mhc主要組織相容復(fù)合物

1、主要組織相容性抗原,概述 人類MHC/HLA復(fù)合體 HLA抗原系統(tǒng) MHC的功能 HLA與醫(yī)學(xué)的關(guān)系,主要內(nèi)容,主 要 內(nèi) 容,移植物的排斥反應(yīng),Immunogenetics of graft rejection,Mice of strain (A x B) are immunologically tolerant to A or B skin,ACCEPTED,REJECTED,Skin from (A x B) mice c

2、arry antigens that are recognised as foreign by parental strains,Transplant rejection,* 組織相容性抗原/移植抗原： 誘發(fā)移植排斥反應(yīng)的抗原。 * 主要組織相容性抗原： 引起快而強(qiáng)排斥反應(yīng)的組織相容性抗原。 *主要組織相容性復(fù)合體(major histocompatibility complex, MHC):

3、 位于哺乳動(dòng)物某一染色體上的一組緊密連鎖的基因群,其編碼產(chǎn)物參與抗原提呈、制約細(xì)胞間相互作用及誘導(dǎo)免疫應(yīng)答?！? 人類MHC → HLA復(fù)合體 → 編碼HLA抗原; * 小鼠MHC → H-2復(fù)合體 → 編碼H-2抗原;,概 念,* 組織相容性抗原/移植抗原： 誘發(fā)移植排斥反應(yīng)的抗原。 * 主要組織相容性抗原： 引起快而強(qiáng)排斥反應(yīng)的組織相容性抗原。 *主要組織相容性復(fù)合體

4、 (major histocompatibility complex, MHC): 位于哺乳動(dòng)物某一染色體上的一組緊密連鎖的基因群,其編碼產(chǎn)物參與抗原提呈、制約細(xì)胞間相互作用及誘導(dǎo)免疫應(yīng)答?！? 人類MHC → HLA復(fù)合體 → 編碼HLA抗原; * 小鼠MHC → H-2復(fù)合體 → 編碼H-2抗原;,概 念,概述 人類MHC-HLA復(fù)合體 HLA抗原系統(tǒng) MHC的功能 HLA與醫(yī)學(xué)的關(guān)

5、系,主要內(nèi)容,主 要 內(nèi) 容,HLA 復(fù)合體,HLA復(fù)合體位于人第六號(hào)染色體短臂, 現(xiàn)發(fā)現(xiàn)239個(gè)基因座位(locus)。 按其產(chǎn)物的結(jié)構(gòu)、分布與功能分為三群。,(Human Leukocyte Antigen, HLA),Simplified map of the HLA region,Maximum of 9 types of antigen presenting molecule allow interaction with

6、a wide range of peptides.,PolygenyCLASS I: 3 types HLA-A, HLA-B, HLA-C (sometimes called class Ia genes),CLASS II: 3 types HLA-DP HLA-DQ HLA-DR.,1．HLA-I類基因 * 經(jīng)典I類基因: HLA-A、-B、-C

7、 參與遞呈內(nèi)源性抗原 *非經(jīng)典I類基因: HLA-E、-G、-F 2．HLA-II類基因 *經(jīng)典II類基因: HLA- DP 、-DQ、- DR 參與遞呈外源性抗原 *非經(jīng)典II類基因: LMP、TAP、tapasin、

8、 HLA-DM、HLA-DO， 參與抗原的加工和轉(zhuǎn)運(yùn)3. HLA-Ⅲ類基因 * 包括編碼補(bǔ)體C4、Bf、C2的基因 * 編碼炎癥相關(guān)分子TNF、HSP70等基因,HLA復(fù)合體的基因組成及定位,MHC的遺傳學(xué)特征,高度多態(tài)性 單元型遺傳 連鎖不平衡,6,9,24,61,10,2

9、8,MHC的多態(tài)性,多態(tài)性：指在一隨機(jī)婚配的群體中，同一基因座位存在兩個(gè)以上等位基因。,多態(tài)性機(jī)制1 復(fù)等位基因,Variation >1% at a single genetic locus in a population of individualsEach polymorphic variant is called an alleleIn the human population, over 1,546 MHC

10、 alleles have been identified,Data from http://www.anthonynolan.org.uk/HIG/index.html July 2002,847 alleles,699 alleles,,Expression of MHC alleles is co-dominant,多態(tài)性機(jī)制2：共顯性遺傳,多態(tài)性機(jī)制3：多基因性,復(fù)等位基因：群體中，位于同一基因座位上有2個(gè)及2個(gè)以上不同的基因

11、; 共顯性遺傳：位于兩條染色體上的等位基因均為顯性基因;多基因性：指HLA具有眾多緊密連鎖的基因座位。,MHC多態(tài)性（polymorphism)的形成機(jī)制,MHC多態(tài)性的意義,利于群體適應(yīng)復(fù)雜多變的環(huán)境及應(yīng)付各種病原體的侵襲，從而維持種群的生存;實(shí)現(xiàn)對(duì)機(jī)體免疫應(yīng)答的遺傳控制;可用于個(gè)體識(shí)別，但不利于尋找同種移植物供者。,,Example: If MHC X was the only type of MHC molecule,Po

12、pulation threatened with extinction,Example: If each individual could make two MHC molecules, MHC X and Y,,From 2 MHC types and 2 variants…….10 different genotypes,Variants of each type of MHC molecule increase the resi

13、stance of the population from rapidly mutating or newly encountered pathogens without increasing the number of types of MHC molecule,Variant MHC molecules protect the population,,,,MHC多態(tài)性的意義,利于群體適應(yīng)復(fù)雜的環(huán)境改變，從而維持種群的生存;實(shí)現(xiàn)對(duì)機(jī)

14、體免疫應(yīng)答的遺傳控制;可用于個(gè)體識(shí)別，但不利于尋找同種移植物供者。,單元型遺傳和連鎖不平衡,單元型(haplotype)：連鎖于同一染色體片段上的若干基因座位上的等位基因組成。HLA單元型遺傳：以單元型作為遺傳基本單位，將MHC遺傳信息由親代遺傳給子代。意義：可用于選擇移植供者和親子鑒定。連鎖不平衡（linkage disequilibrium）：群體中各HLA等位基因非隨機(jī)地組成單元型的現(xiàn)象。,,Inheritance of

15、 MHC haplotypes,單元型遺傳和連鎖不平衡,單元型(haplotype)：連鎖于同一染色體片段上的若干基因座位上的等位基因組成。HLA單元型遺傳：以單元型作為遺傳基本單位，將MHC遺傳信息由親代遺傳給子代。意義：可用于選擇移植供者和親子鑒定。連鎖不平衡（linkage disequilibrium）：群體中各HLA等位基因非隨機(jī)地組成單元型的現(xiàn)象。,概述 人類MHC-HLA復(fù)合體 HLA抗原系統(tǒng) MHC的功能

16、 HLA與醫(yī)學(xué)的關(guān)系,主要內(nèi)容,主 要 內(nèi) 容,MHC-I類分子結(jié)構(gòu),α鏈：43KDa,β鏈：12KDa其基因位于15號(hào)染色體,Structure of MHC class I molecules,?1 and ?2 domains form two segmented ?-helicies on eightanti-parallel ?-strands to form an antigen-binding cleft.,Prope

17、rties of the inner faces of the helicies and floor of the cleft determine which peptides bind to the MHC molecule,HLA-I類抗原,1．分子結(jié)構(gòu)： (1) 肽結(jié)合區(qū)（a1/a2）：結(jié)合抗原肽 (2) Ig恒定區(qū)樣結(jié)構(gòu)（a3）：與CD8結(jié)合 (3) 跨膜區(qū): 固定HLA-I類抗原于膜上 (4) 胞漿區(qū): 信號(hào)轉(zhuǎn)

18、導(dǎo) (5) b2微球蛋白：維持I類分子空間構(gòu)型的穩(wěn) 定性 2．組織分布：分布于所有有核細(xì)胞表面,MHC-II類分子結(jié)構(gòu),α鏈：34KDa,β鏈：29KDa,MHC class II molecule structure,Cleft is made of botha and b chains,1. 分子結(jié)構(gòu)： (1) 肽結(jié)合區(qū)(a1/b1)：結(jié)合抗原肽 (2)

19、Ig恒定區(qū)樣結(jié)構(gòu)(a2/b2)：與CD4結(jié)合 (3) 跨膜區(qū)：固定HLAII類抗原于膜上 (4) 胞漿區(qū)：信號(hào)轉(zhuǎn)導(dǎo)2. 組織分布: 專職APC、活化T細(xì)胞和胸腺上皮細(xì)胞,HLAII類抗原,概述 人類MHC-HLA復(fù)合體 HLA抗原系統(tǒng) MHC的功能 HLA與醫(yī)學(xué)的關(guān)系,主要內(nèi)容,主 要 內(nèi) 容,MHC的功能,一、抗原提呈 MHC分子的抗原結(jié)合凹槽選擇性結(jié)合抗原肽 →形成抗原肽- MHC分子復(fù)合物

20、 →以MHC限制性的方式供給T細(xì)胞識(shí)別 →啟動(dòng)特異性免疫應(yīng)答。,Antigen recognition by T cells requires peptide antigens andpresenting cells that express MHC molecules,T cellresponse,No T cellresponse,No T cellresponse,

21、No T cellresponse,No T cellresponse,Antigen Presentation,MHC class I accommodate accommodatepeptides of 8-10 amino acids,Cleft geometry,MHC class II accommodatepeptides of >13 amino acids,Slices through MHC class

22、I molecules, when viewed from above reveal deep, well conserved pockets,,,,,,,,,,Peptide binding pockets in MHC class I molecules,,,,,,,Slices through MHC class II molecules, when viewed from above reveal shallow, poorly

23、 conserved pockets compared with those in MHC class I molecules,Peptide binding pockets in MHC class II molecules,MHC-binding peptides,Each human usually expresses:3 types of MHC class I (A, B, C) and3 types of MHC cla

24、ss II (DR, DP,DQ),The number of different T cell antigen receptors is estimated to be 1,000,000,000,000,000Each of which may potentially recognise a different peptide antigen,How can 6 invariant molecules have the capa

25、city tobind to 1,000,000,000,000,000 different peptides?,Peptides can be eluted from MHC molecules,,同一MHC分子提呈的不同抗原肽具有共同的基序,Eluted peptides from MHC molecules have different sequences but contain motifs,Peptides bound to

26、 a particular type of MHC class I molecule have conserved patterns of amino acids,Tethering amino acids need not be identical but must be relatedY & F are aromaticV, L & I are hydrophobic,Side chains of anchor

27、residues bind into POCKETS in the MHC molecule,Different types of MHC molecule bind peptides with different patterns of conserved amino acids,A common sequence in a peptide antigen that binds to an MHC molecule is called

28、 a MOTIF,Amino acids common to many peptides tether the peptide to structural features of the MHC moleculeANCHOR RESIDUES,抗原肽和MHC分子相互作用的分子基礎(chǔ)* 錨著殘基（anchor residue） 在抗原肽-MHC分子復(fù)合物中，抗原肽的兩個(gè)或兩個(gè)以上專司和MHC分子結(jié)合的氨基酸殘基稱為錨著殘基。,*

29、錨著位（pocket）MHC分子抗原結(jié)合槽中與抗原肽錨著殘基相對(duì)應(yīng)的氨基酸殘基稱為錨著位。,Complementary anchor residues & pockets provide the broad specificity of a particular type of MHC molecule for peptides,MHC molecules can bind peptides of different leng

30、th,Peptide sequence between anchors can varyNumber of amino acids between anchors can vary,Archedpeptide,不同的MHC分子提呈抗原肽的基序不同,Anchor residues and T cell antigen receptorcontact residues,T cell antigen receptor contactr

31、esidue side-chains point up,MHC anchor residueside-chains point down,T細(xì)胞的TCR識(shí)別pMHC復(fù)合物（雙識(shí)別）,二、參與T細(xì)胞限制性識(shí)別,* TCR識(shí)別抗原肽和自身MHC分子，即MHC限制遺傳背景一致的細(xì)胞相互作用。,二、參與T細(xì)胞限制性識(shí)別,抗原特異性的TCR與Tc之間MHC型別相同 ?識(shí)別,抗原相同MHC型別不同 ?不識(shí)別,MHC型別相同抗原不同

32、 ?不識(shí)別,參與T細(xì)胞限制性識(shí)別,* MHC制約相互作用的細(xì)胞類型, 即MHCI類分子將抗原肽提呈給CD4T細(xì)胞， MHCII類分子將抗原肽提呈給CD8T細(xì)胞。,三、MHC分子的其他生物學(xué)作用,* 參與T細(xì)胞在胸腺的發(fā)育 * 誘導(dǎo)同種移植排斥反應(yīng) * 參與對(duì)免疫應(yīng)答的遺傳控制,,,Allelic polymorphism is concentrated inthe peptide antigen binding

33、site,Polymorphism in the MHC affects peptide antigen bindingAllelic variants may differ by 20 amino acids,,Class II(HLA-DR),Class I,,,,,,,,,,,,,,,,,,,,,,,,Polymorphism in the MHC affects peptide antigen binding,Change

34、s in the pockets, walls and floor of the peptide binding cleft alter peptide MHC interactions and determine which peptides bind.,Products of different MHC alleles bind a different repertoire of peptides,概述 人類MHC-HLA復(fù)合體

35、 HLA抗原系統(tǒng) MHC的功能 HLA與醫(yī)學(xué)的關(guān)系,主要內(nèi)容,主 要 內(nèi) 容,HLA與醫(yī)學(xué)的關(guān)系,(一) HLA與疾病的相關(guān)性 * 攜帶某一HLA型別的個(gè)體對(duì)特定疾病表現(xiàn)為易感性或抗性的現(xiàn)象。(例如：攜帶HLA-B27者易患強(qiáng)直性脊柱炎)。(二) HLA抗原表達(dá)異常與疾病 * 多種腫瘤細(xì)胞HLA-I類抗原表達(dá)減少或缺如； * 自身免疫病的靶細(xì)胞異常表達(dá)HLA-II類抗原。,,(三）HLA與同種器官移植 * 供、受者間組