类风湿性关节炎的基础研究及进展.ppt

类风湿关节炎 -基础研究及进展,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.Curr Opin Rheumatol. 2010 March; 22(2): 109118.,Genetics,RA易感基因-HLA-DRB1位点,Population RA-associated DRB1 allele Caucasian *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) Chinese *0405 (HLA-DR4),Genetics,RA 共同表位(Shared Epitope),HLA-DRB1* Amino acid position 70 71 72 73 74 0101 Q R R A A 0401 Q K R A A 0404 Q R R A A 0405 Q R R A A 0408 Q R R A A 1001 R R R A A 1402 Q R R A A 0402 D E R A A 0403 Q R R A E,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;2011:305656）,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 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 mechanism 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,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, 11:238 (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: Arthritis 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. Rheumatol. 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, 9:203 b 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 表达介导破骨细胞形成，功能、生存,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-containing transcription factor osterix is required for osteoblast differentiationand bone formation, Cell 108 (2002) 1729.,目前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; d:CIA rats treated with nimesulide e/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 damage,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,Articular cartilage,Chondrocytes,HLA,-DR,Production of collagenase and other neutral proteases,Abs,Immune complexes,Articular cartilage,Production of collagenase and other neutral proteases,T cell,APCs,Macrophage,cytokines,Osteoclast,Complements,TNF- IL-1 IL-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(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,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. 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-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 Expression,CD40 Expression,CD20 Expression,CD22 Expression,Pro-B cell,Immature B cell,Mature B cell,Memory B 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,Memory B 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,18,5,1,51,27,12,0,10,20,30,40,50,60,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 cell,在