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Lymphocyte Homing

Lymphocyte Homing. IBS-501, April 20, 2001 Barry D. Shur. Lymphocyte Homing. Lymphocytes isolated from nodes able to “home” back to original node when reinjected Indicative of lymphocytes ability to bind to specific endothelium and invade into stroma. How was this studied?.

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Lymphocyte Homing

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  1. Lymphocyte Homing IBS-501, April 20, 2001 Barry D. Shur

  2. Lymphocyte Homing • Lymphocytes isolated from nodes able to “home” back to original node when reinjected • Indicative of lymphocytes ability to bind to specific endothelium and invade into stroma

  3. How was this studied? • Lymph nodes sliced to reveal high endothelial cell sin postcapillary venules (HEV) • Lymphocytes bound specifically to HEV • Competitive inhibitors • L-fucose @ 150 mM, fucoidin (sulfated polysaccharides) @ 5 µg/ml • Produced blocking antibodies • MEL-14 (L-selectin) that binds to carbohydrate-ligand (addressin) on endothelium

  4. Selectins

  5. Selectins • 3 types thus far: L-, E-, P-selectin • L-selectin expressed on lymphocytes • P- and E-selectin expressed on activated endothelial cells • All bind sialylated Lewis X

  6. Addressins • Mucin-like endothelial glycoproteins • Leukocytes express P-selectin glycoprotein ligand-1 and E-selectin ligand-1 • Activated endothelium expresses ligands for L-selectin (GlyCAM-1, CD34, MAdCAM-1)

  7. Integrin participation • Leukocytes express a4ß7 and aLß2 (LFA-1) integrins (among others) • Antibodies against integrin heterodimers inhibit leukocyte-endothelial interactions • Shear flow models were necessary to define relative roles of selectins and integrins

  8. Integrins

  9. Steps in “homing”

  10. Selectins and integrins act sequentially • Selectins mediate low affinity, fast on-off rates, leads to rolling (P-selectin binds to GlyCAM-1) • Induces activation of integrin (clustering, cytoplasmic domain modification) enabling integrin to bind endothelium (LFA-1 binds to ICAM-1) • Integrins mediate high affinity, stable adhesion

  11. Selectin-based rolling

  12. Integrin activation

  13. Integrin activation by clustering

  14. Knock-out phenotypes • Leukocyte adhesion deficiency 1 (LAD1) in humans is due to defective integrin ß2, elevated leukocytes in circulation due to failure to extravagate, no pus • LAD1 leukocytes still roll (selectin based) • FucTVII knockout produces LAD1 phenotype by preventing ligand synthesis on addressins • P-selectin, E-selectin null unable to roll/extravagate

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