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1、抗肾小球基底膜GBM病,抗肾小球基底膜GBM病,抗GBM病的背景,抗GBM病：循环中出现抗GBM抗体、脏器中沉积为特征的自身免疫病1919: Goodpasture首先报道1例18岁男性病人，咯血、急性肾衰竭主要累及肺和肾脏：Goodpasture病内科危重症：危及生命80%就诊时已进入尿毒症（ESRD）,Goodpasure EM. Am J Med Sci 1919;158: 863-870Cui Z, Zhao MH. Nat Rev Nephrol. 2011 Dec 7:697-706,抗GBM病的背景抗GBM病：循环中出现抗GBM抗体、脏器中沉,少见病：1-2/百万人口本研究所：累
2、计诊断500余例国际上最大的临床资源库治疗依赖血浆置换：昂贵，但多为时已晚,抗GBM病仍然是我国内科医生的重大挑战,抗GBM病的发生情况,Cui Z, Zhao MH. Nat Rev Nephrol. 2011 Dec 7:697-706,少见病：1-2/百万人口抗GBM病仍然是我国内科医生的重大,抗GBM病研究现状,Hudson GB. Vanderbilt UniversityGBM molecular architecture of conformational epitopes,Pusey CD. HammersmithImperial College LondonPE in ant
3、i-GBM diseaseWKY rat modelGenetics of EAG models,Segelmark M & Wieslander JLund UniversityRecombinant antigensDetection of anti-GBM disease,Zhao MH & Cui ZPeking UniversityHuman anti-GBM diseaseLinear epitopesMolecular mimicry,Kitching AR. Monash University.MHC and T cell activationAnimal models,Lou
4、 YH. University of TexasT cell epitopeAnimal model,抗GBM病研究现状Hudson GB. Pusey CD.,抗GBM病是典型的自身免疫病,靶抗原3(IV)NC1 （肺、肾）EpitopeEa和Eb-构象性,Saus J, et al. J Biol Chem 1988;15;263:13374-80Salant DJ. N Engl J Med 2010;363;4:381-391,抗GBM病是典型的自身免疫病靶抗原Saus J, et al,抗GBM病的科学问题,病因表型差异,病因,遗传易感背景,自身免疫,T细胞,B细胞,3(IV)NC1
5、,表型？,免疫耐受？,诱发因素？,6,抗GBM病的科学问题病因病因遗传易自身T细胞B细胞3(IV,抗GBM病的科学问题,病因表型差异肾受累轻重1/3合并ANCA少数合并MN,病因,遗传易感背景,自身免疫,T细胞,B细胞,3(IV)NC1,表型？,免疫耐受？,诱发因素？,7,抗GBM病的科学问题病因病因遗传易自身T细胞B细胞3(IV,23/M间断咯血 4 个月，加重1个月HGB: 71g/L; PO2 58mmHg; Scr 94.0 mol/l尿常规: protein (+), RBC 5-8/HPF血清抗GBM抗体 (+), ANCA (-)肾活检: IgG沿GBM线样沉积,肾小球轻微病变治
6、疗：Pred 1 mg/kg/d x 8w, 无PE和CTX随访7年肾功能正常,Cui Z, et al. Kidney Int 2007;72:1403-8,肾受累轻患者介于正常人与重症患者之间？转换机制？,8,23/MCui Z, et al. Kidney Int 2,既往：健康人血清无抗GBM抗体发现天然抗GBM抗体：中国和瑞典：各10名献血员IgG成分-亲和层析“阴性选择”？如何发展成致病性抗体？,Cui Z, et al. Kidney Int 2006:69:894-9Cui Z, et al. Kidney Int 2010;78:590-7,Natural anti-GBM
7、ab,既往：健康人血清无抗GBM抗体Cui Z, et al. K,抗GBM抗体如何转变成致病性？,天然抗GBM抗体,Anti-GBM (+)严重肾受累,Anti-GBM (+)正常肾功能,正常人,病人A,病人 C,Intra-moleculeEpitope spreading,3, 4,1、2、3、4和5,Subclass switching,IgG2、IgG4,IgG1、IgG2、IgG3和IgG4,治疗个体化T细胞调控,3 Ea、 Eb,3内其他位点,Anti-GBM (+)轻度肾受累,病人B,Cui Z, et al. Kidney Int 2006;69:894-9.Yang R,
8、et al. J Am Soc Nephrol 2007;18(4):1338-43.Cui Z, et al. Kidney Int 2007;72(11):1403-8.Zhao J 8(1):51-8.,Inter-moleculeEpitope spreading,抗GBM抗体如何转变成致病性？天然抗GBM抗体Anti-GB,NATURE REVIEWS | NEPHROLOGY,Cui Z, Zhao MH. Nat Rev Nephrol. 2011 Dec;7:697-706.,Cui Z, Zhao MH. Nat Rev Nephro,抗GBM病的科学问题,病因表型差异肾受累
9、轻重1/3合并ANCA少数合并MN,病因,遗传易感背景,自身免疫,T细胞,B细胞,3(IV)NC1,表型？,免疫耐受？,诱发因素？,抗GBM病的科学问题病因病因遗传易自身T细胞B细胞3(IV,抗GBM病合并MN,个例报道MN GBM damage：释放3 抗GBM 病抗GBM病足细胞损伤：表达M-PLA2R MN,13,抗GBM病合并MN个例报道13,8 patients with MN and anti-GBM diseaseSequential or simultaneousBetter prognosisAnti-3 (+): narrow antigen spectrumAnti-PL
10、A2R (-),Jia XY, et al. Kidney Int2014 Apr;85(4):945-52,8 patients with MN and anti-GB,抗GBM病的科学问题,病因易感性：HLA？诱发因素病因表型差异,病因,遗传易感背景,自身免疫,T细胞,B细胞,3(IV)NC1,表型？,免疫耐受？,诱发因素？,抗GBM病的科学问题病因病因遗传易自身T细胞B细胞3(IV,抗GBM病的免疫学发病机制,Linear toConformational,涉及感染、抗原递呈、抗原决定簇扩展、分子模拟,16,抗GBM病的免疫学发病机制?Linear涉及感染、抗原递呈、,Backgroun
11、d ( HLA ),HLA geneLocation: CHR 6p21.3Classical HLA gene MHC class II molecular: Distribution : DCs、B cells、MStructure: hetero-dimerrecognized by CD4+ T cell Ag processed 、presentation MHC & disease: MS、RA、IDDM、 SLE et al.,Background ( HLA )HLA gene,(Rees, Kid Int, 1999),Dominantly protective allele
12、s DR1 and DR7,No gene dosage effect,MHC II dominant protection,HLA-DRB1*01:01 generates 3136-146 specific regulatory T cells.HLA-DRB1*15:01 generates 3136-146 specific effector T cell precursors.In HLA-DRB1*15:01x01:01 mice, 3136-146 specific effector T cell precursors are dominantly suppressed by 3
13、136-146 specific regulatory T cells,Rees et al, Kidney Int 1999 Ooi et al, J Am Soc Nephrol 2013,18,(Rees, Kid Int, 1999)Dominantl,DRB1*1501 allele：p=1.597107 DRB1*0404 allele：p=0.037 Patients with DRB1*1501 or *0404 had more crescent formation. (p=0.021).,Yang R. et al. Clin Immunol 2009;133:245-25
14、0,DRB1*1501 allele：p=1.597107,Association of HLA alleles (4 digits, P3.55E-4),Determine the significantvariation marker of genotypeCase: 138 vs. Control: 599,rs41541412: the only significant SNP, belongs to DQA1*0502 nonsense mutation, change the 82th AA of DQ polypeptide.,Association of a novel HLA
15、 SNP(P1.9E-4),Unpublished data,Association of HLA alleles (4,Extended haplotypes among HLA-DRB1, DQA1 ,DQB1,DPB1 in anti-GBM disease,Unpublished data,21,Extended haplotypes among HLA-,LOD3:Confirmed linkage. LOD-2: No linkage. LOD=0: the possibility is equal,Linkage analysis among the significant al
16、leles,Unpublished data,LOD3:Confirmed linkage. LOD,抗GBM病的科学问题,病因易感性诱发因素：环境？病因表型差异,病因,遗传易感背景,自身免疫,T细胞,B细胞,3(IV)NC1,表型？,免疫耐受？,诱发因素？,抗GBM病的科学问题病因病因遗传易自身T细胞B细胞3(IV,抗GBM病的科学问题,病因易感性诱发因素病因：感染？表型差异,病因,遗传易感背景,自身免疫,T细胞,B细胞,3(IV)NC1,表型？,免疫耐受？,诱发因素？,24,抗GBM病的科学问题病因病因遗传易自身T细胞B细胞3(IV,假说：微生物可能是抗GBM病的病因之一,1919: Go
17、odpasture首先报道1例18岁男性病人，咯血、急性肾衰竭流感？60%的患者发病前有前驱感染症状病原微生物-分子模拟?,Goodpasure EM. Am J Med Sci 1919;158: 863-870,分子模拟,B细胞表位T细胞表位,25,假说：微生物可能是抗GBM病的病因之一1919: Goodp,B细胞的线性抗原决定簇,合成24条重叠肽段：覆盖3(IV)NC1的234aa起始的线性抗原决定簇：P14（aa129-150）,Initiation epitope?,Risk epitope?,Jia XY, et al. Clin J Am Soc Nephrol 2012 Ju
18、n;7(6):926-33,B细胞的线性抗原决定簇合成24条重叠肽段：Initiatio,P14(22mer)诱发WKY大鼠抗GBM肾炎,P14（aa129-150）分子内抗原决定簇扩展诱发自身免疫性T细胞增殖T/B细胞共同抗原决定簇,Unpublished data,P14(22mer)诱发WKY大鼠抗GBM肾炎P14（aa1,B细胞的关键抗原决定簇与核心氨基酸基序,P14氨基酸序列:P14: TDIPPCPHGWISLWKGFSFIMFP14a:TDIPPCPHGWISLP14b: CPHGWISLWKGFSP14c: ISLWKGFSFIMFT,P14c逐个氨基酸突变B细胞识别的关键氨基
19、酸基序GFxF,Unpublished data,B细胞的关键抗原决定簇与核心氨基酸基序P14氨基酸序列:P1,Critical motif on P14 for pathogenicity,P14-1 ADIPPCPHGWISLWKGFSFIMFP14-2 TAIPPCPHGWISLWKGFSFIMFP14-3 TDAPPCPHGWISLWKGFSFIMFP14-4 TDIAPCPHGWISLWKGFSFIMFP14-5 TDIPACPHGWISLWKGFSFIMFP14-6 TDIPPAPHGWISLWKGFSFIMFP14-7 TDIPPCAHGWISLWKGFSFIMFP14-8 TD
20、IPPCPAGWISLWKGFSFIMFP14-9 TDIPPCPHAWISLWKGFSFIMFP14-10 TDIPPCPHGAISLWKGFSFIMFP14-11 TDIPPCPHGWASLWKGFSFIMFP14-12 TDIPPCPHGWIALWKGFSFIMFP14-13 TDIPPCPHGWISAWKGFSFIMFP14-14 TDIPPCPHGWISLAKGFSFIMFP14-15 TDIPPCPHGWISLWAGFSFIMFP14-16 TDIPPCPHGWISLWKAFSFIMFP14-17 TDIPPCPHGWISLWKGASFIMFP14-18 TDIPPCPHGWISL
21、WKGFAFIMFP14-19 TDIPPCPHGWISLWKGFSAIMFP14-20 TDIPPCPHGWISLWKGFSFAMFP14-21 TDIPPCPHGWISLWKGFSFIAFP14-22 TDIPPCPHGWISLWKGFSFIMA,Unpublished data,Tryptophan138, Isoleucine139, Leucine141, and Tryptophan142,P14129-150: TDIPPCPHGWISLWKGFSFIMF,Critical motif on P14 for path,抗GBM病-病因研究,针对致病微生物的研究细菌、病毒等培养（尚
22、无来源）合成抗原分子利用生物信息学预测可能的T/B细胞抗原决定簇确定抗GBM病患者是否感染血清抗致病微生物蛋白抗体动物实验验证其致病性,抗GBM病-病因研究针对致病微生物的研究,8 patients with MN and anti-GBM diseaseSequential or simultaneousBetter prognosisAnti-3 (+): narrow antigen spectrumAnti-PLA2R (-)原因？,Jia XY, et al. Kidney Int2014 Apr;85(4):945-52,8 patients with MN and anti-GB
23、,人3(IV)NC1诱发了小鼠膜性肾病,DBA/1 mice (vs. WKY rat)rh-a3(IV)NC1Nephrotic SyndromeEM：MN,Zhang JJ, et al. J Immunol. 2012 Apr 1;188(7):3268-77,人3(IV)NC1诱发了小鼠膜性肾病DBA/1 mice,Membranous nephropathy induced by P13, P14, P15 on DBA/1 mice,Unpublished data,Membranous nephropathy induced,Microbial?,HLA-DRB1*1501Lik
24、e H-2?,MHC?,Anti-GBM disease,MN,Podocyte protein?Podocyte 3？,抗原递呈-MHC-II: DBA1 mice vs. WKY ratHuman？靶抗原小鼠3？足细胞抗原？病因-关键氨基酸与分子模拟？,Human 3,Intra-molecule epitope spreading,Inter-molecule epitope spreading,Rat 3,Microbial?HLA-DRB1*1501MHC?Ant,小结,抗GBM病并非罕见, 仍为肾科医生的挑战自身抗体免疫学特性的变化与疾病进展密切相关抗GBM病的病因有待明确和证实,35,小结抗GBM病并非罕见, 仍为肾科医生的挑战35,
