腫瘤免疫生化醫(yī)學(xué)醫(yī)藥PPT課件

1、1. The surveilliance System and cancer2. Natural killer (NK) cell 4. MHC proteins 第1頁(yè)/共66頁(yè)For decades, the immune surveillance system has been credited with protecting the body against cancer. Presumably, cancer develops occasionally during a lifetime and the surveillance system is able to eradicate

2、 it from the body. 1. The surveillance System and cancerIt is only when a cancer escapes this system or the system becomes weakened that cancer can become established. In some cases, the cancer cells are able, biochemically,to escape the immune surveillance system. 第2頁(yè)/共66頁(yè)第3頁(yè)/共66頁(yè)第4頁(yè)/共66頁(yè)機(jī)體的抗腫瘤免疫效應(yīng)

3、機(jī)制包括細(xì)胞免疫和體液免疫細(xì)胞免疫的效應(yīng)細(xì)胞包括T細(xì)胞，NK細(xì)胞，巨噬細(xì)胞，目前認(rèn)為中性粒細(xì)胞、嗜酸性粒細(xì)胞也參與抗腫瘤作用。激活補(bǔ)體系統(tǒng)溶解腫瘤細(xì)胞，抗體依賴(lài)的細(xì)胞介導(dǎo)的細(xì)胞毒作用，抗體的調(diào)理作用，抗體封閉腫瘤細(xì)胞上的 某些受體，抗體使腫瘤細(xì)胞的 粘附特性改變或喪失 The surveilliance System第5頁(yè)/共66頁(yè)2. Natural killer (NK) cell NK cells are subset of T cells that can kill tumor cells (or virus-infected cells) but do not harm normal

4、 cells NK cells also are heterogeneous; they contain subsets of cells, at least one of which (A-NK cells) is capable of killing tumor cells and cells infected with viruses The A-NK cell has a variety of receptors on its cellular surface 第6頁(yè)/共66頁(yè)Tu 15-12Tu 15-12第7頁(yè)/共66頁(yè)Tu 15-12Tu 15-12第8頁(yè)/共66頁(yè)Tu 15-1

5、2Tu 15-12第9頁(yè)/共66頁(yè)圖15-1第10頁(yè)/共66頁(yè) One or more of receptors will recognize an antigen on the surface of the tumor cellThis antigen, not expressed on most normal cells, is an MHC class I chain-related antigen, the antigen binds to NKG2D, a c-lectin-like receptor on the surface of human NK cells The comp

6、lex with the antigen can initiate the killing program through pI3k NKG2D is non-covalently associated to the DAP10 transmembrane signaling adaptor. 第11頁(yè)/共66頁(yè)Killer cells have at least two mechanisms to destroy tumor cells * perforin-granzyme-mediated necrosis * FasL/Fas pathway induce apoptosis第12頁(yè)/

7、共66頁(yè)Tu 15-12Tu 15-12第13頁(yè)/共66頁(yè)Tu 15-3Tu 15-3第14頁(yè)/共66頁(yè)Tu 15-3Tu 15-3第15頁(yè)/共66頁(yè)Tu 15-3Tu 15-3第16頁(yè)/共66頁(yè)Tu 15-3Tu 15-3第17頁(yè)/共66頁(yè)Tu 15-4Tu 15-4第18頁(yè)/共66頁(yè)Why can NK cell kill tumor cells but do not harm normal cells Two of receptors on the surface of the NK cell are killer cell inhibitory receptor KIR, (KIR2D

8、L2), an example of an immunoglobulin-like receptor, and Ly-49A, normal cells express an MHC class I chain-related antigen either at very low levels or not at all, and A-NK cells that are surveying the microenvironment do not attack them on the other hand, NK cells have receptors that recognize norma

9、l antigens on normal cells; this complex inhibits the killing program 第19頁(yè)/共66頁(yè)Tu 15-9第20頁(yè)/共66頁(yè)Tu 15-10第21頁(yè)/共66頁(yè) There are two types of light chains, called x (or ) and , and five types of heavy chains, called ，, and 第22頁(yè)/共66頁(yè)第23頁(yè)/共66頁(yè)CH1VLCLVHCH2 CH3Hinge RegionCarbohydrateDisulfide bond第24頁(yè)/共66頁(yè)四條

10、多肽鏈的對(duì)稱(chēng)結(jié)構(gòu), ,兩條重鏈（H H） 和兩條輕鏈（L L）第25頁(yè)/共66頁(yè)免疫球蛋白的空間構(gòu)象沿結(jié)構(gòu)域長(zhǎng)軸平行方向往返轉(zhuǎn)折而形成兩層折疊二硫鍵位于結(jié)構(gòu)域中央，連接兩層折疊在此基礎(chǔ)上形成球形的結(jié)構(gòu)域第26頁(yè)/共66頁(yè)第27頁(yè)/共66頁(yè)免疫球蛋白的空間構(gòu)象第28頁(yè)/共66頁(yè)Gene of immunoglobulin 人類(lèi)B細(xì)胞有三個(gè)Ig基因座，即H（14）、（2）、（22）。 L、H基因座分別由編碼V區(qū)和C區(qū)的一些基因組成，是多基因家族 H基因座的V區(qū)基因由V基因片段、D基因片段、J基因片段組成。C區(qū)基因呈串聯(lián)排列。第29頁(yè)/共66頁(yè) L基因座的V區(qū)基因由V基因片段、J基因片段組成。C區(qū)基

11、因只有一個(gè)。第30頁(yè)/共66頁(yè)免疫球蛋白的空間構(gòu)象第31頁(yè)/共66頁(yè)第32頁(yè)/共66頁(yè)免疫球蛋白基因重排n在成熟的淋巴細(xì)胞，一種基因片段只有一個(gè)片段參與組成基因n重排是由一系列酶參與的：DNA外切酶、DNA連接酶和V（D）J重組酶系統(tǒng)n重組酶識(shí)別特殊DNA識(shí)別序列也稱(chēng)為重組信號(hào)序列（RSS），重組遵循“12-23”規(guī)則第33頁(yè)/共66頁(yè)第34頁(yè)/共66頁(yè)重鏈基因重排第35頁(yè)/共66頁(yè)第36頁(yè)/共66頁(yè)第37頁(yè)/共66頁(yè)第38頁(yè)/共66頁(yè)第39頁(yè)/共66頁(yè)輕鏈基因重排第40頁(yè)/共66頁(yè)抗體多樣性的形成抗體的多樣性含義：n抗體的種類(lèi)繁多，特異性各不相同n抗體分子的抗原性多種多樣n抗體的生物學(xué)活性多

12、種多樣第41頁(yè)/共66頁(yè)n編碼Ig基因的多樣性n V、D、J基因連接的多樣性 例如輕鏈V基因片段3端5個(gè)核苷酸CCTCC和J基因片段5端4個(gè)核苷酸GTGG連接時(shí)，9個(gè)核苷酸中只有6個(gè)核苷酸編碼輕鏈第95、96位的氨基酸，可產(chǎn)生8中不同的連接方式第42頁(yè)/共66頁(yè)n N區(qū)多樣化 不存在Ig基因座,在重排后插入到VJ或VDJ連接處的核苷酸序列.n體細(xì)胞突變： 體細(xì)胞發(fā)育過(guò)程中在V區(qū)基因常常發(fā)生突變。第43頁(yè)/共66頁(yè)第44頁(yè)/共66頁(yè)Ig的生物合成過(guò)程第45頁(yè)/共66頁(yè)OpsonizationIt is the process by which antibodies bind to an anti

13、gen, especially on the surface of cancer, to enhance attachment of the cancer cell to a phagocytic cell 第46頁(yè)/共66頁(yè)第47頁(yè)/共66頁(yè)第48頁(yè)/共66頁(yè)MHC proteins also are referred to as human leukocyte-associated (HLA) antigens, and these proteins are so diverse that no two people, except for identical twins, are lik

14、ely to have the same MHC proteins 4. MHC proteins 第49頁(yè)/共66頁(yè)MHC分子是機(jī)體免疫系統(tǒng)的重要分子，參與特異性免疫識(shí)別第50頁(yè)/共66頁(yè)MHC structurenClass 1MHC proteins they are located on the surfaces of nucleated cells, and they have one -chain in association with a 2-microglobulin (a small protein). 它分為多肽結(jié)合區(qū)、免疫球蛋白樣區(qū)、跨膜區(qū)和胞內(nèi)區(qū)。第51頁(yè)/共66頁(yè)由1

15、和2兩個(gè)相似的結(jié)構(gòu)域組成肽結(jié)合區(qū)由3和2m兩個(gè)免疫球蛋白樣結(jié)構(gòu)域組成免疫球蛋白樣區(qū)由25個(gè)氨基酸殘基呈螺旋狀結(jié)構(gòu)組成跨膜區(qū)由30個(gè)氨基酸殘基組成胞漿區(qū)第52頁(yè)/共66頁(yè)nClass II MHC proteins they have two membrane-spanning regions, together with an -chain and a -chain. 第53頁(yè)/共66頁(yè)n它分四個(gè)區(qū)，分別為多肽結(jié)合區(qū)、免疫球蛋白樣區(qū)、跨膜區(qū)和胞內(nèi)區(qū)。n由1和 1兩個(gè)相似的結(jié)構(gòu)域形成可以與肽結(jié)合的深槽組成肽結(jié)合區(qū)。n由2和2兩個(gè)免疫球蛋白樣結(jié)構(gòu)域組成免疫球蛋白樣區(qū)第54頁(yè)/共66頁(yè)n由25個(gè)氨基

16、酸殘基呈螺旋狀結(jié)構(gòu)組成跨膜區(qū)。n胞漿區(qū)第55頁(yè)/共66頁(yè)第56頁(yè)/共66頁(yè)人類(lèi)MHC復(fù)合體基因結(jié)構(gòu) *多基因性：MHC由一組位置相鄰的基因座位組成，各自的產(chǎn)物具有相同或相似的功能。 MHC基因復(fù)合體位于人第六號(hào)染色體短臂6p21.31。第57頁(yè)/共66頁(yè)一般將其分為三類(lèi): HLA-I、 HLA-II 和HLA-HLA-I類(lèi)基因集中在遠(yuǎn)離著絲點(diǎn)的一端，主要包括B、C、A三個(gè)座位，其產(chǎn)物是HLA-I類(lèi)分子HLA-II類(lèi)基因在復(fù)合體中位于近著絲點(diǎn)一端，由DP、DQ、DR三個(gè)亞區(qū)組成，編碼和 雙肽鏈分子第58頁(yè)/共66頁(yè)HLA-是免疫功能相關(guān)基因血清補(bǔ)體成分編碼基因 C2、C4A、C4B、Bf編碼腫瘤壞死因子（TNF、）、熱休克蛋白基因等。第59頁(yè)/共66頁(yè)第60頁(yè)/共66頁(yè)* *共顯性：一對(duì)等位基因同為顯性， 稱(chēng)為共顯性 位于一對(duì)同源染色體上對(duì)應(yīng)位置的一對(duì)基因稱(chēng)為等位基因 對(duì)于