Adhesion Proteins

PCOL 582

Adhesion Adhesion ProteinsProteinsIntegrinsIntegrinsIgSfIgSfSelectinsSelectinsCadherinsCadherins

EC EC

L, NL, N

Adhesion ProteinsAdhesion Proteins•White blood cells migrate

through all the tissues of the body.

•Migration:1. attachment2. traversing

•Response to:1. infection2. necrotic tissue

Adhesion ProteinsAdhesion ProteinsOrgan Disease

•Lung Adult Respiratory Distress Syndrome

• Asthma

• Asbestosis

• Emphysema

• Idiopathic pulmonary fibrosis

Adhesion ProteinsAdhesion Proteins

• Organ Disease• Kidney Glomerulonephritis• Interstitial nephritis• Heart Myocardial

reperfusion injury• Ischaemic heart

disease• Joint Rheumatoid arthritis• Gout• SystemicScleroderma Vasculitis

Adhesion Proteins

Adhesion ProteinsAdhesion Proteins

These binding reactions are controlled by a varying array of adhesion molecules on the surface of the T lymphocyte that recognize a complementary array of adhesion molecules on the surface of the cells with which the T cell interacts.

Adhesion ProteinsAdhesion Proteins

The majority of adhesion molecules fall into one of four families;

•cadherins.

• integrins,

• immunoglobulin superfamily (IgSF),

•selectins

Adhesion ProteinsAdhesion Proteins

The majority of adhesion molecules fall into one of four families;

•cadherins.• integrins,

• immunoglobulin superfamily (IgSF),

•selectins

CADHERINSCADHERINS

•They play a fundamental role in maintaining the integrity of multicellular structures and

•are important in the diapedesis of lymphocytes and neutrophils

cadherinscadherins

CADHERINSCADHERINS

• There is strong evidence to suggest that cadherins may be involved in invasion and metastasis of tumor cells.

• Finally, cadherins may play a role in intercellular signalling due to the discovery of kinases regulating cytoplasmic cadherin phosphorylation.

Adhesion ProteinsAdhesion Proteins

The majority of adhesion molecules fall into one of four families;

•cadherins.• integrins,

• immunoglobulin superfamily (IgSF),

•selectins

INTEGRINSINTEGRINS

INTEGRINSINTEGRINS

INTEGRINSINTEGRINS

INTEGRINSImportant roles:

•platelet aggregation,

• inflammation,

• immune function,

•wound healing,

•tumor metastasis,

•tissue migration during embryogenesis.

•signalling pathways, transmitting signals both into and out from cells

Integrins

• Integrins are a large family of heterodimeric proteins that play key roles in extracellular matrix formation, morphogenesis, and cell adhesion. 

• There are 17 alpha subunit types and 8 beta subunit types. 

• Depending on the association of alpha and beta subunits, integrins can bind to collagen, laminin, vitronectin, and fibronectin. 

Inte

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Integrins• Integrins are present in a low-affinity state

in resting T cells. • Chemokines produced by the antigen-

presenting cell (APC) and signals induced by the TCR when it recognizes antigen both act on integrins and lead to their clustering and to conformational changes that increase the affinity of the integrins for their ligands.

• As a result, the integrins bind with high avidity to their ligands on APCs and thus promote T cell activation.

Integrins

• In the immune system, the most important integrins, those of the 1, 2, and 7 subfamilies, participate in T-cell migration and provide stimulatory signals for T-cell proliferation and effector functions.

INTEGRINSINTEGRINS

Lymphocyte function-associated antigen-1 (LFA-1, CD11a/CD18).

This is thought to be the most important adhesion molecule for lymphocyte activation as antibodies to LFA-1 effectively inhibit the activation of both naive and armed effector T cells.

INTEGRINSINTEGRINS

•Expression of the 1 integrins increases significantly late in T-cell activation, and they are thus often called VLA for very late antigen and play an important part in directing armed effector T cells to their target tissues.

INTEGRINSINTEGRINS

•Leukocyte adhesion deficiency (LAD) is a rare inherited disorder in which key functions of leukocytes are impaired, notably the migration of neutrophils to sites of extravascaular inflammation

INTEGRINSINTEGRINS

•CD11a/CD18 (LFA-1) L,N,MICAMs

•CD11b/CD18 (CR3, MAC-1) N, NK, M ICAMs,

iC3b

•CD11c/CD18 (CR4, p150.95)M,N,L, NK iC3b

Adhesion ProteinsAdhesion Proteins

The majority of adhesion molecules fall into one of four families;

•cadherins.• integrins,integrins,

• immunoglobulin superfamily immunoglobulin superfamily (IgSF),(IgSF),

• selectinsselectins

IMMUNOGLOBULIN SUPERFAMILYIMMUNOGLOBULIN SUPERFAMILY

• IgSF members are widely utilized in two areas involving complex interactions among a diverse array of cell types;

• during nervous system development and

• in the regulation of the immune system

IMMUNOGLOBULIN SUPERFAMILYIMMUNOGLOBULIN SUPERFAMILY

• CD2 (LFA-2) T-cells LFA-3

• ICAM-1 (CD54) APCs, lymphocytes LFA-1

• ICAM-2 (CD102) APCs, lymphocytes LFA-1

• ICAM-3 (CD50) APCs LFA-1

• LFA-3 (CD58) APCs, lymphocytes CD2

• VCAM-1 (CD106) EC (activated) VLA-4

IMMUNOGLOBULIN SUPERFAMILYIMMUNOGLOBULIN SUPERFAMILY

IgSFIgSF

IMMUNOGLOBULIN SUPERFAMILYIMMUNOGLOBULIN SUPERFAMILY

• .

IMMUNOGLOBULIN SUPERFAMILYIMMUNOGLOBULIN SUPERFAMILY

• ICAM-1 is expressed by antigen presenting cells.

• Induced or upregulated by IFN, IL-1, TNFand LPS.

•Ligands are CD11a/CD18, CD11b/CD18, CD43 (mucin-like vascular addressin).

•Adhesion is calcium dependent

Adhesion ProteinsAdhesion Proteins

The majority of adhesion molecules fall into one of four families;

•cadherins.• integrins,

• immunoglobulin superfamily (IgSF),

•selectins

SELECTINS

•Are earliest expressed in inflammatory responses

• Lead to neurtophil activation and extravasation

• L-selectin• E-selectin• P-selectin• Bind to SLex of neutrophil

SELECTINS

SELECTINS

•L-selectin down regulated by IL-1

•P-selectin up-regulated by thrombin, histamine, peroxides, TNF-, IL-4, IL-1, and IFN-

•E-selectin up-regualted IL-1, TNF and LPS

SELECTINS

Role of Adhesion Molecules in

Pathology States

Extravasation Extravasation

•First of these is mediated by selectins

•Second step depends upon LFA-1 (CD11a/CD18) and CR3 (CD11b/CD18

•Third step, the leukocyte crosses the endothelial wall, or extravasates

•Fourth step is the migration due to chemoattractant molecules (IL-8)

Diseases Associated with Diseases Associated with Adhesion MoleculesAdhesion Molecules

•Leukocyte adhesion deficiency (LAD) •The involvement of integrins

•Tumor metastasis•Colorectal CD44

•Meleanomas VLA-4 - selectin

•Osteosarcomas VLA-4 - selectin

•Multiple myeloma N-CAM

Adhesion Molecules and Adhesion Molecules and Allograft RejectionAllograft Rejection

•E-selectin and VCAM-1 expression were associated with markers of rejection

•Anti-CD11/CD18 mAbs prevented early rejection

•anti-ICAM-1 could induce allograft tolerance

Reperfusion InjuryReperfusion Injury

•Neutrophil the CD11a/CD18 is expressed subsequently to reperfusion

•The cytokines involved in the modulation of CD11a/CD18 expression, are PAF. C5a, IL-1, TNF, IL-6, and IL-8.

•The ICAM-1 can be controlled by IL-1, TNF, and IFN

Figure 12-2