Paper No.: 10: Immunology Module : 04: Phylogeny and Ontogeny of immune system: Organization and structure of immune system.

Transcription

1 Paper No.: 10: Module : 04: Phylogeny and Ontogeny of immune system: Organization and Development Team Principal Investigator: Co-Principal Investigator: Paper Coordinator: Content Writer: Content Reviewer: Prof. Neeta Sehgal Head, Department of Zoology, University of Delhi Prof. D.K. Singh Department of Zoology, University of Delhi Prof. Anju Srivastava Department of Zoology, University of Delhi Dr. Ravi Toteja Acharya Narendra Dev College, University of Delhi Prof. Sukhmahendra Singh Banaras Hindu University 1

2 Description of Module Subject Name Paper Name Module Name/Title Module ID Keywords Zool 010: Phylogeny and Ontogeny of immune system M04: Organization and Primary lymphoid organs, Secondary Lymphoid organs, lymph, T cell and B cell Maturation Contents 1. Learning Objectives 2. Introduction 3. Organs of Immune System a. Primary Lymphoid Organs b. Secondary Lymphoid Organs 4. Summary 2

3 1. Learning Objectives Organization of immune system in humans What are lymphoid organs? Structure and functions of primary and Secondary lymphoid organs Role of lymphatic system in immune response 2. Introduction The immune system is a complex and highly developed system (Figure 1), yet its mission is simple: to seek and kill invaders. If a person is born with a severely defective immune system, death from infection by a virus, bacterium, fungus or parasite will occur. A lack of immune system cells is also the basis for DiGeorge syndrome: improper development of the thymus gland means that T cell production is diminished. Figure 1: Flow chart showing the overview of immune response in vertebrates. Source: org/wiki/structural_biochemistry/genetic_code/immune_system#/media/file: Immune_Response_Chem114A.jpg 3

4 The immunological system is comprised of the lymphoid tissues and organs of the body. Lymphoid tissues are widely distributed: they are concentrated in bone marrow, lymph nodes, spleen, liver, thymus, and Peyer's patches scattered in linings of the gastro-intestinal tract. The lymphoid system is encompassed by the system of phagocytes. Lymphocytes are the predominant cells, but macrophages, dendritic cells, and plasma cells are also present. Lymphocytes are cells which circulate, alternating between the circulatory blood stream and the lymphatic channels. 3. Organs of Immune System The immune system functions throughout the body (Figure 2, 3). There are, however, certain sites where the cells of the immune system are organised into specific structures. These are classified as Primary Lymphoid Tissues or Central Lymphoid Tissue (bone marrow, thymus) and Secondary Lymphoid Tissues orperipheral Lymphoid Tissue (lymph nodes, spleen, mucosa-associated lymphoid tissue). Blood vessels and lymphatic systems connect these organs & unite them as a whole to function against antigen. Figure 2: Various organs of the immune system of human. Source: 4

5 Figure 3: Various organs of the immune system of human. Source: Organs_Tissues_and_Cells_of_the_Immune_System.html a. Primary Lymphoid Organs Primary lymphoid organs are also called central lymphoid organs. These are responsible for synthesis and maturation of immune-competent cells e.g. bone marrow and thymus. Bone Marrow All cells of the immune system are formed in the bone marrow. During hematopoiesis (the process of formation of blood cells), bone marrow stem cells develop into either mature cells or precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere. The bone marrow produces lymphocytes (B-cells, T-cells, and natural killer cells), granulocytes (eosinophils, basophils, neutrophils), monocytes and dendritic cells, in addition to red blood cells and platelets. Bone marrow (Figure 4) is not a disorderlymass of packed cells, it has a structure and system of its own. If any long bone is cut half lengthways, distinct changes in color can be noticed. Some areas would be very red and these areas would be the site of RBCs production as well as white blood cell production. Other patches would be yellow in color. These yellow coloured patches are as a result of adipose fat cell accumulation. The yellow areas are relatively inactive in healthy people but when an individual s blood system is stressed in some way these yellow patches convert into blood cell forming tissue, so yellow regions are the emergency standby cells 5

6 Figure 4: Structure of the bone showing bone marrow. Source: Bone marrow cells need a scaffolding to help them organize and be systematic in the production and release of cells into the blood stream. This scaffold is provided through three main structures, the blood capillary network, venous sinuses and a reticular fiber framework.in many bones the capillary network originates from a single artery which enters the bone close to its center. Inside the bone it divides and continues to subdivide along the length of the bone. Small capillary branches radiate off the larger blood vessels to reach the extremities of the bone marrow. These capillaries connect up with a second system of vessels called venous sinuses (sinus is Latin for cavity). The connection between venous sinuses and blood capillaries is continuous. Blood from these sinuses is collected by venules and veins which merge together to leave the bone via a single vein. So the blood system of a bone is closed, one entry and one exit (Figure 5). Figure 5: A simplified illustration of cells in bone marrow. Source: Venous sinuses have some exceptional properties that other blood capillaries/arteries/veins don't. Venous sinuses are the vessels into which blood cells are released after being produced from the marrow cells. These sinuses are barrel shaped and expand and contract to accommodate the variable production and release rate of blood cells. The sinuses either have perforated walls or don't have walls at all. Blood cells that are ready to leave the bone migrate to these sinuses and release themselves into the sinuses. If there is a vessel wall present, the new blood cells find a perforation and squeeze 6

7 themselves through the opening. Usually the hole is too small for easy passage of cells so blood cells have to force their way through. The small hole size ensures blood cells already in the vessel don't readily get back into the bone marrow. Finally we have a reticular cell and fiber meshwork which forms the underlying scaffold for supporting the bone marrow cells and helping keep the blood capillaries in position. This "reticular framework" basically stops the marrow cells from sloshing around and getting damaged when we move. General changes in the color of the red marrow can sometimes be observed. If an individual is under challenge from a chronic infection the red marrow changes to pale pink. The marrow switches from producing red blood cells to concentrating on making white blood cells. This may result in anemia as a side effect of combating infection. Thymus The thymus in evolutionary terms is the derivation of fish gills. The thymus is believed to produce lymphocytes, which colonize the lymphoid tissues. This view is supported by several facts: 1. Removal of thymus from newborn mice, leads to the development of a fatal diseases. 2. Congenital absence of the thymus or thymic aplasia (incomplete or defective development of the thymus) results in immunologic deficiencies. 3. In the adult, removal of the thymus leads to a diminished response to new antigens. 4. The thymus produces a hormone, the thymic humoral factor (THF). This factor is believed to regulate lymphopoiesis in the thymus and other lymphoid tissue. Development of the human embryonic thymus begins at around 60 days after fertilization.size and complexity of thyumus gradually increases. This differentiation will only continue for a certain period of time and then stop if it does not receive a stimulus to continue growth. Immature lymphocytes begin to flock at and in the thymus of human embryos at about days after fertilization. Most of these immature lymphocytes have come from the yolk sac and fetal liver rather. In humans, thymus is a bi-lobed structure. In birds, the lobes entirely separate into long nodular sacs one on each side of the jugular veins. For humans and most mammals, the thymus lies at the top of the heart at the vertical midline of the body in the thoracic cavity. The lower parts of the lobes rest over the front of the heart and the top of the thymus wraps around the wind pipe (Figure 6). Each of the two lobes of thyumus are enclosed in a capsule. Within each thymic lobe is a structured organization of lymphocytes and reticular cells. The lobe is divided up in a rough honeycomb appearance by membranes called "trabeculae" or sometimes "septa" which extend from the outer capsule into the thymic lobe. Each division of the tissue by the septa is a "lobule". Each lobule have an outer layer of darkly staining cells called the "cortex" consisting of cells which turn out to be lymphocyte cells mixed in with many blood vessels, and an inner core called the "medulla" consisting of some lymphocytes but predominantly epithelial cells. Immature lymphocytes arrive in the thymus through a single artery. Similar to the bone marrow the thymus has a closed circulatory blood system, one entry and exit point. The blood vessels have several physical layers surrounding them called the "blood-thymus barrier". This barrier consists of membranes, connective tissue and cells which play an important part in restricting which cells are allowed to cross into the medulla of thymic lobules and which cells are flushed straight through the thymus. The blood thymus barrier is known to be much weaker where the vessels pass through the medulla of thymic lobules and cells crossing to and from the vessels can be observed in this region. 7

8 Cells do not apparently cross from or to blood vessels in any other area of the thymus. Immature lymphocytes are allowed to pass from the vessels into the medulla tissue and only mature lymphocytes are allowed to pass back into the blood vessels. Once the immature lymphocytes have passed the blood-thymus barrier they are called "thymocytes". Over 90% of all thymocytes are found densely packed into the cortex regions of lobules with just 10% of thymocytes found in the medulla regions. These cells are at different stages of maturation. Cortex thymocytes are the most immature and medulla thymocytes are close to complete maturation and preparing for release back into the blood stream. Of all the immature lymphocytes that enter the thymus only 10% leave as fully differentiated cells. The rest die at some stage during the maturation process in the cortex or medulla of thymic lobules. Clearly vast numbers of immature Thymus dependant cells (T cells) must be produced by the bone marrow to ensure that enough cells leave the thymus to maintain the adult immune system. Figure 6: Picture showing location and structure of Thymus. Source: _The_Location_Structure_and_Histology_of_the_Thymus.jpg Education of Lymphocytes The bone marrow produces lymphocytes that can attack wide range of antigens including antigens of our own cells. The Bone marrow makes no distinction between those lymphocytes that will benefit us and those that could harm us. Immature lymphocytes are unable to respond to any antigenic challenge so their migration from the bone marrow to the thymus is uneventful and of no consequence, good or bad, to us. This swarm of cells is then educated in the thymus. There is a dispute over which cells in the thymus are the instructors and educators. Some say it is the epithelial (reticular) cells. Others say the education comes from a population of dendritic cells found in the thymus that are possibly a subgroup of phagocyte cells produced in the bone marrow. 8

9 The educating cells present own antigens to the immature thymocytes. Those that are able to respond to the presented antigens die. Those that don't respond are assumed to be protective and beneficial for us and will mature to leave the thymus. This is called negative selection also. Lymphocytes are also exposed to MHC molecule and those lymphocytes which can recognize MHC are selected and can move out of the thymus. This type of selection is known as positive selection. There are some problems however. The cells in the thymus do not have all our antigens available to use in educating thymocytes. Some antigens from specialized organs such as the brain and hair follicles are not present in the thymus. In summary then, the thymus is the educator of T cells into a viable defense force and removes noncompliant and dangerous self-reactive immature T lymphocyte precursors. b. Secondary lymphoid Organs While primary lymphoid organs are concerned with production and maturation of lymphoid cells, these condary orperipheral lymphoid organs are sites where the lymphocytes localize, recognize for eignantigen and mount response against it. These include the lymph nodes, spleen, tonsils, adenoids, appendix, and clumps of lymphoid tissue in the small intestine known as Peyer's patches. They trap and concentrate foreign substances, and they are the main sites of production of antibodies. Some lymphoid organs are capsulated such as lymph node and spleen while others are non-capsulated, which include mostly mucosa-associated lymphoid tissue (MALT). Spleen The spleen (Figure 7) is made up of B cells, T cells, macrophages, dendritic cells, natural killer cells and red blood cells. The spleen filters antigens directly from the blood that passes through it, and migratory macrophages and dendritic cells bring antigens to the spleen via the bloodstream. An immune response is initiated when a macrophage or dendritic cell "presents antigen" to appropriate B or T cells. In the spleen, B cells become activated and produce large amounts of antibody. The spleen has a thin connective tissue capsule from which short septa extend inwards. These septa are, in turn, connected to a complex reticulin framework. There are two distinct components of the spleen, the red pulp and the white pulp. The red pulp consists of large numbers of sinuses and sinusoids filled with blood and is responsible for the filtration function of the spleen. The white pulp consists of aggregates of lymphoid tissue and is responsible for the immunological function of the spleen: Figure 7: Diagram showing the structure of spleen. Source: 9

10 Red pulp There is a complex system of blood vessels within the red pulp arranged to facilitate removal of old or damaged red blood cells from the circulation. A small proportion of the splenic blood flow passes through more rapidly without undergoing this process of filtration. White pulp The white pulp contains T cells, B cells and accessory cells. The purpose of the white pulp is to generate an immunological response to antigens within the blood. The white pulp is present in the form of a periarteriolar lymphoid sheath. This sheath contains B cell follicles and T cells. At the edge of the T zone is a region known as the marginal zone where larger lymphocytes and antigen presenting dendritic cells are located. Lymph Nodes The lymphatic system parallels the circulatory blood system. It is periodically guarded by lymph nodes, which are found throughout the body. Composed mostly of T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most tissues. Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation. In a similar fashion as the spleen, macrophages and dendritic cells capture antigens and present them to T and B cells, consequently initiating an immune response. Lymph nodes are small bean shaped structures lying along the course of lymphatics (Figure 4.9 a, b). They are aggregated in particular sites such as the neck, axillae, groins and para-aortic region. Lymph nodes have two main functions: phagocytic cells act as filters for particulate matter and micro-organisms. antigen is presented to the immune system. Lymph nodes have a fibrous capsule from which trabeculae extend towards the center. The node is made up of three components: lymphatic sinuses blood vessels parenchyma (cortex, paracortex, medulla) Figure 8a: Structure of Lymph node. Source: 10

11 Figure 8b: Diagrammatic sketch of Lymph node. Source: Physiology_of_Animals/Lymphatic_System Cortex B cells: These enter the lymph node via high endothelial venules (HEVs) and pass to the follicles. If activated by antigenic stimulation they proliferate and remain in the node. Unstimulated B cells, however, pass out rapidly from the node to return to the general circulation. Activated B cells within the lymphoid follicles are known as follicle centre cells. The pale staining central area of a secondary follicle is known as a germinal centre and this is surrounded by a mantle zone consisting of small, naive B cells and a few T cells. The follicle centre cells within the germinal centres consist of cells with cleaved nuclei (centrocytes) and cells with larger more open nuclei and several nucleoli (centroblasts). Stimulated mature B cells responding to antigen change into centrocytes and then centroblasts. The centroblasts leave the follicle and pass to the paracortex and medullary sinuses, where they become immunoblasts. The immunoblasts divide to give rise to plasma cells or memory B cells which are ready for their next encounter with specific antigen. Accessory cells: Lymphocytes alone are not to make an effective immune response. They are assisted by so-called accessory cells. These may be grouped as follows: sinus macrophages (highly phagocytic) tingible body macrophages (ingest cellular debris in germinal centres) marginal zone macrophages (found beneath the subcapsular sinus) follicular dendritic cells Paracortex The paracortex contains lymphocytes and accessory cells along with supporting cells and it is the predominant site for T lymphocytes within the lymph node. T cells: The various types of T cell enter the node from the blood via the HEVs. When activated they form lymphoblasts which divide to produce a clone of T cells responding to a specific antigen. Activated T cells then pass into the circulation to reach peripheral sites. 11

12 Accessory cells: Interdigitating cells are numerous in the paracortex and they act as antigen presenting cells. Medulla The medulla comprises: large blood vessels medullary cords medullary sinuses The medullary cords are rich in plasma cells which produce antibodies that pass out of the node via the efferent lymphatic. Macrophages are also numerous within the medulla. Lymphatic System Lymph passes into the node through the afferent lymphatic into the marginal sinus, though the cortical sinuses to reach the medullary sinuses before leaving via the efferent lymphatic. Particulate matter in the lymph is removed by macrophages. Antigens are taken up by antigen presenting cells and these facilitate the specific immune response. Less than 10% of lymphocytes enter the node in the lymph, the large majority entering from the blood via the HEVs (Figure 9, 10). Figure 9: Organization of lymphatic system in humans. Source: Articles/Vital-Role-of-Your-Lymphatic-System-Part-I.html 12

13 Lymphocyte Recirculation Lymphocytes and some mononuclear phagocytes can recirculate between lymphoid and nonlymphoid tissues. This helps in allowing lymphocytes to be exposed to the antigens which they recognise and is, therefore, valuable in the distribution of effector cells of the immune response to the sites where they are needed: Figure 10: Lymphatic system, route of flow of lymph in human body. Source: thefreedictionary.com/_/viewer.aspx?path=mosbymd&name=lymphaticsystem.jpg&url=http%3a%2f%2fme dical-dictionary.thefreedictionary.com%2flymphatic%2bsystem The recirculation is a complex process depending on interactions between the cells of the immune response and other cell types such as endothelial cells. virgin lymphocytes move from the primary to secondary lymphoid tissue via the blood activated lymphocytes move from the spleen, lymph nodes and MALT into the blood and thence to other lymphoid and non-lymphoid tissues antigen presenting cells such as macrophages and dendritic cells may carry antigen back to lymphoid tissues from the periphery. The complex patterns of recircultion depend on the state of activation of the lymphocytes, the adhesion molecules expressed by endothelial cells and the presence of chemotactic molecules which selectively attract particular populations of lymphocytes or macrophages. 13

14 Mucosa-associated Lymphoid Tissue In addition to the lymphoid tissue, concentrated within the lymph nodes and spleen, lymphoid tissue is also found at other sites, most notably the gastrointestinal tract, respiratory tract and urogenital tract. Gut-associated Lymphoid Tissue This comprises: tonsils, adenoids (Waldeyer's ring) Peyer's patches lymphoid aggregates in the appendix and large intestine lymphoid tissue accumulating with age in the stomach small lymphoid aggregates in the oesophagus diffusely distributed lymphoid cells and plasma cells in the lamina propria of the gut Large aggregates of GALT have distinct B cell follicles and T cell areas. Antigen presenting accessory cells are also present. Peyer s Patches These are quite large aggregates of lymphoid tissue found in the small intestine. The overlying 'dome' epithelium contains large numbers of intraepithelial lymphocytes. Some of the epithelial cells have complex microfolds in their surfaces. They are known as M cells and are believed to be important in the transfer of antigen from the gut lumen to Peyer's Patches. Peyer's Patches facilitate the generation of an immune response within the mucosa. B cell precursors and memory cells are stimulated by antigen in Peyer's Patches. Cells pass to the mesenteric lymph nodes where the immune response is amplified. Activated lymphocytes pass into the blood stream via the thoracic duct. These cells then home in the gut and carry out their final effector functions. HEVs are not present in Peyer's Patches and the mechanism by which cells home in on mucosal sites is unknown. 4. Summary Immune system in vertebrates is very complex and is made up of number of organs and cell types. The various cell types are generated by the process oghematopoiesis in the adult bone marrow. Immune organ system is divided into two viz, primary lymphoid organs and peripheral or secondary immune organs. Primary immune organs are Bone marrow and Thymus Peripheral immune organs include spleen, Lymph nodes, Payers patches. 14