临床免疫学：临床免疫学总论完整版

临床免疫学总论

2总论提纲一、免疫相关基本概念二、临床免疫相关疾病三、临床免疫相关机构四、临床免疫相关技术五、临床应用相关进展六、国内外的应用指南3一、免疫相关基本概念4Immunis--免除瘟疫

ThefirstrecordedattemptstoinduceimmunitydeliberatelywereperformedbytheChineseinthe15thcentury.In1718,LadyMaryWortleyMontagu,thewifeoftheBritishambassadortoConstantinople,observedthepositiveeffectsofvariolationonthenativepopulationandhadthetechniqueperformedonherownchildren.ThemethodwassignificantlyimprovedbytheEnglishphysicianEdwardJenner,in1798.Immunology,5thed,Oct2002,byRichardA.GoldsbyIn1885,Pasteuradministeredhisfirstvaccinetoahuman,ayoungboywhohadbeenbittenrepeatedlybyarabiddog5‘prophylacticimmunization’inancientChinesemedicinebooks

葛洪(283-363)：肘后备急方孙思邈(581-682)：备急千金要方CaoX.NatureImmunology2008;9(4)6GeraldM.EdelmanBorn:1July1929,NewYork,NY,USAAffiliationatthetimeoftheaward:RockefellerUniversity,NewYork,NY,USARodneyR.PorterBorn:8October1917,Newton-le-Willows,UnitedKingdomDied:6September1985,Winchester,UnitedKingdomAffiliationatthetimeoftheaward:UniversityofOxford,Oxford,UnitedKingdom1972NobelPrize:"fortheirdiscoveriesconcerningthechemicalstructureofantibodies"7SusumuTonegawaBorn:6September1939,Nagoya,JapanAffiliationatthetimeoftheaward:MassachusettsInstituteofTechnology(MIT),Cambridge,MA,USA1987NobelPrize:"forhisdiscoveryofthegeneticprincipleforgenerationofantibodydiversity"8GeorgesJ.F.KöhlerBorn:17April1946,Munich,GermanyDied:1March1995,FreiburgimBreisgau,GermanyAffiliationatthetimeoftheaward:BaselInstituteforImmunology,Basel,SwitzerlandCésarMilsteinBorn:8October1927,BahiaBlanca,ArgentinaDied:24March2002,Cambridge,UnitedKingdomAffiliationatthetimeoftheaward:MRCLaboratoryofMolecularBiology,Cambridge,UnitedKingdom1984NobelPrize:"fortheoriesconcerningthespecificityindevelopmentandcontroloftheimmunesystemandthediscoveryoftheprincipleforproductionofmonoclonalantibodies"9BarujBenacerrafBorn:29October1920,Caracas,VenezuelaDied:2August2011,Boston,MA,USAAffiliationatthetimeoftheaward:HarvardMedicalSchool,Boston,MA,USAJeanDaussetBorn:19October1916,Toulouse,FranceDied:6June2009,Palma,Majorca,SpainAffiliationatthetimeoftheaward:UniversitédeParis,LaboratoireImmuno-Hématologie,Paris,FranceGeorgeD.SnellBorn:19December1903,Bradford,MA,USADied:6June1996,BarHarbor,ME,USAAffiliationatthetimeoftheaward:JacksonLaboratory,BarHarbor,ME,USA1980NobelPrize:"fortheirdiscoveriesconcerninggeneticallydeterminedstructuresonthecellsurface(MHC)thatregulateimmunologicalreactions"10PeterC.DohertyBorn:15October1940,Brisbane,AustraliaAffiliationatthetimeoftheaward:St.JudeChildren'sResearchHospital,Memphis,TN,USARolfM.ZinkernagelBorn:6January1944,Basel,SwitzerlandAffiliationatthetimeoftheaward:UniversityofZurich,InstituteofExperimentalImmunology,Zurich,Switzerland1996NobelPrize:"fortheirdiscoveriesconcerningthespecificityofthecellmediatedimmunedefence(MHC-Ag-TCR)"11JulesBordetBorn:13June1870,Soignies,BelgiumDied:6April1961,Brussels,BelgiumAffiliationatthetimeoftheaward:BrusselsUniversity,Brussels,Belgium1919NobelPrize:"forhisdiscoveriesrelatingtoimmunity(complement)"*receivedhisNobelPrizeoneyearlater,in1920.

12IlyaIlyichMechnikovBorn:16May1845,Kharkov(nowKharkiv),RussianEmpire(nowUkraine)Died:16July1916,Paris,FranceAffiliationatthetimeoftheaward:InstitutPasteur,Paris,France1908NobelPrize:"inrecognitionoftheirworkonimmunity(phagocytosis)"13BruceA.BeutlerBorn:1957,Chicago,IL,USAAffiliationatthetimeoftheaward:UniversityofTexasSouthwesternMedicalCenteratDallas,Dallas,TX,USA,TheScrippsResearchInstitute,LaJolla,CA,USAJulesA.HoffmannBorn:1941,Echternach,Luxembourg2011NobelPrize:"fortheirdiscoveriesconcerningtheactivationofinnateimmunity"14RalphM.SteinmanBorn:1943,Montreal,CanadaDied:30September2011Affiliationatthetimeoftheaward:RockefellerUniversity,NewYork,NY,USA2011NobelPrize:"forhisdiscoveryofthedendriticcellanditsroleinadaptiveimmunity"15Clinicalandlaboratorydisciplinedealingwiththediagnosisandmanagementofdiseasesinwhichtheimmunesystemisinvolvedineitherpathogenesisortreatmentorboth.

ClinicalImmunologists

ClinicalLaboratoryImmunologistsDefinitionofClinicalImmunologyFaheyJL.TheImmunologist1995;3(3):10416二、临床免疫相关疾病17Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.Cancers

7.TransplantationsClinicalImmunology18FrançoiseBarré-SinoussiBorn:30July1947,Paris,FranceAffiliationatthetimeoftheaward:RegulationofRetroviralInfectionsUnit,VirologyDepartment,InstitutPasteur,Paris,FranceLucMontagnierBorn:18August1932,Chabris,FranceAffiliationatthetimeoftheaward:WorldFoundationforAIDSResearchandPrevention,Paris,France2008NobelPrize:"fortheirdiscoveryofhumanimmunodeficiencyvirus"上海市HIV检测量20Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.cancers

7.TransplantationsClinicalImmunology21Immunoelectrophoresis(-)(+)22FixedImmunoelectrophoresis23Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.cancers

7.TransplantationsClinicalImmunology24CharlesRobertRichetBorn:26August1850,Paris,FranceDied:4December1935,Paris,FranceAffiliationatthetimeoftheaward:SorbonneUniversity,Paris,France1913NobelPrize:"inrecognitionofhisworkonanaphylaxis"25Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.cancers

7.TransplantationsClinicalImmunology26DCTBYYYY自身免疫与自身免疫性疾病27自身免疫性疾病种类累及各个器官，已知的有80多种神经系统疾病内分泌系统皮肤和其它结缔组织眼睛、血液和血管系统28自身免疫性疾病流行情况

中国 4100万巴西 580万墨西哥330万德国260万法国190万俄罗斯450万伊朗

210万埃及240万埃塞俄比亚 230万印度 3300万加拿大 100万泰国 200万29Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.cancers

7.TransplantationsClinicalImmunology30BaruchS.BlumbergBorn:28July1925,NewYork,USADied:5April20111976NobelPrize:"forhisdiscoveriesconcerningnewmechanismsfortheoriginanddisseminationofinfectiousdiseases"31Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.Cancers

7.TransplantationsClinicalImmunology32前十位恶性肿瘤死亡率顺位2004-20051990-19921973-1975疾病名称死亡率(1/10万)疾病名称死亡率(1/10万)疾病名称死亡率(1/10万)1肺癌30.83胃癌25.16胃癌19.542肝癌26.26肝癌20.37食管癌18.833胃癌24.71肺癌17.54肝癌12.544食管癌15.21食管癌17.38肺癌7.095结直肠癌7.25结直肠癌5.30子宫颈癌5.236白血病3.84白血病3.64结直肠癌4.607脑瘤3.13子宫颈癌1.89白血病2.728女性乳腺癌2.90鼻咽癌1.74鼻咽癌2.329胰腺癌2.62女性乳腺癌1.72女性乳腺癌1.6510骨癌1.70

总计134.80

108.26

83.653334HaraldzurHausenBorn:11March1936,Gelsenkirchen,GermanyAffiliationatthetimeoftheaward:GermanCancerResearchCentre,Heidelberg,Germany2008NobelPrize:"forhisdiscoveryofhumanpapillomavirusescausingcervicalcancer"35Sevencategoriesofdiseases:

1.Immunodeficiencies

2.Immunoproliferativediseases

3.Allergies

4.Autoimmunediseases

5.Infectiousdiseases

6.cancers

7.TransplantationsClinicalImmunology36PeterBrianMedawarBorn:28February1915,RiodeJaneiro,BrazilDied:2October1987,London,UnitedKingdomAffiliationatthetimeoftheaward:UniversityCollege,London,UnitedKingdom1960NobelPrize:"fordiscoveryofacquiredimmunologicaltolerance"37ClinicalLaboratoryImmunologySpecificantibodiesto:

microbialantigens;autoantigens;alloantigens;allergensImmunochemistry

immunoglobulinsandtheirfragments;cytokines;complements;acutephaseproteins;specificplasmaproteins;etcCellularstudies lymphocytemarkers;HLAtyping;functionsImmunohistology lymphnodes;renalandskinbiopsiesMolecularbiology

clonality;specificorrelatedgene38三、临床免疫相关机构39IUISCommittees(1971)NomenclatureSubcommittee(1971)EducationCommittee(1971)QualityAssessmentandStandardizationCommittee(1971)ClinicalImmunologyCommittee(1973)VeterinaryImmunologyCommittee(1980)PrimaryImmunodeficiencyExpertCommittee(2008)GenderEqualityandCareerDevelopmentCommittee(2010)ImmunotherapyCommitteeVaccineCommittee40我国临床免疫学学术机构中国免疫学会(1985)

临床免疫学会(1990)中华医学会风湿病学会等(1985)

…

…

检验医学学会(1980)

临床免疫委员会41

专业分会

肿瘤免疫分会

主任委员：曹雪涛

通讯地址：上海市翔殷路800号

上海第二军医大学免疫学研究所（200433）

电话/p>

E-mail：caoxt@

基础免疫分会

主任委员：吴长有

通讯地址：广州市中山二路74号

中山大学中山医学院免疫学教研室（510089）

电话/p>

E-mail：changyou_wu@

神经免疫分会

主任委员：许贤豪

通讯地址：北京市东城区大华路1号

卫生部北京医院（100730）

电话/p>

E-mail：xuxh@

血液免疫分会

主任委员：王德炳

通讯地址：北京市西直门南大街11号北京大学人民医院（100044）

电话5070

E-mail：wangdb@临床免疫分会

主任委员：仲人前

通讯地址：上海市凤阳路415号

上海长征医院（200003）

电话73631

E-mail：rqzhong@

中医药免疫分会

主任委员：王培训

通讯地址：广州市机场路12号

广州中医药大学临床基础研究所（510405）

电话/p>

E-mail：wpx@

生殖免疫分会

主任委员：欧汝强

通讯地址：广东省广州市梅东路17号

广东省计划生育研究所（510600）

电话/p>

E-mail：qianggd@126.com

兽医免疫分会

主任委员：孔宪刚

通讯地址：哈尔滨市南岗区马端街427号

中国农业科学院哈尔滨兽医研究所（150001）

电话/p>

E-mail：xgkong@

名词审定委员会

主任委员：葛锡锐

通讯地址：上海市岳阳路320号

中国科学院细胞库（200031）

电话/p>

E-mail：gexirui@

42四、临床免疫相关技术临床免疫学技术经典免疫学技术现代免疫学技术1890Behring白喉抗毒素（1901Nobel）1958EdelmanGM,PorterRR免疫球蛋白结构(1972Nobel)1974TonegawaS免疫球蛋白基因(1987Nobel)临床免疫学技术经典免疫学技术凝集反应

沉淀反应

溶血反应

免疫电泳1896MaxG,HerbertD细菌凝集；1902LandersteinerK血型凝集（1930Nobel）1897RudolphK；1948JacqueO,OrjanO免疫扩散（1976NobelforHBVBlumbergBS)1894RichardP免疫溶菌；1901JulesB,OctaveG补体结合试验1939TiseliusAW,KabatEA蛋白电泳；1955GrabarP,WilliamsC免疫电泳临床免疫学技术现代免疫学技术免疫比浊技术免疫细胞技术免疫标记技术1964BainB混合淋巴细胞培养；1970GaliliU,CoombsRA玫瑰花环试验；1975MilsteinC,KohlerG单克隆抗体技术（1984Nobel)1941CoonsAH免疫荧光；1960YalowR,BersonS放射免疫检测(1977Nobel)(1922BantinFG胰岛素与糖尿病(1923Nobel)；1971EngvallE,PerlamanPELISA；ELISPOT；1971FaulkWP,TaylorGM免疫胶体金；1972流式细胞术1978VelanB,HalmanM化学发光；1981StarkG免疫印迹；1992TakeshiS免疫PCR；1996AltmanJDMHC四聚体技术2000s电化学发光；2000s抗体/抗原芯片1977SeternberyMJ速率散射比浊OuchterlonydoubleimmunodiffusionABAnti-AAAAnti-AABAnti-ABBABAnti-AB47CounterImmunoelectrophoresis48ManciniradialimmunodiffusionAb49Rocketimmunoelectrophoresis+-Ab50Redbloodcellagglutination51检测器A(透射浊度法)检测器B(散射浊度法)

I0I浑浊样品光源TurbidimetryandNephlometry52Immunofluorescence53OsamuShimomuraBorn:27August1928,Kyoto,JapanAffiliationatthetimeoftheaward:MarineBiologicalLaboratory(MBL),WoodsHole,MA,USA,BostonUniversityMedicalSchool,Massachusetts,MA,USAMartinChalfieBorn:15January1947,Chicago,IL,USAAffiliationatthetimeoftheaward:ColumbiaUniversity,NewYork,NY,USARogerY.TsienBorn:1February1952,NewYork,NY,USAAffiliationatthetimeoftheaward:UniversityofCalifornia,SanDiego,CA,USA,HowardHughesMedicalInstitute2008NobelPrizeforchemistry:"forthediscoveryanddevelopmentofthegreenfluorescentprotein,GFP"54Radioimmunoassay55RosalynYalowBorn:19July1921,NewYork,NY,USADied:30May2011,NewYork,NY,USA1977NobelPrize:"forthedevelopmentofradioimmunoassaysofpeptidehormones"56Enzyme-LinkedImmunoSorbentAssay57Chemiluminescenceimmunoassay58Johnson&JohnsonVitrosECiLuminol(基态）Luminol(激发态）light增强剂(基态）增强剂(激发态）Luminol(基态)Luminol(激发态)lightHRPHRP未增强化学发光增强化学发光59AbbottChemiflexTM

、SiemensCentaur专利的稳定(sulfopropyl)基团专利的发光(sulfonamide)基团60经过最后一步冲洗,磁微粒子上捕捉有免疫复合物Pre-Trigger被加入Pre-Trigger使专利的吖啶酯标记物从固相载体上释放到溶液中磁块吸附磁微粒子被磁块吸附在反应杯的壁上,从而防止磁粒子对光信号检测的干扰Trigger被加入提供一个碱性环境产生光信号吖啶酯标记物被释放产生光信号产生的信号以RelativeLightUnit(RLU)方式表达.61BeckmanAccess、DPCImmuliteAMPPD:碱性磷酸酶底物3-(2-螺旋金刚烷)-4-甲氧基-4-(3-磷氧酰)-苯基-1,2-二氧环乙烷

62RocheECL63RocheECL64FlowCytometry65ImmunoassaysandTheirCharacteristics

Labels(ReporterGroups)B/FSeparation[*]SignalDetectionSensitivityPrecipitationimmunoassaysNotrequiredNotrequiredNakedeye,turbidity,nephrometry≈10μg/mL(1)ParticleimmunoassaysBloodcells,artificialparticles(gelatin,particles,latex,etc.)NotrequiredNakedeye,patternanalyzer,spectrophotometry,particlecounting≈5ng/mL(2)RadioimmunoassaysRadioisotopes(125I,3H)RequiredPhotoncounting≈5pg/mLEnzymeimmunoassaysEnzymesRequiredSpectrophotometry,fluorometry,photoncounting≈5pg/mL

≈0.1pg/mL(3)(CL-EIA)FluorescentimmunoassaysFluorophoresRequiredPhotoncounting≈5pg/mL(4)ChemiluminescentimmunoassaysChemiluminescentcompoundsRequiredPhotoncounting≈5pg/mL(4)66Fluidchip67Proteinchips68Chips69Chips70临床免疫技术的基本要素精密度（EP5）正确度检测线性范围（EP6)

灵敏度特异性结果可报告范围生物参考区间(C28)

试剂稳定性71临床免疫技术的基本要素精密度：在规定条件下，独立测试结果间的一致程度。（1）与真值或规定值无关；（2）以标准差表示。正确度：有大量测试结果得到的平均数与接受参照值间的一致程度。以偏倚（测试结果的期望与接受参照值之差）表示。检测线性范围：

灵敏度：测量仪器响应的变化除以对应的激励变化。又指校准曲线的斜率及对于规定量的变化分析程序产生信号的变化。特异性：分析方法只确定分析物，而对其他相关物质不起作用的能力。结果可报告范围：测量仪器的误差处在规定极限内的一组被测量的值。生物参考区间：通常指95%的正常人某指标所在区间。

试剂稳定性72临床免疫技术的质量控制分析前分析中分析后73临床免疫技术的影响因素CHCH+M:Cross-reaction（交叉反应）

Hookeffect（钩状效应）

Carry-over（携带污染）

HAMA（异嗜性抗体）

Matrixeffect（基质效应） （RF、溶血、脂血、黄疸、药物）74五、临床应用相关进展75临床应用筛查（Screening）检测（Detection）诊断（Diagnosis）危险性分层（Riskstratification）预后（Prognosis）监测（Monitoring）复发（Recurrence)

预测（Prediction)筛查（Screening）Hp抗体:阴性低值(<3U/mL),阴性高值(3–10U/mL),阳性低值(10–50U/mL),阳性高值(>50U/mL).PG(+):PGI≤70ng/mL和PGI/II≤3分四组：A[Hp(−)PG(−)],B[Hp(+)PG(−)],C[Hp(+)PG(+)],D[Hp(−)PG(+)]胃癌危险性：D>C>B>AA组阴性高值者（清除感染）易出现小肠型肿瘤B组阳性高值者（活动性感染）易出现弥漫型肿瘤C组阳性低值者（晚期萎缩性）易出现小肠型肿瘤建议：ABC三组的随访监测（胃镜）时间分别为3、2、1年HelicobacterpyloriAntibodyTiterandGastricCancerScreeningKishikawaH,DiseaseMarkers2015,/10.1155/2015/156719方法结果筛查（Screening）德国380直结肠癌患者和2005-2013做直肠镜的6826患者Luminex检测64种自身抗体（根据文献报道），分二步：Trainingsetandvalidationset抗MAGEA4对早期直结肠癌和晚期腺癌有较高敏感性多种自身抗体组合检测可提高检测的敏感性，但会降低特异性在validationset,联合检测抗TP53,抗IMPDH2,抗MDM2和抗MAGEA4对早期直结肠癌的敏感性为26%(95%CI,13−45%)、特异性90%(95%CI,83−94%)；同时，对晚期腺癌的检出率也达20%(95%CI,13−29%)。Prospectiveevaluationof64serumautoantibodiesasbiomarkersforearlydetectionofcolorectalcancerinatruescreeningsettingChenH,Ondotarget2016,DOI:10.18632/oncotarget.7500方法结果81检测（Detection）评价肝纤维化目的：肝病进展、失代偿、肝癌、对IFN反应间接指标：APRItest（AST/plateletratioindex）,Fornstest,FT（FibroTest）直接指标：typeⅣcollagen,hyaluronicacid,laminin,collagenVI,TGFβ1andmetalloproteinasesortissueinhibitorsofmetalloproteinases(TIMPs),YKL-40（agrowthfactorforfibroblastsandendothelialcells）.超声：Ultrasound-basedtransientelastography核磁：Magneticresonanceelastography金标准：活检Non-invasiveassessmentofliverfibrosis:Betweenprediction/preventionofoutcomesandcost-effectivenessStasiC,WorldJGastroenterol2016;22(4):1711-1720Cut-offvaluesofthefirstindirectmarkersoffibrosisinthediagnosisofsignificantfibrosisandcirrhosisELF（Theenhancedliverfibrosisscoretest）：algorithmcombininghyaluronicacid,amino-terminalpropeptideoftypeⅢcollagen,tissueinhibitorofmatrix-metaloproteinase-1andage83AutoantibodiesindifferentliverdiseasesYangZX,ZhongRQ.Clinicalbiochemistry，2012检测（detection）84诊断（Diagnosis）制备CA19.9的单克隆抗体，并改变重链上糖链，连接中介体DIBO（dibenzocyclooctyne）在DIBO再连上标记物DFO（89Zr4+chelatordesferrioxamine）或NIRF（nearinfraredfluorescence）或同时双标记活体上分析肿瘤可以定位肿瘤，判断肿瘤边界可以发现肿瘤转移灶及淋巴结Site-specificallylabeledCA19.9-targetedimmunoconjugatesforthePET,NIRF,andmultimodalPET/NIRFimagingofpancreaticcancerHoughtonJL，PNAS2015；112（52）：15850–15855方法结果Histology(A–C,Left),autoradiography(A–C,Center),andfluorescencemicroscopy(A–C,Right)ofresectedtumortissuefrommiceinjectedwith89Zr-ssdual-5B1.(A)ABxPC3xenograft,(B)metastaticfocifromamousewithaSuit-2orthotopicxenograft,and(C)theprimarytumorwithsurroundinghealthypancreastissuefromthesamemouseareshown,confirmingcolocalizationofthetracerwithCA19.9expression.(AandB)SerialNIRFimagingusingssFL-5B1(50μg)(A)and89Zr-ssdual-5B1(50μg,92±14μCi)(B).NIRFimagesofarepresentativemousefromeachcohort(n=3)bearingCA19.9-negative(T−,leftflank)andCA19.9-positive(T+,rightflank)tumorsthatwereacquiredat48hand120hareshown.Thescaleofthefluorescencesignalisreportedasradiantefficiency[(p/s/cm2/sr)/(μW/cm2)].PET,PET/CT,andNIRFimagingof89Zr-ssdual-5B1(50μg,84±6μCi)inanorthotopicPDACmodel.(A)Slices(Top,coronal;Bottom,transverse)ofarepresentativemouseat120hp.i.showhighuptakeintheprimarytumor,ametastasis,andsentinellymphnodes(LN,lymphnode;M,metastasis;T,tumor).(B)ArenderingofthePET/CTdataallowsfortheanatomizationofthelesions.(CandD)NIRFimagingofthesentinellymphnodes(C)andtheopenthoraciccavity(D)afterremovaloftheLNsdemonstratesthepotentialof89Zr-ssdual-5B1inanintraoperativesetting.87诊断（Diagnosis）自身免疫性肝炎诊断标准（IAIHG,2008）变量临界值评分ANA或SMA1:401ANA或SMA1:802（自身抗体的附加分值最大值为2）或LKM1:40或SLA阳性IgG>正常范围上界1>正常范围上界1.10倍2肝脏组织（肝炎证据是必需条件）与AIH相似1典型AIH2非病毒性肝炎是26分：可能是AIH7分或以上：确定为AIH88诊断（Diagnosis）关节受累1个大关节

0分2-10个大关节

1分1-3个小关节（无论大关节受累与否）

2分4-10个小关节（无论大关节受累与否）3分>10个关节（至少1个为小关节）5分血清学RF或抗CCP抗体均阴性

0分RF或抗CCP抗体至少1项低滴度阳性（高于正常人上限水平且低于3倍正常人上限水平）

2分RF或抗CCP抗体至少1项高滴度阳性（高于3倍正常人上限水平）3分急性时相

反应物CRP或ESR均正常0分CRP或ESR增高1分症状持续时间<6周0分

≥6周1分6分或以上欧洲和美国风湿病学会的RA诊断标准（2010）89诊断（Diagnosis）临床标准1.急性皮肤狼疮 2.慢性皮肤狼疮3.口腔溃疡4.非疤痕性脱发5.2个以上关节炎 6.浆膜炎（胸膜炎或心包炎）7.神经（癫痫或精神病）8.肾脏（尿蛋白/肌酐比值，尿蛋白>0.5g/24h或红细胞管型）9.溶血性贫血10.白细胞减少症（<4000/ml）1次或淋巴细胞减少症（<1000/ml）1次11.血小板减少症（<100000/ml）至少1次免疫学标准ANA阳性dsDNA抗体阳性（或ELISA>2倍）Sm抗体阳性磷脂抗体阳性(狼疮抗凝物、或梅毒血清试验假阳性、或中高滴度心磷脂抗体（IgA、IgG或IgM）、或抗β2糖蛋白I（IgA、IgG或IgM）阳性）补体下降（C3、C4、CH50）直接Coombs试验阳性（除外溶血性贫血）PetriM,etal.ArthritisRheum2012;64(8):2677-26864条或以上，且各标准1条SLE诊断标准（2012，SLICC）Riskstratificationinnon-STelevationacutecoronarysyndromes:Riskscores,biomarkersandclinicaljudgment危险性分层（Riskstratification）CorcoranD，IntJCardiolHeartVasc2015;8:131-137hs-cTn：99百分位的不精密度≤10%，并在≥95%正常人中可检测出99百分位以下的cTn浓度ESC定义MI：就诊时hs-cTn阴性或接近URL，3小时内50%变化值或绝对值升高7ng/L；就诊时hs-cTn已升高，3小时内20%变化值候选标志物：H-FABP，CRP（系统性炎症），BNP（左心功能不全），copeptin，缺血修饰的白蛋白ECG仍是一线检查，特异性达97%，但敏感性只有28%ESCrapidrule-outofACSwithhs-cTnalgorithmESCdecision-makingalgorithminACSRenaldiseaseinscleroderma:anupdateonevaluation,riskstratification,pathogenesisandmanagement危险性分层（Riskstratification）ShanmugamVK，CurrOpinRheumatol2012；24(6):669–676弥漫型硬皮病有10%发展成硬皮病肾危象(SRC)，后者有很高的死亡率抗RNA多聚酶III：阳性时，25%进展为SRC；阴性时只有2%；在SRC的检出率为9.4-59%抗SCL70和抗U3RNP不是危险因素，抗着丝点抗体则呈负相关早期用类皮质激素是危险因素（前六月每天≥15mg）HLADRB1*0407andHLADRB1*1304为独立危险因素不是危险因素的还有：基础血压、血清肌酐、蛋白尿、血尿预后（Prognosis）

ElevatedIgG4inpatientcirculationisassociatedwiththeriskofdiseaseprogressioninmelanomaIgG4-相关疾病：一个或多个器官或组织肿胀增大，似肿瘤；IgG4阳性淋巴细胞大量增生而导致淋巴细胞增生性浸润和硬化；血清IgG4细胞水平显著增高（>1350mg/L），IgG4阳性淋巴细胞在组织中浸润（IgG4阳性淋巴细胞占淋巴细胞的50%以上）；对糖皮质激素治疗反应良好IgG4升高见于多种肿瘤：胰腺癌、胆管癌、鳞癌、黑色素瘤等KaragiannisP,Oncoimmunol2015/10.1080/2162402X.2015.1032492Experimentalstudydesign,collectionandprocessingofclinicalsamples.Cohortsof171melanomapatientsand104healthyvolunteerswereidentifiedforevaluationsofIgG4.IgGsubclasslevelsweremeasuredusingastandardizedLuminexbeadarrayassay(n=171).CirculatingIgG4(IgG4/IgG4total)serumlevelsinmelanomapatients(n=167)weresignificantly(P=0.007)highervs.IgG4levelsinhealthyvolunteersera(n=104).StatisticalanalysiswasperformedbyMann-WhitneyU-Test;linesrepresentmediansanderrorbarsindicateinterquartilerange.SerumIgGsubclasslevels(ng/mL)forpatientsandhealthyvolunteercohortsareshowninmiddleandright,respectively.BasedonROCanalysis,athresholdvalueof0.034forIgG4wasusedtocomparepatientserumIgG4fortheriskofprogression-freesurvival(PFS)andoverallsurvival(OS).Kaplan-MeierCurveevaluationsrevealedstatisticallysignificantlyworsePFS(HR95%[CI]2.01(1.34–3.35);log-rankP=0.0016)andlowerOS(HR95%[CI]1.90(1.17–3.29);log-rankP=0.0116)observedintheIgG4highgroupcomparedto