1、炎症性肠病的研究进展,消化内科张文俊,IBD 概述,CD和UC是一种疾病的两个阶段或两种疾病目前尚无定论,inflammatory bowel diseases,Crohn disease,Ulcerative colitis,Undeterminated colitis,CH/10/30,炎症性肠病的复杂性,对病因和发病机制进一步研究有助于预防和指导治疗,IBD 现状,病因尚不清楚 治疗措施有限包括非特异性抗炎和免疫抑制治疗,Epidemiology of IBD,1-2 million IBD patients in the U.S.Equal incidence of ulcerativ
2、e colitis and Crohns diseaseApproximately 10,000 new cases diagnosed annually*,*Hanauer S. Inflammatory Bowel Disease. N Engl J Med. 1996;334(13):841-8,VariableFindingTime trends in incidenceIncreased 1960s80swith recent plateauIncidence (per 100,000)5-7Peak age at onset (y)15-30Female-to-male ratio
3、1.1 to 1.8:1Racial/ethnic incidenceHigh in whites, Jews,Epidemiology of IBD: Overview,Andres PG et al. Gastroenterol Clin N Am. 1999;28:255.,Age and Sex Incidence of IBD,IBD 病因,遗传易感性,环境促发因素,精神因素免疫因素,IBD,GENETIC SUSCEPTIBILITY,种族的影响,Basu, D; Am J Gastroenterology 100:2254-2261, 2005,A,Whites had stro
4、nger family history of IBD and colorectal cancer.African Americans with CD had higher incidence of arthritis. Disease severity similar across all groups. P-anca served as a sensitive maker for Mexican Americans as 100% with UC were positive compared with 40% in whites,识别的第一个IBD基因 CARD15/NOD2,糖多肽,CD1
5、4,TLR4,TRAF6,NOD2,NF-kB,细胞核,炎症,单核细胞,C-插入突变 终止码, NF-kB的异常激活,IBD相关基因,Bamias. Ann Intern Med, 2005,143(12):895-904,IBD常见的免疫遗传异常,p-ANCA (Peri-Nuclear Anti-Neutrophil Cytoplasmic Antibodies) ASCA (Anti-Saccharomyces cerevisiae antibodies) UC: +p-ANCA, -ASCASens=57 Spec=97 CD: -p-ANCA, +ASCASens=47 Spec=9
6、7,pANCA 70% of UC,6% of CD；ASCA 50-60% of CD,基因型与IBD的关系,不同基因型不同IBD分型,疾病易感性不同对药物治疗的反应不同,No contribution of NOD2,NOD2 contributes,NOD2 major factor,M. CROHN AND NOD2/CARD15,CP/06/23,Environmental Triggers,Infections,NSAIDs,Stress,Smoking,Diet,Antibiotics,IBD,饮食因素,明确危险因素:过量摄入糖类，尤其是CD 可能危险因素:巧克力和可乐类饮料,高
7、脂 可能保护因素:高纤维食物,水果和蔬菜 其他：丁酸，硫化物，谷氨酸盐,Meta分析: 吸烟者发病危险性为从不吸烟者的2倍吸烟增加CD复发可能性，女性多见（ 4倍）,过量吸烟,CD的危险因素，UC的保护因素,对于CD：,长期吸烟者发病危险性高 戒烟者患病的危险性为从不吸烟者的1.7倍 戒烟者重新吸烟(45)可改善症状 尼古丁治疗可增加活动期UC的症状缓解率,对于UC：,感染,外源性感染：沙门氏菌,志贺氏菌,副结核分枝杆菌, 产单核细胞的李斯特菌属,缠绕杆菌属, 酵母菌,弯曲杆菌属,耶尔森菌属； 阿米巴; 麻疹病毒内源性细菌：大肠杆菌E.coli ?,微生物因素,微生物因素在IBD发生中的作用尚
8、存在争议缺乏足够证据证明IBD的特异性病原体现有研究表明:病原微生物可能是本病的促发因素,J. Nutr. 1995;125:1401-12,The Human Gut Flora,Rapidly colonises gut after birth Comprises more than 1014 organisms Weighs 1-2 kgMore than 400 speciesAn individuals flora is immunologically distinctSymbiotic relationship with hostProbiotics,BALANCE OF COMM
9、ENSAL BACTERIAL COMPONENTS,无菌肠道环境,细菌感染,未见炎症,结肠炎症,免疫激活,基因易感宿主,No Bacteria, No IBD ？,麻疹病毒感染与IBD的相关研究,Ekbom A. Lancet 1996; 348. Lawrenson R. BMJ 1998; 316. Nielsen LLW. BMJ 1998; 316. Afzal MA. Lancet 1998; 351. Haga Y. Gut 1996; 38. Chadwick N. J Med Virol 1998: 55.,假说一：持续麻疹病毒感染与CD相关,来自瑞士的研究: 麻疹流行期出生
10、者CD患病率高在CD病人肠道组织中发现麻疹病毒蛋白和DNA,证据,研究者Wakefield后续的研究不支持自己前期研究 当时检测麻疹病毒的技术不够可靠 来自英、美、日等国的研究存在分歧 血清中未检测到抗麻疹病毒抗体,反证据,麻疹病毒感染与IBD的相关研究,Thomspon NP. Lancet 1995; 345. Gilat T. Scan J Gastroenterology 1987; 22.Pebody RG. BMJ 1998; 316. Feeney M. Lancet 1997; 350.,假说二：麻疹疫苗(非MMR)接种与CD相关,麻疹疫苗接种者IBD发病率较未接种者高,证据,
11、来自欧洲的病例对照研究不支持上述观点 英国和芬兰的研究显示CD与疫苗接种无关,反证据,麻疹病毒感染与IBD的相关研究,Montgomery SM. Gastroenterology 1999, 116; 796-803.Davids RL et al. Archives of Pediatric and Adolescent Medicine 2001; 155: 354-9.,假说三：IBD可能与早期病毒性腮腺炎有关,基于对70年代出生儿童的调查IBD与2岁前野生腮腺炎病毒或与麻疹病毒联合感染相关,证据,上述结果依据双亲对幼年时期患病的回忆调查 （而病毒性腮腺炎多无症状） IBD患者未检测到
12、腮腺炎病毒或抗体 MMR疫苗接种后IBD发病率未见明显升高,反证据,大肠杆菌与IBD的相关研究,假说：鞭毛蛋白在IBD中启动获得性免疫机制,E. Coli,Flagella,大肠杆菌与IBD的相关研究,假说：鞭毛蛋白在IBD中启动获得性免疫机制,常规革兰染色阴性的鞭毛蛋白单体（如大肠杆菌） 在CD中可作为抗原激发获得性免疫反应 这种获得性免疫反应受TLR5介导的先天性免疫调节 粘膜组织中可检测到 非造血细胞产生的细胞因子（如IL-6和TNFa) 获得性免疫与CD发生发展相关,大肠杆菌与IBD的相关研究,社会心理因素,45%的IBD患者认为应激促发IBD 胃肠病学专家认为 社会心理因素在IBD中
13、起重要作用,“Stresshas been positively correlated with exacerbation of disease”,依据：应激增强动物模型肠粘膜炎症反应,Qui. Nature Med. 1999.,依据：无症状UC中应激与直肠炎症有关,Levenstein S, et al. Am J Gastroenterol 1994;89:1219-25.,依据：应激对UC病情影响与持续时间有关,Levenstein S, et al. Am J Gastroenterol 2000;95(5):1213-20.,Levenstein S, et al. Am J Ga
14、stroenterol 2000;95(5):1213-20.,依据：应激对UC病情影响与应激程度有关,不同IBD分型应激的影响不同,Maunder R. Dig Dis Sci 2000;45(11):2127-32.,机制：应激与循环递质,机制：应激与肠壁通透性,Wilson LM. Microcirculation 1999;6:189. .Meddings JB. Gastroent 2000;119:1019.,机制：应激与肠道局部介质,Soderholm JD. Am J Physiol Gastrointest Liver Physiol 2001;280:G7G13.,Mawd
15、sley J E. Gut. 2005,54(10):1481-91.,应激对胃肠道影响的多通路机制,Mawdsley J E. Gut. 2005,54(10):1481-91.,应激与IBD,精神神经免疫学机制,IBD处于血栓前状态 凝血参数大多增高 血栓栓塞发生时给予抗凝治疗 可同时改善IBD病情 血栓栓塞是IBD的严重并发症 多发生于年轻患者急性期； 深静脉血栓和肺栓塞常见； 动脉栓塞和其他则少见,凝血和抗凝平衡紊乱,Schapira M. Acta Gastroenterol Belg. 1999, 62:182.Alfredo Guglielmi. World J Gastroen
16、terol, 2005,7;11:2035.,凝血状态异常是IBD的病因还是结果尚不确定,UC患者肠系膜静脉和门静脉血栓形成,IBD 发病机制 (Pathogenesis),损伤机理： 粘膜屏障受损 粘膜免疫异常 系统免疫失衡 IBD发病机制研究进展： 先天性免疫在IBD中的作用 IBD免疫效应分型Th1/Th2 CD是免疫亢进或免疫缺陷 细胞因子及免疫递质研究进展,ETIOLOGIC HYPOTHESES,Pathogenesis of IBD,NSAIDsAntibioticsInfectionsViralBacterialParasitic,Luminal antigensFood an
17、tigensBacteriaBacterial productsFMLPLPSPGPS,IL-2IFN-IL-12TNF-IL-1TGF- IL-4IL-5IL-10etc.,Translocation of luminal contents,InitiatingEvents,MucosalDamage,AbnormalImmune Response,ChronicInflammation,Courtesy of R Baldassano, 2000.,Chronic Inflammation: Imbalance Between Mediators,Pro-inflammatory,Anti
18、-inflammatory,TNF-a,IL-1b,IL-8,IL-12,IFN-g,TGF-b,IL-10,IL-1ra,IL-4/IL-13,Target“,PG,LTB,PAF,H2O2,Indirect,destruction,InterleukinschemokinesTNFa,Release of factors,Virus,Bac-teria,Protein,Lymphocytes,Uncontrolled reactionto antigen,Macrophages,PMNs,Recruitment of cells,MHC,4,CP/03/48,PRINCIPLES OF P
19、ATHOPHYSIOLOGY OF IBD,APC,Effector T-cell,Uncontrolled T-Cell Responses Induce Chronic Gut Inflammation,正常肠壁有生理性抗炎功能 IBD肠壁渗透性增加 损害肠粘膜屏障的因素： 遗传易感性 环境促发因素,机制一：粘膜屏障受损,Mucosal Immune System,机制二：粘膜免疫失衡,腔内抗原浸润并激活MC 效应细胞产生促炎细胞因子 减少调节性细胞因子产生 级联反应促使炎症反应扩大,粘膜免疫中的肠道微环境和相关基因,机制三：系统免疫失衡,遗传、环境及社会心理等因素共同作用于免疫系统,先天
20、性免疫是非特异性防御病原体的机制 是机体的第一道防线 主要针对抗原产生的化学物质(而非抗原本身) 针对抗原的某种免疫细胞选择性增殖,The Role of the Innate Immune System in IBD,获得性免疫与先天性免疫在IBD中的作用,传统观点认为 Acquired immune system IBD是获得性免疫系统细胞介导的炎症反应,主要识别抗原本身效应T细胞 (Teff) 和调节T细胞 (Treg),Defects in the innate immune system may play an equal or even more important role in
21、 IBD,IBD可有原发性的调节性淋巴细胞和细胞因子 功能失调，如:IL-10、TGF-,导致炎症控制失灵 CD中存在激活的T细胞调亡抵抗,这些现象无法用现有的获得性免疫机制解释,先天性免疫缺陷可能在IBD中起更重要的作用,进一步研究提示,Ann Intern Med, Volume 143(12).December 20, 2005.895-904,NOD2蛋白是细胞内受体主要识别细菌胞壁成分在先天免疫中起作用被认为是IBD的易感基因NOD2突变见于1/3的CD而在UC不是危险因素,支持先天性免疫的证据,先天性免疫中介导微生物-宿主反应的信号通路基因,膜耦联受体 TLRs（toll-like
22、 receptors ） 识别脂多糖等微生物结构组分 细胞质蛋白家族成员： NBS/LRR (Nod1 and Nod2) 特异性识别肽聚糖,MediatesInnate Immune Defense,IBD免疫效应分型Th1/Th2 paradigm,传统观点认为: CD为Th1优势反应 IL-12 和 IFN-等分泌增多,抗IL-12治疗可减少固有层MC分泌细胞因子,传统观点认为: UC为Th2优势反应 IL-5 和 IL-13等分泌增多,抗IL-13治疗有助于改善结肠炎症,Th1,Th2,Crohns Disease,BACTERIA,This will mean something u
23、nique to everyone. The bottom line is this: Were sure that youll have a positive experience with DanActive and that youll be completely satisfied with it. Were also confident that youll want to make DanActive a part of your familys daily wellness routine.,Th1/Th2 新观点的提出,UC和CD的研究发现Th1,Th2免疫分型界限不明显各种细
24、胞因子表达与原有分型差异甚至完全相反基于传统Th1/Th2观点提出 抗TNF单克隆抗体 (Infliximab) 用于CD治疗； 目前的研究发现 Infliximab 对重症UC同样有效； 而对部分CD不能诱导缓解 抗IL-10的制剂不能诱导CD患者缓解,IBD存在免疫反应差异性,这些现象无法用传统的Th1/Th2模式解释,其他T细胞免疫效应途径,Am J Gastroenterol.2002,97:2820. N Engl J Med,2002,347:417. Nat Rev Immunol,2003,3:521. J Exp Med,2002,195:1129. J Clin Inves
25、t. 2004;113:1490.,Th3 /Tr1与口服耐受相关,IBD病程不同免疫分型不同,急性期Th1为主,慢性期Th1/Th2混合型,自身免疫机制是CD发病的关键 遗传易感的宿主对细菌抗原的免疫耐受终止 免疫过度激活导致慢性透壁性炎症,CD是免疫亢进或免疫缺陷,Sands, B E. Inflamm Bowel Dis, 2006,12(2),S 2:p S1,传统观点:IBD包括CD免疫亢进是其主要机制,细菌与肠粘膜粘附性增强 defensins表达降低 defensins治疗有效 IBD存在体液,细胞免疫缺陷 NOD2/CARD15基因突变 损害细胞因子的转录表达GM-CSF治疗有
26、效,支持CD存在免疫缺陷的证据,Christian F. Eur J Gastroenterol Hepatol 2003 15:621626,集落刺激因子改善粒细胞功能缺陷,KORZENIK JR. Dig Dis Sci, 2000 , 45, 6 :1121.,G-CSF and GM-CSF,KORZENIK JR. New Engl J Med, 2005, 352, 21 :2193.,Sargramostim作为一种GM-CSF刺激肠道先天性免疫系统细胞,过氧化物酶增殖活化受体 PPAR- ,Lewis, AJG 2001. Dubuquoy, Gastro 2003,治疗应用,
27、外源物质代谢与IBD密切相关 Pregnane X receptor (PXR) 是配体激活的 转录因子家族成员 PXR可启动外源物质代谢 PXR可被多种内源性或外源性物质激活， 如:激素，胆汁酸，抗生素 PXR 编码基因NR1I2多态性与IBD相关,Pregnane X receptor and IBD,Dring MM. Gastrol, 2006, 130:341348.,Vitamin D 和 IBD,Lim WC. J Gastro & Hepatol, 2005, 2:308.,Clinical Findings,CD/05/105,STRICTURING STENOSIS AT
28、THE ILEOCECAL BORDER,Presentation of UC,DiarrheaBleedingNO abdominal pain (cramps)Extraintestinal manifestations,Ulcerative Colitis: Bleeding,101402.7 Lindenbaum - On-screen 80,Complications of UC,Toxic MegacolonColonic PerforationDysplasia or CancerGrowth failure (pediatrics)Extraintestinal disorde
29、rs(eg, arthritis, and dermatologic, musculoskeletal, ocular, renal, and hepatic disorders),Clinical Vignette: Ulcerative Colitis,22 yo male presents with 15-20 bloody liquid bowel movements a day.He recently quit cigarette smokingHis mother has Crohns diseaseHe takes ibuprofen for left knee arthriti
30、sStool cultures are negative and colonoscopy reveals colitis from the rectum to cecum.,Presentation of CD,DiarrheaChronic abdominal pain and tendernessLoss of appetite and weight lossFeverPerianal diseaseComplications such as fistulasExtraintestinal manifestations,Complications of CD,FistulasAbscess
31、esStricturesGrowth failure (pediatrics)MalnutritionExtraintestinal disorders,Crohns Disease Complications: Fistulas,A tunnel between two sections of the intestines or between the intestines and other organs, including the skin,SmallIntestine,LargeIntestine(Colon),Fistula,Fistula,Crohns Disease Compl
32、ications: Abscesses,A localized collection of pus within the tissue of the GI tract,Stomach,SmallIntestine,LargeIntestine(Colon),Abscess froma fissure in thesmall intestineinto the peritoneal cavity,Complications of CD: Fistulas,Abdominal Fistula,Perianal Fistula,Differential Diagnosis of IBD,Lympho
33、maInfectious etiologiesAppendicitisDiverticulitisCarcinomaIschemic ColitisCeliac disease,Significant factorsUCCDAnatomic location Colon/rectumAny part of GI tractDistributionDiffuseFocal with “skip” areasFistula or abscessRareCommonStricturesUncommonCommonCurrent smokerRareCommonBloody diarrheaCommo
34、nRare,Adapted from Surawicz CM. Contemp Intern Med. 1991;3:17.,Differential Diagnosis,Severe Crohns Colitis,Reprinted by permission of Blackwell Science, Inc. Marion JF et al. In: Di Marino AJ, Benjamin SB (eds). Gastrointestinal Disease: An Endoscopic Approach. 1997:511.,Pseudopolyps in CD,Reprinte
35、d by permission of Blackwell Science, Inc. Marion JF et al. In: Di Marino AJ, Benjamin SB (eds).Gastrointestinal Disease: An Endoscopic Approach. 1997:511.,Fibrostenosis in CD,Courtesy of J-F Colombel, MD.,Intestinal Complications of Ulcerative Colitis Toxicity,101402.7 Lindenbaum - On-screen 95,Gra
36、nuloma of the Ileum in CD,Courtesy of J-F Colombel, MD and K Geboes, MD.,Crypt Abscesses in IBD,Courtesy of J-F Colombel, MD.,ExtraintestinalManifestations,Extraintestinal Manifestations of IBD,Skin disordersErythema nodosumPyoderma gangrenosumJoint disordersPeripheral arthritisSacroiliitisAnkylosin
37、g spondylitisOcular disordersIritis, uveitis, and episcleritis,Extraintestinal Manifestations of IBD,HepatobiliaryGallstonesSclerosing cholangitisCholangiocarcinomaRenalRenal stonesAmyloidosisOther manifestationsAphthous stomatitisHypercoagulable state,Erythema Nodosum in IBD,Courtesy of J-F Colombe
38、l, MD.,Pyoderma Gangrenosum in IBD,Courtesy of J-F Colombel, MD.,Pyoderma Gangrenosum in CD,Sacroiliitis in IBD,Courtesy of J-F Colombel, MD.,Reprinted from the Clinical Slide Collection on the Rheumatic Diseases, copyright 1991, 1995, 1997.Used by permission of the American College of Rheumatology.
39、,Ankylosing Spondylitis,Scleritis in IBD,Courtesy of J-F Colombel, MD.,Aphthous Stomatitis in IBD,Courtesy of J-F Colombel, MD.,Sclerosing Cholangitis in IBD,Courtesy of J-F Colombel, MD.,CD/05/76,SMALL LESIONS IN THE COLON IN CD INVISIBLE IN MRI,CD/05/62,WCE INSMALL BOWELCROHNS DISEASE,CD/05/97,CT-
40、ENTEROCLYSIS CROHNS DISEASE WITH STENOSIS AND PRESTENOTIC DILATATION,n=41,*p4g/d)CorticosteroidsImmunomodulatorsSteroid Dependent or Refractory or Severe Colitis:CyclosporineSurgery,Approach to Medical Treatment of UC,Early or Mild Disease: 5-ASA agents Antibiotics (Flagyl or Cipro)Moderate to Sever
41、e Disease: Corticosteroids Immunomodulators Biologic Response Modifiers: Remicade Fistulizing Crohns Disease: Antibiotics: Flagyl, Cipro Immunomodulators: 6-MP/Imuran Remicade,Approach to Medical Treatment of Crohns disease,SASP,5-ASA,top. SASP/ASA,Prednisolone,Steroid Enema,0,20,40,60,80,100,% Succ
42、ess,Drug,Placebo,TA,39%,TA,41%,TA,56%,TA,56%,TA,45%,CUT/03/21,META-ANALYSIS OF DRUG TREATMENT OF ULCERATIVE COLITIS,Kornbluth, 1993,CUT/01/11,DOSE FINDING FOR 5-ASA IN ACTIVE ULCERATIVE COLITIS,Kruis, AGA 2000,8 weeks3 x 0.5 g3 x 1.0 g3 x 1.5 g(n = 104) (n = 104) (n = 104)Remission (CAI 4)50 66 *55Time to response27.526.521.6 (days, mean)Endoscopic remission (%)28 48 *49Histological improvement (%)42 56 *63Stop due to side effects (n)1179,
