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					第五章 免疫细胞膜分子

   2009.10.19
        Leukocyte Differentiation Antigen
             and Adhesion Molecule




1. Functional molecule on immunocyte surface and
human leukocyte differentiation antigen
2. Adhesion molecule
3. Clinical application of CD and adhesion
molecule as well as their monoclonal antibody
  Section 1 Functional molecule on immunocyte
surface and human leukocyte differentiation antigen




      Electronic microscope image of human T lymphocyte
     (1) Functional Molecule On
           Immunocyte Surface

                Specific antigen-recognition receptor
                Pattern recognition receptor
                Cytokine receptor
• Receptors
                Complement receptor
                NK cell receptor
                Ig Fc receptor

• MHC molecule
• Co-stimulation molecule
• Adhesion molecule
    (2)Definition of Human Leukocyte
       Differentiation Antigen (LDA)



LDA are referred to as the former and present
marker molecules on cell surface in the
differentiation into different lineages, different
stages and activation in blood cells.
• Expressed on leukocyte, erythroid lineage
  and megakaryocyte/thrombocyte lineage
(表达白细胞,红系和巨核细胞/血小板谱系)

• Transmembrane protein or glycoprotein
Classification of LDA:

  •   Immunoglobulin superfamily
  •   Cytokine receptor family
  •   Type C lectin superfamily
  •   Integrin family
  •   TNF superfamily
  •   TNF receptor superfamily
Cluster of Differentiation, CD:

Identified mainly by monoclonal antibody
(mAb), one LDA, which is recognized by mAb
from different labs and whose coding gene and
expression profile have been identified, can be
designated CD.
      Section 2 Adhesion Molecule




Cell Adhesion Molecule, CAM

Molecules that mediate cell-cell or cell-matrix
interaction and binding are transmembrane
glycoproteins in the majority.
The denomination of adhesion molecule and
CD molecule is based on different aspects.
Adhesion molecules are classified by adhesive
function.
Based on structural features


 integrin family
 selectin family
 immnoglobulin superfamily
 mucin-like vascular addressin
 cadherin family
              (1)Integrin Family

Mediate adhesion of cell and extracellular matrix
Elementary structure: heterodimer of ,  chain
14 kinds of  subunits, 8 kinds of  subunits
Expressed extensively
              (2)Selectin Family

Mediate adhesion of leukocyte and endotheliocyte,
occurance of inflammation and homing of
lymphocyte
Elementary structure: transmembrane molecule
L-, P-, E-selectin
Ligands: oligosacchary l
(3)Function of Adhesion Molecule
 Co-receptor and co-stimulation signal in the
recognition of immunocyte
 Homing of Lymphocyte
   Section 3 Clinical Application of CD and
      Adhesion Molecule as well as Their
             Monoclonal Antibody

(1)elucidate pathogenesis
(2)application in diagnosis
(3)application in disease prevention and treatment
     第六章

主要组织相容性复合体及其编码分子
* 组织相容性抗原/移植抗原:
* 主要组织相容性抗原:
* 主要组织相容性复合体(MHC):位于哺乳动物某
一染色体上的一组紧密连锁的基因群 * 人类
MHC → HLA复合体 → 编码HLA抗原。
 * 小鼠MHC → H-2复合体 → 编码H-2抗原;
 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。
      第二节 HLA 复合体


 HLA(human leukocyte antigen)
复合体位于人第6号染色体短臂, 有
224个基因座(locus),按其产物的结
构、分布与功能分为三群。
一、HLA复合体的结构

(一)经典HLA基因

(二)免疫功能相关基因

(三)免疫无关基因
    (一)经典的HLA基因

• 特点:其编码产物直接参与抗原提呈并决定个
  体组织相容性;多态性极为丰富。
1.经典HLA-I类基因
 * 包括HLA-A、-B、-C等30余个基因座。
2.经典HLA-II类基因
* 包括HLA-DR、-DQ、-DP等近30个基因座。
* 编码产物均为双肽链(α、β)分子。
    (二)免疫功能相关基因
特点:无或有限的多态性;不具有激活T细
1.血清补体成分编码基因
 * 包括C4、Bf、C2等30余个基因座。
2.抗原加工提呈相关基因
 1)低分子量多肽(LMP)
 2)抗原肽转运肽(TAP)
 3)HLA-DM基因
 4)HLA-DO基因
 5)TAP相关蛋白基因(tapasin)
3.非经典I类基因
* 即HLA-Ib基因,包括HLA-E、-F、-G等;
* 编码产物的组织分布有限;
* 多态性有限。
4.炎症相关基因
* TNF基因家族:TNF-α和TNF-β
* 热休克蛋白基因家族:HSP

    (三)免疫无关基因
 * 21羟化酶基因
   二、HLA复合体的特征

(一)多基因性(polygenic)

 指HLA具有众多紧密连锁的基因座。
Structure of H-2




Structure of HLA
               class II         class III       class I class I
centromere




             Schematic diagram of HLA embryonic genes
(二)高度多态性(polymorphism)
在一随机婚配的群体中,染色体同一基因座位有两
种以上基因型。
1.HLA多态性的形成机制
 (1)复等位基因(multiple allele)
 (2)共显性遗传
2.HLA多态性的意义
* 利于群体适应复杂的环境改变,从而维持种群的
   生存。
* 可用于个体识别,但不利于寻找同种移植物供者。
 (三)单元型遗传和连锁不平衡

• 单体型(haplotype):连锁于同一染色体片段
  上的等位基因组成。
• HLA单体型遗传:HLA复合体乃紧密连锁的
  基因群, 其作为整体由亲代遗传给子代。
意义:可用于选择移植供者和亲子鉴定。
• 连锁不平衡:群体中各HLA等位基因非随机
  地组成单体型的现象。
      第三节 HLA抗原系统

一 、 HLA-I 类 分 子
的结构
 (1) 肽结合区
 (2) Ig样区
 (3) 跨膜区
 (4) 胞浆区
2.组织分布
 HLA molecules encoded by MHC
         I and II genes

1. Distributions :
Class I (HLA-A/B/C): all nucleated cells
 Class II (HLA-DR/DP/DQ): APC(Mf,DC,B),
thymic epithelial cells, activated T cells
2. Structure:
Class I :  ( 1  2  3 Tm C), 2m
Class II:  ( 1  2 Tm C),  ( 1  2 Tm C)
MHC-I类分子结构

             α链:43KDa




             β链:12KDa
二、HLA-II类抗原
1. 分子结构
(1) 肽结合区
(2) Ig样区
(3) 跨膜区
(4) 胞浆区
2. 组织分布
MHC-II类分子结构

          α链:34KDa




          β链:29KDa
              MHC class I molecule   MHC class II molecule



Peptide-
binding
domain




Immunoglo
bin-like
domain


Transmembr
ane segment


Cytoplasm
ic tail
MHC分子的肽结合沟
      Immune related genes


1. Genes encoding serum complement
components :
    C4B、C4A、Bf、C2
        2. Genes associated with antigen
           processing and presentation
•   Gene encoding low molecular weight
    polypeptide(LMP)
•   Gene encoding transporter associated
    with antigen processing(TAP)
•   HLA-DM gene
•   HLA-DO gene
•   Gene encoding TAP associated proteins
            tapasin
3. Non-classical MHC I(Ib)genes:

     HLA-E, HLA-G, HLA-F
Immune related genes




                            Genes        Inflamm
   Genes associated with                 ation     non-
                            encoding               classical
   antigen processing and                related
                            complement             MHC I
   presentation                          genes
                            components             genes



Related encoding products
Inflammation associated genes

• Tumour necrosis factor gene family
  TNF、LTA、LTB
• Transcriptional regulating gene or
  transcriptional factor-like gene family
     I-B、B144、ZNF173、ZNF178
• MHC I related gene(MIC)family
• Hot shock protein gene family
  HSP70(molecular chaperone)
     第四节 MHC的功能

一、参与抗原加工和提呈

MHC分子的抗原结合凹槽选择性结合抗原肽
 →形成MHC分子-抗原肽复合物
  →以MHC限制性的方式供T细胞识别
    →启动特异性免疫应答
           MHC限制性




抗原X特异性的TCR与
APC之间MHC型别相同   抗原相同,但MHC型别   MHC型别相同,但抗原
               不同
  识别           不识别
                             不同
                              不识别
二、MHC分子的其他生物学作用


* 参与对免疫应答的遗传控制
* 免疫细胞间相互作用的限制性
* 参与免疫调节
* 参与T细胞分化及中枢耐受的建立
   五、HLA与医学的关系

(一) HLA与疾病的相关性
 * 携带某一HLA型别的个体对特定疾病表现
  为易感性或抗性的现象。(例如:携带HLA-
  B27者易患强直性脊柱炎)。
(二) HLA抗原表达异常与疾病
* 多种肿瘤细胞HLA-I类抗原表达减少或缺如;
* 自身免疫病的靶细胞异常表达HLA-II类抗原。
(三) HLA与器官移植
* 供、受者间组织相容性主要取决于HLA型别
 相合程度。
(四) HLA的其他临床意义
 * HLA与输血
 * HLA与母胎关系
(五) HLA与法医
 * HLA型别分析应用于个体识别和亲子鉴定。
 第七章

固有免疫细胞
Cells in innate immunity and their functions


一. Tissue,cells and molecules of the innate
  immune system
二.Phases of innate immune responses
三.Characteristics of innate immune response
  and its relationship with adaptive immune
  response
Section I Tissue,cells and molecules of the
innate immune system
Innate Immunity
                                Acquired Immunity

Native Immunity
                                Adaptive Immunity

Nonspecific Immunity
                                Specific Immunity


    Species development, formed evolutionally
    Possess from the time of birth,react rapidly
    Non-specific anti-infection immunity, also involved
    in specific immunity
一. Tissue barriers and their effection

(一)The skin and mucosal surfaces provide protective
barriers against infection
  Physical barriers: epithelial, cilia, mucus
 Chemical barriers: lactic acid, unsaturated fatty acid,
gastric acid
 Biological barriers: microorganisms
(二) Blood-brain barrier

(三) blood –fetus barrier
二. Cells involved in innate immunity and
             their functions
         Phagocute
         Natural killer cells
          T cells
         NKT cells
         B1 cells
                1. phagocytes


      Mononuclear phagocyte                  neutrophils
            system




monocyte              macrophage

              microglial cells, Kupffer,Osteoclast
Macrophage
Long-lived( up to several months)
Large, pleomorphism and rich in
lysosomes in the cytoplasm.
MHC-I/II and many adhension
molecules
Many receptors
Neutrophil
Short-lived
Small and round
Large quantities, replaced
rapidly
Large amount of
azurophil granule and
neutrophil granule in the
cytoplasm
MHC-I and receptor of
adhension molecules
Phagocytes
Biological functions
     Antimicrobial and cytotoxic activity
            Oxygen-dependent, Oxygen-independent

    Secretion of factors
            Cytokines, Inflammantory mediators

    Antigen presentation
            Intrinsic, Extrinsic

     Anti-tumour
Antimicrobial and cytotoxic activity

   Oxygen-dependent killing mechanisms
       Reactive oxygen intermediates(ROIs)活性氧中间体
       Neutrophil myeloperoxidase(MPO)中性粒细胞髓过氧化物酶
       Reactive nitrogen intermediates(RNIs)活性氮中间体

   Oxygen-dependent killing mechanisms
   acid pH, lysozyme , lactoferrin, cationic protein, elastase
             溶菌酶, 乳铁蛋白,阳离子蛋白,弹性蛋白酶
Secretion of factors
Released in appropriate or large quantities
Cytokines:TNF-, IL-1, IL-6, IL-8, IL-12, MCP-1
Inflammation mediators:prostaglandin E, LTB4, PAF, phosphatidase,
peroxidate
 Local inflammatory reaction(TNF-、IL-1、 LTB4)
 Fever and acute phase reaction(CRP、MBL)
 Immunoregulation(IL-1、IL-6、IL-12)
Phagocytes
Biological functions
         Anti-infection
          Anti-tumor: directly contact and fuse with the
tumour cell membrane ; cytotoxic substance,
proteinase, cytolysin, TNF-α,ADCC mediated by tumor
specific antibody
        Antigen processing and presentation
        Immunoregulation
2. NK Cells


              PBMC, Spleen
              Large amount of azurophil granule in the
              cytoplasma
              Kill the target cells directly with no
              needs of preactivation
              surface markers:CD3-, CD56+,
              CD16+
NK cells
  Molecular recognition: killer activatory receptor(KAR)
                           killer inhibitory receptor(KIR)
  KAR
  KAR recognize cell carbohydrate ligands →ITAM→transduce
  activation signals
  KIR
  The extracellular region of KIR recognize MHC-I of self cells
  →ITIM→ transduce inhibitory signals
  Regulation of NK cell killing effect by two receptors
NK cells
Biological Functions
Anti-infection:lysis, IFN- and TNF-
Anti-tumor: directly contact and fuse with tumour cells
membrane; ADCC mediated by tumor specific antibodies
Immunoregulation:
3.  T cell
Distributions: epithelia, mucosa
surface markers: γδTCR, CD2/3/16/25/45, LFA-1,DN
Molecular recognition:
Narrow spectrum(窄谱)of antigen recognition:HSP, CD1
complex, viral proteins (VP)
The same group of cells express only one kind of γδTCR : same
specificity of antigen recognition—response to common antigen
Biological Function:
anti-infection in skin and mucosa, anti-tumor, immunoregulation
4. NKT cells
Distribution: liver, bone marrow, thymus
surface marker: NK1.1, TCR-CD3 complex
molecular recognition
Narrow spectrum of antigen recognition :CD1 complex,
without MHC restriction
Biological function:
anti-infection, anti-tumor, involved in immunoregulation by
secreting cytokines
5. B1 cell
Distribution: abdomen, thoracic cavity,et al
Features: appear early in the ontogenesis(个体发生),self-renewal
Surface markers: CD5+、CD11+、mIgM+,CD23-
Molecular recognition
Narrow spectrum of antigen recognition : TI-2 polysaccharide
antigen, TI-1 polysaccharide antigen(LPS), self -antigen
Features of response
Other types of cells involved in the innate immunity:


Dendritic cell
Eosinophil granulocyte
Basophilic granulocyte
Mast cell
三. Innate effector molecules and their
main function


   (一)complement system
(二)Cytokines
1. Cytokines to induce anti-viral ability
2. Cytokines to induce and promote
Inflammatory reactions
3. Cytokines to induce and enhance anti-
tumor abilities
Section 2 Phases of innate immune
response

       Transient phase of innate immune
       response
       Early phase of innate immune response
       Induction Phase of adaptive immune
       response
Section 3 Characteristics of
Innate Immune Response and Its
Relationship with Adaptive
Immune Response
Ⅰ. Characteristics of innate immune
response

(一)Recognition features of innate immune cells
   1. Pattern-recognition receptors (PRRs) and
pathogen-associated molecular patterns (PAMPs)
(1)Pattern-recognition Receptors, PRRs
        Expressed on the surface of innate immune cells with the
ability of recognizing one or more PAMPs
       Lack of diversity, non-clonal expression, mediating rapid
biological response
       Main types: Mannose-binding receptor(甘露糖结合受
体), scavenger receptor(清道夫受体), Toll-like receptor,
Biological functions:
Opsonization, activation of complement system, phagocytosis,
initializing cell activation and transduction of inflammatory
signal, induction of apoptosis
(2) Pathogen Associated Molecular Patterns, PAMPs
   Some non-specific and highly conserved molecular structures
shared by a class /group of specified microbial pathogens , that can
be recognized by non-specific immune cells.
For example: lipopolysaccharide (LPS), mannose, bacterial
DNA/RNA. et al.

Features:
Commonly specific for pathogens
Required for the microbes’ survival and pathogenicity
Molecular basis for the pan(泛)-specific recognition of the host
2. Signal transduction mediated
by PRRs(TLRs)
  Peptidoglycan , Teichoic
  acid(G+)
  Bacterium lipoprotein      LPS(G-)              dsDNA
  LPS(leptospire)            teichoic acid (G+)       +)Flagellin
  Cell walls of         RSV F protein                           Unmethylated
  Mycobacterium Zymosan
                                                                CpGDNA



TLR6      TLR2       TLR1    CD14          TLR4      TLR3    TLR5    TLR9
                                     MD2
Ⅱ Features of Innate Immune Cell
Response
Various chemokine receptors on the surface
Direct activation in the inflammation site
Short-lived, without memory
Ⅲ Relationship between Innate Immune
Reponse and Adaptive Immune Response


ⅰ Innate immune response initializes(启动) adaptive
immune response
ⅱ Innate immune response influences the type of
adaptive immune response


ⅲ Innate immune response assists adaptive immune
response
           Non-specific immunity                specific immunity

Cells           epithelium mucosal cells,
involved        phagocyte, NK, NK1.1+T,          T, B, APC
                B-1B, γδT

phase          instant~96h                            after 96h

                                                specific,exclusive
              non-specific, broad spectrum of
features                                        antigen recognition, to
              antigen recognition, to take
                                                take effect with
              effect without requirement of
                                                requirement of clonal
              clonal expansion and
                                                expansion and
              differentiation
                                                differentiation
              no immunological                   With immunological
duration
              memory,short                       memory ,long duration
              duration
Biological significances of innate
immunity
Participating and regulating the initiation of adaptive
immune response
Affecting the strength of adaptive immune response
Affecting the type of adaptive immune response
Affecting B cell memory , negative selection , self
tolerance

				
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posted:10/25/2012
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