식품알레르기와 면역관용 성균관의과대학 삼성서울병원 소아과 안 강 모

Prevalence studies of Food allergy Suspected FA is extraordinarily common in early childhood. True FA can be confirmed in 5% to 10% of young children with a peak prevalence at ~1 year of age. Most FA is lost over time. Children who begin with 1 FA, especially if it is an IgE- mediated allergy, have a very high chance of developing additional FA as well as inhalant allergies.

A nationwide survey for the Prevalences of Asthma and Diseases in Korean Children - ISAAC by KAPARD - A nationwide survey for the Prevalences of Asthma and Allergic Diseases in Korean Children - ISAAC by KAPARD Elementary school (6-12 yr) Middle school (13-15yr) Elementary school (6-12 yr) Middle school (13-15 yr) No of schools34 No of subjects25,11714,94627,83115,214 No of responses (%)

Prevalence (%) Prevalences of Allergic Diseases in Korean Children in 1995 and ISAAC by KAPARD AsthmaAllergic rhinitis Allergic conjunctivitis EczemaFood Allergy Drug Allergy

Prevalence of Food Allergy in Elementary School Children in Seoul, Korea - ISAAC by KAPARD 1995 (95% CI)2000 (95% CI)2005 (95% CI) Symptom, ever13.1% ( )9.5% ( )11.7% ( ) Symptom, last 12 m7.7% ( )5.9% ( )7.5% ( ) Diagnosis, ever4.6% ( )5.2% ( )6.2% ( ) Treatment, last 12 m2.9% ( )2.7% ( )2.8% ( ) (Pediatr Allergy Respir Dis(Korea) 2007;17: s55-66)

InfantsChildrenOlder children/Adults Cow’s milk Peanut Eggs Tree nuts Peanut Fish Soy Shellfish Wheat Tree nuts (walnut, cashew, etc.) Fish Shellfish (J Allergy Clin Immunol 1996;97:851-2) Common Food Allergens

Geographic variations Bird nest soup allergy in Singapore Royal jelly allergy in in Hong Kong Mustard allergy in France Buckwheat allergy in Korea/Japan

APC Th2 B Th0 APC Th1 BB IL-12 IL-4 IgE

Other Factors Genetic Factor Progressive Disease Th2-dominant Immune status IgE Sensitization Allergic Inflammation Allergen Exposure Hygiene hypothesis Dietary fat hypothesis Antioxidant hypothesis Vit. D hypothesis

Hygiene hypothesis “ Microbial burden ” : indigenous intestinal microbiota or environmental bacterial products rather than “ specific infection ” ⇒ influence the development of atopic disease

(Immunol Rev 2006;213:82-100)

Mechanism of oral tolerance (J Allergy Clin Immunol 2005;115:3-12)

Different type of regulatory T cells Regulatory cellCytokines producedCell surface markers TH1TH1 IFN- , IL-12 CD4 TH3TH3 TGF-  CD4 TR1TR1IL-10CD4 TRTR IL-10CD4 CD25+ IL-10, TGF-  CD4, CD25, GITR, Foxp3 NKT IL-4, IL-13, IFN- , restricted TCR repertoire CD4 or double negative (neither CD4 or CD8) (J Allergy Clin Immunol 2003;112:480-7)

Site of antigen uptake and presentation to T cells Pathogenic organism ; Peyer ’ s patches Oral tolerance ; mesenteric lymph node (MLN) (?)

How does antigen reach the DCs in the MLN? DCs in LP, not in PP, account for the majority of protein uptake from intestine. MLN DCs share many more phenotypic markers with LP-derived DCs rather that PP DCs. CCR7-dependent migration of DCs from LP to MLN is required for the induction of oral tolerance.

Factors important in tolerance Antigen properties - solubility : raw vs roasted peanut - epitope :  s1 -casein,  -casein,  -casein Route of exposure - cutaneous exposure vs ingestion Genetics - C3H/HeSn, AKR/J, BALB/c, C3H/HeJ Age of the host

B-cell epitopes as a screening instrument for persistent cow’s milk allergy (J Allergy Clin Immunol 2002;110:293-7)

Dual-allergen-exposure hypothesis (J Allergy Clin Immunol 2008;121:1331-6)

Cow ’ s milk allergy

Egg allergy Ford RPK, et al. (Arch Dis Child 1982;57: ) - 25 children (7 mo – 9 yr; median 17 mo) - Challenge-confirmed egg allergy - F/U duration; 2 – 2.5 yr - Tolerant; 11 (44%) Dannaeus A, et al. (Clin Allergy 1981;11: ) - 36% ; egg-tolerant - 44% ; less sensitive to egg

Soy, Wheat Typically outgrown in the preschool-age years No large studies on the natural course of these food allergies Sampson HA, et al (1989) - Of children with FA and AD, soy allergy was outgrown in 50% and 67% of children over a 1- to 2-year F/U, compared with 25% and 33% for wheat.

Peanut, Tree nuts, Fish, Shellfish Usually not outgrown Dannaeus A, et al (1981) - 26 children with nut allergy  no loss of sensitivity during 2 to 5 year f/u - 32 children with fish allergy  5 of whom seemed to lose their allergy Daul CB, et al (1990) - 11 children with shrimp allergy  no change in IgE levels

아토피피부염에서의 식품 알레르겐 감작 대상 : 1998 년부터 2003 년까지 삼성의료원을 내원한 아토피피부염 18 세이하의 환아 3783 명 ( 남 1983 명, 여 1800 명 ) 감작률 조사 : 14 종 식품 알레르겐 ( 계란, 우유, 대두, 땅콩, 밀, 메밀, 쇠고기, 돼지고기, 닭고기, 새우, 게, 연어, 고등어, 참치 ) 연령별 감작률 변화 : 3 세미만군 /3 세이상군 감작된 식품 알레르겐간의 상관관계 : 2 가지 이상의 알레르겐에 감작되어 있는 경우 식품 알레르겐에 대한 특이 IgE : CAP assay(Pharmacia, Sweden) 상 0.7 kU/L 이상인 경우를 양성으로 간주 통계 : 카이제곱 검정, Spearman 상관분석

연령별 감작률 변화 전체

소아 아토피피부염에서 감작된 식품 알레르겐 수의 분포

소아 아토피피부염에서의 성별 감작률 668/1983 = 33.7(%) 511/1800 = 28.4(%) * 감작룔 (%) (*, p<0.05)

Sensitization rate by the age in children with atopic dermatitis in SMC (Korean J Community Nutrition 2004;9:90-97) eggCow’s milk wheatpeanutsoy Buck- wheat crabshrimpmack- erel Sal- mon tunabeefporkchicken N=3783 (M/F=1983/1800, age 0-18 years)

A comparison of sensitization rate by the age in children with atopic dermatitis in SMC  3 years > 3 yearsChi-square Egg 33.6% (677/2015)10.3% (138/1345)p< Cow’s milk 20.9% (419/2009)9.2% (123/1340)p< Soybean 13.8% (171/1237)9.7% (41/424)p=0.02 Peanut 17.5% (20/114)9.6% (5/52)p=0.19 Wheat 18.7% (101/540)14.8% (27/183)p=0.22 Buckwheat 9.6% (35/366)10.3% (23/223)p=0.76 Crab 11.8% (4/34)12.0% (49/408)p=0.92 Shrimp 13.8% (8/58)11.3% (47/415)p=0.38 Mackerel 16.2% (12/74)5.0% (21/424)p< Salmon 15.4% (4/26)4.8% (19/395)p=0.02 Tuna 14.3% (4/28)1.7% (7/404)p< Beef 4.8% (40/840)2.7% (36/1311)p<0.01 Pork 3.3% (28/836)3.4% (45/1324)p=0.95 Chicken 2.3% (19/815)1.5% (14/923)p=0.16

Natural course of Egg Allergy in infants with AD Study population: children (68 boys and 48 girls) - Age : 1-12 months (mean 3 months) - Diagnosis : AD and egg allergy before 12 months of age. Diagnosis of egg allergy: - convincing history or egg white specific IgE > 2 KU A /L by ImmunoCAP (Pharmacia, Uppsala, Sweden). Follow-up: - Egg restriction - Follow-up duration ; months (median 49 months) (2008 AAAAI, abstract)

Natural course of Egg Allergy in infants with AD (2008 AAAAI, abstract) Fig. 1. Kaplan-Meier survival curve of egg allergy in children with AD. Median survival age : 60 months

Variables Median Hazard ratio 95% CIP value TransientPersistent Logarithm of total IgE (Total IgE) (128) (332) Logarithm of EW-sIgE (EW-sIgE) (10.7) (33.3) (2008 AAAAI, abstract) Natural course of Egg Allergy in infants with AD

Natural course of Cow ’ s Milk Allergy in Infants with AD Median survival age : 48 months (2007 Annual meeting of KAPARD, abstract) Fig. 2. Kaplan-Meier survival curve of cow’s milk allergy in children with AD.

variables Median Hazard ratio 95% C.I. P value TransientPersistent Logarithm of Total IgE (Total IgE) 6.14 (462.5) 7.83 (2556.5) <0.001 Logarithm of CM-sIgE (CM-sIgE) 2.37 (3.74) 4.62 (63.55) <0.001 Natural course of Cow ’ s Milk Allergy in Infants with AD (2007 Annual meeting of KAPARD, abstract)

Recommendations for treatment (tertiary prevention) of food allergy in infancy

Recommendations for prophylaxis (primary prevention) of food allergy

Studies eliminating food allergens during pregnancy, lactation, and infancy have consistently failed to reduce long-term IgE-mediated food allergy in children Allergen reduction measures have not been sufficient in previous studies, and dietary elimination was not sufficiently stringent. Sensitization to food allergens does not occur as a result of consumption but can occur through other routes of exposure. The paradigm of allergen avoidance is flawed, and early oral exposure can be required to prevent the development of allergy.

Effects of early nutritional interventions on the development of atopic disease in infants and children : The role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas Pediatrics 2008;121: Although solid foods should not be introduced before 4 to 6 months of age, there no current convincing evidence that delaying their introduction beyond this period has a significant protective effect on the development of atopic disease regardless of whether infants are fed cow milk protein formula or human milk. This includes delaying the introduction of foods that are considered to be highly allergic, such as fish, eggs, and foods containing peanut protein. For infants after 4 to 6 months of age, there are insufficient data to support a protective effect of any dietary intervention for the development of atopic disease.

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