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IMMUNOLOGY
Major Histocompatibility Complex
(MHC) and its encoding molecules
Xiaojian Wang
0571-88206268
科研楼B819
[email protected]
MHC
1. Introduction
2. Structure of MHC genes and products
3. Polymorphism of MHC
4. Interactions of MHC molecules with
antigenic peptides
5. Biological function of MHC molecules
6. MHC and clinical medicine
Introduction
MHC
1. Histocompatibility antigen
The Ags primarily responsible for rejection of
genetically different tissues are known as
histocompatibility Ags.
Histocompatibility
The ability to accept grafts between individuals.
2. Histocompatibility antigen system
Major histocompatibility antigen
Minor histocompatibility antigen
MHC
3.Major histocompatibility complex,MHC
A cluster of genes on chromosome 6 in
humans, encoding major histocompatibility
antigen which regulates immune response.
4. Human: Human leukocyte antigens (HLA)
mouse: H-2
Mouse
Ir基因
MHC = H-2
human MHC = HLA
Mouse MHC = H-2
1996 Nobel Prize (MHC
restriction)
MHC
Organization and Structure of
MHC Genes and Products
1. Organization of MHC genes
2. Products of MHC class I and MHC
class II genes---HLA molecules
3. Immune function related genes
MHC
1. Organization of MHC genes
H-2
I
K
Ⅰ
AβAα
S
EβEα C4 Bf C2 D
IA
IE
Ⅱ
Ⅱ
Chromosome 17 (mouse)
Ⅲ
Ⅰ
L
Ⅰ
MHC
Organization of MHC genes
HLA DP
DQ
DR
BA
BA
BB A
Ⅱ
Ⅱ
Ⅱ
C4
B C A
B A Bf C2
Ⅲ
Chromosome 6 (human)6p21.31
ⅠⅠ Ⅰ
Organization of MHC genes
MHC
2. Products of MHC class I and
class II genes---HLA molecules
1) HLA class I molecules
MHC
1) HLA class I molecules
Genes: A, B, C
Distribution: every nucleated cell
Structure: α chain (45kD)
β2m (12kD) chromosome 15
peptide-binding cleft: α1+α2
CD8 binding: α3
Function: recognize and present the
endogenous Ags to CD8+ T cells
MHC
HLA class I molecule
MHC
Structure of HLA I molecule
HLA I molecule
2) HLA class II
molecules
MHC
MHC
2) HLA class II molecules
Genes: DR, DQ, DP
Distribution: APC (B, DC, MΦ)
thymic epithelial cell, activated T cell
Structure: α chain (35kD)
β chain (28kD)
peptide-binding cleft: α1+β1
CD4 binding: β2
Function: recognize and present the
exogenous Ags to CD4+ T cells
MHC
Structure of HLA II molecule
HLA class II molecule
MHC
Structure of HLA molecule
HLA-Ⅰ、Ⅱ类抗原的分布
组织
MHC I类分子
MHC II类分子
T细胞
B细胞
巨噬细胞
树突状细胞
+++
+++
+++
+++
+/+++
++
+++
胸腺上皮细胞
肝细胞
肾脏细胞
脑细胞
红细胞
滋养层细胞
+
+++
+
+-
+++
-
MHC
3. Immune function related genes
1. Serum complement coded genes
HLA class III
C4B, C4A,Bf, C2
2. Antigen presenting function related genes
HLA class II
LMP (proteasome subunit beta type, psmb):LMP2/7
encoding proteosome beta subunit
Function: process endogenous Ag
TAP (transporter associated with Ag processing):
TAP1, TAP2
Function: transport endogenous Ag peptides
Tapasin (TAP associated protein) Function: :
participate in the endogenous pathways , help the
assemble of the MHCI in ER
MHC
HLA-DM: DMA and DMB participate in the
exogenous pathways, help the peptide
binding to the MHCII
HLA-DO: negative regulation to DM
The function of HLA-DM
HLA-DM catalyses the removal of CLIP
HLA-DM
Replaces CLIP with a
peptide antigen using a
catalytic mechanism (i.e.
efficient at substoichiometric levels)
Discovered using mutant
cell lines that failed to
present antigen
HLA-DR
HLA-DM
MIIC compartment
HLA-DO may also play a
role in peptide exchange
Sequence in cytoplasmic
tail retains HLA-DM in
endosomes
MHC
3. Non-classic class I gene (HLA Ib)
HLA-E, HLA-G: inhibit NK cell activity
＊HLA-E：
结合NK细胞和部分CTL细胞表面的C型凝集素受体超家族
CD94/NKG2家族.抑制NK 细胞功能
表达于各种组织细胞，在羊膜和滋养层细胞表面高表达。
功能： A.生理状态下NK处于抑制状态。
B.母胎耐受
＊HLA-G：由α链和β2m组成，有15种等位基因。
分布：主要分布于母胎界面绒毛外滋养层细胞，
受体：杀伤细胞免疫球蛋白样受体（KIR）家族和白细
胞免疫球蛋白样受体（LIR）家族的某些成员。
功能：在母胎耐受中发挥功能。
MHC
4. Inflammation related genes
TNF gene family: TNF, LTA, LTB
Transcript factor gene family: I-κBL,
ZNF173
MIC family: MIC A(高多态性), 激活NK 细胞性
MIC B
Heat shock protein gene family: HSP70
Immune function related genes
Ag processing-related
genes
Complement
encoding
genes
Inflammationrelated genes
Non-classical
MHC I genes
MHC
Polymorphism of MHC
Concept of polymorphism
The phenomenon of having multiple allels at
given genetic locus in the population
1.Mutiple-allele
EMBL-EBI HLA Sequence Database
(http://www.ebi.ac.uk/imgt/hla/stats.html)
HLA alleles: 3,201 (class I:2,215, class II: 986)
(last updated:07/2010 )
HLA-A
HLA-B
HLA-C
HLA-E
HLA-F
HLA-G
673 alleles
1077
360
9
21
36
HLA-DPA1
HLA-DPB1
HLA-DQA1
HLA-DQB1
HLA-DRA
HLA-DRB
HLA-DRB1
HLA-DRB3
HLA-DRB4
HLA-DRB5
27
128
34
93
3
669
585
45
13
18
Naming of HLA alleles
allele allele
Locus
group number
HLA-A* 02 01
HLA-DRB1* 1102
2. Codominant expression: MHC genes are
codominantly expressed in each individual
(therefore each individual has 6 class I and 6 class
II MHC molecules), which means the alleles
inherited from both parents are expressed equally.
This maximizes the number of MHC molecules
available to bind peptides for presentation to T
cells.
Linkage disequilibrium and haplotype
Linkage disequilibrium: the phenomenon
that certain MHC alleles at different loci are
inherited together more frequently than
would be predicted by random assortment.
e.g., DRB1*0901 DQB1*0701
15.6%
21.9% 11.3%
(0.156×0.219=3.4%)
the set of MHC alleles on each chromosome
A2-B46-Cw3-DR9-DQ9-Dw23
MHC
HLA多态性
＊产生基础为变异，涉及基因突变、基因重组（染色体
同源部分的交换）和基因转换（染色体非同源部分
DNA片段的转移）等。
＊MHC变异属于偶发事件，这些偶发变异能否以新等位
基因的形式被遗传下来，取决于自然选择。
例如：HLA-B53在抗疟疾流行中的作用
白种人和黄种人频率低不到1％，中非人高达28-40％，
当地疟疾患者中B53的频率明显降低（17％）——B53
具有保护作用。
白种人和黄种人群中，没有持续的疟疾流行，B53基因
不显示“优越性”，没有保留下来。在中非的疟疾流行
区，B53的保护作用引起阳性自然选择效应，构成选择
压力，使得B53基因频率上升。
MHC
The significance of MHC polymorphism:
Almost all of the polymorphism among MHC
alleles involves amino acid residues located in and
around the peptide-binding groove. As a result,
each allelic form has its own unique peptidebinding properties.
Affect the ability to make immune responses
(e.g. resistance or susceptibility to infectious
diseases)
MHC
Interactions of MHC molecules with
antigenic peptides
1. Molecular basis
(1) Antigen-binding cleft
class I Molecules: 1/2
closed at both ends
8~10 amino acids
class II Molecules: 1/1
open at both ends
13~17 amino acids
Cleft geometry
-chain
-chain
Peptide
2-M
MHC class I accommodate
peptides of 8-10 amino acids
Peptide
-chain
MHC class II accommodate
peptides of 13-17 amino acids
HLA-Ⅰ,Ⅱ类分子抗原肽复合物的三维图
MHC
(2) Anchor site and anchor residue
anchor site
anchor residue
consensus motif
MHC
2. Characteristics of peptide-MHC
binding
(1) Specificity: special anchor residue
The important point is that peptide
binding by a given MHC protein.
(2) Flexibility: a series of antigenic
peptides with consensus motif can be
presented by a given MHC molecule. is
somewhat selective but mush less
specific than antigen binding by a TCR or
an Ig.
HLA molecules bind to different peptides with
the same consensus binding motif
Consensus binding motif
HLA
molecules
1
2
Class I
A*0201
X
X
X
X
X
X
X
B*2705
X
L
M
R
X
X
X
X
X
X
X
X
I
L
E
V
Y
X
N
S
T
Q
V
X
X
Class II
DRB1*0405
I
F
Y
V
3
4
5
6
7
8
9
L
V
L
F
E
D
Biological function of MHC
1. Participate in the adaptive immune
response
serving
as
presenting molecules
antigen
1) T cells recognize both the antigenic
peptide and MHC molecules by TCR
(double recognition)
MHCI present
endogenous
antigen
MHCII present
enxogenous antigen
CLIP:Class IIassociated invariant
chain peptide
2) MHC
molecules can present both
autoantigens and allogenic MHC
molecules
3) MHC
molecules
participate
in
selection and differentiation of T cells
in the thymus.
4) MHC is the crucial determinant of
disease susceptibility in different
individuals；
5) MHC contributes to the genetic
heterogeneity of the population
2. Participate in the innate immunity
serving as regulatory molecules
1) Classical MHC class III genes encode
complement, hereby participating in
complement reaction and the
pathogenesis of some immune diseases.
2) Non-classical HLA class I molecules
(HLA-E, G) regulate the activity of NK
cells.
3) Inflammation related genes initiate and
control inflammation. They also play a
role in stress. (such as HSP).
MHC
HLA/MHC and clinical medicine
1. HLA and transplantation
HLA typing; cross-match
2. Abnormal expression of HLA
Tumor: class I molecule↓
Autoimmune diseases: class II molecule↑
3. HLA and disease susceptibility
Ankylosing apondylitis: B27 58%-97%
4. HLA and medical jurisprudence
一、 HLA与器官移植
＊ HLA等位基因的匹配程度直接影响器官移植的
成败。
＊ HLA分子相同的同卵双生子之间进行移植, 可
长期存活；亲子之间有一条单倍型相同, 存活率
也较高；无关人群之间进行器官移植, 存活率就
较低，需进行HLA配型。
HLA-DR对移植排斥最为重要，其次是HLA-B
和HLA-A。
二、HLA分子的异常表达和临床疾病
＊恶变细胞表达I类分子下调或缺如，造成免疫逃逸；
＊自身免疫性疾病中，原先不表达II类分子的组织细胞诱
导表达II类分子，导致免疫应答的异常激活和病理作
用。
如胰岛素依赖性糖尿病中的胰岛β细胞、乳糜泻中的肠
道细胞、萎缩性胃炎中的胃壁细胞等。
三、HLA与疾病的关联
1、HLA是机体对疾病易感的主要免疫遗传成分
＊ 某些特定HLA型别的个体易感某一疾病（阳性关联）
或对该疾病有较强的抵抗力（阴性关联）。
＊与HLA关联的疾病大部分为自身免疫性疾病。
＊如HLA-B27与强直性脊柱炎呈阳性关联，高达58－97％，
而健康人群仅为1－8％。相对风险程度（RR）为55～
376。
四. HLA与输血反应 抗HLA
五. HLA与亲子鉴定和法医学
利用HLA系统的多基因性和多态性进行亲子鉴
定和法医学鉴定。
MHC more…?
Thanks for your attention!
思考题(MHC)：
问答题：
1. MHC分子的生物学功能。
2. HLA 1 类和II 类抗原的结构，组织分布和功能特点