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1、类风湿关节炎-基础研究及进展,福州市第二医院风湿血液科 医师 王颖、杨华娟,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,WHAT CAUSES RA?,病因,基因在RA遗传易感性和疾病严重程度中的关键作用,遗传易感性显示基因在RA的致病作用中占50% 60%的比重,Genetics,RA的基因,Genetics,Chibnik LB, et al. PLoS One. 2011; 6(9): e24380; Bax M, et al. Immunogenetics. 2011 August; 63(8): 459466; Raychaudhuri B
2、.Curr Opin Rheumatol. 2010 March; 22(2): 109118.,Genetics,RA易感基因-HLA-DRB1位点,PopulationRA-associated DRB1 alleleCaucasian *0401 (HLA-DR4) Ashkenazi 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) Chines
3、e *0405 (HLA-DR4),Genetics,RA 共同表位(Shared Epitope),HLA-DRB1*Amino acid position7071727374 0101QRRAA 0401QKRAA 0404QRRAA 0405QRRAA 0408QRRAA 1001RRRAA 1402QRRAA 0402DERAA 0403QRRAE,Genetics,非II类MHC与RA关联,Genetics,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BTL
4、A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;2011:305656）,Genetics,Genetics,Genetics of rheumatoid arthritis: time for a change!,de Vries, Ren,Current Opinion in Rheumatology: May 2011 p 227232,I conclude that if you want to find more
5、 genes you should have a lot of patience, time and money, stop with convential GWAS and invest in large-scale sequencing 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 mech
6、anism of the known associations!,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；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：,环境因素,Geograph,Smoking,Infections,Others,病因,环境因素致 RA的风险,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,地理位置与R
7、A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,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 2009, 11:2
8、38 (doi:10.1186/ar2751),Smoking,基因与吸烟交互作用促发RA发病,Klareskog L et al. Arthritis Rheum 2006; 54: 38-46,SE和吸烟史共同作用于aCCP+RA患者的风险,Smoking,吸烟- anti-CCPs发生的高危因素,Smoking,吸烟在RA发病机制中的复杂作用,Smoking,感染因素-RA,Infections,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: Arth
9、ritis Rheum 2000 ,43:2160,.),Infections,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,病机-滑膜炎,自身免疫性-RA,细胞因子网络-RA,Bone homeostasis in healthy and RA joints,Yongwon Choi. et al. Nat Rev Rheumatol. 2009; 5(10): 543548.,骨侵蚀的机理,Damage and lack of repair in rheumatoid arthritis.,Lories, R. Nat. Rev. Rheumato
10、l. 2011; 7: 700707.,破骨细胞在关节炎骨侵蚀起核心作用,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):S2,a,b,软骨下骨盐部分,软骨下骨,表层软骨,炎性滑膜（血管翳）,RANK-Ligand 表
11、达介导破骨细胞形成，功能、生存,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.,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,目前
12、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
13、使Osx表达水平（RT-PCR）提高三倍。,CIA大鼠的骨保护作用-MRI,Refer：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 with MTX;
14、 d:CIA rats treated with nimesulidee/f: CIA rats treated with T614; g: CIA rats treated with T-614 and MTX,soft 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。,影像学评估 X线和CT,T-614 offered significant protection against joint damag
15、e,Naive Vehicle MTX nimesulide T614 (5) T614 (20) MTX+T614(10),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。,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,基础研究引导RA的靶向治疗,T cell,APCs,B cell or macrophage,Synoviocytes,Pannus,Articularcartilage,Chondrocytes,HLA,-DR,Production of collagenase and other neutral protease
16、s,Abs,Immune complexes,Articularcartilage,Production of collagenase and other neutral proteases,T cell,APCs,Macrophage,cytokines,Osteoclast,Complements,TNF-IL-1IL-6,RA治疗方法的递进,靶向治疗使RA的治疗目标更高,靶向治疗的种类,TNF-a在RA病理中的作用,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(MM
17、Ps)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,TNFBA+MTX治疗52周对RA放射学的影响,Breedveld FC, et al. Arthritis Rheum. 2006.54:26-37. St Clair EW, et al. Arthri
18、ts 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-nave,PREMIER: 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,Ann Rheum Dis 2010; 69:88-96.,IL-6 受体治疗靶向(Actemra- tocilizuma),Anti-IL-6,BL的进展,CD19 Expr
19、ession,CD40 Expression,CD20 Expression,CD22 Expression,Pro-B cell,ImmatureB cell,MatureB cell,MemoryB cell,IgM,IgM,IgD,B Blast,Ig,GC B cell,Plasma cell,Ig,CD27+CD38+/+IgD-,CD27-,CD38+IgD-,CD27+CD38-IgD-,Plasmablast,IgM,IgD,MemoryB cell,CD27+CD38-,Anti-B cell in RA,抗CD20单抗在 TNF拮抗剂治疗RA患者中的疗效 : 疗程6月,18
20、,5,1,51,27,12,0,10,20,30,40,50,60,ACR20,ACR50,ACR70,% Patients,Placebo (N=201),Rituximab (N=298),p 0.0001,p 0.0001,p 0.0001,Cohen S, et al. Arthritis and Rheumatism 2006:54(9):2793-2806,Anti-T cell,CTLA4lg,CTLA4lg (Abatacept) Effectively Blocks CD28 Dependent Costimulatory Signals,抑制T细胞激活,Anti-T cel
21、l,在RA 患者中通过阻断共刺激途径抑制T细胞活化,1. Kremer et al. Annals of Internal Medicine: 2006; 144:865-876,ACR 20,ACR 50,ACR 70,Placebo + MTX,Abatacept + MTX,ACR Response,抑制细胞信号传导通路,原理抑制酪氨酸激酶CIA有效性成功RA治疗的病例报道 p38 MAPK 抑制剂PamapimodSCIO-469phase II RCT: 缺乏有效性,抑制B细胞和细胞因子,Keiichi Tanaka, Iguratimod (T-614):a novel disea
22、se-modifying anti-rheumatic drug. Rheumatology Reports 2009; volume 1:e4,生物制剂治疗,抑止细胞因子或细胞因子受体的TNFa拮抗剂：依那西普（Etanercept）、英夫利西单抗（Infliximab）、阿达木单抗（Adalimumab）、赛妥珠单抗（Certolizumab）、戈利木单抗（Golimumab）IL-6拮抗剂：托珠单抗（Tocilizumab）IL-1拮抗剂：阿那白滞素（Anakinra）抑止细胞活化的T细胞：阿巴西普（ Abatacept）共刺激阻断B细胞：利妥昔单抗（Rituximab）B细胞清除剂抑制信号小分子化合物小分子化合物，分子量小于1KD，针对细胞内信号途径的，调节细胞生存、增殖、细胞因子或金属蛋白酶的合成。,感谢聆听,
