临床免疫学笔记

1、目录 TOC o 1-5 h z HYPERLINK l bookmark4 o Current Document 肿瘤免疫2 HYPERLINK l bookmark8 o Current Document 免疫预防和治疗8 HYPERLINK l bookmark10 o Current Document 移植免疫12 HYPERLINK l bookmark14 o Current Document 免疫药理学仃 HYPERLINK l bookmark16 o Current Document 免疫缺陷病19 HYPERLINK l bookmark20 o Current Docum

2、ent 自身免疫性疾病23 HYPERLINK l bookmark34 o Current Document 抗感染与免疫27 HYPERLINK l bookmark50 o Current Document 回忆真题30肿瘤免疫肿瘤抗原：细胞癌变过程中出现的新抗原(neoantigen)物质的总称。TSA(tumor specific antigen)：仅在肿瘤细胞表达而止常细胞所没有的抗原；TSTA(Tumor specific transplantation antigen) /TRA(tumor rejection antigen)：表达于肿瘤细 胞表而的能引起有效的抗肿痫免疫应答

3、，导致肿瘤被排斥的肿瘤抗原；TAA(tumor associated antigen)：非肿瘤细胞所特有，在止常细胞上也表达的，细胞癌变吋 其含量刖显增加或界位表达的抗原。按来源分：正常细胞基因编码的肿瘤抗原：“沉默”基因表达的肿瘤抗原：原指正常时不表达而细胞恶变时表达的基因，如 MAGE(mela no ma an tige nen codi ng gene)；胚胎抗原(fetal antigen): AFP; CEA；分化抗原(differentiation antigen)： B细胞白血病表达的Smlg, T细胞白血病表达的CD4 或CD8可明显高于正常细胞许多倍；突变细胞基因编码的肿瘤

4、抗原：表达TSA,但极人多数存在于细胞内，而不能诱导有效的抗肿瘤免疫应答：如p21ras, p53；病毒基因编码的肿瘤抗原：DNA 病毒： 疱疹病毒(herpes virus):皮肤癌;EBV: NPC, Burkitts lymphoma： CMV: HIV 相关的Kaposi肉瘤；乳头状瘤病(papilloma virus): HPV:宫颈癌，皮肤癌，乳头状 瘤：乙肝病毒(HBV):少原发性肝癌有关；RNA肿瘤病毒：仅逆转录病毒有致瘤性，与人类肿瘤有关的RNA病毒有：HTLV-I： 弓I起人类T细胞白血病/淋巴瘤HTLV-II：与毛细胞口血病有关未知基因起源的产物：理化因素如紫外线或MCA

5、诱发的肿瘤所表达的抗原。机体抗肿瘤的免疫效应：1967Burnet免疫监视(immune surveillance)学说B细胞和抗体：B细胞在抗肿瘤效应中具有双重作用：细胞递呈肿瘤抗原，诱导CD4+T细胞对肿瘤的应答。抗体的抗肿瘤作用：CDC：不同的肿瘤细胞对CDC的敏感性不同，口血病细胞较敏感，而肉瘤不敏感。对 防止癌细胞的转移有一定的作用ADCC： NK细胞介导免疫调理作用：FcR其他抗瘤作用：封闭受体(如转铁蛋白受体)；改变瘤细胞的黏附特性乙T细胞的抗肿瘤作用：CTL的抗瘤作用：CD8+CTL细胞毒途径(穿孔素/颗粒鮒)、凋亡途径(Fas)；Th的抗肿瘤作用：释放细胞因子：如GM-CSF

6、-M活化；IL2,IFNY，etc.-T细胞、NK细胞活化CD40L与DC表而CD40结合上调DC表达协同刺激分子(B7、ICAM-1)-激活CTLNK细胞的抗瘤作用：能抗同系、同种或异种肿瘤细胞。对淋巴瘤及白血病细胞尤为冇 效，但对实体瘤的作用较差。直接杀伤：穿孔素/颗粒腮KIR：识別MHC-I类分子-传递抑制信号KAR：识别肿瘤细胞表而糖类配体一活化信号ADCCCKs： IL-2, IFN-y等巨噬细胞的抗肿瘤作用：瘤灶屮浸润的M (TAM)与肿瘤的转移率呈负相关。递呈肿瘤抗原分泌活性产物抑制肿瘤生长：溶晦体酶，NO, TNF,氧口由基ADCC与T细胞、抗体及补体协同发挥抗肿瘤作川通过膜受

7、体直接与瘤细胞结合并杀伤之其他细胞的抗肿瘤作用：LAK 细胞，TIL, CD3AK 等肿瘤逃避免疫攻击的机制肿瘤细胞膜分子表达异常MHC分子表达界常：多数肿瘤MHC-I类分子表达！或表型改变：逃避CTL的攻击某些肿瘤能表达非经典的I类分子：逃避NK的攻击LMP和TAP的丢失：卵巢癌TAP和LMP表达缺陷者达62.5%大多数肿瘤细胞不表达II类分子：不能诱导CD4+T细胞共刺激分子表达界常：如B7、ICAM-1等丢失Fas,表达FasL：脑胶质瘤、结直肠癌、肝癌、黑色素瘤、肺癌等肿瘤细胞，膜表 血Fas表达显著减少或丢失，而FasL的表达增强。从而一方面能抵抗肿瘤细胞凋亡，另 一方面能使肿瘤细胞

8、诱导免疫细胞的凋亡。表达mCRP(膜结合补体调节蛋口)分子降解补体分子,免受CDCo肿瘤细胞分泌抑制性CKs及可溶性粘附分子TGF-p, IL-10, VEGF(vascular endothelium growth factor), slCAM-1 等。TGF-p能抑制多种免疫细胞活化、增殖、分化；能封闭信号传导途径IL-10抑制Thl细胞、促进Th2细胞、下调II类分子VEGF促进肿瘤血管形成肿瘤生长因子的分泌如骨髓瘤、毛细胞白血病、肾细胞癌-分泌IL-6；淋巴瘤一分泌TNF、IL-10肿瘤细胞的抗原性弱及抗原调变抗原性弱：TAA或TSA与正常细胞的膜分了差异很小。抗原调变：宿主对肿瘤抗原

9、的免疫应答导致肿瘤细胞表面抗原的表达减少或丢失，使肿 瘤细胞不易被宿主免疫系统识别，得以逃逸机体的免疫攻击。肿瘤微环境中免疫增强CKs含量IAPC释放IL1的能力显著降低，影响Th细胞的活化，进而影响CTL的活化。IL-2、IFN 等 I抑制性细胞亚群 Inhibitory cell subsets肿瘤调节性 T 细胞 tumor regulatory T cellsjreg肿瘤相关巨噬细胞(tumoeassociated macrophages, TAM)：1）表达低水平MHC-II2）抗原呈递功能低下3）分泌高水平的免疫抑制性细胞因了如IL-10和TGF-p4）炎症性细胞因了 IL12、I

10、L6、IL-ip. TNFa的产生显著低下5）产生较低水平的NO、ROIs等髙:IL-12JL-23JL-1JL-6JNF 低：IL10高：RNI, ROI高：IL-10, decoy IL-1RII, IL-1R antagonist 低:IL 细胞免疫、 体液免疫功能降低伴其他严重缺陷 的免疫缺陷病4、非特异性免疫 缺陷病吞噬细胞缺陷病慢性肉芽肿病白细胞粘附缺陷病补体系统缺陷病C1INH缺陷病遗传性血管神经性水肿获得性免疫缺陷病（acquired immunodeficiency disease, AIDD）概念：继发于其他疾病或因理化因索等分类：1）非感染性因素：医源性SIDD：化疗/放

11、疗示的T细胞缺陷症；营养不良；恶性肿瘤：霍奇金病、骨髄瘤2）感染：HIV、EB、风疹病毒等获得性免疫缺陷综合征(AIDS)Stage 1 PrimaryShort, flu-like illness - occurs one to six weeks after infection no symptoms at allIn fected pers on can in feet other peopleStage2 AsymptomaticLasts for an average of ten yearsThis stage is free from symptomsThe level of H

12、IV in the blood drops to very low levelsHIV antibodies are detectable in the bloodStage 3 - SymptomaticThe symptoms are mildThe immune system deteriorates emergence of opportunistic infections and cancersStage 4HIVAIDSThe immune system weakensThe illnesses become more severe leading to an AIDS diagn

13、osis细胞基础：CD4+ T4辅助细胞数量减少；发展到后期!l! CD8+细胞毒性杀伤细胞数量减少。HIV病毒：gp41是一个穿膜蛋口，而gpl20则在膜外侧，以非共价键与膜相连，是一个膜外 侧的周围蛋口。(1) CD4分子IgSF第1受体胞外区：4个结构域(D1-D4)D1(V区)含CDR1、CDR2、CDR3IHIV gp120的C4结合(2)趋化因子受体：第2受体CXCR4(fusin) CCR5gp120与CD4结合Igp120构象改变，产生被CCR5识别的位点Igp120与CCR5结合，暴Bgp41疏水N端IHIV与靶细胞膜融合表面糖蛋白gp120(SU)含V1V5HIV外膜蛋白C

14、1-C5跨膜艳蛋白gp41(TM)趋化因子受体：第2受体CCR5是嗜单核一巨噬细胞(非合胞体诱导型,NSI或称R5型)HIV-1的第二受体CXCR4 (fusin,融合因子)是嗜T细胞(合胞体诱导型,SI或称X4型)HIV-1的第二受体R5型病毒是HIV-1感染初期和潜伏期的主耍病毒型，其复制能力较弱；X4型病毒常在HIV-1感染后期和感染者发病后出现，复制能力綾强。疾病的进程与病毒从R5到X4的表型转换有关损伤免疫细胞机制：(1)损伤感染的CD4+ T细胞HIV的肓接致病变作用：抑制细胞蛋白、合成V.DNA毒性、gpl20损伤细胞膜HIV间接杀伤靶细胞：CTL、ADCC、超抗原样作用CD4+

15、T细胞凋亡HIV蛋口诱导的细胞凋亡gpl20 - CD4分了连接T细胞Fas表达增加凋亡Vpr能通过线粒体途径诱导宿主细胞凋亡Tat和Vpu蛋白能上调未感染细胞表血Fas和FasL的表达，从而增加对Fas途径致凋广 的頌感性活化诱导的细胞死口AICD)超抗原合胞体形成细胞因子紊乱致炎性细胞因子如TNFa、IL-6、IL-1 a常常升高而IL-2常降低。随着病程进展，IL2、IFN- Y水平进一步F降,而IL-4和IL-10含量增加。即由Thl型细胞因子向Th2型细胞因子漂移。 诱发自身免疫应答gpl20和MHCII类分子均可与CD4分子结合抗gpl20能作用于组织细胞表面的MHCII类分子即1

16、20、gp41的C末端肽段是B细胞超抗原多种自身抗体产生巨噬细胞、树突状细胞和NK细胞受损单核巨噬细胞：功能界常DC：抗原提呈功能降低NK细胞:gpl20能通过抑制NK细胞IFN-Y的产生而抑制NK细胞的细胞毒活性;Tat可 以通过封阳.NK细胞表血的L型钙离子通道而抑制NK细胞的功能oCD16弱阳CD56阴性NK 细胞增加。诊断HIV抗原检测：核心抗原p24 (急性感染期、AIDS晩期)抗HIV抗体检测CD4、CD8T淋巴细胞计数HIV核酸检测 治疗尚无冇效的治疗措丿施临床采用的高效抗逆转录病毒治疗(highly active anti-retroviral therapy, HAART)即

17、选择一 种蛋白陆抑制剂与两种逆转录酚抑制剂联合用药，能収得较好的疗效。另用IL-2, GM-CSF 等细胞因子可改善病人的免疫状态预防控制性传播、静脉吸毒、加强对高危人群及献血员的HIV检测HIV疫苗正在研制中”尚无明确应用前景的疫苗，原因:对HIV致病机制了解不多； HIV变界株不断出现。自身免疫性疾病Autoimmunity: immune response against self-antigens (components)Autoimm une disease, AID: Diseases in duced by in appropriate response of the immun

18、e system against self-componentsGeneral principles:-Significant health burden, 5% of population (USA)-Multiple factors con tribute to autoimm unity,Including genetic predisposition (遗传倾向),infections-Fundamental problem is the failure of self-toleraneeProblems:Failure to identify target antigens, het

19、erogeneous (异质性)disease manifestations, disease usually presents long after initiation.Characters of AIDHigh titer auto-antibody in serum and/or self-reactive T cells against self-components.Damage to organs and tissue destruction caused by auto-antibody & self-reactive T cells .Repeat, Chronic, Per

20、sistent, ProgressAnimal model replication and transferable.Inherited tendency, female susceptibleNo obvious reasonsClassification of Autoimmune Diseases一 Type II: Antibody against cell-surface antigen or matrix antigens-Type III: Immune-complex disease- Type IV: T cell-mediated diseaseType II Antibo

21、dy-mediated DiseasesTABLE 18-2 Examples of Diseases Caused by Cell- or Tissue-Specific AntibodiesDiseaseTarget AntigenMechanisms of DiseaseClinicopathologic ManifestationsAutoimmune hemolytic anemiaErythrocyte membrane proteins (Rh blood group antigens. 1 antigen)Opsonization and phagocytosis of ery

22、throcytes, complement mediated lysisHemolysis, anemiaAutoimmune thrombocytopenic purpuraPlatelet membrane proteins (gpllb-llla integrin)Ops on ization 合 nd phagocytosis of plateletsBleedingPemphigus vulgarisProteins in intercellular junctions of epidermal cells (desmoglein)Antibody-mediated activati

23、on of proteases, disruption of intercellular adhesionsSkin vesicles (bullae)Vasculitis caused by ANCANeutrophil granule proteins, presumably released from activated neutrophilsNeutrophil degranulation and inflammationVasculitisGoodpastures syndromeNon-collagenous NCI protein of basement membrane in

24、glomeruli and lungComplement and Fc receptor- mediated inflammationNephritis, lunQ hemorrhageAcute rheumatic feverStreptococcal cell wall antigen; antibody cross reacts with myocardial antigenInflammation. macrophage activationMyocarditis, arthritisMyastlienia gravisAcetylcholine receptorAntibody in

25、hibits acetylcholine binding, downmodulates receptorsMuscle weakness, paralysisGraves* disease (hyperthyroidism)TSH receptorAntibody-mediated stimulation of TSH receptorsHyperthyroidismInsulin-resistant diabetesInsulin receptorAntibody inhibits binding of insulinHyperglycemia, ketoacidosisPernicious

26、 anemiaIntrinsic factor of gastric parietal cellsNeutralization of intrinsic factor; decreased absorption of vitamin B12Abnormal erythropoiesis, anemiaANCA. antineutrophil cytoplasmic antibodies; TSH. thyroid-stimulating hormoneImmune-complex disease (type III)Subacute bacterial endocarditisBacteria

27、l antigenGlomerulonephritisMixed essential cryoglobulinemiaRheumatoid factor IgG complexes (with or without hepatitis C antigens)Systemic vasculitisSystemic lupus erythematosusDNA, histones, ribosomes, snRNP, scRNPGlomerulonephritis, vasculitis, arthritisT cell-mediated disease (type IV)Insulin-depe

28、ndent diabetes mellitusPancreatic3-cell antigen/S-cell destructionRheumatoid arthritisUnknown synovial joint antigenJoint inflammation and destructionMultiple sclerosisMyelin basic protein, proteolipid proteinBrain degeneration. ParalysisCeliac disease r t缺质过做览Gluten modified by tissue transglutamin

29、aseMalabsorption of nutrients Atrophy of intestinal villiTypes of ToleranceCentral Tolerance - happens during lymphocyte development. Negative selection or clonal deletion of T and B cells that have receptors for self-antigens. Selected on thymic epithelial MHC against highly reactive clones against

30、 self antigen 95% of immature lymphocyte die in thymus/bone marrow.Peripheral Tolerance occurs in the periphery after lymphocyte development.Ignorance： low dose or immunologically privileged sites;Anergy： Lack of costimulatory molecules during T cell activetion;Clonal contraction and A ICO： Both LPR

31、 Fas deficient, Gid FasL deficient have autoimmune phenotypes Cannot regulate duration of responseSuppression: specific immune regulation through regulatory T cells,Consequences: apoptosis, anergy, inactivationAutoimmunity is so complicated, how can we figure out how it happens?Answer: l)Use genetic

32、s-Genetic Reasons 2) Animal modelsGenetic basis of autoimmunityGenetic predisposition of autoimmune diseasesIn creased in cide nee in twins一 Identification of disease-associated genes by breeding and genomic approachesMultiple genes are associated with autoimmunityMHC genes一 Major genetic associatio

33、n with autoimmune diseases- Disease-associated alleles may be found in normal individualsNon-MHC genes一 Many loci identified by genomic methods, animal studiesMutations in complement genes predispose to lupusAnimal models of autoimmunity丁 Explore Disease mechanisms (genetic and environmental)V Test

34、Treatment drug or strategySpontanuous Disease models:NOD mouse model of type 1 diabetesNZBxNZW mouse-model of LupusKBxN mouse-model of rheumatoid ArthritisInducible Disease models：EAE- induced model of multiple sclerosis whereby disease is induced by injecting proteins of the myelin sheath with adju

35、vantKnock-outs:Knockouts that get autoimmunityCombined Kos with spontanuous/inducible models/ How HLA confer susceptibility and /or protectionCapacity to present antigens and to induce positive selection but not negative selectionSome HLAs are more potent in presenting self-antigens (peripheral)Link

36、ed to other non-MHC disease causing genes (indirect)Other unknown reasonsWhat triggers autoimmune diseases?Altered antigen or antigen presentatiorvRelease of sequestered antigensViral infections and autoimmune diseaseIn appropriate expressi on of class II MHC molecules on non-APCsInfections trigger

37、autoimmune reactions,but some autoimmune diseases are reduced or prevented by infections( uhygiene hypothesis M originally proposed to describe effects of infections on asthma)Molecular mimicryBysta nder Activatio nEpitope spreadingresponsible for the relapse of diseaseGut microbiota and autoimmune

38、diseaseEndocrine factors引起自身免疫耐受异常的机制引起自身反应性淋巴细胞克隆的异常阴性选择、克隆清除异常免疫忽视的打破微生物感染刺激DC协同刺激分子表达增 高；细菌超抗原；TLR淋巴细胞的多克隆激活活化诱导的细胞死亡障碍效应淋巴细胞长期存在调节性T细胞功能异常MHCII类分子表达异常 therapeutic approaches for immune disordersCostimulatory blockade： CTLA-4-lg, Anti-CTLA-4-AntibodyInhibiting the inhibitor 一 anti-tumor immune th

39、erapyAnti-CD3 mAb Treatment for Autoimmunitydowrvregulate product!on or inhibit TNFa effects (in Crohs Disease (CD),Rheumatoid Arthritis)自身免疫病的防治原则去除引起耐受异常的因素预防微生物感染谨淇使用药物应用免疫抑制剂，如环胞素，FK-506,皮质激素抑制对自身抗原的免疫应答应用抗细胞因子及其受体的抗体或阻断剂应用抗免疫细胞表面分子抗体应用单价抗原或表位肽重建对自身抗原的免疫耐受通过口服抗原诱导免疫耐受模拟胸腺阴性选择诱导免疫耐受其他脾切除；补充B12抗感染

40、与免疫抗感染免疫的组成；固有免疫应答；适应性免疫应答；抗感染免疫的基本特征:由固有免疫和适应性免疫组成针对不同的病原微牛物，机休通过不同的免疫应答发挥效应；病原微牛物的致病性其逃避机体的免疫防御和对免疫应答产物的抵抗性有关。病原微生物引起的纽织损伤和致病性打宿主的免疫应答冇关固有性抗感染免疫：防御作用；炎症反应；激活和调节适应性免疫应答屏障结构：皮肤和黏膜(机械屏障；化学物质；肠道菌群等)固冇免疫体液分子：补体系统、防御素、溶菌猶、抗菌肽、急性期蛋白、NO、氧口由基、脂质介 质等免疫细胞：吞噬细胞;NK细胞;NKT细胞；gT细胞;DC； Bl细胞;肥大细 胞固有免疫识别的理论(2011 Nob

41、el Prize)/ PAMP：是一类病原微生物进化屮保守的抗原分子，即不同病原体屮相应 的特定结构的分子，这些分子大多数病原微生物所共有的组成性表达的分 子,结构保守，称为病原相关分子模式(pathogen-associated molecular pattern,PAMP)。通常为病原微生物所特有；为微生物生存和致病所必需; 为模式识别受体(PRR)泛特异性识别的分了基础/ 模式识别受体(pattern recognition receptor, PRR)：是类主要农达在天然 免疫细胞表血、非克隆性分布、可识别种或多种PAMP的识别分子。1.跨模型：TLR： Toll样受体、CLR： C型

42、凝集素受体乙胞内型：RLR： RLG-I-样受体；NLR： NOD样受体3.分泌型：胶原凝集素Collectins,纤维胶原蛋白；正五聚蛋白NLRsCLRsNOD2&M|NLRC4Dectin-1NucleiTLRsMlncleEnd osorrwRLRsTLR7MD-2TLR4Mannose RTLRs- Toll样受体：是一种模式识別受体，识別病原微生物进化中保守分子，如脂多糖 （LPS）、肽聚糖、酵母多糖以及病原微生物的核酸等等。一般为二聚体；与病原微生物不 同配体结合，涉及信号转导：1）IVlvD88dependent pathways： TLR1, 2, 4, 5, 7, 8, 92

43、）TRIF-ckpendent pathways： TLR3, 4TLR4TLR4活化效应：活性氧H由基；细胞因子；牛长因子；增加MHC表达，共刺激分子等RLRs （视黄酸诱导基因1样家族）RIG-I的配体：dsRNA中的5三磷酸-ssRNA； RNA聚合酶III （Pol III）的转录产物RNA:能识别 ssRNA viruses 和_些 dsDNA viruses.1. MDA5 :较长的dsRNA结构，一般存在于感染（+ ） ssRNA病毒感染的细胞质屮Viral transcripts andreplication Intermediates(e.gM measles andEpst

44、ein-Barr virus) Total RNA from Viral genomic Infected cells RNA (e.g. flu and (e.g.t flu virus) rabies virus)ln-vltrotranscribed RNA(base-paired/ products)Shortened poly l:CPol III transcribed RNA5-p-httttttds-ollgorlbo UIUU1 nucleotidesc. DOO Blunt-end 5PPP J. i!,1! ds-ollgorlbo-nucleotidesRNase L cleaved s