김현정외 아토피피부염과피부장벽이상 Allergy Asthma Respir Dis 물리적장벽, 지질, 산, 리소좀, 항균펩타이드 (antimicrobial peptide) 로구성된화학적 / 생화학적장벽, 감염성질환에대한면역장벽등이있다. 또한편으로는과거각질층의구조적인특성에

pissn: 2288-0402 eissn: 2288-0410 Allergy Asthma Respir Dis 1(1):20-28, March 2013 http://dx.doi.org/10.4168/aard.2013.1.1.20 REVIEW ARTICLE 아토피피부염과피부장벽이상 김현정 1, 신정우 2, 이광훈 2 1 서울의료원피부과 아토피천식센터및의학연구소아토피연구실, 2 연세대학교의과대학피부과학교실및피부생물학연구소 Atopic dermatitis and skin barrier dysfunction Hyunjung Kim 1, Jung U Shin 2, Kwang Hoon Lee 2 1 Department of Dermatology, Atopy and Asthma Center, Medical Research Institute, Seoul Medical Center, Seoul; 2 Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, Seoul, Korea Atopic dermatitis is a chronic relapsing eczematous dermatosis, which usually starts in childhood, and various causes are intricately associated with the development of the disease. Recently, various abnormalities in barrier function have been identified as the cause of atopic dermatitis. Loss-of-function mutation of filaggrin, a significant constituent of skin barrier, has been revealed as a cause for atopic dermatitis, and factors like enhanced protease activity, and decreased synthesis of the lipid lamellae especially ceramides also plays an important role in barrier dysfunction. Not only these genetic causes but also environmental factors are associated in barrier dysfunction, such as soap or detergents which increases skin ph, or proteases of dust mites or cockroaches which enhances epidermal barrier breakdown. Lately, skin barrier dysfunction is also thought to play an important role in the early stage of other allergic diseases such as asthma. Therefore, comprehension of the function of skin barrier can provide help in understanding various allergic diseases. (Allergy Asthma Respir Dis 1(1):20-28, 2013) Keywords: Atopic dermatitis, Skin barrier, Filaggrin, Ceramide 서론아토피피부염은알레르기비염이나천식과같은다른아토피질환과자주동반되는건조증, 소양증, 홍반성습진을특징으로하는만성염증성피부질환이다. 아토피피부염의원인은유전적인소인과환경적인원인, 면역학적이상반응과피부장벽의이상등이주요발병원인으로생각되고있다. 여기에두가지가설이크게대두되고있다. 하나는일차적인면역학적이상으로말미암아특정알레르겐에대한면역글로불린 E(immunoglobulin E) 감작이일어나서혈청면역글로불린 E를상승시키고제2형보조 T세포활성, 수지상세포, 호산구등의활성이일어난후염증반응의결과로피부장벽의이상을초래한다는설 (inside-outside 가설 ) 이고또하나는일차적으로피부장벽의이상을일으키는유전적변이가선행되고그로인해면역학적변화가발생한다는설 (outside-inside 가설 ) 이다. 1) 면역학의발달과함께최근까지도아토피피부염의주된연구 방향은면역이상에초점이맞추어져있었다. 2) 그러나모든환자에서알레르겐에대한감작을비롯한면역반응의이상이나타나는것이아니기때문에이에대한보충설명이필요하였으며 1990년대에이르러 Elias 등 3) 과 Taieb 4) 는피부장벽의손상이아토피피부염발병의초기기전임을처음제시하였다. 이종설에서저자들은최근까지밝혀진피부장벽의미세구조및기능과함께아토피피부염의발병기전에관여하는구체적인피부장벽의이상들에대해기술하고자한다. 피부장벽의구조와기능피부는인체의가장외부에존재하는기관으로체내수분을보호하고외부침입인자 ( 항원, 감염원등 ) 의내부침입을보호하는필수적인장벽기능을수행한다. 피부는장벽기능에따른몇가지장벽을보유하고있다. 즉, 피부각질층, tight junction으로구성된 Correspondence to: Kwang Hoon Lee Department of Dermatology, Cutaneous Biology Research Institute, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 120-749, Korea Tel: +82-2-2228-2080, Fax: +82-2-393-9157, E-mail: kwanglee@yuhs.ac This work was supported by National Research Foundation of Korea Grant funded by the Korean Government (2011-0016636). Received: March 4, 2013 Accepted: March 25, 2013 20 2013 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 (http://creativecommons.org/licenses/by-nc/3.0/). http://www.aard.or.kr

김현정외 아토피피부염과피부장벽이상 Allergy Asthma Respir Dis 물리적장벽, 지질, 산, 리소좀, 항균펩타이드 (antimicrobial peptide) 로구성된화학적 / 생화학적장벽, 감염성질환에대한면역장벽등이있다. 또한편으로는과거각질층의구조적인특성에근거한 brick and mortar 로대변되는피부각질층개념 5) 에서최근에는 tight junction, 6,7) 랑게르한스세포의항원제시반응에근거한새로운피부장벽의개념이도입되면서, 이제는공기- 액체장벽 (airliquid barrier) 으로서의각질층의기능을설명하는피부장벽, 액체-액체장벽 (liquid-liquid barrier) 으로서 tight junction 단백질에의한피부장벽, 면역장벽 (immune barrier) 인랑게르한스세포네트워크로설명되는통합적인피부장벽의개념이제시되고있다. 8) 1. 물리적장벽 1) 각질층 (stratum corneum) 피부각질층은약 10 20 μm 두께의구조물로서체내수분손실방지와외부유해물질의침입을막아주는장벽기능에있어가장중요한역할을담당한다. 기저층 (stratum basale) 에서유래한각질형성세포 (keratinocyte) 가증식과최종분화를통해각질세포 (corneocyte) 로변화하게되며, 각질세포는각질층내에존재하는다양한단백질분해효소 (protease) 에의해궁극적으로탈락하게된다. 이러한분화과정중최종단계에서다양한단백질과지질이생성되며, 이렇게생성된각질층의구조와기능을 brick and mortar 모델로설명할수있다. 9) Brick and mortar 모델은약 40% 의단백질, 20% 의지질과수분으로이루어진각질층을각질세포는벽돌로, 각질세포간지질 (intercellular lipids) 을회반죽으로비유하여설명하고있다. 이외에각질세포를연결하는단백질구조체인각질교소체 (corneodesmosome) 와각질세포를둘러싸고있는각질세포단백질외막 (cornified protein envelope) 과각질세포지질외막 (cornified lipid envelope) 등이각질층을구성하고있는대표적인성분이다. 10,11) (1) 각질세포 (Corneocyte) 각질형성세포는표피세포의 95% 를차지하는구성성분이며표피는보통기저층, 가시층 (stratum spinosum), 과립층 (stratum granulosum), 각질층의 4층으로나뉘어져있다. 각질형성세포는기저층에서상층부인과립층으로올라갈수록최종분화과정을거치게된다. 분화과정을통하여각질형성세포내의케라틴중간미세섬유 (keratin intermediate microfilament) 가증가하고, 분화단백질이집중되어있는세포내소기관인각질유리과립 (keratohyalin granule) 과각질세포간지질및기타단백질이포함되어있는층판소체 (lamella body) 가형성된다. 각질형성세포가과립층에서각질층으로이동하면서납작한모양의핵이없는각질세포로변형되고케라틴을포함한각질유리과립내의단백질이세포질내의다른단백질과교차결합되어각질세포를둘러싸는각질세포외막이형성된다 (Fig. 1A). 11) 이각질세포외막은약 10 nm 두께의각질세포단백질외막 (cornified protein envelope) 과 5 nm 두께의각질세포지질외막 (cornified lipid envelope) 으로이루어져있다 (Fig. 1B). 각질세포단백질외막은물리적장벽의역할을담당하며 involucrin, loricrin, trichohyalin, small proline-rich proteins 등의단백질이교차결합되어형성된다 (Fig. 1C). 12,13) 각질세포지질외막은각질세포내에존재하는 involucrin 을주축으로하는각질세포단백질외막을구성하는단백질이각질세포외부의지질중 ω-hydroxyceramid와의공유결합으로연결되면서생성되는지질막이다. 14) 각질세포지질외막은각질세포간지질의다중층상구조형성을유도하는비계 (scaffold) 역할을하면서완전한피부장벽구조를형성 Stratum corneum Corneodesmosome Tight junction Cornified lipid envelope Cornified protein envelope Lipid depeleted corneocyte Lipid bilayers Stratum granulosum Lamellar body B Stratum spinosum Stratum basale A Lipid Involucrin Loricrin SPR Keratin Filaggrin C Fig. 1. Normal skin anatomy. (A) Normal skin is composed of five distinct layers: stratum basale, stratum spinosum, stratum granulosum, and stratum corneum. Among these five parts, the uppermost layer stratum corneum is responsible for skin barrier s function and supplements the functions of tight junction in the granular layer. (B) The brick and mortar model. When the granular layer is observed closely, it is composed of stacked up bricks of corneocytes made up of proteins and lipids surrounded by lipid-renriched intercellular matrix like a mortar. (C) The cornified envelope. The protein layer of the cornified envelope is composed of proteins such as involucrin, loricrin, and small proline-rich (SPR). Filaggrin, which binds keratin fibers, also plays an important role in the skin barrier function. The lipid layer of corneocyte is usually composed of lipid substances that are attached to involucrin. http://dx.doi.org/10.4168/aard.2013.1.1.20 21

Allergy Asthma Respir Dis Kim H, et al. Atopic dermatitis and skin barrier dysfunction Alkaline soap ph SP PAR2 Pro-IL-1 TSLP ll-1 Th2 cytokine Inflammation DSG Corneodesmosome SC cohesion Filaggrin PAR2 b-glucocerebrosidase Acid sphingomyelinase Lamellar body secretion Ceramide Permeability barrier Osmolytes SC hydration Fig. 2. Atopic dermatitis pathogenesis model based on filaggrin deficiency. SP, serine protease; PAR2, protease activated receptor 2; TSLP, thymic stromal lymphopoietin; DSG, desmoglein; SC, stratum corneum. 하도록한다. 각질세포외막과케라틴중간미세섬유를연결하는중요한역할을하는단백질중하나인 filaggrin은최근아토피피부염의유전적소인중하나로주목을받고있다. 정상적인피부에서 filaggrin은전구체인 profilaggrin 의형태로각질유리과립내에존재하다가단백질분해효소에의해분해되고, 이후탈인산화를거쳐 filaggrin이된다. Filament aggregating protein 이라는이름에서알수있듯이 filaggrin은케라틴을서로붙게하는접착제의역할을하여케라틴섬유들은견고하게붙게되고궁극적으로각질세포의형태도점점평평해지면서피부장벽의강력한물리적인지지력에기여하게된다. 15) Filaggrin은 Peptidylarginine deiminase isoforms 1과 3에의해탈아미노산화가일어나면케라틴중간미세섬유에의한접착력이떨어지고분리된 filaggrin 단위체는 caspase14, calpain, bleomycin hydrolase 등에의해최종분해산물인 pyrrocarboxylic acid (PCA) 나 trans-urocanic acid (UCA) 등의아미노산으로분해된다. 이는천연함습인자 (natural moisturizing factor) 로서피부보습을유지하는기능과함께각질층의약산성을유지하고, 자외선에의한손상으로부터피부를보호하는기능을한다. 16) 이러한 filaggrin이유전적변이나후천적요인으로감소되었을때피부장벽에초래할수있는이상을 Fig. 2에나타내었다. (2) 표피지질 (epidermal lipid) 각질형성세포의최종분화를통하여나타나는세포소기관인층판소체는가시층에서나타나기시작하여과립층에서가장많이존재한다. 17) 층판소체에는각질세포간지질을구성할지질성분또는지질성분의전구체와이러한지질전구체의세포외변환반응을촉매하는지질변환효소, 각질세포의탈락에관여하는단백질분해효소와단백질분해효소저해제, 항균기능을담당하는항균펩타이드등이포함되어있다. 18) 층판소체에존재하는지질및지질전구체는과립층과각질층경계부에서분비된후지질변환효 소에의한세포외변환과정을거치며특징적인다층지질막구조로배열된다. 18) 각질세포지질은주로세라마이드, 콜레스테롤, 자유지방산으로이루어져있으며, 각각이약 1:1:1 의몰비율로구성되어있다. 각각의지질성분중특히세라마이드는아토피피부염환자의피부에서발현이감소되어있으며, 19) 콜레스테롤의경우노화피부에서의피부장벽기능저하와연관되어있다고알려져있어, 20) 이를이용한다양한보습제개발의근거가되고있다. 자유지방산의경우, 각질층을약산성으로유지하여장벽기능의항상성유지에기여한다. 21) 2) Tight Junction 각질층의구조와기능에초점을맞춘전통적인개념의피부장벽에서최근에는표피층에존재하는 tight junction 단백질과랑게르한스세포까지포함하여, 피부전체적인관점에서장벽기능을설명하고자하는시도가이루어지고 8,22) 최근의종설에서 Kubo 등 8) 은피부의장벽기능에는크게세가지의방어막이존재함을제시한바있다. 피부의가장바깥에위치해외부와직접접하고있는각질층은공기- 액체장벽의역할을하게되며, 이는앞서언급한다양한단백질, 지질성분에의해서인체내부의수분소실을막는기능과함께외부유해물질의침입을막는역할을수행하게된다. Tight junction 은표피의과립층에서발현되며, 단층상피조직에서와마찬가지로각질형성세포사이의공간을통한액체의이동을제어한다. Tight junction 을구성하는단백질로서는막투과단백질 (transmembrane protein) 인 claudin을비롯하여, occludin junctional adhesion molecule A, zonula occludens proteins (ZO)-1, 2, multi- PDZ domain protein 1, cingulin, symplkin 등이있다. 다양한단백질중특히 claudin의고리형태의구조가세포사이의공간을채우는형태로연결되어, 세포간이동경로를효율적으로막게된다. 23) 이러한 tight junction 은피부장벽으로서각질층과상호보완적인기능을수행하는것으로생각된다. 24,25) 22 http://dx.doi.org/10.4168/aard.2013.1.1.20

김현정외 아토피피부염과피부장벽이상 Allergy Asthma Respir Dis 2. 항균펩타이드장벽피부는또한피부의항균장벽의기능도갖고있다. 이러한항균장벽기능은피부각질층을구성하고있는각질층내각질세포간지질의투과장벽기능과피부표면의낮은산성도, 각질층내항균펩타이드등에의해유지된다. 항균펩타이드는선천면역을구성하는가장중요한요소중하나로서다양한기능적인특성을나타내는중요한구성성분이다. 일반적으로항균펩타이드는비교적단순한구조로이루어진양이온성펩타이드 (cationic peptide) 화합물로서그람양성균 (gram-positive bacteria), 그람음성균 (gramnegative bacteria), 진균, 바이러스등에대한광범위한항균스펙트럼을지니고있으며, 그기전이완전히밝혀져있지는않지만일반적으로미생물의세포막을파괴하는작용기전을통하여항균력을나타내는것으로알려져있다. 26) 피부에서분비되는항균펩타이드에는디펜신 (human betadefensin), cathelicidin (LL-37), lysozyme, RNase 7, Elafin, psoriasin, dermcidin, adrenomedullin 등이있으며, 새로운항균펩타이드가지속적으로발견되고있다. 27) 이러한항균펩타이드는주로층판소체를통하여각질층으로분비되며 28) 정상피부에서는비교적낮은상태로유지되고있다가감염이나상처가발생하는경우발현이급격히증가하면서피부의항균력을증진하는기능을하게된다. 최근에디펜신이나 cathelicidin 과같은항균펩타이드의경우항균력을나타나는것이외에도호중구, 비만세포, 단핵구, T세포등과같은후천성면역에관여하는세포를활성화하고감염부위나상처부위로끌어들여 2차적인방어기능을수행할수있음이보고되었다. 아토피피부염에서피부장벽의이상피부장벽기능의손상과이와관련된면역반응이주요한병인이된다는아토피피부염의연구결과는많은종설들에서설명된바있으며 29,30) 또한아토피피부염에서아토피행진 (atopy march) 으로발전되는기전에서중요한원인이되는것으로설명되고있다. 31) 최근에는아토피피부염환자의병변부위뿐만아니라비병변부위의피부에서도경피수분손실 (transepidermal water loss) 의증가, 각질층내수분량의감소, 피부표면 ph의증가와같은장벽기능의이상이관찰되면, 이러한이상이병변의중증도와연관이있다는결과가지속적으로보고되고있다. 32,33) 1. Filaggrin Filaggrin은대표적인아토피피부염의유전적인인자로생각되고있다. 34-37) 2006년 Smith 등 38) 이 R501X 과 2282del4 를유럽인구집단에서변이를발견한이후 S3247X 와 R2447X를포함하여이후 exon3에서 20개이상의 filaggrin의기능결함돌연변이 (loss of function mutation) 또는틀이동돌연변이 (frame shift mutation) 유전자변이가발견되었다. 유럽의아토피피부염을가진환자의 10 50% 가 R501X 과 2282del4 를가진다고한다. 39) 같은유럽이라도지중해지역은이러한유전자변이가거의관찰되지않으며 40) 아프리카인에서는보고된바가없다. 41) 아시아인에서는유럽인에비해그비율이낮고특정유전자에편중되기보다는다양한위치에서의변이가보고되며특히 3321del4 의변이가그중에서는다빈도로보고되고있다. 42-44) 이처럼 filaggrin 유전자변이는인구집단에서의차이점이두드러짐을알수있다. 45) Filaggrin 변이들은아토피피부염, 천식, 알레르기비염의주소인으로보고되었으며, 변이가있는경우좀더심하고, 성인아토피피부염으로지속되는임상양상으로나타날수있는가능성등 filaggrin과아토피피부염의연관성은중요한연구주제로떠오르고있다. 34,35,38,46) Filaggrin 변이가없는사람의급성아토피피부염병변은정상부위에비하여 filaggrin 발현이감소되어있고, 피부에서 interleukin (IL)-4 와 IL-13 이과발현되어있었으며, IL-4와 IL-13 은분화된각질형성세포에서 filaggrin 발현을감소시킨다고보고된바있다. 47) 그러므로아토피피부염에서 filaggrin의선천적, 후천적결함이밀접하게관련되어있을것으로생각된다. 또한, filaggrin은분해되어자연보습인자인아미노산및 PCA, trans-uca 로대사된다. 그러므로 filaggrin의감소는각질층의수분함유감소로이어질수있다. 최근 filaggrin과피부장벽그리고아토피피부염의연관성은 filaggrin의 homozygous frame-shift null mutation 을가진 flaky tail mice에대한연구로인해좀더명확하게밝혀졌다. Filaggrin 변이는세포간이동장벽이상을유발하여층판소체의분비이상및각질층의세포외막의변형을가져오게되며외부자극물질및합텐에대한염증을잘일으키도록한다. 48) 또한 filaggrin 변이는 Th17- 우성피부염증이일어나기도한다. 49) 즉, filaggrin 변이는피부장벽의손상을유발하고손상된피부장벽을통해면역글로불린 E 감작이용이해지며궁극적으로아토피피부염에서보이는피부염증반응이쉽게일어나는것이다. 36) 이러한관계는아토피피부염환자의 60% 이상이감작되었다고알려진 Dermatophagoides pteronyssinus 추출물을지속적으로 flaky tail mice에도포한연구결과에서알수있는데유전적으로아토피피부염이있는경우환경적으로진드기등항원에의해노출되면쉽게감작되고피부염이악화될수있음으로재확인되었다. 50) Filaggrin 유전자는염색체의 1q21 부위의피부분화에연관된 60개의유전자집단인 epidermal differentiation complex (EDC) 에존재한다. EDC는 classical S100 proteins, loricrin, involucrin, small proline-rich proteins, 그리고 late cornified envelope protein 들로구성되어있다. Filaggrin은그중에서도 N-terminal에 S100 calcium-binding motif를가져 S-100 융합단백질류에속한다. S100 융합단백질류에는 filaggrin, filaggrin-2, hornerin, trichohy- http://dx.doi.org/10.4168/aard.2013.1.1.20 23

Allergy Asthma Respir Dis Kim H, et al. Atopic dermatitis and skin barrier dysfunction alin, trichohyalin-like 1, cornulin과 repetin 등이있다. 51) 아토피피부염환자에서는 filaggrin의유전자변이와더불어다른 S-100 융합단백질류들의유전적변이가발견되는데그대표적인예가 hornerin 이다. 아토피피부염환자에서 single-nucleotide polymorphism이관찰되었고, 52) 실제아토피피부염환자에서그발현이감소되어있다. 53,54) Filaggrin-2 역시장벽기능에중요한역할을하는데 55,56) 임상적으로는 eczema herpeticum을동반한아토피피부염환자에서그발현이저하되고 SNP가관찰되었다. 57) 2. 표피지질아토피피부염에서는각질층내의세라마이드가감소되어있다. 58) 세라마이드는각질세포의외부를둘러싸고있는대표적인수분보존물질 (water-retaining molecules) 로다양한종류의세라마이드가존재하나아토피피부염에서는특히세라마이드 1이감소되어있다. 59) 세라마이드가감소하는원인은 glucocylceramidase 및 sphingomyelinase 에의한세라마이드의합성이상과함께 spingomyelin deacylase 와 glucosyl ceramide deacylase 의증가에의한세라마이드의비정상적인대사의증가그리고 ceramidease에의한세라마이드의과도한분해때문이다. 60) 피부장벽지질의중요한요소인세라마이드의합성감소는층판소체형성및지질층판구조형성의장애그리고전반적인표피지질의감소를유발함으로써 mortar 기능의이상으로나타나게된다. 또한 deacylase 에인해생성된 sphingosylphosphorylcholine 등세라마이드의비정상적대사산물들은 intercellular cell adhesion molecule-1, prostaglandin E2, IL-6, tumor necrosis factor (TNF)-α를통해아토피피부염의염증반응을악화시킨다. 3. ph, protease와 protease activated receptor 2 (PAR2) 피부분화과정의최종산물인각질은계속해서떨어져나가고새로운분화과정을거친각질세포로대치된다. 각질세포의정상적인적절한탈락을위해서는각질교소체가단백질분해효소에의해분해되면서세포간결합이적절히끊어져야하는데각질교소체유지및분해의항상성이깨진경우병적인상황이유발된다. 예를들어아토피피부염등의습진성질환에서단백질분해효소의활성이급격이증가하면서각질층의급격한탈락이일어나며, 반대로건선에서는각질세포가적절히탈락되지못하고두껍게쌓이는증상이나타나게된다. 각질세포의탈락에관여하는단백질분해효소는각질층의 ph에의해활성이조절된다. 건강한피부의각질층 ph는 4.5 5.5로약산성이며이는다양한기전에의해서피부산성도를유지하게된다. 이에따라각질층의 ph는피부장벽의항상성유지에중요한역할을하게되며이는약산성의보습제개발의근거중하나로제시된다. 61,62) 피부의약산성을유지하는기전은첫째, 표피의과립층과각질층 의경계선상에분비된 phospholipase (spla2) 에의해서 phospholipids가자유지방산으로대사되면서산성을형성한다. 21) 둘째는나트륨이온과수소이온을교환하는통로인 sodium hydrogen exchanger 1에의한것이다. 이는과립층의상층에분포함으로써과립층과각질층의경계부, 각질층의하부의산성을형성한다. 63) 또하나의기전은 fillagrin의단백질분해산물로써탈아미노화된카르복실산인 trans-uca 에의한산성화를생각해볼수있다. 64) 최근에는표피의 ceramidase 에의한각질층의산성화도하나의기전으로생각되고있다. 65) 이러한피부의산성도는각질세포의탈락에관여하는단백질분해효소의활성을조절하는데중요한역할을한다. 각질세포의탈락에관여하는단백질분해효소로는 serine protease (kallikrein-5, kallikrein-7), cysteine protease (stratum corneum thiol protease), aspartate (cathepsin D) protease 가있다. 66) 이러한단백질분해효소들은 serine protease를제외하고는산성에서최적의활성화를나타내고정상적인상황에서피부의탈락을주로담당한다. 그러나피부염에의하거나장벽손상에의해피부표면의 ph가지속적으로증가하면표피전층에걸쳐서 ph 상승에따른 serine protease 의활성이증가하고비정상적으로 desmoglein 1같은각질교소체의구성성분을분해함으로써각질층의응집력이상을초래한다. 67,68) 심각한각질화과정에이상을보이는 Netherton syndrome 에서각질층의 serine protease 인 kallikrein-5 (SC tryptic enzyme) 와 kallikrein-7 (SC chymotyptic enzyme) 과그저해제인 lymphoepitherial Kazal-type inhibitor 1의유전적인결함이발견됨으로써이러한 serine protease 의기능이밝혀졌다. 아토피피부염에서병변부위의피부가비병변부위보다 ph가더높게측정되며증가된 ph는다양한경로로피부장벽기능을손상시키게된다. 69) 즉, 성숙한각질세포간지질층을만드는효소들의활성을저해하고, 중성이상의 ph에서활성화된 serine protease 는직접적으로피부의지질대사를담당하는효소인 beta-glucocerebrosidase (beta-glccer'ase) 와 acidic sphingomyelinase (asmase) 의분해를유도하여정상적인피부지질장벽기능을수행하지못하게한다. 70) 또한, 활성화된 serine protease 에의해비정상적으로각질교소체를분해함으로써각질층의응집력이상을초래한다. 71) 또한산성의각질층은세균, 효모, 진균류등감염에대한방어의기능을충분히수행하지만, 산성이유지되지못하고각질층의 ph 가증가한다면정상세균총의증식대신 Staphylococcus aureus, Staphylococcus pyogenes 및다른병원체의군락화가촉진되고항균펩타이드가감소되어있으므로피부감염이증가하게된다. 69) 또다른단백분해효소저해제인 cystatin A는과립층과각질층에서발현되는데이는아토피피부염환자의피부에서감소되어있다. Cystatin A는내인성단백분해효소저해제의역할을하며, 땀으로도분비되어집먼지진드기나포도상구균에의해생성되는외 24 http://dx.doi.org/10.4168/aard.2013.1.1.20

김현정외 아토피피부염과피부장벽이상 Allergy Asthma Respir Dis 인성단백분해효소를저해하여피부를보호하는기능을가지고있다. 다양한단백분해효소의활성화는 PAR2를통해염증반응및가려움증을유발하게된다. 72) PAR2는 G단백연관수용체의아형으로피부에서는각질세포, 비만세포, 혈관내피세포에존재하며다양한염증반응, 색소생성과피부장벽기능에관여한다. 활성화된 PAR2는각질형성세포내칼슘농도의변화를유발하며, 층판소체의분비를억제함으로서표피투과장벽의이상을가져오게된다. 70) 집먼지진드기와바퀴벌레의항원은자체가단백분해효소활성도를가지며이는 PAR2를활성화시켜서직접적으로피부장벽에손상을주게된다. 장벽기능이상이있는경우집먼지진드기와바퀴벌레등다양한항원의투과를증가시켜서, 면역반응을유발하여아토피피부염을악화시킴과동시에이러한항원자체가아토피피부염에서피부장벽의항상성유지를직접적으로방해하게되는것이다. 73) 각질층의단백분해효소를저해하거나직접 PAR2 저해제를사용하면장벽회복속도가빨라지며염증반응이감소하게되므로새로운아토피피부염치료제로고려되고있다. 4. 항균장벽아토피피부염환자의피부에서항균펩타이드의발현이감소되어있다는다수의연구결과가보고된바있다. 74-76) 아토피피부염의병엔에서중요한역할을하는 Th2 cytokine인 IL-4, IL-10, IL-13 등에의하여항균펩타이드가감소된다는여러보고는아토피피부염에서항균펩타이드가감소되어있는원인을설명해준다. 77,78) 이러한항균펩타이드의감소는아토피피부염에서흔히나타나는 2차감염, 특히 S. aureus에의한감염과밀접한관련이있는것으로생각된다. 79) 이와함께, 심리적인스트레스도항균펩타이드의발현을억제하는것으로보고된바있으며, 이는스트레스에의하여분비되는스테로이드호르몬에의한것으로알려져있다. 80) 이러한연구결과를종합할때, 아토피피부염에서나타나는다양한요인과함께증상의치료제로사용되는외용스테로이드제등이병변부위의항균펩타이드발현을감소시키는것으로생각되며, 이로인하여 2차감염등이쉽게나타나는것으로여겨진다. 따라서, 이러한증상을개선하기위한외용항균펩타이드제제의개발이나항균펩타이드의발현을조절하는물질의개발등이아토피피부염의개선이나치료에효과적일것으로기대된다. 5. Tight Junction 손상된피부장벽이병인으로작용하는피부질환에서 tight junction 단백질은각질층손상에따른외부알레르겐침입에대하여추가적인장벽기능을수행하게된다. 물리적인손상등으로인한위험신호에의해 tight junction 의결합이느슨해지면서, 랑게르한스세포가느슨해진 tight junction 사이로수지 (dendrite) 를내어 서항원을인식하게된다. 최근아토피피부염에서도 tight junction 의이상에대한보고가이어지고있다. De Benedetto 등 6) 은 tight junction 을구성하는단백질인 claudin-1 과 claudin-23 이아토피피부염환자에서감소되어있는것을확인하였으며 claudin-1 의발현은 Th2 면역반응과는역상관관계에있는것을보고하였다. 또한아토피피부염에서는 pattern recognition receptor 인 Toll-like receptor 2 (TLR2) 가감소되어있는데 TLR2가 tight junction 의기능을증강시킨다는보고가있어아토피피부염의병인과연관되어있을것으로생각된다. 81) 아토피피부염의치료제로흔하게쓰이는스테로이드와칼시뉴린억제제는 tight junction 에서로다른영향을주게되는데스테로이드는 tight junction 구성단백질의발현을감소시키지만칼시뉴린억제제는이러한단백질을감소시키지않아 tight junction 의기능을저하시키지않으며 82) 이는아토피피부염을치료하는데있어고려해야할요소이다. 6. 사이토카인아토피피부염의급성피부병변에는 Th2 사이토카인이과발현되는데, 이러한 Th2 사이토카인은알레르기반응을유발할뿐만아니라선천성면역반응을저하시킨다. 최근 Th2 면역반응으로생성된사이토카인이직접적으로장벽기능을저하시킨다는보고가있어피부장벽이상과면역학적이상에대한새로운개념이제시되고있다. 83) 그예로 Th2 사이토카인인 IL-4는피부장벽손상후회복을저해하고, 세라마이드합성과항균펩타이드의발현및 filaggrin, desmoglein3, loricrine, involucrin 의발현을억제한다. 84-86) 또한아토피피부염에서 S100/A11 과 p21이감소되어있으며, IL-4/ IL-13 에의한 human beta defensin-3 와 filaggrin의억제는이들에의해서나타난다고보고되었다. 87) 이외에도 serine protease 활동의증가는피부장벽의이상을초래할뿐아니라활성화된 IL-1을증가시킨다. 아토피피부염에서또하나의중요한사이토카인인 thymic stromal lymphopoietin (TSLP) 는 CD11c+ myeloid dendritic cell을유도하여 Th2 염증반응을일으키는것으로알려져있다. 88) 이러한 TSLP는아토피피부염환자의병변부에서증가되어있으며아토피피부염의중증도와도연관되어있다. 89) 7. Outside -inside -outside Outside-inside 가설을주장하는학자들은아토피피부염의활성도는장벽이상과상관되고 90) 실험적으로피부장벽을손상시키면사이토카인 (IL-1αβ, TNF-α, granulocyte-macrophage colonystimulating factor 등의분비와생성을일켜염증을일으키고피부염이발생한다는근거를제시하고있다. 91,92) 또다른실험에서는인위적인피부장벽의손상이 Th2 염증반응을일으키며호산구의침윤과함께 thymus activation regulated chemokine (TARC) 와 reg- http://dx.doi.org/10.4168/aard.2013.1.1.20 25

Allergy Asthma Respir Dis Kim H, et al. Atopic dermatitis and skin barrier dysfunction ulated on activation, normal T cell expressed and secreted (RAN- TES) 의발현을증가시키는것이확인되었다. 93) 그외에도아토피피 부염에서중요한사이토카인인 TSLP 의발현이 PAR2 의활성화에 의한다는보고도이러한가설을뒷받침한다. 94,95) 반대로 insideoutside 가설을주장하는학자들은 Th2 면역계의이상이피부장 벽의파괴를초래한다는근거들을제시한다. 그러한근거들로는 IL-4 가피부장벽의손상시세라마이드의회복을억제하고 84,96) IL-4, IL-13, IL-31 등이피부장벽의주요구성단백인 involucrin, loricrin, filaggrin 의발현을감소시키는것이있다. 47,85,97) 또한 Th2 면역반응이외에도 IL-17, IL-22 등이피부장벽이상을초래한다는 보고도있다. 98,99) 이러한결과들로볼때면역계와피부장벽은서 로독립적이지않고유기적으로연결되어있음을알수있으며이 들관계에대한연구는앞으로도지속될것으로예상된다. 결론 아토피피부염은환경과유전자간의상호작용에의해일어나며 다양한발현양상을갖는유전적질환으로유전적, 환경적인자간 의상호작용이질병의중증도를결정한다. 여러가지원인중표피 장벽의이상이중요한요소로자리잡고있으며앞에서살펴본보 고들을통해일차적이든이차적이든표피장벽의이상이아토피의 발병의초기단계에관여할가능을생각해볼수있다. 앞으로는이 러한표피장벽의이상에초점을맞춘국소도포제의개발이아토 피피부염의새로운치료방법이될수있을것으로생각된다. REFERENCES 1. Bieber T. Atopic dermatitis. N Engl J Med 2008;358:1483-94. 2. Williams HC. What is atopic dermatitis and how should it be defined in epidemiological studies? 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