Chapter Notes for Lecture: E.N. Marieb, HUMAN ANATOMY & PHYSIOLOGY,5^TH 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 (T_H)

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

• Other types of T cells are:

• Delayed hypersensitivity T cells (T_DH)

• Suppressor T cells (T_S)

• 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 – T_H and T_C bind to different classes of MHC proteins

• T_H 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

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

• APCs produce costimulatory molecules that are required for T_C 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 (T_H)

• 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 T_H, there is no immune response

• T_H cells interact directly with B cells that have antigen fragments on their surfaces bound to MHC II receptors

• T_H cells stimulate B cells to divide more rapidly and begin antibody formation

• B cells may be activated without T_H cells by binding to T cell–independent antigens

• Most antigens, however, require T_H costimulation to activate B cells

• Cytokines released by T_H amplify nonspecific defenses

Cytotoxic T Cells (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

• 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 T_C Action

• In some cases, T_C cells:

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

• Perforin causes cell lysis by creating transmembrane pores

• Other T_C 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 (T_S) – regulatory cells that release cytokines, which suppress the activity of both T cells and B cells

• Delayed-type hypersensitivity cells (T_DH) – 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 T_H 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 T_C 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 (T_DH cells) and cytotoxic T cells (T_C cells)

• Cytokines from activated T_C 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

• T_H2 lymphocytes predominate in the newborn, and the T_H1 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