类风湿性关节炎的基础研究及进展课件(PPT 48页)

1、类风湿关节炎-基础研究及进展第1页，共48页。目录病因 -基因因素 -环境因素病机 -RA滑膜炎 -RA骨侵蚀基础研究引导治疗的发展第2页，共48页。WHAT CAUSES RA? 个体易感基因环境促发因素免疫反应RA病因第3页，共48页。基因在RA遗传易感性和疾病严重程度中的关键作用024681012141618general populationsiblingsdizygoticmonozygoticThe prevalence of RA (%)遗传易感性显示基因在RA的致病作用中占50% 60%的比重Genetics第4页，共48页。RA的基因Genetics of RAMHC Loc

2、iNon-MHCGenetics第5页，共48页。 RA的易感基因Chibnik LB, et al. PLoS One. 2011; 6(9): e24380; Bax M, et al. Immunogenetics. 2011 August; 63(8): 459466; Raychaudhuri B.Curr Opin Rheumatol. 2010 March; 22(2): 109118. Genetics第6页，共48页。RA易感基因-HLA-DRB1位点PopulationRA-associated DRB1 alleleCaucasian *0401 (HLA-DR4) As

3、hkenazi Jewish*0101 (HLA-DR1)Asian Indian*0101 (HLA-DR1)Spanish*1001 (HLA-DR10)Israeli*1001 (HLA-DR10) Yakima Indian*1402 (HLA-DR6)Japanese*0405 (HLA-DR4) Chinese *0405 (HLA-DR4)Genetics第7页，共48页。RA 共同表位(Shared Epitope)HLA-DRB1*Amino acid position7071727374 0101QRRAA 0401QKRAA 0404QRRAA 0405QRRAA 040

4、8QRRAA 1001RRRAA 1402QRRAA 0402DERAA 0403QRRAEGenetics第8页，共48页。非II类MHC与RA关联 Genetics第9页，共48页。RA遗传学到了转变的时候 RA易感基因的功能学研究相对匮乏，仅有3篇相关报道例如：BTLA为一种表达于免疫细胞表面的抑制性受体， BTLA缺陷鼠可发生多种自身免疫病。已发现BTLA基因多态型与RA易感性相关。而且，在体外研究显示，BTLA 590C等位基因的出现使该基因丧失对Jurkat T细胞由Con A或抗CD3单抗诱导的IL-2产生的抑制作用。（Clin Dev Immunol. 2011;2011:30

5、5656）Genetics第10页，共48页。GeneticsGenetics of rheumatoid arthritis: time for a change!de Vries, RenCurrent Opinion in Rheumatology: May 2011 p 227232I conclude that if you want to find more genes you should have a lot of patience, time and money, stop with convential GWAS and invest in large-scale sequ

6、encing of selected patients and controls. I have a better suggestion, however: use the information that is already available to perform functional studies in order to understand the mechanism of the known associations!第11页，共48页。1、对前期发现的RA易感基因在不同人种中的验证工作仍 在继续；2、不同RA亚群与易感基因的关系得到进一步的理解；3、发现新RA易感基因的势头减缓

7、；4、对RA易感基因的功能学研究仍显匮乏，遗传学研究到 了需要转变观念的时候。Genetics遗传学研究总体态势：第12页，共48页。环境因素GeographSmokingInfectionsOthers病因环境因素致 RA的风险第13页，共48页。(0.691.95)1.1653,60517Southeast(1.031.83)1.37286,470108New England(1.051.70)1.33923,854332Mid-Atlantic(1.141.94)1.49399,231160Midwest(ref)1.00321,17589WestAt Age 30*(0.882.44)

8、1.4746,95720Southeast(1.071.98)1.45297,261126New England(0.911.57)1.20973,570334Mid-Atlantic(0.941.69)1.26447,363162Midwest(ref)1.00219,18564WestAt Age 15*MultivariableRR (95% CI)Person-yearsobservationCasesGeographic regions相比西部地区患者，居住在东北区域的患者其发生RA的风险高达45%。相比高纬度的患者，居住在低纬度的RA患者起病更 早。地理区域所致RA的相对风险地理位

9、置与RA风险的相关性Costenbader KH, et al. Arch Intern Med.2008 August 11;168(15): 16641670. Ramos-Remus C, et al. Clin Rheumatol 2007;26:17251728.Geograph第14页，共48页。吸烟与不吸烟者发生血清阳性RA的相对危险度差异吸烟-RA已知环境因素中高危险因素Krishnan E, et al. Arthritis Res Ther.2003;5(3): R158R162; Baka Z, et al. Arthritis Research & Therapy 20

10、09, 11:238 (doi:10.1186/ar2751)Smoking第15页，共48页。基因与吸烟交互作用促发RA发病Klareskog L et al. Arthritis Rheum 2006; 54: 38-46WomenRR (95%CI)MenRR (95%CI)SE hetero. / Smk6.0 (9.3-38.5)15.1 (2.3-100.0)SE homo. / Smk19.0 (9.3-38.5)59.2 (7.7-457.3)SE和吸烟史共同作用于aCCP+RA患者的风险Smoking第16页，共48页。吸烟- anti-CCPs发生的高危因素Smoking第

11、17页，共48页。吸烟在RA发病机制中的复杂作用Smoking第18页，共48页。感染因素-RA Infections第19页，共48页。A 、 B, 免疫组化显示滑膜细胞中 肽聚糖(红色) . C, 双染显示细菌肽聚糖聚积在滑液的巨噬细胞(箭头所示) . RA中聚积的细菌肽聚糖Schrijver IA, et al: Arthritis Rheum 2000 ,43:2160,.)Infections第20页，共48页。目录病因 -基因因素 -环境因素病机 -RA滑膜炎 -RA骨侵蚀基础研究引导治疗的发展第21页，共48页。病机-滑膜炎自身免疫反应血管生长细胞因子致炎性细胞因子趋化因子滑膜增

12、生炎性细胞浸润血管翳形成滑膜炎细胞因子第22页，共48页。自身免疫性-RA第23页，共48页。细胞因子网络-RA第24页，共48页。Bone homeostasis in healthy and RA jointsYongwon Choi. et al. Nat Rev Rheumatol. 2009; 5(10): 543548.骨侵蚀的机理第25页，共48页。Damage and lack of repair in rheumatoid arthritis. Lories, R. Nat. Rev. Rheumatol. 2011; 7: 700707.第26页，共48页。破骨细胞在关节炎

13、骨侵蚀起核心作用第27页，共48页。来自炎性滑膜的破骨细胞正侵蚀软骨下骨盐a Georg Schett Cells of the synovium in rheumatoid arthritis-Osteoclasts , Arthritis Research & Therapy 2007, 9:203b Georg Schett, Erosive arthritis Arthritis Research & Therapy 2007, 9(Suppl 1):S2ab软骨下骨盐部分软骨下骨表层软骨炎性滑膜（血管翳）第28页，共48页。RANK-Ligand 表达介导破骨细胞形成，功能、生存第2

14、9页，共48页。成骨细胞的分化对于骨重建至关重要，其中osterix是目前已经促进成骨细胞分化的关键转录因子K. Nakashima, X. Zhou, G. Kunkel, Z. Zhang, J.M. Deng, R.R. Behringer, B. de Crombrugghe, The novel zinc finger-containingtranscription factor osterix is required for osteoblast differentiationand bone formation, Cell 108 (2002) 1729.第30页，共48页。目前

15、已知中国上市的艾拉莫德片通过促进Osterix表达，促进成骨细胞生成Kuriyama K,Higuchi C,Tanaka K,Yoshikawa H,Itoh K.A novel anti-rheumatic drug, T-614, stimulates osteoblastic differentiation in vitro and bone morphogenetic protein-2-induced bone formation in vivo. Biochem Biophys Res Commun.2002 Dec 20;299(5):903-9.艾得辛在BMP存在的条件下使O

16、sx表达水平（RT-PCR）提高三倍。第31页，共48页。CIA大鼠的骨保护作用-MRIRefer：Fang Du,liang-jing Lv,et al. T-614,a novel immunomodulator,attenuates inflammation and articular damage in collagen induced arthritis. Arthritis Research & Therapy 2008,10:R136 a: normal rats; b: CIA rats treated with vehicle; c: CIA rats treated wit

17、h MTX; d:CIA rats treated with nimesulidee/f: CIA rats treated with T614; g: CIA rats treated with T-614 and MTXabcdefgsoft tissue swelling (yellow arrow) and localization of bone marrow edema (yellow triangle) MRI检测结果：艾得辛能够几乎完全抑制CIA的炎症和骨髓内水肿。第32页，共48页。影像学评估 X线和CTT-614 offered significant protection

18、 against joint damageabcdefgA Naive Vehicle MTX nimesulide T614 (5) T614 (20) MTX+T614(10) abcdefgC X线平片和CT检测结果显示：艾得辛还能够显著抑制骨吸收和关节破坏。第33页，共48页。目录病因 -基因因素 -环境因素病机 -RA滑膜炎 -RA骨侵蚀基础研究引导治疗的发展第34页，共48页。基础研究引导RA的靶向治疗T cellAPCsB cell or macrophageSynoviocytesPannusArticularcartilageChondrocytesHLA-DRProduct

19、ion of collagenase and other neutral proteasesAbsImmune complexesArticularcartilageProduction of collagenase and other neutral proteasesT cellAPCsMacrophageB cellB cellcytokinesOsteoclastComplementsTNF-IL-1IL-6第35页，共48页。RA治疗方法的递进DrugsObjectivesConcepts1980sMTX, D-PA, Gold.Signs & symptomspyramid1990

20、sDMARDs joint damageCombinationLeflunomide2000Bi-DMARDsPrevent joint damageEarly treatmentStop joint damageTight control2008RemissionEarly intensive ttt靶向治疗使RA的治疗目标更高第36页，共48页。TargetNameFunctionAnti-TNFEtanercept Soluable TNF receptorInfiximabChimeric anti-TNF MabAdalimumabFully human anti-TNF MabGo

21、limumabFully human anti-TNF MabCertolizumab Pegol Pegylated Fab fragment of a humanized MoAb against TNFAnti-IL-1anakinraIL-1raRilonaceptDimeric fusion protein: extracellular IL-1R & IgG1-FcAnti-IL-6TocilizumabHumanized anti-human IL-6 receptor antibody UstekinumabMoAb against receptor (p40) of IL-1

22、2 & IL-23, Effective for PsA (phase III)B cellsRituximabanti-CD20 monoclonal antibody that selectively depletes CD20+ B cellsOcrelizumabcompletely humanized anti-CD20Ofatumumabtargets a different CD20 epitope than rituximabEpratuzumabanti-CD22 monoclonal antibodyBelimumabAn anti-BLyS (BAFF) monoclon

23、al antibody AtaciceptTACI-Ig, significant reductions in Ig levels (41 44% in RF in RA pt)T cellsAbataceptCTLA-4 & IgG1-Fc, prevents CD28 from binding to CD80/CD86AlefaceptBlockage of CD2OsteoclastDenosumabHumanized monoclonal antibody against RANKL Othersanti-complement, 靶向治疗的种类第37页，共48页。TNF-a在RA病理中

24、的作用促进滑膜细胞增殖 诱导趋化因子分泌募集白细胞上调血管粘附分子表达白细胞渗出抑制细胞调亡促进血管生长细胞因子分泌新生血管增加前炎性细胞因子等炎性介质产生刺激基质金属蛋白酶(MMPs)表达促进破骨细胞分化、成熟TNF炎性细胞浸润、聚集滑膜增生血管翳形成滑液渗出软骨降解骨侵蚀Choy, E. H.S. et al. N Engl J Med 2001;344:907-916；M M J Herenius,1 R M Thurlings et al. Ann Rheum Dis. 2011 June 1; 70(6): 11601162. TNF拮抗剂第38页，共48页。TNFBA+MTX治疗5

25、2周对RA放射学的影响Breedveld FC, et al. Arthritis Rheum. 2006.54:26-37. St Clair EW, et al. Arthrits Rheum. 2004;50:3432-43.Emery P, et al. Lancet. 2008;372:375-82.Klareskog L, et al. Lancet 2004; 363: 67581.TSS自基线变化均值 均为随机双盲安慰剂对照 入组条件: MTX-navePREMIER: 阿达木; ASPIRE: 英夫利昔; COMET和TEMPO: 依那西普TNFBA显著抑制RA放射学进展第3

26、9页，共48页。Ann Rheum Dis 2010; 69:88-96. IL-6 受体治疗靶向(Actemra- tocilizuma)Anti-IL-6第40页，共48页。BL的进展CD19 ExpressionCD40 ExpressionCD20 ExpressionCD22 ExpressionPro-B cellImmatureB cellMatureB cellMemoryB cellIgMIgMIgDB BlastIgGC B cellPlasma cellIgCD27+CD38+/+IgD-CD27-CD38+IgD-CD27+CD38-IgD-PlasmablastIgMIgDMemoryB cellCD27+CD38-Anti-B cell in RA第41页，共48页。 抗CD20单抗在 TNF拮抗剂治疗RA患者中的疗效 : 疗程6月18515127120102030405060ACR20ACR50ACR70% PatientsPlacebo (N=201)Rituximab (N=298)p 0.0001p 0.0001p 0.0001Coh