1. 2025_Concept Related to the Immun System.pdf
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Concepts Related to the Immune System Assoc. Prof. Sevim MESE Istanbul University, Istanbul Medical Faculty Division of Virology and Fundemental Immunology Learning Objectives 1. The origins of immunology and important developments that lead to a better understan...
Concepts Related to the Immune System Assoc. Prof. Sevim MESE Istanbul University, Istanbul Medical Faculty Division of Virology and Fundemental Immunology Learning Objectives 1. The origins of immunology and important developments that lead to a better understanding of immunology 2. Assumptions and definition related to immunology 3. Categorization of features unique to the immune system. 4. Anatomical structure and cells in the immun system A Historical Perspective of Immunology “Immunitas” (Latin) legal exemption It states that Roman senators are exempt from tax Immunity Exemption provided by a past infection to the individual. It has been known since ancient times that individuals who have had some infectious diseases do not get this disease for the second time. A Historical Perspective of Immunology Variolation In China, around 1000-1500 AD, dried, pulverized scab from smallpox lesions was blown into the nose to immunize the population. At the same time, liquid taken from smallpox lesions was applied to the scratched skin of healthy people in India and midle asia. A Historical Perspective of Immunology Vaccination In 1798, Edward Jenner published the results of his studies based on the vaccination of cowpox virus to stimulate the immune system against smallpox in humans. Edward Jenner (1749 -1823) The first modern concept of immunology A Historical Perspective of Immunology In 1885, Pasteur serially passaged different types of rabies virus, using virulence-attenuated strains to protect against rabies. Koch and other great 19th century microbiologists discovered that vaccines can also be produced from attenuated micro-organisms. Louis Pasteur (1822- 1895) World History Archive Alamy Stock Photo Immunology Is about More than Just Vaccines and Infectious Disease Autoimmune reactions in inflammatory diseases, such as rheumatic conditions, multiple sclerosis and diabetes. Allergy Tumor Tranpslantation Immunodeficiency Diseases HIV- Acquired immune deficiency syndrome (AIDS) Immune Sytem Involves Both Humoral and Cellular Components In 1883, Elie Metchnikoff, Nobel Prize winner, demonstrated that some cells contribute to the immune state of an animal. He observed that certain white blood cells, which he termed phagocytes, ingested microorganisms and other foreign material. Metchnikoff hypothesized that cells, rather than serum components, were the major effectors of Drawing by Elie Metchnikoff of immunity. phagocytic cells surrounding a foreign particle. Immun System Involves Both Humoral and Cellular Components Emil von Behring and Kitasato demonstrated that serum from animals previously immunized with diphtheria could transfer the immune state to unimmunized animals. Behring won the first medicine Nobel Prize in 1901 for the development of serum therapies (contain antinodies) against diphtheria. Immunity Involves Both Humoral and Cellular Components Humoral immunity involves combating pathogens via antibodies, which are produced by B cells and can be found in bodily fluids. Antibodies can be transferred between individuals to provide protection. Cell-mediated immunity involves the work of pathogen-specific T cells, which can act directly to eradicate the infectious agent as well as aiding other cells in their work. What is the concept of antigen? A molecule that has the ability to bind with immune response products is called an antigen. Immunogens, when given to the organism, it has the feature of creating a humoral and/or cellular immune response. While all immunogens have antigenic properties, not all antigens show immunogenic properties. The antigen may originate from within the body "self-protein" or from the external environment "non-self". What is the concept antibodies? The soluble active molecules in the immunoglobulin fraction of serum are commonly referred to as antibodies. Antibodies are are specific for the infectious pathogen. The presence of antibodies indicates the immunization The Immunity Divides Innate and Adaptive Immunity. The immune system has two fundamental lines of defense against pathogens: Innate immunity Adaptive immunity. Both work together to protect the body from infection. Innate Immunity Innate immunity is a fundamental component of the immune system, serving as the body's first line of defense against pathogens. Innate immunity acts quickly, typically within minutes to hours after exposure to pathogens. It does not target specific pathogens but instead employs general mechanisms to combat a wide range of threats. It does not develop memory immunity of past infections. It does not provide long-term immunity. The Components of Innate Immunity Physical Barriers: The innate immune system includes physical barriers such as skin and mucous membranes, which prevent pathogens from entering the body. Chemical barriers, including enzymes and antimicrobial peptides, also play a crucial role in neutralizing potential threats The Components of Innate Immunity Cytokines and Complement System: Cytokines are signaling molecules that mediate and regulate immunity, inflammation, and hematopoiesis. The complement system consists of proteins that enhance the ability of antibodies and phagocytic cells to clear pathogens from an organism. The Components of Innate Immunity Cellular Components: Various types of white blood cells (leukocytes) are integral to innate immunity. These include: Neutrophils: Rapid responders that engulf and destroy pathogens. Macrophages: Larger phagocytic cells that consume pathogens and debris. Natural Killer (NK) Cells: Specialized cells that target and destroy infected or cancerous cells. Mast Cells: Involved in inflammatory responses, particularly in allergies Adaptive Immunity Adaptive immunity, also known as acquired immunity, is a specialized and highly specific immune response that vertebrates have evolved to combat pathogens. One of the hallmark features of adaptive immunity is its ability to create immunological memory. This enables a faster and more robust response upon subsequent exposures, often leading to long-lasting protection The Components of Adaptive Immunity The adaptive immune system primarily involves two types of lymphocytes: B Cells: These cells are responsible for humoral immunity. Upon activation, they differentiate into plasma cells that produce antibodies. Antibodies bind to specific antigens, neutralizing pathogens and marking them for destruction by other immune cells. T Cells: These cells are involved in cell-mediated immunity. They can be further categorized into: Helper T Cells: Assist in activating B cells and other immune cells. Cytotoxic T Cells: Directly kill infected or cancerous cells by recognizing specific antigens presented on their surface Innate Immunity Adaptive Immunity Key Elements of Innate and Acquired Immune Responses Immun System Adaptive Immunity Innate Immunity Macrophages Cellular Neutrophils Monocytes Lymphocytes NK cells Dendritic cells Mast cells NKT cells Anti mikrobiyal Compleman Humoral Antibodies peptidler Cytokines How Are Foreign Substances Recognized by the Immune System? In fact, the major feature that renders our immune system so effective is its ability to distinguish our body’s own cells (the self) from that which it considers foreign (termed the nonself). If this ability is lost (e.g., when “self” tissue is seen as foreign), then our immune system launches an aggressive response against our own tissues. This is what happens during autoimmunity, where destruction of the self leads to clinical disease. How Are Foreign Substances Recognized by the Immune System? Antigen-specific immunity relies on surface molecules, called B- and T-cell receptors, unique to each individual lymphocyte. These receptors bind to a specific antigen of pathogens. To explain this high degree of specificity the selective theory was proposed. The selective theory of antibody production, also known as clonal selection theory, explains how the immune system generates a diverse repertoire of antibodies capable of recognizing a vast array of antigens. Generation of diversity and clonal selection in T and B lymphocytes Clonal selection and expansion are the process by which individual T and B lymphocytes are engaged by antigen and cloned to create a population of antigen-reactive cells with identical antigen specificity. Self and nonself discrimination Innate Immunity Adaptive Immunity Innate immune recognition is Adaptative immunity somatically mainly based on a series of generates large repertories of germline encoded receptors that receptors which collectively have been selected by evolution recognize any nonself antigen. to recognize nonself molecules These receptors are randomly present in microorganisms. generated, and the adaptive PRR PAMP immune system has to learn MBL Mannoz how to eliminate cells with high avidity receptors for self molecules. Immunization Active Passive Natural: Natural: It occurs when an immune Newborns receive natural passive immunity from maternal immunoglobulin that crosses response is stimulated because of the placenta or is present in the mother’s challenge with an immunogen, such as milk. exposure to an infectious agent. Acquired: Acquired (Vaccination): Immune serum globulin (Human, Equine) To ensure the formation of an immune Specific immunoglobulins response by exposure to non-pathogenic Monoclonal antibodies forms of microorganisms. Adoptive transfer of cells Differences between active and passive Immunization Whereas the aim of passive immunization is transient protection or alleviation of an existing condition, the goal of active immunization is to trigger the adaptive immune response in a way that will elicit protective immunity and immunologic memory. Passive immunization Active Immunization Fast protection (minutes or hours) Late protection (days, weeks) Short time Long time with immunoglobulin with exposure of antigen Conditions requiring passif immunization: To prevent disease after a known exposure (e.g., needlestick injury with blood that is contaminated with HBV) Toxin or venom exposure with immediate threat to life. To protect immunodeficient individuals, especially B-cell defects Exposure to pathogens that can cause death faster than an effective immune response can develop To ameliorate the symptoms of an ongoing disease, Anatomy of the Immune System Primary lymphoid organs, such as the bone marrow and thymus, are the major sites of lymphopoiesis (lymphoid hematopoiesis) and the locales where lymphocytes differentiate. Secondary lymphoid organs, such as the spleen and lymph nodes, are sites where antigen-driven proliferation and maturation of lymphocytes occur. CELLS OF THE IMMUNE SYSTEM Leukocytes is the term given to This population of cells can be white blood cells that play a broken into two main groups, functional role in either innate referred to as myeloid or or adaptive responses. lymphoid cells, depending on which developmental path was taken by the stem cells in the bone marrow during development Hematopoietic Stem Cell Pluripotent stem cell All the cellular elements of blood, Bone marrow including the lymphocytes of the immune system, arise from hematopoietic stem cells in the bone marrow. Blood Myeloid Cells Myeloid cells are considered as the first line of defense and thus constitute the major cell types involved in innate immunity. Myeloid cells include highly phagocytic, motile neutrophils, monocytes, and macrophages, as well as dendritic cells (DCs), which provide relatively immediate protection against most pathogens. The other myeloid cells, including eosinophils, basophils, and their tissue counterparts, mast cells, are involved in the defense against parasites and the genesis of allergic reactions. Lymphoid cells Lymphoid cell types include those that mediate specific immunity; simply put, they are the cell types that have defined receptors to physically interact with and recognize foreign materials. These types of cells fall into the acquired category and include the B lymphocytes and the T lymphocytes that were mentioned previously. In addition, a group of cells called natural killer T (NKT) cells exist, which is a specialized subset of lymphocytes. A functionally related set of lymphoid cells that are also considered lymphoid in origin are the natural killer (NK) cells. Although similar in name, but NK cells are distinct from NKT cells. Neutrophils Neutrophils are the most abundant of the myeloid populations. Neutrophils constitute the majority (50% to 70%) of circulating leukocytes They are stored in the bone marrow and are readily released during infection. Neutrophils are highly adherent, motile, phagocytic leukocytes that are typically the first cells recruited to acute inflammatory sites. Neutrophils Neutrophils engulf (phagocytose) the pathogens, after which they use specialized destructive “granular” enzymes and toxic molecules to kill the ingested organism. Many of these enzymes regulate reactive oxygen species, such as superoxide and nitric oxide, to mediate killing. This respiratory burst, the phase of elevated oxygen consumption shortly after the cellular ingestion of organisms, allows the neutrophil to limit expansion and growth of pathogen. Eosinophil constitutes 1-3 % of circulating leukocytes. Its granules are larger and more. While the neutrophil is proficient at engulfing smaller organisms, the eosinophil is successful against large multicellular parasites They primarily defend against extracellular targets. Activated by IL5 released by Th2 Basophils Basophils, and their tissue counterparts, mast cells, produce cytokines, which help defend against parasites. However, these cells are best known clinically for their role in allergic inflammation. Basophils and mast cells display surface membrane receptors for a specific class of antibodies (IgE); they release a host of molecules, such as histamine and vascular mediators that affect blood flow, when cell-bound antibodies recognize allergens. Macrophages These cells are highly adherent, motile, and phagocytic; they regulate other cells of the immune system, such as T lymphocytes. Macrophages can reside for long periods in tissues. Macrophages are involved in phagocytosis and the intracellular killing of microorganisms. Macrophages produces cytokines (TNFα, IL2, ) to protect against bacteria and viruses. Antigen presenting T lymphocytes proliferation and differentiation (IL12) Opsonization (IgG and C3b) Tissue-Specific Macrophages In a similar manner to the macrophage, DCs also provide a critical link between innate and adaptive immunity by interacting with T cells. DCs recognize foreign agents through a series of unique receptors that recognize general motifs on foreign organisms. Different cellular subsets exist (myeloid DCs and plasmacytoid DCs), enabling this group of cells to both prime and dictate how subsequent responses will develop. Plasmacytoid DCs secrete Type I interferons and chemokines Follicular dendritic cells (FDCs) are located in the germinal center of the lymphoid organs. They regulate the activation of B cells. Antigen Presenting Cells (APCs) Macrophages and DCs are called APCs. After they destroy pathogens, they present chopped pieces to T lymphocytes, thereby mediating a connection with the adaptive immune response. All nucleer cells have the capacity to present peptides from internal proteins using MHC class I molecules; however, APCs also have the ability to present peptides from external sources using MHC class II molecules MHC-I CD4-T cell MHC-II CD-8 T cell ADAPTIVE AVENGERS: THE LYMPHOID CELLS Lymphoid cells provide efficient, specific, and long-lasting immunity against microbes and pathogens and are responsible for acquired immunity. Lymphocytes differentiate into separate lineages. The B lymphocytes secrete antibodies. The T lymphocytes operate in a supervising role to mediate cellular and humoral immunity. B and T lymphocytes produce and express specific receptors for antigens. B Lymphocytes (B Cell) The B lymphocyte (B cell) derived its letter designation the bursa of Fabricius in birds; the name turned out to be apt, as bone marrow is its major site of maturation in mammals. The B-cell antigen receptor is the surface immunoglobulin, an integral membrane protein with unique regions to bind specific antigenic. There can be thousands of identical copies of the receptor present on the surface of a single B lymphocyte. B lymphocytes also improve their ability to bind antigen through a process known as somatic hypermutation and can generate antibodies of several different functional classes through a process known as class switching. The immunoglobulin B-cell receptor; BCR Plasma cells B-cell activation occurs when the receptor encounters the antigen. This leads to a morphological change in B cells, which now multiply to become secretory factories to make and release soluble Igs, or antibodies. B cells that actively secrete antibodies are called plasma cells. Plasma cells lose expression of surface immunoglobulin and become highly specialized for secretion of antibody. Plasma cells do not divide and, although some travel to the bone marrow and live for years, others die within 1 or 2 weeks. T lymphocyte (T Cell) The T lymphocyte matures as it passes through the thymus. Like its B-cell counter part, it also has a surface receptor, the T-cell receptor, called the TCR. The TCR is structurally similar to the antibody; it too recognizes specific pieces of the antigen. Unlike the antibody, the TCR is present only on its surface and is not secreted when T cells are activated. T lymphocyte (T Cell) The process of T cell activation is quite complex and requires a group of cells to show pieces of the antigen physically to the T cell. These assisting cells are the APCs described here. The surface molecules on the presenting cell which show antigen to the T cells are also involved as tags for “self” identity. These molecules are called major histocompatibility complex (MHC) molecules. T lymphocyte (T Cell) T cells displaying CD4 generally function as helper (T ) cells and recognize peptide antigen associated with MHC class II, whereas those displaying CD8 generally function as cytotoxic (T ) cells and recognize peptide antigen associated with MHC class I. T lymphocyte (T Cell) The T lymphocytes are the true ring leaders of the adaptive response. Different subsets control different functions. Th2 helps that B cells produce antibodies. Others help the myeloid cells become more efficient at destroying pathogens (Th1). Some preferentially function to kill viral infected cells or tumor cell targets (Cytotoxic T cell) Finally, some function as regulators, conferring immune tolerance or establishing limits on responsiveness (Treg). Nature Rev Immunol 2004;4:841 Naturell Killer (NK Cell) A third lineage of lymphoid cells, called natural killer cells, lack antigen specific receptors and are part of the innate immune system. These cells circulate in the blood as large lymphocytes with distinctive cytotoxic granules (perforine and granzyme). They are able to recognize and kill some abnormal cells, for example some tumor cells and virus-infected cells, and are thought to be important in the innate immune defense against intracellular pathogens. NK cell secretes IFNɤ that inducing macrophage activation and phagosytosis Naturell Killer (NK Cell) Efficient cell killers, they use two different strategies to attack a variety of abnormal cells. The first strategy is to attack cells that lack MHC class I molecules: Infection by certain viruses or mutations occurring in tumor cells often cause those cells to down regulate MHC class I. NK cells encounter cells that have lost their MHC class I, these inhibiting receptors are no longer engaged and NK cells can release their cytotoxic granules, killing the target cell. Second, NK cells express receptors (called Fc receptors or FcRs; CD16) for some antibodies: By linking these receptors to antibodies, NK cells can arm themselves with antibodies specific for pathogenic proteins. Than, the NK cell releases its granules and induces cell death, a process known as antibody- dependent cell cytotoxicity (ADCC). NK Cell Non-activated NK cell Macrophage IL4, IL12, IL15 Antigen Activated NK cell presenting CD+4 T IL21 helper Differentiation of NK cell Apoptosis of NK cell (CD16 exhibition) Cytotoxic effect Naturel Killer T Cell (NKT) Another type of cell in the lymphoid lineage, the NKT cell, shares features with both adaptive and innate immune cells. Like T cells, NKT cells have TCRs and some express CD4. Unlike most T cells, however, the TCRs of NKT cells are not diverse. Rather than recognize protein peptides, they recognize specific lipids and glycolipids. NKT cells also have receptors classically associated with innate immune cells. Activated NKT cells release cytotoxic granules that kill target cells, but also release large quantities of cytokines that can both enhance and suppress the immune response. They appear to be involved in human asthma, but also may inhibit the development of autoimmunity and cancer. Understanding the exact role of NKT cells in immunity is one research priority. Innate Lymphoid Cells (ILCs) Investigators recognize a group of cells that are derived from common lymphoid progenitors, but do not express antigen-specific receptors: innate lymphoid cells (ILCs). Currently they are subdivided into three groups (ILC1, ILC2, and ILC3), distinguished by the cytokines they secrete, which mirror those produced by distinct helper T-cell subsets. Many provide a first line of defense against pathogens in the skin and at mucosal tissues ILC helper subsets are the focus of active investigation. CLUSTER OF DIFFERENTIATION (CD) Surface proteins expressed by cells of the immune system (as well as some other cells) are often referred to by the CD nomenclature. This nomenclature was established in 1982 by an international group of investigators who recognized that many of the new antibodies produced by laboratories all over the world were binding to the same proteins, and hence some proteins were given multiple names by different labs. The official listing of determinants has identified more than 400 individual and unique markers. Common CD markers used to distinguish functional lymphocyte subpopulations LYMPHOCYTES Abbreviations CLP: Common Lymphoid Progenitor; ILC: Innate Lymphoid Cell; NKT: Naturel Killer T cell; T H1, T 2, T 17: Helper T type 1, 2, and 17 cells; TREG: Regulatory T cell
