The Immune System PDF

The Immune System  Objectives Differentiate between innate and adaptive defense systems. Describe surface membrane barriers and their protective functions. Explain the importance of each of the internal defenses (phagocytes, NK cells, inflammation, antimicrobial proteins,...

The Immune System  Objectives Differentiate between innate and adaptive defense systems. Describe surface membrane barriers and their protective functions. Explain the importance of each of the internal defenses (phagocytes, NK cells, inflammation, antimicrobial proteins, and fever).  Define these terms Infection Pathogens immunity  Definition of terms Infection—a condition caused by the presence of a disease-causing agent. Pathogens—disease-causing agents including viruses, bacteria, fungi, protozoans and other parasitic forms of life. Immunity—defense mechanisms that help prevent the entrance of pathogens or destroy them if they enter tissues.  Overview of the immune system Immune system Innate defenses Adaptive defenses (nonspecific) (Specific) Surface barriers Humoral immunity Internal defenses Cellular immunity  Discuss with a partner What is the difference between specific and non-specific immunity? Innate defenses: Skin and mucous membranes Innate (nonspecific) system responds quickly and consists of: – First line of defense – intact skin and mucosae prevent entry of microorganisms – Second line of defense – antimicrobial proteins, phagocytes, and other cells Inhibit spread of invaders throughout the body Inflammation is its hallmark and most important mechanism  Adaptive defenses: humoral and cellular immunity Adaptive (specific) defense system – Third line of defense – mounts attack against particular foreign substances Takes longer to react than the innate system Works in conjunction with the innate system  Surface barriers Skin, mucous membranes, and their secretions make up the first line of defense Keratin in the skin: – Presents a formidable physical barrier to most microorganisms – Is resistant to weak acids and bases, bacterial enzymes, and toxins Mucosae provide similar mechanical barriers  Epithelial chemical barriers Epithelial membranes produce protective chemicals that destroy microorganisms – Skin acidity (pH of 3 to 5) inhibits bacterial growth – Sebum contains chemicals toxic to bacteria – Stomach mucosae secrete concentrated HCl and protein-digesting enzymes – Saliva and lacrimal fluid contain lysozyme – Mucus traps microorganisms that enter the digestive and respiratory systems  Respiratory tract mucosae Mucus-coated hairs in the nose trap inhaled particles Mucosa of the upper respiratory tract is ciliated – Cilia sweep dust- and bacteria-laden mucus away from lower respiratory passages  Internal defenses: Cells and chemicals The body uses nonspecific cellular and chemical devices to protect itself – Phagocytes and natural killer (NK) cells – Antimicrobial proteins in blood and tissue fluid – Inflammatory response enlists macrophages, mast cells, WBCs, and chemicals Harmful substances are identified by surface carbohydrates unique to infectious organisms  Phagocytes Macrophages are the chief phagocytic cells Free macrophages wander throughout a region in search of cellular debris Kupffer cells (liver) and microglia (brain) are fixed macrophages Neutrophils become phagocytic when encountering infectious material Eosinophils are weakly phagocytic against parasitic worms Mast cells bind and ingest a wide range of bacteria Mechanism of phagocytosis  Natural Killer (NK) Cells Cells that can lyse and kill cancer cells and virus-infected cells Natural killer cells: – Are a small, distinct group of large granular lymphocytes – React nonspecifically and eliminate cancerous and virus-infected cells – Kill their target cells by releasing perforins and other cytolytic chemicals – Secrete potent chemicals that enhance the inflammatory response  Inflammation: Tissue response to injury The inflammatory response is triggered whenever body tissues are injured – Prevents the spread of damaging agents to nearby tissues – Disposes of cell debris and pathogens – Sets the stage for repair processes The four cardinal signs of acute inflammation are redness, heat, swelling, and pain  Inflammation response Begins with a flood of inflammatory chemicals released into the extracellular fluid Inflammatory mediators: – Include kinins, prostaglandins (PGs), complement, and cytokines – Are released by injured tissue, phagocytes, lymphocytes, and mast cells – Cause local small blood vessels to dilate  Inflammatory response Chemicals liberated by the inflammatory response increase the permeability of local capillaries Exudate (fluid containing proteins, clotting factors, and antibodies): – Seeps into tissue spaces causing local edema (swelling), which contributes to the sensation of pain  Inflammatory response The surge of protein-rich fluids into tissue spaces (edema): – Helps to dilute harmful substances – Brings in large quantities of oxygen and nutrients needed for repair – Allows entry of clotting proteins, which prevents the spread of bacteria  Inflammatory response Occurs in four main phases: – Leukocytosis – neutrophils are released from the bone marrow in response to leukocytosis-inducing factors released by injured cells – Margination – neutrophils cling to the walls of capillaries in the injured area – Diapedesis – neutrophils squeeze through capillary walls and begin phagocytosis – Chemotaxis – inflammatory chemicals attract neutrophils to the injury site Inflammatory response Events of inflammation  Anti-microbial proteins Enhance the innate defenses by: – Attacking microorganisms directly – Hindering microorganisms’ ability to reproduce The most important antimicrobial proteins are: – Interferon – Complement proteins  Interferon (IFN) Genes that synthesize IFN are activated when a host cell is invaded by a virus Interferon molecules leave the infected cell and enter neighboring cells Interferon stimulates the neighboring cells to activate genes for PKR (an antiviral protein) PKR nonspecifically blocks viral reproduction in the neighboring cell Interferon  Interferon family Interferons are a family of related proteins each with slightly different physiological effects Lymphocytes secrete gamma (γ) interferon, but most other WBCs secrete alpha (α) interferon Fibroblasts secrete beta (β) interferon Interferons also activate macrophages and mobilize NKs FDA-approved alpha IFN is used: – As an antiviral drug against hepatitis C virus – To treat genital warts caused by the herpes virus  Complement (proteins) 20 or so proteins that circulate in the blood in an inactive form Proteins include C1 through C9, factors B, D, and P, and regulatory proteins Provides a major mechanism for destroying foreign substances in the body  Complement Amplifies all aspects of the inflammatory response Kills bacteria and certain other cell types (our cells are immune to complement) Enhances the effectiveness of both nonspecific and specific defenses  Fever Abnormally high body temperature in response to invading microorganisms The body’s thermostat is reset upwards in response to pyrogens, chemicals secreted by leukocytes and macrophages exposed to bacteria and other foreign substances  Fever High fevers are dangerous as they can denature enzymes Moderate fever can be beneficial, as it causes: – The liver and spleen to sequester iron and zinc (needed by microorganisms) – An increase in the metabolic rate, which speeds up tissue repair Lets review-In groups, complete the chart Innate defenses Surface barriers Internal defenses  Assignment Find an autoimmune disease. Read about it and be prepared to share the information next class.  Adaptive Immunity: Summary Two-fisted defensive system that uses lymphocytes, APCs, and specific molecules to identify and destroy nonself particles Its response depends upon the ability of its cells to: – Recognize foreign substances (antigens) by binding to them – Communicate with one another so that the whole system mounts a response specific to those antigens  Humoral Immunity Response Antigen challenge – first encounter between an antigen and a naive immunocompetent cell Takes place in the spleen or other lymphoid organ If the lymphocyte is a B cell: – The challenging antigen provokes a humoral immune response Antibodies are produced against the challenger  Clonal Selection Stimulated B cell growth forms clones bearing the same antigen-specific receptors A naive, immunocompetent B cell is activated when antigens bind to its surface receptors and cross-link adjacent receptors Antigen binding is followed by receptor-mediated endocytosis of the cross-linked antigen-receptor complexes Clonal Selection Figure 21.9  Fate of the Clones Most clone cells become antibody-secreting plasma cells Plasma cells secrete specific antibody at the rate of 2000 molecules per second  Fate of the Clones Secreted antibodies: – Bind to free antigens – Mark the antigens for destruction by specific or nonspecific mechanisms Clones that do not become plasma cells become memory cells that can mount an immediate response to subsequent exposures of the same antigen  Immunological Memory Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen – Lag period: 3 to 6 days after antigen challenge – Peak levels of plasma antibody are achieved in 10 days – Antibody levels then decline  Immunological Memory Secondary immune response – re-exposure to the same antigen – Sensitized memory cells respond within hours – Antibody levels peak in 2 to 3 days at much higher levels than in the primary response – Antibodies bind with greater affinity, and their levels in the blood can remain high for weeks to months  Active Humoral Immunity B cells encounter antigens and produce antibodies against them – Naturally acquired – response to a bacterial or viral infection – Artificially acquired – response to a vaccine of dead or attenuated pathogens Vaccines – spare us the symptoms of disease, and their weakened antigens provide antigenic determinants that are immunogenic and reactive  Passive Humoral Immunity Differs from active immunity in the antibody source and the degree of protection – B cells are not challenged by antigens – Immunological memory does not occur – Protection ends when antigens naturally degrade in the body Naturally acquired – from the mother to her fetus via the placenta Artificially acquired – from the injection of serum, such as gamma globulin Types of Acquired Immunity Figure 21.11  Antibodies Also called immunoglobulins – Constitute the gamma globulin portion of blood proteins – Are soluble proteins secreted by activated B cells and plasma cells in response to an antigen – Are capable of binding specifically with that antigen There are five classes of antibodies: IgD, IgM, IgG, IgA, and IgE  Classes of Antibodies IgD – monomer attached to the surface of B cells, important in B cell activation IgM – pentamer released by plasma cells during the primary immune response IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces IgE – monomer that binds to mast cells and basophils, causing histamine release when activated  Basic Antibody Structure Consists of four looping polypeptide chains linked together with disulfide bonds – Two identical heavy (H) chains and two identical light (L) chains The four chains bound together form an antibody monomer Each chain has a variable (V) region at one end and a constant (C) region at the other Variable regions of the heavy and light chains combine to form the Basic Antibody Structure Figure 21.12a, b  Antibody Structure Antibodies responding to different antigens have different V regions but the C region is the same for all antibodies in a given class C regions form the stem of the Y-shaped antibody and: – Determine the class of the antibody – Serve common functions in all antibodies – Dictate the cells and chemicals that the antibody can bind to – Determine how the antibody class will function in elimination of antigens  Antibody Targets Antibodies themselves do not destroy antigen; they inactivate and tag it for destruction All antibodies form an antigen-antibody (immune) complex Defensive mechanisms used by antibodies are neutralization, agglutination, precipitation, and complement fixation  Complement Fixation and Activation Complement fixation is the main mechanism used against cellular antigens Antibodies bound to cells change shape and expose complement binding sites This triggers complement fixation and cell lysis Complement activation: – Enhances the inflammatory response – Uses a positive feedback cycle to promote phagocytosis – Enlists more and more defensive elements  Other Mechanisms of Antibody Action Neutralization – antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells  Other Mechanisms of Antibody Action Agglutination – antibodies bind the same determinant on more than one antigen – Makes antigen-antibody complexes that are cross-linked into large lattices – Cell-bound antigens are cross-linked, causing clumping (agglutination) Precipitation – soluble molecules are cross-linked into large insoluble complexes Mechanisms of Antibody Action Figure 21.13  Monoclonal Antibodies Commercially prepared antibodies are used: – To provide passive immunity – In research, clinical testing, and treatment of certain cancers Monoclonal antibodies are pure antibody preparations – Specific for a single antigenic determinant – Produced from descendents of a single cell Cell-Mediated Immune Response Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed Two major populations of T cells mediate cellular immunity – CD4 cells (T4 cells) are primarily helper T cells (TH) – CD8 cells (T8 cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens Other types of T cells are: – Suppressor T cells (TS) – Memory T cells Major Types of T Cells Figure 21.14 Importance of Humoral Response Soluble antibodies – The simplest ammunition of the immune response – Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph Importance of Cellular Response T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells T cells are best suited for cell-to-cell interactions, and target: – Cells infected with viruses, bacteria, or intracellular parasites – Abnormal or cancerous cells – Cells of infused or transplanted foreign tissue  Antigen Recognition and MHC Restriction Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen T cells must simultaneously recognize: – Nonself (the antigen) – Self (a MHC protein of a body cell)  MHC Proteins Both types of MHC proteins are important to T cell activation Class I MHC proteins – Always recognized by CD8 T cells – Display peptides from endogenous antigens  Class I MHC Proteins Endogenous antigens are: – Degraded by proteases and enter the endoplasmic reticulum – Transported via TAP (transporter associated with antigen processing) – Loaded onto class I MHC molecules – Displayed on the cell surface in association with a class I MHC molecule Class I MHC Proteins Figure 21.15a  Class II MHC Proteins Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells A phagosome containing pathogens (with exogenous antigens) merges with a lysosome Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum  Class II MHC Proteins Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells Class II MHC Proteins Figure 21.15b T Cell Activation: Step One – Antigen Binding Figure 21.16  T Cell Activation: Step Two – Co-stimulation Before a T cell can undergo clonal expansion, it must recognize one or more co-stimulatory signals This recognition may require binding to other surface receptors on an APC – Macrophages produce surface B7 proteins when nonspecific defenses are mobilized – B7 binding with the CD28 receptor on the surface of T cells is a crucial co-stimulatory signal Other co-stimulatory signals include cytokines and interleukin 1 and 2  T Cell Activation: Step Two – Co-stimulation Depending on receptor type, co-stimulators can cause T cells to complete their activation or abort activation Without co-stimulation, T cells: – Become tolerant to that antigen – Are unable to divide – Do not secrete cytokines  T Cell Activation: Step Two – Co-stimulation T cells that are activated: – Enlarge, proliferate, and form clones – Differentiate and perform functions according to their T cell class  Cytokines Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages Some are co-stimulators of T cells and T cell proliferation Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to: – Release interleukin 2 (IL-2)  Cytokines IL-2 is a key growth factor, which sets up a positive feedback cycle that encourages activated T cells to divide – It is used therapeutically to enhance the body’s defenses against cancer Other cytokines amplify and regulate immune and nonspecific responses  Cytokines Examples include: – Perforin and lymphotoxin – cell toxins – Gamma interferon – enhances the killing power of macrophages – Inflammatory factors  Helper T Cells (TH) Regulatory cells that play a central role in the immune response Once primed by APC presentation of antigen, they: – Chemically or directly stimulate proliferation of other T cells – Stimulate B cells that have already become bound to antigen Without TH, there is no immune response Helper T Cells (TH) Figure 21.17a  Helper T Cell TH cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors TH cells stimulate B cells to divide more rapidly and begin antibody formation B cells may be activated without TH cells by binding to T cell–independent antigens Most antigens, however, require TH co-stimulation to activate B cells Cytokines released by TH amplify nonspecific defenses Helper T Cells Figure 21.17b  Cytotoxic T Cell (Tc) TC cells, or killer T cells, are the only T cells that can directly attack and kill other cells They circulate throughout the body in search of body cells that display the antigen to which they have been sensitized Their targets include: – Virus-infected cells – Cells with intracellular bacteria or parasites – Cancer cells – Foreign cells from blood transfusions or transplants  Cytotoxic T Cells Bind to self-antiself complexes on all body cells Infected or abnormal cells can be destroyed as long as appropriate antigen and co-stimulatory stimuli (e.g., IL-2) are present Natural killer cells activate their killing machinery when they bind to MICA receptor MICA receptor – MHC-related cell surface  Mechanisms of Tc Action In some cases, TC cells: – Bind to the target cell and release perforin into its membrane In the presence of Ca2+ perforin causes cell lysis by creating transmembrane pores Other TC cells induce cell death by: – Secreting lymphotoxin, which fragments the target cell’s DNA – Secreting gamma interferon, which stimulates phagocytosis by macrophages Mechanisms of Tc Action Figure 21.18a, b  Other T Cells Suppressor T cells (TS) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells Gamma delta T cells (Tgd) – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors  Organ Transplants The four major types of grafts are: – Autografts – graft transplanted from one site on the body to another in the same person – Isografts – grafts between identical twins – Allografts – transplants between individuals that are not identical twins, but belong to same species – Xenografts – grafts taken from another animal species  Prevention of Rejection Prevention of tissue rejection is accomplished by using immunosuppressive drugs However, these drugs depress patient’s immune system so it cannot fight off foreign agents  Immunodeficiencies Congenital and acquired conditions in which the function or production of immune cells, phagocytes, or complement is abnormal – SCID – severe combined immunodeficiency (SCID) syndromes; genetic defects that produce: A marked deficit in B and T cells Abnormalities in interleukin receptors Defective adenosine deaminase (ADA) enzyme – Metabolites lethal to T cells accumulate – SCID is fatal if untreated; treatment is with bone marrow transplants  Acquired Immunodeficiencies Hodgkin’s disease – cancer of the lymph nodes leads to immunodeficiency by depressing lymph node cells Acquired immune deficiency syndrome (AIDS) – cripples the immune system by interfering with the activity of helper T (CD4) cells – Characterized by severe weight loss, night sweats, and swollen lymph nodes – Opportunistic infections occur, including pneumocystis pneumonia and Kaposi’s sarcoma