천식의면역학적기전 종설 고려대학교의과대학내과학교실이상엽, 인광호 Immunopathogenesis of Asthma Sang Yeub Lee, M.D., and Kwang Ho In, M.D. Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital, Seoul, Korea 서론천식은인구의 4~5% 를차지하는흔한질환이다. 최근조사에의하면천식은전세계적으로증가하는추세이다. 따라서우리나라에서도천식인구는증가할것으로생각된다. 천식의원인과기전은다양하고복잡하여그동안많은연구에도불구하고아직확실히밝혀져있지않다. 그러나최근연구에의하면천식의기본기전은기도의만성염증에의한기류장애와기도과민성으로생각되고있다. 천식의병리기전을이해하기위해서는기도염증을유발하고, 강화시키며또한조절하는인자들을확인해야한다. 따라서기도염증에관여하는면역학적, 생물학적과정을이해하는것이기본이라할수있을것이다. 본종설에서는기도염증반응에관여하는면역학적기전 (IgE- 매개성기전 ) 과염증매개물질및 innate immunity에대하여설명한다. 천식의면역조직병리학 도내로탈락된상피세포덩어리들을관찰할수있었다. 또한기도평활근의과다형성및비대와배상세포의증식이있었다. 그런데이런염증소견들은천식으로사망한환자의부검소견이므로치명적인천식환자만의소견인지아니면경증의천식에도나타날수있는소견인지는구분할수없었다 1. 최근에천식환자들에서기관지내시경을이용한기도조직검사와기관지폐포세척술이용이해지므로경증및중등증천식의기도염증을확인할수있었다. 조직검사에서활성화된비만세포, 대식세포, 호산구, T-림프구등의염증세포가발견되었고, 기관지폐포세척에는림프구, 비만세포, 호산구및활성화된대식세포등이증가해있음을보았다. 이런소견들은증상이없는경증천식환자에도나타난다. 따라서천식은기도염증질환이라고일반화해서말할수있게되었다 2-4. 기도에나타나는여러염증세포들은대부분활성화되어있으며각종매개물질들을분비하므로천식을유발한다. 천식의기도염증에대한증거천식의기도염증소견은천식으로사망한환자의부검에서처음확인되었다. 기도안은끈적거리는점액물질로기도폐쇄를보였으며기도벽은호산구, 림프구등의염증세포가침착되어있었으며부어있었다. 기도상피세포는부분적으로탈락되어있었으며기 Address for correspondence : Kwang Ho In, M.D., Division of Respiratory and Critical Care Medicine, Department of Internal Medicine, College of Medicine, Korea University Anam Hospital 126-1, 5Ka, Anam-Dong, Sungbuk-Ku, Seoul, Korea, 136-075 Phone : 02)920-5316 Fax : 02)929-2045 E-mail : khin@kumc.or.kr 천식에서알레르기성염증알레르기성천식은 IgE와관련되어있다 5. 대기중의알레르기항원이기도로들어와서 IgE를생성하는과정은알레르기항원이항원전달세포 (antigen presenting cell) 인가지세포 (dendritic cell) 와결합하여림프절로이동하는것으로부터시작된다 6. 항원과결합된항원전달세포가림프절내의 naïve T-helper cell(th0) 에작용하여 Th0가분화되는과정은확실히밝혀져있지않다. 천식의기도염증에서는 type 2 helper T(Th2) 세포가우세한데그기전은확실히규 1
SY Lee et al. : Immunopathogenesis of asthma Figure 1. A Simplified Scheme of the System of Type 1 helper T (Th1) and Type 2 Helper T (Th2) cells. The differentiation of Th1 and Th2 cells depends on interleukin-12 and interleukin-4, cytokines produced by antigenstimulated precursor CD4 T cells. In a regulatory loop, interferon-γ from Th1 cells inhibits Th2 cells and interleukin-4 from Th2 cells inhibits Th1 cells. An imbalance that favors Th2 cells may be important in asthma. Reproduced from reference 7. 명되지않았지만 Th0세포의일차분화시기에알레르기항원에의해자극된전구 CD4 T-세포에서분비되는 IL-4에의해 Th2 세포로분화된다. 반면바이러스, 세균등의항원에의해서대식세포로부터분비되는 IL-12에의해 type 1 helper T(Th1) 세포로분화된다고알려져있다 7. 또한같은항원이라도항원의양이많으면 Th2 세포로분화되며적당량의항원에는 Th1 세포로분화된다고알려져있다. Th2세포에서는 IL-4, 5, 6, 9, 13 등이분비되며이들은알레르기성기도염증을유발시키며, 특히 IL-4 는 B-세포를자극하여 IgE의생산을증가시킨다. 반면 Th1 세포에서는 INF-γ, IL-2가분비되며이들은대식세포, cytotoxic T-세포등을자극하여바이러스및세포내미생물체사멸에관여한다. 이들두세포 (Th1, Th2) 에서분비되는각종사이토카인들은면역조절고리를형성하여 Th1 세포에서나오는사이토카인은 Th2 세포를억제하며, Th2 세포에서분비되는사이토카인들은 Th1 세포를억제한다 (Fig.1) 7. 따라서천식의면역기전을정리하면다음과같다. 대기의항원이항원전달세포 (antigen-presenting cell) 인가지세포 (dendritic cell) 에들어오면림프내의 ThO 세포가 Th2 세포로분화되어 IL-3, 4, 5, 13등이분비된다. 이들은각종세포들을자극하여 IgE 및염증매개물질들을분비시켜기관지과민성과기도폐쇄를일으켜천식증상을발생시킨다 (Fig.2) 8. B-세포에서 IgE를생성하는과정은다음두단계를거친다. 첫째는 B-세포에있는수용체에 Th2 세포에서분비된 IL-4, IL-13이달라붙어야하며 STAT-6라는신호전달경로를통하게된다 9. 두번째신호는 B-세포에있는 CD40 이라는수용체에 T-세포에있는 ligand인 CD40L이달라붙으므로 B-세포가 IgE를생산하게된다 10. 그과정을설명하면다음과같다. 항원이 B-세포표면의 IgM에부착하면 IgM/ 항원복합체가 B-세포내로들어가게되고 endosomal processing을거쳐, B-세포표면의 2
Tuberculosis and Respiratory Diseases Vol. 60. No. 4, Apr. 2006 Figure 2. Overview of Asthma Pathogenesis. Reproduced from reference 8. MHCⅡ에부착된다. 그러면 T-세포에있는 T-세포수용체 (T-cell receptor, TCR) 와결합하게되며, 이로인해 T-세포의 CD40L의발현이증가하게된다. B- 세포의 CD40과 CD40L이연결되면 B-세포내의 CD80(B7) 의발현이증가하게된다. T-세포의 CD28 과 B-세포의 CD80(B7) 이결합하면 T-세포를자극시키는보조자극신호 (co-stimulatory signal) 가활성화되어 T-세포가성장하며, 사이토카인 (IL-4) 이분비되어 B-세포에붙게된다. 그러면 B-세포는성장과함께 IgE를분비하게된다 (Fig.3) 10. B-세포에서생산된 IgE는혈관내로순환하다조직내의비만세포와말초혈액내의호염구 (basophil) 의표면에있는 high-affinity IgE 수용체 (FcεRI) 와림프구, 호산구, 혈소판, 대식세포의표면에있는 low-affinity IgE 수용체 (FcεRⅡ, 혹은 CD23) 에부착 된다. High-affinity 수용체에 IgE가달라붙은후알레르기항원이 IgE와붙으면비만세포가활성화되어 histamine, leukotrienes, 사이토카인등여러매개물질 (mediators) 들이분비된다. 그러나 low-affinity 수용체에 IgE가붙은후림프구, 호산구, 혈소판, 대식세포가활성화되어기도염증에관여하는지에대해서는알려져있지않다 (Fig.4) 1,11. 염증세포들비만세포비만세포는골수에서기원하여혈관내로는 CD34+ 단핵구형태로순환한다. 이세포는 stem-cell factor 와 FcεRⅠ 양성으로기도내의점막및점막 3
SY Lee et al. : Immunopathogenesis of asthma Figure 3. scheme of T-and B-cell interactions involved in IgE synthesis. For explanation, see text. Reproduced from reference 9. Figure 4. Interactions between CD4 T Cells and B Cells That Are Important in IgE Synthesis. Interleukin-4 and interleukin-13 provide the first signal to B cells to switch to the production of the IgE isotype. Once formed, IgE antibody circulates in the blood, eventually binding to both high-affinity IgE receptors (FcεRI) and low-affinity IgE receptors (FcRII, or CD23). After subsequent encounters with antigens, binding of the high-affinity IgE receptors produces the release of preformed and newly generated mediators. Once present in various tissues, mediators may produce various physiological effects, depending on the target organ. Reproduced from reference 1. 4
Tuberculosis and Respiratory Diseases Vol. 60. No. 4, Apr. 2006 하로이동하여성숙하게된다 11. 비만세포에부착되어있는 IgE에알레르기항원이붙으면이세포에존재해있던 histamine, leukotriene 들이방출된다 13. 비만세포는 tryptase, chymase, proteoglycan 등을함유하고있으며 IL-1, 2, 3, 4, 5, GM-CSF, INF-γ, TNF-α등도생산한다. 따라서비만세포는천식의급성및만성염증반응에기여한다 14,15. 천식환자에서기도내로알레르기항원이들어오면비만세포로부터 histamine, leukotriene 등이분비되서기관지수축이일어나는데이반응은알레르기항원유입후초기에나타나므로초기반응 (earlyphase reaction) 이라부른다. 1시간정도지나면회복된다. 초기반응후 4~6시간후에후기반응 (latephase reaction) 이발생하는데, 이것은기도내의여러염증세포로부터사이토카인들이분비되기때문이다 (Fig.4) 1,16. 호산구호산구는골수에서 IL-3, 5, GM-CSF에의해조절되어생성된다. IL-5는미성숙한호산구를성숙한세포로분화시킨다 16. 호산구는 major basic protein, eosinophilic-derived neurotoxin, cationic protein, peroxidase 등의염증성단백질을함유하고있다. major basic protein은기도상피세포에직접손상을주고, 기도과민성을증가시키며비만세포의 degranulation을유발하여천식발병에중요한역할을한다. 또한 leukotriene을함유하고있어기도수축, 혈관투과성을증가시킨다 18. IL-5는호산구의혈관내방출을증가시키고생존을증가시킨다. 그러나 IL-5 단독이기도내의호산구성염증을유발시킨다는것에대해서는규명되지않았다 17. 혈관내의호산구가기도염증을일으키기위해서는기도내로빠져나와야한다 1,19,20. 첫번째과정은호산구표면에있는 P-selectin 에의해 cell rolling이발생한다. Cell rolling 은호산구를활성화시킨다. 두번째과정은호산구표면에있는 β 1 integrin인 α 4 β 1 integrin (VLA-4) 과 β 2 integrin이혈관내피에발현된 ligand인 VCAM-1, ICAM-1 등 부착물질과결합하여호산구가혈관벽을통하여혈관밖으로빠져나간다 1,21,22. 혈관밖으로빠져나간호산구는기도로이동해야하는데이때작용하는물질이 chemokines 이다. RANTES, MIP-lα, eotoxin, MCP-1등이여기에속한다. 이들 chemokines는상피세포, 대식세포, 림프구, 호산구등에서만들어진다 (Fig.5) 1,23. 림프구 T-림프구는천식의염증에중요한역할을한다. CD4+ T-세포에는 Th1 세포와 Th2 세포가있다. Th1 세포는 IL-2, IFN-γ 를분비하며세포방어기전에관여한다. Th2 세포는 IL-4, 5, 6, 9, 13를분비하며알레르기염증반응에관여한다. 따라서알레르기성 ( 천식 ) 염증반응은 Th2 세포매개로이루어진다 7. 사람의천식에서 Th2 세포매개에의한알레르기성염증이나타난다는것은여러실험에서입증되었다. 천식환자의기도조직검사에서전사인자인 GATA-3의 mrna 가매우높게나타났는데, 이전사인자는 Th2 세포에국한되서발현된다 24. 천식환자의기관지폐포세척액의세포에서 IL-3, 4, 5, GM-CSF의 mrna가정상인보다높게나왔다. 반면에 Th1 세포에서분비되는 IF-γ의 mrna는천식환자와정상인에서차이가없었다 25. 또한천식환자의기관지폐포세척액의 IL-5 농도는다른폐질환을가진환자보다높았다. 이것은천식환자의기도내세포는 Th2 세포가우세하다는것을말해준다 26. 대식세포정상인에서대식세포는 T-세포의생성을억제하지만, 천식에서는알레르기항원에폭로되면 T-세포생성의억제작용이감소한다 27,28. 천식에서알레르기항원이대식세포표면의 low affinity IgE receptor (FcεRⅡ) 에붙으면, 대식세포가활성화되어 IL-1, TNF-α, IL-6 등이분비되어기도상피세포에작용한다. 기도상피세포는이영향으로 GM-CSF, IL-8, RANTES 등의매개물질을분비하므로기도염증을일으킨다 (Fig.6) 29. 그러나이런작용 5
SY Lee et al. : Immunopathogenesis of asthma Figure 5. The Role of Eosinophils in Allergic Inflammation. Interleukin-5 travels to the bone marrow and causes terminal differentiation of eosinophils. Circulating eosinophils enter the area of allergic inflammation and begin migrating to the lung by rolling, through interactions with selectins, and eventually adhering to endothelium through the binding of integrins to members of the immunoglobulin superfamily of adhesion proteins: vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). Reproduced from reference 1. 은확실치않다. 기도상피세포 기도상피세포도염증매개물질을분비한다. PD- GF, TGF-β 등을분비하여기도평활근의증식과 myofibroblast 의증식을유발시킨다. 여러성장인자들을분비하여기저막에콜라젠을침착시켜기도개형에관여하기도한다 (Fig.6) 29-32. 6
Tuberculosis and Respiratory Diseases Vol. 60. No. 4, Apr. 2006 Figure 6. Interations between resident and inflammatory cells and cytokines in the airways. Reproduced from reference 28. 염증매개물질많은종류의염증매개물질이천식과관련되어있다. 이들매개물질에의해서기도에다양한변화가발생하며, 이것에의해천식의특이적인병리학적특징들이나타나게된다. 그러나아직까지천식병인기전에있어서이들의역할에대해서는명확히밝혀져있지않다. cysteinyl-leukotriene(cys-lt) 인 LTC4, LTD4, LTE4는강력한기도수축작용을가지고있으며, 기도과민성을증가시키고, 천식의병인기전에중요한역할을하는것으로알려져있다. Leukotriene은천식의기도염증을지속시키고, 혈관투과성을증가시키며, 점액 (mucus) 생산을촉진하고, 기관지평활근을수축시켜직접적으로기류폐쇄를발생시킨다. 또한기도개형 (remodeling) 에도기여하는것으로추정된다. Leukotriene 이이와같은생물학적작용을나타내기위해서는특정한수용체 (receptor) 와결합하는것이필요하다. 현재까지 2개의 cys-lt 수용체 (cys LT1, cyslt2) 가알려져있으며 33, non-cys-lt인 LTB4 수용체 B leukotriene receptor(blt) 가알려져있다 34. 대부분의 cys-lt 의작용은 cys-lt1 수용체가매개하는데, cyslt1 수용체는기도의평활근, CD34+ granulocytic precursor cells, 호산구, 단핵구, 대식세포, 호염구, B-림프구, 호중구, 비만세포에존재한다. Cys-LT은 cyslt1 수용체와결합하여기도평활근을수축시키고, 화학주성 (chemotaxis), 혈관투과성증가, 점액분비등을촉진시킨다. LTC4와 LTD4의기관지수축력은 histamine 이나 methacholine 의 10000배정도에해당할정도로아주강력한기관지수축작용을하는것으로알려져있다. CysLT2 수용체는기관지혈관의평활근수축을매개하며, BLT 수용체는호중구화학주성을매개하는것으로알려져있다. 혈소판활성인자 (PAF, platelet-activating factor) 는강력한염증매개물질로써, 호산구의모집과활성화, 기도과민성증가와관련이있는것으로알려져있다. PAF 대사효소인 PAF acetyl hydrolase를억제시키는유전적돌연변이가천식환자에서높은빈도로관찰되었고 35, 이것은중증천식과관련이있다고보고되었다 36. 싸이토카인많은염증세포 ( 대식세포, 비만세포, 호산구, 림프구 ) 와상피세포, 내피세포들에서싸이토카인이생성 7
SY Lee et al. : Immunopathogenesis of asthma 되고분비된다. Histamine, leukotriene 등과같은염증매개물질이급성, 아급성염증반응과급성악화에중요한역할을하는반면에, 싸이토카인은주로만성염증반응과관련이있다. T-림프구에서분비되는림프카인이특히중요하다. IL-3는비만세포의생존에중요하며, IL-4는 B-림프구에서의 IgE의생성과, 내피세포에서 VCAM-1의발현에결정적인역할을한다. IL-13도 IL-4와마찬가지로 IgE 생성에중요하며, IL-5는호산구의분화, 생존에결정적인역할을한다. IL-9은 IL-4, IL-5의반응에대한감수성을증가시킨다 37-39. 대식세포와상피세포에서분비되는 IL-1β, IL-6, TNF-α, GM- CSF는염증반응을증폭시킨다. TNF-α와 IL-Iβ는 NF-κB (muclear factor-kb) 와 AP-1(activator protein-1) 을활성화시킨다. 기타물질들보체천식에서보체의역할은대부분도외시되어왔었다. 그러나마우스연구에의하면 C5a 수용체의결손이있는경우, 알러젠에대한기관지과민성의감소가관찰되었으며 40, C5a에대한유전자가기도과민성의표현형과연관이있는것으로보고되었다 41. 또한, 천식환자에서알러젠에노출시킨후, 기관지폐포액에서 C5a peptide 가발견되었다 40. Oxidative stress 다른염증질환과마찬가지로, 천식에서도 oxidative stress가증가되어있으며, 대식세포와호산구에서활성산소물질을생성한다. oxidative stress의증가는중증도와관련이있으며, 염증반응을더욱증가시키고, 스테로이드에대한반응을감소시킨다. Endothelin endothelin 은혈관과기관지를수축시키는강력한매개물질이다. endothelin-1이천식환자의객담에서증가되어있고, 이것의농도는알러젠노출정도와스테로이드치료에따라좌우된다 42-44. endothelin은또 한기관지평활근세포의증식을유도하며섬유화를촉진하여천식의만성염증에중요한역할을한다. Nitric oxide Nitric oxide(no) 는 NO synthases에의하여기도의다양한세포에서생성된다 45. 정상인과비교하여천식환자의호기가스에서 NO 가증가되어있다는것이밝혀져있다 45-47. 천식환자에서 NO의증가는, NO가천식의병인기전에직접적으로관여한다기보다는염증반응을반영하는것으로생각되고있다 48,49. oxidative stress 의증가와 NO가결합하여강력한라디칼인 peroxynitrite를형성하고, 이것은기도내의단백질의 nitrosylation을초래한다. Transcription factors 천식의만성염증은싸이토카인, 효소, 수용체, adhesion molecule과같은다양한염증단백질의발현이증가하기때문이다. 이들염증단백질은선택된표적유전자의전사를증가시키는 DNA binding factor인 transcription factor에의해유도된다. 천식에서결정적인역할을하는 transcription factor 중의하나가 nuclear factor-kappa B (NF-κB) 이다. NF-κB 는 protein kinase C activator, IL-1β, TNF-α등에의해활성화된다 50. 천식환자의기도에서 NF-κB 의활성이증가되어있으며, 특히상피세포와대식세포에서활성이증가되어있다 51. NF-κB 는천식환자의기도에서과발현되어있는중요한유전자인싸이토카인 (IL-1β, TNF-α, GM-CSF), chemokines (RANTES, MIP-1α, eotaxin), adhesion molecules (ICAM-1, VCAM-1), 염증효소 (cycloxygenase-2, inos) 의발현을제어한다. 항염증기전에관여하는물질들대부분염증기전에대해서만강조가되어있지만, 항염증기전도중요하며, 천식에서이것의결함이결국기도내의염증반응을더욱증가시키게된다. 체내의코티솔이알레르기염증반응조절에중요 8
Tuberculosis and Respiratory Diseases Vol. 60. No. 4, Apr. 2006 Figure 7. The receptors Involved in the Interplay of the Innate and Adaptive Immune Systems. The recognition of pathogen-associated molecular patterns by toll-like receptors leads to the activation of signaling pathways that induce the expression of cytokines, chemokines, and costimulatory molecules. Therefore, pattern-recognition receptors have a role in the generation of both the peptide-mhc-molecule complex and the costimulation required for the activation of T cells. Reproduced from reference 58. 한데, 천식의야간발작이혈중코티솔의일중감소와관련이있다. 코티솔은기도내조직에존재하는효소인 11β-hydroxysteroid dehydrogenase에의해비활성코티손으로전환된다. 천식환자에서는이효소기능이비정상적이며, 이것은천식의중증도를좌우할수있을것으로생각된다. 다양한싸이토카인이항염증작용을가진다. IL-1 수용체길항체 (IL-1ra) 는 IL-1과수용체의결합을방해하여천식에서항염증작용을나타낸다 52. IL-12와 IFN-γ 는 Th1 세포의작용을억제한다. 천식환자에서는 IL-12 의발현이손상되어있다 53. 싸이토카인생성억제인자인 IL-10은여러가지다양한싸이토카인 (TNF-α, IL-1β, GM-CSF), chemokines, 염증효소 (inos, COX-2) 의발현을억제한다 54. 아마도이작용은 NF-κB 를억제함으로써이루어지는것으로생각된다 55. 이와같은 IL-10 의분비와전사가천식에서는결함이있는것으로밝혀져있고, 이것은천식염증반응을증가시키고, 중증도를좌우할수있을것으로생각된다 56,57. 매개물질들도또한항염증작용과면역억 제작용을가진다. PGE2는대식세포, 상피세포, 호산구의작용을억제한다. 15-HETE 와 lipoxin은 cysteinyl-leukotriene 을억제한다. adrenomedullin은기관지확장작용을가지고있고, 대식세포의싸이토카인분비를억제한다. 기도및폐포대식세포는 T-세포의증식을억제한다. 대식세포에의한면역억제기전은현재까지확실하게밝혀져있진않으나, PGE2와 IL-10이관여하는것으로생각된다. 천식환자에서는이와같은대식세포의면역억제작용이감소되어있고, 따라서 T-세포의증식이증가되어있다 58. 천식에서의 Innate Immunity 천식의주기전인 Th2 면역반응을 adaptive immunity 라고한다. 반면감염에의한방어기전으로작용하는 Th1 면역반응을 innate immunity라고한다. 최근까지의천식면역기전은 Th2 면역반응에주안점을두어 Th2 면역반응이 Th1 면역반응보다우세 9
SY Lee et al. : Immunopathogenesis of asthma 하게작용하여두면역반응의균형이깨지면발생한다는 Hygiene hypothesis 로설명하고있다 1. 따라서천식의면역기전에서 Th1 면역반응에대한관심이적었다. 그러나 Hygiene hypothesis 는너무단순화되어있는학설이라는점과천식면역기전에 Th1 면역반응이관여한다는증거가나오면서천식면역기전으로 innate immunity에대한연구가많이진행되고있기에소개하고자한다. Innate 면역반응은외부의병원체 (ligand) 와이를받아들이는항원전달세포 (antigen-presenting cell) 에있는수용체 (receptor) 에의해서이루어진다. 세균, 바이러스, 기생충, 곰팡이등의병원체는 conserved motif를갖고있어서병원체의종류와상관없이동일한 ligand로작용하는데이것을 pathogen-associated molecular pattern (PAMP) 라고한다. 또한 antigen -presenting cell에는 PAMP 를받아들이는수용체인 pattern-recognition receptor(prr) 가있으며대표적인것이 Toll-like receptors이다 59. PAMP가 PRR에달라붙으면 innate immune반응 (Th1 면역반응 ) 이발생한다 60. Innate immune 반응이천식의면역기전에관여한다는것은천식환자의 BAL leukocytes 에서 TNF-α 및 INF-γ 가증가했다는보고와알레르기천식환자의 BAL 및혈액에서 Th1 및 Th2 세포사이토카인이증가했다는보고등이뒷받침해준다 61,62. 최근연구에의하면천식동물실험에서 Toll-like receptor의활성화는 Th2 면역반응증가시킨다고하여 innate 면역반응 (Th1 면역반응 ) 이 adaptive 면역반응 (Th2 면역반응 ) 을증가시키는것으로생각되고있다 59,63 (Fig.7). 따라서항원에의한 adaptive 면역반응은 innate 면역반응이선행되어야만이루어진다는가설도제기되고있다. 예를들면, T-세포가활성화되기위해서는적어도 2개의신호가필요한데, 하나는, MHC molecule과 peptide 결합체이고, 다른하나는항원전달세포표면에존재하는 CD80, CD86 molecule에의해서매개되는보조자극신호이다. 그런데 CD80, CD86 molecules의발현은 innate 면역반응에의해조절된다. 즉, 병원체에의한감염이발생하여, PA- MP와 TLR (Toll-like receptor) 가결합하면, TLR가 CD80, CD86 molecules의발현을유도한다 (Fig.7). Walter 등 64 은최근천식기전의발달사 (evolution of asthma paradigms) 라는종설을통해천식기전을 innate와 adaptive 면역반응의합작품으로설명하여 기도상피세포-바이러스-알러젠 paradigm (Epi-Vir -all paradigm) 을발표하였다. 결 천식기전의개념이과거에비해많이발전하였다. 특히 IgE-의존성기전에입각한면역학적반응에대한연구는기도염증에대한이해를증진시켰으며더불어치료의발전에도큰기여를했다. 따라서천식의면역학적기전에대한이해와연구는천식치료제의개발에큰역할을할것이다. 론 참고문헌 1. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med 2001;344:350-62. 2. Haley KJ, Sunday ME, Wiggs BR, et al. Inflammatory cell distribution within and along asthmatic airways. Am J Respir Crit Care Med 1998;158:565-72. 3. Kraft M, Djukanovic R, Wilson S, Holgate ST, Martin RJ. Alveolar tissue inflammation in asthma. Am J Respir Crit Care Med 1996;154:1505-10 4. Vignola AM, Chanez P, Campbell AM, et al. Airway inflammation in mild intermittent and in persistent asthma. Am J Respir Crit Care Med 1998;157: 403-409. 5. Burrows B, Martinez FD, Halonen M, Barbee RA, Cline MG. Association of asthma with serum IgE levels and skin-test reactivity to allergens. N Engl J Med 1989;320:271-277. 6. Noah TL, Becker S. Chemokines in nasal secretions of normal adults experimentally infected with respiratory syncytial virus. Clin Immunol 2000;97:43-49. 7. Schwartz RS. A new element in the mechanism of asthma. N Engl J Med 2002;346:857-858 8. National Asthma Education and Prevention Program. Guidelines for the diagnosis and management of asthma. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health; 2004. 9. Wills-Karp M, Luyimbazi J, Xu X, et al. 10
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