cellular adhesion molecules

Cellular Adhesion Molecule

Cell adhesion molecules (CAMs) - important molecules

to selective recruitment of circulating leukocytes to sites

of inflammation by promoting cell–cell and cell–matrix

interactions

Middleton 7th edition

CAMs subdivided 3 main families

1. Selectins

2. Integrins

3. Immunoglobulin gene super family (IgSF) members

4. Other; gelectin, cadherin and CD44


Selectin

Selectins are a family of CAMs which bind to specific

sugar determinants on the surface of adjacent cells

Selectin family

leukocyte-expressed L-selectin (CD62L)

endothelial-expressed E-selectin (CD62E)

P-selectin (CD62P) which is expressed by both platelets and

endothelial cells


Klaus Ley and Kansas GS. Nat Rev Immunol 2004 (4):1-11

critical 120-amino acid N-terminal Ca2+-

dependent (C-type) lectin

epidermal growth

factor-like region

2-9 consensus repeats similar to those found in

complement regulatory proteins, a

transmembrane region

17–35 amino acid cytoplasmic tail


L-selectin

L-selectin was originally identified as a peripheral lymph

node homing receptor responsible for lymphocyte

adhesion to high endothelial venules in lymph nodes

Expressed on the tips of the microvilli of most leukocytes,

neutrophils, eosinophils, monocytes, naïve T and B cells as

well as on the surface of some activated T cells and

memory T cells


L-selectin

L-selectin mediates leukocyte margination and tethering

to endothelium under conditions of shear stress

associated with blood flow

L-selectin is irreversibly and rapidly shed from the

leukocyte cell surface by endogenous membrane-bound

proteases


E-selectin

E-selectin is not expressed on the surface of unstimulated

endothelium but is induced within several hours following

exposure to either IL-1, TNF-α, or bacterial endotoxin

Surface expression of E-selectin in vitro is relatively

transient, with endothelial expression levels peaking at 4–

6h and approaching baseline levels by 24 h


P-selectin

P-selectin functions as a vascular ligand for most myeloid

and lymphoid cells

Expressed by activated platelets

P-selectin is stored in intracellular granules (Weibel-

Palade bodies and in α granules of platelets)and can be

rapidly translocated to the cell surface when endothelial

cells are stimulated with agents such as C5a, histamine,

thrombin, phorbol esters or leukotriene C4


Leukocyte interaction with endothelial P-selectin has

been shown to alter leukocyte cellular functions, including

superoxide production, integrin-mediated phagocytosis,

and production of cytokines and chemokines


Selectin ligands

All 3 selectins can recognize glycoproteins and/or

glycolipids containing the tetrasaccharide sialyl-LewisX

(sialyl-CD15, sLeX) and in some cases its isomer sialyl-

Lewis


Selectin Ligands Distribution

E-selectin Sialylated Lewis X and related glycans(eg. CLA1)

Endothelium activated by cytokines (IL1, TNF)

P-selectin Sialylated Lewis X and related glycans on PSGL-1 (P-selectin glycoprotein ligand-1)

Storage granules & surface of endothelium and platelets

L-selectin GlyCAM-1(HEV)

MadCAM-1(GALT)

CD 34

Lymphocytes (high expression on Naive T cell)

Integrin

Structurally related non-covalently linked α and β

heterodimeric cell adhesion receptors

α and β subunits are type I transmembrane proteins

containing large extracellular domains (700–1100 amino

acids) and relatively small cytoplasmic domains (30–50

amino acids)

In vertebrates there are 18 α subunits and 8 β subunits

combining to form 24 integrins


4 of the β subunits are expressed on leukocytes (ie, β1,

β2, β3, and β7)

β2 and β7 expression limited to leukocytes, and β1

expression occurring on most of the body’s cell types.


Globular heads contain divalent cation-binding

domains

Divalent cation: integrin receptor function, interact

with integrin ligands

Stalks: Extend from globular heads to plasma membrane transmembrane segment and cytoplasmic tails

Extracellular domains bind: extracellular matrix glycoproteins, activated complement component and proteins on surface of other cells

Cytoplasmic domains bind cytoskeletalcomponent (vinculin, talin, actin


Structure of β2 integrin. Schematic representation of the structure of the β2

integrin heterodimer. The I domain and divalent cation-binding domains on the α

subunit that contribute to adhesive function are shown, as is the cysteine-rich

repeat region of the β2 subunit that is conserved among integrin β subunits.

β1 Integrin

VLA molecules (very late activation)

a1b1 and a2b1: express on T cell 2-4 wks after repetitive stimulation

CD49a-fCD29

Most express on leukocytes

VLA4 (a4b1): constitutively express on some T cell or rapidly induced homing lymphocytes to endothelium at peripheral site of

inflammation binds to VCAM-1


Subunit (CD, name) Ligands Lymph

o

Mon

o

Neutr

o

Eosino Baso Mast

α1β1 (49a/29, VLA-1) Laminin, collagen + − − − − −

α2β1 (49b/29, VLA-2) Collagen, laminin + + − − − −

α3β1 (49c/29, VLA-3) Collagen, laminin, fibronectin + − − − − +

α4β1 (49d/29, VLA-4) VCAM-1, fibronectin CS-1

domain

+ + − + + +

α5β1 (49e/29, VLA-5) Fibronectin + + + − + +

α6β1 (49f/29, VLA-6) Laminin + + + + − −

αLβ2 (11a/18, LFA-1) ICAM-1,-2,-3,-4, and -5 + + + + + −

αMβ2 (11b/18, Mac-1) ICAM-1 and -2, C3bi,

fibrinogen, heparin

− + + + + −

αXβ2 (11c/18, p150,95) C3bi, fibrinogen + + + + + +

αdβ2 (αd/18) ICAM-3, VCAM-1 + + + + + −

αvβ3 (51/61) Vitronectin, PECAM-1, other

RGD peptides

− + − − − +

α4β7 (49d/β7, ACT-1) MAdCAM-1, VCAM-1,

fibronectin CS-1 domain

+ + − + + −

αEβ7 (103/β7, HML-1) E-cadherin + − − − − −

β2 Integrin

CD11a-cCD18

Expression restricted to leukocytes

CD11aCD18 = LFA-1(leukocyte function-associated antigen-1) Important role in adhesion of lymphocytes with other cell ex. APCs, vascular endothelium


Mac-1 (CR3) & CR4 mediate leukocyte attachment to endothelial cell & subsequent extravasation

For all leukocytes : processes dependent on β2 integrins Firm adhesion

Locomotion

Transendothelial migration


Integrin signaling

Inside-out signaling

activation of the cytoplasmic tail of the integrin sends a signal

to the extracellular domain of the integrin to change its

conformation

important in a key step of the adhesion of leukocytes to

endothelium

Outside-in signaling

transduce the extracellular signal from the cell surface to the

interior of the cell

influence cell proliferation, differentiation, migration, gene

transcription, and apoptosis


Inside-out signaling

Chemokine and Integrin

Activation by chemokines can enhance or inhibit integrin

avidity

CCR3: enhance LFA-1 function but inhibiting VLA-4

function

Chemokines, such as eotaxin and IL-8, are potential in situ

regulators of integrin activity on leukocytes (i.e.

eosinophils and neutrophils, respectively) interacting with

vessel walls or migrating across the extracellular matrix


IMMUNOGLOBULIN GENE SUPERFAMILY

consists of more than 25 molecules

Have a series of globular Ig-like domains, formed by

disulfide bonds

Structure of immunoglobulin gene superfamily. Schematic representation of several

immunoglobulin gene superfamily molecules expressed on endothelial cells and leukocytes. The

counterligands, most of which are integrins, are also shown.

leukocyte endothelial cell adhesion,

as well as in endothelial cell-

endothelial cell, and leukocyte-

leukocyte adhesion

Intercellular adhesion molecule (ICAM)

ICAM-1 (CD54)

increase following stimulation by cytokines (IL-1, TNF-α, IFN-γ),

or bacterial endotoxin

IFN-γ selectively induces ICAM-1 expression without affecting

expression of other adhesion molecules

Ligands for the most N-terminal domain of ICAM-1 include

LFA-1, fibrinogen, and most serotypes of rhinovirus, whereas

the third domain is recognized by Mac-1


ICAM-2 (CD102)

2 Ig-like extracellular domains that possess 34% homology to

the first two domains of ICAM-1

ligand binding site for LFA-1

ICAM-2 is constitutively expressed on mononuclear cells,

basophils, mast cells, and platelets, and expression appears to

be unaffected by cytokines


ICAM-3 (CD50)

functions as an LFA-1 ligand , αdβ2 integrin

expressed on all leukocytes and on mast cells

ICAM-3 cross-linking results in calcium mobilization, tyrosine

phosphorylation, enhanced adhesion, chemokine secretion, and

modulation of basophil mediator release


Vascular cell adhesion molecule

VCAM-1 (CD106) is a cytokine-inducible endothelial cell

adhesion molecule

Expressed on macrophage, DC, astrocytes, & BM stromalcells and respiratory epithelium cell line

Expression on umbilical vein endothelial cells induced by IL-1, TNF-α, or LPS

Expression on endothelial cells induced by IL-4, IL-13

Platelet-endothelial cell adhesion

molecule

PECAM-1 (CD31) is a cell adhesion molecule expressed

on endothelial cells and circulating leukocyte

plays an important role in mediating neutrophil and

monocyte transendothelial migration


Other adhesion molecules

Galectins

family of β-galactose-recognizing proteins that exhibit a

conserved ≈130 amino acid carbohydrate-recognition domain

(CRD)

Cadherins

transmembrane proteins that mediate intercellular adhesion in

epithelial and endothelial cells

found on structural cells, including endothelium and epithelium

and are potentially involved in maintaining tissue integrity, cell–

cell recognition, signaling, communication, growth, and

angiogenesis


CD44

found in high levels on most leukocytes, endothelial cells,

epithelial cells, and other cells

has been implicated in a variety of biological processes

including lymphopoiesis, angiogenesis, wound healing, leukocyte

extravasation at inflammatory sites, and tumor metastasis

IL3, IL5, GM-CSF increase CD44 levels on eosinophil


DISEASE ASSOCIATED WITH ADHESION MOLECULE DEFICIENCY

Human syndrome Adhesion molecule

defect

Clinical phenotype

LAD-I β2 integrin structure

(mutation CD18)

Absent or near-absent expression of all β2 integrins;

blood neutrophilia with tissue neutropenia, delayed

umbilical cord separation, recurrent soft tissue

infections (e.g., skin, periodontal), impaired pus

formation and wound healing; reduced or absent

neutrophil adhesion, transendothelial migration, and

chemotactic responses; normal rolling adhesion

LAD-I variants β2 integrin function β2 integrins expressed but dysfunctional; biologic

consequences identical to those of LAD-I

LAD-II GFTP gene

(guanosine

diphosphate-fucose

transporter gene)and sLeX

Defect in fucosylation of many structures, including

sialyl-Lewis-X (sLeX); developmental abnormalities (e.g.,

severe mental retardation, short stature, distinctive facial

appearance). (hh) blood phenotype, impaired pus

formation, pneumonia, periodontitis, and otitis;

neutrophil studies, reduced or absent sLeX expression,

reduced rolling adhesion, normal firm adhesion

LAD-III Integrin signaling

(failed inside-out

signaling)

LAD-III is a very rare disorder characterized by severe

recurrent infections, a bleeding tendency and marked

leukocytosis. Leukocytes and platelets have normal

expression of CD18 (defective in LAD-I), normal

expression of CD15a (defective in LAD-II), but defective

integrin signaling

E-selectin E-selectin Case report of child with clinical presentation similar to

LAD disease but whose neutrophils expressed normal

levels of β1 integrins, L-selectin, and sLeX; staining of

inflamed tissue revealed no E-selectin


cellular adhesion molecules

Health & Medicine

eselectin eselectin

selectin ligands

selectin selectins

endothelial pselectin

platelets pselectin

selectin cd62l endothelial

plateletslselectin glycam

surface of p