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Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007

Leukocyte/Lymphocyte Trafficking. Adhesion Molecules. Functions in Immune Response:. Homing of naïve/effector/memory cells. Recruitment of phagocytic cells. Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007

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Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007

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  1. Leukocyte/Lymphocyte Trafficking Adhesion Molecules Functions in Immune Response: Homing of naïve/effector/memory cells Recruitment of phagocytic cells Excellent review article : Ley et al., Nature Immunology Reviews, 7:678, 2007 Video Acknowledgments to Dr. Tim Springer, Harvard University

  2. Leukocyte Recirculation

  3. IMMUNOSURVEILLANCE Critical for Effective Immune Responses Constant Process – required for rapidly controlling infections Leukocyte adhesion deficiencies – highlight the role of certain adhesion molecules in this process

  4. The Big Picture Activation Rolling Firm Adhesion Diapedesis Endothelial Cells Blood Flow --> PMN

  5. ADHESION MOLECULE FAMILIES (and related proteins) 1. 2. 3. 4. Selectins - Family of C-type Lectins Integrins - Family of Heterodimeric Receptors b2-integrins Cell Adhesion Molecules (CAMs) - Composed of Ig Domains Signaling Molecules (Receptors/Ligands) - Chemoattractant and Chemokine Receptors

  6. Physical Factors Influencing Lymphocyte/Leukocyte Migration 1. 2. 3. Blood Flow Physical Barriers Ability to Detect Infection

  7. Step 1: Rolling

  8. Selectins &CHO Ligands Endothelium Leukocyte * * * Sialyl Lewis X and others Step 1: Rolling P-Selectin L-Selectin E-Selectin

  9. Intravital Microscopy. The mouse mesentery preparation. The following in vivo microscopy is of postcapillary venules from a different type of preparation, hamster cheek pouch Timothy A. Springer, Harvard Medical School

  10. Timothy A. Springer, Harvard Medical School

  11. IMMUNOSURVEILLANCE Incomplete glycosylation of sLewx: no binding to selectins LAD II - Leukocyte Adhesion Deficiency Type 2

  12. Step 2: Activation

  13. FMLP IL-1 Infection TNF-a C5a Chemotactic Receptors &Ligands Step 2: Activation 1. Activates both cell types – endothelial and leukocyte 2. Causes “inside-out signaling 3. Gradient-dependent migration of leukocytes

  14.  b2-integrins and Inflammatory Activators C5a PAF FMLP IL-8 NH2 COOH G protein Complex

  15. Inside-Out Signaling

  16. Cell Adhesion Molecules - CAMS S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S S PECAM VCAM ICAM-2 ICAM-1 Endothelium

  17. Step 3: Firm Adhesion

  18. Infection Inflammatory Mediators

  19. Inflammatory Mediators

  20. LAD I - Leukocyte Adhesion Deficiency Type 1 Missing functional CD18 : no expression of CD11a-d

  21. Step 4: Diapedesis Integrin:ICAM PECAM:PECAM JAM-1:JAM-1 JAM-1:Integrin

  22. Endothelial Cells Blood Flow 2 1 Activation Rolling 3 Firm Adhesion 4 Leukocyte Migration Selectin-mediated Integrin-mediated Cytokine-mediated

  23. S S S S S S S S S S Naïve Lymphocyte Homing in Lymph Nodes Rolling Activation Firm Adhesion LFA-1 CCR7 L-Selectin CCL19 ICAM-1 PNAd

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