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Molecular medicine Immunology 5 Tissues of the Immune system Role of the thymus https://medicine.tcd.ie/immunology/st udent-area/index.php Learning objectives • Key role of certain tissues in immune system (IS) • The thymus - site of T cell education • Bone marrow - source of cells of IS • Lymph nodes - site of immune reactions • NB - cells of IS operate in tissues, not in blood Lymphatic circulation Lymphatic circulation Third network of circulation Function • Collects fluid from tissues • Lymph passes through chain of lymph nodes • Lymphatic vessels drain to large ducts e.g. thoracic duct • Ducts drain into subclavian veins Thoracic duct Lymphatic circulation • High content of lymphocytes • If lymph is drained from animals lymphocyte count drops • If the lymphatics are blocked - fluid collects in tissues - “ lymphoedema ” Also • Fat is absorbed from intestine via lymphatic Swelling due to blocked lymphatics Damaged caused by radiation therapy, axilla Antigen delivery to lymph nodes Lymphatic circulation Immune response • Antigen brought to lymph nodes - via lymph draining to nodes • Carried by antigen presenting cells e.g. dendritic cells • Lymphocytes stimulated by antigen in nodes • stimulated lymphocytes enter blood and circulate Lymphoid tissues Lymphoid tissues Lymphoid tissues Central • Bone marrow • Thymus • Bursa Lymphoid tissues Central • Bone marrow • Thymus • Bursa Peripheral • Lymph nodes • Spleen • Unencapsulated -appendix, tonsil, adenoids, Peyer’s patches Lymph nodes in neck Cancer - enlarged nodes Lymph nodes in axilla Cancer spread to lymph node Cancer cells “secondaries” or metastasis Lymph nodes in groin Bone marrow - cell origin Stem cells now used for bone marrow transplants Bone marrow - cartoon Bone marrow biopsy Bone marrow - what happens ? • generation of cells of IS and other cells - RBC, platelets • location of B cell maturation “bursa” in humans? • site of antibody production by plasma cells Damage due to cancer therapy • Chemotherapy • Radiation therapy Cause damage to bone marrow • Cell production reduced - neutrophils • Antibody production impaired Thymus - human Thymus - chicken Thymus 1. Location • Behind sternum - over heart • Bi-lobed • Lobules - 2 zones • Outer zone = cortex • Inner zone = medulla Thymus structures Thymus - histology Thymus - cartoon Thymus 2. Cortex • Immature “pro-T” cells arrive here • Learn function of T lymphocytes • Densely cellular • 90% of cells die - lymphocyte graveyard ! • Surviving cells migrate to medulla Thymus 3. Medulla • mature lymphocytes migrate from cortex - cells then enter into blood circulation • Hassal’s corpuscles - characteristic structure of medulla, function unknown • Thymus atrophies after puberty - BUT continues to produce lymphocytes to end ….. Thymus - chicken Bursa in humans • No identified equivalent of bursa • Bone marrow may carry out function of bursa • Maturation of pro-B cells in this site Lymph node - cartoon Alberts et al. Lymph node - histology Lymphoid follicles Lymph nodes 1. • • • • • • Distributed throughout body Linked by lymphatics “afferent” lymphatics - drain to nodes “efferent” lymphatics - drain from nodes Blood supply - arterial, venous Capsule Lymph nodes 2. Structure - cortex and medulla • Cortex - distinct T and B cell areas • B cells found in round structures - lymphoid follicles • Follicles enlarge after antigen stimulation • Stimulated B cells - migrate to medulla antibody producing “plasma cells” Lymph nodes 3. T cell area in cortex • Surround lymphoid follicles • Stimulated T cells migrate to medulla and enter circulation Other cell populations • Antigen presenting cells - dendritic cells, macrophages Spleen Spleen - cartoon Spleen - histology Phagocytic area Lymphocyte area Spleen 1. Location • Under left rib cage • Blood supply - very vascular • Accidents - splenectomy Spleen 1b. Function 1. Phagocytic organ - removal of dying cells 2. Lymph node type function 3. Storage - platelets Spleen 2. Lymph node area • “white pulp” - 20% of spleen • Distinct T and B follicular areas • Respond to circulating antigen - important in response to certain bacteria* • “Red pulp” area - phagocytic cells, storage of other cell types Spleen 3. “Red pulp” area - phagocytic cells, storage • remove particulate matter • graveyard for aged or damaged RBC, white cells, platelets • reservoir - rapid source of platelets and monocytes Other lymphoid tissues • • • • • Tonsils Appendix Adenoids Peyer’s patch These tissues have lymph node like structure and function but no capsule Lymphocyte collections in organs • • • • • Gut Lung Liver Placenta Etc. Gut lymphocyte structures Events in lymphoid tissue • Immune response happens here • Metastasis - cancer cells can spread to nodes • Circulating lymphocytes ‘visit’ nodes - to see if specific antigen has arrived here • Lymphocytes may rest in nodes - memory cells So, back to the thymus ….. Thymic education cortex medulla CD 2 CD8 CD4 CD8 Pro-T cell CD3 CD4 - acquire T cell molecules - react with self MHC Thymic education cortex medulla CD 2 CD8 CD4 CD8 Pro-T cell CD3 CD4 - express CD2 first -then CD3, TCR - then CD4 and CD8 in cortex T cell rosette - CD2 T cells bind to sheep red cells, forming a flower type shape: CD2 on T cell binds to sheep cell. Used to identify T cells, before monoclonal abys T cells use CD2 to bind targets CD2 Th LFA-3 APC LFA-3 is present on many target cells, including APC - additional molecule for T cell adherence T cell elimination - 95% of cells die in cortex cortex medulla CD 2 CD8 CD4 CD8 CD3 CD4 THYMUS T cell maturation – role of IL-7 IL-7 cortex medulla CD 2 CD8 CD4 CD8 CD3 CD4 THYMUS T cell elimination of - cells that over-react with MHC - cells that under-react with MHC cortex medulla CD 2 CD8 CD4 CD8 CD3 CD4 THYMUS Over-reaction of T cell in thymus APC T cell self antigen Results in apoptosis of T cell – clone eliminated – “negative selection” Under-reaction of T cell in thymus APC T cell weak self antigen Results in apoptosis of T cell T cell elimination • Prevents self-reactivity [ reactivity with one’s “self antigens” ] • Called “self-tolerance” • Self-tolerance prevents auto-immunity • Other mechanisms of self-tolerance also exist T cells learn to react with self MHC + antigen in thymus T cell APC T helper cell reacting with antigen and self MHC in thymus diGeorge syndrome DiGeorge syndrome Genetic defect found on chromosome 22