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  1. 1. PHSC.328 -- Immune System Page 1 Immune System Overview The immune system is composed of many interdependent cell types that collectively protect the body from bacterial, parasitic, fungal, or viral infections, and from the growth of some tumor cells. Innate immunity refers to antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any antigen. This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection. Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize a few highly conserved structures present in many different microorganisms. The structures recognized are called pathogen-associated molecular patterns and include LPS from the gram-negative cell wall, peptidoglycan, lipotechoic acids from the gram-positive cell wall, the sugar mannose (common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial DNA, N-formylmethionine found in bacterial proteins, double-stranded RNA from viruses, and glucans from fungal cell walls. Most body defense cells have pattern-recognition receptors for these common pathogen-associated molecular patterns and so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 molecular patterns. The innate immune responses involve: • phagocytic cells (neutrophils, monocytes, and macrophages); • cells that release inflammatory mediators (basophils, mast cells, and eosinophils); • natural killer cells (NK cells); and • molecules such as complement proteins, acute phase proteins, and cytokines. Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, fever, and the acute phase response Adaptive (acquired) immunity, refers to antigen-specific defense mechanisms that take several days to become protective and are designed to react with and remove a specific antigen. This is the immunity one develops throughout life. An antigen is defined as a substance that reacts with antibody molecules and antigen receptors on lymphocytes. An immunogen is an antigen that is recognized by the body as nonself and stimulates an adaptive immune response. For simplicity we will use the term antigen when referring to both antigens and immunogens. The actual portions or fragments of an antigen that react with antibodies and lymphocyte receptors are called epitopes. The body recognizes an antigen as foreign when epitopes of that antigen bind to B-lymphocytes and T- lymphocytes by means of epitope-specific receptor molecules having a shape complementary to that of the epitope. The epitope receptor on the surface of a B-lymphocyte is called a B-cell receptor and is actually an antibody molecule called surface immunoglobulin (sIg). The receptor on a T-lymphocyte is called a T-cell receptor (TCR). It is thought that the human body has the genetic ability to recognize 107 - 109 different epitopes. In otherwords, the body has 107 - 109 distinct clones of both B-lymphocytes and T-lymphocytes, each with a unique B-cell receptor or T-cell receptor. In this variety of B-cell receptors and T-cell receptors there is bound to be at least one that has an epitope-binding site able to fit, at least to some degree, any antigen the immune system eventually encounters. With the adaptive immune responses, the body is able to recognize any conceivable antigen it may eventually encounter.
  2. 2. PHSC.328 -- Immune System Page 2 The downside to the specificity of adaptive immunity is that only a few B-cells and T-cells in the body recognize any one epitope. These few cells then must rapidly proliferate in order to produce enough cells to mount an effective immune response against that particular epitope, and that typically takes several days. During this time the pathogen could be causing considerable harm, and that is why innate immunity is also essential. Adaptive immunity usually improves upon repeated exposure to a given infection and involves: • antigen-presenting cells (APCs) such as macrophages and dendritic cells; • the activation and proliferation of antigen-specific B-lymphocytes; • the activation and proliferation of antigen-specific T-lymphocytes; and • the production of antibody molecules, cytotoxic T-lymphocytes (CTLs), activated macrophages and NK cells, and cytokines. There are two major branches of the adaptive immune responses: humoral immunity and cell-mediated immunity. 1. humoral immunity: humoral immunity involves the production of antibody molecules in response to an antigen and is mediated by B-lymphocytes. 2. cell-mediated immunity: Cell-mediated immunity involves the production of cytotoxic T-lymphocytes, activated macrophages, activated NK cells, and cytokines in response to an antigen and is mediated by T- lymphocytes.
  3. 3. PHSC.328 -- Immune System Page 3 The Organs of the Immune System Bone Marrow -- All the cells of the immune system are initially derived from the bone marrow. They form through a process called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells differentiate into either mature cells of the immune system or into precursors of cells that migrate out of the bone marrow to continue their maturation elsewhere. The bone marrow produces B cells, natural killer cells, granulocytes and immature thymocytes, in addition to red blood cells and platelets. Thymus -- The function of the thymus is to produce mature T cells. Immature thymocytes, also known as prothymocytes, leave the bone marrow and migrate into the thymus. Through a remarkable maturation process sometimes referred to as thymic education, T cells that are beneficial to the immune system are spared, while those T cells that might evoke a detrimental autoimmune response are eliminated. The mature T cells are then released into the bloodstream. Spleen -- The spleen is an immunologic filter of the blood. It is made up of B cells, T cells, macrophages, dendritic cells, natural killer cells and red blood cells. In addition to capturing foreign materials (antigens) from the blood that passes through the spleen, migratory macrophages and dendritic cells bring antigens to the spleen via the bloodstream. An immune response is initiated when the macrophage or dendritic cells present the antigen to the appropriate B or T cells. This organ can be thought of as an immunological conference center. In the spleen, B cells become activated and produce large amounts of antibody. Also, old red blood cells are destroyed in the spleen. Lymph Nodes -- The lymph nodes function as an immunologic filter for the bodily fluid known as lymph. Lymph nodes are found throughout the body. Inhabited primarily by T cells, B cells, dendritic cells and macrophages, the nodes drain fluid from most of our tissues. Antigens are filtered out of the lymph in the lymph node before returning the lymph to the circulation. In a similar fashion as the spleen, the macrophages and dendritic cells that capture antigens present these foreign materials to T and B cells, consequently initiating an immune response.
  4. 4. PHSC.328 -- Immune System Page 4 Cells of the Immune System – OVERVIEW: T cells -- T lymphocytes are usually divided into two major subsets or four specific types that are functionally and phenotypically (identifiably) different. The phenotypic differences relate to surface expression of CD4 or CD8 proteins. The T helper cell (CD4+) is a coordinator of immune regulation. The main function of the T helper cell is to stimulate immune responses by the secretion of specialized factors that activate other white blood cells to fight off infection. The CD8+ T cells are the killer cells and suppressor cells. The T killer cells are important in directly killing certain tumor cells, viral-infected cells and sometimes parasites. The CD8+ T suppressor cells are important in down-regulation of immune responses. Both types of T cells can be found throughout the body. They often depend on the secondary lymphoid organs (the lymph nodes and spleen) as sites where activation occurs, but they are also found in other tissues of the body, most conspicuously the liver, lung, blood, and intestinal and reproductive tracts. T-Cells – • arise from stem cells in the bone marrow • migrate to the thymus where they differentiate into mature T-cells - surface proteins expressed (TCR, CD4 or CD8) • leave thymus: - circulate in bloodstream - go to peripheral lymphoid tissues
  5. 5. PHSC.328 -- Immune System Page 5 Four types of T-cells: Cellular Immunity: (1) Cytotoxic T cells (Tc) • cytolytic for: – cells with foreign HLA – virally infected cells – some tumor cells • all express CD8 (2) Delayed Hypersensitivity T cells (Tdh) • all express CD4 Regulatory T-cells: (3) Helper T-cells (Th) • promote proliferation and differentiation of Tc and B cells • all express CD4 (4) Suppressor T cells (Ts) • suppress cellular and humoral immunity • all express CD8 NATURAL KILLER (NK) CELLS and KILLER (K) CELLS ‚ (LARGE GRANULAR LYMPHOCYTES) Natural killer cells, often referred to as NK cells, are similar to the killer T cell subset (CD8+ T cells). They function as effector cells that directly kill certain tumors such as melanomas, lymphomas and viral-infected cells, most notably herpes and cytomegalovirus-infected cells. NK cells, unlike the CD8+ (killer) T cells, kill their targets without a prior "conference" in the lymphoid organs. However, NK cells that have been activated by secretions from CD4+ T cells will kill their tumor or viral-infected targets more effectively. 1. (a) NK cells possess cell-surface markers that are restricted to lymphocytes, but lack those markers characteristic of B cells and T cells. (b) have azurophilic granules containing cytolytic enzymes (e.g. perforin). (c) able to lyse a wide variety of tumor cells and virally infected cells. (d) non-specific, no prior antigen exposure needed (no memory), no MHC restrictions, recognition system unknown. (e) NK activity enhanced by lymphokines, specifically -interferon, also IL-2 2. (a) K cells have Fc receptors on their surface by which they recognize and exert cytotoxic activity toward antibody-coated target cells (called antibody-dependent cell-mediated cytotoxicity or ADCC). (b) contain azurophilic granules, and are very closely related to NK cells.
  6. 6. PHSC.328 -- Immune System Page 6 B Cells - The major function of B lymphocytes is the production of antibodies in response to foreign proteins of bacteria, viruses, and tumor cells. Antibodies are specialized proteins that specifically recognize and bind to one particular protein. Antibody production and binding to a foreign substance or antigen, often is critical as a means of signaling other cells to engulf, kill or remove that substance from the body. B lymphocytes: (1) arise from stem cells in bone marrow (2) upon reaching functionally mature stage, they emigrate to peripheral lymphoid organs. (3) upon contact with appropriate antigen, a B-cell differentiates into an antibody-producing plasma cell. Cell Surface Markers: New cytoplasmic and surface markers appear at each step of the B-cell differentiation. (a) All B-cells possess antigen-specific surface Ig, both monomeric IgM and IgD, which are capable of recognizing and interacting with only a single predetermined antigenic determinant. (b) The antigen-specific surface Ig on any given B-cell represents only one of the several million possible DNA combinatorial rearrangements of the Ig genes. Granulocytes or Polymorphonuclear (PMN) Leukocytes -- Another group of white blood cells is collectively referred to as granulocytes or polymorphonuclear leukocytes (PMNs). Granulocytes are composed of three cell types identified as neutrophils, eosinophils and basophils, based on their staining characteristics with certain dyes. These cells are predominantly important in the removal of bacteria and parasites from the body. They engulf these foreign bodies and degrade them using their powerful enzymes. Macrophages -- Macrophages are important in the regulation of immune responses. They are often referred to as scavengers or antigen-presenting cells (APC) because they pick up and ingest foreign materials and present these antigens to other cells of the immune system such as T cells and B cells. This is one of the important first steps in the initiation of an immune response. Stimulated macrophages exhibit increased levels of phagocytosis and are also secretory. Dendritic Cells -- Another cell type is the dendritic cell, which also originate in the bone marrow, and function as antigen presenting cells (APC). In fact, the dendritic cells are more efficient APCs than macrophages. These cells are usually found in the structural compartment of the lymphoid organs such as the thymus, lymph nodes and spleen. However, they are also found in the bloodstream and other tissues of the body. DENDRITIC and LANGERHANS' CELLS: - highly branched dendritic cytoplasmic processes. - high concentration of HLA Class II antigens. - dendritic cells found in lymphoid tissues. - called langerhans cells when found in epidermis. - poorly phagocytic - highly efficient antigen presenting cells (APC).
  7. 7. PHSC.328 -- Immune System Page 7 HISTOCOMPATIBILITY ANTIGENS (HLA COMPLEX) - originally identified as antigens that evoke rejection of transplanted organs; also important in regulating other immune responses. - area on the short arm of human chromosome 6 where these genes are found is called major histocompatibility complex (MHC). - In humans MHC is called human leukocyte antigen (HLA) - MHC gene products are classified into 3 categories (based on structure, distribution and function). Class 1 antigens - coded by three regions designated HLA-A, HLA-B, & HLA-C. - found on all nucleated cells and platelets. Class II antigens - coded by region known as HLA-D (which also contains 3 subregions; DP, DQ, & DR). - found mainly on "immunocompetent cells" (monocytes, macrophages, T cells, B cells, APCs). Class III proteins - components of the complement system (C2, C4a, C4b, & Bf) - do not act as histocompatibility antigens - Each individual expresses two sets of each HLA-type • one set from each parent • co-dominant (therefore heterozygous individual will express 6 different HLA-1 antigens on each cell)
  8. 8. PHSC.328 -- Immune System Page 8 Significance of HLA Complex 1. Transplantation, graft rejection 2. Regulation of immune response Class I - recognition of virally infected cells by CD8+ cytotoxic T cells. Class II - cell-to-cell interaction (e.g. Th induction activation) - govern magnitude of immune response (Ir). ANTIBODIES Antibodies are one of two important antigen recognition molecules of the immune system. The other antigen recognition molecule is found on the T Cell, called the T cell receptor (TcR). Antibodies also act as receptors on B cells but usually we think of antibodies as the soluble factors secreted by plasma cells. Soluble, or secreted, antibody is structurally slightly different than the antibody on the surface of B cells but the antigen recognition sites are similar. There are five different classes of antibodies or immunoglobulins (Ig) known as IgD, IgA, IgM, IgE and IgG. There are four subclasses of IgG and two subclasses of IgA.
  9. 9. PHSC.328 -- Immune System Page 9 Antibodies recognize antigen. An antigen is a substance capable of inducing a specific immune response. The term is derived from the generation of antibodies to such substances. Specific immune responses require recognition molecules like the T cell receptor or antibodies which recognize the antigen, or parts of it, and stimulate a response by the specific arm of the immune response (T or B cells). Often antigens are foreign proteins (or parts of them) that enter the body via an infection. Sometimes, however, the body's own proteins, expressed in an inappropriate manner (where or when they are not usually seen), are treated like antigens by the immune system. It is important to recognize that bacteria or viruses are not themselves antigens but they contain antigens both on their surface and inside them. Such antigens can be isolated and used to safely vaccinate against infection with the whole organism. Antigens are recognized by B cells and their surface antibodies (sIgM) or by the T cell receptor on T cells. Recognition leads to the growth of specific clones of B and T cells which recognize the antigen. Although T and B cells may respond to the same antigen, they are usually responding to different parts of the same molecule. Antibodies on the surface of B cells for example are very good at recognizing the tertiary structure of a protein (ie - the way it folds). T cells on the other hand, require the same protein to be ingested, degraded and presented on the surface of a special cell aptly named the antigen presenting cell. Proteins or glycoproteins make the best antigens because they are the best at stimulating antigen recognition molecules.Each part of the antigen that is recognized by either an antibody or a T cell receptor is known as an epitope. Depending on the size of the protein or polysaccharide, there may be hundreds of B cell epitopes (recognized by different antibodies) or T cell epitopes (presented by antigen presenting cells to different T cells) in the same molecule. This actually helps the body have a better response to the antigen as many T and B cells can be activated to respond to a single target. The ability of antibodies to recognize specific antigen is an important characteristic . Antigen recognition and binding allows antibodies to perform three important functions. • opsonization • activating complement • neutralizing toxins and toxic organisms Opsonization is a process where bacteria, virus- infected cells and others are 'tagged' for destruction. Antibodies are the 'tags' (or opsonins) because one end (Fab) binds to an antigen on the surface of the organism. The other end of the antibody (Fc) binds to receptors on phagocytic cells like macrophages and neutrophils. The antibody signals the phagocyte to engulf and destroy the organism or cell. Antibodies may also stimulate extracellular killing with an oxidative burst and the release from phagocytes of free radicals and destructive enzymes. Complement components, like C3b, also act as opsonins (C3b opsinization). Antibody also helps to kill foreign organisms by activating complement. IgM and IgG are very good at this, resulting in the lysing of the target by the C5-9 complex (MAC attack). In the circulation and in tissues, antibody will bind to toxins to remove them by forming easily recognized antibody-antigen complexes which are phagocytosed in the liver and elsewhere. Antibodies can also immobilize and agglutinate infectious agents by binding to surface antigens and prevent them from attaching to sites of infection like the intestinal mucosa) or from penetrating cells (such as in the case of virus').
  10. 10. PHSC.328 -- Immune System Page 10 The Immune Response An immune response to foreign antigen requires the presence of an antigen-presenting cell (APC), (usually either a macrophage or dendritic cell) in combination with a B cell or T cell. When an APC presents an antigen on its cell surface to a B cell, the B cell is signaled to proliferate and produce antibodies that specifically bind to that antigen. If the antibodies bind to antigens on bacteria or parasites it acts as a signal for neutrophils or macrophages to engulf (phagocytose) and kill them. Another important function of antibodies is to initiate the “complement destruction cascade.” When antibodies bind to cells or bacteria, serum proteins called complement bind to the immobilized antibodies and destroy the bacteria by creating holes in them. Antibodies can also signal natural killer cells and macrophages to kill viral or bacterial-infected cells. If the APC presents the antigen to T cells, the T cells become activated. Activated T cells proliferate and become secretory in the case of Th (CD4+) cells, or, if they are Tc (CD8+) cells, they become activated to kill target cells that specifically express the antigen presented by the APC. The production of antibodies and the activity of CD8+ killer T cells are highly regulated by the CD4+ helper T cell subset. The CD4+ Th cells provide growth factors or signals to these cells that signal them to proliferate and function more efficiently. This multitude of interleukins or cytokines that are produced and secreted by CD4+ Th cells are often crucial to ensure the activation of natural killer cells, macrophages, CD8+ Tc cells, and PMNs.
  11. 11. PHSC.328 -- Immune System Page 11 MACROPHAGES Functions in Immune Responses: (a) process and present antigen to Th (primarily) (b) produce IL-1 - promotes differentiation of both T & B cells. (c) antitumor lysing activity (secrete Tumor Necrosis Factor) (d) delayed hypersensitivity reaction CYTOKINES - polypeptide messenger molecules of the immune system. A. Cytokines induce their effects in three ways: 1. autocrine effect - act on same cell that produces them - e.g. IL-2 produced by activated T cells promotes T-cell growth. 2. paracrine effect - affect other cells in their vicinity - e.g. IL-1 produced by APCs promotes proliferation of CD4+ cells and IL-2 release from them. 3. endocrine effect - affect many cells systemically - e.g. IL-1 and TNF-α produce acute-phase response during inflammation. B. Receptors -- cytokines mediate their effects by binding to specific high-affinity receptors on their target cells.
  12. 12. PHSC.328 -- Immune System Page 12