chapter 21:the immune system

Immunological Memory • Primary immune response

Occurs on the first exposure to a specific antigen • Lag period: three to six days • Peak levels of plasma antibody are reached in 10 days • Antibody levels then decline

Classes of Antibodies • IgM

• A pentamer; first antibody released • Potent agglutinating agent • Readily fixes and activates complement

T Cell Activation

• APCs (most often a dendritic cell) migrate to lymph nodes and other lymphoid tissues to present their antigens to T cells • T cell activation is a two-step process 1. Antigen binding 2. Co-stimulation

• Activated complement

• Activated complement • Enhances inflammation • Promotes phagocytosis • Causes cell lysis • C3b initiates formation of a membrane attack complex (MAC) • MAC causes cell lysis by inducing a massive influx of water • C3b also causes opsonization, and C3a causes inflammation

Interferons • Functions

• Anti-viral • Reduce inflammation • Activate macrophages and mobilize NK cells • Genetically engineered IFNs for • Antiviral agents against hepatitis and genital warts virus • Multiple sclerosis treatment

Agglutination

• Antibodies bind the same determinant on more than one cell-bound antigen • Cross-linked antigen-antibody complexes agglutinate • Example: clumping of mismatched blood cells

Antibody Targets

• Antibodies inactivate and tag antigens • Form antigen-antibody (immune) complexes • Defensive mechanisms used by antibodies • Neutralization and agglutination (the two most important) • Precipitation and complement fixation

Comparison of Humoral and Cell-Mediated Response

• Antibodies of the humoral response • The simplest ammunition of the immune response • Targets • Bacteria and molecules in extracellular environments (body secretions, tissue fluid, blood, and lymph)

Humoral Immunity Response

• Antigen challenge • First encounter between an antigen and a naive immunocompetent lymphocyte • Usually occurs in the spleen or a lymph node • If the lymphocyte is a B cell • The antigen provokes a humoral immune response • Antibodies are produced

Passive Humoral Immunity

• B cells are not challenged by antigens • Immunological memory does not occur

B Cells

• B cells mature in red bone marrow • Self-reactive B cells • Are eliminated by apoptosis (clonal deletion) or • Undergo receptor editing - rearrangement of their receptors • Are inactivated (anergy) if they escape from the bone marrow

Comparison of Humoral and Cell-Mediated Response

T cells of the cell-mediated response • Recognize and respond only to processed fragments of antigen displayed on the surface of body cells • Targets • Body cells infected by viruses or bacteria • Abnormal or cancerous cells • Cells of infused or transplanted foreign tissue

Generating Antibody Diversity

• Billions of antibodies result from somatic recombination of gene segments • Hypervariable regions of some genes increase antibody variation through somatic mutations • Each plasma cell can switch the type of H chain produced, making an antibody of a different class

Cytotoxic T Cells

• Bind to a self-nonself complex • Can destroy all infected or abnormal cells • Lethal hit • Tc cell releases perforins and granzymes by exocytosis • Perforins create pores through which granzymes enter the target cell • Granzymes stimulate apoptosis • In some cases, TC cell binds with a Fas receptor on the target cell, and stimulates apoptosis

Class I MHC Proteins

• Bind with fragment of a protein synthesized in the cell (endogenous antigen) • Endogenous antigen is a self-antigen in a normal cell; a nonself antigen in an infected or abnormal cell • Informs cytotoxic T cells of the presence of microorganisms hiding in cells (cytotoxic T cells ignore displayed self-antigens)

Class II MHC Proteins

• Bind with fragments of exogenous antigens that have been engulfed and broken down in a phagolysosome • Recognized by helper T cells

T Cell Activation: Antigen Binding

• CD4 and CD8 cells bind to different classes of MHC proteins (MHC restriction) • CD4 cells bind to antigen linked to class II MHC proteins of APCs • CD8 cells are activated by antigen fragments linked to class I MHC of APCs

• Major types of T cells

• CD4 cells become helper T cells (TH) when activated • CD8 cells become cytotoxic T cells (TC) that destroy cells harboring foreign antigens • Regulatory T cells (TREG) • Memory T cells

Antigenic Determinants

• Certain parts of an entire antigen that are immunogenic • Antibodies and lymphocyte receptors bind to them

MHC Proteins

• Classes of MHC proteins • Class I MHC proteins, found on virtually all body cells • Class II MHC proteins, found on certain cells in the immune response • MHC proteins display peptides (usually self-antigens) • In infected cells, MHC proteins display fragments of foreign antigens, which help mobilize

Monoclonal Antibodies

• Commercially prepared pure antibody • Produced by hybridomas • Cell hybrids: fusion of a tumor cell and a B cell • Proliferate indefinitely and have the ability to produce a single type of antibody • Used in research, clinical testing, and cancer treatment

Mechanism of Phagocytosis

• Destruction of pathogens • Acidification and digestion by lysosomal enzymes • Respiratory burst • Release of cell-killing free radicals • Activation of additional enzymes • Oxidizing chemicals (e.g. H2O2) • Defensins (in neutrophils)

Roles of Cytotoxic T(TC) Cells

• Directly attack and kill other cells • Activated TC cells circulate in blood and lymph and lymphoid organs in search of body cells displaying antigen they recognize

Complement Activation

• Each pathway involves activation of proteins in an orderly sequence • Each step catalyzes the next • Both pathways converge on C3, which cleaves into C3a and C3b

Antigen-Presenting Cells (APCs)

• Engulf antigens • Present fragments of antigens to be recognized by T cells • Major types • Dendritic cells in connective tissues and epidermis • Macrophages in connective tissues and lymphoid organs • B cells

• Dendritic cells are able to obtain other cells' endogenous antigens by

• Engulfing dying virus-infected or tumor cells • Importing antigens through temporary gap junctions with infected cells • Dendritic cells then display the endogenous antigens on both class I and class II MHCs

• T cells that are activated

• Enlarge, proliferate, and form clones • Differentiate and perform functions according to their T cell class

Step 1: Adherence of phagocyte to pathogen

• Facilitated by opsonization—coating of pathogen by complement proteins or antibodies

1. Innate defense system has two lines of defense

• First line of defense is external body membranes (skin and mucosae) • Second line of defense is antimicrobial proteins, phagocytes, and other cells • Inhibit spread of invaders • Inflammation is its most important mechanism

Organ Transplants

• Four varieties • Autografts: from one body site to another in the same person • Isografts: between identical twins • Allografts: between individuals who are not identical twins • Xenografts: from another animal species

Inflammatory Response: Edema

• Functions of the surge of exudate • Moves foreign material into lymphatic vessels • Delivers clotting proteins to form a scaffold for repair and to isolate the area

Fever

• High fevers are dangerous because heat denatures enzymes • Benefits of moderate fever • Causes the liver and spleen to sequester iron and zinc (needed by microorganisms) • Increases metabolic rate, which speeds up repair

Antigen Recognition

• Immunocompetent T cells are activated when their surface receptors bind to a recognized antigen (nonself) • T cells must simultaneously recognize • Nonself (the antigen) • Self (an MHC protein of a body cell)

Antibodies

• Immunoglobulins—gamma globulin portion of blood • Proteins secreted by plasma cells • Capable of binding specifically with antigen detected by B cells

Complete Antigens

• Important functional properties • Immunogenicity: ability to stimulate proliferation of specific lymphocytes and antibodies • Reactivity: ability to react with products of activated lymphocytes and antibodies released • Examples: foreign protein, polysaccharides, lipids, and nucleic acids

Vasodilation and Increased Vascular Permeability

• Inflammatory chemicals cause • Dilation of arterioles, resulting in hyperemia • Increased permeability of local capillaries and edema (leakage of exudate) • Exudate contains proteins, clotting factors, and antibodies

• Inflammatory mediators

• Inflammatory mediators • Histamine (from mast cells) • Blood proteins • Kinins, prostaglandins (PGs), leukotrienes, and complement • Released by injured tissue, phagocytes, lymphocytes, basophils, and mast cells

• Immune system has two intrinsic systems

• Innate (nonspecific) defense system • Adaptive (specific) defense system

Helper T Cells

• Interact directly with B cells displaying antigen fragments bound to MHC II receptors • 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 require TH co-stimulation to activate B cells

Antimicrobial Proteins

• Interferons (IFNs) and complement proteins • Attack microorganisms directly • Hinder microorganisms' ability to reproduce

• Adaptive immune response

• Is specific • Is systemic • Has memory

Natural Killer (NK) Cells

• Large granular lymphocytes • Target cells that lack "self" cell-surface receptors • Induce apoptosis in cancer cells and virus-infected cells • Secrete potent chemicals that enhance the inflammatory response

Antigen Receptor Diversity

• Lymphocytes make up to a billion different types of antigen receptors • Coded for by ~25,000 genes • Gene segments are shuffled by somatic recombination • Genes determine which foreign substances the immune system will recognize and resist

Interferons • Produced by a variety of body cells

• Lymphocytes produce gamma (), or immune, interferon • Most other WBCs produce alpha () interferon • Fibroblasts produce beta () interferon • Interferons also activate macrophages and mobilize NKs

Clonal Selection

1. B cell is activated when antigens bind to its surface receptors and cross-link them 2. Receptor-mediated endocytosis of cross-linked antigen-receptor complexes occurs 3. Stimulated B cell grows to form a clone of identical cells bearing the same antigen-specific receptors (T cells are usually required to help B cells achieve full activation)

Complement Activation • Two pathways

1. Classical pathway • Antibodies bind to invading organisms • C1 binds to the antigen-antibody complexes (complement fixation) 2. Alternative pathway • Triggered when activated C3, B, D, and P interact on the surface of microorganisms

• Two separate overlapping arms

1. Humoral (antibody-mediated) immunity 2. Cellular (cell-mediated) immunity

Phagocyte Mobilization

1. Leukocytosis: release of neutrophils from bone marrow in response to leukocytosis-inducing factors from injured cells 2. Margination: neutrophils cling to the walls of capillaries in the inflamed area 3. Diapedesis of neutrophils 4. Chemotaxis: inflammatory chemicals (chemotactic agent) promote positive chemotaxis of neutrophils

• Cardinal signs of acute inflammation:

1. Redness 2. Heat 3. Swelling 4. Pain (And sometimes 5. Impairment of function)

• Activated complement functions

Amplifies the inflammatory response • Opsonization • Enlists more and more defensive elements

Inflammatory Response

• Macrophages and epithelial cells of boundary tissues bear Toll-like receptors (TLRs) • TLRs recognize specific classes of infecting microbes • Activated TLRs trigger the release of cytokines that promote inflammation

Phagocytes: Macrophages

• Macrophages develop from monocytes to become the chief phagocytic cells • Free macrophages wander through tissue spaces • E.g., alveolar macrophages • Fixed macrophages are permanent residents of some organs • E.g., Kupffer cells (liver) and microglia (brain)

Complement Fixation and Activation

• Main antibody defense against cellular antigens • Several antibodies bind close together on a cellular antigen • Their complement-binding sites trigger complement fixation into the cell's surface • Complement triggers cell lysis

Cytokines

• Mediate cell development, differentiation, and responses in the immune system • Include interleukins and interferons • Interleukin 1 (IL-1) released by macrophages co-stimulates bound T cells to • Release interleukin 2 (IL-2) • Synthesize more IL-2 receptors • IL-2 is a key growth factor, acting on cells that release it and other T cells • Encourages activated T cells to divide rapidly • Used therapeutically to treat melanoma and kidney cancers • Other cytokines amplify and regulate innate and adaptive responses

• Most naturally occurring antigens have numerous antigenic determinants that

• Mobilize several different lymphocyte populations • Form different kinds of antibodies against it • Large, chemically simple molecules (e.g., plastics) have little or no immunogenicity

• IgE

• Monomer active in some allergies and parasitic infections • Causes mast cells and basophils to release histamine

• IgD

• Monomer attached to the surface of B cells • Functions as a B cell receptor

• IgA (secretory IgA)

• Monomer or dimer; in mucus and other secretions • Helps prevent entry of pathogens

• IgG

• Monomer; 75-85% of antibodies in plasma • From secondary and late primary responses • Crosses the placental barrier

Fate of the Clones

• Most clone cells become plasma cells • secrete specific antibodies at the rate of 2000 molecules per second for four to five days • Secreted antibodies • Circulate in blood or lymph • Bind to free antigens • Mark the antigens for destruction • Clone cells that do not become plasma cells become memory cells • Provide immunological memory • Mount an immediate response to future exposures of the same antigen

• Respiratory system modifications

• Mucus-coated hairs in the nose • Cilia of upper respiratory tract sweep dust- and bacteria-laden mucus from lower respiratory passages

Internal Defenses: Cells and Chemicals

• Necessary if microorganisms invade deeper tissues • Phagocytes • Natural killer (NK) cells • Inflammatory response (macrophages, mast cells, WBCs, and inflammatory chemicals) • Antimicrobial proteins (interferons and complement proteins) • Fever

Phagocytes: Neutrophils

• Neutrophils • Become phagocytic on encountering infectious material in tissues

Immunological Memory • Secondary immune response

• Occurs on re-exposure to the same antigen • Sensitized memory cells respond within hours • Antibody levels peak in two to three days at much higher levels • Antibodies bind with greater affinity • Antibody level can remain high for weeks to months

Active Humoral Immunity

• Occurs when B cells encounter antigens and produce specific antibodies against them • Two types • Naturally acquired—response to a bacterial or viral infection • Artificially acquired—response to a vaccine of dead or attenuated pathogens

Lymphocytes

• Originate in red bone marrow • B cells mature in the red bone marrow • T cells mature in the thymus

Roles of Helper T(TH) Cells

• Play a central role in the adaptive immune response • Once primed by APC presentation of antigen, they • Help activate T and B cells • Induce T and B cell proliferation • Activate macrophages and recruit other immune cells • Without TH, there is no immune response

Macrophages and Dendritic Cells

• Present antigens and activate T cells • Macrophages mostly remain fixed in the lymphoid organs • Dendritic cells internalize pathogens and enter lymphatics to present the antigens to T cells in lymphoid organs • Activated T cells release chemicals that • Prod macrophages to become insatiable phagocytes and to secrete bactericidal chemicals

T Cell Activation: Co-Stimulation

• Primary T cell response peaks within a week • T cell apoptosis occurs between days 7 and 30 • Effector activity wanes as the amount of antigen declines • Benefit of apoptosis: activated T cells are a hazard • Memory T cells remain and mediate secondary responses

Self-Antigens: MHC Proteins

• Protein molecules (self-antigens) on the surface of cells • Antigenic to others in transfusions or grafts • Example: MHC proteins • Coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual

T Cell Activation: Co-Stimulation

• Requires T cell binding to other surface receptors on an APC • Dendritic cells and macrophages produce surface B7 proteins when innate defenses are mobilized • B7 binding with a CD28 receptor on a T cell is a crucial co-stimulatory signal • Cytokines (interleukin 1 and 2 from APCs or T cells) trigger proliferation and differentiation of activated T cell

Immunity

• Resistance to disease

Neutralization

• Simplest mechanism • Antibodies block specific sites on viruses or bacterial exotoxins • Prevent these antigens from binding to receptors on tissue cells • Antigen-antibody complexes undergo phagocytosis

• Protective chemicals inhibit or destroy microorganisms

• Skin acidity • Lipids in sebum and dermcidin in sweat • HCl and protein-digesting enzymes of stomach mucosae • Lysozyme of saliva and lacrimal fluid • Mucus

Innate Defenses

• Skin, mucous membranes, and their secretions • Physical barrier to most microorganisms • Keratin is resistant to weak acids and bases, bacterial enzymes, and toxins • Mucosae provide similar mechanical barriers

Haptens (Incomplete Antigens)

• Small molecules (peptides, nucleotides, and hormones) • Not immunogenic by themselves • Are immunogenic when attached to body proteins • Cause the immune system to mount a harmful attack • Examples: poison ivy, animal dander, detergents, and cosmetics

Precipitation

• Soluble molecules are cross-linked • Complexes precipitate and are subject to phagocytosis

Active Humoral Immunity • Vaccines

• Spare us the symptoms of the primary response • Provide antigenic determinants that are immunogenic and reactive • Target only one type of helper T cell, so fail to fully establish cellular immunological memory

Antigens

• Substances that can mobilize the adaptive defenses and provoke an immune response • Most are large, complex molecules not normally found in the body (nonself)

Fever

• Systemic response to invading microorganisms • Leukocytes and macrophages exposed to foreign substances secrete pyrogens • Pyrogens reset the body's thermostat upward

• Without co-stimulation, anergy occurs

• T cells • Become tolerant to that antigen • Are unable to divide • Do not secrete cytokines

T Cells

• T cells mature in the thymus under negative and positive selection pressures • Positive selection • Selects T cells capable of binding to self-MHC proteins (MHC restriction) • Negative selection • Prompts apoptosis of T cells that bind to self-antigens displayed by self-MHC • Ensures self-tolerance

Cell-Mediated Immune Response

• T cells provide defense against intracellular antigens • Two types of surface receptors of T cells • T cell antigen receptors • Cell differentiation glycoproteins • CD4 or CD8 • Play a role in T cell interactions with other cells

Basic Antibody Structure

• T-or Y-shaped monomer of four looping linked polypeptide chains • Two identical heavy (H) chains and two identical light (L) chains • Variable (V) regions of each arm combine to form two identical antigen-binding sites • Constant (C) region of stem determines • The antibody class (IgM, IgA, IgD, IgG, or IgE) • The cells and chemicals that the antibody can bind to • How the antibody class functions in antigen elimination

T Cell Activation: Antigen Binding

• TCR that recognizes the nonself-self complex is linked to multiple intracellular signaling pathways • Other T cell surface proteins are involved in antigen binding (e.g., CD4 and CD8 help maintain coupling during antigen recognition) • Antigen binding stimulates the T cell, but co-stimulation is required before proliferation can occur

Adaptive Defenses

• The adaptive immune (specific defense) system • Protects against infectious agents and abnormal body cells • Amplifies the inflammatory response • Activates complement

2. Adaptive defense system

• Third line of defense attacks particular foreign substances • Takes longer to react than the innate system • Innate and adaptive defenses are deeply intertwined

Inflammatory Response

• Triggered whenever body tissues are injured or infected • Prevents the spread of damaging agents • Disposes of cell debris and pathogens • Sets the stage for repair

Passive Humoral Immunity • Two types

• Two types 1. Naturally acquired—antibodies delivered to a fetus via the placenta or to infant through milk 2. Artificially acquired—injection of serum, such as gamma globulin • Protection is immediate but ends when antibodies naturally degrade in the body

MHC Proteins

• Two types of MHC proteins are important to T cell activation • Class I MHC proteins - displayed by all cells except RBCs • Class II MHC proteins - displayed by APCs (dendritic cells, macrophages and B cells) • Both types are synthesized at the ER and bind to peptide fragments

Cells of the Adaptive Immune System

• Two types of lymphocytes • B lymphocytes (B cells)—humoral immunity • T lymphocytes (T cells)—cell-mediated immunity • Antigen-presenting cells (APCs) • Do not respond to specific antigens • Play essential auxiliary roles in immunity

Adaptive Immunity: Summary

• Uses lymphocytes, APCs, and specific molecules to identify and destroy nonself substances • Depends upon the ability of its cells to • Recognize antigens by binding to them • Communicate with one another so that the whole system mounts a specific response

Interferons

• Viral-infected cells are activated to secrete IFNs • IFNs enter neighboring cells • Neighboring cells produce antiviral proteins that block viral reproduction

Roles of Cytotoxic T(TC) Cells • Targets

• Virus-infected cells • Cells with intracellular bacteria or parasites • Cancer cells • Foreign cells (transfusions or transplants

Mature Lymphocytes

• When mature, they have • Immunocompetence; they are able to recognize and bind to a specific antigen • Self-tolerance - unresponsive to self antigens • Naive (unexposed) B and T cells are exported to lymph nodes, spleen, and other lymphoid organs

Complement

• ~20 blood proteins that circulate in an inactive form • Include C1-C9, factors B, D, and P, and regulatory proteins • Major mechanism for destroying foreign substances • Amplifies all aspects of the inflammatory response • Kills bacteria and certain other cell types by cell lysis • Enhances both nonspecific and specific defenses