细胞与分子免疫学课程课件示范课件.ppt
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1、细胞与分子免疫学课程课件细胞与分子免疫学课程课件(优选)细胞与分子免疫学课程课件3Chapter 7 Lymphocyte Maturation and Expression of Antigen Receptor Genes4nGeneral Features of Lymphocyte Maturation The maturation of B and T lymphocytes consists of:1.Lineage commitment and proliferation2.Expression of antigen receptor genes3.Selection of th
2、e mature repertories5p Early maturation:1.Pluripotent stem cells give rise to all lineages of blood cells1)It is difficult to precisely define the mechanisms by which stem cells become to the lymphoid lineage.2)B cell:bone borrow T cell:thymus3)By the gene mutations in experimental animals or human
3、patients.i.Transcription factors ii.Growth factors iii.Growth factors receptor6Example 1Bubble boy disease 1.Mutated in IL-7 gene and IL-7 receptor gene have profound deficiencies in mature T and B cells.2.Mutations in a chain of the IL-2 receptor g g chain,leads to an immunodeficiency disease:X-lin
4、ked severe combined immunodeficiency disease,bubble boy.7p Antigen Receptor Gene Recombination and Expression1.There may be 107 or more different T and B lymphocyte clones in one individual,each clone produce one specific antigen receptor.2.By somatic recombination,each individual does not need to h
5、ave such enormously genes.3.During the pre-B cell or pre-T cell stage,an immature form of antigen receptor is formed which to transduce signals to induce further maturation4.In more mature lymphocytes,complete antigen receptor expressed,which promote cell maturation.8pSelection Process That Shape th
6、e B and T Lymphocyte Repertoires1.The preservation of useful specificities is called positive selection:T cells in thymus.B cells maturing are not well known.2.Negative selection is the process that eliminates developing lymphocytes with strong binding to self-antigen.9pAcquisition of Functional Com
7、petence1.B cells can secrete antibodies.2.T cells can differentiate into distinct subsets of T cells.3.Expression of a variety of cell surface and intracellular molecules that participate in lymphocyte activation and effector functions.10n Formation of Functional Antigen Receptor Genes in B and T Ly
8、mphocytesElucidation of the mechanisms of antigen receptor gene expression is one of the landmark achievements of mordern immunology1 胚系理论胚系理论(Germline Theory)在胚系基因组中包含了免疫基因库,可对外界的众多抗在胚系基因组中包含了免疫基因库,可对外界的众多抗原发生应答,并能遗传。原发生应答,并能遗传。What are the problems with this theory?2 体细胞突变理论(体细胞突变理论(Somatic Mutati
9、on Model)基因组中的免疫球蛋白基因相对较少,抗体的多样性主基因组中的免疫球蛋白基因相对较少,抗体的多样性主要是由体细胞基因突变引起的。要是由体细胞基因突变引起的。What are the problems with this theory?11胚系理论与体细胞突变理论所遇到的问题胚系理论与体细胞突变理论所遇到的问题1 胚系理论胚系理论1)基因的种类少于抗体的多样性)基因的种类少于抗体的多样性So many specificities so few genes2 体细胞突变理论(体细胞突变理论(Somatic Mutation Model)1)部分编码)部分编码V区基因有众多的变化但部分
10、编码区基因有众多的变化但部分编码C区的区的基因却相对稳定。基因却相对稳定。2)不同类的同型的免疫球蛋白具有相同的)不同类的同型的免疫球蛋白具有相同的V区。区。Same variable regions on different isotypes123 Dreyer Bennett 假说:假说:免疫球蛋白单一的肽链是由两个分隔的基因编码:免疫球蛋白单一的肽链是由两个分隔的基因编码:每个免疫球蛋白类基因可能只有单个每个免疫球蛋白类基因可能只有单个C区基因,在胚区基因,在胚系基因组中与系基因组中与V区基因是分隔开的。区基因是分隔开的。在抗体产生细胞的发育过程中,其中一个独立的在抗体产生细胞的发育过程
11、中,其中一个独立的V区区基因序列将与基因序列将与C区序列结合成为完整的区序列结合成为完整的VC基因,然基因,然后在细胞内表达。后在细胞内表达。两个基因两个基因 一条多肽链:一条多肽链:此模型可以解释如下问题:此模型可以解释如下问题:1)一个基因的部分片断是多变的,而另一部分相对)一个基因的部分片断是多变的,而另一部分相对不变。不变。2)一个)一个V区可以与不同类的区可以与不同类的C区结合,产生出不同类区结合,产生出不同类型的抗体。型的抗体。134 The genetic foundation of antibody diversityThe Nobel Prize in Physiology
12、or Medicine 1987for his discovery of the genetic principle for generation of antibody diversity“in1976.Susumu Tonegawa Japan Massachusetts Institute of Technology(MIT)Cambridge,MA,USA b.193914Proof of the Dreyer-Bennett hypothesisVVVVVVVVVVVVVA mechanism to rearrange V and C genes in the genome so t
13、hat they can fuse to form a complete Immunoglobulin gene.CVCA single C region gene encoded in the germline and separate from the multiple V region genesFind a way to show the existence of multiple V genes and rearrangement to the C gene15Proof of the Dreyer-Bennett hypothesisVVVCVVVVVVSize fractiona
14、te by gel electrophoresisCVVVVVVVVVCVVVVVVVVVCut germline DNA with restriction enzymesVVVVVVVVVCA range of fragment sizes is generatedBlot with a V region probeBlot with a C region probeThe following example describes events on only ONE of the chromosomesC:two C genes in each of the human TCR b and
15、TCR g chain,one C gene in each of TCR a,d chain.The thymus is the major site of maturation of T cells.Tolerance induced in immature lymphocytes by recognition of self antigen in the generative lymphoid organs is also called central tolerance.Vb-to-DJb rearrangements occur在抗体产生细胞的发育过程中,其中一个独立的V区基因序列将
16、与C区序列结合成为完整的VC基因,然后在细胞内表达。The stimuli come from cells including:Maturation of T lymphocytes3)RAG proteins are first expressedSo many specificities so few genesmembrane-bound antigen receptor is not expressed;In three separate loci:在抗体产生细胞的发育过程中,其中一个独立的V区基因序列将与C区序列结合成为完整的VC基因,然后在细胞内表达。Mature B cellIn
17、fluence the specificities of the T cells.AT GTGACAC2 体细胞突变理论(Somatic Mutation Model)其中P碱基与N碱基的加入是导致抗体出现多样性的主要原因:RAG-1 and RAG-2 are first expressed.Organization of Ig Gene LociElucidation of the mechanisms of antigen receptor gene expression is one of the landmark achievements of mordern immunology1
18、6CVVVVVCVVVVVSize fractionate by gel electrophoresisVVVVCVBlot with a V region probeBlot with a C region probeCut mature B cell DNA with restriction enzymesVVVBlot with a V region probeBlot with a C region probeCVVVVVVSize fractionate by gel electrophoresis-compare the pattern of bandswith germline
19、DNAV and C probes detect the same fragmentSome V regions are missingThe C fragment has got largerVVVVCVEvidence for gene recombination17Organization of Ig and TCR Genes in the Germline1.Organization of Ig Gene Loci1)Three separate loci encode the Ig chains.chromosome 14:H chain locus chromosome 2:k
20、k chain chromosome 22:l l chain2)Multiple copies of at least three different types of gene segments:V:300 base,separate by noncoding DNA,at the 5 end of each V region is a nucleotide sequence which is called leader peptide.18C,each Ig locus has a distinct arrangement and number of C gene.In human:Ig
21、 k k light chain:a single C geneIg l l light chain:four functional C genesIg H heavy chain:nine different Ig isotypes and subtypes.J segments,30-50 base pairs long.D segments,in the human Ig heavy chain locus.1.Organization of Ig Gene Loci192.Organization of TCR Gene LociIn three separate loci:TCR a
22、,da,d chain:chromosome 14TCR b b chain:chromosome 7TCR g g chain:chromosome 7V:like Ig V geneC:two C genes in each of the human TCR b b and TCR g g chain,one C gene in each of TCR a,da,d chain.J:in all TCR loci,between V and C genes.D:in TCR b b chain and d d chain.20Antigen Receptor Gene Recombinat
23、ionDiversity of antigen receptor genes21Mechanisms of Somatic Recombination of Anitgen Receptor Genes1.有限的有限的DNA是怎样产生无限的专一是怎样产生无限的专一 性的性的?2.V区是怎样找到区是怎样找到J区的?为什么区的?为什么V区不与区不与V区相连?区相连?3.DNA是怎样断裂的?是怎样断裂的?4.DNA是怎样重新组合的?是怎样重新组合的?22RSS(重排信号序列重排信号序列),recombinase(重组酶重组酶),12-23 rule(一个一个规则规则)。1、Recombination
24、 Signal Sequences(RSS),重排信号序列:重排信号序列:v基因片断两端存在两个基因片断两端存在两个特异的保守序列:特异的保守序列:7聚体聚体与与9聚体。聚体。v 7聚体与聚体与9聚体之间间隔聚体之间间隔是是23bp或者是或者是12bp。vRSS:7聚体聚体-间隔间隔-九聚九聚体体(The heptamer The heptamer spacer spacer nonamer)nonamer)Mechanisms of Somatic Recombination of Anitgen Receptor Genes23 RSS(重排信号序列(重排信号序列)242、重组酶:、重组酶
25、:一组参与一组参与V、(、(D)、)、J基因片断重组的酶,包括以下几种:基因片断重组的酶,包括以下几种:RAG-1与与RAG-2(recombination-activating genes):一种内切酶,一种内切酶,只表达在只表达在T和和B淋巴细胞淋巴细胞不成熟阶段。不成熟阶段。末端脱氧核苷酸转移酶末端脱氧核苷酸转移酶(terminal deoxynucleotidyl transferase,TdT):表达于:表达于T、B细胞前体,此酶可将数个核苷酸通过不细胞前体,此酶可将数个核苷酸通过不需要模板的方式加到需要模板的方式加到DNA的断段。的断段。其他其他 切开发夹结构的内切酶,参与修复切开
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