免疫炎性疾病新認識及中西醫(yī)結(jié)合臨床對策

1、免疫炎性疾病新認識及中西醫(yī)結(jié)合臨床對策,南方醫(yī)科大學珠江醫(yī)院風濕免疫科于清宏2014年9月13日沈陽,3/24/2024,,,3/24/2024,,,3/24/2024,,,非可控性炎癥——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,炎癥定義,Inflamm

2、ation is a two-edged sword,serves as a protective response, but is often a major cause of tissue damage in infectious, immunologic, and vascular diseases, as well as after trauma.,,紅腫熱痛功能障礙,促炎/抗炎細胞因子平衡,炎癥是一個程序化過程,炎癥細胞表

3、型轉(zhuǎn)變,Heredity, Nonresolving inflammation and autoimmune diseases,先天稟賦,外感內(nèi)傷,證候,部分自身免疫性疾病,免疫介導的炎性疾病,Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulationRA, IBD, MS, psoriasis, ma

4、ny othersAffect 2-5% of people, incidence increasingMay result from immune responses against self antigens (autoimmunity) or microbial antigens (Crohn’s disease?)May be caused by T cells and antibodiesMay be syste

5、mic or organ-specific,自身免疫病理過程,Susceptibility genes,Environmental trigger(e.g. infections, tissue injury),,,Failure ofself-tolerance,Activation ofself-reactive lymphocytes,Immune responses against self tissues,Persi

6、stence of functionalself-reactive lymphocytes,,,,,,ActivationEffector T cells,,Normal: reactions against pathogensInflammatorydisease, e.g. reactions against self,ToleranceRegulatory T cells,,No response to selfCon

7、trolled response to pathogens,淋巴細胞活化及控制的平衡,陽,陰,自身免疫的遺傳背景,Human autoimmune diseases are complex polygenic traitsIdentified by genome-wide association mappingSingle gene mutations are useful for pathway analysisSome po

8、lymorphisms are associated with multiple diseasesMay control general mechanisms of tolerance and immune regulationOther genetic associations are disease-specificMay influence end-organ damage,NOD2: polymorphism assoc

9、iated with ~25% of Crohn’s diseaseMicrobial sensorPTPN22: commonest autoimmunity-associated gene; polymorphism in RA, SLE, othersPhosphataseCD25 (IL-2R?): associated with MS, others; genome-wide association mappingR

10、ole in Tregs,自身免疫遺傳背景: 最近發(fā)現(xiàn),感染與自身免疫,Infections trigger autoimmune reactionsClinical prodromes, animal modelsAutoimmunity develops after infection is eradicated (i.e. the autoimmune disease is precipitated by infection

11、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 “h

12、ygiene hypothesis”,主要免疫反應類型決定疾病自然病程Th1 response: inflammation, autoantibody production; autoimmune diseasesTh2 response: IgE+eosinophil-mediated inflammation; allergic reactionsTh17 response: acute (and chronic?) inf

13、lammation; increasingly recognized in immune-mediated diseases,,,,,Th1 cells (IFN-g),Th2 cells (IL-4, IL-5),Th17 cells (IL-17),Naïve CD4T cell,CD4 細胞亞群: 產(chǎn)生及功能,,Regulatory T cells,IFN-?, IL-12:T-bet, Stat4,IL-4:GA

14、TA3, Stat6,TGF-? + IL-6:ROR?t, Stat3,TGF-???IL-2:Foxp3, Stat5,Host defense: many microbesSystemic and organ-specific autoimmune diseases,Host defense: helminthsAllergic diseases,Host defense: fungi, bacteria Organ-

15、specific autoimmune diseases,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

16、 antigen.,部分隱蔽抗原,器官特異性自身免疫病理,Current therapies target late stages of the reaction (lymphocyte activation, inflammation).Ultimate goal should be to tackle the underlying cause and restore control of the abnormally d

17、irected response,免疫炎性疾病代表疾病,類風濕關節(jié)炎?,脊柱關節(jié)炎?,血管炎?,類風濕關節(jié)炎免疫炎癥機制研究狀況,HLA表型與等位基因變異檢測,,,類風濕關節(jié)炎相關HLA-DR4結(jié)合表位,RA相關共享表位氨基酸序列,多基因疾病,,脊柱關節(jié)炎免疫炎癥機制研究現(xiàn)狀,強直性脊柱炎的易感基因,Nature Genetics 2013;45(7):730-8,IBD / subclinical ileitisHLA-B27,,e

18、xcess 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;18:1069–76,ERAP1 associated with HLA-B27+ve AS,Nat

19、ure Genetics 2011;43:761-767,Picture courtesy of Dr. Eric Reits,ERAP1/ERAP2 process antigenic peptide epitopes before loading onto HLA-B27,,,Nucleus,Immunoreceptor

20、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 SNP N392K affects both

21、 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 & Genomic Medicine 2013; 1(2): 98–107,Evnouchidou

22、et al. J Immunol 2012; 189(5):2383,ERAP1 SNPs at positions 528 and 730 affect both enzyme activity and antigen presentation,kcat/KM,Ki,MHCI levels,Evnouchidou et al. J Immunol 2011,Length selection can be altered by p

23、olymorphic variation,Garcia et al. MCP, 2012,Evnouchidou et al. J Immunol 2012; 189(5):2383,SNPs are “scattered” all over the protein structure,AS易感基因的貢獻值,腸道菌微生態(tài)與免疫炎性疾病,AS,CD,HC,Bacteroides,Acintobacteria,Firmicutes,Fu

24、sobacteria,Proteobacteria,AS gut microbiome is different to CD and HC,,Bacterial control,機械壓力的骨贅形成的作用,Ann Rheum Dis 2013,遺傳和環(huán)境因素共同導致疾病的發(fā)生,Nature Med 2012;18:1018,IL23介導的T細胞參與了AS的致病,強直性脊柱炎的致病機理假說,,,IL-17IL-1IL-6TNF-α,N

25、ature 2014,Connection of biological RA risk genes to drug targets,Scher et al. eLife 2013;2:e01202. DOI: 10.7554/eLife.01202,Prevotella copri correlates with enhanced susceptibility to arthritis,,血管炎發(fā)病機制研究現(xiàn)狀,免疫學新進展-,免疫系統(tǒng)

26、,,創(chuàng)新點選擇-,免疫學新進展-應答類型,腸道上皮細胞的正常屏障作用,Microbial recognition promotes IEC health and function,Nature Review Immunology, 2013, 13:75-87,新的免疫細胞-ILC（innate Lymphoid cells),模式識別受體（pattern recognition receptors, PRRs):TLRs,NLR,n

27、udeotide oligmerization domain（NOD）-like receptors, NLRs,CARD: Caspase activation and recruitment domainASC: Apoptosis-associated speck-like protein containing CARD,3/24/2024,NOD-like receptors, NLRs,NLRP3,植物藥抗炎機制研究舉例,調(diào)

28、節(jié)免疫功能紊亂,,Wei W et al, Int Immunophar, 2002,2005,2009梁君山，魏偉，等. 中國藥理學通報，1989,5:354-357 王興旺，魏偉，等. 中國藥理學通報，1990,6:363-366 周玲玲，魏 偉，等 .中國藥理學通報，2002,18::175-177,白芍總苷機理研究,TGP是否能夠作用與DC及相應后果？,,DC分化發(fā)育和成熟,MDP：Lin- CX3CR1+ CD11b

29、- CD115+ cKit+ CD135+CDP：Lin- CD115+ Flt3+ CD117lo,Flt3：FMS樣酪氨酸激酶3， (Flt3L，配體),,imDC,mDC,TGP,白芍總苷（total glucosides of paeonia，TGP）,,,,,,OVA免疫,明確現(xiàn)象---TGP抑制免疫應答,抑制T細胞活化增殖,抑制機體對于新入侵抗原的免疫應答,探討關鍵表型--TGP抑制DC成熟,被動轉(zhuǎn)移實驗：mDC恢復小鼠對

30、于OVA反應,,,證實TGP抑制DC成熟而導致免疫應答降低,探討機理--TGP抑制TLR-MyD88/NF-kB活化,,與疾病治療-RA-CIA模型,CII+CFACII+IFA,,,,細胞亞群、細胞因子、信號轉(zhuǎn)導,,,n=10/組3次重復16分評分,DBA1,,明確現(xiàn)象-TGP延緩和減輕CIA發(fā)病與炎癥,提前使用TGP，延緩并減輕CIA發(fā)病,,,,,機理-TGP抑制DC成熟 降低CII免疫應答,明確表型-TGP降低Th1/Th

31、17細胞亞群和功能,,臨床驗證-TGP降低RA患者Th1/Th17,,,,TNFa產(chǎn)生細胞減少,PSA? TGP?,TGP作用后PSA樣小鼠體內(nèi)M1細胞活性降低,TGP – 抑制M1，上調(diào)M2（體外）,The Novel Role of Total Glucosides of Paeony in Regulating Type I and II Macrophages Activities in vivo and in vitro, E

32、xperimental Dermatology, 2014, in revision,,TGP干擾TLR4與LPS結(jié)合，阻斷信號轉(zhuǎn)導Int Immunophar,2012,12:275-82,,TLR4和TGP,TLR4-MD2-LPS Complex (Nature 2009),,,TLR4-LPS結(jié)合部位,,,,TLR4和TGP,免疫炎性疾病治療現(xiàn)狀,糖皮質(zhì)激素作用機制,糖皮質(zhì)激素受體（GCR）有核細胞都有GCR直接或間接影

33、響基因轉(zhuǎn)錄10-100個基因具有GC反應元素（GC response element送，GCE）直接抑制NF-kB,抑制細胞因子產(chǎn)生間接抑制NF-kB 、I-kB影響轉(zhuǎn)錄后過程mRNA翻譯、蛋白質(zhì)合成、蛋白質(zhì)分泌,抑制促炎因子IL-1、IL-6、IL-13、GM-CSF、TNF-a減少炎癥部位白細胞聚集?通過抑制促炎癥因子、 NF-kB抑制黏附分子E-selectin、VCAM-1、ICAM-1抑制烷酸產(chǎn)物如白三

34、烯（leukotriene）降低血管滲透性,皮質(zhì)類固醇 抗炎作用 相當劑量 鹽皮激效應 藥理T1/2 血漿T1/2 h min氫化可的松 1 20 2＋ 8～12 90

35、 可的松 0.8 25 2＋ 8～12 30強的松 3.5 5 1＋ 12～36 60強的松龍 4

36、 5 1＋ 12～36 200甲強龍 5 4 0 12～36 180曲安西龍 5 4

37、 0 24～48 300 地塞米松 30 0.75 0 36～54 100 ～300 倍他米松 25 0.80 0

38、 36～54 100 ～300 氯地米松 40 0.50 0,全身性應用皮質(zhì)類固醇的當量比較,,,,,,,,,,,,糖皮質(zhì)激素全身應用副作用,內(nèi)分泌系統(tǒng)抑制腎上腺抑制生長、兒童性成熟延遲體重增加、柯興貌糖尿病代謝紊亂低血鉀癥、高血糖、高血脂骨骼肌肉系統(tǒng)骨質(zhì)疏松、椎骨壓縮性骨折骨無菌性壞死（髖、肩、膝）肌?。?/p>

39、急性或慢性）皮膚皮膚變薄紫紋痤瘡多毛,眼白內(nèi)障青光眼免疫系統(tǒng)IgG降低喪失延遲性過敏反應感染增加?心血管系統(tǒng)高血壓動脈粥樣硬化血液系統(tǒng)淋巴細胞減少嗜酸細胞減少中性粒細胞增加精神/神經(jīng)情緒反常精神分裂,免疫抑制劑類型,Calcineurin inhibitorsCyclosporineTacrolimusPurine synthesis inhibitorsAzathioprin

40、eMycophenolate mofetilNonspecificprednisone,Target of Rapamycin inhibitorSirolimusPolyclonal antibodies (bind several CD’s)Thymoglobulin ?Atgam ?Monoclonal AntibodiesBlocks IL-2 receptorDaclizumabBasilixmabOK

41、T3 (anti-CD3),,,,,,,,,,,,,,,,,,,,,,,IL-2R,G0,G0,G1,S,G2/M,G1/0,,,,,,,,,,T-cell,STEROIDCTLA-4-FcγFUSION PROTEINU. V.,CYCLOSPORINFK506STEROID,RAPAMYCIN,AZATHIOPRINE(6MP)METHOTREXATEMIZORBINEMYCOPHENOLICBREQUINAR

42、,CYCLOSPHOSPHAMIDEX-RAYS,Activationby antigen,IL-2response,DNAsynthase,Mitosis,ANTI: TCRCD3CD4/8CD45RBLFA-1ICAM1,ANTI-IL-2R±TOXINS,IL-2R,Cytokinesynthesis,Therapeuticmonoclonals,Drugs and othertreatment

43、s,部分免疫抑制劑轉(zhuǎn)環(huán)節(jié),Reduce inflammation TNF-alpha blockers (RA, Crohn’s dis., psoriasis)e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Ab’s against IL6R and IL-15R Statins, shown to lower CRP (RA, M

44、S) Rituxin = monoclonal Ab = anti-CD20Eliminates B cells in non-Hodgkins lymphoma (maybe also RA, and other Ab-mediated autoimmune diseases),免疫炎性疾病生物制劑治療,其他可能的治療通道,,T cell vaccines (against activated Ag-speci

45、fic 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 mice than human

46、s,其他可能的治療通道,,中西醫(yī)結(jié)合抗炎機制研究思路,炎癥的消退是多個協(xié)同作用的結(jié)果；多機制通道可以恢復細胞環(huán)境；內(nèi)源性抗炎因子產(chǎn)生的機制有待深入研究；調(diào)節(jié)炎癥產(chǎn)生的環(huán)境是新的治療選擇 。,中藥抗炎藥物應用的思路,如何調(diào)節(jié)炎癥產(chǎn)生的環(huán)境？氧化應激和自由基；氧化-抗氧化狀態(tài)的不平衡；氧化-抗氧化的再平衡。,中藥抗炎藥物應用的思路,植物抗氧化劑:安全和有效的慢性抗炎藥物? 炎癥介質(zhì)、促炎的細胞因子和自由基產(chǎn)生的復雜機制。植物

47、藥物中和自由基，而不破壞細胞存在的生物環(huán)境機制。,天然抗炎藥物應用的思路,抗炎中藥優(yōu)勢設想：第一、多通道阻斷炎癥介質(zhì)產(chǎn)生；第二、多成分低濃度調(diào)節(jié)局部環(huán)境；第三、整體溫和作用和動員機體本身的抗炎機制調(diào)節(jié)環(huán)境第四、增強抗炎能力、防止組織損傷同時不會因過分強烈的作用干擾正常的細胞信號和免疫反應，抑制內(nèi)源性的抗炎信號通道。,中藥抗炎藥物應用的思路,1）激素、甾體或類似物調(diào)節(jié)應激狀態(tài)，阻斷炎癥介質(zhì)及衍生物的產(chǎn)生。 如豨薟草

48、、白花蛇舌草、虎杖、甘草、土茯苓、金剛藤、牛膝、知母、浙貝母、半夏、天南星等。2）環(huán)氧化酶和脂氧化酶抑制藥物阻斷炎癥介質(zhì)分子生成。 如豨薟草、白花蛇舌草、虎杖、乳香、沒藥、黃連、黃柏、黃芩、蒲公英、卷柏、車前草、積雪草等。3) 黃酮和酚類成分的藥物抗擊氧自由基，調(diào)節(jié)氧化-抗氧化平衡。 如豨薟草、白花蛇舌草、半枝蓮、金錢草、姜黃、郁金、葛根等。,中藥調(diào)節(jié)生物環(huán)境的具體方法,4）免疫調(diào)節(jié)功能的藥物促進炎性組織被破壞、

49、吞噬和轉(zhuǎn)移。 如豨薟草、白花蛇舌草、虎杖、黃芪、黨參、太子參、茯苓、豬苓、冬蟲夏草等。5）促進血液循環(huán)、利尿和通便的藥物促使被破壞的炎癥組織、代謝廢物轉(zhuǎn)移和排出體外。 如豨薟草、白花蛇舌草、虎杖、丹參、當歸、紅花、山楂、三七、三棱、莪術、陳皮、薏苡仁、赤小豆、車前子、大黃等。6）具有抗菌和抗病毒作用藥物，某些成分具有蛋白多肽親和作用，可以靜默抗原遞呈進而阻斷炎性分子的持續(xù)產(chǎn)生。7） 一些藥物很可能有多重