1、免疫炎性疾病新认识及中西医结合临床对策,南方医科大学珠江医院风湿免疫科于清宏2014年9月13日沈阳,7/22/2018,7/22/2018,7/22/2018,非可控性炎症免疫炎性疾病病的共同通道,A cellular, immune and metabolic response to injury and infection,Definition of inflammation,炎症定义,Inflammation is a two-edged sword,serves as a protective response, but is often a major cause of tissu
2、e damage in infectious, immunologic, and vascular diseases, as well as after trauma.,红肿热痛功能障碍,促炎/抗炎细胞因子平衡,炎症是一个程序化过程,炎症细胞表型转变,Heredity, Nonresolving inflammation and autoimmune diseases,先天禀赋,外感内伤,证候,部分自身免疫性疾病,免疫介导的炎性疾病,Chronic diseases with prominent inflammation, often caused by failure of toleranc
3、e or regulationRA, IBD, MS, psoriasis, many othersAffect 2-5% of people, incidence increasingMay result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohns disease?)May be caused by T cells and antibodiesMay be systemic or organ-specific,自身免疫病理过程,Susceptibility g
4、enes,Environmental trigger(e.g. infections, tissue injury),Failure ofself-tolerance,Activation ofself-reactive lymphocytes,Immune responses against self tissues,Persistence of functionalself-reactive lymphocytes,ActivationEffector T cells,Normal: reactions against pathogensInflammatorydisease, e.g.
5、reactions against self,ToleranceRegulatory T cells,No response to selfControlled response to pathogens,淋巴细胞活化及控制的平衡,阳,阴,自身免疫的遗传背景,Human autoimmune diseases are complex polygenic traitsIdentified by genome-wide association mappingSingle gene mutations are useful for pathway analysisSome polymorphisms
6、 are associated with multiple diseasesMay control general mechanisms of tolerance and immune regulationOther genetic associations are disease-specificMay influence end-organ damage,NOD2: polymorphism associated with 25% of Crohns diseaseMicrobial sensorPTPN22: commonest autoimmunity-associated gene;
7、 polymorphism in RA, SLE, othersPhosphataseCD25 (IL-2R): associated with MS, others; genome-wide association mappingRole in Tregs,自身免疫遗传背景: 最近发现,感染与自身免疫,Infections trigger autoimmune reactionsClinical prodromes, animal modelsAutoimmunity develops after infection is eradicated (i.e. the autoimmune di
8、sease is precipitated by infection but is not directly caused by the infection)Some autoimmune diseases are prevented by infections (type 1 diabetes, multiple sclerosis, others? - increasing incidence in developed countries): mechanism unknownThe “hygiene hypothesis”,主要免疫反应类型决定疾病自然病程Th1 response: in
9、flammation, autoantibody production; autoimmune diseasesTh2 response: IgE+eosinophil-mediated inflammation; allergic reactionsTh17 response: acute (and chronic?) inflammation; increasingly recognized in immune-mediated diseases,Th1 cells (IFN-g),Th2 cells (IL-4, IL-5),Th17 cells (IL-17),Nave CD4T ce
10、ll,CD4 细胞亚群: 产生及功能,Regulatory T cells,IFN-, IL-12:T-bet, Stat4,IL-4:GATA3, Stat6,TGF- + IL-6:RORt, Stat3,TGF-IL-2:Foxp3, Stat5,Host defense: many microbesSystemic and organ-specific autoimmune diseases,Host defense: helminthsAllergic diseases,Host defense: fungi, bacteria Organ-specific autoimmune d
11、iseases,After a microbial infection, activa-ted microbe-speci-fic TH1 (mTH1) cells migrate to the infected organ. A. Molecular mimicry. B. Epitope spre-ading. C. Bystander activation. D. Cryptic antigen.,部分隐蔽抗原,器官特异性自身免疫病理,Current therapies target late stages of the reaction (lymphocyte activation,
12、inflammation).Ultimate goal should be to tackle the underlying cause and restore control of the abnormally directed response,免疫炎性疾病代表疾病,类风湿关节炎?,脊柱关节炎?,血管炎?,类风湿关节炎免疫炎症机制研究状况,HLA表型与等位基因变异检测,类风湿关节炎相关HLA-DR4结合表位,RA相关共享表位氨基酸序列,多基因疾病,脊柱关节炎免疫炎症机制研究现状,强直性脊柱炎的易感基因,Nature Genetics 2013;45(7):730-8,IBD / subcl
13、inical ileitisHLA-B27,excess IL-23,Excess IL-23R sensitivity (SNPs),The IL-23R+ spondyloarthropogenic cell,Cua and Sherlock, Nat Med. 2011 Sep 7;17(9):1055-6.,Sherlock JP, et al. Nat Med. 2012;18:106976,ERAP1 associated with HLA-B27+ve AS,Nature Genetics 2011;43:761-767,Picture courtesy of Dr. Eric
14、Reits,ERAP1/ERAP2 process antigenic peptide epitopes before loading onto HLA-B27,Nucleus,Immunoreceptor Recognition of Aberrant B27,Arthritogenic Peptides and Autoreactive T Cells,B27 Misfolding,ER Stress, and UPR Activation,No defining mechanism by which HLA-B27 causes AS,Altered APC Function,ERAP2
15、 SNP N392K affects both enzyme activity and specificity,The kcat of the enzyme changes by 25-fold,Effects on trimming rate are substrate-specific!,Vanhille et al. Molecular Genetics 1(2): 98107,Evnouchidou et al. J Immunol 2012; 189(5):2383,ERAP1 SNPs at positions 528 and 730 affect both enzyme acti
16、vity and antigen presentation,kcat/KM,Ki,MHCI levels,Evnouchidou et al. J Immunol 2011,Length selection can be altered by polymorphic variation,Garcia et al. MCP, 2012,Evnouchidou et al. J Immunol 2012; 189(5):2383,SNPs are “scattered” all over the protein structure,AS易感基因的贡献值,肠道菌微生态与免疫炎性疾病,AS,CD,HC
17、,Bacteroides,Acintobacteria,Firmicutes,Fusobacteria,Proteobacteria,AS gut microbiome is different to CD and HC,Bacterial control,机械压力的骨赘形成的作用,Ann Rheum Dis 2013,遗传和环境因素共同导致疾病的发生,Nature Med 2012;18:1018,IL23介导的T细胞参与了AS的致病,强直性脊柱炎的致病机理假说,IL-17IL-1IL-6TNF-,Nature 2014,Connection of biological RA risk ge
18、nes to drug targets,Scher et al. eLife 2013;2:e01202. DOI: 10.7554/eLife.01202,Prevotella copri correlates with enhanced susceptibility to arthritis,血管炎发病机制研究现状,免疫学新进展-,免疫系统,创新点选择-,免疫学新进展-应答类型,肠道上皮细胞的正常屏障作用,Microbial recognition promotes IEC health and function,Nature Review Immunology, 2013, 13:75-
19、87,新的免疫细胞-ILC（innate Lymphoid cells),模式识别受体（pattern recognition receptors, PRRs):TLRs,NLR,nudeotide oligmerization domain（NOD）-like receptors, NLRs,CARD: Caspase activation and recruitment domainASC: Apoptosis-associated speck-like protein containing CARD,7/22/2018,NOD-like receptors, NLRs,NLRP3,植物药
20、抗炎机制研究举例,调节免疫功能紊乱,Wei W et al, Int Immunophar, 2002,2005,2009梁君山，魏伟，等. 中国药理学通报，1989,5:354-357 王兴旺，魏伟，等. 中国药理学通报，1990,6:363-366 周玲玲，魏 伟，等 .中国药理学通报，2002,18:175-177,白芍总苷机理研究,TGP是否能够作用与DC及相应后果？,DC分化发育和成熟,MDP：Lin- CX3CR1+ CD11b- CD115+ cKit+ CD135+CDP：Lin- CD115+ Flt3+ CD117lo,Flt3：FMS样酪氨酸激酶3， (Flt3L，配体)
21、,imDC,mDC,TGP,白芍总苷（total glucosides of paeonia，TGP）,OVA免疫,明确现象-TGP抑制免疫应答,抑制T细胞活化增殖,抑制机体对于新入侵抗原的免疫应答,探讨关键表型-TGP抑制DC成熟,被动转移实验：mDC恢复小鼠对于OVA反应,证实TGP抑制DC成熟而导致免疫应答降低,探讨机理-TGP抑制TLR-MyD88/NF-kB活化,与疾病治疗-RA-CIA模型,CII+CFACII+IFA,细胞亚群、细胞因子、信号转导,n=10/组3次重复16分评分,DBA1,明确现象-TGP延缓和减轻CIA发病与炎症,提前使用TGP，延缓并减轻CIA发病,机理-TG
22、P抑制DC成熟 降低CII免疫应答,明确表型-TGP降低Th1/Th17细胞亚群和功能,临床验证-TGP降低RA患者Th1/Th17,TNFa产生细胞减少,PSA? TGP?,TGP作用后PSA样小鼠体内M1细胞活性降低,TGP 抑制M1，上调M2（体外）,The Novel Role of Total Glucosides of Paeony in Regulating Type I and II Macrophages Activities in vivo and in vitro, Experimental Dermatology, 2014, in revision,TGP干扰TLR4
23、与LPS结合，阻断信号转导Int Immunophar,2012,12:275-82,TLR4和TGP,TLR4-MD2-LPS Complex (Nature 2009),TLR4-LPS结合部位,TLR4和TGP,免疫炎性疾病治疗现状,糖皮质激素作用机制,糖皮质激素受体（GCR）有核细胞都有GCR直接或间接影响基因转录10-100个基因具有GC反应元素（GC response element送，GCE）直接抑制NF-kB,抑制细胞因子产生间接抑制NF-kB 、I-kB影响转录后过程mRNA翻译、蛋白质合成、蛋白质分泌,抑制促炎因子IL-1、IL-6、IL-13、GM-CSF、TNF-a减少
24、炎症部位白细胞聚集通过抑制促炎症因子、 NF-kB抑制黏附分子E-selectin、VCAM-1、ICAM-1抑制烷酸产物如白三烯（leukotriene）降低血管渗透性,皮质类固醇 抗炎作用 相当剂量 盐皮激效应 药理T1/2 血浆T1/2 h min氢化可的松 1 20 2 812 90 可的松 0.8 25 2 812 30强的松 3.5 5 1 1236 60强的松龙 4 5 1 1236 200甲强龙 5 4 0 1236 180曲安西龙 5 4 0 2448 300 地塞米松 30 0.75 0 3654 100 300 倍他米松 25 0.80 0 3654 100 300 氯地
25、米松 40 0.50 0,全身性应用皮质类固醇的当量比较,糖皮质激素全身应用副作用,内分泌系统抑制肾上腺抑制生长、儿童性成熟延迟体重增加、柯兴貌糖尿病代谢紊乱低血钾症、高血糖、高血脂骨骼肌肉系统骨质疏松、椎骨压缩性骨折骨无菌性坏死（髋、肩、膝）肌病（急性或慢性）皮肤皮肤变薄紫纹痤疮多毛,眼白内障青光眼免疫系统IgG降低丧失延迟性过敏反应感染增加心血管系统高血压动脉粥样硬化血液系统淋巴细胞减少嗜酸细胞减少中性粒细胞增加精神/神经情绪反常精神分裂,免疫抑制剂类型,Calcineurin inhibitorsCyclosporineTacrolimusPurine synthesis inhibit
26、orsAzathioprineMycophenolate mofetilNonspecificprednisone,Target of Rapamycin inhibitorSirolimusPolyclonal antibodies (bind several CDs)Thymoglobulin Atgam Monoclonal AntibodiesBlocks IL-2 receptorDaclizumabBasilixmabOKT3 (anti-CD3),IL-2R,G0,G0,G1,S,G2/M,G1/0,T-cell,STEROIDCTLA-4-FcFUSION PROTEINU.
27、V.,CYCLOSPORINFK506STEROID,RAPAMYCIN,AZATHIOPRINE(6MP)METHOTREXATEMIZORBINEMYCOPHENOLICBREQUINAR,CYCLOSPHOSPHAMIDEX-RAYS,Activationby antigen,IL-2response,DNAsynthase,Mitosis,ANTI: TCRCD3CD4/8CD45RBLFA-1ICAM1,ANTI-IL-2RTOXINS,IL-2R,Cytokinesynthesis,Therapeuticmonoclonals,Drugs and othertreatments,部
28、分免疫抑制剂转环节,Reduce inflammation TNF-alpha blockers (RA, Crohns dis., psoriasis)e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Abs against IL6R and IL-15R Statins, shown to lower CRP (RA, MS) Rituxin = monoclonal Ab = anti-CD20Eliminates B cells in non-Hodgkins lymphoma (maybe also RA, an
29、d other Ab-mediated autoimmune diseases),免疫炎性疾病生物制剂治疗,其他可能的治疗通道,T cell vaccines (against activated Ag-specific T cells)Interfere with antigen presentation (anti-MHC)Monoclonal antibodies against a variety of target antigensOral induction of tolerance (MS) So far, efforts have been more successfulin
30、mice than humans,其他可能的治疗通道,中西医结合抗炎机制研究思路,炎症的消退是多个协同作用的结果；多机制通道可以恢复细胞环境；内源性抗炎因子产生的机制有待深入研究；调节炎症产生的环境是新的治疗选择 。,中药抗炎药物应用的思路,如何调节炎症产生的环境？氧化应激和自由基；氧化-抗氧化状态的不平衡；氧化-抗氧化的再平衡。,中药抗炎药物应用的思路,植物抗氧化剂:安全和有效的慢性抗炎药物? 炎症介质、促炎的细胞因子和自由基产生的复杂机制。植物药物中和自由基，而不破坏细胞存在的生物环境机制。,天然抗炎药物应用的思路,抗炎中药优势设想：第一、多通道阻断炎症介质产生；第二、多成分低浓度调节局部
31、环境；第三、整体温和作用和动员机体本身的抗炎机制调节环境第四、增强抗炎能力、防止组织损伤同时不会因过分强烈的作用干扰正常的细胞信号和免疫反应，抑制内源性的抗炎信号通道。,中药抗炎药物应用的思路,1）激素、甾体或类似物调节应激状态，阻断炎症介质及衍生物的产生。 如豨莶草、白花蛇舌草、虎杖、甘草、土茯苓、金刚藤、牛膝、知母、浙贝母、半夏、天南星等。2）环氧化酶和脂氧化酶抑制药物阻断炎症介质分子生成。 如豨莶草、白花蛇舌草、虎杖、乳香、没药、黄连、黄柏、黄芩、蒲公英、卷柏、车前草、积雪草等。3) 黄酮和酚类成分的药物抗击氧自由基，调节氧化-抗氧化平衡。 如豨莶草、白花蛇舌草、半枝莲、金钱草、姜黄、郁
32、金、葛根等。,中药调节生物环境的具体方法,4）免疫调节功能的药物促进炎性组织被破坏、吞噬和转移。 如豨莶草、白花蛇舌草、虎杖、黄芪、党参、太子参、茯苓、猪苓、冬虫夏草等。5）促进血液循环、利尿和通便的药物促使被破坏的炎症组织、代谢废物转移和排出体外。 如豨莶草、白花蛇舌草、虎杖、丹参、当归、红花、山楂、三七、三棱、莪术、陈皮、薏苡仁、赤小豆、车前子、大黄等。6）具有抗菌和抗病毒作用药物，某些成分具有蛋白多肽亲和作用，可以静默抗原递呈进而阻断炎性分子的持续产生。7） 一些药物很可能有多重作用。每一个治疗慢性炎症的处方，都可能不同程度地运用了各种类型的药物和各种方法。,中药调节生物环境的具体方法,缓病缓治，对于慢性疾病，以培养机体的正气为主，让机体逐渐恢复；而不主张用大剂量的攻药和泻药以求迅速缓解病情。调节细胞生物环境，用药物辅助恢复机体自身平衡及调节功能。中医药的这些治疗慢性病的思路，值得系统整理、挖掘、研究。,中医药调节生物环境的核心思想,多谢聆听！请批评指正!,
