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Adaptive Immunity An introduction
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Immunity Innate immunity: defenses against any pathogen
Macrophages Dendritic cells (DCs) NK cells Paneth cells Adaptive immunity: induced resistance to a specific pathogen Rarely cross-protective
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Humoral vs cell-mediated
Antibody-mediated (think B cells) Control extracellular pathogens Cell-mediated T cell-mediated Control intracellular pathogens
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Figure 17.8 Differentiation of T cells and B cells.
Stem cells develop in bone marrow or in fetal liver Stem cell (diverges into two cell lines) Red bone marrow of adults Thymus Differentiate to B cells in adult red bone marrow Differentiate to T cells in thymus B cell T cell Migrate to lymphoid tissue such as spleen, but especially lymph nodes
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The Nature of Antigens Antigen (Ag): a substance that causes the body to produce specific antibodies or sensitized T cells Antibodies (Ab) interact with epitopes, or antigenic determinants Hapten: antigen is combined with carrier molecules
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Epitopes (antigenic determinants) on antigen
Figure 17.1 Epitopes (antigenic determinants). Antibody A Epitopes (antigenic determinants) on antigen Antigens: components of cell wall Binding sites Bacterial cell Antibody B
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The Nature of Antigens Antigen (Ag): a substance that causes the body to produce specific antibodies or sensitized T cells Antibodies (Ab) interact with epitopes, or antigenic determinants Hapten: antigen is combined with carrier molecules
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Hapten-carrier conjugate
Figure 17.2 Haptens. Hapten molecules Carrier molecule Hapten-carrier conjugate
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The Nature of Antibodies
Antibodies are soluble B cell receptors B cells that recognize an epitope of an antigen on a pathogen do so through the B cell receptor If that B cell develops into a plasma cell, the antibodies will have an identical specificity Globular proteins called immunoglobulins The number of antigen-binding sites determines valence B cell receptor
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Figure 17.3ab The structure of a typical antibody molecule.
Antigen- binding site Heavy chain Light chain Fc (stem) region Hinge region Antibody molecule Epitope (antigenic determinant) Antigen Antigen- binding site Enlarged antigen-binding site bound to an epitope
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Antibody molecules shown by atomic force microscopy (see page 64)
Figure 17.3c The structure of a typical antibody molecule. Antibodies Antibody molecules shown by atomic force microscopy (see page 64)
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IgG Antibodies Monomer 80% of serum antibodies Fix complement
In blood, lymph, and intestine Cross placenta Enhance phagocytosis; neutralize toxins and viruses; protect fetus and newborn Half-life = 23 days
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IgM Antibodies Pentamer 5–10% of serum antibodies Fix complement
In blood, in lymph, and on B cells Agglutinate microbes; first Ab produced in response to infection Half-life = 5 days Disulfide bond J chain
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IgA Antibodies Dimer 10–15% of serum antibodies In secretions
Mucosal protection Half-life = 6 days J chain Secretory component
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IgD Antibodies Monomer 0.2% of serum antibodies
In blood, in lymph, and on B cells On B cells, initiate immune response Half-life = 3 days
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IgE Antibodies Monomer 0.002% of serum antibodies
On mast cells, on basophils, and in blood Allergic reactions; lysis of parasitic worms Half-life = 2 days
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Activation of B Cells Major histocompatibility complex (MHC) expressed on mammalian cells T-dependent antigens Ag presented with (self) MHC to TH cell TH cell produces cytokines that activate the B cell T-independent antigens Stimulate the B cell to make Abs
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(T-independent antigen)
Figure 17.6 T-independent antigens. Polysaccharide (T-independent antigen) Epitopes B cell receptors
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Activation of B Cells Major histocompatibility complex (MHC) expressed on mammalian cells. Present extracellular antigens to immune cells T-dependent antigens Ag presented with (self) MHC to TH cell TH cell produces cytokines that activate the B cell T-independent antigens Stimulate the B cell to make Abs
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Figure 17.4 Activation of B cells to produce antibodies.
Extracellular antigens MHC class II with Ag fragment displayed on surface MHC class II with Ag fragment Ag fragment Antibodies B cell B cell Immunoglobulin receptors coating B cell surface Plasma cell TH cell B cell Cytokines Immunoglobulin receptors on B cell surface recognize and attach to antigen, which is then internalized and processed. Within the B cell a fragment of the antigen combines with MHC class II. MHC class II–antigen-fragment complex is displayed on B cell surface. Receptor on the T helper cell (TH) recognizes complex of MHC class II and antigen fragment and is activated— producing cytokines, which activate the B cell. The TH cell has been previously activated by an antigen displayed on a dendritic cell (see Figure 17.10). B cell is activated by cytokines and begins clonal expansion. Some of the progeny become antibody-producing plasma cells.
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Figure 17.5 Clonal selection and differentiation of B cells.
Stem cell Stem cells differentiate into mature B cells, each bearing surface immunoglobulins against a specific antigen. Antigen B cells B cell III complexes with its specific antigen and proliferates. I II III IV Memory cells Some B cells proliferate into long-lived memory cells, which at a later date can be stimulated to become antibody-producing plasma cells. See Figure Other B cells proliferate into antibody-producing plasma cells. Plasma cells Plasma cells secrete antibodies into circulation. Antigens in circulation now attached to circulating antibodies Cardiovascular system
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Figure 17.7 The results of antigen–antibody binding.
PROCTECTIVE MECHANISM OF BINDING ANTIBODIES TO ANTIGENS Agglutination (see also Figure 18.5) Activation of complement (see also Figure 16.9) Reduces number of infectious units to be dealt with Causes inflammation and cell lysis Complement Bacteria Bacterium Lysis Antibody-dependent cell-mediated cytotoxicity (see also Figure 17.16) Opsonization (see also Figure 16.9) Coating antigen with antibody enhances phagocytosis Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells Phagocyte Eosinophil Epitopes Large target cell (parasite) Neutralization (see also Figure 18.9) Perforin and lytic enzymes Blocks adhesion of bacteria and viruses to mucosa Blocks attachment of toxin Virus Toxin Bacterium
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T Cells and Cellular Immunity
T cells mature in the thymus Thymic selection eliminates many immature T cells
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Table 17.2 Principal Cells That Function in Cell-Mediated Immunity
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T Cells and Cellular Immunity
T cells respond to Ag by T-cell receptors (TCRs) T cells require antigen-presenting cells (APCs) Pathogens entering the gastrointestinal or respiratory tracts pass through: M (microfold) cells over Peyer’s patches, which contain APCs
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Antigen M cell TH cell Pocket B cells Macrophage Epithelial cell
Figure 17.9 M cells. M cell on Peyer’s patch. Note the tips of the closely packed microvilli on the surrounding epithelial cells. (a) Microvilli on epithelial cell Antigen M cell TH cell Pocket B cells Macrophage Epithelial cell (b) M cells facilitate contact between the antigens passing through the intestinal tract and cells of the body’s immune system.
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T Helper Cells CD4+ or TH cells TCRs recognize Ags and MHC II on APC
TLRs are a costimulatory signal on APC and TH TH cells produce cytokines and differentiate into: TH1cells TH2 cells TH17 cells Memory cells
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T Helper Cells TH1 produce IFN-gwhich activates cells related to cell-mediated immunity, macrophages, and Abs TH2 activate eosinophils and B cells to produce IgE TH17 stimulate the innate immune system. Also involved in autoimmune diseases
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Figure 17.11 Lineage of effector T helper cell classes and pathogens targeted.
Antibodies B cell TH1 cells TH2 cells TH17 cells Cell-mediated immunity; control of intracellular pathogens, delayed hypersensitivity reactions (page 535); stimulates macrophages. Recruits neutrophils; provides protection against extracellular bacteria and fungi TH cell TH17 cells IL-17 IFN-g TH1 cells IL-4 TH2 cells Fungi Extracellular bacteria Neutrophil Macrophage Intracellular bacteria and protozoa Mast cell Basophil Eosinophil Important in allergic responses, especially by production of IgE Stimulates activity of eosinophils to control extracellular parasites such as helminths (see ADCC, page 495). Helminth
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Complex of MHC class II molecule and antigen fragment
Figure Activation of CD4+T helper cells. An APC encounters and ingests a microorganism. The antigen is enzymatically processed into short peptides, which combine with MHC class II molecules and are displayed on the surface of the APC. A receptor (TCR) on the surface of the CD4+T helper cell (TH cell) binds to the MHC–antigen complex. If this includes a Toll-like receptor, the APC is stimulated to secrete a costimulatory molecule. These two signals activate the TH cell, which produces cytokines. TH cell receptor (TCR) The cytokines cause the TH cell (which recognizes a dendritic cell that is producing costimulatory molecules) to become activated. APC (dendritic cell) T helper cell Antigen Complex of MHC class II molecule and antigen fragment Cytokines Antigen fragment (short peptides) Microorganism carrying antigens Costimulatory molecule, (required to activate T cells that have not previously encountered antigen)
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T Cytotoxic Cells CD8+ or TC cells
Target cells are self-cells carrying endogenous antigens Activated into cytotoxic T lymphocytes (CTLs) CTLs recognize Ag + MHC I Induce apoptosis in target cell CTL releases perforin and granzymes
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Figure 17.12 Killing of virus-infected target cell by cytotoxic T lymphocyte.
Processed antigen presented with MHC class I T cell receptors Infected target cell is lysed Processed antigen MHC class I CTL Virus-infected cell (example of endogenous antigen) Virus-infected cell Cytotoxic T lymphocyte (CTL) A normal cell will not trigger a response by a cytotoxic T lymphocyte (CTL), but a virus-infected cell (shown here) or a cancer cell produces abnormal endogenous antigens. The abnormal antigen is presented on the cell surface in association with MHC class I molecules. CD8+T cells with receptors for the antigen are transformed into CTLs. The CTL induces destruction of the virus-infected cell by apoptosis.
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Figure Apoptosis.
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Figure 17.20 The dual nature of the adaptive immune system.
Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune system Control of freely circulating pathogens Control of intracellular pathogens Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite. Extracellular antigens A B cell binds to the antigen for which it is specific. A T-dependent B cell requires cooperation with a T helper (TH) cell. A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors). T cell Cytokines activate T helper (TH) cell. Cytokines activate macrophage. Cytokines Cytokines B cell Cytokines from the TH cell transform B cells into antibody-producing plasma cells. Activation of macrophage (enhanced phagocytic activity). The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells. TH cell The CD8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell. Plasma cell Cytotoxic T lymphocyte Plasma cells proliferate and produce antibodies against the antigen. Memory cell Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen. Lysed target cell
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T Regulatory Cells Treg cells Suppress T cells against self
CD4 and CD25 on surface Suppress T cells against self
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Antigen-Presenting Cells
Digest antigen Ag fragments on APC surface with MHC B cells Dendritic cells Activated macrophages
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Figure 17.14 A dendritic cell.
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Figure 17.15 Activated macrophages.
Resting (inactive) macrophage
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Natural Killer (NK) Cells
Granular leukocytes destroy cells that don’t express MHC I Kill virus-infected and tumor cells Attack parasites
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ADCC Antibody-dependent cell-mediated cytotoxicity
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Figure 17.16 Antibody-dependent cell-mediated cytotoxicity (ADCC).
KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Large parasite Epitope Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally. Eosinophils Fluke (b) Eosinophils adhering to the larval stage of a parasitic fluke
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Figure 17.16a Antibody-dependent cell-mediated cytotoxicity (ADCC).
KEY Macrophage Cytotoxic cytokines Lytic enzymes Perforin enzymes Eosinophil Extracellular damage Fc region Epitope Large parasite Antibody (a) Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally.
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Eosinophils adhering to the larval stage of a parasitic fluke.
Figure 17.16b Antibody-dependent cell-mediated cytotoxicity (ADCC). Eosinophils Fluke Eosinophils adhering to the larval stage of a parasitic fluke.
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Cells Communicate via Cytokines
Representative Activity Interleukin-1 (IL-1) Stimulates TH cells in presence of antigens; attracts phagocytes Interleukin-2 (IL-2) Proliferation of antigen-stimulated CD4+ T helper cells, proliferation and differentiation of B cells; activation of CD8+ T cells and NK cells Interleukin-12 (IL-12) Inhibits humoral immunity; activates TH1 cellular immunity
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Cells Communicate via Cytokines
Representative Activity Chemokines Induce the migration of leukocytes TNF-α Promotes inflammation Hematopoietic cytokines Influence differentiation of blood stem cells IFN- and IFN- Response to viral infection; interfere with protein synthesis IFN- Stimulates macrophage activity
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Immunological Memory Antibody titer is the amount of Ab in serum
Primary response occurs after initial contact with Ag Secondary (memory or anamnestic) response occurs after second exposure
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Second exposure to antigen
Figure The primary and secondary immune responses to an antigen (T cell-dependent). IgG IgM Second exposure to antigen Initial exposure to antigen Antibody titer in serum Time (days)
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Types of Adaptive Immunity
Naturally acquired active immunity Resulting from infection Naturally acquired passive immunity Transplacental or via colostrum/breastmilk Artificially acquired active immunity Injection of Ag (vaccination) Artificially acquired passive immunity Injection of Ab
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Terminology of Adaptive Immunity
Serology: the study of reactions between antibodies and antigens Antiserum: the generic term for serum because it contains Ab Globulins: serum proteins Immunoglobulins: antibodies
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