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1 pissn: eissn: (2):73-78, March ORIGINAL ARTICLE 아토피피부염환아에서혈청페리오스틴과편평상피암항원 최우혁, 박태영, 김수영, 유리타미영, 반지은, 양승, 황일태, 백혜성 한림대학교강동성심병원소아청소년과 Serum periostin levels and squamous cell carcinoma-related antigen levels in children with atopic dermatitis Woo-Hyeok Choi, Tae-Young Park, Su-Yeong Kim, Rita Yu, Ji-Eun Ban, Seong Yang, Il-Tae Hwang, Hey-Sung Baek Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, Seoul, Korea Purpose: It was found that periostin and squamous cell carcinoma-related antigens (SCCAs) were strongly interleukin-13-inducible gene products. This study measures the serum periostin and SCCA levels in children suffering from atopic dermatitis (AD) and to evaluate the association between the severity of AD and their values. Methods: Seventy AD children aged 1 month to 10 years were included in our study. Subjects were characterized as having atopic eczema (AE; n= 55) or non-ae (NAE; n= 15) by atopic sensitization. Serum SCCA and periostin levels were measured. Results: The serum periostin levels were significantly higher in children with AE than in those with NAE (geometric mean [95% confidence interval]: ng/ml [ ng/ml] vs ng/ml [ ] ng/ml, P= 0.020). The serum concentrations of both SCCA1 and SCCA2 were significantly higher in children with AE than in those with NAE (geometric mean [95% confidence interval]: [ ] ng/ml vs [ ] ng/ml, P= for SCCA1) (1.178 [ ] ng/ml vs [ ] ng/ml, P= for SCCA2). The serum periostin levels were significantly correlated with disease severity and with peripheral blood eosinophil counts. The SCCA levels were not significantly correlated with disease severity. Both SCCA1 and SCCA2 were significantly correlated with serum periostin levels and blood eosinophil counts. Conclusion: Serum periostin levels may be significantly correlated with disease severity and blood eosinophil counts in children with AD. Serum SCCA levels can be significantly correlated with serum periostin levels and blood eosinophil counts in children with AD. ( 2017:5:73-78) Keywords: Atopic dermatitis, Periostin, Squamous cell carcinoma-related antigens, Child 서론 아토피피부염은소아에서가장흔한만성재발성피부질환으로 건조한피부와심한소양증을특징으로하며그유병률이과거에 비해현저히증가하고있다. 1 아토피피부염은 Th2 형 T 세포반응을 특징으로하는알레르기와매우깊은관련성이있는피부의염증 성질환으로, interleukin (IL)-4, IL-5, IL-13 과같은 Th2 cytokines 이높게발현되는데, 이들에의해유도된호산구와 IgE 의증가가아 토피피부염의주요한특징이다. 2-4 아토피피부염의병태생리에는 Th1 형면역반응또한관여한다. 5,6 일반적으로급성아토피피부염 Correspondence to: Hey-Sung Baek Department of Pediatrics, Hallym University Kangdong Sacred Heart Hospital, 150 Seongan-ro, Gangdong-gu, Seoul 05355, Korea Tel: , Fax: , paviola7@hanmail.net This research was supported by Hallym University Kangdong Sacred Heart hospital Research Fund (grant number: ). Received: August 16, 2016 Revised: October 12, 2016 Accepted: October 15, 2016 환자의피부병변에는 Th2 형세포의수가증가되고, 심한가려움증, 홍반성구진, 줄까짐등이관찰되나, 5,6 만성아토피피부염환자의 피부병변에서는 Th1 형세포수가증가되어있고, 발병전에비해피 부가건성으로변하고피부주름이뚜렷하며태선화와, 결절성발 진양상을보이며가려움을동반한다. 세포외기질단백질 (extracellular matrix protein) 중의하나인페 리오스틴은조직과기관의구조를유지하는데기여하고병적조건 에서는섬유화에관여한다. 7,8 Masuoka 등 9 은페리오스틴이아토피 피부염환자의피부조직과혈청에서높게발현되고아토피피부염 의중증도, 조직내림프구, epidermal thickness 와연관됨을보고하 2017 The Korean Academy of Pediatric Allergy and Respiratory Disease The Korean Academy of Asthma, Allergy and Clinical Immunology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( 73

2 Choi WH, et al. Serum periostin levels and SCCA levels in children with AD 였다. 또한마우스모델에서집먼지진드기추출액으로피부를감작시켰을때페리오스틴단백질이대량으로만들어진다는것을확인하였고, 생성된페리오스틴은다시피부각질세포의기능적페리오스틴수용체인 αv integrin에작용하여 proinflammatory cytokine 생성을유도하고이는 Th2형면역반응을가속화하는것을밝혔다. 편평상피암항원 (squamous cell carcinoma antigen, SCCA) 은원래사람의자궁경부편평상피암세포에서추출되었으며, 10 다양한편평상피암에서높은농도로검출되기때문에종양표지자로이용되고있다. Yuyama 등 11 은 SCCA1과 SCCA2가 IL-4 또는 IL-13 에의해유도된유전체임을밝혔고, 혈청 SCCA 수치는천식, 알레르기비염, 아토피피부염환자에서증가되어있음을발표하였다 아토피피부염진단에특이적이거나중증도를반영하는생물학적지표는없으며, 면역반응이아토피피부염중증도에기여하는지여부는논란의여지가있다. 이번연구는아토피피부염소아의혈청에서페리오스틴과 SCCA를측정하고아토피피부염중증도와연관성이있는지알아보고자하였다. 의크기로정의하였다. 팽진의크기가 3 mm 이상이면서양성대조보다큰경우를양성으로정의하였고한가지이상의항원에양성을보인경우를아토피양성으로판정하였다. 2) 혈청특이항체치측정대상자들에서집먼지진드기 (Dermatophagodes farinae) 와계란흰자, 우유, 밀가루, 땅콩, 콩 6종에대한혈청특이 IgE 항체치를 ImmunoCAP system (Phadia AB, Uppsala, Sweden) 으로측정하였고, 제조사가제시한기준인특이 IgE 항체수치 0.35 ku/l 이상인경우양성반응으로정의하였으며, 한가지이상의항원에양성을보인경우를아토피양성으로판정하였다. 3. 혈청 biomarker 측정효소면역측정법 (enzyme-linked immunosorbent assay) 에의한혈액내페리오스틴, SCCA1, SCCA2를일본에소재한 Shino test (Kanagawa, Japan) 에서각각측정하였다. 11,17 대상및방법 1. 대상 2012년 9월부터 2014년 9월까지한림대학교강동성심병원소아청소년과알레르기클리닉을방문한아토피피부염환아 70명을대상으로하였다. 아토피피부염진단은 Hanifin and Rajka Criteria에근거하였다. 15 아토피피부염의중증도는 SCORing Atopic Dermatitis (SCORAD) Index를이용하여평가하였다. 16 대상환아들의아토피병력과가족력, 알레르기약제투약력등을조사하였다. 모든과정은한림대학교강동성심병원임상연구심의위원회의승인을받았다 ( 승인번호 : ). 2. 알레르기검사기본알레르기검사로서혈청총 IgE 수치, 말초혈액호산구수를측정하였다. 1) 피부반응시험대상자들에서흔한흡입성알레르겐중집먼지진드기 2종 (Dermatophagodes pteronyssinus 과 Dermatophagodes farinae), 개상피와고양이상피, 자작나무 (Birch), 돼지풀, 곰팡이 1종 (alternaria) 과흔한식품알레르겐인계란흰자, 우유, 밀가루, 땅콩, 콩을포함하여돼지고기, 닭고기, 소고기, 새우, 대구, 호두, 개암나무열매, 감자, 셀러리, 토마토, 사과, 복숭아 (Allergopharma, Reinbek, Germany) 에대한피부반응시험 (skin prick test, SPT) 을시행하였다. 알레르겐에의한팽진 (wheal) 의장경과장경의중간지점에서수직으로교차하는지점의단경을측정하여이들을평균한값을팽진 4. 통계분석통계적분석은 IBM SPSS ver (IBM Co., Armonk, NY, USA) 을이용하였다. 두군간의비교에서연속형변수는 Mann- Whitney검사로분석하였다. 범주형변수는 chi-square test를수행하였고 number (%) 로표현하였다. 측정치는정규분포를따르는경우평균 ± 표준편차, 정규분포를따르지않는경우기하평균 (95% 신뢰구간 ) 으로표현하였다. 페리오스틴, SCCA1 및 SCCA2와말초혈액호산구수, 혈청총 IgE, 호산구음이온단백, SCORAD index 와의연관성은 Spearman correlation coefficients 를구하였다. 페리오스틴, 혈청총 IgE는정규분포를따르지않아로그값을구하여분석하였다. 페리오스틴로그값과 SCORAD index연관성은연령, 혈청총 IgE, 말초혈액호산구수를보정하여선형회귀분석을실시하였고추정매개변수를구하였다. P 값이 0.05 미만일때통계적으로유의하다고판정하였다. 결과 1. 대상자의특징, 아토피표지연구에포함된 70명의아토피피부염소아중, 피부반응시험또는혈청특이항체치측정에서아토피양성을보인외인성아토피피부염소아는 55명 (78.6%), 음성을보인내인성아토피피부염소아는 15명 (21.4%) 이었다. 두아토피피부염군간에평균연령, 성별은차이가없었다 (Table 1). SCORAD index는내인성아토피피부염군에비해외인성아토피피부염군에서통계적으로유의하게높았다 (37.67±13.29 vs ±9.16, P < 0.001) (Table 1). 알레르기지표로서혈청총 IgE (geometric mean [95% confidence interval]:

3 최우혁외 아토피피부염환아에서혈청페리오스틴과편평상피암항원 [ ,545.6] IU/mL vs [ ] IU/mL, P<0.001) (Table 1), 말초혈액호산구 (581.3±519.6/μL, vs ±150.7/μL, P < 0.001) (Table 1), 호산구음이온단백 (geometric mean [95% confidence interval]: [ ] ng/ml vs [ ] ng/ml, P<0.001) (Table 1) 은내인성아토피피부염군에비해외인 성아토피피부염군에서통계적으로유의하게높았다. 2. 혈청페리오스틴과 SCCA 혈청페리오스틴은내인성아토피피부염군에비해외인성아토 피피부염군에서통계적으로유의하게높았다 (geometric mean [95% confidence interval]: ( ) ng/ml vs ( ) ng/ml, P = 0.020) (Table 1, Fig. 1). 혈청 SCCA1 (geometric mean [95% confidence interval]: [ ] ng/ml Table 1. Characteristics of the subjects included in the study Characteristic AE (n= 55) NAE (n= 15) P-value Age (yr) 5.1± ± * Male sex (%) SCORAD Index 37.67± ± 9.16 < 0.001* PB eosinophil (/μl) 581.3± ± < 0.001* ECP (ng/ml) ( ) 15.2 ( ) < 0.001* Total IgE (IU/mL) ( ,545.6) 35.2 ( ) < 0.001* Periostin (ng/ml) ( ) ( ) 0.020* SCCA1 (ng/ml) ( ) ( ) 0.039* SCCA2 (ng/ml) ( ) ( ) 0.025* Values are presented as mean± standard deviation or geometric mean (95% confidence interval) unless otherwise indicated. AE, Atopic eczema; NAE, nonatopic eczema; SCORAD, SCORing Atopic Dermatitis; PB, peripheral blood; ECP, eosinophilic cationic protein; SCCA, squamous cell carcinoma antigen. *Mann-Whitney test. Chi-square test. P= vs [ ] ng/ml, P = 0.039) 과 SCCA2 (1.178 [ ] ng/ml vs [ ] ng/ml, P = 0.025) 모두내인 성아토피피부염군에비해외인성아토피피부염군에서통계적으 로유의하게높았다 (Table 1, Fig. 2). 3. 혈청페리오스틴, SCCA 와아토피피부염의중증도, 아토피 Serum periostin (ng/ml) 표지자와의관계 혈청페리오스틴은아토피피부염환아에서연령과의미있는음 의상관관계를보였고 (r = , P = 0.001) (Table 2), 말초혈액호 산구수 (r = 0.323, P = 0.007) (Table 2), SCORAD index (r = 0.335, P = 0.005) (Table 2) 와통계적으로의미있는양의상관관계를보였 AE (n=55) P= NAE (n=15) Fig. 1. Serum periostin levels were significantly higher in children with atopic eczema (AE) than in children with nonatopic eczema (NAE). P= Serum SCCA1 (ng/ml) AE (n=55) NAE (n=15) Serum SCCA2 (ng/ml) AE (n=55) NAE (n=15) Fig. 2. Serum concentrations of both SCCA1 (A) and SCCA 2 (B) were significantly higher in children with atopic eczema (AE) than in children with nonatopic eczema (NAE). SCCA, squamous cell carcinoma antigen. 75

4 Choi WH, et al. Serum periostin levels and SCCA levels in children with AD Table 2. Spearman correlation coefficients between age, SCORAD index, markers of atopy, periostin, SCCA1, and SCCA2 Variable Periostin SCCA1 SCCA2 r P-value r P-value r P-value Age < < SCORAD index Total IgE PB eosinophil ECP Periostin < SCORAD, SCORing Atopic Dermatitis; PB, peripheral blood; ECP, eosinophilic cationic protein; SCCA, squamous cell carcinoma antigen. r = Spearman correlation coefficient. Table 3. Multiple linear regression models for SCORAD in the study Variable 다. 혈청페리오스틴은호산구음이온단백, 혈청총 IgE 와는통계 적으로의미있는상관관계가없었다. 선형회귀분석을실시하였고 연령, 말초혈액호산구수, 혈청총 IgE 를보정하였을때 log 페리오 스틴은 SCORAD index 와통계적으로의미있는상관관계가있었 다 (Estimate , P = 0.004) (Table 3). 혈청 SCCA1, SCCA2 는모두혈청페리오스틴과통계적으로의 미있는양의상관관계를보였다 (r = 0.393, P = for SCCA1; r = 0.428, P<0.001 for SCCA2) (Table 2). 혈청 SCCA1, SCCA2 는 모두연령과통계적으로의미있는음의상관관계를보였고 (r = P<0.001 for SCCA1; r = , P<0.001 for SCCA2) (Table 2), 말초혈액호산구수와통계적으로의미있는양의상관관계 를보였다 (r = 0.393, P = for SCCA1; r = 0.328, P = for SCCA2) (Table 2). 혈청 SCCA1, SCCA2 모두혈청총 IgE, 호산구 음이온단백과는의미있는상관관계가없었다. 고찰 본연구에서는아토피피부염소아의혈청에서페리오스틴과 SCCA 를측정하였고, 아토피피부염중증도와의연관성을알아보 았다. 혈청페리오스틴은외인성아토피피부염환자에서내인성아 토피피부염환자보다통계적으로의미있게증가되어있었고아토 피피부염의중증도와연관성이있었다. SCORAD index Estimate 95% CI P-value* Age Total IgE PB eosinophil Log periostin level SCORAD, SCORing Atopic Dermatitis; CI, confidence interval; PB, peripheral blood. *P-values were computed using a regression model evaluating differences of estimates (slopes) from zero. 아토피피부염이나천식과같은알레르기질환의발생을촉발하 는알레르기항원은수지상세포 (Dendritic cell), 호염기구또는상피세포로구성되는고유면역계에의해인식되고, 이어서 Th2형반응이주가되는후천면역반응이활성화된다. 9,18,19 일반적으로, 지속적으로외인성알레르기항원에노출되는경우에알레르기질환이만성화되는것으로이해하고있지만이에관한정확한기전은알려져있지않다. 그리고알레르기질환의병소는면역계세포들이비면역계세포인상피세포, 섬유아세포, 내피세포및평활근세포등에의해둘러싸여있는형태로나타난다. 면역계세포들과비면역계세포들간에는상호작용이존재하며, 그러한상호작용이알레르기염증반응에서중요한역할을수행할수있을것으로생각되나구체적으로이들이어떻게상호작용하고비면역계세포들이알레르기질환의발병에어떤형태로기여하는지는아직명확하지않다. Masuoka 등 9 은마우스모델에서집먼지진드기추출액으로피부를감작시켰을때페리오스틴단백질이진피 (dermis) 에서발현되고페리오스틴이다시 pro-inflammatory cytokine 생성을유도하여 Th2형면역반응을가속화하는것을발견하여비면역계세포에서유도된페리오스틴이면역반응을가속하고이는다시페리오스틴을유도하여면역계세포와비면역계세포가상호작용하고염증의만성화에기여하는것을제시하였다. 또한, 페리오스틴과수용체의결합을막는항체를실험용쥐에투여한뒤집먼지진드기추출물을마우스피부에바르면아토피피부염이일어나지않는다는사실을확인하였다. 이번연구에서저자들은혈청페리오스틴이외인성아토피피부염환아에서내인성아토피피부염환아보다통계적으로유의하게증가되어있음을확인하였다. 또한, 혈청페리오스틴은말초혈액호산구수와통계적으로의미있는양의상관관계를보였다. 하지만혈청페리오스틴이혈청총 IgE와유의한상관관계를보였던 Izuhara 그룹과는다르게, 20 이번연구에서는통계적으로의미있는상관관계를보이지못했다. 이는이번연구에포함된환자수가적어좀더대규모연구가필요할것으로생각한다. 페리오스틴은세포외기질단백으로조직과기관의구조유지에작용하여 7,8 골전환율 (bone turnover) 과성장이빠른소아에서는수치가높을것으로예 76

5 최우혁외 아토피피부염환아에서혈청페리오스틴과편평상피암항원 상된다. 1세에서 10세사이의아토피피부염환자를대상으로한이번연구에서혈청페리오스틴은연령과의미있는음의상관관계를보여어린영아일수록페리오스틴값이높았다. 아토피피부염중증도와페리오스틴과의상관관계를알기위해연령, 말초혈액호산구수, 혈청총 IgE 등의영향인자를보정하였고보정후에도아토피피부염중증도와페리오스틴수치는통계적으로유의한양의상관관계를보였다. 대규모추가적인연구가필요할것이지만혈청페리오스틴측정은아토피피부염중증도를평가하는데도움이될수있으리라생각한다. SCCA1과 SCCA2는사람의자궁경부편평상피암세포에서유래되었으며 SCCA1과 SCCA2는동족체 (homologous) 로아미노산농도 (amino acid concentration) 가 91% 일치한다. SCCA1과 SCCA2 는뚜렷한특징과기질특이성을갖는데 SCCA1은 papain-like cysteine proteases (papain, cathepsin-s, -K and -L) 를억제하는반면 SCCA2는 serine proteases (cathepsin G and mast cell chymase) 와 cysteine proteases (Der p 1 and Der f 1, major mite antigens) 모두를억제한다. 21 Yuyama 등 11 은이전연구에서기관지상피세포에 IL-13 혹은 IL-4를처리하면 SCCA 유전자인 SERPINB3와 SER- PINB4의발현이다른유전자보다훨씬높게증가하는것을보고하였다. 연구자들은천식환자뿐만아니라아토피피부염환자의피부병변에서 IL-4와 IL-13이각질세포 (keratinocyte) 에작용하여 SCCA 유전자인 SERPINB3와 SERPINB4 발현을증가시키고, SCCA가분비됨을밝혔고, 아토피피부염환자의혈청 SCCA level 이통계적으로유의하게아토피피부염중증도와연관됨을확인하여 Th2형염증이아토피피부염의임상적중증도를조절하고 SCCA가 Th2형염증과임상적중증도를반영하는아토피피부염의생체지표로적합하다고제시하였다. 13,22 이번연구에서저자들은혈청 SCCA1, SCCA2 모두외인성아토피피부염군에서내인성아토피피부염군보다통계적으로유의하게증가되어있음을확인하였고 SCCA1, SCCA2 모두혈청페리오스틴, 말초혈액호산구수와통계적으로의미있는상관관계가있음을확인하였다. 하지만이번연구에서혈청 SCCA는 SCORAD, 즉, 아토피피부염중증도와혈청총 IgE와는통계적으로의미있는상관관계가없었고호산구음이온단백과도상관관계가없었으므로아토피피부염의생물학적지표로서 SCCA 측정은좀더많은연구가필요하리라생각한다. 이번연구의한계점으로는정상대조군이없었고대상자수가 70 명으로비교적많지않았다. 그러나아직국내아토피피부염환자에서혈청페리오스틴과 SCCA를측정한연구는없으므로임상적의미가있다. 앞으로페리오스틴과 SCCA, 그리고아토피피부염의상관관계를더욱명확하게하기위해서는치료에따른혈청페리오스틴, SCCA 측정치변화와대규모전향적무작위연구가필요할것으로생각한다. 결론적으로혈청페리오스틴은아토피피부염의중증도를반영 하고, 이는페리오스틴이아토피피부염의병리적기전이해및예후 제시등에중요한역할을할수있을것을시사한다. SCCA1, SCCA2 는비록이번연구에서는아토피피부염의중증도와관련성 을보여주지는못하였지만, 모두외인성아토피피부염환자에서내 인성아토피피부염환자보다증가되어있었고, 혈청페리오스틴과 도의미있는상관관계를보여역시아토피피부염의병리적기전이 해에중요한역할을할수있을것으로보인다. REFERENCES 1. Asher MI, Montefort S, Björkstén B, Lai CK, Strachan DP, Weiland SK, et al. Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys. Lancet 2006;368: Hamid Q, Boguniewicz M, Leung DY. Differential in situ cytokine gene expression in acute versus chronic atopic dermatitis. J Clin Invest 1994; 94: Hamid Q, Naseer T, Minshall EM, Song YL, Boguniewicz M, Leung DY. In vivo expression of IL-12 and IL-13 in atopic dermatitis. J Allergy Clin Immunol 1996;98: Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol 2003;112: Leung DY, Boguniewicz M, Howell MD, Nomura I, Hamid QA. New insights into atopic dermatitis. J Clin Invest 2004;113: Grewe M, Bruijnzeel-Koomen CA, Schöpf E, Thepen T, Langeveld-Wildschut AG, Ruzicka T, et al. A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today 1998;19: Kii I, Amizuka N, Minqi L, Kitajima S, Saga Y, Kudo A. Periostin is an extracellular matrix protein required for eruption of incisors in mice. Biochem Biophys Res Commun 2006;342: Kikuchi Y, Kashima TG, Nishiyama T, Shimazu K, Morishita Y, Shimazaki M, et al. Periostin is expressed in pericryptal fibroblasts and cancer-associated fibroblasts in the colon. J Histochem Cytochem 2008;56: Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, et al. Periostin promotes chronic allergic inflammation in response to Th2 cytokines. J Clin Invest 2012;122: Kato H, Torigoe T. Radioimmunoassay for tumor antigen of human cervical squamous cell carcinoma. Cancer 1977;40: Yuyama N, Davies DE, Akaiwa M, Matsui K, Hamasaki Y, Suminami Y, et al. Analysis of novel disease-related genes in bronchial asthma. Cytokine 2002;19: Nishi N, Miyazaki M, Tsuji K, Hitomi T, Muro E, Zaitsu M, et al. Squamous cell carcinoma-related antigen in children with acute asthma. Ann Allergy Asthma Immunol 2005;94: Mitsuishi K, Nakamura T, Sakata Y, Yuyama N, Arima K, Sugita Y, et al. The squamous cell carcinoma antigens as relevant biomarkers of atopic dermatitis. Clin Exp Allergy 2005;35: Suzuki K, Inokuchi A, Miyazaki J, Kuratomi Y, Izuhara K. Relationship between squamous cell carcinoma antigen and the clinical severity of allergic rhinitis caused by Dermatophagoides farinae and Japanese cedar pollen. Ann Otol Rhinol Laryngol 2010;119: Hanifin JM, Rajka, G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980;92: Severity scoring of atopic dermatitis: the SCORAD index. Consensus Re- 77

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ÀÇÇÐ°�ÁÂc00Ì»óÀÏ˘ Common Allergic Diseases in Children Sang - Il Lee, M.D. Department of pediatrics Sungkyunkwan University School of Medicine, Samsung Medical Center E - mail : silee@smc.samsung.co.kr Abstract Allergy