소아알레르기 예방
DESCRIPTION
제일병원 이희철 교수TRANSCRIPT
20 세기 후반부터 질병의 형태가 변하고 있다
세균성질환의 감소
바이러스 질환의 증가 : SARS, H1N1 Flu. 성인병의 증가 종양환자의 증가
알레르기 질환의 급증
- 공해 ? 산업화
- 환경의 변화 ?, 서구화된 생활
- 세균감염의 감소 : 환경위생학설 (Hygiene Hypothesis) ?
Regulatory T cell
알레르기란 ?
역사 : 성경인물인 욥이 피부 가려움으로 피가 나도록 긁었다
중요성 : 호흡 – 인간 (Host) – 음식 상호관계에서 발생 사랑이 없으면 안된다 .
Atopy 어원 : 그리스어 ‘ Atopia ’ ; different, out of place 알레르겐에 대한 IgE 항체를 생성하는 유전적 소인 환자의 대다수에서 혈청내 IgE 상승 , 피부반응 검사에서 특정 알레르겐에 양성 반응
Epicutaneous sensitization leads to systemic immune response
Spergel JM et al. J Clin Invest 1998;101:1614–22
- 땅콩 단백질함유 피부연화제 국소도포 : 땅콩 감작이 증가- 천식 (+) AD(-) vs 천식 (-) AD(+) : 두군 모두 집먼지진드기에 기도 과민성 , 아세틸콜린에 AD 환아에서 천식범위의반응 > 피부감작이 기도 감작으로 발전 .
아토피피부염
알레르기 질환 , 소양증 , 연령대별 특징적 병변의 부위와 모양 만성 혹은 재발성 경과 , 본인 또는 가족의 아토피 병력
아토피피부염
알레르기 가족력 (+) : 부모 한쪽 30 %, 부모 모두 (+) : 50% 이상 부모 모두 AR : 자녀가 같은 질환 2/3
중등도 와 중증 아토피피부염 : 약 40% 에서 식품 알레르기 연관성 .
유병률 : 15-20 % worldwide. 다양한 원인 , 확고한 치료 방법이 없는 상태 유전적 소인을 가진 사람이 환경의 영향을 받아서 30 -40% 천식 , 50-70% 비염으로 진행 중요성 : 복잡한 병태생리와 다양한 위험요인 파악과 이를 기초로 한 조기관리는 아토피피부염의 예방뿐 아니라 천식 및 비염 등의 알레르기 진행을 차단 피부장벽 / 외피 분화 gene 과 면역반응 / 숙주 방어 gene : AD 의 발현에 중요한 역할 담당
아토피피부염
지루성 피부염 가려움이 적고 호전되는 자연경과
아토피피부염
이차적 바이러스 . 세균감염 곰팡이 감염
아토피피부염
만성화 , 태선화 , 심한 소양증
아토피피부염 발생기전
아토피피부염
유 전 유 전 환 경 환 경
환경에 대한 비정상적인 Th2 면역반응
환경에 대한 비정상적인 Th2 면역반응
염증자극에 대한 피부의 과잉반응
염증자극에 대한 피부의 과잉반응
피부 장벽의 기능장애
피부 장벽의 기능장애
아토피피부염 위험요소
아토피피부염
유 전유 전 환 경 환 경
•Candidate gene•Family History
•Candidate gene•Family History
• Allergen - Food
- Aeroallergen
• Gem free-like state - Vaccinations, anti-microbial• Food consumption pattern• Stress• Irritants
• Allergen - Food
- Aeroallergen
• Gem free-like state - Vaccinations, anti-microbial• Food consumption pattern• Stress• Irritants
Genetics
Inflammation & desquamation
Immune Response(host depense genes)
Immune Response(host depense genes)
Skin Barrier(epidermal differenciation genes)
Skin Barrier(epidermal differenciation genes)
TEWL(impaired barrier formation)
Filaggrin(Loss-of–function mutation)
Protein
SPINK5 gene (uppermost epidermist)LEKT1 inhition 2 serine protease
Imbalance of protease vs protease inhibitor
impaired barrier function
Family historyFamily history
• Adult with AD , 60% children with AD- Both parents with AD 81%, - One parents with AD and the other with respiratory allergy
59%• A stronger correlation between siblings than between siblings and
parents
Candidate genes for atopy and AD
Candidate genes for atopy and AD
Immunopathology
IgE and IgE receptorsIgE and IgE receptors
• 80% : increased serum IgE levels, sensitization against aeroallergens and food allergens, and/or concomitant AR and BA• High-affinity receptor for IgE (FceRI) can be found in the epidermal skin lesions of patients with AD
Allergen
Extrinsic or IntrinsicExtrinsic or Intrinsic
Two types of AD have been identified - Allergic, or extrinsic, form, 70% to 80% of the adult patients with AD , sensitization toward environmental allergens, increased serum IgE levels
- Nonallergic or intrinsic form, 20% to 30% of adult patients with AD, low IgE serum levels and the absence of any detectable allergen sensitization
Allergen
Sensitization to food allergensSensitization to food allergens
• Associated with infantile AD and related to disease severity• Predictive for persistence of symptoms throughout childhood• Clinically relevant food allergies are estimated in about 35 - 40% of children
with AD (Clin Exp Allergy 1999; 29:91-6) • The overall prevalence of food allergy in infants with AD ranged from 20 to 80%
in various studies, and may be estimated at 30%.
Allergen
Aeroallerens (pets, mites and pollens)Aeroallerens (pets, mites and pollens)
• Increase the risk factors for AD and AD severity (Allergy 2004;59(suppl 78):53-60)
• Trigger for exacerbations in adult AD• Many AD patients have IgE Ab to inhalant allergens in
keeping with their skin tests. (J Allergy Clin Immunol 1983;72:27-33)
• Inhalant allergens applied to skin of AD patients by patch test
induce acute eczematous lesions. (J Invest Dermatol 1984;83:290-5)
• Severity of AD is correlated with the degree of sensitization to
aeroallergens. (J Allergy Clin Immunol 1999;104:1280-4.)
• These studies suggest that inhalation or contact with
aeroallergens may be involved in the pathogenesis of AD.
• Homes of patients with eczema have higher numbers of HDM than homes of healthy people. (Br J Dermatol 1992;127:322–7.)
• HDM might cause an exacerbation of the eczematous skin lesions in a high number of AD patients. (J Allergy Clin Immunol 1996;97:1064–70.)
• Eczematous skin lesion and ear swelling caused by repeated application of Der p crude extract in NC/Nga mice has a Th2-dominant background. (International Immunopharmacology 2006;6:1616–22.)
• Der p 1 exposure resulted in a significant rise of dermal blood flow after 48 h in patients with AD. (Clin Exp Allergy 2006;36:338-45.)
• Der p 1 content in mattresses is not associated with disease activity in patients with AD. (Clin Exp Allergy 1999;29:920–5.)
• No effect was observed in patients with atopic eczema after undertaking HDM avoidance measures. (Lancet 2001;358:188–93.)
House dust mite (HDM)House dust mite (HDM)
Allergen
• Hypothesis– decreasing antioxidant (fruit and vegetables), increased n-6
polyunsaturated fatty acid (PUFA;(margarine, vegetable oil), decreased n-3 PUFA (oily fish) intakes have contributed to the recent increases in asthma and atopic disease. (UK)
• Epidemiologic studies– Dietary changes between dietary antioxidants and lipids : allergic
disease.
– n-6 vs n-3 PUFA metabolism
4-series LT : proinflammatory activity
2- series PGE2: immunomodulatory promotion Th2 phenotype
EPA & DHA : inhibition linoleic acid metabolism , COX-2 gene expression and activity
– Intake during pregnancy and early childhood : area of active investigation.
Nutrients
Diet as a risk factor for atopy and asthmaDiet as a risk factor for atopy and asthma
StressStress
• Increased levels of nerve growth factor and substance P
MicroorganismsMicroorganisms
• S. aureus - secreting toxins called superantigens• Disseminated infections with herpes simplex or vaccinia virus• Smallpox vaccination is contraindicated in patients with AD unless thereis imminent danger of exposure to smallpox• Fungal infections
Irritant factorsIrritant factors
Skin barrier dysfunctionSkin barrier dysfunction
• Dry skin and increased transepidermal water loss• Reduced ceramides, changes in stratum corneum pH levels, overexpression of stratum corneum chymotryptic enzyme
Etc
2. 이차 예방2. 이차 예방
감작된 후의 질병 발생을 억제 한다 .
Allergy prevention
1. 일차예방1. 일차예방
항원에 대해 감작 (IgE-mediated) 이 되지 않도록 하는 것
3. 삼차예방3. 삼차예방
알레르기 질환 발생 후 증상을 경감시킨다 .
Pediatr Allergy Immunol 2004: 15 (Suppl. 16): 9–32
Development of allergic diseaseDevelopment of allergic disease
Allergy Prevention
Primary prevention
Secondary prevention
• Development of the immune system– Lymphocytes in thymus at 8-9 week– IgE in 11 week– T cell migrate into fetal circulation at 15-16 weeks
• Fetal exposure to allergen– Allergen in maternal circulation → placenta by passively
diffusion → fetus– Allergens with maternal IgG actively across the placenta– Allergens are detected in amniotic fluid at 16 week and fetal
circulation at term – Proliferation of fetal cell to allergen in 2nd trimester.
• Cord blood IgE and sensitization– IgE not cross the placenta, low sensitivity, fetal igE– Predisposing factor for atopy
Intrauterine environmentIntrauterine environment
• 태아감작 : 2nd trimeser 태반 통해
• 항원은 수용성 형태 혹은 IgG-complexed 펩타이드 분획형태로 태반을 통과
• 제대혈 T 세포 : 흡인항원이나 식품항원에 모두 증식반응 : 아토피가족력 있거나 후에 아토피가 발생하는 환아에서 더욱 강
한 반응을 보이나 , 비아토피 신생아도 제대혈 T 세포가 항원에 증식반응 ; 모든
신생아 이미 태내에서 항원에 감작이 일어남을 시사
• 임신중 태아와 모체는 Th1 반응이 억제 , 상대적 Th2 우세 반응 : 태아 T 세포가 알레르겐에 노출시 자연스럽게 Th2 반응을
일으킬 수 있는 환경
태내감작의 증거들태내감작의 증거들
Th2 type reactivity before and after
birth.
Th2 type reactivity before and after
birth.
Potential pathway of IgE-mediated antigen focusing occurring via interaction of foetal gastrointestinal tract and
amniotic fluid.
Potential pathway of IgE-mediated antigen focusing occurring via interaction of foetal gastrointestinal tract and
amniotic fluid.
Hypothesis( 엄마의 특이 IgE + 산모를 통한 항원 노출 ) → 두 위험요소가 결합하여 아기의 면역을 Th2 로 유지하게 하여 출생 후 아토피 질환에 영향을 미칠
것이다 .
Holloway JA. Warner JO. Does atopic disease start in foetal life?.
Allergy. 55(1):2-10, 2000
Th2 type reactivity before and after birth.
( Bjorksten,1998 )
Th2 type reactivity before and after birth.
( Bjorksten,1998 )
Primary immune responses to allergens encountered early in life include TH 1- and TH 2-like immunity. ( Bjorksten,1998 )
Primary immune responses to allergens encountered early in life include TH 1- and TH 2-like immunity. ( Bjorksten,1998 )
Allergy Prevention
Correa JMM et alii J Pediatr (Rio J) 2001; 77 (6): 441-46
Allergy Prevention
XXX
Prevention
Primary preventionPrimary prevention
• Prediction of allergy- Allergy genes : 11q13, 5q31-33- Family history : 60-80% in a child born to two allergic patients- Cord blood IgE : 26% sensitive, 74% specific
• Dietary manipulation during pregnancy : peanut avoidance• Breastfeeding : exclusive breastfeeding for 6 mo• Maternal avoidance diets during lactation : peanuts and nuts (consider avoiding eggs, cow’s milk, fish) • Protein hydrolysate formula
Secondary preventionSecondary prevention
• To prevent progression of the “atopic march” : in research
Tertiary preventionTertiary prevention
• Avoidance of offending food, teaching action plan• Allergen avoidance, skin care for atopic dermatitis
Allergy Prevention
05
101520253035404550
위약투여군 LactobacillusGG
3 차원 세로 막 1대형
아토피 유병율
알레르기 질환에서 Lactobacillus GG 투여 효과
31/68(46%)
15/64(23%)
Probiotics in primary prevention of atopic disease, Lancet. 2001;357:1076-9
ProbioticsProbiotics
•장내 세균총의 균형 유지 , 살아있거 나 비활성화시킨 미생물: Lactobacilli, Bifidobacteria•Metchinikoff : 사람의 건강과 장수•위장관 , 알레르기 질환 , 암 : 위장관 면역조절 > 예방및 치료• 장내 항상성 유지• 식품항원에 대한 면역 관용• 위장관 병적세균 제거
Allergy Prevention
Dietary prevention recommendations/comments from several professional organizationsDietary prevention recommendations/comments from several professional organizations
J Allergy Clin Immunol 2008;122:29-33
Allergy Prevention
• 임신 3 기 , 계란 우유 섭취 제한- 알레르기 질환의 예방효과 미약- 영양면 체중감소 등 부작용
• 미국 (AAP), 유럽- 필수 영양소 섭취 제한의 알레르겐 회피식은 권유되지 않는다 .
• 땅콩 : 태아감작으로 출생후 땅콩알레르기 발생 , 고위험군 산모에서 제한 권유 (AAP), 최근 연구 결과는 차이 없다 쪽으로
임신중 모체의 식이제한임신중 모체의 식이제한
Allergy Prevention
Dietary preventionDietary prevention
Studies
• A birth cohort study consisting of a baseline of 4,146 frequency of consumption of fruit, vegetables, fish, egg, milk, milk products, nuts, and nut products during the last month followed until 8 years of age assess associations between maternal diet during pregnancy and childhood asthma outcomes over 8 years. an increased risk of daily versus rare consumption of nut products during pregnancy on childhood asthma outcomes Am J Respir Crit Care Med Vol 178. pp 124–131, 2008
• 2641 children at 2 y of age, German prospective birth cohort study (LISA) Maternal diet during the last 4 wk of pregnancy, a semiquantitative food-frequency questionnaire
Intake of allergenic foods and foods rich in n6 polyunsaturated fatty acids during pregnancy may increase and foods rich in n3 polyunsaturated fatty acids may decrease the risk of allergic diseases in the offspring Am J Clin Nutr 2007;85:530 –7
Studies
• To investigate the relationship between allergen specific cord blood (CB) IgE levels, parental sensitization, CB cytokine production, and environmental influences.• 922 neonates, 922 mothers, and 835 fathers
allergen-specific IgE antibodies against 20 common seasonal, perennial, and food allergens Supernatants from stimulated CB cells, the production of IL-5, IFN-g, IL-10, and TNF-a. Contamination with maternal serum was excluded by several means of analyses, including the absence of IgA antibodies
Allergen-specific IgE antibodies were detectable in 23.9% of newborns Clear correlation between maternal and fetal IgE was found only for hen’s egg, cow’s milk, and soybean allergen Fetal IgE correlated negatively with the level of IFN-g production Conclusion: Allergen-specific IgE antibodies most probably of fetal origin are detectable in CB and correlate with a lowered CB IFN-g production
(J Allergy Clin Immunol 2008;122: 711-6.)
I Pregnancy: physiological T helper type 2 priming; intrauterine allergen exposure.II Neonatal period: the establishment of gut microbiota and neonatal antigen exposure. III Critical windowcounterregulatory mechanisms.IV Early symptoms of allergic disease: V Fully established allergic disease: European journal of gastroenterology & hepatology17(12), December 2005
Allergen free
Nutrients
Conclusions Individual variation in the responses to foods & aeroallergens. : high- risk group.
Dietary antioxidant & lipid intake during pregnancy : immunomodulation effect,
Limits the ability to draw firm conclusions regarding pregnancy and lactation avoidance diets and the timing of introducing specific allergenic foods : lack of convincing evidence.
Further research : in particular the role of dietary intervention to individual susceptibility
Allergy Prevention