01-2hr antigen.pptx

1、Chapter 3,Antigens:抗原,一、Definitions 释义,Immunogen免疫原 Antigen (Ag) Hapten半抗原 Epitope or Antigenic Determinant 抗原表面决定簇,immunogen,Any substance capable of inducing an immune response is called an immunogen and is said to be immunogenic. 任何可诱导生物体产生免疫反应的物质称为免疫原，也称为具有免疫原性。,Definition of Antigen,Big molecul

2、es (MW 104 ) that are recognized by a particular immunoglobulin or TCR, and so can serve as the target of an immune response, are called antigens and are said to be antigenic.,A molecule that can be recognised by the immune system 识别性 Usually foreign to the body although our own molecules can serve

3、as antigens 外源性 Proteins eg:Grass pollen, egg albumin. bacterial endotoxin, 蛋白质 Haptens eg:Nickel salts which bind to proteins 半抗原,Antigen,All immunogens are also antigens,Antigens,Antigen (Ag) the molecule an antibody (Ab) binds to usually a foreign substance 外来物质 each antigen has different sites t

4、hat antibodies can bind to, so that one antigen can be bound by several different antibodies 不同的结合位点，作用于不同的抗体 examples in the case of allergy could be pollen, cat dander, or a chemical in soap 对于花粉、猫屑、肥皂,How Antibody Binds to Antigen,The top part of this figure shows how different shaped antigens ca

5、n fit into the binding site of antibodies: left, pocket口袋状; center, groove槽状; right, extended surface外表面. The panels below show space-filling or computer-generated models indicating where contact between the peptide antigen and antibody occurs.,二、Specificity of antigen,Hapten-carrier effect半抗原-携递作用,

6、By manipulating the cell populations in these experiments, it was shown that TH cells are responsible for recognizing the carrier, whereas the B cells recognize hapten. 试验证明：T cell识别 呈递子，同时B细胞识别半抗原 Hapten+carrier =complete antigen,Hapten-carrier conjugates,Definition,Structure native determinants ha

7、ptenic determinants,According to the different response，antigen including three species：,Immunogen Allergen(变应原) Tolerogen（耐受原 ）,Antigenic specificity,The specific characteristic that the antigen bond with the TCR and BCR (or Ab). 特异性的结合T、B细胞受体、或者抗体 The specific set of chemical features that are rec

8、ognized （特殊化学结构识别位点）by a given antibody and TCR/BCR is called an epitope (抗原决定簇). In generally, the epitope is made up of 5 amino acid residues(氨基酸残基),5-7 monosaccharide(单糖) or 6-8 nucleotide residues（核苷酸基团）.,Classification of epitope,Classification rules: 1、structure 2、cell species of recognition o

9、f epitope,1、structure of epitope,CE: conformational epitope 构象型/non- linear epitope 非线性：made up of residues located at two or more discontinuous sites along the linear sequence of an antigen 抗原序列不同位点的非连续性残基结合位点 LE: linear epitope 线性/sequential epitope 顺次性 ：positioned sequentially in the linear seque

10、nce of a protein or polysaccharide antigen. 连续性的 蛋白或多聚糖线性结构位点,Antigenic Determinants (Epitopes),2、cell species of recognition of epitope,T cell epitope B cell epitope Functional epitope 功能型 Hidden epitope 隐蔽型,T cells do not recognise native antigens,Y,Y,Y,Y,Y,Y,Proliferation and antibody production,

11、No proliferation No cytokine release,Cross-linking of surface membrane Ig,B cell epitopes are usually different from those recognized by TCRs,Properties of B cell epitope,Antigenic Determinants Recognized by B cells and Ab,Composition Proteins, polysaccharides, nucleic acids Sequence (linear) determ

12、inants Conformational determinants Size 4-8 residues Number Limited (immunodominant epitopes) Located on the external surfaces of the Ag,Antigenic Determinants Recognized by T cells,Composition Proteins (some lipids) Sequence determinants Processed MHC presentation (lipid presentation by MHC-like CD

13、1) Size 8 -15 residues Number Limited to those that can bind to MHC,Properties of T/B cell epitope,Recognize only processed antigen. T cell epitope usually the sequential epitope or linear epitope）. T cell epitope recognize only the peptide. MHCII1220peptides; MHCI 812 peptides；,Recognize directly a

14、lways the native (or unprocessed) antigen. B cell epitopes usually recognize the conformational epitopes on the surface of antigen, but also including the sequential epitopes occasionally.,For example, the human hormone glucagon(人胰高血糖素), which is only 29 amino acids long, contains separate B cell (N

15、-terminal) and T cell(C-terminal) epitopic regions . When mice are immunized with human glucagons, they produce antibodies only against aminoterminal part of the molecule, whereas their T cells respond only to the C-terminal portion. Humoral and cell-mediated immune responses can be directed against

16、 different regions of a single molecule.,A molecule including two epitopes,Comparison of T cell epitope and B cell epitope,Antigenic valence 抗原共价键,The total number of antigen determinant of a antigen molecule binding the specific Ab. Hapten: antigenic valence=1 natural antigen=n(n2).,Determinants Re

17、cognized by the Innate Immune System,Innate Immune System -Broad Molecular Patterns 广谱性 Reacts with a variety of pathogens Adaptive Immune System -Discrete Determinants 非关联 Reacts with a specific pathogen,Determinants Recognized by the Innate Immune System,PAMPs Pathogen Associated Molecular Pattern

18、s（病原相关分子模式） PRRs Pattern Recognition Receptors （模式识别受体）,Character of antigen: foreignness,Most important, however, is foreignness: the immune system normally discriminates between self and nonself, so that only molecules that are foreign to the host are immunogenic.,三、Classification of antigens： -Ac

19、cording to different standard，there are lots of kinds of antigens.,1. According to immunogenicity of the antigens,Antigen hapten,2. According to the dependence of T cells,Thymus-dependent antigen, TD-Ag The immune response to most antigens depends on both T cells and B cells recognizing the antigen

20、in a linked fashion, such as proteins . Thymus-independent antigens, TI-Ag Some antigens do not required the presence of helper T cells, such as capsular polysaccharides膜被多聚糖, LPS, flagella鞭毛.,3、依据抗原诱生抗体时对T细胞的依赖性分类： 胸腺依赖性（TD-Ag)及非胸腺依赖性抗原 (TI-Ag),胸腺依赖性抗原(thymus dependent antigen, TD antigen) ：亦称T细胞依赖

21、抗原，其刺激机体产生抗体依赖于T细胞辅助，绝大多数蛋白质抗原及细胞抗原属TD抗原。 非胸腺依赖抗原(thymus independent antigen, TI antigen)：亦称T细胞非依赖性抗原，其刺激机体产生抗体无需T细胞辅助。如LPS 、荚膜多糖、聚合鞭毛素等。特点是由同一构成单位重复排列而成,（TD-Ag)及 (TI-Ag)的比较,TD-Ag TI-Ag 组成 细胞表位 重复细胞表位 细胞辅助必需无需 免疫应答类型体液和细胞免疫体液免疫 抗体类型多种IgM 免疫记忆有无,Types of Antigens：T-independent,Polysaccharides多聚糖,Prop

22、erties Polymeric structure Polyclonal B cell activation Resistance to degradation,Examples Microbial proteins Non-self or Altered-self proteins,Proteins,3.According to the source of antigens,Xenoantigens(异种）：The antigen come from different genus and generic. （pathogenic microorganism, plant protein,

23、 animal serum and heterogenity organ implant） Alloantigens（同种）：The specific antigen exists in different individual of same genus. （red cell blood type antigen, included ABO red cell blood type antigen, Rh antigen system, human leukocyte antigen (HLA). Autoantigens（自身）： oneself component can induce b

24、ody to self immune response Heterophilic antigens（异嗜）： common antigen in a strain hemolytic streptococcus（溶血链球菌） surface component and cardiac muscle self-tissue, Forssman antigen（福氏抗原，嗜异性抗原 ）,ABO blood group antigens and ABO blood types,ABO blood types,Blood transfusion,-Human RBC lack MHC antigens

25、,antigen=agglutinogen(凝集原),antibody= agglutinin(凝集素),Agglutinin exists in the serum can agglutinate with RBC A type: Agglutinin ； B type: Agglutinin ； O type: both and AB type: neither nor ,Landsteiner: agglutinogen is on the surface of red blood cell (RBC) A type: A agglutinogen； B type: B agglutin

26、ogen； AB type: both A and B O type: neither A nor B,Hyperacute rejection,Endothelial cells 内皮express ABO antigens,Common antigens and cross-reaction交叉反应,Some antigens can react with antibody or activate lymphocytes by other inducing, these antigen frequent strip multi-antigen epitope. These differen

27、t antigens contain sameness or similitude antigen epitope is common antigen. Antigen or activate lymphocyte react with sameness or similitude antigen epitope in different antigen, it is cross-reaction.一个抗体与免疫原以外的其他抗原可以结合，大多数抗原都能与关系相近的抗原发生交叉反应。,Cross-Reaction,A,B,C,D,anti-A,anti-B,anti-C,anti-D,Immun

28、ize,Immunogen,Cross-reactive antigen,A,E,F,G,A,B,C,D,Reactivity with Rabbit antiserum,Cross Reactivity,The ability of an individual Ab combining site to react with more than one antigenic determinant. The ability of a population of Ab molecules to react with more than one Ag,Reason of cross-reaction

29、,1、heterogeneity（异质性） of antigen 2、common epitope 3、similar epitope,四、Factors Influencing ImmunogenicityContribution of the Immunogen免疫原的免疫原性,Foreignness Size,Chemical Composition 化学构成 Primary Structure Secondary Structure Tertiary Structure Quarternary Structure,Factors Influencing ImmunogenicityCo

30、ntribution of the Immunogen,Physical Form 物理结构 Particulate Soluble Denatured Native,Degradability 降解性 Ag processing by Ag Presenting Cells (APC),明胶分子量很大（100KD），直链氨基酸，稳定性差，易被体内酶降解，抗原弱加入酪氨酸抗原性增强 人工合成的多聚丙氨酸多聚赖氨酸复合物，分子量可达10KD以上，但因属直链，免疫原性差加酪、苯丙氨酸等芳香族氨基酸，可使免疫原性增强 存在有苯环的芳香族氨基酸或带杂环的氨基酸是决定性因素，如胰导素（5734）、鲱精蛋

31、白（5000），只1820AA，低分子蛋白质，但结构复杂，良好免疫原性。,一般来说，颗粒性抗原的免疫原性比可溶性抗原的强；聚合状态的蛋白质比其单体的免疫原性强；具有环状结构的蛋白质的免疫原性比直链的强。 分子结构和空间构象越复杂的物质免疫原性越强，结合状态的蛋白质比单体蛋白质免疫原性要强。,Factors Influencing ImmunogenicityContribution of the Biological System,Genetics Species Individual Responders vs Non-responders Age,Factors Influencing I

32、mmunogenicity Method of Administration,Dose 剂量 Route 途径 Subcutaneous（皮下） Intravenous（静脉） Intragastric（胃） Adjuvant 佐剂 Substances that enhance an immune response to an Ag,Chemical Nature of Immunogens,Proteins Polysaccharides Nucleic Acids Lipids Some glycolipids 糖脂and phospholipids磷脂 can be immunogen

33、ic for T cells and illicit a cell mediated immune response,五、Super antigen，SAg,Monoclonal/Oligoclonal T cell response 1:104 - 1:105,超抗原 Super antigen,是一类由细菌外毒素和逆转录病毒蛋白构成的不同于促有丝分裂原的物质，具有强大的激活能力，少量分子可以使大量T细胞活化的高效能抗原。它可使宿主20%的的T细胞活化，而通常的多肽抗原在初次免疫应答中只能使0.001%-0.1%的T细胞激活。 它可分为外源性超抗原（如金黄色葡萄球菌外毒素，链球菌外毒素）和内

34、源性超抗原（主要是逆转录病毒感染机体后，病毒DNA整合到宿主基因组中，持续表达的病毒蛋白产物）。,Classification of SAg,According to the source Endogenous (virus): Retrovirus (HIV, mouse mammary tumor virus, MMTV) rhabdovirus(棒状病毒）, EBV, Rabies virus Exogenous (bacterial): Staphylococcal enterotoxins (SEA- SEE)（肠毒素） Staphylococcal protein A (SPA)

35、Staphylococcal toxic shock toxin（中毒性休克毒素 ） Staphylococcal exfoliating toxin（剥落毒素） Streptococcal pyrogenic exotoxins（致热外毒素） Streptococcal A (M protein),According to stimulate the cell,T cell SAg TCR type： Endogenous+Exogenous TCR type：HSP、Mycobacteria (分枝杆菌)、surface molecule of some tumor cell B cell

36、 SAg Staphylococcal 葡萄球菌 protein A (SPA) HIV gp120,Biology significance of SAg,Immune activate binding with MHC II ，activate CD4 and CD8 T , contribution to the defence of body,toxic HSP syndrome, default of multi-organ, antoimmunity disease。 2. Immune inhibit 3. Immune tolerance,六、Mitogen (有丝分裂原),A

37、ctivation can be induced under artificial conditions by cross-linking other types of surface molecules. Eg: phytohemagglutinin（PHA，植物血凝素 ）、concanavalin A（Con A，刀豆蛋白A ）、pokweed mitoglu （ phytolacca americana ） （PWM，美洲商陆）、lipopolysaccharide（LPS） 、 staphylococcal protein A( SPA)。,The effect of mitogens

38、 on T and B cells of human and mice,The response to an immunogen can often be enhanced if it is administered as a mixture with substances called adjuvant. 增强免疫性,七、Adjuvant 佐剂,Classification,1.biology ： Bacillus Calmette-Guerin (BCG,卡介苗) 2.mineral: KAl(SO4 )2 、Al2(SO4 )3、 Al(OH)3 3.organic：complete F

39、reunds adjuvant (CFA), incomplete Freunds adjuvant (IFA) ；propolis (蜂胶佐剂)，LPS。 pound ：polyinosinic acidpolycytidylic acid (多聚肌苷酸), cytidine monophosphate(胞苷酸).,Freunds adjuvant,为乳化的水油佐剂，由美籍匈牙利细菌学家弗罗伊德（Freund）于1935年研制成功，可显著提高疫苗的免疫效果。包含高度纯化的石蜡油、乳化剂（如羊毛脂或单油酸甘露醇酐）和加热杀死的抗酸菌（如结核分支杆菌或卡介苗）。 与抗原液充分混匀后，成为油包水型稳定乳剂，可延长机体吸收抗原的时间，刺激免疫系统，增强机