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Adhesion Proteins PCOL 582

Adhesion Proteins PCOL 582. Adhesion Proteins Integrins IgSf Selectins Cadherins. L, N. L, N. EC. EC. Adhesion Proteins. White blood cells migrate through all the tissues of the body. Migration: 1. attachment 2. traversing Response to: 1. infection 2. necrotic tissue.

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Adhesion Proteins PCOL 582

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  1. Adhesion ProteinsPCOL 582

  2. Adhesion ProteinsIntegrinsIgSfSelectinsCadherins L, N L, N EC EC

  3. Adhesion Proteins • White blood cells migrate through all the tissues of the body. • Migration: 1. attachment 2. traversing • Response to: 1. infection 2. necrotic tissue

  4. Adhesion Proteins Organ Disease • Lung Adult Respiratory Distress Syndrome • Asthma • Asbestosis • Emphysema • Idiopathic pulmonary fibrosis

  5. Adhesion Proteins • Organ Disease • Kidney Glomerulonephritis • Interstitial nephritis • Heart Myocardial reperfusion injury • Ischaemic heart disease • Joint Rheumatoid arthritis • Gout • Systemic Scleroderma Vasculitis

  6. Adhesion Proteins

  7. Adhesion 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.

  8. Adhesion Proteins The majority of adhesion molecules fall into one of four families; • cadherins. • integrins, • immunoglobulin superfamily (IgSF), • selectins

  9. Adhesion Proteins The majority of adhesion molecules fall into one of four families; • cadherins. • integrins, • immunoglobulin superfamily (IgSF), • selectins

  10. CADHERINS • They play a fundamental role in maintaining the integrity of multicellular structures and • are important in the diapedesis of lymphocytes and neutrophils

  11. cadherins

  12. CADHERINS • 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.

  13. Adhesion Proteins The majority of adhesion molecules fall into one of four families; • cadherins. • integrins, • immunoglobulin superfamily (IgSF), • selectins

  14. INTEGRINS

  15. INTEGRINS

  16. INTEGRINS

  17. Important 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

  18. 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. 

  19. Integrins Page 120

  20. 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.

  21. Integrins • In the immune system, the most important integrins, those of the b1, b2, and b7 subfamilies, participate in T-cell migration and provide stimulatory signals for T-cell proliferation and effector functions.

  22. INTEGRINS 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.

  23. INTEGRINS • Expression of the b1 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.

  24. INTEGRINS • 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

  25. INTEGRINS • CD11a/CD18 (LFA-1)L,N,M ICAMs • CD11b/CD18 (CR3, MAC-1)N, NK, M ICAMs, iC3b • CD11c/CD18 (CR4, p150.95)M,N,L, NK iC3b

  26. Adhesion Proteins The majority of adhesion molecules fall into one of four families; • cadherins. • integrins, • immunoglobulin superfamily (IgSF), • selectins

  27. IMMUNOGLOBULIN 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

  28. IMMUNOGLOBULIN 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

  29. IMMUNOGLOBULIN SUPERFAMILY IgSF

  30. IMMUNOGLOBULIN SUPERFAMILY • .

  31. IMMUNOGLOBULIN SUPERFAMILY • ICAM-1 is expressed by antigen presenting cells. • Induced or upregulated by IFNg, IL-1b, TNFa and LPS. • Ligands are CD11a/CD18, CD11b/CD18, CD43 (mucin-like vascular addressin). • Adhesion is calcium dependent

  32. Adhesion Proteins The majority of adhesion molecules fall into one of four families; • cadherins. • integrins, • immunoglobulin superfamily (IgSF), • selectins

  33. SELECTINS • Are earliest expressed in inflammatory responses • Lead to neurtophil activation and extravasation • L-selectin • E-selectin • P-selectin • Bind to SLex of neutrophil

  34. SELECTINS

  35. SELECTINS • L-selectin down regulated by IL-1 • P-selectin up-regulated by thrombin, histamine, peroxides, TNF-a, IL-4, IL-1, and IFN-g • E-selectin up-regualted IL-1b, TNFa and LPS

  36. SELECTINS

  37. Role of Adhesion Molecules in Pathology States

  38. 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)

  39. Diseases Associated with Adhesion 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

  40. Adhesion Molecules and Allograft 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

  41. Reperfusion 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 IFNg

  42. Figure 12-2

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