Lectures 1_2_Cells and Tissues of the Immune System_8262024.pptx

Cells and Tissues of the Immune System Carlos A. Barrero M.D. Assistant Professor School of Pharmacy-Temple University  Learning objectives i. Comprehend, get familiar with, and utilize the languages of immunology and biotechnology....

Cells and Tissues of the Immune System Carlos A. Barrero M.D. Assistant Professor School of Pharmacy-Temple University  Learning objectives i. Comprehend, get familiar with, and utilize the languages of immunology and biotechnology. ii. Elaborate on how the adaptive and acquired immune systems collaborate to safeguard the body against pathogenic organisms. iii. Clarify the molecular mechanisms underlying humoral and cell-mediated immunity. Apply this understanding to grasp the molecular foundation of passive and active immunization, as well as immune-mediated diseases. iv. Describe the molecular basis of inflammation and potential therapeutic approaches. Apply this knowledge to comprehend the molecular origins of chronic inflammatory diseases. v. Apply your understanding of immunology and antibodies to grasp the concepts of immunotherapies and the utilization of therapeutic antibodies. vi. Engage in a discussion about the molecular principles behind immunoassays, utilizing specific antibodies to identify, characterize, and quantify biomolecules of interest.  How can I benefit from the course? Get to know the outcomes of learning Immunology and biotechnology. Be familiar with how those subjects are found in pharmacy practice and their applications in the pharmaceutical industry. This course will enhance my capabilities and empower my skills, along with other courses within the PharmD program. Will provide foundations for alternative jobs in the pharmaceutical industries.  Lecture goals Capable of understanding:  Innate and Adaptive Immunity  Cardinal Features of Adaptive Immune Responses  Humoral and Cell-Mediated Immunity  Initiation and Development of Adaptive Immune Responses  Humoral Immunity  Cell-Mediated Immunity  What is Immunology?  The term immunity is derived from the Latin word immunitas, which referred to the protection from legal prosecution offered to Roman senators during their tenures in office.  Immunology is the study of the immune responses.  Immunity means protection from disease and, more specifically, infectious disease.  The tissues, cells and molecules responsible for immunity constitute the immune system, and their collective and coordinated response to the introduction of foreign substances is called the immune response.  The Immune System  The function of the immune system is defense against infectious microbes. However, even noninfectious foreign substances can elicit immune responses.  The immune response is a reaction to components of microbes as well as to macromolecule, such as proteins and polysaccharides, and small chemicals that are recognized as foreign, regardless of the physiologic or pathologic consequence of such a reaction. Immune Response Bee sting reaction Bee sting venom contains proteins that affect skin cells and the immune system, causing pain and swelling around the sting area. In people with a bee sting allergy, bee venom can trigger a more-serious immune system reaction  Immune Response Allergies to sulfonamides Patients experiencing a sulfonamide antimicrobial allergy may experience a variety of clinical manifestations. These may include hypersensitivity reactions from each of the Gel and Coombs classifications. Type 1 immunoglubulin E (IgE)-mediated reactions result in manifestations such as anaphylaxis, angioedema, and urticaria. The most common manifestation of a true sulfonamide antimicrobial reaction is a maculopapular eruption. This rash, which may occur in conjunction with a fever, typically presents 1–2 weeks following the introduction of SMX therapy and often dissipates over a similar time course, within 1–2 weeks of withdrawal of the sulfonamide antimicrobial The Color Atlas of Family Medicine, Second Edition.  What is the Immune System?  The immune system is composed of the innate immunity which occurs in the early phase of a reaction and the adaptive immunity which occurs in the later phase.  Innate Immunity  Innate immunity (also called natural or native immunity) provides the early line of defense against microbes.  It consists of cellular and biochemical defense mechanisms that are in place even before infection and are poised to respond rapidly to infections.  These mechanisms react to microbes and to the products of injured cells, and they respond in essentially the same way to repeated infections  Components of the Innate Immunity 1. Physical and chemical barriers, such as epithelia and antimicrobial chemicals produced at epithelial surfaces. 2. Phagocytic cells (neutrophils, macrophages), dendritic cells, and natural killer (NK) cells. 3. Blood proteins, including members of the complement system and other mediators of inflammation. 4. Proteins called cytokines that regulate and coordinate many of the activities of the cells of innate immunity.  Blood proteins Complement  Bacterial surfaces can activate the complement system, inducing a cascade of proteolytic reactions that coat the microbes with fragments of specific proteins of the complement system.  Microbes coated in this way are recognized by specific complement receptors on macrophages and neutrophils, taken up by phagocytosis, and destroyed. Cytokines  Cytokines are responsible for many of the cellular responses of innate and adaptive immunity and thus function as the “messenger molecules” of the immune system.  Cytokines secreted by helper T lymphocytes stimulate the proliferation and differentiation of the T cells themselves and activate other cells, including B cells, macrophages, and other leukocytes.  Adaptive Immunity  The defining characteristics of adaptive immunity are exquisite specificity for distinct molecules and an ability to “remember” and respond more vigorously to repeated exposures to the same microbe.  The adaptive immune system is able to recognize and react to a large number of microbial and nonmicrobial substances.  It is also sometimes called acquired immunity, to emphasize that potent protective responses are “acquired” by experience.  Components of the Adaptive Immunity  The main components of adaptive immunity are cells called lymphocytes and their secreted products, such as antibodies.  Foreign substances that induce specific immune responses or are recognized by lymphocytes or antibodies are called antigens. Innate vs Adaptive immunity recognitions mechanisms  Immune System Cells  The common myeloid progenitor (CMP) is the precursor of the macrophages, granulocytes (the collective term for the white blood cells called neutrophils, eosinophils, and basophils), mast cells, and dendritic cells of the innate immune system. Macrophages, granulocytes, and dendritic cells make up the three types of phagocytes in the immune system.  Phagocytes  Phagocytes, including neutrophils and macrophages, are cells whose primary function is to identify, ingest, and destroy microbes  The functional responses of phagocytes in host defense consist of sequential steps: recruitment of the cells to the sites of infection, recognition of and activation by microbes, ingestion of the microbes by the process of phagocytosis, and destruction of ingested microbes.  In addition, through direct contact and by secreting proteins, phagocytes communicate with other cells in ways that promote or regulate immune responses. Neutrophils  Innate Immune Response NETosis Tobias A. Fuchs, et al., JCB, Vol 176, Number 2 2007  Macrophage  Resides in almost all tissues  Many tissue-resident macrophages arise during embryonic development, but some macrophage that arise later from the bone marrow, which are the mature form of monocytes, which circulate in the blood and continually migrate into tissues, where they differentiate.  Mononuclear Phagocytes The mononuclear phagocyte system includes circulating bone marrow–derived cells called monocytes, many of which become macrophages when they migrate into tissues, and tissue-resident macrophages, which are initially derived from yolk sac or hematopoietic precursors during fetal life.  Subsets of Monocytes and Macrophage  Classical or inflammatory monocytes  Nonclassical monocytes (repair)  Classical macrophage activation M1: M1 macrophages become efficient at killing microbes  Alternative macrophage activation M2: M2 macrophages promote tissue remodeling and repair  Macrophage Role  Engulf and kill invading microorganisms. This phagocytic function provides a first defense in innate immunity.  Macrophages also dispose of pathogens and infected cells targeted by an adaptive immune response.  They help induce inflammation, which, as we shall see, is a prerequisite to a successful immune response, and they produce many inflammatory mediators that activate other immune-system cells and recruit them into an immune response.  Innate Immune Response Clearance of Intra-cellular Pathogens Electron micrograph of an alveolar macrophage isolated by broncholavage from a tuberculosis patient in Malawi. The cell is heavily loaded with bacteria that reside within vacuoles. The vacuoles vary both in size and in the number of bacteria. This degree of heterogeneity in vacuole morphology is not observed in infections in culture. Russell DG, et al., JCB, 2002  Role of the Phagocytic cells in the Immune System Macrophages have a defensive function against pathogens such as microbes and play an important role in the homeostatic maintenance of the body through the disposal of internal waste materials and tissue repair. However, as macrophages have the ability to present antigens to T cells and function as effectors for cell-mediated immunity, it is known that they affect the development of infectious diseases, cancers, and chronic inflammatory diseases such as arteriosclerosis. Neutrophils vs. Macrophages  Mast Cells, Basophils, Eosinophils  Mast cells, basophils, and eosinophils are three additional cells that play roles in innate and adaptive immune responses.  All three cell types share the common feature of having cytoplasmic granules filled with various inflammatory and antimicrobial mediators.  Another common feature of these cells is their involvement in immune responses that protect against helminths and immune responses that cause allergic diseases Mast Cells Basophils Eosinophils Mast Cells Basophils Eosinophils Dendritic Cells Dendritic Cells (DCs) Dendritic Cells  Summary Immune Cells Role Phagocytes and killing for microorganisms. Macrophage Activation of T cells and initiation of immune response. Phagocytes and killing for microorganisms. Neutrophils Activation of T cells and initiation of adaptive immune Dendritic Cells responses Expulsion of parasites from body through release of Mast Cells granules containing histamine and other active agents Basophils Controlling immune responses to parasites Killing of antibody-coated parasites through release of Eosinophils granule contents  Lymphocytes  Lymphocytes are the cells that specifically recognize and respond to foreign antigens and are therefore the mediators of humoral and cellular immunity.  Classes of Lymphocytes:  B lymphocyte  Helper T lymphocyte  Cytotoxic T lymphocyte  Regulatory T lymphocyte  Natural Killer (NK) Cells  Lymphocytes Classes of Lymphocytes Roles Naturalization of microbe, B Lymphocyte phagocytosis, complement activation Activation of macrophages Inflammation Helper T Lymphocyte Activation of (proliferation and differentiation) of T and B lymphocytes Cytotoxic T Lymphocyte Killing of infected cell Regulatory T Lymphocyte Suppression of immune response Natural Killer (NK) Cells Killing of infected cell  Lymphocytes Naive lymphocytes that have matured in the bone marrow or thymus migrate into secondary (peripheral) lymphoid organs, where they are activated by antigens to proliferate and differentiate into effector and memory cells. The mature T cells that emerge from the thymus are called naive T lymphocytes. B cells undergo most of their development in the bone marrow, but the final steps that generate mature naive B lymphocytes occur in the spleen. Lymphocytes  Lymphocytes Resting Activated Naive lymphocytes are mature T or B cells that have never encountered foreign antigen. (The term naive refers to the idea that these cells are immunologically inexperienced.) Naive lymphocytes are found in the circulation and secondary lymphoid organs. Naive and memory lymphocytes are both called resting lymphocytes because they are not actively dividing or performing effector functions and are in a state of rest, or in the G0 stage of the cell cycle, before antigenic stimulation.  Plasma Cells Many antibody-secreting B cells are morphologically identifiable in stained tissue sections as plasma cells. They have characteristic nuclei placed eccentrically in the cell with the chromatin distributed around the nuclear membrane in a cartwheel pattern; abundant cytoplasm containing dense, rough endoplasmic reticulum that is the site where antibodies (and other secreted and membrane proteins) are synthesized; and distinct perinuclear Golgi complexes, where antibody molecules are post-translationally modified to their final forms and packaged for secretion. Tissues of the Immune System  Tissues of the Immune System  Lymphoid tissues are classified as generative organs, also called primary or central lymphoid organs, where lymphocytes first express antigen receptors and attain phenotypic and functional maturity, and as peripheral organs, also called secondary lymphoid organs, where lymphocyte responses to foreign antigens are initiated and developed.  Bone Marrow  The bone marrow is the site of generation of most mature circulating blood cells, including red cells, granulocytes, and monocytes, and the site of early events in B cell maturation.  The generation of all blood cells, called hematopoiesis  At birth, hematopoiesis takes place mainly in the bones throughout the skeleton, but it becomes restricted increasingly to the marrow of the flat bones so that by puberty, hematopoiesis occurs mostly in the sternum, vertebrae, iliac bones, and ribs.  Red cells, granulocytes, monocytes, dendritic cells, platelets, B and T lymphocytes, and NK cells all originate from a common hematopoietic stem cell (HSC) in the bone marrow Immune system cells with different functions all derive from hematopoietic stem cells Immune cells all originate from a common hematopoietic stem cell (HSC) in the bone marrow. HSCs are pluripotent, meaning that a single HSC can generate all different types of mature blood cells. HSCs are also self-renewing because each time they divide, at least one daughter cell maintains the properties of a stem cell while the other can differentiate along a particular lineage https://stemcells.nih.gov/info/Regenerative_Medicine/2006Chapter2.htm  Bone Marrow  Thymus  The thymus is the site of T cell maturation  Immature T cells are made in the bone marrow and move to the thymus for maturation  Thymus  The thymus is the site of T cell maturation. It is a bilobed organ situated in the anterior mediastinum, which involutes after puberty so that it is not detectable in adults. Each lobe is divided into multiple lobules by fibrous septa, and each lobule consists of an outer cortex and an inner medulla.  Thymic cortical epithelial cells produce IL-7, which is required early in T cell development, and these cells also present self antigens to developing T cells during their maturation.  The thymus has a rich vascular supply and efferent lymphatic vessels that drain into mediastinal lymph nodes.  A different type of epithelial cell found only in the medulla, called medullary thymic epithelial cells (MTECs), plays a special role in presenting self antigens to developing T cells and causing their elimination. This is one mechanism for ensuring that the immune system remains tolerant to self antigens.  The Lymphatic System The Lymphatic System consists of specialized vessels that drain fluid from tissues into and out of lymph nodes and then into the blood, it is essential for tissue fluid homeostasis and immune responses. Lymph Nodes Lymph nodes are encapsulated, vascularized secondary lymphoid organs with anatomic features that favor the initiation of adaptive immune responses to antigens carried from tissues by lymphatics.  Lymph Nodes  Lymph draining from the extracellular spaces of the body carries antigens in phagocytic dendritic cells and phagocytic macrophages via the afferent lymphatics.  Lymph leaves via the efferent lymphatics in the medulla. The medulla consists of strings of macrophages and antibody-secreting plasma cells known as the medullary cords.  Naive lymphocytes enter the node from the bloodstream through specialized postcapillary venules and leave with the lymph through the efferent lymphatic.  Lymph Nodes  When an immune response is under way, some of the follicle known as secondary lymphoid follicles contain central areas of intense B-cell proliferation called germinal centers. Spleen  The spleen is a highly vascularized organ whose major functions are to remove aging and damaged blood cells and particles (such as immune complexes and opsonized microbes) from the circulation and to initiate adaptive immune responses to blood-borne antigens.  Individuals lacking a spleen are highly susceptible to infections with encapsulated bacteria such as pneumococci and meningococci. B cell Zone T cell Zone Immune system cells Distribution Immune system cells counts Immune system cells in Sepsis GM-CSF and inflammation  Selected reading Cells of the Immune System L. Amon, C.H.K. Lehmann, L. Heger, et al.: The ontogenetic path of human dendritic cells. Mol Immunol. 120:122-129 2020 pmid 32114182 Cooper et al., 1966M.D. ∗Cooper, D.A. Raymond, R.D. Peterson, et al.: The functions of the thymus system and the bursa system in the chicken. J Exp Med. 123:75-106 1966 pmid 14474038 J.F. Miller: Immunological function of the thymus. Lancet. 2:748-749 1961 (The discoveries that T and B cell lineages are respectively responsible for cell-mediated and humoral immunity.) S.C. Eisenbarth: Dendritic cell subsets in T cell programming: location dictates function. Nat Rev Immunol. 19:89- 103 2019 pmid 30464294 X. Fan, A.Y. Rudensky: Hallmarks of tissue-resident lymphocytes. Cell. 164:1198-1211 2016 pmid 26967286 Tissues of the Immune System V. Bronte, M.J. Pittet: The spleen in local and systemic regulation of immunity. Immunity. 39:806-818 2013 24238338 A.M. Farley, L.X. Morris, E. Vroegindeweij, et al.: Dynamics of thymus organogenesis and colonization in early human development. Development. 140:2015-2026 2013 23571219 Evolution of the immune system T. Boehm, J.B. Swann: Origin and evolution of adaptive immunity. Annu Rev Anim Biosci. 2:259-283 2014 25384143 M.F. Flajnik: A cold-blooded view of adaptive immunity. Nat Rev Immunol. 18:438-453 2018 29556016  Questions What’s the difference between innate and adaptive immunity? What are the main Immune cells and their role in defending against microorganisms? How does our immune system defend SARS-Cov-2 virus?