplacental

� IgG is actively transported to fetus across the placenta from

maternal vasculature � Der p 1 carried in complexes with IgG?maternal vasculature � Der p 1 carried in complexes with IgG?Holloway JA et al. Lancet 356:1900–1902 (2000)

www.dima-matratzenreinigung.de/





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� OVA, β-Lactoglobulin, Bet v 1, Der p 1 found in fetal circulation or

amniotic fluid

� enhanced uptake when IgG (polyclonal) is added (ex vivo model)

Szepfalusi Z et al. Ped Res 48:404-407 (2000)

� part of normal development of immunity?� part of normal development of immunity?

Uthoff H et al. J Immunol 171:3485–3492 (2003)

Mouse model





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Allergenic Food

� Early exposure to peanut allergens in utero or via breast milk

increases risk of peanut allergy in predisposed children

Des Roches A et al. J Invest Allergol Clin Immunol 20:289-294 (2010)

� More peanut during pregnancy � elevated peanut IgE in children � More peanut during pregnancy � elevated peanut IgE in children

with egg and milk allergy Sicherer SH et al. JACI, in press (2011)

� Contrasting to:

“Advice on avoiding peanuts in

pregnancy should be withdrawn.”

Kmietowicz Z. BMJ 335:633 (2007)





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� however, allergens mainly retained in placenta � therefore, no

direct dose/immune response relation found in cord blood

Szepfalusi Z et al. Clin Exp Allergy 36: 1130–1137 (2006)

Human model





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Maternal allergen exposure during pregnancy

� elevated dust mite levels prenatally � increased cord blood IgE to

dust mite

� elevated cockroach allergen prenatally � not assoc. with cord blood

IgE, but indirect relation via maternal total IgE

Peters JL, JACI 123:1041-1046 (2009)

www.immunopaedia.org.za/index.php?eID=tx_cms_showpic&

file=uploads%2Fpics%2FInnate_immune_responses_in_neona

tes.jpg&width=1000&height=600m&bodyTag=%3Cbody%20st

yle%3D%22margin%3A0%3B%20background%3A%23fff%3B%

22%3E&wrap=%3Ca%20href%3D%22javascript%3Aclose%28%

29%3B%22%3E%20%7C%20%3C%2Fa%3E&md5=31d5731bc0

8db90fe9e73e855c7ae351





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Other factors transferred from mother to child

� maternal DNA in cord blood

Bauer M et al. Am J Obstet Gynecol 186:117—120 (2002)

� leukocyte trafficking from mother to fetus in utero

Kruse A et al. Biol Reprod 66:333-345 (2002)

labs.fhcrc.org/lnelson/science.html





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Mother living on a farm

� early-life contact with livestock and fodder, and consumption of

unprocessed cow’s milk = most protective exposure

� intense microbial exposure modulates innate & adaptive immunity

Von Mutius & Vercelli. Nature Rev Immunol 10:861-868 (2010)





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Mother living on a farm

� intense microbial exposure � TNF, IL-10 � Treg � suppress Th2 �

� CD14 not inhibited � more PRR � amplification of innate response;

� IFN-y in children via DC and NK with TLR via microbes � counteracts

Th2, accelerates Th1 by activating DC IL-12 production

Von Mutius & Vercelli. Nature Rev Immunol 10:861-868 (2010)Von Mutius & Vercelli. Nature Rev Immunol 10:861-868 (2010)





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Mode of birth

� Cesarean section � increased allergic rhinitis and atopy among

children of atopic parents Pistiner M et al. JACI 122:274-279 (2008)

� Higher number of wheezing episodes and food-specific IgE during

first 2 yrs Negele K et al. Pediatr Allergy Immunol 15:48-54 (2004)

blogs.monografias.com/sistema-limbico-neurociencias/2010/04/26/want-to-

know-all-about-cesarean-sections-multiple-languages/





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Prematurity and low birth weight

� not associated with food allergy Liem JJ et al. JACI 119:1203-1209 (2007)

� even preventive for AD at 1 year Bührer C et al. Lancet 353:1674 (1999)

� however: born extremely preterm decreases lung function in

adolescents Halvorsen T et al. Acta Paediatr 93:1294-1300 (2004)

www.rafed.net/en/index.php?option=com_content&view=article&id=3708:what-

are-preterm-labor-and-preterm-birth&catid=135:pregnancy&Itemid=989





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Birth order

� higher is better: CBMC proliferation to grass and dust mite allergen

(and to ConA and Mycobact. PPD) higher when first pregnancy

Devereux G, Clin Exp Allergy 32:43-50 (2002)

� means of IgE after the first, second, and third or higher delivery were

74.4, 66.6, and 43.0kU/L (significant direct effect of birth order on

maternal IgE) Karmaus W et al. Clin Exp Allergy 34:853-859 (2004)maternal IgE) Karmaus W et al. Clin Exp Allergy 34:853-859 (2004)

www.bonhoeffer-schule-re.de/Kurzbiographie%20DB.html





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Diet of the mother

Antigen via breast milk

� Antigen via breast milk in early and recent studies

thought to induce sensitization (eg. peanut, milk, egg)

Des Roches A et al. J Investig Allergol Clin Immunol 20:289-294 (2010)

� however: � however:

� mothers of sensitized children consumed no different amounts

� mothers avoidance did not protect from sensitization

Gerrard JW et al. Ann Allergy 56:351-354 (1986)

Vadas P et al. JAMA 285:1746-1748 (2001)

Cant A et al. BMJ 291:932-935 (1985)





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Diet of the mother


� Antigen via breast milk induces tolerance and protection from allergic

asthma:

lower IgE, IgG1, IgA, IL-4, IL-5, IL-10, IL-13, collagen in lung, lower eos

and mucus, lower CD40L+CD4+T-cellsand mucus, lower CD40L+CD4+T-cells

� worked also in B-cell-deficient disrupted transmembrane µ exon or

RAG-2-KO (lymphocyte deficient) mice

� no antibodies necessary Verhasselt V et al. Nat Med 14:170-175 (2008)





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Diet of the mother


� Antigen via breast milk induces tolerance

� Dependent on additional immune-regulatory factors:

� TGF-β2 is the predominant cytokine present in human milk

Penttila IA. J Pediatr 156:S21-S25 (2010)Penttila IA. J Pediatr 156:S21-S25 (2010)

� TGF-β together with allergen � CD4+ Tregs � allergen-specific protection)

Verhasselt V et al. Curr Opin Immunol 22:623-630 (2010)





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Diet of the mother


� Form of antigens dependent on handling by mother’s organism,

e.g. digestion


� Does acid-suppression also influence antigens in

breast milk???

� acid-suppression drugs papers cited by Verhasselt

� Does acid-suppression also influence microbiotic

milieu???





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Diet of the mother







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Diet of the mother

� In summary no strong evidence for an allergen-avoidance diet during

lactation, even in high-risk breast-feeding mothers, for preventing atopy

in child

Kramer MS et al. Cochrane Database Syst Rev 3:CD000133 (2006)





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Antibodies via breast milk

� mainly sIgA & IgA2 Labbok MH et al. Nat Rev Immunol 4:565-572 (2004 )

� colostrum also contains IgG (mainly bovine colostrum)

en.wikipedia.org/wiki/Colostrum#Human_colostrum

Palmeira P et al. Pediatr Allergy Immunol 20: 528–535 (2009)





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Antibodies via breast milk

� OVA-specific IgG transferred via breast milk � asthma-prevention

in mice (IgG via placenta or breast milk induces tolerance)

Polte T et al. JACI 122:1022-1030 (2008)





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Other factors transferred into breast milk

� e.g. Chemokines IL-8, RANTES, IP-10, MIG in breast milk

Michie CA et al. Eur Cytokine Netw 9:123-129 (1998)

Takahata Y et al. Acta Paediatr 92:659-665 (2003)





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Breastfeeding vs. formula diet

PH whey-based formula

EH casein-based formular

Greer FR et al. Pediatrics 121:183-191 (2008)

Von Berg A et al. JACI 119:718-725 (2008)

0 5 10 15 20

breast-fed

cow's milk-based formula

EH whey-based formula

% children





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Breastfeeding vs. formula diet

� Prevention up to 6 years of age � mainly delay of disease onset

Brand PI et al. Pediatr Allergy Immunol 18:475-479 (2007)

� In summary: insufficient data for dietary intervention of child

between 4-6 months

Greer FR et al. Pediatrics 121:183-191 (2008)





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Exposure route to antigens

� “Dual-allergen-exposure hypothesis”: exposure route to antigen

(esp. food) may determine IR with environmental contact, e.g.

Skin � sensitization

Oral � tolerance

� Environmental contact in absence of food consumption � increased � Environmental contact in absence of food consumption � increased

risk for food allergy

Lack G. JACI 121: 1331-1336 (2008)

ideal zur Hautpflege im Windelbereich

sorgt dafür, das Babys Po nicht wund wird und hilft bei Hautreizungen und Rötungen

ist sehr weich und läßt sich aus Windeln gut auswaschen

ist frei von Parfüm und Konservierungsstoffen und deshalb besonders gut verträglich

Inhaltsstoffe: Vaseline, Lanolin, Wasser, Erdnußöl, Glycerin, essigsaure Tonerde

www.leyh-pharma.de





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� Influence factors on allergy development during babyhood






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Complementary feeding

� no delay of complementary food after 4 months of age

(not before 17 weeks, but not delayed beyond 26 weeks)

� prolonged exclusive breast-feeding/delayed introduction may

even be risk factor for AD, asthma or atopyChuang CH et al. Pediatr Allergy Immunol 22:43-49 (2011)

Pohlabeln H et al. J Investig Allergol Clin Immunol 20:195-200 (2010)

� no special diet, even when high-risk infant

� fish during 1st year of life � preventive for atopic diseases

� gluten (max. 7g cereals with gluten/day) between 5 and 7 months in

parallel to breast-feeding � preventive for celiac disease

ESPGHAN Committee on Nutrition. J Pediatr Gastroent Nutr 46:99-110 (2008)

Tarini BA et al. Arch Pediatr Adolesc Med 160:502-507 (2006)

Norris JM et al. JAMA 293:2343-2351 (2005)

Ivarsson A et al. Am J Clin Nutr 75:914-921 (2002)

www.baby.at/396/beikost-baby-einfuehren





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Early vitamin supplementation

� Vitamin supplementation within first 6 months

� increased risk for asthma in black children

� increased food allergies in exclusively formula-fed children

Milner JD et al. Pediatrics 114:27-32 (2004)





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Antibiotic usage in early infancy

� antibiotic use within the first 6 months of life

� exposure was associated with increased risk of asthma and allergy

at 6 years of ageRisnes KR et al. Am J Epidemiol 173:310-318 (2011)

www2c.cdc.gov/ecards/message/mes

sage.asp?cardid=200&category=165

images.meredith.com/ab/images/2

007/12/p_Fotolia_5236378.jpg





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….

Living on farm with lifestock and fodder, i.e. exposure to environmental

bacteria

Epigenetics (diet of mother,

diesel exhaust particles, diesel exhaust particles,

wood smoke, road traffic,

smoking of grandmother…)

Pets/house dust

Passive smoking

….

www.freiligrathschule-ahlen.de/klassen/07_11bru/3a002.htm





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� Summary of preventive measures

� avoid tobacco smoke in passive and active form

� avoid alcohol consumption

� no special diet for mother during pregnancy or lactation

(except when allergy is diagnosed)

� no avoidance of other allergen sources (except when allergy is � no avoidance of other allergen sources (except when allergy is

diagnosed)

� breastfeeding: min. 4 mo, max. 9 mo exclusively

� EHPF or AA-based formula only for high-risk children

� avoid non-prescription drugs and substances/supplements





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Diagnosis

� detailed medical history and symptom analysis

� diary of allergy symptoms and avoidance of specific allergens

accompanied by monitoring of changes of allergic symptoms

� do not put the mother on a rigid elimination diet

� In vitro diagnostic tools such as serological testing � In vitro diagnostic tools such as serological testing

(e.g. RAST) are preferred to in vivo testing

� although not contraindicated, skin prick testing

should be postponed until after birth

� also in vivo tests (food challenge tests and patch tests)





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Treatment

• Food allergy � avoid offending food

• Other allergens � avoid allergen contact

• Recommendations for treatment of asthma and allergies in pregnancy

Drugs preferred for use during pregnancy

Anti-inflammatory: cromolyn beclomethasone, prednisoneAnti-inflammatory: cromolyn beclomethasone, prednisone

Bronchodilator: inhaled β2-adrenergic agonist, theophylline

Antihistamine: chlorpheniramine, tripelennamine

Decongestant: pseudoephedrine, oxymetazoline

Cough: guaifenesin, dextromethorphan

Antibiotic: amoxicillin

Drugs that generally should be avoided during pregnancy

α-Adrenergic compounds (other than pseudoephedrine)

Epinephrine (other than for anaphylaxis)

Iodides

Sulfonamides (in late pregnancy)

Tetracyclines

Quinolones

Adapted from the NAEPP expert panel report. JACI 115:34–46 (2005)

Pali-Schöll I et al. World Allergy Organiz J 2: 26–36 (2009)





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Treatment

Hyposensitization (immunotherapy)

� should not be initiated during pregnancy because of the risk of

systemic reactions

� patients who were already on immunotherapy before the pregnancy,

maintenance treatment may be continued � allergen dose should maintenance treatment may be continued � allergen dose should

not be increased during pregnancy but rather reduced if necessary

� don’t stop, don’t start, don’t increase dose!Dykewicz MS et al. Ann Allergy Asthma Immunol 81:478-518 (1998)

Yawn B et al. J Am Board Fam Med 20:289-98 (2007)

� Active or passive allergen-specific vaccination of mothers may

represent a feasible strategy for the prevention of allergic

sensitization in childhood Flicker S et al. JACI 124:1358-1360 (2009)





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Thank you for your attention!

lecture 514.094 the pathophysiologyof allergy chapter 12 ... · isabella pali-schöll ipa...

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