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 Chapter Notes for Lecture: E.N. Marieb, HUMAN ANATOMY & PHYSIOLOGY,5TH Edition, , Benjamine Cummings Publisher, 2001 Prepare from : V.A. Austin’s PowerPpoint Presentation (ISBN: 0-8053-5469-7), CD ROM: Pearson Education, Inc. , 2003.ter

22

The Immune System: Innate and Adaptive Body Defenses

Immunity: Two Intrinsic Defense Systems

•      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 invaders spread throughout the body

•   Inflammation is its hallmark and most important mechanism

Immunity: Two Intrinsic Defense Systems

•      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

•      Microbes adhere to the phagocyte

•      Pseudopods engulf the particle (antigen) into a phagosome

•      Phagosomes fuse with a lysosome to form a phagolysosome

•      Microbes in the phagolysosome are enzymatically digested

•      Indigestible and residual material is removed by exocytosis

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 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

Inflammatory 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, resulting in hyperemia

Inflammatory Response: Vascular Permeability

•      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)

•   The edema contributes to the sensation of pain

Inflammatory Response: Edema

•      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 prevent the spread of bacteria

Inflammatory Response: Phagocytic Mobilization

•      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

Antimicrobial 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 Family

•      Interferons are a family of related proteins each with slightly different physiological effects

•      Lymphocytes secrete gamma (g) interferon, but most other WBCs secrete alpha (a) interferon

•      Fibroblasts secrete beta (b) interferon

•      Interferons also activate macrophages and mobilize NKs

•      FDA-approve alpha IFN is used:

•    As an antiviral drug against hepatitis C virus

•    To treat genital warts caused by a herpes virus

Complement

•      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

Complement Pathways

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

•      Classical pathway is linked to the immune system

•    Depends upon 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 an orderly sequence and 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)

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

•      C3b also causes opsonization, and C3a causes inflammation

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 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

Adaptive (Specific) Defenses

•      The adaptive immune system is a functional system that:

•    Recognizes specific foreign substances

•    Acts to immobilize, neutralize, or destroy them

•    Amplifies inflammatory response and activates complement

Adaptive Immune Defenses

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

•      It has two separate but overlapping arms

•    Humoral, or antibody-mediated immunity

•    Cellular, or cell-mediated immunity

Antigens (Ags)

•      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)

Complete Antigens

•      Important functional properties:

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

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

•      Complete antigens include foreign protein, nucleic acid, some lipids, and large polysaccharides

Haptens (Incomplete Antigens)

•      Small molecules, such as peptides, nucleotides, and many hormones, that are not immunogenic but are reactive when attached to protein carriers

•      If they link up with the body’s proteins, the adaptive immune system may recognize them as foreign and mount a harmful attack (allergy)

•      Haptens are found in poison ivy, dander, some detergents, and cosmetics

Antigenic Determinants

•      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

•      Large, chemically-simple molecules (e.g., plastics) have little or no immunogenicity

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 of these, 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 immune response

MHC Proteins

•      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

•      Antigen-presenting cells (APCs):

•    Do not respond to specific antigens

•    Play essential auxiliary roles in immunity

Lymphocytes

•      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

T Cells and B Cells

•      T cells mature in the thymus under negative and positive selection pressures

•    Negative selection – eliminates T cells that are strongly anti-self

•    Positive selection – selects T cells with a weak response to self-antigens, which thus become both immunocompetent and self-tolerant

•      B cells become immunocompetent and self-tolerant in bone marrow

Immunocompetent B or T cells

•      Display a unique type of receptor that responds to a distinct antigen

•      Become immunocompetent before they encounter antigens they may later attack

•      Are exported to secondary lymphoid tissue where encounters with antigens occur

•      Mature into fully functional antigen-activated cells upon binding with their recognized antigen

•      It is genes, not antigen, that determine which foreign substance our immune system will recognize and resist

Antigen-Presenting Cells (APCs)

•      Major rolls in immunity are:

•    To engulf foreign particles

•    To present fragment of antigens on their own surfaces, to be recognized by T cells

•      Major APCs are dendritic cells (DCs), macrophages, and activated B cells

•      The major initiators of adaptive immunity are DCs, which actively migrate to the lymph nodes and secondary lymphoid organs and present antigens to T and B cells

Macrophages and Dendritic Cells

•      Secrete soluble proteins that active T cells

•      Activated T cells in turn release chemicals that:

•    Rev up the maturation and mobilization of DCs

•    Prod macrophages to become activated macrophages, which are insatiable phagocytes and release bactericidal chemicals

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 and 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

•      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 to an 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

•      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

Immunological Memory

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 antigen

•    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

Antibodies (Ab)

•      Also called immunoglobulins (Igs)

•    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

•      Consist 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 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

Mechanisms of Antibody Diversity

•      Plasma cells make over a billion different types of antibodies

•      Each cell, however, only contains 100,000 genes that code for these polypeptides

•      To code for this many antibodies, somatic recombination takes place

•    Gene segments are shuffled and combined in different ways by each B cell as it becomes immunocompetent

•    Information of the newly assembled genes is expressed as B cell receptors and as antibodies

Antibody Diversity

•      Random mixing of gene segments makes unique antibody genes that:

•    Code for H and L chains

•    Account for part of the variability in antibodies

•      V gene segments, called hypervariable regions, mutate and increase antibody variation

•      Plasma cells can switch H chains, making two or more classes with the same V region

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

•      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

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

•      Hybridomas – cell hybrids made from a fusion of a tumor cell and a B cell

•    Have desirable properties of both parent cells – indefinite proliferation as well as the ability to produce a single type of antibody

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 (T4cells) are primarily helper T cells (TH)

•    CD8 cells (T8cells) are cytotoxic T cells (TC) that destroy cells harboring foreign antigens

•      Other types of T cells are:

•    Delayed hypersensitivity T cells (TDH)

•    Suppressor T cells (TS)

•    Memory T cells

Importance of Humoral and Cellular Responses

•      Humoral Response

•    Soluble antibodies

•   The simplest ammunition of the immune response

•   Interact in extracellular environments such as body secretions, tissue fluid, blood, and lymph

•      Cellular Response

•    T cells recognize and respond only to processed fragments of antigen displayed 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 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 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

Antigen Recognition

•      Provides the key for the immune system to recognize the presence of intracellular microorganisms

•      MHC proteins are ignored by T cells if they are complexed with self protein fragments

•      If MHC proteins are complexed with endogenous or exogenous antigenic peptides, they:

•    Indicate the presence of intracellular infectious microorganisms

•    Act as antigen holders

•    Form the self part of the self-antiself complexes recognized by T cells

T Cell Activation: Step One – Antigen Binding

•      T cell antigen receptors (TCRs):

•    Bind to an antigen–MHC protein complex

•    Have variable and constant regions consisting of two chains (alpha and beta)

•      MHC restriction – TH and TC bind to different classes of MHC proteins

•      TH cells bind to antigen linked to class II MHC proteins

•      Mobile APCs (Langerhans’ cells) quickly alert the body to the presence of antigen by migrating to the lymph nodes and presenting antigen

•      TC cells are activated by antigen fragments complexed with class I MHC proteins

•      APCs produce costimulatory molecules that are required for TC activation

•      TCR that acts to recognize the self-antiself 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)

T Cell Activation: Step Two – Costimulation

•      Before a T cell can undergo clonal expansion, it must recognize one or more costimulatory 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 costimulatory signal

•      Other costimulatory signals include cytokines and interleukin 1 and 2

•      Depending upon receptor type, costimulators can cause T cells to complete their activation or abort activation

•      Without costimulation, T cells:

•    Become tolerant to that antigen

•    Are unable to divide

•    Do not secrete cytokines

•      T cells that are activated:

•    Enlarge, proliferate, and form clones

•    Differentiate and perform functions according to their T cell class

•      Primary T cell response peaks within a week after signal exposure

•      T cells then undergo apoptosis between days 7 and 30

•      Effector activity wanes as the amount of antigen declines

•      The disposal of activated effector cells is a protective mechanism for the body

•      Memory T cells remain and mediate secondary responses to the same antigen

Cytokines

•      Mediators involved in cellular immunity, including hormonelike glycoproteins released by activated T cells and macrophages

•      Some are costimulators of T cells and T cell proliferation

•      Interleukin 1 (IL-1) released by macrophages costimulates bound T cells to:

•    Release interleukin 2 (IL-2)

•    Synthesize more IL-2 receptors

•      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

•      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

•      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 costimulation to activate B cells

•      Cytokines released by TH amplify nonspecific defenses

Cytotoxic T Cells (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

•      Bind to self-antiself complexes on all body cells

•      Infected or abnormal cells can be destroyed as long as appropriate antigen and costimulatory 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 protein in cancer cells, virus-infected cells, and cells of transplanted organs

Mechanisms of TC Action

•      In some cases, TC cells:

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

•   Perforin causes cell lysis by creating transmembrane pores

•      Other TC cells induce cell death by:

•    Secreting lymphotoxin, which fragments the target cell’s DNA

•    Releasing tumor necrosis factor (TNF), which triggers apoptosis

•    Secreting gamma interferon, which stimulates phagocytosis by macrophages

Other T Cells

•      Suppressor T cells (TS) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells

•      Delayed-type hypersensitivity cells (TDH) – cells instrumental in promoting allergic reactions called delayed hypersensitivity reactions

•      Gamma delta T cells – 10% of all T cells found in the intestines that are triggered by binding to MICA receptors

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) enzymes

•   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

AIDS

•      Caused by human immunodeficiency virus (HIV) transmitted via body fluids – blood, semen, and vaginal secretions

•      HIV enters the body via:

•    Blood transfusions

•    Contaminated needles

•    Intimate sexual contact, including oral sex

•      HIV:

•    Destroys TH cells

•    Depresses cell-mediated immunity

•      HIV multiplies in lymph nodes throughout the asymptomatic period

•      Symptoms appear in a few months to 10 years

•      Attachment

•    HIV’s coat protein (gp120) attaches to the CD4 receptor

•    A nearby protein (gp41) fuses the virus to the target cell

•      HIV enters the cell and uses reverse transcriptase to produce DNA from viral RNA

•      This DNA (provirus) directs the host cell to make viral RNA (and proteins), enabling the virus to reproduce and infect other cells

•      HIV reverse transcriptase is not accurate and produces frequent transcription errors

•    This high mutation rate causes resistance to drugs

•      Treatments include:

•    Reverse transcriptase inhibitors (AZT)

•    Protease inhibitors (saquinavir and ritonavir)

•    New drugs that are currently being developed, which block HIV’s entry to helper T cells

Autoimmune Diseases

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

•      The body produces autoantibodies and sensitized TC cells that destroy its own tissues

•      Examples include multiple sclerosis, myasthenia gravis, Graves’ disease, Type I (juvenile) diabetes mellitus, systemic lupus erythematosus (SLE), glomerulonephritis, and rheumatoid arthritis

Mechanisms of Autoimmune Disease

•      Ineffective lymphocyte programming – self-reactive T and B cells that should have been eliminated in the thymus and bone marrow escape into the circulation

•      New self-antigens appear, generated by:

•    Gene mutations that cause new proteins to appear

•    Changes in self-antigens by hapten attachment or as a result of infectious damage

•      Foreign antigens resemble self-antigens:

•    Antibodies made against foreign antigens cross-react with self-antigens

Hypersensitivity

•      Immune responses that cause tissue damage

•      Different types of hypersensitivity reactions are distinguished by:

•    Their time course

•    Whether antibodies or T cells are the principle immune elements involved

•      Antibody-mediated allergies are immediate and subacute hypersensitivities

•      The most important cell-mediated allergic condition is delayed hypersensitivity

Immediate Hypersensitivity

•      Acute (type I) hypersensitivities begin in seconds after contact with allergen

•      Anaphylaxis – initial allergen contact is asymptomatic but sensitizes the person

•    Subsequent exposures to allergen cause:

•   Release of histamine and inflammatory chemicals

•   Systemic or local responses

•    The mechanism involves IL-4 secreted by T cells

•    IL-4 stimulates B cells to produce IgE

•    IgE binds to mast cells and basophils causing them to degranulate, resulting in a flood of histamine release and inducing the inflammatory response

Local Type I Responses

•      Reactions include runny nose, itching reddened skin, and watery eyes

•      If allergen is inhaled, asthmatic symptoms appear – constriction of bronchioles and restricted airflow

•      If allergen is ingested, cramping, vomiting, and diarrhea occur

•      Antihistamines counteract these effects

Systemic Response: Anaphylactic Shock

•      Response to allergen that directly enters the blood (e.g., insect bite, injection)

•      Basophils and mast cells are enlisted throughout the body

•      Systemic histamine releases may result in:

•    Constriction of bronchioles

•    Sudden vasodilation and fluid loss from the bloodstream

•    Hypotensive shock and death

•      Treatment – epinephrine is the drug of choice

Subacute Hypersensitivities

•      Caused by IgM and IgG, and transferred via blood plasma or serum

•    Onset is slow (1–3 hours) after antigen exposure

•    Duration is long lasting (10–15 hours)

•      Cytotoxic (type II) reactions

•    Antibodies bind to antigens on specific body cells, stimulating phagocytosis and complement-mediated lysis of the cellular antigens

•    Example: mismatched blood transfusion reaction

Subacute Hypersensitivities

•      Immune complex (type III) hypersensitivity

•    Antigens are widely distributed through the body or blood

•    Insoluble antigen-antibody complexes form

•    Complexes cannot be cleared from a particular area of the body

•    Intense inflammation, local cell lysis, and death may result

•    Example: systemic lupus erythematosus (SLE)

Delayed Hypersensitivities (Type IV)

•      Onset is slow (1–3 days)

•      Mediated by mechanisms involving delayed hypersensitivity T cells (TDH cells) and cytotoxic T cells (TC cells)

•      Cytokines from activated TC are the mediators of the inflammatory response

•      Antihistamines are ineffective and corticosteroid drugs are used to provide relief

•      Example: allergic contact dermatitis (e.g., poison ivy)

•      Involved in protective reactions against viruses, bacteria, fungi, protozoa, cancer, and rejection of foreign grafts or transplants

Developmental Aspects

•      Immune system stem cells develop in the liver and spleen by the ninth week

•      Later, bone marrow becomes the primary source of stem cells

•      Lymphocyte development continues in the bone marrow and thymus

•      TH2 lymphocytes predominate in the newborn, and the TH1 system is educated as the person encounters antigens

•      The immune system is impaired by stress and depression

•      With age, the immune system begins to wane