Defense System

® Nonspecific defenses

® Present at birth

® Specific defenses

® Develop in response to invasion / injury

Immunity: Two Intrinsic Defense Systems

® Innate (nonspecific) system responds quickly and consists of:

® First line of defense – 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 most important mechanism

® 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

Innate and Adaptive Defenses

Surface Barriers

® Skin, mucous membranes, and their secretions make up the first line of defense

® Keratin in the skin:

® Presents a physical barrier to most microorganisms

® Is resistant to weak acids and bases, bacterial enzymes, and toxins

® Mucosae provide similar mechanical barriers

® 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

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

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

Nonspecific Defenses

® Phagocytes

® Neutrophils

® Become phagocytic when encountering infectious material

® Macrophages

® Chief phagocytic cells

® Wandering

l Wander throughout a region in search of cellular debris

® Fixed

l Kupffer cells (liver) and microglia (brain) are fixed macrophages

Mechanism of Phagocytosis

® Microbes adhere to the phagocyte

® Pseudopods engulf the particle (antigen) into a phagosome

® Phagosomes fuse with a lysosome to form a phagolysosome

® Invaders in the phagolysosome are digested by proteolytic enzymes

® Indigestible and residual material is removed by exocytosis

Nonspecific Defenses

® Natural Killer (NK) Cells

® Are a small, distinct group of large granular lymphocytes

® Kill their target cells by releasing perforins and other cytolytic chemicals

® Secrete potent chemicals that enhance the inflammatory response

® Several steps

® Recognition

® Adhesion

® Perforin release

® Apoptosis

Nonspecific Defenses

® Inflammatory response

® 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

® Vasodilation

® Increased permeability of blood vessels

® Mediated by

® Histamine

® Kinins

® Prostaglandins

® Leukotrienes

® Complement proteins

Antimicrobial Proteins

® Enhance the innate defenses by:

® Attacking microorganisms directly

® Hindering microorganisms’ ability to reproduce

® The most important antimicrobial proteins are:

® Interferons

® Complement proteins

Interferons (IFN)

® Genes that synthesize IFN are activated when a host cell is invaded by a virus

® Interferons are released from the infected cell and act on receptors on neighboring cells

® Interferon stimulates the neighboring cells to activate genes for PKR (an antiviral protein)

® PKR nonspecifically blocks viral reproduction in the neighboring cell

Complement System

® 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

® 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

® Effects

® Inflammation

® Enhance phagocytosis

® Opsonization

® Cytolysis

® Membrane attack complex (MAC)

^®MAC causes cell lysis by interfering with a cell’s ability to eject Ca²⁺

Complement Pathways

® Complement can be activated by two pathways: classical and alternative

® Classical pathway is linked to the immune system

® Depends on the binding of antibodies to invading organisms

® Subsequent binding of C1 to the antigen-antibody complexes (complement fixation)

® Alternative pathway is triggered by interaction among factors B, D, and P, and polysaccharide molecules present on microorganisms

® Each pathway involves a cascade in which complement proteins are activated in a sequence where each step catalyzes the next

® Both pathways converge on C3, which cleaves into C3a and C3b

® C3b initiates formation of a membrane attack complex (MAC)

® C3b also causes opsonization, and C3a causes inflammation

Complement Pathways

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

® High fevers are dangerous because 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

Adaptive (Specific) Defenses

® The adaptive immune system is a functional system that:

® Recognizes specific foreign substances

® Acts to immobilize, neutralize, or destroy foreign substances

® Amplifies inflammatory response and activates complement

® The adaptive immune system is antigen-specific, systemic, and has memory

® Tolerance

® Self vs. nonself antigens

® It has two separate specific defenses:

® Humoral, or antibody-mediated immunity

® Cellular, or cell-mediated immunity

ANTIGENS

® Substances that can mobilize the immune system and provoke an immune response

® The ultimate targets of all immune responses are mostly large, complex molecules not normally found in the body (nonself)

® Important functional properties:

® Immunogenicity – ability to stimulate proliferation of specific lymphocytes and antibody production

® Reactivity – ability to react with products of activated lymphocytes and the antibodies released in response to them

Antigenic Determinants

® Also called epitopes

® Only certain parts of an entire antigen are immunogenic

® Antibodies and activated lymphocytes bind to these antigenic determinants

® Most naturally occurring antigens have numerous antigenic determinants that:

® Mobilize several different lymphocyte populations

® Form different kinds of antibodies against it

Self-Antigens: MHC Proteins

® Our cells are dotted with protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others

® One type, MHC proteins, mark a cell as self

® The two classes of MHC proteins are:

® Class I MHC proteins – found on virtually all body cells

® Class II MHC proteins – found on certain cells in the immune response

® Are coded for by genes of the major histocompatibility complex (MHC) and are unique to an individual

® Each MHC molecule has a deep groove that displays a peptide, which is a normal cellular product of protein recycling

® In infected cells, MHC proteins bind to fragments of foreign antigens, which play a crucial role in mobilizing the immune system

Cells of the Adaptive Immune System

® Two types of lymphocytes

® B lymphocytes – oversee humoral immunity

® T lymphocytes – non-antibody-producing cells that constitute the cell-mediated arm of immunity

® Immature lymphocytes released from bone marrow are essentially identical

® Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent

® B cells mature in the bone marrow

® T cells mature in the thymus

Clonal Selection

® Stimulated B cell growth forms clones bearing the same antigen-specific receptors

® A 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

® These activating events, plus T cell interactions, trigger clonal selection

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

® 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

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

® 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

Antibody Structure

® Variable regions of the heavy and light chains combine to form the antigen-binding site

® 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

Basic Antibody Structure

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:

® Neutralization

® Antibodies bind to and block specific sites on viruses or exotoxins, thus preventing these antigens from binding to receptors on tissue cells

® Agglutination/precipitation

® Antibodies bind the same determinant on more than one antigen

® Complement activation

® Attract phagocytes

Mechanisms of Antibody Action

Antibody Responses

® Primary response

® Cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen

® Antibody titer

® Lag period: 3 to 6 days after antigen challenge

® Peak levels of plasma antibody are achieved in 10 days

® Antibody levels then decline

® Secondary 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

Primary and Secondary Humoral Responses

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

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 (T_H)

® CD8 cells (T8 cells) are cytotoxic T cells (T_C) that destroy cells harboring foreign antigens

® Other types of T cells are:

® Regulatory T cells (T_Reg)

® Release cytokines, which suppress the activity of both T cells and B cells

® Memory T cells

® T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells

® Double recognition - T cells must simultaneously recognize:

® Nonself (the antigen)

® Self (a MHC protein of a body cell)

® Both types of MHC proteins are important to T cell activation

Class I MHC Proteins

® Class I MHC proteins

® Always recognized by CD8 T cells

® Display peptides from endogenous antigens

® 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

Class II MHC Proteins

® Class II MHC proteins are found only on mature B cells, dendrite cells, and macrophages

® 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 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

T Cells

® Activation

® T-cell receptors (TCRs)

® Costimulation

® Proliferation

® Differentiation

® Clone

® Elimination

Helper T Cells (T_H)

® 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 T_H, there is no immune response

Cytotoxic T Cell (T_c)

® T_C 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

® Perforin

® Bind to the target cell and release perforin into its membrane

® In the presence of Ca²⁺ perforin creates transmembrane pores and stimulates apoptois (cell suicide)

® Gamma-interferon

® Secreting gamma interferon, which stimulates phagocytosis by macrophages

Mechanisms of T_c Action

Major Types of T Cells

Immune Disorders

® Autoimmune diseases

® Loss of the immune system’s ability to distinguish self from nonself

® The body produces autoantibodies and sensitized T_C cells that destroy its own tissues

® Examples include Type I (juvenile) diabetes mellitus, glomerulonephritis, and rheumatoid arthritis

Immune Disorders

® Immunodeficiency diseases

® 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

® SCID is fatal if untreated; treatment is with bone marrow transplants

® Acquired immune deficiency syndrome (AIDS) – cripples the immune system by interfering with the activity of helper T (CD4) cells