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The Immune System: Innate and Adaptive Body
Defenses: Part B
Antibodies
• Immunoglobulins—gamma globulin portion of blood
• Proteins secreted by plasma cells
• Capable of binding specifically with antigen detected by B 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
Basic Antibody Structure
• 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
Classes of Antibodies
• IgM
• A pentamer; first antibody released
• Potent agglutinating agent
• Readily fixes and activates complement
• IgA (secretory IgA)
• Monomer or dimer; in mucus and other secretions
• Helps prevent entry of pathogens
Classes of Antibodies
• IgD
• Monomer attached to the surface of B cells
• Functions as a B cell receptor
• IgG
• Monomer; 75–85% of antibodies in plasma
• From secondary and late primary responses
• Crosses the placental barrier
Classes of Antibodies
• IgE
• Monomer active in some allergies and parasitic infections
• Causes mast cells and basophils to release histamine
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
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
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
Agglutination
• Antibodies bind the same determinant on more than one cellbound antigen
• Cross-linked antigen-antibody complexes agglutinate
• Example: clumping of mismatched blood cells
Precipitation
• Soluble molecules are cross-linked
• Complexes precipitate and are subject to phagocytosis
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
Complement Fixation and Activation
• Activated complement functions
• Amplifies the inflammatory response
• Opsonization
• Enlists more and more defensive elements
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
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
Cell-Mediated Immune Response
• 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
• Other types of T cells
• Regulatory T cells (TREG)
• Memory T cells
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)
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
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)
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
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
• 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
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
T Cell Activation: Antigen Binding
• 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 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
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
T Cell Activation: Co-Stimulation
• Without co-stimulation, anergy occurs
• T cells
• Become tolerant to that antigen
• Are unable to divide
• Do not secrete cytokines
T Cell Activation: Co-Stimulation
• T cells that are activated
• Enlarge, proliferate, and form clones
• Differentiate and perform functions according to their T cell class
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
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
Cytokines
• 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
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
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
Helper T Cells
• Cause dendritic cells to express co-stimulatory molecules
required for CD8 cell activation
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
Roles of Cytotoxic T(TC) Cells
• Targets
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Virus-infected cells
Cells with intracellular bacteria or parasites
Cancer cells
Foreign cells (transfusions or transplants)
Cytotoxic T Cells
• Bind to a self-nonself complex
• Can destroy all infected or abnormal cells
Cytotoxic T 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
Natural Killer Cells
• Recognize other signs of abnormality
• Lack of class I MHC
• Antibody coating a target cell
• Different surface marker on stressed cells
• Use the same key mechanisms as Tc cells for killing their target
cells
Regulatory T (TReg) Cells
• Dampen the immune response by direct contact or by inhibitory
cytokines
• Important in preventing autoimmune reactions
Organ Transplants
• Four varieties
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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
Prevention of Rejection
• Depends on the similarity of the tissues
• Patient is treated with immunosuppressive therapy
• Corticosteroid drugs to suppress inflammation
• Antiproliferative drugs
• Immunosuppressant drugs
• Many of these have severe side effects
Immunodeficiencies
• Congenital and acquired conditions that cause immune cells,
phagocytes, or complement to behave abnormally
Severe Combined Immunodeficiency (SCID) Syndrome
• Genetic defect
• Marked deficit in B and T cells
• Abnormalities in interleukin receptors
• Defective adenosine deaminase (ADA) enzyme
• Metabolites lethal to T cells accumulate
• SCID is fatal if untreated; treatment is with bone marrow
transplants
Hodgkin’s Disease
• An acquired immunodeficiency
• Cancer of the B cells
• 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 cells
• Characterized by severe weight loss, night sweats, and swollen
lymph nodes
• Opportunistic infections occur, including pneumocystis
pneumonia and Kaposi’s sarcoma
Acquired Immune Deficiency Syndrome (AIDS)
• Caused by human immunodeficiency virus (HIV) transmitted via body
fluids—blood, semen, and vaginal secretions
• HIV enters the body via
• Blood transfusions
• Blood-contaminated needles
• Sexual intercourse and oral sex
• HIV
• Destroys TH cells
• Depresses cell-mediated immunity
Acquired Immune Deficiency Syndrome (AIDS)
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HIV multiplies in lymph nodes throughout the asymptomatic period
Symptoms appear in a few months to 10 years
HIV-coated glycoprotein complex attaches to the CD4 receptor
HIV enters the cell and uses reverse transcriptase to produce DNA from
viral RNA
• The DNA copy (a provirus) directs the host cell to make viral RNA and
proteins, enabling the virus to reproduce
Acquired Immune Deficiency Syndrome (AIDS)
• HIV reverse transcriptase produces frequent transcription
errors; high mutation rate and resistance to drugs
• Treatment with antiviral drugs
• Reverse transcriptase inhibitors (AZT)
• Protease inhibitors (saquinavir and ritonavir)
• New Fusion inhibitors that block HIV’s entry to helper T cells
Autoimmune Diseases
• Immune system loses the ability to distinguish self from foreign
• Production of autoantibodies and sensitized TC cells that
destroy body tissues
• Examples include multiple sclerosis, myasthenia gravis,
Graves’ disease, type I diabetes mellitus, systemic lupus
erythematosus (SLE), glomerulonephritis, and rheumatoid
arthritis
Mechanisms of Autoimmune Diseases
1.Foreign antigens may resemble self-antigens
• Antibodies against the foreign antigen may cross-react with self-antigen
2.New self-antigens may appear, generated by
• Gene mutations
• Changes in self-antigens by hapten attachment or as a result of infectious
damage
Mechanisms of Autoimmune Diseases
3.Release of novel self-antigens by trauma of a barrier (e.g., the
blood-brain barrier)
Hypersensitivities
• Immune responses to a perceived (otherwise harmless) threat
• Causes tissue damage
• Different types are distinguished by
• Their time course
• Whether antibodies or T cells are involved
• Antibodies cause immediate and subacute hypersensitivities
• T cells cause delayed hypersensitivity
Immediate Hypersensitivity
• Acute (type I) hypersensitivities (allergies) begin in seconds
after contact with allergen
• Initial contact is asymptomatic but sensitizes the person
• Reaction may be local or systemic
Immediate Hypersensitivity
• The mechanism involves IL-4 secreted by T cells
• IL-4 stimulates B cells to produce IgE
• IgE binds to mast cells and basophils, resulting in a flood of
histamine release and inducing the inflammatory response
Anaphylactic Shock
• Systemic response to allergen that directly enters the blood
• Basophils and mast cells are enlisted throughout the body
• Systemic histamine releases may cause
• Constriction of bronchioles
• Sudden vasodilation and fluid loss from the bloodstream
• Hypotensive shock and death
• Treatment: epinephrine
Subacute Hypersensitivities
• Caused by IgM and IgG transferred via blood plasma or serum
• Slow onset (1–3 hours) and long duration (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
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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)
• Slow onset (one to three days)
• Mechanism depends on helper T cells
• Cytokine-activated macrophages and cytotoxic T cells cause
damage
• Example: allergic contact dermatitis (e.g., poison ivy)
Developmental Aspects
• Immune system stem cells develop in the liver and spleen by
the ninth week
• Bone marrow becomes the primary source of stem cells
• Lymphocyte development continues in the bone marrow and
thymus
Developmental Aspects
• 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, and incidence of
cancer increases