CELLS & ORGANS OF IMMUNE SYSTEM

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1 17 CHAPTER - 3 CELLS & ORGANS OF IMMUNE SYSTEM Carried within the blood and lymphoid organs are various white blood cells, or leukocytes, that participate in the immune response. Thus, make up cells of immune system. All these cells are formed in the process of haematopoiesis. HAEMATOPOIESIS : It is the formation of all types of blood cells. These cells arise from a common precursor cell, called as haematopoietic stem cells or HSCs. Stem cells are self-renewing, so they maintain their population level by cell division. These stem cells are pluripotent stem cells, as they can give rise to all types of blood cells. In humans, haematopoiesis begins in embryonic yolk sac during early weeks of development. In 3 rd month of gestation, HSCs migrate from yolk sae to fetal liver and then to spleen. These two organs are the major sites of haematopoiesis from the 3 rd to 7 th month of gestation. After 7 th month of gestation, differentiation of HSCs in bone marrow becomes major source of haematopoiesis. After birth, bone marrow is sole site of haematopoiesis. Figure : Haematopoiesis

2 In bone marrow, stromal cells from a meshwork that supports growth and differentiation of HSCs into various blood cells. Stromal cells are non-haematopoiesis cells and these include fat cells, endothelial cells, fibroblasts and macrophages. HSCs can be identified with the help of cell surface markers. These markers are sea-1, CD34 and C-kit. CELLS OF THE IMMUNE SYSTEM : The cells of the immune system are of 2 types : (i) Granulocytes : These have dark staining granules in them. They include neutrophil, cosinophil and basophil. (ii) Agranulocytes : These lack dark staining granules in their cytoplasm. These cells further have 2 types : (1) Lymphocytes : It includes B-cells, T-cells and natural killer (NK) cells. (2) Mononuclear phagocytes : It includes monocytes and macrophages. GRANULOCYTES : It includes neutrophils, eosinophils and basophils. (1). NEUTROPHILS : Its cytoplasm is granulated and stains with acid and basic dyes both. It has a multilobed nucleus and due to this, it is also called as polymorphonuclear leukocyte (PMN). It constitute 50-70% of circulating WBCs. They have short life span, usually less than 6 days. These are the first cells to arrive at a site of inflammation. In many infections, bone marrow produces large number of neutrophils. It causes a transient increase in their count. This increased neutrophil count in circulation is called leukocytosis. It is medical indication of infection. Neutrophils are phagocytic cells and contain primary and secondary granules. These granules contain many hydrolytic enzymes such as lysozyme, peroxidase, collagenase etc. Both these granules fuse with phagosomes produce many reactive oxygen intermediates (superoxide or peroxide radicals) and reactive nitrogen intermediates (NO or nitric oxide). These help kill the pathogen. They also produce defensin proteins that disrupt pathogen membrane and kill them. (2). EOSINOPHIL : It has a granulated cytoplasm that stains with acid dye eosin red, hence, its name. It has a bilobed nucleus. It is a phagocytic cell and plays a role in defence against parasitic organisms. Contents from its granules are secreted and damage parasite membrane. (3). BASOPHIL : It has a heavily granulated cytoplasm that stains with basic dye methylene blue. It has a single lobed nucleus. It is a non-phagocytic cell. It is important in many allergic responses. AGRANULOCYTES A. MONONUCLEAR PHAGOCYTES : It includes monocytes circulating in the blood and macrophages in tissues. Monocytes are formed in bone marrow and released in blood circulation. Monocytes circulate in the blood stream for about 8 hours. During their course of circulation, they enlarge and then migrate into tissues. In tissues, they differentiate into specific tissue macrophages. This differentiation of monocytes macrophages, involves increases in cell size, increase in intracellular organelles and increased phagocytic ability. Thus, monocytes and macrophages both are phagocytic cells. Macrophages being more capable. Macrophages in different tissues are named differently. 18

3 Organ Lung Liver Kidney Brain Bone Name of macrophage Alveolar macrophage Kupffer cells Mesangial cells Microglial cells Osteoclasts Macrophages are phagocytic. It means they can ingest and digest exogenous antigens such as whole microbes and insoluble particles and endogenous matter such as dead host cells, cellular debris and activated clotting factors. 19 Figure : Steps in phagocytosis NOTE:A concept associated with the study and activity of macrophages is opsonization. It is explained below: The cell membrane of macrophage has receptors for some classes of antibody. If an antigen (e.g., bacterium) is coated with the antibody and this complex binds to antibody receptors on the macrophage membrane, then phagocytosis of antigen and hence, its removal is enhanced. This process that makes an antigen more susceptible to phagocytosis is called as opsonization. The antibody acts as a molecule that binds to both antigen and macrophage. It enhances the phagocytosis. Such molecule are called opsonin. Figure : Opsonization Promoting Phagocytosis

4 HOW MACROPHAGES KILL? Macrophages wonder in tissues as resting macrophages. Their interaction with antigen activates them. These activated macrophages are very efficient at killing and removing the antigen. They mainly kill by 2 methods describeds below: (1). OXYGEN-DEPENDENT KILLING MECHANISM : Activated macrophages show respiratory burst. It leads to increased production of reactive oxygen intermediates and reactive nitrogen intermediates. Reactive oxygen intermediates involve superoxide and peroxide ion. These are toxic to pathogen. Periodic ion combine with chloride anion to produce hypochlorite to kill pathogen. Reactive nitrogen intermediates include nitric oxide (NO) and its derivatives. NO is produced by following reaction. L-arginine + O 2 + NADPH Nitric oxide Synthetase NO + L-citrulline + NADP Antimicrobial activity of macrophages against bacteria, fungi, parasitic worms and protozoa is due to NO and its derivatives. (2). OXYGEN-INDEPENDENT KILLING MECHANISM : It involves such killing mechanisms that do not require O 2. It includes activity of various hydrolytic enzymes such as lysozyme. Release of antimicrobial peptides called defensins. B. LYMPHOCYTES : They make up 20-40% of body WBCs and 99% of cells in lymph. Lymphocytes circulate in blood and lymph and are capable of migrating into tissue spaces and lymphoid organs. Lymphocytes are of 3-types, described below : (1). B-CELLS : These are cells of adaptive immune system. They are born and mature in bone marrow. Mature B-cells have membranes bound antibody as antigen receptor. It is also called B-cell receptor (BCR). B-cell membranes also have class-ii MHC molecule. It enables B-cells when activated by antigen presenting cell (APC). B-cells when activated by antigen undergo rapid cell division and expand into Plasma cells : They secrete antibody that helps clear antigen. Memory cells : They store memory of antigen interaction and help into rapid secondary response. 20 Plasma cell Memory cell Cycle repeats Naive B-cell (G -stage) 0 M-phase Antigen activation induces cell cycle G 2 S-phase G 1 Figure : Differentiation of B-cells (2). T-CELLS : These are also called T-lymphocytes and derive their name from their site of maturation i.e. thymus. They are born in bone marrow and migrate to thymus for maturation. Receptor on T-cell membrane is called T-cell receptor (TCR). It does not recognize free antigen unlike BCR.

5 TCR recognizes only such antigen that is bound to a particular class of MHC molecules. T-cells are of 2 basic types based on whether they express CD 4 or CD 8 cell surface molecule alongwith TCR. CD 4 and CD 8 are called co-receptors. CD 4 T-CELLS : They have CD 4 co-receptor alongwith TCR. They are also called as T-helper (T H ) cells. They recognize antigen bound to class-ii MHC molecules. Thus, they are said to be MHC class-ii restricted. T H -cells are of following types : T H1 -cells that produce cytokines that support inflammation and activities T-cells and macrophages for immune response. T H2 -cells that activate mainly B-cells and immune responses that need antibody. CD 8 T-CELLS : They have CD 8 co-receptor alongwith TCR. They are also called as cytotoxic T(T C ) cells. They recognize antigen bound to class-i MHC molecules. Thus, they are said to be MHC class-i restricted. Ratio of CD 4 : CD 8 T-cells in human blood is 2 : 1. (3). NATURAL KILLER CELLS (NK CELLS) : They are lymphocytes with granules. They do not express receptors found in B and T-cells. They are important in defence against tumors and viruses. They are important for antibody dependent cell mediated cytotoxicity (ADCC) response. Genetic defects in NK cell function had to Chediak-Higashi syndrome. ORGANS OF IMMUNE SYSTEM : Organs of immune system are of 2 types : A. Primary lymphoid organs : They provide appropriate sites for development and maturation of lymphocytes. E.g. Bone marrow and thymus. B. Secondary lymphoid organs : They trap antigen from defined tissues or vascular spaces, so they have high density of antigen. Thus, they are sites where mature lymphocytes can interact effectively with antigen. E.g. Lymph node, spleen, MALT and CALT. PRIMARY LYMPHOID ORGANS : Immature lymphocytes generated in hematopoiesis mature and become antigenically committed. Only after a lymphocyte has matured within a primary lymphoid organ is the cell immunocompetent i.e. capable of mounting an immune response. (1). THYMUS GLAND : Thymus is the site of T-cell development and maturation. It is a bilobed organ situated above heart. Function of thymus gland declines with ageing. This decline is responsible for less immune function in elderly humans. Thymus reaches its maximum size at puberty (70 g) and then show atrophy i.e. degeneration by cell death, so that its weight in elderly is about 3g. Mice that lack thymus gland are called nude mice. 21

6 (2). BONE MARROW : In simple terms, it is, soft, blood forming tissue that fills the cavities of bones. Bone marrow is found in every major bone in body. Thus, all major bones have a primary lymphoid organ. In humans and mice, bone marrow is the site of B-cell origin and development. But, bone marrow is not the site of B-cell origin and development in all species. In birds, bursa of fabricius is the site of B-cell maturation. It is a lymphoid tissue found in gut. In cattle and sheep, ideal Peyer s patch is the site of B-cell maturation and development. It is found in wall of intestine and thus, is a gut associated lymphoid tissue. In rabbits, appendix is the primary lymphoid organ for B-cell origin and development. LYMPHATIC SYSTEM : It is important to know basics of lymphatic system before secondary lymphoid organs, especially lymph nodes, are explained. Blood circulates under pressure and its fluid component (plasma) seeps through the thin wall of capillary, into the surrounding tissues. This seeped fluid is called interstitial fluid. Most of it returns to the blood through capillary membranes. The remaining part of interstitial fluid, is called, lymph. It flows from spaces in tissues, into a network of small, open lymphatic capillaries and then into larger lymphatic vessels. The lymphatic vessels drain into blood vessels. E.g. largest lymphatic vessels, the thoracic duet, empties into left subilavian vein near heart. Thus, lymphatic system captures fluid lost from the blood and returns it to the blood. This ensures steady state levels of fluid within circulatory system. When an antigen gains entrance to tissues, it is drained by lymphatic system and carried to an organized lymphoid tissues that can trap the antigen. As lymph drains from tissues to lymphatic vessels, it also gets enriched in lymphocytes. Thus, lymphatic system serves to increase the density of antigen and lymphocytes in the defined space/limit of lymphoid organ. This increases the probability of interaction between antigen and lymphocytes and resulting immune response. SECONDARY LYMPHOID ORGAN : It refers to various types of organized lymphoid tissues that are located along vessels of lymphatic system. (1). LYMPH NODES : Lymph nodes are 1 st organized lymphoid structure to encounter antigens from tissues spaces. Thus, lymph nodes are the site where immune responses are generated against in lymph. Lymph nodes have a complex structure, suffice to say that they have B-cells, T-cells and macrophages in them. When these cell encounter antigen, they are activated, undergo cell division and generate immune response. After activation, B-cells are clustered in areas called secondary follicle. The center of this follicle is called as germinal center. B-cell in germinal center produce large amounts of antibody against pathogen. These antibodies come out with lymph from lymph node and reach circulation. Thus, afferent lymphatic vessel that brings lymph into the node also brings antigen into lymph node. Efferent lymphatic vessel that takes lymph away from node, carries antibodies against antigen trapped in node. (2). SPLEEN : It is a large secondary lymphoid organ located high in the left abdominal cavity. Spleen is a blood filtering organ, thus, traps blood-borne antigens. 22

7 So, spleen plays major role in mounting immune responses to antigens in blood stream. Thus, it responds to systemic infections. Spleen is not supplied by lymph vessels. Blood borne antigens and lymphocytes are carried into spleen via splenic artery. Spleen has two zones viz. red pulp and white pulp. (i) Red pulp : It contains large number of RBCs and macrophages. It is the site where old and defective RBCs are destroyed and removed. (ii) White pulp : It is zone around splenic artery. It contains T-cells and B-cells that generate immune response against antigens in blood. Red pulp and white pulp are separated by marginal zone. Marginal zone contains lymphocytes and macrophages. Antibody secreting secondary follicles are also formed in marginal zone. (3). MALT : It stands for mucosol associated lymphoid tissues. Mucous membranes that line the digestive, respiratory and urogenital systems are membrane surfaces vulnerable to pathogen attack and entry. They are defended by a group of organized lymphoid tissues, collectively called as MALT. Functional importance of MALT in body s defences are attested by fast that polulation of antibody producing plasma cells in MALT for exceeds plasma cell population in spleen lymph node and bone marrow combined. Examples of MALT are Tonsils Lamina propria of intestinal villi Peyer s patches in submucosal layer of intestinal lining Appendix (4). CALT : It stands for cutaneous associated lymphoid tissues. It refers to immune tissues/cells associated with skin and related structures. Keratinocytes and Langerhans cells are important cells associated with this CALT. EVOLUTIONARY COMPARISON OF LYMPHOID CELLS AND ORGANS : Innate immune system of different capacity are found in invertebrates and plants alongwith vertebrates. However, adaptive immune response mediated by antibodies and T-cells evolved only among vertebrates. Evolution in vertebrates (from pisces to mammalia) can be seen in addition of organs and cells to immune system within vertebrata. All vertebrates have gut associated lymphoid tissues (GALT). Most vertebrates have thymus and spleen. However, bone marrow for haematopoiesis and lymph nodes with germinal centre forming ability are not found in all vertebrates. Primitive fishes are jawless and are called agnatha. They lack T and B lymphocytes. Formation of T and B lymphocytes is 1 st seen in jawed fishes called gnathostomata. Sharks are the earliest example of jawed fishes or gnathostomata. Thus, sharks are among earliest examples to have T and B lymphocytes. 23

8 24 Figure : Evolution of Immune System Organs

9 25 PRACTICE SET SECTION - A : [Multiple Choice Questions (MCQ)] 1. Which among following cells is not a granulocyte? (a) Neutrophil (b) Macrophage (c) Basophil (d) Eosinophil 2. Which of the following cells has a multilobed nucleus and can be stained with both acidic and basic dyes? (a) Macrophage (b) Basophil (c) Neutrophil (d) Eosinophil 3. First cell to arrive at site of inflammation is (a) Basophil (b) B-cell (c) Macrophage (d) Neutrophil 4. All blood cells are produced in a process called haematopoiesis. The site for haematopoiesis is adult humans is (a) Blood vessel (b) Bone marrow (c) Kidney (d) Muscles 5. A cell important in defence against parasites and stained with acidic dye is (a) Neutrophil (b) Basophil (c) Eosinophil (d) Monocyte 6. One of the following cells is NOT phagocytic (a) Monocyte (b) Neutrophil (c) Basophil (d) Eosinophil 7. A granulocyte that is also important in allergic reactions is (a) Neutrophil (b) Basophil (c) NK cells (d) Eosinophil 8. Macrophages found in liver are called (a) Kupffer cells (b) Mesangial cells (c) Microglial cells (d) Parenchyma cells 9. Amino acid required for synthesis of NO (nitric oxide) in macrophages is (a) Arginine (b) Citrulline (c) Glycine (d) Proline 10. One of the following cells is NOT a lymphocyte (a) Macrophage (b) T-cells (c) NK-cells (d) B-cells 11. A naive B-cell is mature but has not interacted with its antigen. In which stage of cell cycle are these naive B- cells found? (a) G 1 (b) G 0 (c) G 2 (d) S 12. FALSE statement about B-cells is (a) It is born and mature in bone marrow (c) B-cells act as APC (b) B-cell receptor is membrane bound antibody (d) It is born in bone marrow but matures in spleen 13. Antibody secreting B-cell is called (a) Memory B-cell (b) Plasma cell (c) Naive B-cell (d) None 14. A lymphocyte that is important is define against tumors and virsus (a) B-cells (b) NK cells (c) Macrophage (d) Neutrophil 15. Chediak-Higashi syndrome results due to genetic defects is (a) Epithelial cells (b) Neurons (c) NK cells (d) Osteoclasts SECTION - B : [Multiple Select Questions (MSQ)] 1. Which among following are secondary lymphoid organs? (a) MALT (b) Lymph nodes (c) Spleen (d) CALT 2. Choose correct statements about thymus glans (a) It is site of T-cells development and maturation (b) It is multilobed organ situated below heart

10 26 (c) It degenerates with ageing (d) Mice with thymus gland are called nude mice 3. Choose FALSE statements about bone marrow (a) Bone marrow is site of haematopoiesis in all animal (b) All major bones of body have bone marrow (c) It is a hard tissue found on surface of bone (d) Bone marrow contains haematopoietic stem cells and stromal cells 4. Which of the following are TRUE for lymph nodes (b) They are primary lymphoid organ (b) They encounter antigens from tissue spaces (c) They have B-cells that produce and secrete Ab when activated by Ag (d) They have B-cells, T-cells and macrophages in them 5. Choose TRUE statements about spleen (a) It is a secondary lymphoid organ (c) It contains red pulp and white pulp (b) It is found in right side of abdominal cavity (d) It encounters blood-borne antigens ANSWER KEY SECTION - A : [Multiple Choice Questions (MCQ)] 1. (b) 2. (c) 3. (d) 4. (b) 5. (c) 6. (c) 7. (b) 8. (a) 9. (a) 10. (a) 11. (b) 12. (d) 13. (b) 14. (b) 15. (c) SECTION - B : [Multiple Select Questions (MSQ)] 1. (a, b, c, d) 2. (a, c) 3. (a, c) 4. (b, c, d) 5. (a, c, d) *********************