Chapter 6Chapter 6

Conception of termes related to MHC Conception of termes related to MHC

Human MHC --- HLA complex Human MHC --- HLA complex

Characteristics of MHC Characteristics of MHC

Interaction between MHC molecules anInteraction between MHC molecules and antigen-peptide d antigen-peptide Functions of MHC Functions of MHC molecules molecules

HLA & clinical medicineHLA & clinical medicine

OutlineOutline

ⅠⅠ. Conception of Terms. Conception of Terms

1.Histocompatibility antigen1.Histocompatibility antigen

--- 代表个体特异性的同种异型抗原称为组织相容性抗原

2.Major histocompatibility antigen 2.Major histocompatibility antigen

--- 引起强而迅速排斥反应的组织相容性抗原为主要组织相容性抗原

Related to MHC Related to MHC

位于同一染色体片段上 , 编码主要组织相容性抗原的一组紧密连锁的基因群。

Mouse MHC: H-2 complex (Chromosome 17)

Human MHC: HLA complex (Chromosome 6)

3.Major histocompatibility3.Major histocompatibility complex complex (MHC)(MHC)

A.ConceptionA.Conception

B.Nomemclature of MHCB.Nomemclature of MHC

其编码的产物是参与抗原提呈和 T 细胞 激活的关键分子 , 在免疫应答的启动和 免疫调节中发挥重要作用

HLA complexHLA complex A.Conception of HLA complex A.Conception of HLA complex

人类主要组织相容性抗原是存在所有有核细胞表人类主要组织相容性抗原是存在所有有核细胞表面一组能识别和排斥外来组织的抗原面一组能识别和排斥外来组织的抗原 ,, 它首先在白它首先在白细胞表面被发现且含量最高细胞表面被发现且含量最高 ,, 故人类主要组织相容故人类主要组织相容性抗原称为人白细胞抗原性抗原称为人白细胞抗原 ((human leukocyte Ag, Hhuman leukocyte Ag, HLA)LA) 。编码。编码 HLAHLA 的基因群称为的基因群称为 HLAHLA 复合体复合体

---on the chromosome 6p---on the chromosome 6pB.B. LocationLocation注意区别： 注意区别： *HLA complex & HLA antigen/molecule *Human MHC & HLA complex and MHC molecule & HLA antigen/molecule

ⅡⅡ.Human MHC .Human MHC --- HLA complex --- HLA complex

1.Structure of HLA complex 1.Structure of HLA complex

2.Expressive products of class Ⅰ2.Expressive products of class Ⅰ gene and class gene ---HLAⅡgene and class gene ---HLAⅡ moleculesmolecules

A.Classical HLA gene B.Genes associated with immune functionC.CYP21 基因（ 21 羟化酶基因）

class genes Ⅰclass genes ⅠClass genesⅡ

A.Classical HLA geneA.Classical HLA gene ---Class gene and Class geneⅠ Ⅱ

HLA-B,HLA-C,HLA-AHLA-B,HLA-C,HLA-AHLA-DP,HLA-DQ,HLA-DR

(HLA a gene)Ⅰ(HLA a gene)ⅠHLA complex

1.Structure of HLA complex1.Structure of HLA complex

B.Genes associated with B.Genes associated with immune function immune function

Genes encoding for C4 ,C2 and Bf Genes encoding for C4 ,C2 and Bf

Inflammation related geneInflammation related gene E GF

Non-classical class geneⅠNon-classical class geneⅠ( HLA- b gene)Ⅰ

DODO

A

Genes associated with Ag-processing and presentingGenes associated with Ag-processing and presenting•LMP2/7 ( 低分子量多肽 ) gene

•TAP1/2 ( 抗原肽加工相关转运体 )

gene •HLA-DM gene

•HLA-DO and TAP-associated protein gene

ff

StructurStructuree peptide-binding cleft ( 肽结合槽 )

DistributionDistribution

*peptide-binding region*peptide-binding region

•• consists of chain and chain •• divided into four region

2m2m

与抗原肽结合及被 T 细胞识别的部位

*Ig-like region*Ig-like region

*transmebrane region*transmebrane region与 T 细胞表面 CD8/CD4 分子结合部位

*cytolasmic region*cytolasmic region

2.Expressive products of 2.Expressive products of classⅠgene and classⅡgene ---HLA classⅠgene and classⅡgene ---HLA moleculesmolecules

1515 号染色号染色体编码体编码

1.Polygenic properties 1.Polygenic properties ( 多基因性 )

2.Haplotype 2.Haplotype ( 单元型 )

3.Polymorphism 3.Polymorphism ( 多态性 )

4.Linkage disequilibrium 4.Linkage disequilibrium ( 连锁不平衡 )

ⅢⅢ.Characteristics of MHC.Characteristics of MHC

多基因性多基因性 :: 指指 MHCMHC 是是由一组位置相邻由一组位置相邻 (( 或紧密连或紧密连锁锁 )) 的基因座位的基因座位 (locus)(locus) 组成组成

1.Polygenic properties of MHC1.Polygenic properties of MHC

2.Haplotype 2.Haplotype

p53

p58

连锁在同一条染色体上 HLA 不同基因座位等位基因的特定组合 , 称为单元型

共有 224 个基因座位

A24

B12

DRB6

DQ3

allele

每一个体的细胞表面均表达一组每一个体的细胞表面均表达一组 HLAHLA 分子分子 (( 各具不同抗原肽结合特各具不同抗原肽结合特性性 ))

3. 3. PolymorphismPolymorphism p57 群体中同一基因座位上存在两个以上等位基因的现象称多态性HLA-A(151) 、 HLA-B (301) 、 HLA-DRB1(227) … 共 1031 个(( 至至 2003.07.312003.07.31 止止 : A(282), B(53: A(282), B(537), DRB (418)……7), DRB (418)…… 共共 16951695 个个 ))

A24 24 A 2 A2 B12 12 B 32 B32

DRB6 6 DRB

DQ3 3 DQ 8 DQ8

16 DRB16

random combination and co-dominance ( 共显性 )

expression of alleles variation & selection pressure

phenotype ( 表型 )

a ba b

（（ HLA-AHLA-A* * 01030103 ））

haplotypehaplotypea:A24-B12-DRB6-DQ3a:A24-B12-DRB6-DQ3b:A2-B32-DRB6-DQ8b:A2-B32-DRB6-DQ8

4.linkage disequilibrium4.linkage disequilibrium--- 两个或两个以上基因座位上的某些等位基因 同时出现于同一染色体上的几率高于随机出现的频率，此现象称为连锁不平衡

• 北欧白人具特征性的单元型北欧白人具特征性的单元型 : A1-B8: A1-B8

•• 汉族人特征性的单元型：汉族人特征性的单元型： A2-B46-Cw3-DR9-DQ9-Dw23A2-B46-Cw3-DR9-DQ9-Dw23 （南方人）（南方人） A33-B17-Cw2-DR3-DQ2-Dw3 (A33-B17-Cw2-DR3-DQ2-Dw3 ( 北方人北方人 ))

p58

ⅣⅣ.The Interaction between MHC .The Interaction between MHC molecules and antigen peptide molecules and antigen peptide1.Molecular base of interaction1.Molecular base of interactionAnchor position or “pocket” ( 锚定位 ) and anchor residue( 锚定残基 )

--- 在抗原肽 -MHC 复合物中 , 抗原肽的两个或两个以上专司与 MHC 分子结合的氨基酸残基 (Y 和I), 称为锚 定残基 ; MHC 分子抗原结合糟中与抗原肽锚定残基相对应的氨基酸残基称为锚定位

Ag-peptide

异亮氨

酸酪氨

酸 anchoranchorresidueresidue

anchor position “pocket”

( ( p60p60 概念概念 ))

抗原肽 (8~10aa)

锚定残基

抗原肽 (13~17aa)

------Different MHC molecules selectively Different MHC molecules selectively bind different peptides that have bind different peptides that have specific anchor residue specific anchor residue

锚定残基

( 不同 MHC 分子选择性结合具有特定锚定残基的不同抗原肽 )

锚定位

锚定位

2.Characteristics of interaction2.Characteristics of interactionA.Relative specificityA.Relative specificity

( 相对专一性）

BB.Flexibility.Flexibility ( 包容性 )---Given MHC molecule can present or ---Given MHC molecule can present or recognize a group antigen peptide with recognize a group antigen peptide with consensue motifconsensue motif

( 特定 MHC 分子可提呈或识别带有特定共同基序的一群抗原肽 )

p61 表 6-3

H-2Kd

H-2Kb

Y: 酪氨酸 I: 异亮氨酸 V: 缬氨酸 L: 亮氨酸 F: 苯丙氨酸 F: 苯丙氨酸

以上表明以上表明 :: 与同一与同一 MHCMHC 分子结合的不同抗分子结合的不同抗原肽原肽 ,, 其锚定残基往往相同或相似其锚定残基往往相同或相似 (( 均显示一个特均显示一个特征性的共同基序征性的共同基序 ) )

共同基序

xY*xxxxxV/I*

xxxxY/F*xxL*

V . Functions of MHC V . Functions of MHC moleculesmolecules1. Antigen processing and presenting1. Antigen processing and presenting

A. Take part in genetic control of immune- reA. Take part in genetic control of immune- regulation gulation (17 章 )

B. Induce allogeneic graft rejection B. Induce allogeneic graft rejection (23 章 )

C. Take part in differentiation of T cell C. Take part in differentiation of T cell (12 章 )

D. Take part in restriction-recognition of T ceD. Take part in restriction-recognition of T cellll

2. Other functions of MHC molecules2. Other functions of MHC molecules

(14 章 )

(p54(p54 表表 : /ⅠⅡ: /ⅠⅡ类分子对类分子对 CTL/ThCTL/Th 的识别起限制作的识别起限制作用用 ))

2

受 MHC-Ⅱ类分子限制

受 MHC-Ⅰ类分子限制

CD4+T 细胞

APC靶细胞

MHCMHC 分子参与分子参与 TT 细胞限制性识别细胞限制性识别 A.CD8A.CD8++ T T 细胞的细胞的 TCRTCR 识别抗原肽的同时识别抗原肽的同时 ,, 需识别需识别 MHC-ⅠMHC-Ⅰ类分类分子子

BA

B.CD4B.CD4++ T T 细胞的细胞的 TCRTCR 识别抗原肽的同时识别抗原肽的同时 ,, 需识别需识别 MHC-ⅡMHC-Ⅱ类分类分子子

Ag 肽

CD8+T 细胞

2424

MHC 限制性 : 指 TCR 在识别 APC 或靶细胞表面抗原肽的同时 ,还须识别与抗原肽结合成复合物的 MHC 分子的现象

T T 细胞细胞

(anchor position)

MHCMHC 分子的限制性识别分子的限制性识别

ⅥⅥ.HLA & Clinical .HLA & Clinical MedicineMedicine1.HLA & organ-transplantation1.HLA & organ-transplantation

2.Abnormal expression of MHC2.Abnormal expression of MHC

molecules & clinical diseases molecules & clinical diseases

3.Association of HLA with diseases 3.Association of HLA with diseases

4.HLA & legal medicine 5.4.HLA & legal medicine 5.HLA & transfusionHLA & transfusion

(key of success or failure, HLA typing)

(tumor,AID)

(positive association and negative association)