Lymphatic System PDF

Lymphatic system Professor Zbigniew Kmieć, MD, PhD Lymphoid organs and main paths of lymphatic vessels The lymphoid system consists of: (i) capsulated lymphoid organs...

Lymphatic system Professor Zbigniew Kmieć, MD, PhD Lymphoid organs and main paths of lymphatic vessels The lymphoid system consists of: (i) capsulated lymphoid organs (thymus, spleen, tonsils, and lymph nodes); (ii) diffuse lymphoid tissue; Four basic cell types (lymphoid cells) are: T lymphocytes (T cells), B lymphocytes (B cells), NK cells, dendritic cells and macrophages. Another common features is the presence of reticular tissue and fibroblast-like reticular cells. Pawlina W, Histology, 2020 Types of immunity The innate immune system is active in non-specific defenses against inavading micoorgamisms and bodie’s own tumor cells It consists of: complement system of ca. 20 plasma proteins, mononuclear phagocytes (neutrophils, monocytes and tissue macrophages), NK cells mastocytes dendritic cells (DCs) which act at the interface of innate and adaptive immunity Junqueira, Basic Histol, 11 ed Important features of Natural Killer (NK) cells: (1) they kill virus-infected cells and tumor cells and (2) they produce IFN-γ that activates macrophages to kill bacteria that they have ingested (3) they do NOT have surface CD3 marker, present on all T cells ND = not obligatory  The adaptive immune system The adaptive immune system (specific) has four characteristics: - specificity - diversity, - memory, - self-tolerance. ability to recognize self molecules from nonself ones The cells of the adaptive immune system, T and B cells, and Antigen-Presenting Cells (APCs), communicate with one another by the use of signaling molecules (cytokines). Antigen-presenting cells (APCs): a) „professional” APCs: macrophages, dendritic cells (DCs), Langerhans cells (epidermis), some B cells b) „Non-professional” APCs: NK cells, and follicular dendritic cells (FDCs) Junqueira, Basic Histol, 15 ed Adaptive immune system functions to defend the organism by mounting: humoral immune responses against soluble antigens (foreign substances) – production of antibodies (Abs) by B cells AND T cell-mediated immune responses against present on the cell surface antigens of: - microorganisms, - tumor and transplanted cells, and - virus-infected cells. Dendritic cells (DCs) are unique APCs. DCs monitor the local environment for foreign substances that they then process and present to antigen-specific T cells. They are much more efficient in antigen presentation than other APCs and can present virtually any form of protein antigen on both MHC I and MHC II molecules. They express an exceptionally high level of MHC II and costimulatory molecules necessary for activation of T cells. In the lymph node, DCs are usually localized in T lymphocyte– rich areas. Dendritic cells (DCs) are primarily located in barrier tissues, including skin and the mucosa of the gastrointestinal, respiratory, and genitourinary tracts As with macrophages, dendritic cells engulf foreign material, process it into peptide fragments, or antigens, and present the antigens on MHC proteins to interact with cytotoxic T cells (through class I MHC proteins) and with helper T cells (through class II MHC proteins). However, DCs collect antigens and then migrate from these barrier locations, through the draining lymphatic vessels, and into local lymph nodes. To do this, the DCcell uses the C-C chemokine receptor 7, or CCR7, a receptor on its cell surface, to sense and migrate toward chemokines that are produced by stromal cells (called fibroblastic reticular cells) in the lymphoid tissue. Once in the lymph node, the DC presents antigen complexed with MHC proteins to “naïve” T cells in the T-cell zone. Thus, DCs, and not macrophages, are responsible for priming naïve T cells to become activated during the initiation of an adaptive immune response. Macrophages only interact with already-activated T cells in the peripheral inflamed tissue.  Bone marrow is a central or PRIMARY lymphoid organ: it contains precursors of T, B, and NK cells. B cell precursors differentiate in bone marrow microenvironment into mature B lymphocytes. T cell precursors travel in blood into THYMUS which is a CENTRAL LYMPHOID organ for T cell development. Differentiation of B and T cells into imunocompetent mature cells occurs mainly during fetal life! ‘Immunocompetent’ B and T cells leave central lymphoid organs and settle in SECONDARY LYMPHOID ORGANS and Th = Tc = connective tissues. helper cyto- toxic They encounter specific antigens there and differente into antigen-specific B and/or T cells. Kierszenbaum & Tres, Histology and Cell Biology, 5th ed.  Major Histocompatibility Complex (MHC) molecules Class I MHC proteins are present on the surface of virtually all nucleated cells. The complete class I protein is composed of a 45 kD heavy (alpha) chain noncov- alently bound to a β2-microglobulin. The alpha chain is highly polymorphic what is important in the recognition of self and nonself. It is similar to an Ig molecule; its hypervariable regions bind and present short peptides to T cells. The heavy chain also has a constant CD4 and CD8 molecules are co-receptors, their region where the CD8 protein of the presence defines type of the cell-mediated response cytotoxic T cell binds. Class II MHC proteins are glycoproteins found ONLY on the surface of professional APCs. They are highly polymorphic composed of two chains (alpha and beta) that are noncovalently bound. MHC class II proteins also have hypervariable regions that present the short peptides to T cells and provide much of the polymorphism. The two peptides also have a constant region where the CD4 protein of the helper T cells binds. General features of T cells = antigen Kierszenbaum & Tres, Histology and Cell Biology, 5th ed. Kierszenbaum & Tres, Histology and Cell Biology, 5th ed. ‚cytolytic’ = cytotoxic = CTL or, nowadays, Tc (CD8+) cell Kierszenbaum & Tres, Histology and Cell Biology, 5th ed.  IgG structure: 2 heavy and 2 light chains After papain digestion one gets: Fab – Antigen-binding fragment, and Fc fragment that binds the antibody molecule to the cell membrane Types of light chains: κ Heavy chains are different (isotypes):  Their presense determines CL, constant part Ig CLASSES, Ig A,D,E,G,M of light chain 2 light chains and 2 heavy chains form an antibody molecule (“monomer”). The chains are linked by disulfide (S-S) bonds. The variable regions (Fab) near the amino end of the light and heavy chains Site of Ig binding to bind the antigen. plasma membrane receptor on several The constant region (or Fc) of the cell types molecule may bind to its surface receptors on various cell types. Pawlina, Histology. Text&Atlas, 2020 Various specific and nonspecific functions of antibodies. Junqueira's Basic Histology, 14e, 2016 The important mechanisms by which the most common antibodies act in immunity. (a) Specific binding of antigens can neutralize or precipitate antigens, or cause microorganisms bearing the antigens to clump (agglutinate) for easier removal. (b) Complement proteins and surface receptors on many leukocytes bind the Fc portions of antibodies attached to cell- surface antigens, producing active complement, more efficient phagocytosis (opsonization), and NK-cell activation. Development of naïve lymphocytes. Common lymphoid progenitors give rise to B-cell precursors, which develop into mature B lymphocytes in the bone marrow, and T cell precursors, which leave the bone marrow and complete their development into mature CD4-positive or CD8-positive T cells in the thymus. Mature naïve/virgin lymphocytes (immunocompetent cells) migrate throughout the secondary lymphoid tissue surveying for antigen. CD = cluster of differentiation. CD8+ Maturation of B cells. B cells arise from lymphoid progenitor stem cells and differentiate into pre-B cells expressing μ heavy chains in the cytoplasm and then into mature B cells expressing monomer IgM on the surface. This occurs independent of antigen. Activation of B cells, class switching, and differentiation into memory B cells and plasma cells occurs after exposure to antigen (red star) and is enhanced by T-cell help. μ, mu heavy chains in cytoplasm; Y, IgM (blue) or IgG (purple). Antibody synthesis in the primary and secondary responses. In the primary response, immunoglobulin (Ig) M is the first type of antibody to appear. In the secondary response, IgG and IgM appear but IgG shows a more rapid rise and a higher final concentration than in the primary response.  Developmental categories Primary = central lymphatic organs – those in which lymphocytes’ precursors differentiate and mature – red bone marrow, thymus Secondary = peripheral lymphatic organs – those in which mature lymphocytes play active roles in immune defense reactions, proliferate, and complete differentiation – red bone marrow, lymph nodes, spleen, tonsils, and various isolated microscopic lymphatic nodules, especially those found in lamina propria of the mucosa of the GI, respiratory, urinary, and reproductive tracts, i.e., MALT = mucosa- associated lymphatic tissue ora BALT.  Lymphoid nodule/ follicle is a site of proliferation and differentiation of lymphocytes in active immune responses accumulation of ‘unencapsulated’, spherical masses of dense aggregates of: small B lymphocytes in an outer core the germinal center, a central mass of: - antigen-presenting macrophages and - larger, more metabolically active, proliferating B lymphocytes that finally differentiate into plasma cells primary 2 types secondary  Uncapsulated lymph nodule: in the middle germinal center – rich in dividing B cells (lymphoblasts, centroblasts). Its dark, peripheral region, marginal zone, (corona, mantle), contains mainly small, newly formed adult B cells (centrocytes) and some T cells Other cell types: FDCs (follicular dendritic cells), macrophages, Th cells, and reticular cells. Wheather’s Funct Histol, 4 ed Thymus is primary lymphatic and an endocrine organ responsible for T cell development. It is made of many pseudolobules. Each lobule has an outer cortex and an inner medulla. The lobules are separated by connective tissue septa in the cortex. The pink thymic epitehelial cells (TECs) network forms a cytoplasmic framework for thymic lymphocytes. The outer darker area (cortex) contains many immature T cells which will go through selection or "education" of lymphocytes. This is the 1st step in making T cells immunocompetent = able to distinguish foreign antigens from self antigens A.D.A.M. The thymus is most active and prominent before puberty and undergoes involution with less activity in the adult. Thymus atrophy is caused by increased blood level of sex hormones. Active thymic lymphatic tissue is substituted after 20th year of life by adipose tissue, at a yearly rate 3% between 20-40 y, and 1% afterwards Junqueira, Basic Histol, 11 ed The main cell types of the thymus (Thymus does NOT contain lymphoid nodules). Differentiation of thymocytes occurs in the thymus cortex. Thymic medulla contains immuno- competent ‚naive’ or ‚virgin’ Th (helper, CD4+) or Tc (cytotoxic, CD8+) cells Kierszenbaum & Tres, Histology and Cell Biology, 5th ed. Thymic Epithelial Cells (TECs) originate from endoderm and form a meshwork in which T cells are tightly packed. RECs are pale cells with large, ovoid nucleus. They have long processes that surround the thymic cortex, isolating it from both connective tissue septa and medulla. The processes, which are filled with bundles of tonofilaments, form desmosomal contacts with each other. Each TEC surrounds ca. 50-200 immature T cells (thymocytes) in the thymus cortex, they are called ‘nourishing’ or ‘nurse’ cells Junqueira, Basic Histol, 11 ed  Thymocytes Thymocytes are immature T cells present within thymic cortex in different stages of differentiation. They are surrounded by processes of RECs, which segr-egate thymocytes from antigens during their maturation. They migrate toward the medulla as they mature. However, those T cells whose receptors recognize self proteins (self-antigens) undergo apoptosis and never reach the medulla. Most T cells (95%) die in the cortex and are phagocytosed by macrophages. Surviving T cells are naïve, ie. not specifically immuno-competent. They leave the thymus and are distributed to secondary lymphoid organs by vascular and lymphatic systems.  Blood-thymus barrier It exists in the cortex only, making it an immunologically protected region. It ensures that antigens escaping from the bloodstream do not reach T cells that develop in thymic cortex. It consists of the following layers: - endothelium of the thymic capillaries and associated basal lamina, - perivascular connective tissue and - cells: pericytes, macrophages, and TEC  Thymus - medulla TECs produce thymosin, serum thymic factor, TSLP and thymopoietin which The inner lighter area, help in the transformation of immature medulla, contains larger, T cells into immunocompetent T cells. more mature T-lymphocytes going through the final TECs are of six types. Some TEC developemental stage. present MHC I and MHC II molecules to REC developing T cells. Hassall corpuscles are accumulations of altered Besides TECs thymus stroma contains REC in thymic medulla. macrophages and dendritic cells (only They display various stages in the medulla and at the cortex- of keratinization and medulla border). increase in number with age. Unknown function. Structure of a lymph node Wheather’s Funct Histol, 4 ed Circulation of lymphocytes in the body Pawlina W, Histology, 2020 Lymphocytes enter lymph nodes by two routes: afferent lymphatic vessels and through the wall of high endothelial venules (HEVs, inset) in the deep cortex. Some lymphocytes move to the T and B domains of the lymph node; others pass through the parenchyma of the node and leave via an efferent lymphatic vessel. Ultimately, lymphocytes enter the right lymphatic trunk—that opens into the junction of the right internal jugular and right subclavian vein. Then, lymphocytes get into right heart, and via arteries of the systemic circulation enter lymphatic tissues of the body or to tissues where they participate in immune reactions. From the lymphatic tissues, lymphocytes again return to the lymph nodes to gain entry via the HEVs.  DIRECTION OF LYMPH FLOW in a lymph node: Afferent lymph vesselS Subcapsular sinus  Intermediate (radial or trabecular) sinuses  Medullary sinuses  Efferent lymph vessel emerges out of hilum. Staining reveals retiular fibers present in the stroma of the lymph node. Pawlina, Histology. Text&Atlas, 2020. Cap, capsule, SS, subcapsular sinus, TS, trabecular or radial sinus, MS, medullary sinus Paracortex or inner/deep cortex is located between cortex and medulla of a lymph node. It is composed of a non-nodular arrangement of mostly T cells (T-dependent area of the lymph node). In paracortex circulating lymphocytes gain access to lymph nodes via postcapillary (high endothelial) venules, HEVs. Medullary sinuses are endothelium-lined spaces that receive lymph from the trabecular = radial = cortical sinuses. Medullary cords are the accumulations of mainly macrophages and plasma cells in the medulla. Junqueira, Basic Histol, 11 ed  High endothelial venules (HEVs) - places of lymphocyte migration (ARROWS) from blood into lymphatic nodule: information about antigens ENCOUNTERED IN BLOOD is carried through HEV’s walls to the site of antibodies’ production Junqueira, Basic Histol, 11 ed Sinuses are endothelium-lined spaces that extend along the capsule and trabeculae and therefore are called subcapsular and cortical (radial) sinuses Main regions of a secondary nodule in a lymph node Kierszenbaum, 2nd ed. Rapid proliferation of antigen-activated B lymphoblasts in the germinal center causes smaller, mature lymphocytes to be pushed aside and crowded together peripherally as the follicular mantle (M, mantle zone).  Main cell types present in a lymph node B and T cells Anti CD3 antibody Macrophages (APCs) (T cell marker Dendritic cells (APCs) Follicular dendritic cells (FDCs) Reticular cells (fibroblast-like) Pawlina W, Histology, 2020 FDCs within the lymph nodes are able to retain antigens and virions for a prolonged duration, i.e. for months to years. Anti CD20 antibody (B cell marker) Follicular dendritic cell FDCs have multiple, thin, hair-like (FDCs) branching cytoplasmic processes that interdigitate between B cells in the germinal centers (Figure). Antigen–antibody complexes adhere to the dendritic cytoplasmic processes by means of the antibody’s Fc receptors, and the cell can retain antigen on its surface for weeks, months, or years. Although this mechanism is similar to the adhesion of antigen–antibody complexes to macrophages, the antigen is not generally endocytosed, as it is by the macrophage. FDCs are not classical APCs because they lack MHC II molecules. They are of lymphoid, not myeloid origin. Junqueira, Basic Histol, 11 ed  Lymph node functions Production and maintenance of T and B cells, and storage of memory cells (especially Th cells). Accumulation of antigens delivered to lymph nodes to be recognized by T cells, inside and at the surface of APCs; thus initiation of an immune response. Lymph filtration, phagocytosis of lymph components: microorganisms, neoplastic cells, cell rests. Site of lymphocytes recirculation: blood lymph node lymph blood due to the presence of HEVs.  Spleen A large, dark-red, oval, highly vascular lymphatic organ, located to the left of the stomach below the diaphragm, organized into areas of red pulp and white pulp. Junqueira, Basic Histol, 11 ed Main components of the SPLEEN: capsule with its trabeculae, accumulation of lymphocytes (‘white pulp’), and ‘red pulp’: reticular tissue filled up with blood corpuscules Red pulp of the spleen - contains many reticular White pulp of the spleen = many cells, (old) red blood cells, macrophages, lymphocytes around central lymphocytes and (old) platelets. artery present in lymphoid Old erythrocytes express a carbohydrate marker, nodule (mainly B cells) + PALS which macrophages recognize, bind and then (periarterial lymphatic sheath layer rich in phagocytose old RBCs. T cells, T-dependent zone) Spleen is major destruction site of old platelets.  Trabecular artery has its own intima and media, trabecular vein – only own intima; rest of the vessels’ wall is composed of the connective tissue of the trabecula Stevens, 2002  Blood flow in the spleen Spleen a. trabecular a. central artery encircled by PALS = periarterial lymphatic sheath made of T cells penicillar arterioles pulp arterioles, macrophage-sheathed capillaries, terminal arterial Pawlina, Histology. Text&Atlas, 2020 capillaries SINUSOIDS pulp veins trabecular veins spleen vein Electron micrograph of the red pulp of the spleen. The junction of two splenic sinuses is visible in the center; the sinuses are surrounded by the stromal cells of the red pulp. Elongated nuclei belong to the rod- like endothelial (EnC) cells lining the sinuses. Note many profiles of red blood cells in the red pulp and in the splenic sinuses (RBC); several of them are in the process of passing through intercellular spaces between endothelial cells. Reticular cells (RC) are adjacent to The sinuses do not possess a continuous basal the wall of the sinus. lamina. Strands of basal lamina containing collagen IV Many red pulp macrophages (M) and laminin loop around the outside of the sinus much like are visible outside the wall of the the hoops that loop around the staves of a barrel. sinus. These strands are at right angles to the long axes of the P, plasmocyte; Mc, monocyte; N, endothelial cells. neutrophil. ×2,800. Neither smooth muscle nor pericytes are present in the wall of splenic sinuses.  Marginal zone of spleen’s lymphoid nodule It is a sinusoidal region between the red and white pulp, located at periphery of lymph nodules and PALS Receives blood from capillary loops derived from the central artery and thus is the first site where blood contacts the splenic parenchyma Is richly supplied by avidly phagocytic macrophages and other APCs (dendritic cells, B lymphocytes) It is the region where circulating T and B lymphocytes enter the spleen white pulp before becoming segregated to their specific locations within organ.  Functions of the spleen IMMUNOLOGICAL FUNCTIONS (white pulp) Antigen presentation by APCs (mostly dendritic cells and macrophages) and initiation of immune response to blood-borne antigens Antigen activation and proliferation of B and T lymphocytes Production of antibodies against antigen present in circulating blood Production of antibodies by B-cells (plasma cells) HEMOPOIETIC FUNCTIONS (red pulp) Removal and destruction of senescent, damaged, and abnormal erythrocytes and platelets Retrieval of iron from erythrocyte hemoglobin and its storage as ferritin or hemosiderin for future use (the heme portion of the molecule is broken down to bilirubi Formation of erythrocytes during early fetal life The role of the red pulp is primarily blood filtration (i.e., removal of particulate material; macromolecular antigens; and aged RBCs and platelets) by macrophages. People can live after splenectomy performed after capsule’s rupture (car crash) or in some hematologic diseases  MALT: Mucous-associated lymphatic tissue; in the brochial wall defined as BALT (Bronchus-associat…), and in the gut wall as GALT, lymphatic nodules are also present in the wall of genito-urinary ducts Junqueira, Basic Histol, 11 ed  Comparisons of the Major Lymphatic Organs Pawlina, Histology. Text&Atlas, 2020 Kierszenbaum, 3rd ed.