免疫学免疫不知名课件

1、Immune SystemOrgans and tissues antibodyCytokinesAntigen MHCComplementCellsMoleculesGranuocytesMonocytesMacrophageDendritic cellsLymphocytesPrimary lymphoid organsSecondary lymphoid organsBone MarrowThymusLymph nodesSpleenMucosa-associated lymphoid tissuesChapter 5 Immune Molecules IImmune SystemOrg

2、ans and tissues CellsMoleculesantibodyCytokinesAntigen MHCComplementAntigenAntibodyVaccine5.1 AntigenAntigen is a substance that stimulates an immune response, especially the production of antibodies. Antigens are usually proteins or polysaccharides, but can be any type of molecule, including small

3、molecules (haptens) coupled to a carrier-protein.5.1.1 Characteristics of AntigenForeignnessSize: High molecular weightChemical ComplexityConformational determinantsSequence determinantsPrimary StructureSecondary StructureTertiary StructureQuarternary Structure5.1.2 Types of antigens Immunogen - Any

4、 substance that provokes the immune response when introduced into the body. An immunogen is always a macromolecule (protein, polysaccharide). Its ability to stimulate the immune reaction depends on its commonness to the host, molecular size, chemical composition and heterogeneity (e.g. similar to am

5、ino acids in a protein). Tolerogen - An antigen that invokes a specific immune non-responsiveness due to its molecular form resulting from a previous exposure to the same antigen . If its molecular form is changed, a tolerogen can e an immunogen. Allergen- An allergen is a substance that causes the

6、allergic reaction. It can be ingested, inhaled, injected or brought into contact with skin5.1.3 Chemical Nature of Immunogens Proteins BSA, Microbial proteins, Non-self or Altered-self proteins Polysaccharides Pneumococcal polysaccharide, lipopolysaccharide Nucleic Acids CpG containing DNA, U-rich s

7、ingle stranded viral RNA Lipids Gram + bacteria, Yeast cell wall components5.1.4 Origin of antigens Exogenous antigens Endogenous antigens Autoantigens Tumor antigens DoseRouteSubcutaneous(皮下) Intravenous (i.v 静脉) Intraperitoneal （i.p,腹腔) Intragastric(胃腔)Adjuvant(佐剂) Substances that enhance an immun

8、e response to an AgFactors Influencing ImmunogenicityMethod of AdministrationTypes of adjuvantsInorganic adjvants ： Alum precipitate（明矾）Organic adjvants ：Microorganisms and their metabolizing products (toxins and polysaccharides)Synthesized adjvants：BCG (Bacillus Calmette-Guerin)Freunds plete adjvan

9、t： consists of a water-in oil emulsion,液体石蜡与羊毛脂混合Freunds complete adjvant： Freunds plete adjvant and killed Mycobacterium tuberculosis or BCGNew type adjvants： C3d, CpG motif(purine-purine-CpG-pyrimidine-pyrimidine)Immunologic Adjvants5.2 AntibodyAntibodies are soluable glycoproteins.They are found

10、in serum and tissue fluids They can bind to specific antigensImmunoglobulinAntibody (Ab)Immune serum(免疫血清)Ag adsorbed serum12+-albuminglobulinsMobilityAmount of proteinElectrophoretic separation of serum proteinsImmunoglobulins vs AntibodyImmunoglobulin (Ig): A general term for all antibody molecule

11、s including those globulin with the similar structure but with uncertain function. Each Ig unit is made up of two heavy chains and two light chains.All antibodies are Immunoglobulin, but not all Ig are with antibody activities.5.2.1 Structure of AntibodyHypervariable region binding site of the antib

12、ody molecule.Complementarity determining regions (CDRs): the heavy-chain and light-chain CDR regions are located on the loops that connect the strands of the VH and VL domains. CDRs are the antigen-binding regions of antibodies. Structure/Function RelationshipsFab(Fragment antigen binding) Ag bindin

13、gValence = 1Specificity determined by VH and VLPapainFcFabFc (Fragment crystallizable) Effector functionscontain CH2 and CH3 domaincontain the light chain and the VH and CH1 domains (木瓜蛋白酶)Structure/Function RelationshipsFabAg bindingFcEffector functionsF(ab)2divalentPepsinFc PeptidesF(ab)2(胃蛋白酶)Str

14、ucture/Function RelationshipsAg BindingComplement Binding SitePlacental TransferBinding to Fc Receptors5.2.2 Human Immunoglobulin classesIgG - Gamma () heavy chainsIgM - Mu () heavy chainsIgA - Alpha () heavy chainsIgD - Delta ( ) heavy chainsIgE - Epsilon ( ) heavy chainsTypes of antibodiesIgG: Maj

15、or serum Ig; Placental transfer IgA: 2nd highest serum Ig, Major secretory Ig Tears, saliva, gastric and pulmonary secretions IgM: Pentamer, First Ig made by fetus and B cells, Agglutinating IgIgD: B cell surface IgIgE : Allergic reactions, Parasitic infections, C4J ChainThe antigenic determinants,

16、or epitopes, on immunoglobulin molecules fall into three major categories: isotypic, allotypic, and idiotypic determinants.(同种)异型独特型同型Types of antibodiesHuman Immunoglobulin Subclasses (类)Based on small differences in the amino acid sequences in the constant region of the heavy chains. IgG Subclasse

17、sIgG1 - Gamma 1 (1) heavy chainsIgG2 - Gamma 2 (2) heavy chainsIgG3 - Gamma 3 (3) heavy chainsIgG4 - Gamma 4 (4) heavy chainsHuman Immunoglobulin Subclasses(亚类)Based on small differences in the amino acid sequences in the constant region of the heavy chains. IgA subclassesIgA1 - Alpha 1 (1) heavy ch

18、ainsIgA2 - Alpha 2 (2) heavy chainsHuman ImmunoglobulinLight Chain Types(型）Immunoglobulins can also be classified by the type of light chain that they have. Light chain types are based on differences in the amino acid sequence in the constant region of the light chain. These differences are detected

19、 by serological means.Kappa () light chains or Lambda () light chainsIgG StructureMonomer (7S)IgG1, IgG2 and IgG4IgG375% of serum Ig is IgG; Major Ig in extravascular (血管外的) spaces is IgG; Only IgG (except IgG2) can cross the placenta (胎盘);Ig G can fixe complement (except IgG4). Not all subclasses f

20、ix equally well IgG3IgG1IgG2; Ig G can bind to Fc receptors (except IgG2, IgG4) to help phagosis (Macrophages, monocytes, PMNs and some lymphocytes ) and opsonization (调理) such as K cells ADCC（antibody dependent cell-mediated cytotoxiticy) （抗体依赖的细胞介导的细胞毒性）IgG PropertiesFixation of C1 by IgG and IgM

21、AbsC1rC1sC1qC1rC1sC1qinactivativeActivativeIgA StructureSerum - monomer(7S)Secretions (sIgA) Dimer (11S)J chainSecretory component (T piece)J ChainSecretory PieceThe secretory piece is made in epithelial cells and is added to the IgA as it passes into the secretions. The secretory piece helps IgA to

22、 be transported across mucosa and also protects it from degradation in the secretions.Origin of Secretory Component of sIgAYYYYYY30% of serum Ig is IgA; 2nd highest serum Ig;80% of secretory Ig IgA; (Mucosal or Local Immunity) tears, saliva(唾液), gastric(胃部的)and pulmonary(肺的) secretions important in

23、local (mucosal) immunity. Ig A can bind to Fc receptors on some cells -PMNs and some lymphocytes.IgA PropertiesIgM StructurePentamer（五聚体）, (19S) Extra domain (CH4)J chainIn the pentameric form of IgM all heavy and light chains are identical. C4J ChainIgM Properties5-10% of serum Ig is IgM; 3rd highe

24、st serum Ig;First Ig made by fetus and B cells;IgM is a good complement fixing Ig. Thus, IgM antibodies are very efficient in leading to the lysis of microorganisms.)Agglutinating IgBinds to Fc receptorsB cell surface Ig_B Cell Receptor (BCR)B Cell Antigen Receptor (BCR)Ig- Ig-Ig- Ig- B-cell recepto

25、r (BCR) is a transmembrane protein posed of mIg and disulfide-linked heterodimers called Iga/Igb. IgD StructureMonomer (7S)Tail pieceTail PieceAbout 1% of serum Ig is IgG; B cell surface Ig: B Cell Receptor (BCR)IgD is primarily found on B cell surfaces where it functions as a receptor for antigen.I

26、gD PropertiesIgE StructureMonomer (7S)Extra domain (CH4)Least common serum Ig;Allergic reactions. IgE can bind to basophils and mast cells and is involved in allergic reactions.Parasitic infections (Helminths). It binds to Fc receptor on eosinophils.Does not fix complementIgE PropertiesC45.2.3 Produ

27、ction of AntibodiesPolyclonal antibodies a mixture of immunoglobulin molecules secreted against a specific antigen, derived from different B-cell lines.Monoclonal antibodies (mAb) Identical immunoglobulin molecule, produced by one type of immune cell and are all clones of a single parent cell.Geneti

28、c engineering Ab Polyclonal antiserumMonoclonal antibodiesProduction of Antibody Class variation: 1o IgM; 2o - IgG, IgA or IgECellular Events in 1o Response to T-dependent AgsLagClonal selectionLogIgMClass switchingStationaryDeclineMemory Cell PoolIgMMemory CellsIgG1o AgLag phaseVirgin cellsMemory c

29、ellsLog phasePool sizeIgG, IgA or IgEStationaryDeclineSustained productionIgMMemory CellsIgGIgGMemory CellsMemory PoolVirgin B cellCellular Events in 2o Response to T-dependent AgsMemory T cellsThMemory CellsThThMemory CellsMemory PoolVirgin cellT CellsVirgin cellsMemory cellsTh cellsCytokinesLong T

30、erm Memory5.2.4 Function of AbsNeutralization Agglutination Activation of complement Activation of effector cellsSpecificity of antigen-antibody binding5.2.5 Immunologic Adjvantsadjuvant : a substance which, when mixed with an immunogen, enhance the immune response against the immunogen.Types of adj

31、uvantsInorganic adjvants eg. Alum precipitate（明矾）Organic adjvants eg. Microorganisms and their metabolizing products (toxins and polysaccharides)Synthesized adjvants eg. BCG (卡介苗 Bacillus Calmette-Guerin)Freunds complete adjvants（弗氏完全佐剂）which consists of a water-in oil emulsion, and killed Mycobacte

32、rium tuberculosis or butyricum.New type adjvants C3d, CpG motif(purine-purine-CpG-pyrimidine-pyrimidine)5.2.6 Detection of Antibody or AntigenEnzyme Linked Immunosorbent Assay ELISA Muromonab (OKT-3) the first FDA-approved therapeutic monoclonal antibody in 1986. It was a murine IgG2a CD3 specific t

33、ransplant rejection drug. 18 FDA-approved therapies 150 therapies undergoing clinical trial, most are concerned with immunological and oncological targets. 5.2.7 Application of AntibodiesMonoclonal antibodies for cancer treatment5.2.8 Nanobodiesa type of single-domain, only 1215 kDa and a few nanome

34、ters in length antibodies derived from camels, and is an antibody fragment consisting of a single monomeric variable antibody domain. After the discovery that camelidea (camels and llamas) possess fully functional antibodies that lack light chains. It is able to bind selectively to a specific antige

35、n.20世纪获得诺贝尔医学生理学奖的免疫学家 年代 学者姓名 国籍 获奖成就 1901 Behring 德国 发现抗毒素，开创免疫血清疗法 1905 Koch 德国 发现病原菌 1908 Ehrlich 德国 提出抗体生成侧链学说和体液免疫学说 Metchnikoff 俄国 发现细胞吞噬作用，提出细胞免疫学说 1912 Carrel 法国 器官移植 1913 Richet 法国 发现过敏现象 1919 Bordet 比利时 发现补体 1930 Landsteiner 奥地利 发现人红细胞血型 1951 Theler 南非 发明黄热病疫苗 1957 Bovet 意大利 抗组胺药治疗超敏反应 19

36、60 Burnet 澳大利亚 提出抗体生成的克隆选择学说 Medawar 英国 发现获得性移植免疫耐受性 20世纪获得诺贝尔医学生理学奖的免疫学家 年代 学者姓名 国籍 获奖成就1972 Edelman 美国 阐明抗体的化学结构 Porte 英国 阐明抗体的化学结构1977 Yallow 美国 创立放射免疫测定法1980 Dausset 法国 发现人白细胞抗原 Snell 美国 发现小鼠H-2系统 Benacerraf 美国 发现免疫应答的遗传控制1984 Jerne 丹麦 提出免疫网络学说 Kohler 德国 杂交瘤技术制备单克隆抗体 Milstein 英国 单克隆抗体技术及Ig基因表达的遗

37、传控制1987 Tonegawa 日本 抗体多样性的遗传基础1990 Marray 美国 1954年第一例肾移植成功 Thomas 美国 1950年第一例骨髓移植成功1996 Doherty 美国 1974年首先提出MHC限制性，即T细胞 Zinkernagel 瑞士 的双识别模式 5.3 Vaccine一般孩子出生之后按照我们国家常规的免疫规划程序，月龄打第一针，一岁半打第二针，完成国家规划的接种剂次，即可达到较好的免疫效果。年实行消除麻疹的目标，将麻疹发病率降到万以下，消除本土麻疹病毒传播。麻疹强化免疫9月11日起，我国将对适龄儿童开展大规模的麻疹疫苗强化免疫。麻疹疫苗系用麻疹病毒减毒株接种鸡胚细胞经培养收获病毒液后冻干制成。Pre- & post-vaccine incidence of common preventable diseases5.3.1 Types of vac