1_Lecture_Introduction_to_the_Immune_System PDF

DEN 230-6 IMMUNOLOGY Introduction to the Immune System Assist. Prof. Meltem ERCAN, PhD. IAU Faculty of Medicine (Eng.) Medical Biology & Genetics 20/02/2024 [email protected] Office: M-9910 INTRODUCTION  Immunology  The study of immune system or immunity  The study of all aspects of host d...

DEN 230-6 IMMUNOLOGY Introduction to the Immune System Assist. Prof. Meltem ERCAN, PhD. IAU Faculty of Medicine (Eng.) Medical Biology & Genetics 20/02/2024 [email protected] Office: M-9910 INTRODUCTION  Immunology  The study of immune system or immunity  The study of all aspects of host defense against infection and of adverse consequences of immune responses.  The study of the physiological mechanisms which enable the body to recognize materials as foreign and to neutralize, metabolize or eliminate them without injury to the host tissue. 2 “immunity”  referred to resistance to pathogens;  reactions to some noninfectious substances (including harmless environmental molecules, tumors, and even unaltered host components) are also considered forms of immunity (allergy, tumor immunity, and autoimmunity).  The collection of cells, tissues, and molecules that mediate these reactions is called the immune system.  The coordinated response of these cells and molecules to pathogens and other substances comprises an immune response. 3 Importance of the Immune System in Health and Disease Figure 1: Role of the immune system. 4  The importance of the immune system for health is dramatically illustrated by the frequent observation that individuals with defective immune responses are susceptible to serious, often life-threatening infections.  Stimulating immune responses against microbes through vaccination is the most effective method for protecting individuals against infections. Figure 2: Effectiveness of vaccination for some common infectious diseases in the United States. 5 IMMUN SYSTEM Figure 3: Immun System 6 INNATE AND ADAPTIVE IMMUNITY  Host defenses are grouped under; innate immunity, which provides immediate protection against microbial invasion, and adaptive immunity, which develops more slowly and provides more specialized defense against infections. Innate immunity, also called natural immunity or native immunity, is always present in healthy individuals Adaptive immunity, also called specific immunity or acquired immunity, requires proliferation and differentiation of lymphocytes in response to microbes before it can provide effective defense (i.e., it adapts to the presence of microbial invaders) 7  In innate immunity, the first line of defense is provided by epithelial barriers of the skin and mucosal tissues and by cells and natural antibiotics present in epithelia, all of which function to block the entry of microbes.  If microbes enter the tissues or circulation, several other components of the innate immune system defend against them, including phagocytes and innate lymphoid cells, and several plasma proteins, such as the complement system. Innate immune responses are required to initiate adaptive immune responses. The adaptive immune system consists of lymphocytes with highly diverse and variable receptors for foreign substances, and the products of these cells, such as antibodies.  Any molecule that is specifically recognized by lymphocytes or antibodies is called an antigen. 8 Principal mechanisms of innate and adaptive immunity  The mechanisms of innate immunity provide the initial defense against infections. Some mechanisms (e.g., epithelial barriers) prevent infections, and other mechanisms (e.g., phagocytes, natural killer [NK] cells and other innate lymphoid cells [ILCs], the complement system) eliminate microbes.  Adaptive immune responses develop later and are mediated by lymphocytes and their products. Antibodies block infections and eliminate microbes, and T lymphocytes eradicate intracellular microbes. Figure 4: Principal mechanisms of innate and adaptive immunity. 9  The cells of the immune system are located in different tissues and serve different roles in host defense. Most of these cells are derived from bone marrow precursors that circulate in the blood and are called leukocytes (white blood cells). Others are present in tissues at all times.  The cells of the immune system are grouped into two broad categories lymphoid cells (most of which are the mediators of adaptive immune responses) nonlymphoid cells, also called myeloid cells, which play diverse roles, including in innate immune responses. 10 TYPES OF ADAPTIVE IMMUNITY  Humoral immunity is mediated by proteins called antibodies, which are produced by cells called B lymphocytes. Defense against microbes that have already entered host cells is called cell-mediated immunity because it is mediated by cells, which are called T lymphocytes. Figure 5: Types of adaptive immunity 11 Immunity may be induced in an individual by infection or vaccination (active immunity) or conferred on an individual by transfer of antibodies or lymphocytes from an actively immunized individual (passive immunity). In active immunity, an individual exposed to the antigens of a microbe mounts a response to eradicate the infection and develops resistance to later infection by that microbe. Such an individual is said to be immune to that microbe, in contrast with.  In passive immunity, a naive individual receives antibodies or cells (e.g., lymphocytes) from another individual already immune to an infection or protective antibodies that have been synthesized using modern bioengineering techniques. The only physiologic example of passive immunity is seen in newborns, whose immune systems are not mature enough to respond to many pathogens but who are protected against infections by acquiring antibodies during fetal life from their mothers through the placenta and in the neonatal period from breast milk. 12 PROPERTIES OF ADAPTIVE IMMUNE RESPONSES 1 2 3 4 5 6 7 Figure 6: Properties of adaptive immune responses. 13 Specifity and Diversity  The adaptive immune system is capable of distinguishing millions of different antigens or portions of antigens, a feature that is referred to as specificity.  The total collection of lymphocyte specificities, sometimes called the lymphocyte repertoire, is extremely diverse.  The molecular basis for the generation of this remarkable diversity of lymphocytes is the clonal selection. 14 Clonal Selection  Mature lymphocytes with receptors for many antigens develop before encountering these antigens.  A clone refers to a population of lymphocytes with identical antigen receptors and therefore specificities; all of these cells are presumably derived from one precursor cell.  Each antigen (e.g., X and Y) selects a preexisting clone of specific lymphocytes and stimulates the proliferation and differentiation of that clone. Figure 7: Clonal Selection 15 Memory  The adaptive immune system mounts faster, larger and more effective responses to repeated exposure to the same antigen.  The immune system remembers every encounter with antigen, and this property of adaptive immunity is therefore called immunologic memory.  The response to the first exposure to antigen, called the primary immune response, is initiated by lymphocytes called naive lymphocytes that are seeing antigen for the first time. Figure 8: Primary and secondary immune responses. Subsequent encounters with the same antigen lead to responses called secondary immune responses that usually are more rapid, larger, and better able to eliminate the antigen than primary responses. 16 Other Features of Adaptive Immunity  When naive or memory lymphocytes are activated by antigens, they undergo proliferation, generating many thousands of cells, all with the same antigen receptors and specificity. This process, called clonal expansion.  Immune responses are specialized, and different responses are designed to defend best against different types of microbes.  All immune responses are self-limited and decline as the infection is eliminated, allowing the system to return to a resting state (homeostasis), prepared to respond to another infection. The immune system normally does not react against the host’s own potentially antigenic substances- so-called self antigens.  This unresponsiveness to self is called immunological tolerance, referring to the ability of the immune system to coexist with (tolerate) potentially antigenic self molecules, cells, and tissues. 17 CELLS OF THE ADAPTIVE IMMUNE SYSTEM Figure 9: Principal cells of the adaptive immune system. 18 Lymphocytes  B lymphocytes recognize soluble or microbial surface antigens and differentiate into antibodysecreting cells called plasma cells.  Both helper T cells and cytotoxic T lymphocytes recognize peptides derived from intracellular microbial proteins displayed on the cell surface  Helper T cells recognize these peptides displayed on the surface of macrophages or other antigen presenting cells, and secrete cytokines that stimulate different mechanisms of immunity and inflammation.  Cytotoxic T lymphocytes recognize peptides displayed by any type of infected cell type (or tumor cell), and kill these cells.  Regulatory T cells limit the activation of other lymphocytes, especially of T cells, and prevent autoimmunity. Figure 10: Classes of lymphocytes. 19 Maturation and Tissue Distribution of Lymphocytes  Lymphocytes develop from precursors in the generative lymphoid organs (bone marrow and thymus). B lymphocytes mature in the bone marrow, and T lymphocytes mature in an organ called the thymus.  Mature lymphocytes enter the peripheral lymphoid organs, where they respond to foreign antigens and recirculate in the blood and lymph. Figure 11: Maturation and tissue distribution of lymphocytes. 20 Stages in the Life History of Lymphocytes  Naive lymphocytes recognize foreign antigens to initiate adaptive immune responses.  Effector cells, which develop from naive cells, function to eliminate antigens. The effector cells of the B lymphocyte lineage are antibody-secreting plasma cells. The effector cells of the T lymphocyte lineage produce cytokines. Other progeny of the antigen-stimulated lymphocytes differentiate into long-lived memory cells. Figure 12-A: Stages in the life history of lymphocytes 21  The important characteristics of naive, effector, and memory cells in the B and T lymphocyte lineages are summarized. Figure 12-B: Stages in the life history of lymphocytes 22  Memory cells can survive for long periods in the absence of antigen.  The frequency of memory cells increases with age, presumably because of exposure to environmental microbes. In fact, memory cells make up less than 5% of peripheral blood T cells in a newborn but 50% or more in an adult.  As individuals age, the gradual accumulation of memory cells compensates for the reduced output of new, naive T cells from the thymus,. Memory cells are functionally inactive; they do not perform effector functions unless stimulated by antigen.  When memory cells encounter the same antigen that induced their development, the cells rapidly respond to initiate secondary immune responses. Figure 13: Change in proportions of naive and memory T cells with age. The proportions of naive and memory T cells are based on data from multiple healthy individuals. The estimate of thymic output is an approximation. 23 Antigen-Presenting Cells The common portals of entry for microbes—the skin and gastrointestinal, respiratory, and genitourinary tracts—contain specialized cells located in the epithelium that capture antigens, transport them to peripheral lymphoid tissues, and display (present) them to lymphocytes. This function of antigen capture and presentation is best understood for dendritic cells, the most specialized antigen-presenting cells (APCs) in the immune system.  Dendritic cells capture protein antigens of microbes that cross epithelial barriers and transport these antigens to regional lymph nodes, where they display fragments of the proteins for recognition by T lymphocytes. If a microbe has invaded through the epithelium, it may be phagocytosed and presented by tissue macrophages. Microbes or their antigens that enter lymphoid organs may be captured by dendritic cells or macrophages that reside in these organs and presented to lymphocytes. 24 TISSUES OF THE IMMUNE SYSTEM  The tissues of the immune system consist of the generative lymphoid organs, in which T and B lymphocytes mature and become competent to respond to antigens, and the peripheral lymphoid organs, in which adaptive immune responses to microbes are initiated.  Most of the lymphocytes in a healthy human are found in lymphoid organs and other tissues.  The generative lymphoid organs are bone marrow and thymus. Figure 14: Distribution of lymphocytes in lymphoid organs and other tissues. 25 Peripheral (Secondary) Lymphoid Organs and Tissues The peripheral lymphoid organs and tissues, which consist of the lymph nodes, the spleen, and the mucosal and cutaneous immune systems, are organized in a way that promotes the development of adaptive immune responses.  The anatomic organization of peripheral lymphoid organs enables APCs to concentrate antigens in these organs and lymphocytes to locate and respond to the antigens.  The major peripheral lymphoid organs share many characteristics but also have some unique features. 26 Lymph Nodes Lymph nodes are encapsulated nodular aggregates of lymphoid tissues located along lymphatic channels throughout the body. Fluid constantly leaks out of small blood vessels in all epithelia and connective tissues and most parenchymal organs. This fluid, called lymph, is drained by lymphatic vessels from the tissues to the lymph nodes and eventually back into the blood circulation. Therefore the lymph contains a mixture of substances absorbed from epithelia and tissues. Figure 15-A: Morphology of lymph nodes. Schematic diagram shows the structural organization of a lymph node. 27 Lymph Nodes As the lymph passes through lymph nodes, APCs in the nodes are able to sample the antigens of microbes that may enter through epithelia into tissues. In addition, dendritic cells pick up antigens of microbes from epithelia and other tissues and transport these antigens to the lymph nodes. The net result of these processes of antigen capture and transport is that the antigens of microbes entering through epithelia or colonizing tissues become concentrated in draining lymph nodes. Figure 15-B: Morphology of lymph nodes. Light micrograph shows a cross section of a lymph node with numerous follicles in the cortex, some of which contain lightly stained central areas (germinal centers). 28 Spleen The spleen is a highly vascularized abdominal organ that serves the same role in immune responses to blood-borne antigens as that of lymph nodes in responses to lymphborne antigens. Blood entering the spleen flows through a network of channels (sinusoids). Blood-borne antigens are captured and concentrated by dendritic cells and macrophages in the spleen. The spleen contains abundant phagocytes that line the sinusoids, which ingest and destroy microbes in the blood.  These macrophages also ingest and destroy old red blood cells. Figure 16-A: Morphology of the spleen. Schematic diagram shows a splenic arteriole surrounded by the periarteriolar lymphoid sheath (PALS) and attached follicles. The PALS and lymphoid follicles together constitute the white pulp. The marginal zone with its sinus is the indistinct boundary between the white pulp and the red pulp. 29 Spleen Figure 16-B: Morphology of the spleen. Light micrograph of a section of spleen shows an arteriole with the PALS and a follicle with a prominent germinal center. These are surrounded by the red pulp, which is rich in vascular sinusoids. 30 The Cutaneous Immune System and Mucosal Immune System  The cutaneous immune system and mucosal immune system are specialized collections of lymphoid tissues and APCs located in and under the epithelia of the skin and the gastrointestinal and respiratory tracts, respectively.  Although most of the immune cells in these tissues are diffusely scattered beneath the epithelial barriers, there are discrete collections of lymphocytes and APCs organized in a similar way as in lymph nodes.  For example, tonsils in the pharynx and Peyer patches in the intestine are two anatomically defined mucosal lymphoid tissues. 31 The Mucosal Immune System Schematic diagram of the mucosal immune system uses the small bowel as an example. Many commensal bacteria are present in the lumen. The mucus-secreting epithelium provides an innate barrier to microbial invasion. Specialized epithelial cells, such as M cells, promote the transport of antigens from the lumen into underlying tissues. Cells in the lamina propria, including dendritic cells, T lymphocytes, and macrophages, provide innate and adaptive immune defense against invading microbes; some of these cells are organized into specialized structures, such as Peyer patches in the small intestine. Immunoglobulin A (IgA) is a type of antibody abundantly produced in mucosal tissues that is transported into the lumen, where it binds and neutralizes microbes. Figure 17: Mucosal immune system. 32 The Cutaneous Immune System  The major components of the cutaneous immune system shown in this schematic diagram include keratinocytes, Langerhans cells, and intraepithelial lymphocytes, all located in the epidermis, and T lymphocytes, dendritic cells, and macrophages, located in the dermis Figure 18: Cutaneous immune system. 33  Within the peripheral lymphoid organs, T lymphocytes and B lymphocytes are segregated into different anatomic compartments.  In lymph nodes, the B cells are concentrated in discrete structures, called follicles, located around the periphery, or cortex, of each node.  If the B cells in a follicle have recently responded to a protein antigen and received signals from helper T cells, this follicle may contain a central lightly staining region called a germinal center. Figure 19: Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs. 34 The T lymphocytes are concentrated outside but adjacent to the follicles, in the paracortex. The follicles contain the follicular dendritic cells (FDCs) that are involved in the activation of B cells, and the paracortex contains dendritic cells that present antigens to T lymphocytes. In the spleen, T lymphocytes are concentrated in periarteriolar lymphoid sheaths surrounding small arterioles, and B cells reside in the follicles. UPPPP Figure 19: Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs. 35  Schematic diagram illustrates the path by which naive T and B lymphocytes migrate to different areas of a lymph node.  Naive B and T lymphocytes enter through a high endothelial venule (HEV), shown in cross section, and are drawn to different areas of the node by chemokines that are produced in these areas and bind selectively to either cell type. B lymphocytes are attracted to and retained in the follicles because of the action of a class of cytokines called chemokines (chemoattractant cytokines). Also shown is the migration of dendritic cells, which pick up antigens from epithelia, enter through afferent lymphatic vessels, and migrate to the T cell–rich areas of the node. Figure 19-A: Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs. 36  In this histologic section of a lymph node, the B lymphocytes, located in the follicles, are stained green, and the T cells, in the parafollicular cortex, are stained red using immunofluorescence. In this technique, a section of the tissue is stained with antibodies specific for T or B cells coupled to fluorochromes that emit different colors when excited at the appropriate wavelengths. Figure 19-B: Segregation of T and B lymphocytes in different regions of peripheral lymphoid organs. 37 Lymphocyte Recirculation and Migration into Tissues Naive lymphocytes constantly recirculate between the blood and peripheral lymphoid organs, where they may be activated by antigens to become effector cells, and the effector lymphocytes migrate from lymphoid tissues to sites of infection, where microbes are eliminated. Naive T lymphocytes migrate from the blood through high endothelial venules (HEVs) into the T cell zones of lymph nodes, where the cells are activated by antigens. Activated T cells exit the nodes, enter the bloodstream, and migrate preferentially to peripheral tissues at sites of infection and inflammation. Figure 20: Migration of T lymphocytes. 38 SUMMARY The physiologic function of the immune system is to protect individuals against infections and cancers. Different populations of lymphocytes serve distinct functions and may be distinguished by the surface expression of particular membrane molecules.  Innate immunity is the early line of defense, mediated by cells and molecules that are always present and ready to eliminate infectious microbes. B lymphocytes are the only cells that produce antibodies. B lymphocytes express membrane antibodies that recognize antigens, and the progeny of activated B cells, called plasma cells, secrete the antibodies that neutralize and eliminate the antigen.  Adaptive immunity is mediated by lymphocytes stimulated by microbial antigens, which leads to the proliferation and differentiation of the lymphocytes and generation of effector cells, and responds more effectively against each successive exposure to a microbe. Lymphocytes are the cells of adaptive immunity and are the only cells with clonally distributed receptors specific for different antigens. Adaptive immunity consists of humoral immunity, in which antibodies neutralize and eradicate extracellular microbes and toxins, and cell-mediated immunity, in which T lymphocytes eradicate intracellular microbes. Adaptive immune responses consist of sequential phases: antigen recognition by lymphocytes, activation of the lymphocytes to proliferate and to differentiate into effector and memory cells, elimination of the microbes, decline of the immune response, and long-lived memory. T lymphocytes recognize peptide fragments of protein antigens displayed on other cells. Helper T lymphocytes produce cytokines that activate phagocytes to destroy ingested microbes, recruit leukocytes, and activate B lymphocytes to produce antibodies. Cytotoxic T lymphocytes (CTLs) kill infected cells harboring microbes in the cytoplasm. Antigen-presenting cells (APCs) capture antigens of microbes that enter through epithelia, concentrate these antigens in lymphoid organs, and display the antigens for recognition by T cells. Lymphocytes and APCs are organized in peripheral (secondary) lymphoid organs, where immune responses are initiated and develop. Naive lymphocytes circulate through peripheral lymphoid organs, searching for foreign antigens. Effector T lymphocytes migrate to peripheral sites of infection, where they function to eliminate infectious microbes. Plasma cells remain in lymphoid organs and the bone marrow, where they secrete antibodies that enter the circulation and find and eliminate microbes. 39 Thank you for your attention… Next Lecture: Innate Immunity 40