Chapter VII Leukocyte differentiation antigen and Adhesion molecule.

Chapter VIIChapter VII

Leukocyte differentiation antigen Leukocyte differentiation antigen and and

Adhesion moleculeAdhesion molecule

1. LDA ， CD ， CAM

2. Functional molecule and human leukocyte differentiation antigen on immunocyte surface

3. Clinical application of CD and adhesion molecule as well as their monoclonal antibody

Cell Surface MoleculesCell Surface Molecules

• Leukocyte differentiation antigen(LDA) :The cell surface markers which express or disappear on the different leukocytes in the different stage of differentiation and activation.

LDALDA

• Expressed on leukocyte, erythroid lineage and megakaryocyte or thrombocyte lineage

• Other non-hematopoietic cells• Transmembrane protein or

glycoprotein• Some are anchored on plasma

membrane with GPI conjuction

• Immunoglobulin superfamily

• Cytokine receptor family• Type C lectin superfamily• Integrin family• TNF superfamily• TNF receptor superfamily

Classification of LDAClassification of LDA

Cell Surface MoleculesCell Surface Molecules

• CD (cluster of differentiation) : Cell surface molecules of leucocytes that are distinguishable with monoclonal antibodies as an immunologic marker.

• HCDM （ Human cell differentiation molecules）

Cell Surface Molecules and Cell Surface Molecules and HLDAHLDA

• Surface Molecules of Immune cells Receptors: TCR, BCR, PRR, CKR,

CR MHC: MHCⅠⅡ Co-stimulatory Molecules: CD28 Adhesion Molecules:

integrin,selectin

一、 CD molecules of T lymphocytes(p98)

11 ，， CD3CD3

• Consists of 5 proteins that are designated as , , , and .

• Three dimers: , , ()

• The cytoplasmic domain contains ITAM (immunoreceptor tyrosine-based activation motif) YxxL/V

• Function: transduction of signals that lead to T cell activation.

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2. CD4 and CD82. CD4 and CD8 Coreceptors Involved in MHC-

Restricted T Cell Activation Function:CD4 and CD8 are T cell proteins

that bind to nonpolymorphic regions of MHC molecules and transduce signals that together with signals delivered by the TCR complex initiate T cell activation.

CD4:Receptor of HIV gp120

Structure of CD4

Structure of CD8

3. CD28 and CTLA-43. CD28 and CTLA-4 CD28: its ligands are B7 family molecules,

including B7-1/2 (CD80/CD86)

Function: costimulation, activation of

T cells

CTLA-4(CD152): homodimer, homologous to CD28.

Function: inhibits T cell costimulation (the cytoplasmic domain contains ITIM)

44 、、 CD154CD154 （（ CD40LCD40L ））

二、 CD molecules of B lymphocytes(p92)

1,Ig1,Ig/Ig/Ig (CD79a/CD79b) (CD79a/CD79b)

• heterodimer cytoplasmic domains contain ITAM.

Function: 1. transfers the signals that

lead to B cell activation.

2. transports the Ig

2. CD19/CD21/CD81/CD225 CD19/CD21/CD81 interactions with

complement associated with antigen play a role in antigen-induced B-cell activation.

CD21=CR2, C3dR, EBV R

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4 ， CD40 interacts with CD40L (Th cell)

5 ， CD80(B7.1), CD86(B7.2)

expressed on activated B cells

6 ， ICAM-1, LFA-1

三、 Ig Fc Receptor

Cell adhesion moleculesCell adhesion molecules

• CAM: A group of proteins involved in adhesion of cell to cell or cell to extra-cellular matrix (ECM), such as ICAM-1, ICAM-2, ICAM-3, VCAM-1 and PECAM etc.

Cell adhesion moleculesCell adhesion molecules

• Cellular recognition, activation, proliferation, differentiation, migration

• Immune response

• Inflammation

• Tumour

The denomination of adhesion molecule and CD molecule is based on different aspects.

Adhesion molecules are classified by adhesive function.

Most adhesion molecules possess a CD number, however, some do not.

Cell adhesion moleculesCell adhesion molecules

Categories of CAMCategories of CAM

1. Integrin family2. Selectin family

3. Cadherin4. IGSF (Ig superfamily)5. Mucin-like family 6. Others:PNAd, CD44, CD36

1, Integrin Family1, Integrin Family

1)Integrin:Mediate adhesion of cell and extracellular matrix

2)Elementary structure: heterodimer of , chain

14 kinds of subunits, 8 kinds of subunits

IntegrinIntegrin

3)Integrin family β1: VLA(very late appearing antigen) β2: LFA-1(lymphocyte function associated antigen-1) ligand:ICAM-1,2,3 β3: gpⅡbⅢa4)Distribution:Expressed extensively

22 、、 Selectin FamilySelectin Family

Selectins are carbohydrate-binding proteins present on leukocytes, endothelial cells, and platelets; their principal function is to regulate the migration of leukocytes to various tissues

Selectin Size Distribution Ligand

L-selectin (CD62L)

90-110 kD (variation due to glycosylation)

Lymphocytes (high expression on naive T cells, low expression on activated effector and memory cells)

Sulfated glycosamino-glycans on GlyCAM-1, CD34, MadCAM-1, others

E-selectin (CD62E)

110 kD Endothelium activated by cytokines (TNF, IL-1)

Sialylated Lewis X and related glycans (e.g., CLA-1) on various glycoproteins

P-selectin (CD62P)

140 kD Storage granules and surface of endothelium and platelets

Sialylated Lewis X and related glycans on PSGL-1 and other glycoproteins

Functions of CAMFunctions of CAM

1. As co-receptors and co-stimulating

signal in immune cells recognition

T cell ←------ APC:

TCR Ag-MHC molecule

CD4/CD8 MHC /Ⅰ Ⅱ

CD28 B7(CD80/CD86)

LFA-1 ICAM-1

2. Adhesion between leukocytes and

vascular endothelial cells in

inflammation

3. Lymphocyte homing

(1) The migration of mature lymphocytes from

primary to secondary lymphoid tissues.

(2) lymphocyte recirculation

(3) The migration of lymphocytes into the

inflammatory site.

Lymphocyte homing receptor---vascular

addressin

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Application of CD, CAM and Their Application of CD, CAM and Their McAbMcAb

1. Investigate the mechanism of diseases

CD4 and AIDS

CD18 and LAD (Leukocyte adhesion deficiency)

2. Application in diagnosis

leukemia, AIDS (ratio of CD4/CD8 T cells)

3. Prophylactic and Therapeutic application

Graft rejection: Anti-CD3, Anti-CD25

non-Hodgkin’s lymphoma: Anti-CD20