Transcript lymph node
MIGRATION OF IMMUNE CELLS LYMPHOCYTE HOMING AND RECIRCULATION NEUTROPHIL GRANULOCYTES ARE RECRUITED FROM THE BONE MARROW RESERVOIRE TO INFECTED TISSUES LYMPHOCYTE RECIRCULATION 1. Homing – most lymphocytes reside in lymphoid organs, few in circulation 2. Recruitment – chemokines and chemokine receptors, chemotaxis Few antigen-specific lymphocytes should be recruited to the site of antigen entry – ANTIGEN RECOGNITION (lymph node) The appropriate effector lymphocytes shoud migrate to the site of antigen EFFECTOR/MEMORY CELLS (tissue, lymphoid tissue) 3. Migration Among tissues, organs Lymph node - Lymph node, Lymph node - Tissues BLOOD CIRCULATION - LYMPHATICS 4. Adhesion molecules HOMING RECEPTORS Antigen independent appearance (dependent on activation state of lymphocyte Selectins Integrins Ig supergene family molecules LIGANDS FOR VASCULAR ENDOTHELIAL CELL RECEPTORS Adressin ligands INTERACTION WITH THE EXTRAVASCULAR CONNECTIVE TISSUE Binding, detachement MIGRATION OF LYMPHOCYTES IN CENTRAL AND PERIPHERAL LYMPHOID ORGANS B BONE MARROW MALT SALT BALT SPLEEN T THYMUS BLOOD HEV TISSUES LYMPH NODES Lymphatics Thoracic duct 1. The central lymphoid organs are not connected to lymphatics – Isolated from the environment 2. The spleen has no lymph circulation – immune response to blood borne antigens 3. HEV – high endothelial venules – special entry sites of blood circulating lymphocytes to peripheral lymphoid organs 4. 1 lymph node circle/hour, 25 billion lymphocytes (25x109)/lymph nodes/day LYMPH CIRCULATION HEV Role of endothelial cells in trafficking and recirculation Endothelial cells are involved in: Vasomotor tone, vascular permeability, regulation of coagulation, immune modulation and lymphocyte extravasation High endothelial venules Post-capillary venules Constitutively present in secondary lymphoid tissue Present in non-lymphoid tissues Need to allow egress of naïve cells from the circulation Molecules expressed by endothelial cells regulate trafficking and recirculation through lymphoid and non-lymphoid tissues High endothelial venules Post capillary venules in 2º lymphoid tissue are called HIGH ENDOTHELIAL VENULES. Specialised to allow lymphocytes and nothing else into the lymph node HEV Post capillary venules in other tissues are lined by simple squamous epithelium Blood enters lymph node via the artery Post capillary venules in the paracortex have cuboidal endothelial cells HIGH ENDOTHELIAL VENULES - specialised properties to allow lymphocytes and nothing else into the lymph node MIGRATION OF LYMPHOCYTES NAIVE LYMPHOCYTES Homing to lymphoid tissues Homing receptor on naive lymphocyte L-selectin – carbohydrate binding Ligand on HEV - mucin-like adressin CD34+ and GlyCAM-1 sulphated sialyl-Lewisx Lymph node - PNAd – retention (peripheral node addressin) Naive lymphocyte L-selectin CD34 HEV HIGH ENDOTHELIAL VENULES HEV Lymphocytes slow down and bind to HEV LFA-1 integrin – ICAM-1/2 Ig family CCL21 chemokine and CCR7 chemokine receptor An estimated 5X106 lymphocytes exit blood through HEVs each second! Limfocyte Homing I NAIVE LYMPHOCYTES Homing to lymphoid tissues Homing receptor on naive lymphocyte L-selectin – carbohydrate binding Ligand on HEV – mucin-like adressin CD34+ and GlyCAM-1 sulphated sialyl-Lewisx PSGL-1 Lymph node – PNAd - retention HOMING OF B LYMPHOCYTES TO LYMPH NODES Naive B lymphocytes migrate to lymph node through HEV Naive B cells are recruited to HEV by CCL21 kemokin produced by stromal cells CCL21 and CCL19 chemokines produced by dendritic cells target B lymphocytes to lymph nodes Limfocita Homing II Extravasation HIGH ENDOTHELIAL VENULES HEV Lymphocytes slow down and bind to HEV LFA-1 integrin – ICAM-1/2 Ig family CCL21 chemokine and CCR7 chemokine receptor Initial lymphocyte adhesion to antigen presenting cells in LN Different adhesion molecules of naive, armed and effector CD4+ T cells CD44 LFA-1 CD45RA CD2 CD45RO VLA-4 Activated L-selectin Naïve Associates with TcR and CD4 - phosphatase activity reduces threshold of T cell signalling + + + + + - - - ++ ++ ++ - + ++ Homing to lymph node Adhesion molecules Homing Differential to inflamed splicing of vascular CD45 mRNA in naïve & armed endothelium T cells EFFECTOR/MEMORY LYMPHOCYTES Return to the site of stimulation (antigen) Mucosal surface- MADCAM-1 Retention in spleen, lymph node LFA-1 – ICAM-1/2 integrin – cell and extracellular matrix Migration through activated endothelial cells of inflammed tissues Lamina propria in gut Mucosal epithelium Dermis in skin Activated/effector/memory lymphocyte LFA-1 ICAM-1 VLA-4 VCAM-1 Activated endothel ALTERED EXPRESSION OF CELL SURFACE ADHESION MOLECULES T-cell activated in mucosal tissue associated lymphoid tissues return to MALT Activated T cell Naive T cell Adhesion molecules and chemokines controlling T- cell homing to lamina propria T-cells activated in mucosal tissue associated lymphoid tissues return to MALT LPAM-1 Lymphocyte Peyer’s patch adhesion molecule-1 (α4β7) Elephantiasis caused by blockage of lymphatic vessels with Wuchereria bancrofti microfilariae