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1 KISEP Information Korean J Otolaryngol 2006;49: 점막면역체계 서울대학교의과대학이비인후과학교실 김동영 Mucosal Immune System Dong-Young Kim, MD Department of Otorhinolaryngology, Seoul National University College of Medicine, Seoul, Korea 서론 인체에서호흡기, 소화기, 비뇨기, 생식기등의내면은점막에의해서덮여있으며, 항상외부로부터들어오는무수히많은항원이나병원균들에노출되어있다. 따라서점막은단순히통과경로의역할만을하는것이아니라, 점막면역체계 (mucosal immune system) 를통하여물리적 (physical), 면역학적 (immunological) 으로일차적인방어체계로서의역할도담당한다. 또한숙주 (host) 와 endogenous microorganism(commensal bacteria) 사이의공생관계 (symbiotic relationship) 를매개하는역할도담당하고있다. 1) 점막면역체계는자연면역 (innate immunity) 과획득면역 (acquired immunity) 을통해넓은 epithelial surface area 의 immunological homeostasis를유지하고있다. 최근에는특히비과영역에서, 알레르기비염의병태생리및치료에점막면역체계가깊이관련되어있어, 이에대한관심이점차커지고있다. 이에이논문에서는점막면역체계에대한지식을증대시킴으로써알레르기비염에대한이해및치료에도움을주고자, 점막면역체계의구성및기능, 특징들에대해기술하고, 후반부에이비인후과영역에서주된관심사인상기도점막의면역학적특징에대해기술하고자한다. The Uniqueness of Mucosal Immunity Common mucosal immune system(cmis) 일반적으로외부항원과병원균 (pathogen) 은섭취 (ingestion) 나흡입 (inhalation) 과같은정상적인생리적기전을통해서우리몸속으로들어오게된다. 따라서우리의 몸은이러한점막항원 (mucosal antigen) 과병원균에대한항원특이적면역반응 (antigen-specific immune response) 을유도하기에좋은위치에 organized lymphoid tissue를형성시켜놓았다. 대표적인 organized lymphoid tissue 로는소장의 Peyer s patch 와비강연관림프조직 (nasal-associated lymphoid tissue, NALT) 이있으며, 이들은점막의대표적인면역글로불린인 IgA 생성을유도하는 inductive site로알려져있다. 이들은또한 dendritic cell과 macrophage와같은 antigen-presenting cell(apc) 과의상호작용을통해서 effector and memory B cell, T cell 을생성하는데필요한 B cell, T helper(th) cell, cytotoxic T lymphocyte(ctl) 와같은모든 immunocompetent cell 을보유하고있다. 이러한항원특이적 B cell 과 T cell 은림프관을통해서 inductive site 를떠나게되고, 혈류를타고순환하여멀리떨어진 mucosal effector site 로이동하게된다. 이러한 effector site는위장관 (gastrointestinal tract), 호흡기 (respiratory tract), 비뇨생식기 (genitourinary tract) 등의점막고유층 (lamina propria, LP) 에해당한다 (Fig. 1). 이 mucosal effector site 에서항원특이적 IgA-committed B cell, Th1 cell, Th2 cell은 regulatory cytokine을통해서서로상호작용을하여, secretory IgA(S-IgA) 항체를생성하기위한각자의역할을수행하게된다. 이렇게생성된 S-IgA 항체는점막표면에서외부로부터침입하는항원과병원균에대한최일선의방어역할을담당하게된다. 2) 따라서 IgA-committed B cell 을생성하는 inductive site(peyer s patch나 NALT와같은 organized lymphoid tissues) 와, S-IgA 를생산하는 effector site(lamina propria) 로구성되는 common mucosal immune system(cmis) 은, mucosal 1136

2 김동영 Inductive sites Antigen Effector sites Secretory IgA Epithelial cell Dendritic cell Polymeric Ig receptor Dimeric IgA Peptide- MHC TCR B cell CD4 + T cell Plasma cell IL-6 IL-5 CD4 + TH2 cell IgA Blood circulation Fig. 1. The common mucosal immune system. Luminal antigens are transported to the nasopharynx-associated lymphoid tissue (NALT) and Peyer s patches through microfold (M) cells that are present in the epithelium overlying NALT and Peyer s patch follicles. Dendritic cells process and present antigens to T cells in these lymphoid tissues. CD4 + T cells that are stimulated by dendritic cells then preferentially induce IgA-committed B-cell development in the germinal center of the lymphoid follicle. After IgA class switching and affinity maturation, B cells rapidly migrate from NALT and Peyer s patches to the regional cervical lymph nodes and mesenteric lymph nodes respectively, through the efferent lymphatics. Finally, antigen-specific CD4 + T cells and IgA + B cells migrate to effector sites (such as the nasal passage and intestinal lamina propria) through the thoracic duct and blood circulation. IgA + B cells and plasmablasts then differentiate into IgA-producing plasma cells in the presence of cytokines (such as interleukin-5 (IL-5) and IL-6) that are produced by T helper 2 (Th2) cells, and they subsequently produce dimeric (or polymeric) forms of IgA. These dimeric forms of IgA then become secretory IgA by binding to polymeric Ig receptors (which become the secretory component in the process of secretory IgA formation) that are displayed on the monolayer of epithelial cells lining the mucosa. Secretory IgA is then released into the nasal passage and intestinal tract. TCR, T-cell receptor (Adapted from Nat Rev Immunol 2004;4: ). vaccine과 mucosal adjuvant의개발에필수불가결한요소인것이다. Inductive sites for mucosal immunity Peyer s patch, 충수 (appendix), 단독성림프결절 (solitary lymphoid nodule) 등은통칭해서소화기연관림프조직 (gut-associated lymphoid tissue, GALT) 이라고불리는데, 위장관의 mucosal inductive site로서작용하고, 반면에편도 (tonsil) 와아데노이드 (adenoid) 는설치류의비강연관림프조직 (nasal-associated lymphoid tissue, NALT) 에해당하는것으로서상부호흡기와비강, 구강의 inductive site 로서작용한다. 3) 최근의연구에서는 isolated lymphoid follicle(ilf) 이 Peyer s patch 와유사한면역학적 특징을가지는것으로밝혀져, GALT 의일부분으로서받아들여지고있다. 4) Mucosal inductive tissue의한예로서쥐의소화기에존재하는 Peyer s patch 의특징들에대한연구가가장활발히진행되고있다. 5,6) Peyer s patch 의표면은 follicleassociated epithelium(fae) 이라고알려진독특한상피층으로덮여있다. 이 follicle-associated epithelium에는특수화된 antigen-sampling cell인 microfold(m) cell이풍부하게존재하는데, M cell은 cilia를갖는주변의 enterocyte와는달리 irregular and shortened microvilli를가지는특징이있다. 7) 또한 M cell 은 basal membrane 쪽에명백한 pocket structure 를형성하며, 그 pocket 속에는 T cell, B cell, macrophage 또는 dendritic cell 등이 1137

3 점막면역체계 존재한다. 그외에 M cell은작은 cytoplasmic vesicle과소수의 lysosome 도갖는것으로알려져있는데, 이러한형태학적특징들은위장관내에존재하는항원을 uptake 해서 transport 하는데용이하도록고안된것이라고생각된다. 8) M cell에의해 uptake된 antigen은분해 (degradation) 나변성되지않고, 아래에존재하는 antigen-presenting cell 에온전한 (intact) 상태로전달되는것으로알려져있다. 9) M cell 은위장관내항원의 uptake 및 transport 에관여할뿐아니라, 병원균 (pathogen) 의침입통로 (port of entry) 로서도작용한다. Invasive Salmonella와 reovirus 는 Peyer s patch 에존재하는 M cell 을통해서침입하여감염을일으키게된다. 10,11) 따라서 M cell은 mucosal immune system 으로통하는입구 (gateway) 와같은역할을하는것으로생각되어진다. Peyer s patch 는해부학적으로 dome 형태를띠며, follicle-associated epithelium 바로아래에는항원특이적면역반응의유발에필요한 IgA-committed B cell, Th1 cell, Th2 cell, macrophage, dendritic cell 등이풍부하게존재하는영역이있다. M cell 을통해항원이 uptake 되고 delivery 된후, 항원은 antigen-presenting cell 인 dendritic cell 에의해즉시처리되어진다. 12) Peyer s patch에는최소한세가지종류의 dendritic cell(dc) subpopulation 이있는것으로알려져있다 : Myeloid DC(CD11b + ), lymphoid DC(CD8α + ), double-negative DC. 13) Myeloid DC는 subepithelial dome(sed) 영역에존재하며, DEC-205 와같은 maturation marker 를발현하지않기때문에미성숙한 (immature) 것으로생각된다. Lymphoid DC와 double negative DC는 cell-mediated immunity (CMI) 를유발시키는 Th1 cell의분화 (differentiation) 를유도할수있으며, 반면에 myeloid DC는 mucosal effector site에서 IgA immune response를유발하는 Th2 cell 을생성한다. 따라서 lymphoid DC와 double negative DC는 DC1 subtype으로분류되고, myeloid DC는 DC2 subtype으로분류된다. 14,15) 또한 myeloid DC는무해한음식항원 (food antigen) 에노출된후 IL-10 과 transforming growth factor-β(tgf-β) 를생성하며, 구강을통해주입된항원에대한 systemic unresponsiveness( 구강면역관용, oral tolerance) 를유발하는 Th3 또는 regulatory T(Treg) cell의분화를매개하는것으로생각된다. 13) Subepithelial dome 영역에존재하는 myeloid DC 는 chemokine receptor CCR6 를발현하고, 그 ligand 인 CCL20 는 follicle-associated epithelium에서발현된다. 성숙한 myeloid DC는 chemokine receptor CCR7을과 1138 발현하고, subepithelial dome 영역에서 interfollicular region(ifr) 으로이동하여 T cell 과상호작용을하게된다. 13) B cell의분열 (division) 이활발히일어나는곳인 germinal center를포함하는 follicle(b cell 영역 ) 은 Peyer s patch 의 dome 영역밑에위치한다. Peyer s patch의 germinal center에는 μ- to α-gene conversion에필수적인 activation-induced cytidine deaminase(aid) 를발현하는많은수의 IgM + B220 + B cell이존재한다. 16) 이전의연구에서, Peyer s patch로부터분리된 IgM + IgA - B cell을 TGF-β와함께배양하였을때, IgM - IgA + B cell 이생성된다는보고가있었다 ) 따라서, Peyer s patch 의 germinal center는 IgM에서 IgA로의빈번한 B cell isotype switch 와함께 affinity maturation 이일어나는곳으로생각되며, 18) surface IgA positive(siga + ) B cell 의대부분이존재한다. 이런 post-switch IgA-committed B cell은, chemokine receptor와그 ligand의상호작용 (α 4 β 7 -integrin-madcam1, CCR9-CCL25) 에의해서 mucosal effector tissue(intestinal lamina propria) 로이동한다. 20,21) 모든주요한 T cell subset 은 B cell 영역에인접해서발견된다 (T cell-dependent zone). 이 T cell들은성숙한것으로서, 거의모두가 αβtcr + T cell(αβt cell) 이다. 약 65% 의 αβt cell은 CD4 + CD8 - T cell로서, T helper cell 의특성을나타낸다. 위에서언급한바와같이, 독특한 dendritic cell subset에의해항원이제공 (presentation) 된후에, 이 T helper cell은각각 antigen-specific cellmediated immunity 또는 IgA response의 induction과 regulation에관여하는 Th1 또는 Th2 type cell 로분화될수있다. 약 30% 의 αβt cell은 CD4 - CD8 + T cell로서, cytotoxic T lymphocyte의전구세포 (precursor) 를포함한다. 22) 따라서, organized inductive tissue는항원특이적점막면역반응을유발하는데필요한모든 immunocompetent cell 을갖고있다는것을알수있다. Effector sites for mucosal immunity Mucosal inductive site 에서항원에처음노출된후, siga + B cell, CD4 + Th1/Th2 cell, CD8 + T cell과같은 mucosal lymphocyte들은멀리떨어진 mucosal effector tissue로이동하기위해 common mucosal immune system의 peripheral lymph node, thoracic duct, bloodstream을통해 inductive site 를떠나게된다 (Fig. 1). IgA isotype 중의하나인 S-IgA는 mucosal surface 에서방어역할을담당하는주된면역글로불린으로서, Peyer s Korean J Otolaryngol 2006;49:

4 김동영 patch나 NALT와같은 organized lymphoid inductive tissue에서기원하는 immunocompetent cell에의해위장관, 상부호흡기, 비강, 중이, uterine and reproductive mucosa, glandular tissue(salivary, lactating mammary, prostate) 등에서국소적으로생성된다. 이런별개의두 site, 즉, 항원의 uptake가최초로이루어지는 inductive site 와, S-IgA 가생성되는 effector site 는 common mucosal immune system의개념에서가장중요한부분이다. 23) Peyer s patch 와마찬가지로, 위장관의점막고유층은가장많은연구가진행된 mucosal effector tissue 이다. Effector site에서 siga + B cell 은 S-IgA 를생성하기위해최종적으로 IgA plasma cell 로분화하는데, 이과정은항원특이적 Th1 cell, Th2 cell, siga + B cell, 그리고 epithelial cell 에의해서형성된 mucosal intranet 에의해촉진된다. 이러한 mucosal effector site 에는특징적으로 Th1 과 Th2 cytokine array 가존재하는데, 이는많은숫자의 IgA antibody-producing cell을공급하는데필요한특징적인 B-cell differentiation pathway 를촉진하는데적합한환경을제공한다. 즉, Th1-derived IL-2와 Th2- derived IL-5, IL-6, IL-10은, siga + B cell의 preferential activation 과 clonal expansion 그리고 IgA plasma cell로의최종적인분화를위해중요한 IgA-enhancing cytokine이다. 24) 이 plasma cell들은 dimeric 또는 polymeric 형태의 IgA를생성하고, 이는 epithelial cell에의해서생성되는 secretory component(sc) 와결합하여 S-IgA를형성하게된다. Secretory component의생성은, Th1(IFN-γ) 과 Th2(IL-4) cytokine에의해모두 upregulation 된다는것이알려져있다 (Fig. 1). 24) 이중요한 mucosal IgA binding molecule인 secretory component는, intestinal lamina propria의 IgA plasma cell 에의해생성된 dimeric 또는 polymeric 형태의 IgA 를상피세포를통해 active transport하는 polymeric Ig receptor(pigr) 의일부분으로알려져있다. 25) 로하는 B-cell response와연관된다. IFN-γ는쥐에서 IgG2a antibody 생성을담당하는주요한 cytokine이다. 27) 한편, soluble protein antigen과함께 mucosal adjuvant로서사용되는 cholera toxin(ct) 은, IL-4, IL- 5, IL-6, IL-10을생성하는항원특이적 Th2 cell을유도한다. 28) 이러한 Th2-type cytokine 중에서는, IL-4 가 μ heavy chain을 γ subclass(igg1) 와 ε subclass(ige) 로변환 (switch) 시킨다고알려져있다. 29) 또한, Th2 cell 은쥐에서 IL-5와 IL-6의생성을통해서 IgA response 를지원하는주요한 helper phenotype 으로생각된다. 게다가, Th1 과 Th2 cell 은모두자신들이분비하는 cytokine 에의해서상호적으로 (reciprocally) 조절되고있다. 즉, Th1 cell은 IFN-γ에의해서, Th2 cell은 IL-4와 IL-10에의해서조절된다. 30,31) 이러한 cytokine들은 mucosa-associated compartment에서적절한 immunological homeostasis 를유지하는데중요한역할을담당하고있다 (Fig. 2). 최근의연구에서, naive precursor 로부터 Th1 또는 Th2 type cell로의분화는독특한 dendritic cell(dc) subtype, 즉, DC1 과 DC2 에의해서조절된다고밝혀졌다. 14) 이러한점에서, 세균감염은최초로 toll-like receptor(tlr:tlr2와 TLR4) 를자극하여 dendritic cell을활성화시키고, 주로 IL-12와같은 Th1-type inducing cytokine의생성을유도한다. 32) 따라서, TLR-stimulated dendritic cell은 Th1 cell type으로의 T cell differentiation 을유도하는경향이있다 (Fig. 2). 그러나, 기생충이나특정세균에노출된후, 어떤 toll-like receptor 의자 Role of mucosal Th1 cells, Th2 cells and Tr cells in the induction and regulation of IgA response 점막면역 (mucosal immunization) 은, 사용된항원, adjuvant, antigen delivery vehicle의성질에따라항원특이적 Th1- 또는 Th2-type response를유발한다. 예를들면, Salmonella와같은 intracellular pathogen을주입하면, IFN-γ, IL-2, TNF-β를분비하는 Th1 cell 을형성하게된다. 26) in vivo에서, 쥐의 Th1-type immune response는 cell-mediated immunity 와 IgG2a 생성을특징으 Fig. 2. Type of immuno-responses induced by mucosal administration (Adapted from Rev Med Virol 2003;13: ). 1139

5 점막면역체계 극에의해서 dendritic cell이 Th2 cell differentiation을유발시킬수있는지는아직불확실하다. 33) 비록 IL-4가 Th2 pathway 를유도하는데주요한역할을담당하고있다고알려져있으나, 이초기 IL-4 의 cellular source 는명확히밝혀져야할부분이다. 34) 한편으로는, NKT cell 이 IL-4 생성에효과적인세포군으로알려져있다. 35) 최근에, Th3 cell과 Treg cell과같은 immune-suppressive cytokine(il-10, TGF-β)-producing T cell 이보고되었다. 이런 suppressor-type cell 은 protein antigen 이구강을통해노출 (oral exposure) 된후유도될수있다. 36,37) Th3 cell이생성한 TGF-β는 IgA isotype switch 를촉진시키고, Th1 과 Th2 cell 모두에대해억제적인특성을갖는다. 37) Treg cell은 IL-4 대신에 IL-10 을생성하고, Th cell response 를억제하는특징을갖고있다. 36) Treg cell과 Th3 cell에의해서생성되는 regulatory( 또는 suppressive) cytokine은점막표면에서특징적인편향된면역침묵 (polarized quiescent condition) 을유발하는데기여하는것으로생각된다 (Fig. 2). Immunological Features of NALT 쥐에서 NALT는 nasopharyngeal duct의양쪽에, cartilaginous soft palate의 dorsal side에서발견되며, 인간의 Waldeyer s ring 에해당되는것으로간주된다. 38,39) 또한최근의연구에서, NALT 와유사하게 follicle을형성하는 lymphocyte aggregate가인간의 nasal mucosa, 특히 2세이하소아의 middle concha에서발견되었다. 40) 이는쥐의 NALT 에해당하는것이인간에서도발생할수있다는것을보여주는것이다. NALT 는 Peyer s patch와유사하게 follicle-associated epithelium, high endothelial venule(hev), T-cell과 B-cell-enriched area로구성되어있으며, antigen-sampling cell인 M cell이 NALT 의 epithelium 에존재한다. 41) Antigen-presenting cell인 dendritic cell과 macrophage도역시 NALT에서발견된다. 42) 따라서 NALT 도비강으로주입된항원에대한 mucosal immune response 를유발하고조절하는데필요한모든 lymphoid cell들을갖고있다. 예를들어 reovirus를비강내로주입하면, NALT 에서 germinal center 가형성되고, 호흡기와소화기에서 antigen-induced IgA + B cell 의 clonal expansion이유발되어 reovirus-specific IgA 가생성된다. 43) 또한 NALT 에서 reovirus-specific cytotoxic T lymphocyte가높은빈도로유도된다. 이러한소견들은 NALT가 mucosal immune system에서호흡기 1140 의강력한 inductive site라는것을보여주는것이다. Positive immune response 를유발하는것외에도, 비강으로주입된항원은 systemic unresponsiveness-mucosally induced tolerance 의한형태- 의유발에도역시효과적이라는것이밝혀졌다. 44) 따라서, NALT는각각 antigen-specific immunity와 tolerance를유도하기위해 positive- 와 negative-regulatory signal 을생성하는데관여한다고알려져있다. 그러나, NALT 에서점막에노출된항원에대한 tolerance 가유발되는기전은아직확실치않다. Th0 environment 쥐의 NALT 에서분리된 CD4 + T cell에서 Th1과 Th2 cytokine 을생성하는 mrna를분석하였을때, Th0 cell 의 cytokine profile 이우세함을보였다. 이는이 Th0 cell 이비강을통해항원에노출된직후 Th1 또는 Th2 cell 로분화될수있음을뜻하는것이다 ) Naive wild-type mice 의 NALT 로부터분리된 CD4 + T cell은 Th0 cell이며, 46) 따라서그들은비강으로주입된항원의성질에따라 Th1 또는 Th2 cell로분화할수있다. Cholera toxin과같은 mucosal adjuvant 와함께비강으로주입된단백질항원 (bacterial cell-wall component 또는 virus-associated antigen 등 ) 은비강뿐만아니라비뇨생식기, 호흡기, 소화기등과같은멀리떨어진 mucosal effector site 에서항원특이적 IgA-producing B cell의생성을촉진시키는 Th2-type response 를유발시킨다. 45,48,49) 반면에, 특정항원을발현하는 recombinant Mycobacterium bovis bacillus Calmette-Guérin(rBCG) 로비강면역을시도하면, Th1-cell-mediated immunity가유발된다. 47) IgA class switching IgA-specific class-switch recombination(csr) 이 diffuse mucosal effector tissue에서도발생할수있다는보고는소화기에서 organized mucosal tissue가 IgA-committed B cell 의생성에반드시필요한것은아니라는것을의미한다. 50) 그러나, 이러한새로운소견은여전히논란의여지가많다. 51,52) Intestinal IgA는두종류의세포, 즉 B1 과 B2 cell 에의해서생성될수있다고알려져있기때문에, 51,53,54) 흥미로운가설은, B1 cell 의 IgA-specific classswitch recombination은 organized lymphoid structure 를필요로하지않고, 반면에 B2 cell 의 IgA-isotype switching 에서는필수적이라는것이다. 이러한가설을지지하는것으로서, gut-associated lymphoid tissue에존재하는대부분의 B cell은 B2 cell이고, 반면에 B1 cell은선택 Korean J Otolaryngol 2006;49:

6 김동영 적으로 intestinal lamina propria region에존재한다는것이보고되었다. 54) 따라서, B2 cell의 IgA-isotype switching 을유도하는최초의항원자극은 Peyer s patch의 dome epithelium( 또는 follicle-associated epithelium) 에존재하는 M cell을통한 antigen sampling에의해서제공되고, 반면에 B1 cell에의한 IgA-specific classswitch recombination process 는, 최근에새로발견되었으며, 뚜렷한 lymphoid-like structure를갖지않고, lamina propria region에인접한 villous M cell을통해 uptake된항원에의해서유도된다고생각된다. 55) NALT는 IgA + B-cell response 를유발하는데있어서 Peyer s patch 와마찬가지로중요하므로, nasal passage 에서도 IgA-isotype switching이일어날수있는지여부에대한연구가진행되었다. Isotype switching 에필요한 IgM + B220 + B cell은 organized inductive site(nalt) 에서는발견되었으나, respiratory mucosal immune system의 diffuse effector tissue(nasal passage) 에서는발견되지않았다. 56) 마찬가지로, IgM + B220 + B cell은위장관의 organized Peyer s patch에서는발견되었으나, intestinal lamina propria 에서는발견되지않았다. 따라서, 이연구에서, IgA class switching 을수행하기위해사전에준비된 IgM + B220 + B cell은, NALT와 Peyer s patch 같은 organized mucosa-associated inductive tissue에만선택적으로존재함이밝혀졌다. 56) 이사실은 AID, Iα-C μ circular transcript, Iμ-Cα transcript 에특이한 IgA CSR-associated mrna의분석에서다시한번입증되었다. AID와 Iα-Cμ circular transcript 의발현은 μ- to α-gene conversion 동안에선택적으로 up-regulation 되었다가급속히 down-regulation 되기때문에, 이러한 molecular event는 IgA class switching을수행하고있는 B cell 의표지 (hallmark) 로서인식되고있다. 57) Iμ-Cα transcript 의발현은 IgA-specific CSR의종결을나타낸다. 50) 이분석에서, AID, Iα-Cμ circular transcript, I μ-cα transcript 특이적 mrna의발현은 NALT와 Peyer s patch 같은 organized mucosal inductive tissue 에국한되었고, nasal passage 와 intestinal lamina propria 같은 diffuse effector tissue 에서는발견되지않았다. 56) 또한이러한 organized mucosal lymphoid tissue는 B2 cell 과연관되어있다고알려져있다. 54) 따라서이런소견으로부터, 최소한 B2 cell에의한 IgA class switching은 aero-digestive tract에서 NALT와 Peyer s patch 같은 organized lymphoid structure를필요로한다는것을알 수있다. 또한 NALT 는 high-affinity IgA 를분비하는 memory B cell 의생성에중요한부위라고최근에밝혀졌다. 58) 이상을종합하여볼때, NALT 는항원특이적 Th1 또는 Th2-cell-mediated response와 B-cell immune response의유도와조절에필요한모든 immunocompetent cell 을갖고있다는것을알수있다. Differences between NALT- and Peyer s patch-initiated immune responses NALT와 Peyer s patch는같은형태의 immunocompetent cell 들을갖고있을뿐만아니라, 유사한면역학적특징과생물학적기능을갖는것으로생각된다. 따라서구강면역 (oral immunization) 과마찬가지로, 비강면역 (nasal immunization) 도멀리떨어진 mucosal effector tissue 에서항원특이적 Th1- 또는 Th2-cell-mediated response와 IgA response를유발할수있다고알려져있다. 1,45,47-49,59) 그러나, 일반적으로 NALT-targeted immunization 은호흡기와생식기에서효과적으로항원특이적면역반응을유발하고, 반면에 Peyer s patch-targeted immunization은위장관에서보호면역 (protective immunity) 의생성을촉진시킨다. 1,59) 또한, 비강면역은 IgAcommitted B cell에서 CCR10과 α 4 β 1 -integrin을높은수준으로발현시키고, 이들의 ligand 인 CCL28 과 VCAM1 을발현하는호흡기와비뇨생식기로 IgA-committed B cell 의이동을효과적으로유도한다는사실은, 구획화된 (compartmentalized) common mucosal immune system 의개념을뒷받침하는것이다. 60,61) 이와는반대로, 구강면역에의해유발된 IgA-committed B cell 은 α 4 β 7 과 α 4 β 1 -integrin뿐만아니라 CCR9과 CCR10을발현하고, 따라서 MADCAM1 또는 VCAM1과 CCL25 또는 CCL28 을발현하는소장 (small intestine) 과같은부위로이동한다. 62) NALT와 Peyer s patch는둘다 mucosal inductive tissue 에속하는데도불구하고면역학적특징과생물학적인기능에서차이가나는것은해부학적으로그리고환경적으로독특한그들의존재위치에기인한다고여겨진다. 따라서 common mucosal immune system 을겨냥하여 NALT 와 Peyer s patch-initiated mucosal immune response 를이용함으로써, mucosal compartment 의전체또는특정부위에서뿐만아니라전신에서항원특이적면역반응- Th1-cell 또는 Th2-cell response, cytotoxic T lymphocyte response, 그리고 IgA와 IgG response-을유 1141

7 점막면역체계 발하는 2 세대점막 ( 비강또는구강 ) 백신 (mucosal vaccine) 을개발하는것은이론적인근거가있다고할수있다 (Fig. 1) 맺음말 이상에서기술한바와같이점막면역체계 (mucosal immune system) 를이용한점막면역 (mucosal immunization) 의가장큰장점은, 지금까지일반적으로사용되고있는주사형백신 (injection vaccine) 의경우전신면역반응 (systemic immune response) 만유발할수있는데반해, 점막 ( 비강또는구강 ) 백신 (mucosal vaccine) 은점막표면 (mucosal surface) 에서항원특이적 secretory IgA 를생산하는점막면역반응 (mucosal immune response) 뿐만아니라항원특이적 serum IgG 를생산하는전신면역반응까지동시에유발할수있다는점이다. 앞으로안전하고, 주사침을사용하지않아서통증이없으며, 효과적인미래형백신개발이필요한데, 이런요건을충족시킬수있는것이바로점막백신이며, 점막면역학 (mucosal immunology) 분야에서의궁극적인목표라고할수있다. 즉, 주사를맞는대신코에주입하거나먹는약으로감염성질환을예방할수있는날이오리라기대된다. 알레르기질환에있어서도, 이전부터사용해왔던면역주사요법이심각한부작용으로인해그사용빈도가점차줄어들면서, 앞으로는 sublingual immunotherapy나 nasal immunotherapy 와같은 mucosa-targeting immunotherapy 로점차대체되어나갈것으로생각되며, 이런점에서점막면역체계에대한이해와연구가이비인후과의사들에게더욱중요한의미를갖게한다고하겠다. REFERENCES 1) Mestecky J, Blumberg R, Kiyono H, McGhee JR. Ch. 31. In: Paul WE, editor. Fundamental Immunology. 5th ed. San Diego: Academic Press;2003. p ) McGhee JR, Mestecky J, Elson CO, Kiyono H. 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