Cells of the Immune System PDF

Cells of Immune System  Immune system consist of various cells and organs each with specific functions The blood cells arise through the process called Hematopoiesis – From a single type of cell called hematopoietic stem cell (HSC) Stem cell have three basic properties...

Cells of Immune System  Immune system consist of various cells and organs each with specific functions The blood cells arise through the process called Hematopoiesis – From a single type of cell called hematopoietic stem cell (HSC) Stem cell have three basic properties – Self renewability – Cell division – Differentiation -- into different cell types Hematopoiesis  Cells of the Immune System - Lymphocytes bearing antigen receptors are the central cells of the immune system - responsible for adaptive immunity - and the immunologic attributes such as - Diversity, Specificity, Memory and Self/nonself recognition. - The other types of white blood cells play important roles in engulfing and destroying microorganisms, presenting antigens, and secreting cytokines. Overall cell of immune system can be divided in to three broad categories Lymphoid Cells Mononuclear Phagocytes Granulocytic Cells – B Lymphocytes – Monocytes – Neutrophils – T Lymphocytes – Macrophages – Eosinophils – NK Cells – Basophils – Mast Cells – Dendritic Cells  Lymphpoid Cells Lymphoid progenitor cell gives rise to all lymphocytes – Lymphocytes constitute 20%–40% of the body’s white blood cells 99% of the cells in the lymph. – They continually circulate in the blood and lymph – They are capable of migrating into the tissue spaces and lymphoid organs  On the basis of function and cell-membrane components The lymphocytes can be broadly subdivided into three populations 1. B cells – express receptor with diversity for foreign antigens 2. T cells – express receptor with diversity for foreign antigens 3. Natural killer cells - large, granular lymphocytes, express a limited set of invariant, non-rearranging receptors Resting B and T lymphocytes are small, motile, non-phagocytic cells, – cannot be distinguished morphologically. – B and T lymphocytes that have not interacted with antigen referred to as naive, or unprimed—are resting cells in the G phase of the cell cycle. – Known as small lymphocytes, these cells are only about 6 µm in diameter; – Interaction of small lymphocytes with antigen, induces these cells to enter the cell cycle by progressing from G into G1 and subsequently into S, G2 , and M phase as they progress through the cell cycle, lymphocytes enlarge into 15µm diameter blast cells, called lymphoblasts A small resting naïve lymphocyte resides in the G phase of the cell cycle. At this stage, B and T lymphocytes cannot be distinguished morphologically. After antigen activation, a B or T cell enters the cell cycle and enlarges into a lymphoblast, which undergoes several rounds of cell division and, eventually, generates effector cells and memory cells.  B LYMPHOCYTES B-derived from the bursa of Fabricius in birds; – bone marrow is its major site of maturation in a number of mammalian species, including humans and mice. Each B cell produces a single species of antibody. A single B cell express approximately 1.5 x 105 antibodies on the membrane. These antibodies have identical binding sites for a givene antigen.  Other than Antibody (BCR) and class II MHC, the molecules expressed on the membrane of mature B cells are: CD80 (B7-1) and CD86 (B7-2 ) provides a costimulatory signal necessary for T cell activation CD40 is a molecule that interacts with CD40 Ligand (CD40L) on the surface of helper T cells B220 (a form of CD45) is used as a marker of B cells. FcRII (CD32) is a receptor for Fc region of IgG, a type of antibody. Fragment crystallizable region (Fc region) is the tail region of an antibody that interacts with cell surface receptors called Fc CR1 (CD35) and CR2 (CD21) receptors and some proteins of the are receptors for certain complement system. complement products.  Interaction between antigen and the membrane- bound antibody on a mature naive B cell, as well as interactions with T cells and macrophages, – induces the activation and differentiation of B-cell In this process, the B cell divides repeatedly and differentiates over a 4- to 5-day period, generating a population of plasma cells and memory cells. Plasma cells are terminally differentiated cells, and many die in 1 or 2 weeks.  T LYMPHOCYTES T lymphocytes derive their name from their site of maturation in the thymus. Like B lymphocytes, these cells have membrane receptors for antigen called T-cell receptor The fundamental difference between the humoral and cell-mediated branches of the immune system is that the B cell is capable of binding soluble antigen, whereas the T cell is restricted to binding antigen displayed on self- cells. Humoral Immunity Humoral immunity involves the production of antibodies by B cells (B lymphocytes) and provides defense against extracellular pathogens. 1.B Cell Activation: When B cells encounter antigens, they become activated. This process often requires assistance from helper T cells (CD4+ T cells). 2.Differentiation: Activated B cells differentiate into plasma cells, which are responsible for producing antibodies specific to the antigen encountered. Some B cells become memory B cells, which provide long- term immunity. 3.Antibodies: The antibodies produced by plasma cells circulate in the bloodstream and lymphatic system. They bind to extracellular pathogens or toxins, neutralizing them or marking them for destruction by other immune cells (e.g., macrophages and neutrophils). Cell-Mediated Immunity Cell-mediated immunity involves T cells (T lymphocytes) and provides defense against intracellular pathogens (e.g., viruses, some bacteria), cancer cells, and transplanted tissues. 1.Helper T Cells (CD4+ T Cells): These cells recognize antigens presented by antigen-presenting cells (APCs) on MHC class II molecules. They help activate other immune cells, including B cells and cytotoxic T cells, by releasing cytokines. 2.Cytotoxic T Cells (CD8+ T Cells): These cells recognize antigens presented by infected cells on MHC class I molecules. Once activated, cytotoxic T cells directly kill infected cells by inducing apoptosis. 3.Memory T Cells: Some activated T cells become memory T cells, which remain in the body long-term and respond more rapidly upon re-exposure to the same antigen.  To be recognized by most T cells, this antigen must be displayed together with MHC molecules on the surface of antigen-presenting cells or on virus-infected cells, cancer cells, and grafts. Like B cells, T cells also express distinctive membrane molecules. All T-cell subpopulations express the – T-cell receptor, a complex of polypeptides CD3 is essential for signal transduction, allowing the TCR to send activation signals into the T cell upon antigen recognition. – and most can be distinguished by the presence of one or the other of two membrane molecules, CD4 and CD8.  Most mature T cells also express the following membrane molecules CD28, a receptor for the co-stimulatory B7 family of molecules present on B cells and other antigen presenting cells CD40L, ligand for CD40 of B- cell The ratio of T cells in a sample can be approximated by assaying the number of CD4 and CD8 T cells. This ratio is approximately 2:1 in normal human peripheral blood, The ratio may be significantly altered by immunodeficiency diseases, autoimmune diseases etc  The classification of CD4+ as TH cells and CD8+ as Tc cells is not absolute. Some CD4 cells can act as killer cells. Also, some TC cells have been shown to secrete a variety of cytokines – and exert an effect on other cells similar to that of TH cells.  CD4: Refers to the molecule itself. CD4+: Refers to cells that express the CD4 molecule, most notably the helper T cells.  TH cells are activated by recognition of – an antigen–class II MHC complex on an antigen- presenting cell. After activation, the TH cell begins to divide and gives rise to a clone of effector cells, – each specific for the same antigen–class II MHC complex. – These TH cells secrete various cytokines, which play a central role in the activation of B cells, T cells, and other cells that participate in the immune response.  Changes in the pattern of cytokines produced by TH cells can change the type of immune response that develops among other leukocytes. For example, the TH1 response produces a cytokine profile that supports inflammation and activates mainly certain T cells and macrophages whereas the TH 2 response activates mainly B cells and immune responses that depend upon antibodies.  TC cells are activated when they interact with an antigen–class I MHC complex on the surface of an altered self-cell (e.g., a virus- infected cell or a tumor cell) in the presence of appropriate cytokines. This activation, which results in proliferation, causes the TC cell to differentiate into an effector cell called a cytotoxic T lymphocyte (CTL)  Another subpopulation of T lymphocytes called T suppressor (TS ) cells aka T regulatory cells has been postulated. Function to suppress or down regulate induction and proliferation of effector T cells  NATURAL KILLER CELLS (NK Cells) Constitute 5%–10% of lymphocytes in human They are large, granular lymphocytes – that display cytotoxic activity against a wide range of tumor cells – also against cells infected with some viruses.  Although NK cells do not have T-cell receptors or immunoglobulin incorporated in their plasma membranes, – they can recognize potential target cells in two different ways. 1. In some cases, an NK cell employs inhibitory receptors to distinguish abnormalities, such as reduction in the expression of class I MHC molecules by the infected cell  Model of how cytotoxic activity of NK cells is restricted to altered self cells. An activating receptor on NK cells interacts with its ligand on normal and altered self cells, inducing an activation signal that results in killing. However, binding of inhibitory NK-cell receptors such as inhibitory KIRs and CD94- NKG2 to class I MHC molecules delivers an inhibition signal that counteracts the activation signal. Expression of class I molecules on normal cells (a) thus prevents their destruction by NK cells. Because class I expression is often decreased on altered self cells (b), the killing signal predominates, leading to their destruction.  Another way in which NK cells recognize ADCC potential target cells depends upon the fact that – some tumor cells and certain virus infected cells display antigens and B cells makes antibody response, These antibodies are bound to tumor/ virus infected cells. Since NK cells express CD16, a membrane receptor for the carboxyl-terminal end of the IgG molecule, called the Fc region, they can attach to these antibodies and subsequently destroy the targeted cells by the action of Perforin protein and Granzymes – Granzynes are serine proteases that induce programmed cell death in the target cell. This is an example of a process known as antibody-dependent cell-mediated cytotoxicity (ADCC).  Mononuclear Phagocytes These are: a. Monocytes circulating in the blood and b. Macrophages in the tissues  During hematopoiesis in the bone marrow, – Granulocyte-monocyte progenitor cells differentiate into promonocytes, – These promonocytes, leave the bone marrow and enter the blood, – In blood, they differentiate into mature Monocytes. These Monocytes circulate in the bloodstream for about 8 h, during which they enlarge; – and then migrate into the tissues and differentiate into specific tissue macrophages – or, into dendritic cells.  Macrophages are dispersed throughout the body. Categorized as: 1. Fixed macrophages: – When they reside in particular tissues 2. Free, or wandering, macrophages. – Motile and travel by amoeboid movement throughout the tissues.  Some of tissue macrophages are as follows: Alveolar macrophages in the lung Histiocytes in connective tissues Kupffer cells in the liver Mesangial cells in the kidney Microglial cells in the brain Osteoclasts in bone  Macrophages are activated by : – Phagocytosis of particulate antigens – macrophage activity is further enhanced by cytokines secreted by activated TH cells such as interferon gamma (IFN-) mediators of the inflammatory response such Histamines components of bacterial cell walls e.g., LPS  Activated macrophages – exhibit greater phagocytic activity – increased secretion of inflammatory mediators – an increased ability to activate T cells Activated macrophages also secrets various reactive forms of oxygen , cytotoxic peptides/proteins such as defensins/ lysozymes that help them eliminate a broad range of pathogens, – including virus-infected cells, tumor cells, and intracellular bacteria  Activated macrophages also express higher levels of class II MHC molecules, – allowing them to function more effectively as antigen-presenting cells. – Thus, macrophages and T cells facilitate each other’s activation during the immune response.  Phagocytosis by Macrophages Macrophages are capable of ingesting and digesting exogenous antigens, – such as whole microorganisms and insoluble particles, – and endogenous matter, such as injured or dead host cells, cellular debris, and activated clotting factors. Macrophages are attracted by and move toward a variety of substances generated in an immune response; this process is called chemotaxis. The next step in phagocytosis is adherence of the antigen to the macrophage cell membrane. Complex antigens, such as whole bacterial cells or viral particles, tend to adhere well and are readily phagocytosed; – isolated proteins and encapsulated bacteria tend to adhere poorly and are less readily phagocytosed. Adherence induces membrane protrusions, called pseudopodia, to extend around the attached material – Fusion of the pseudopodia encloses the material within a membrane-bounded structure called a phagosome, which then enters the endocytic processing pathway (a) Scanning electron micrograph of a macrophage. Long pseudopodia extending toward and making contact with bacterial cells, an early step in phagocytosis. (b) Phagocytosis and processing of exogenous antigen by macrophages. Most of the products resulting from digestion of ingested material are exocytosed, but some peptide products may interact with class II MHC molecules, forming complexes that move to the cell surface, where they are presented to T cells.  Phagosome fuses with a lysosome to form a phagolysosome. Lysosomes contain lysozyme and a variety of other hydrolytic enzymes that digest the ingested material. The digested contents of the phagolysosome are then eliminated in a process called exocytosis  Opsonization The macrophage membrane has receptors for certain classes of antibody. If an antigen is coated with the appropriate antibody e.g., IgG-coating a pathogen – the complex of antigen and antibody binds to antibody receptors on the macrophage membrane more readily than antigen alone and this enhances the process of phagocytosis. Thus, antibody functions as an Opsonin, – So opsonin can be defined as a molecule (e.g., an antibody or C3b) that binds to both antigen and macrophage or any appropriate phagocytic cell and enhances phagocytosis. C3b is an important component of the complement system, which is part of the innate immune response. And the process by which antigens are rendered more susceptible to phagocytosis is called opsonization. Opsonization by antibodies and/or complement factors C5a/C3a which allows effective phagocytosis  Antigen Processing and Presentation by Macrophages Phagocytosed antigen is digested into peptides – that associate with Class II MHC molecules; these peptide–class II MHC complexes then move to the macrophage membrane. Activation of macrophages induces increased expression of both class II MHC molecules and the co-stimulatory B7 family of membrane molecules, – that renders the macrophages more effective in activating TH cells. This processing and presentation of antigen, is critical to TH -cell activation, – which is important the development of both humoral and cell-mediated immune responses.  A number of important proteins involved in the development of immune responses are secreted by activated macrophages E.g., – cytokines, such as interleukin 1 (IL-1), TNF- and interleukin 6 (IL-6), that promote inflammatory responses. IL-1 activates lymphocytes; and IL-1, IL-6, and TNF- promote fever by affecting the thermoregulatory center in the hypothalamus.  Granulocytic Cells The granulocytes are classified as neutrophils, eosinophils, or basophils on the basis of cellular morphology and cytoplasmic staining characteristics The neutrophil has a multilobed nucleus and a granulated cytoplasm that stains with both acid and basic dyes; it is often called a polymorphonuclear leukocyte (PMN) for its multilobed nucleus. The eosinophil has a bilobed nucleus and a granulated cytoplasm that stains with the acid dye eosin red. The basophil has a lobed nucleus and heavily granulated cytoplasm that stains with the basic dye Methylene blue. Both neutrophils and eosinophils are phagocytic, whereas basophils are not.  NEUTROPHILS Neutrophils are produced by hematopoiesis in the bone marrow. They are motile phagocytic cells They are released into the peripheral blood and circulate for 7–10 h before migrating into the tissues, where they have a life span of only a few days. In response to many types of infections, the bone marrow releases more than the usual number of neutrophils. Neutrophils are generally the immune cells that arrive first at a site of inflammation. The resulting transient increase in the number of circulating neutrophils is called leukocytosis- which is an indication of infection  EOSINOPHILS Eosinophils, like neutrophils, – are motile phagocytic cells that can migrate from the blood into the tissue spaces. Their phagocytic role is significantly less important than that of neutrophils, – and it is thought that they play a role in the defense against parasitic organisms The secreted contents of eosinophilic granules may damage the parasite membrane.  BASOPHILS Basophils are non-phagocytic granulocytes that function by releasing pharmacologically active substances from their cytoplasmic granules such as histamine, which is a vasodilator These substances play a major role in certain allergic responses.  MAST CELLS Mast-cell precursors, which are formed in the bone marrow by hematopoiesis, – are released into the blood as undifferentiated cells; they do not differentiate until they leave the blood and enter the tissues. Mast cells can be found in a wide variety of tissues, including the skin, connective tissues of various organs, and mucosal epithelial tissue of the respiratory, genitourinary, and digestive tracts. Like circulating basophils, these cells have large numbers of cytoplasmic granules that contain histamine and other pharmacologically active substances. Mast cells, together with blood basophils, play an important role in the development of allergies.  DENDRITIC CELLS The dendritic cell (DC) acquired its name because it is covered with long membrane extensions that resemble the dendrites of nerve cells. They internalize extracellular antigens through receptor-mediated endocytosis, phagocytosis, and macropinocytosis. – Major function of the Dendritic cell is the presentation of antigen to TH cells. All dentritic cells constitutively express high levels of both class II MHC molecules and members of the co- stimulatory B7 family Four types of dendritic cells are known  Exceptional type of dendritic cell is the follicular dendritic cell that – does not arise in bone marrow and does not express class II MHC molecules Therefore no antigen-presentation These dendritic cells are located in the lymph follicles of lymph node Follicular dendritic cells express high levels of membrane receptors for antibody, which allows the binding of antigen- antibody complexes – When B cells encounter an antigen presented by FDCs, their BCRs bind to the antigen.