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Lecture 1. Cells and Organs of the Immune System. Introduction. The many cells, organs and tissues of the immune system are found throughout the body. They are functionally classified into two main groups. Primary lymphoid organs: Bone marrow and thymus
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Lecture 1 Cells and Organs of the Immune System
Introduction • The many cells, organs and tissues of the immune system are found throughout the body. • They are functionally classified into two main groups. • Primary lymphoid organs:Bone marrow and thymus Provide appropriate microenvironment for the development and maturation of lymphocytes. • Secondary lymphoid organs: Trap antigen, generally from nearby tissues or vascular spaces and are sites where mature lymphocytes can interact effectively with antigen. Secondary lymphoid organs include the: lymph nodes, spleen, mucosa-associated lymphoid tissue (MALT) which also includegut associated lymphoid tissue (GALT) (e.g., Peyer’s patches) and bronchus associated lymphoid tissue (BALT) e.g., tonsils, appendix)
Human Lymphatic System • Consists of lymph glands found in: • Neck • Armpits • Groin • Lymphatics – small vessels • Lymph - watery fluid
Introduction • Blood vessels and lymphatic systems connect these organs, uniting them into a functional whole. • Carried within the blood and lymph and populating the lymphoid organs are various cells of the immune system. • Only the antigen-specific lymphocytes posses the attributes of diversity, specificity, memory and self-nonself recognition, the hallmarks of an adaptive immune response. • Other leukocytes also play important roles, some as antigen presenting cells and others participating as effector cells in the elimination of antigen by phagocytosis or the secretion of immune effector molecules. • Some leukocytes, especially T lymphocytes, secrete various protein molecules called cytokines. • These molecules act as immunoregulatory hormones and play important roles in the coordination and regulation of immune responses.
Hematopoiesis • All blood cells arise from a type of cell called the hematopoietic stem cell (HSC). • Stem cells are cells that can differentiate into other cell types. • They are self renewing, maintaining their population level by cell division. • In humans, hematopoiesis, the formation and development of red and white blood cells, begins in the embryonic yolk sac during the first weeks of development. • Yolk sac stem cells differentiate into primitive erythroid cells that contain embryonic hemoglobin. • By the third month of gestation, hematopoietic stem cells have migrated from the yolk sac to the fetal liver and subsequently colinize the spleen; theses two organs have major roles in hematopoiesis from the third to the seventh months of gestation. • After that, the differentiation of HSCs in the bone marrow becomes the major factor in hematopoiesis, and by birth there is little or no hematopoiesis in the liver and spleen.
Hematopoiesis • In bone marrow, hematopoietic cells and their descendants grow, differentiate, and mature on a mesh-like scaffold of stromal cells, which include: • fat cells, • endothelial cells, • fibroblasts, and • macrophages. • Stromal cells influence the differentiation of hematopoietic stem cells by providing a hematopoietic-inducing microenvironment (HIM) consisting of a cellular matrix and factors that promote growth and differentiation.
Hematopoietic HomeostasisInvolves Many Factors • Hematopoiesis is a steady-state process in which mature blood cells are produced at the same rate at which they are lost. • The principle cause of blood cell loss is aging. • The average erythrocyte has a life-span of 120 days before it is phagocytosed and digested by macrophages in the spleen. • The various white blood cells have life spans ranging from a day , for neutrophils, to as long as 20 to 30 years for some T lymphocytes. • To maintain steady-state levels, the average human being must produce an estimated 3.7 × 1011 white blood cells per day. • This massive system is regulated by complex mechanisms that affect all of the individual cell types, and ultimately, the number of cells in any hematopoietic lineage is set by a balance between the number of cells removed by cell death and the number that arise from division and differentiation.
Programmed Cell Death is an Essential Homeostatic Mechanism • Programmed cell death is a critical factor in the homeostatic regulation of many types of cell populations, including those of the hematopoietic system. • Cells undergoing programmed cell death often exhibit distinctive morphologic changes, collectively referred to as apoptosis. • These changes include: • A pronounced decrease in cell volume. • Modification of the cytoskeleton, which results in membrane blebbing. • A condensation of the of the chromatin and degradation of the DNA into fragments. • Following these morphologic changes, an apoptotic cell sheds tiny membrane-bound apoptotic bodies containing intact organelles. • Macrophages phagocytose apoptotic bodies and cells in the advanced stages of apoptosis. • This ensures that their intracellular contents, including proteolytic and other lytic enzymes, cationic proteins, and oxidizing molecules, are not released into the surrounding tissue. • Apoptosis does not induce a local inflammatory response
Comparison of Morphologic Changes that Occur in Apoptosis & Necrosis
Genes Regulate Apoptosis • The expression of several genes accompanies apoptosis in leukocytes and other cell types. • Some of the proteins specified by these genes induce apoptosis, others are critical as apoptosis progresses, and still others inhibit apoptosis.
Lymphoid Cells • Lymphocytes: • Constitute 20% to 40% of the bodies white blood cells and 99% of the cells in the lymph. • There are approximately a trillion (1012) lymphocytes in the human body. • Circulate continuously in the blood and lymph and are capable of migrating into the tissue spaces and lymphoid organs, serving thereby as a bridge between parts of the immune system. • Broadly subdivided into three major populations – B cells, T cells, and natural killer cells – on the basis of function and cell membrane components. • Key cells of adaptive immunity, B cells and T cells each bear their own distinctive antigen receptors. • Natural killer (NK) cells are large granular lymphocytes (granular refers to their grainy appearance under a microscope) that are the part of the innate immune system and do not express the set of surface markers that characterize B or T cells.
Granulocytic Cells The granulocytes are classified as neutrophils, eosinophils, or basophils on the basis of cellular morphology and cytoplasmic-staining characteristics
Different Kinds of Dendritic Cells & Their Origins
Bacterial Structures that are Recognized by PRRs • Peptidoglycans in bacterial cell wall • Mannans, bacterial cell surface polysaccharides • Gram negative bacteria (such as E. coli, Pseudomonas, Salmonella etc) all make Lipopolysaccharide (LPS/endotoxin), which is made up Lipid A and carbohydrates. • Teichoicacids and lipoteichoic acids, not found in vertebrate cells. Teichoic acids are phosphate linked polymers of ribitol or glycerol • The N-terminal amino acid of most bacterial proteins is formyl-methionine. • Bacterial lipoproteins (BLPs) contain a unique N-terminal lipo-amino acid, N-acyl S-diacylglycerylcysteine. • Bacterial DNA contains specific unmethylatedCpG repeats that are not found in vertebrate DNA
Toll Like Receptors (TLRs) • PRRs (Pattern Recognition Receptors) that activate phagocytes and DCs
Dendritic cells initiate immune responsesll Immature dendriticces constantly internalize and process proteins, debris, and microbes, when present. Binding of microbial components to Toll-Like Receptors (TLRs) activates the maturation of the DC so that it ceases to internalize any new material, moves to the lymph node, up-regulates MHC II, B7 and B7.1 molecules for antigen presentation, and produces cytokines to activate T cells. Release of IL-6 inhibits release of TGF B; and IL-10 by T regulatory cells. The cytokines produced by DC and its interaction with TH0 cells initiate immune responses. IL-12 and IL-2 promote TH1 responses while IL-4 promotes TH2 responses. Most of the T cells divide to enlarge the response, but some remain as memory cells. Memory cells can be activated by DC, macrophage, or B cell presentation of antigen for a secondary response
Cells of the Immune Response *Monocyte/macrophage lineage.APCs, antigen-presenting cells; CNS, central nervous system; DTH, delayed-type hypersensitivity; IFN, interferon; Ig, immunoglobulin; IL, interleukin; LT, lymphotoxin; MHC, major histocompatibility complex; TNF, tumor necrosis factor.
Major Cytokine-Producing Cells • Innate (acute phase responses) • Dendritic cells and macrophages: IL-1, TNF-α, TNF-β, IL-6, IL-12, GM-CSF, chemokines, interferons α,β. • Immune: T cells (CD4 and CD8) • TH1 cells: IL-2, IL-3, GM-CSF, interferon-γ, TNF-α, TNF-β. • TH2 cells: IL-4, IL-5, IL-6, IL-10, IL-3, IL-9, IL-13, GM-CSF, TNF-α.
Thymus • Derived from the third and fourth pharyngeal pouches during the embryonic life and attracts (by chemoattractive molecules) circulating T- cell precursors derived from HSC in the bone marrow. • Site of T-cell development and maturation. • Flat, bilobed organ situated behind the sternum, above and in front of the heart. • Each lobe surrounded by a capsule and divided into lobules, which are separated from each other by strands of connective tissue called trabeculae. • Each lobule is organized into two compartments. • Cortex: The outer compartment, is densely packed with immature T cells, called thymocytes. • Medulla: The inner compartment, is sparsely populated with thymocytes.
Thymus • Both the cortex and the medulla are criss-crossed by a three dimensional stromal cell network composed of epithelial cells, dentritic cells, and macrophages, which make up the framework of the organ and contribute to the growth and maturation of the thymocytes. • The accessory cells are important in the differentiation of the immigrating T cell precursors and their education (positive and negative selection), prior to their migration into the secondary lymphoid tissues. • Thymic epithelial cells produces the hormones thymosin and thymopoietin and in concert with cytokines such as IL-7 are probably important for the development and maturation of thymocytes into mature cells. • The thymic cortex is the major site of activity and thymocyte proliferation, with a complete turnover of cells approximately every 72 hours.
Thymus • These thymocytes then move into the medulla, where they undergo further differentiation and selection and finally migrate via circulation to the secondary lymphoid organs/ tissues where they are able to respond to microbial antigens. • Most (95%) of the thymocytes generated each day in the thymus die by apoptosis with less than 5% surrviving. • Molecules important to T cell function such as CD4, CD8 and T cell receptor develop at different stages during the differentiation process. • The main functions of the thymus as a primary lymphoid organ are: • To produce sufficient numbers (millions) of different T cells each expressing unique T cell receptors such that, within this group, there are at least some cells potentially specific for huge number of microbial antigens in our environment (generation of diversity). • To select for survival those T cells which bind weakly to self MHC molecules (positive selection), but then to eliminate those which bind too strongly to these same self MHC molecules (negative selection) so that the chance for an autoimmune response is minimized.
Changes in the Thymus with Age • Thymic function is known to decline with age. • The thymus reaches its maximal size at puberty and then atrophies, with a significant decrease in both cortical and medullary cells and an increase in the total fat content of the organ. • The average weight of the thymus in human infants is 30 grams and only 3 grams in the elderly. • The age dependent loss in mass is accompanied by a decline in T-cell output. • By age 35, the thymic generation of T cells has dropped to 20% of production in newborns, and by age 65, the output has fallen to only 2% of the newborn rate.
Thymus Diagrammatic cross section ofa portion of the thymus, showing several lobules separated by connective tissue strands (trabeculae). The densely populated outer cortex contains many immature thymocytes (blue), which undergo rapid proliferation coupled with an enormous rate of cell death. The medulla is sparsely populated and contains thymocytes that are more mature. During their stay within the thymus, thymocytes interact with various stromal cells, including cortical epithelial cells (light red), medullary epithelial cells (tan), dendritic cells (purple), and macrophages (yellow). These cells produce regulatory factors and express high levels of class I and class II MHC molecules. Hassall’s corpuscles, found in the medulla, contain concentric layers of degenerating epithelial cells. [Adapted with permission from W.van Ewijk, 1991, Annual Review of Immunology9:591 by Annual Reviews.]
Structure of a Lymph Node The three layers of a lymph node support distinct microenvironments.
Structure of a Lymph Node The left side depicts the arrangement of reticulum and lymphocytes within the various regions of a lymph node. Macrophages and dendritic cells, which trap antigen, are present in the cortex and paracortex. THcells are concentrated in the paracortex; B cells are primarily in the cortex, within follicles and germinal centers. The medulla is populated largely by antibody-producing plasma cells. Lymphocytes circulating in the lymph are carried into the node by afferent lymphatic vessels, they either enter the reticular matrix of the node or pass through it and leave by the efferent lymphatic vessel. The right side depicts the lymphatic artery and vein and the postcapillary venules. Lymphocytes in the circulation can pass into the node from the postcapillary venules by a process called extravasation (inset) .
