Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,克罗恩病研究进展,流行病学研究概况,发病率分别为,4-12/10,5,近,20,年来,CD,增加明显,欧美多见,中国和亚洲国家少见,青壮年多见,儿童和老年人少见,流行病学研究概况,经济发达地区的发病危险性高于落后地区,城市地区高于农村,当人群从疾病低发区移居到高发区后,发病率也会上升,亚洲国家克罗恩病发病率在上升,国家,报告时间,CD,日本,1965,0.01,1979,0.78,1986,0.60,1991,0.51,1998,1.2,新加坡,1956-1970,0.04,1992,1.3,国内近,15,年克罗恩病病例数,年代,CD,89-93,236,94-98,1041,99-03,1633,小计,2910,提高城市化：公共卫生水平,增加,CD,的发病率,饮用热水成为习惯：,OR 5.0(95%CI1.4-17.3),不再使用公共浴室：,OR 3.3(95%CI1.3,8.3),儿童期胃肠道感染可能是,CD,的保护因素,?,Gent,Lancet,1994,克 罗 恩 病,病因、发病机制迄今未明。,主要集中在,环境、遗传和免疫,异常等方面。,Genetic Linkages and CD,Chr.16q12 -IBD1 NOD2,6p-IBD3 MHC,和,14q -IBD4 TCR,/,复合体,5q-IBD5 IL-3,IL-4,IL-519p-IBD6 TB4H,C3,Others:-Chr 1,2,3,7,X,NOD2,基因,NOD2/CARD15,基因,CD,相关基因,Hugot,等1996年发现在,IBD1,位点,仅见于,CD,而非,UC,，约,20%-30%,的,CD,患者,欧美澳三洲12个研究组613个家庭研究证实,NOD2,基因产物是一种细胞内的内毒素结合蛋白,野生型能清除入侵病原体,.,NOD2,突变可引起肠道菌群改变导致的免疫激活异常,NOD2,突变还可使细胞凋亡机制失常,导致,CD,慢性炎症和组织破坏,突变杂合子患病危险性增加,3,倍,纯合子增加,23,倍,.,NOD2,突变破坏了细胞对细菌的天然,(,先天性,),免疫反应,特异性获得性免疫反应增强引起,CD,的组织损伤,编码蛋白在单核细胞表达可使,NF-,B,活化，对,LPS,反应,免 疫 异 常,细胞中介免疫反应异常,T,细胞中心地位，激活后产生各种细胞因子、炎性介质，引起和放大粘膜炎症,-,Th1,类型免疫反应,遗传决定因素使普通肠菌抗原引起,上调的细胞免疫反应,巨噬细胞,幼稚的,CD4,细胞,凋亡,Th1,IFN-,TNF,IL-2,延迟超敏反,应肉芽肿,Th2,IL-4,IL-5,IL-10,体液免疫,变态反应,IL,12,IFN-,IL-4,克罗恩病,的粘膜免疫反应,Role for Targeted Biologic Therapy in Crohns Disease(CD),Disease Mechanisms:,Chronic Immune Activation,Natural History of Crohns Disease:Chronic Progression,Monoclonal Antibodies for the Treatment of CD,Etiology of CD:Chronic Activation of the Mucosal Immune Response,Environmental factors,Genetic factors,T cell,Th1 cell,TNF-,IL-12,IFN-,Macrophage,Inflammation,Th1 cell,Th1 cell,Th1 cell,TNF-,IFN-,IL-12,Crohns disease state,Normal state,Chronic uncontrolled inflammation due to Th1 cell apoptotic defect,Normal controlled inflammation via apoptosis of Th1 cells(programmed cell death),Gately MK et al.,Annu Rev Immunol.,1998;16:495-521;,Ina K et al.,J Immunol,.1999;163:1081-1090;,Podolsky DK.,N Engl J Med.,2002;347:417-429,Cytokine Imbalance in Chronic Inflammation,Pro-inflammatory,Anti-inflammatory,IL-1,b,IL-12,TNF-,a,IL-8,IFN-,g,TGF-,b,IL-10,IL-1ra,IL-4 IL-13,adapted from Papachristou G et al.,Pract Gastroenterol,.2004;28:18-30.,Key Inflammatory Mediators in CD,Antigen,APC cell,T cell,CD4,APC cell,Activated T cell,Th1 cell,TNF-,TNF-,Activated macrophage,IL-12,IFN-,Gately MK et al.,Annu Rev Immunol.,1998;16:495-521;,Podolsky DK.,N Engl J Med.,2002;347:417-429,Interleukin 12(IL-12)Promotes Th1 Responses in CD,Antigen,APC cell,T cell,CD4,APC cell,Activated T cell,Th1 cell,TNF-,TNF-,Activated macrophage,IL-12,IFN-,Gately MK et al.,Annu Rev Immunol.,1998;16:495-521;,Podolsky DK.,N Engl J Med.,2002;347:417-429,Resting memory T cells,IL-12,IFN,Th1 cell,Nave T cells,Differentiation,Gately MK et al.,Annu Rev Immunol.,1998;16:495-521,Additional Mechanisms for IL-12-induced Th1 Reponses,Clinical Evidence of Increased Expression of IL-12 in CD,Clinical Evidence,Location/Cell Type,IL-12 expression,Mononuclear cells in actively inflamed tissue,Clustered IL-12,-positive cells,Ileal lamina propria and gastric mucosa,IL-12-containing macrophages,Lamina/muscularis propria,IL-12 mRNA expression,Lamina propria and CD4+T cells,Kakazu T et al.,Am J Gastroenterol.,1999;94:2149-2155.,Colpaert S et al.,Eur Cytokine Netw,.2002;13:431-437.,Berrebi D et al.,Am J Pathol,.1998;152:667-672.,Parronchi P et al.,Am J Pathol,.1997;150:823-832.,Monteleone G et al.,Gastroenterology,.1997;112:1169-1178.,Nielsen OH et al.,Scand J Gastroenterol,.2003;38:180-185.,Tumor Necrosis Factor(TNF)Sustains Th1 Responses in CD,Antigen,APC cell,T cell,CD4,APC cell,Activated T cell,Th1 cell,TNF-,TNF-,Activated macrophage,IL-12,IFN-,Gately MK et al.,Annu Rev Immunol,.1998;16:495-521;Podolsky DK.,N Engl J Med.,2002;347:417-429,TNF Promotes CD Activity and Pathogenesis Through Multiple Pathways,Adapted from Holtmann et al.,Z Gastroenterol.,2002;40:587-600.,Tissue destruction&,inflammation,Macrophage,TNF-,TNF-,TNF-,IFN-,IL-12,Activated T cell,Th1 cell,Coagulation,(increased production of thrombin),Ulcer,Inflammation,Inflammatory cells,Clinical Evidence of Increased Expression of TNF in CD,Clinical Evidence,Location/Cell Type,Correlation,TNF-,a,levels,Stool(children),Disease activity,TNF-,a,secretion,Lamina propria mononuclear cells,Mucosal involvement,density/frequency of TNF-,a,positive cells,Lamina propria cells,TNF-,mRNA expression,Colonoscopic biopsies,Braegger CP al.,Lancet,.1992;339:89-91.,Reinecker HC et al.,Clin Exp Immunol,.1993;94:174-181,Murch SH et al.,Gut.,1993;34:1705-1709.,Breese EJ et al.,Gastroenterology,.1994;106:1455-1466.,MacDonald TT et al.,Clin Exp Immunol,.1990;81:301-305.,Cappello M et al.,Gut,.1992;33:1214-1219.,Current Concepts in Crohns Disease(CD),Disease Mechanisms:Chronic Immune Activation,Natural History of Crohns Disease:,Chronic Progression,Monoclonal Antibodies for the Treatment of CD,The Likelihood for Disease Complications in CD Increases Over Time,Cosnes J et al.,Inflamm Bowel Dis,.2002;8: