抗体及其基因、B细胞发育(English version)(1).ppt

Antibody Molecules,Their Genes and B Cell Development ANTIBODY 抗体 NOBEL PRIZES FOR ANTIBODY RESEARCH Ig gene rearrangement Tonegawa 1987 Monoclonal Ab Koler,Milstein IgG4 does not fix complement f) Binding to cells Macrophages, monocytes,.- Opsonization. NK cell, Macrophages-mediating ADCC SPACoagglutination Test IgG IgG 3.Biological Activities major antibody against infections anti-bacterial effect anti-viral effect anti-toxic effect Opsonization Mediating ADCC Fixation complement Neutralizing virus & toxin mediating hypersensitivity II,III mediating autoimmunity IgG molecule opsonization NK 靶细胞 Mediating ADCC 1.structure & presence Secreted IgM (sIgM): pentamer Membrane-bound IgM(mIgM): monomer J 链 Ig Igb Ig Igb IgM 2. Properties a) the 3rd highest serum Ig b) the first Ig made by fetus and B cells c) intravascular Ig d) Fixation complement classical pathway e)the largest size of molecule f)agglutinating microbes e) Binding to cells Macrophages, monocytes,.- Opsonization. NK cell, Macrophages-mediating ADCC IgM J 链 IgM 3.Biological Activities pioneer antibody against infections the strongest anti- bacterial effect (5001000IgG) anti-viral effect anti-toxic effect Opsonization (the strongest ) Fixation complement Neutralizing virus & toxin Agglutinating microbes Mediating ADCC mediating hypersensitivity II,III mediating autoimmunity IgA IgA dimer 2.properties: 1)the 2nd most common Ig (serum IgA) 2)the major Ig in secretions. (secretory IgA,sIgA.5-15g/d) Saliva, tears, breast milk, nasal mucus secretions, bronchial secretions, vaginal secretions, prostatic fluid, mucous secretions of small intestine. SC J chain IgA 3) sIgA :transferred to the newborn through colostrum(初乳） sIgA 3.Biological Activities the important antibody against mucosal infections Preventing attachment of pathogens to mucosal cells. Neutralizing virus & toxin Salmonella, Vibrio Cholerae, Neisseria Gonorrhoeae Reovirus.Pilio,influenza anti-bacterial effect anti-viral effect anti-toxic effect IgE Structure of IgE molecule IgE2.properties 1)the least common Ig 2)binds to basophils & mast cells (FcR) Cytophilic Ab:IgE binds very tightly to Fc recrpters on Basophils & mast cells even before interacting with Ag. 3)not fix complement IgE 3.Biological Activities involved in allergic reactions ( hypersensitivity I) Binding to basophils & mast cells Resulting in the release of various pharmaco- logical mediatorsEosinophils have FcR for IgE,binding of Eosinophils ,to IgE- coated helminths (蠕虫）results in killing of the parasite. anti-parasitic infections structure of IgD molecule IgD 1.structure:monomer 2.presence: aon the surface of mature B cell serving as BCR (mature marker of B cell) bin serum(uncertain Ab activity) IgD 表7-1 人抗体分子的特性 抗体类别 IgG IgA IgM IgD IgE 重链类别 重链亚类 1, 2, 3, 4 1, 2 轻链类别 和 和 和 和 和 分子式 22 或 22 22或(22)5SCJ 22或(22)5SCJ (22)5J 或 (22)5J 22 或22 22 或 22 分子量（kDa） 150 160 或400 900 180 190 固定补体能力 + 0 + 0 0 血清浓度 (mg/100ml) 1000 200 120 3 0.05 血清半衰期(天) 236 5 3 2 穿过胎盘 0 0 0 0 肥大细胞和嗜碱 性细胞脱颗粒 ？ 0 0 0 + 裂解细菌能力 + + + ? ? 抗病毒能力 + + + ? ? a unique angenic determinant present on homogeneous Ab.The idiotype appears to represent the antigenicity of theAg-binding site of an Ab and is therefore located in the V region Idiotype: GOD Generation of Diversity 7-5 Ig and TCR Gene Rearrangement Susumu Tonegama Nobel Prize 1987 mRNA RNA转录本 蛋白质多肽链 基因1基因2基因3基因4 染色体DNA 外显子1 内含子 外显子2外显子4外显子3 内含子内含子 完整基因 基 因 的 结 构、 转 录 与 翻 译 V V V V V V V V J J J J J K 着丝粒 V V V V V V VPREB1 V V J1 L1 J2 L2 J3 L3 J4 L4 J5 L5 J6 L6 J7 L7 IGLL1 IGLL2 IGLL3 免 疫 球 蛋 白 基 因 结 构 V V D D D D V V D D D D J J J J M D G3 G1 EP1 A1 GP G2 G4 E1 A2 95个 IGHV 23个 IGHD 9个 IGHD 9个 IGHJ 11个 IGHC 900 kb 240Kb 22Kb 35Kb 300Kb IGH （位于染色体 14q32） IGK （位于染色体 2p12-p11） 1.85M b0.85M b 多于90个 IGKV 5个 IGKJ IGKC 11个 IGKV orphons IGL （位于染色体 22q11） 60个 IGLV 800K b 14K b 60K b 670Kb 30Kb 150Kb 7个 IGLJ 与 7个 IGLC 交替排列 3个 IGLL 基因座 IGH基因群包括95个V（50个是功能基因）、32个D、6个J以及以及9个C基因 片段。其中23个D片段位于V片段之间。IGHC基因按照如下顺序排列：IGHM、 IGHD、IGHG3、IGHG1、IGHA1、IGHG2、IGHG4、IGHE、IGHA2。IGL基因组包 括60个V（30个是功能基因，20个为假基因）、7个J基因片段和7个C区基因 （3个假基因）。人IGK基因群包括70个V（约半数为假基因）、5个J基因片 段和1个C区基因。 表7-2 人Ig基因片段 * 基因片段 Ig基因VDJC IGH95 （ 50 ）23 9 （6） 11 （ 9） IGK90 （ 60 ）051 IGL60 （ 30 ）07 7 （4） *：表中显示各基因片段的总数，括号中为除假基因以及无效基因之外 的功能基因片段数。 IGHIGKIGL VDJ 基因片段的组合 V D J V x D x J 50 12 6 3600 60 5 300 30 7 210 IGH/IGK(IGL)3600x(300+210)=1.6x10 6 Imprecise Joining 多样性至少增加100 倍 Nucleotide Addition 多样性增加 2000 倍 Potential Variation 10 10-1011 Somatic hypermutation 突变频率是其它基因的百万倍以上。 使抗体对抗原的亲和力增加100-1000 倍。 V3VnJ1J2J3J4V1V2CJ5前 B 细胞 DNA V1V2 V3 Vn J3 J1 J2 J4CJ5基因重排 V1V2J4CJ5成熟 B 细胞 DNA J5 C RNA 剪切 V2J4 初级转录本V1V2J4CJ5 J4V2C mRNA VL CL 抗体 VL CL 抗体 1.胚系基因 V1 V2 V3 Vn D1 D2 D3 Dn J1 J2 J3 J4 C C C C C 2.基因重排 V1 V2 D2 J3 J4 C C C C C 3.重排基因 V1 V2 D2 J3 J4 C C C C C 5.mRNA剪切 V2D2J3 C C V2D2J3 C C J4 J4 6.成熟mRNA V2 D2 J3 C V2 D2 J3 C L VH C 7.Ig前体多肽 L VH C V2D2J3 J4 C C 4.RNA转录本 Ig 重 链 基 因 重 排 Heavy chain diversity created by variable recombination AA T A G A G A T A G A G A T G A G G C G TA CA C TGG TG T AA TA CA C TGG TG T AA GA CA C TGG TG T AA A CC TGG TGTA C CG TGTA C G TGA CGTTTGT A CC C AspArg Arg Arg Asn AspAspAsp Tyr Tyr Try Try Try Gly Gly GlyAsn Ser Ser Tyr Tyr Trp Trp GlySerTyrPhe TyrSer Thr JHVHD S107 M603 M167 S107 M603 M167 1.重排基因 V1 V2 D2J3 J4 C C C C C V2 D2J3 J4 C 3.RNA转录本 V2D2 J3 C V2D2J3 C 4.mRNA剪切 V2 D2 J3 C 5.成熟mRNA L VH C 6.Ig 前体多肽 Ig 分 子 类 别 转 换 的 机 理 V1 V2 D2J3 J4 C C C 2.D