Lymphoid System Organs PDF

The Immune System & Lymphoid Organs Fevziye Figen Kaymaz M.D., Ph.D. Prof. of Histology & Embryology [email protected] Learning goals • Identify lenfoid organs such as thymus, lymph node, tonsilla, spleen Lymph Nodes Lymph nodes are bean-shaped, encapsulated structures, generally only 10 mm...

The Immune System & Lymphoid Organs Fevziye Figen Kaymaz M.D., Ph.D. Prof. of Histology & Embryology [email protected] Learning goals • Identify lenfoid organs such as thymus, lymph node, tonsilla, spleen Lymph Nodes Lymph nodes are bean-shaped, encapsulated structures, generally only 10 mm by 2.5 cm in size, distributed throughout the body along the lymphatic vessels A total of of 400 to 450 lymph nodes are present, most abundantly in the axillae (armpits), along the major vessels of the neck, and in the thorax and abdomen, especially in mesenteries. • The nodes constitute a series of in-line filters of lymph that defend against microorganisms and tumor cells and provide enclosed environments that facilitate production of plasma cells • Before merging with the bloodstream, all lymph is filtered and has antibodies added by at least one lymph node. • • • • 3 4 • Embedded in loose connective tissue • convex surface where afferent lymphatics enter • Concave depression, the hilum, where an efferent lymphatic leaves and where an artery, vein, and nerve penetrate the organ • A dense connective tissue capsule surrounds the lymph node, extending trabeculae internally through which the blood vessels branch. • Valves in the lymphatics ensure that lymph flow is unidirectional. • The most abundant cells of lymph nodes are lymphocytes of all types, plasma cells, dendritic cells, macrophages, and other APCs. FDCs are present within lymphoid nodules. • All of these cells are arranged in a stroma of reticulin fibers and reticular cells to form three major regions: an outer cortex, a central medulla, and a smaller area between these two called the paracortex 5 6 Cortex • A subcapsular sinus, immediately inside the capsule,receives lymph from the afferent lymphatics • lined by a very thin, discontinuous endothelium penetrated by reticulin fibers and processes of dendritic cells. • Lymph containing antigens, lymphocytes, and APCs 7 • Lymphoid nodules, with or without germinal centers, fill most cortical areas • proliferating B lymphoblasts • Each nodule is organized around the long, interdigitating processes of follicular dendritic cells • (FDCs), • Numerous macrophages are also present for removal of newly formed defective B cells. 8 Cortex- outer cortex . 9 paracortex • lack of B-cell lymphoid nodules • lymphoid tissue rich T cells • Specialized postcapillary venules, high endothelial venules (HEVs) represent an important entry point for most (90%) lymphocytes into lymph nodes. • endothelial lining – cuboidal cells, • HEVs also occur in the large accumulations of MALT 10 Paracortex 11 12 medulla • Medullary cords are branched cordlike masses of lymphoid tissue extending from the paracortex. • contain T and B lymphocytes and many plasma cells. • Medullary sinuses are dilated spaces lined by discontinuous endothelium that separate the medullary cords. • the lumens of medullary sinuses include a meshwork of processes from reticular cells, macrophages and sometimes • They are continuous with the cortical sinuses and converge at the hilum as the efferent lymphatic vessel 13 14 Role of Lymph Nodes in the Immune Response • The lymph arriving at a lymph node draining from an infected or inflamed region, lymph may also contain microorganisms and cytokines. Antigens not yet phagocytosed will be internalized by APCs in the lymph nodes and presented on MHC class II molecules. • Circulating B and T lymphocytes traffic from node to node, entering via the lymph or HEVs, where B cells contact antigens on FDCs and T cells sample antigens presented on dendritic cells and other APCs. 15 16 • Lymphocytes whose receptors recognize such antigens will be activated. B cells will proliferate rapidly in germinal centers of follicles with the help of Th cells, often enlarging the entire lymph node. • Activated cytotoxic T cells in the paracortex proliferate to a much lesser extent without forming follicles. • Many newly made B cells, now activated against a specific antigen, differentiate as plasma cells and move to the medulla or to downstream sites beyond the lymph node where they produce antibodies. Specific Th cells, CTLs, and Tregs also recirculate in the efferent lymph and with the antibodies spread the immune defenses against those microorganisms 17 Clinical correlations • In the presence of antigens or bacteria, lymphocytes of the lymph node rapidly proliferate, and the node may increase to several times its normal size, becoming hard and palpable to the touch. 18 Clinical correlations • Lymph nodes are located along the paths of lymph vessels and form a chain of lymph nodes so that lymph flows from one node to the next. For this reason, infection can spread and malignant cells may metastasize through a chain of nodes to remote regions of the body 19 Clinical correlations • Metastatic cancer cells detached from a primary tumor can enter lymphatics and are carried to nearby lymph nodes, • Cells from well-established tumors are often immunosuppressive themselves and may continue growth as a secondary tumor within lymph nodes. During cancer surgery lymph nodes in the lymphatics draining the tumor area are examined by pathologists for the presence of cancer cells. The presence of such metastatic cells in lymph nodes is a key determinant in most staging systems for various types of cancer and an important prognostic indicator. 20 MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) • GALT / BALT / NALT • The mucosa or inner lining of the digestive, respiratory, and genitourinary tracts is a common site of invasion by pathogens because their lumens open to the external environment. • To protect against such invaders mucosal connective tissue of these tracts contains large and diffuse collections of lymphocytes, IgA-secreting plasma cells, APCs, and lymphoid nodules, all of which comprise the MALT. • Lymphocytes are also present within the epithelial lining of such mucosae. • tonsils, the Peyer patches in the ileum, and the appendix. • the MALT is one of the largest lymphoid organs, containing • up to 70% of all the body’s immune cells. Most of the lymphocytes • here are B cells; among T cells, CD4+ helper T cells predominate. 21 GALT – İleum – Peyer patches • MALT extends from the pharynx along the entire gastrointestinal tract • the ileum. - the Peyer patches 22 23 • M cells; (microfold cells) • The simple columnar epithelium that covers the lymphoid nodules of Peyer patches includes large epithelial M cells with apical microfolds • On the basal side of lymphocytes and dendritic cells 24 • Antigens in the intestinal lumen are transferred to the immune cells in the pockets. Lymphocytes and dendritic cells leaving the M cell pockets through the basement membrane pores interact and initiate adaptive responses to the antigens, which results in formation of the secondary lymphoid nodules. • Locally produced B cells give rise to plasma cells secreting IgA, which is transported by enterocytes into the intestinal lumen to • bind and neutralize potentially harmful antigens. 25 appendix • Another significant collection of MALT occurs in the mucosa of the appendix, a short, small-diameter projection from the cecum. Typically the mucosa of the appendix is almost completely filled with lymphoid tissue, • The lumen contains the normal bacterial flora of the large intestine and may serve to retain some of these beneficial bacteria there during diarrheal illnesses. 26 BALT 27 • BALT is located in the walls of bronchi, especially in regions where bronchi and bronchioles bifurcate. • the epithelial cover over these lymphoid nodules changes from a pseudostratified ciliated columnar with goblet cells to M cells. • Afferent lymph vessels are absent, although lymph drainage has been demonstrated. 28 Tonsils 29 Named by their location • Palatine tonsils • Lingual tonsils • pharyngeal tonsils • (Waldeyer‘s lymphatic ring PA: Pharyngopalatine arches PTo: Palatine tonsil GA: Glossopalatine 30 Palatine tonsils • located posteriorly on the soft palate, are covered by stratified squamous epithelium. • The surface area of each is enlarged with 10-20 deep invaginations or tonsillar crypts in which the epithelial lining is densely infiltrated with lymphocytes and other leukocytes, many secondary lymphoid nodules around the crypts. AROUND • This tissue is underlain by dense connective tissue that acts as a partial capsule. 31 32 33 pharyngeal tonsil • situated in the posterior wall of the nasopharynx, is covered by pseudostratified ciliated columnar epithelium, and has a thin underlying capsule. The mucosa with diffuse lymphoid tissue and lymphoid nodules is invaginated with shallow infoldings but lacks crypts. 34 Lingual tonsils • situated along the base of the tongue, are also covered by stratified squamous epithelium with crypts, and have many of the same features as palatine tonsils but lack distinct capsules. 35 Medical aplications • Inflammation of the tonsils, tonsillitis, is more common in children than adults. • Chronic inflammation of the pharyngeal lymphoid tissue and tonsils of children often produces hyperplasia and enlargement of the tonsils to form “adenoids,” which can obstruct the eustachian tube and lead to middle ear infections. 36 Spleen • • • • • • • • • • Largest lymphoid organ İmmulogical filter of the blood idefense against blood-borne antigens. he main site of old erythrocyte destruction. Capsula / trabeculae -dense CT- miyofibroblast White pulp Red pulp White pulp : PALS (periarteriolar lymphoid sheath), germinal centers No cortex and medulla Red pulp: irreguler branching venous sinuses, pulp cords ( Cords of Billroth) Marginal zone Special blood circulation (open and/ or closed type) • filled with reticular tissue containing reticular cells and fibers, many lymphocytes and other blood cells, macrophages, and APCs. • Splenic pulp has two components: the white pulp (20% of the spleen) and the red pulp. • The small masses of white pulp consist of lymphoid nodules and the periarteriolar lymphoid sheaths • the red pulp consists of bloodfilled sinusoids and splenic cords. • Splenic a. - Branching from the hilum, small trabecular arteries leave the trabecular connective tissue and enter the parenchyma as arterioles enveloped by the PALS, which consists primarily of T cells with some macrophages, DCs, and plasma cells as part of the white pulp. Surrounded by the PALS, these vessels are known as central arterioles • Each central arteriole eventually leaves the white pulp and enters the red pulp, losing its sheath of lymphocytes and branching as several short straight penicillar arterioles that continue as capillaries. Some of these capillaries are sheathed with APCs for additional immune surveillance of blood. Figure 14—30. Lymphoid nodule of the spleen surrounded by red pulp. A germinative center (1) and the (eccentric) central artery (2), which is characteristic of the spleen, are clearly visible. Two small sections of sheathed arteries are seen to the right of the nodule. H&E stain. Medium magnification. (Courtesy of PA Abrahamsohn.) • B cells located within the PALS may be activated by a trapped antigen from the blood and form a temporary lymphoid nodule like those of other secondary lymphoid organs • In growing nodules the arteriole is pushed to an eccentric position but is still called the central arteriole. These arterioles send capillaries throughout the white pulp and to small sinuses in a peripheral marginal zone of developing B cells around each lymphoid nodule • The red pulp is composed almost entirely of splenic cords (of Billroth) and splenic sinusoids and is the site where effete RBCs in blood are removed. • The splenic cords contain a network of reticular cells and fibers filled with T and B lymphocytes, macrophages, other leukocytes, and red blood cells. • The splenic cords are separated by the sinusoids. Unusual elongated endothelial cells called stave cells line these sinusoids, oriented parallel to the blood flow and sparsely wrapped in reticular fibers and highly discontinuous basal lamina • Blood flow through the splenic red pulp can take either of two routes • In the closed circulation, capillaries branching from the penicillar arterioles connect directly to the sinusoids and the blood is always enclosed by endothelium. • In the open cırculation, capilleries from penicillar arterioles are uniquely openended, dumping blood into the stroma of the splenic cords. In this route plasma and all the formed elements of blood must reenter the vasculature by passing through narrow slits between the stave cells into the sinusoids . Swollen RBCs at their normal life span of 120 days are blocked from passing between the stave cells and undergo selective removal by macrophages 46 • From the sinusoids blood proceeds to small red pulp veins that converge as the trabecular veins, which in turn form the splenic vein. The trabecular veins lack significant smooth muscle and resemble endothelium-lined channels hollowed out in the trabecular connective tissue. • Removal of defective RBCs and recycling of their iron are major functions of the red pulp. Iron released from hemoglobin during the degradation of RBCs is stored by macrophages within complexes of ferritin proteins or bound to transferrin, returned to the circulation, and reused primarily for erythropoiesis. Iron-free heme is either bound to its transport protein, hemopexin, or is metabolized to bilirubin and excreted in the bile by liver cells. After surgical removal of the spleen (splenectomy), the number of abnormal erythrocytes in the circu- lation increases although most such cells are then removed by macrophages in sinusoids of the bone marrow and liver. MEDICAL APPLICATION • enlargement of the spleen, splenomegaly, can occur from a variety of causes, including lymphoma or other malignant growth, infections such as mononucleosis, or sickle cell disease and other types of anemia. The splenic capsule traumatic rupture, a potentially life-threatening occurrence due to loss of blood into the abdominal cavity. Such rupture may require prompt surgical removal of the spleen, splenectomy, after which most functions of the organ are carried out by other lymphoid organs, with erythrocyte removal occurring in the liver and bone marrow. Thymus • Primary lymphoid organ form a specific microenvironmet for the development/ maturation of T lymphocytes • a bilobed structure in the mediastinum, • Stroma consist of a capsula and septa which divide the parenchyme into many incomplete lobules • Each lobule has a cortex and a medulla • T cell pecursors slowly migrates from C To M by making intimate contacts with epithelial reticular cells, bone marrow derived IDC • Maturation continues in the medulla ( more mature cells in medulla Thymus • Immature B lymphocytes emerge from the bone marrow, • the primary lymphoid organ in which T cells are produced is the thymus • A main function of the thymus is induction of central tolerance, which along with regulatory T cells prevents autoimmunity. • The organ originates from the embryo’s third pair of pharyngeal pouches (endoderm), with precursor lymphoblasts circulating from the bone marrow to invade and proliferate in this unique thymic epithelium during its development. • Fully formed and functional at birth, the thymus remains large and very active in T-cell production until puberty, during which it undergoes involution, decreasing greatly in size and activity and becoming largely filled with adipose tissue Components • Developing /maturing T lymphocytes or (thymocytes) • Epithelial reticular cells( endoderm 3 pharyngeal pouch and ectoderm) • Macrophages • Bone marrow derived IDC at the corticomedullary boundry • No reticuler stroma Epithelial reticular cells (thymic epithelial cells) • Form a cytoreticulum in a very close association with thymocytes • Type I (Squamous ) subcapsular and perivasculer joined by desmosomes and occluding junctions, line the connective tissue of the capsule and septa and surround the microvasculature.This creates an isolated cortical compartment and, together with the vascular endothelial cells and pericytes, form Blood thymus barrier Type II Thymic nurse cells in the mid cortex • processes containing keratin tonofilaments joined by desmosomes, form a cytoreticulum to which macrophages and developing lymphocytes attach instead of to reticulin fibers • APCs, expressing MHC class II molecules in addition to MHC class I. They also secrete numerous cytokines for T-cell development and other immune functions 58 Type III cortical TECs also express MHC class II molecules but form a sheetlike structure contributing to a functional corticomedullary barrier between these two regions of each lobule. Type IV A second layer of the boundary between cortex and medulla TypeV in medulla. A cytoreticulum that (1) supports less densely packed T lymphocytes, dendritic cells, and macrophages, and (2) expresses many specialized proteins specific to cells of other organs. typeVI in medulla. Hassall corpuscles secrete several cytokines that control activity of local dendritic cells, including factors that promote development of regulatory T cells for peripheral tolerance. Tip VI hücreler: birbirlerinin üzerine sarılarak Hassall cisimlerini ypr. Yaş ile sayıları artar. Sitokin salgılayarak yerel dendritik hücrelerin aktivitesini ve periferik tolerans için gerekli Regulatuvar (düzenleyici) T lenfositlerin farklanmasını kontrol eder. Medulla da hücre ölüm alanları olabileceği düşünülüyor. 61 T lymphoblasts arriving in the thymus do not yet express CD4, CD8, or a TCR . These cells populate the cortex and begin to proliferate, recombine variable regions of the TCR α and β chain genes, and then express these TCR proteins as well as both CD4 and CD8. • two-stage selection process of quality control, which ensures that mature T cells have TCRs that are fully functional but do not recognize and strongly bind MHC with self-antigens. • The selection process for each pre–T lymphocyte begins in the cortex, ends in the medulla, and lasts about 2 weeks. • TECs in the cytoreticulum of the cortex present the developing thymocytes with peptides on both MHC class I and class II proteins, which are important for development of CD8 and CD4 T cells, respectively. This interaction determines whether the newly made TCR proteins of these cells are functional. The cells are examined by positive selection, with a cell’s survival depending on whether its TCRs can recognize and bind antigens on the MHC molecules properly. • nonfunctional and completely useless cells (as many as 80% of the total) undergo apoptosis and are removed by the macrophages. T cells with normal binding to antigens on either MHC class I or class II are positively selected and move to the medullary compartment • In the medulla T cells with functional TCRs encounter antigens presented on both cytoreticular TECs and dendritic cells. Here the focus is on removing T cells whose TCRs strongly bind self-antigens, a process called negative selection because survival depends on a cell not binding to MHC molecules with such peptides • T cells that strongly bind MHCs containing these selfpeptides undergo apoptosis, which is important because release of any such cells from the thymus would lead to a damaging autoimmune response. Only about 2% of all developing T lymphocytes pass both the positive and negative selection ests and survive to exit the thymus as immunocompetent T cells. Depending on which class of MHC they interacted with, most of these lymphocytes will have stopped expressing either CD8 or CD4, and become either helper T cells or cyto- toxic T cells • Deletion of self-reactive helper and cytotoxic T lympho- cytes in the thymus is the basis for the central immunotolerance produced there. Supplementing this throughout the body is the peripheral tolerance mediated by regulatory T cells, which also develop initially in the thymic medulla under the influence of cytokines from Hassall corpuscles. • • • • • • • • Early thymocytes at the periphery of the cortex begin to synthesize TCR also proliferation markers Genes encoding TCR show somatic recombination random assortment a large number of gene segments to produce functional receptors capable of recognizing all possible antigens CD4 and CD 8 appear double positive Cortical epıthelial cells present MHCI and MHCII Cells carrying receptors which make adequate bındıng with self MHC positively selected are allowed to differentiate further. Rest are eliminated by apoptosıs and are phagocytosed by macrophages İf positively selected thymocytes have receptörs that recognize self commponents presented to them by largely İDC or by some epıthelial cells at the CM boundry and in the medulla negatively selected -eliminated Entry of self reactive cells to general circulation causes autoimmunıty Central peripheric tolerance Medulla • More mature thymocytes • Prominent cytoreticulum of epıthelial cells • Hassall’s corpuscles • Macrophages