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Lesson 11Adaptive Immunity“Specific Immunity”
March 31,2015
Immunity Review
• Innate Immunity: defenses against any pathogen– Skin– Phagocytes– Inflammation– Fever
• Adaptive Immunity: induced resistance to a specific pathogen– Humoral (antibodies)– Cell-mediated
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.
The B cell, often with stimulation by cytokines from a TH cell, differentiates into a plasma cell. Some B cells become memory cells.
Plasma cells proliferate and produce antibodies against the antigen.
Intracellular antigens are expressed on the surface of an APC, a cell infected by a virus, a bacterium, or a parasite.
A T cell binds to MHC–antigen complexes on the surface of the infected cell, activating the T cell (with its cytokine receptors).
Activation of macrophage (enhanced phagocytic activity).
The CD8+T cell becomes a cytotoxic T lymphocyte (CTL) able to induce apoptosis of the target cell.
B cell
Plasma cell
T cell
TH cell
Cytotoxic T lymphocyte
CytokinesCytokines
Lysed target cell
Cytokines activate macrophage.
Cytokines from the TH cell transform B cells into antibody-producing plasma cells.
Cytokines activate T helper (TH) cell.
Memory cell
Some T and B cells differentiate into memory cells that respond rapidly to any secondary encounter with an antigen.
Humoral (antibody-mediated) immune system Cellular (cell-mediated) immune systemControl of freely circulating pathogens Control of intracellular pathogens
Figure 17.20 The dual nature of the adaptive immune system.
Dual Nature of Adaptive Immunity
• Main components of Adaptive Immunity are T cells and B cells
• The fetal liver serves as the source of both T and B cells early in development and in bone marrow in adulthood– T cells develop in thymus in adults– B cells develop in the red bone marrow in adults
Stem cells develop in bone marrow or in fetal liver
Stem cell(diverges intotwo cell lines)
Red bone marrow of adults
Differentiate to B cells in adult red bone marrow
B cell
Thymus
Differentiate toT cells in thymus
T cell
Migrate to lymphoid tissue such as spleen, but especially lymph nodes
Figure 17.8 Differentiation of T cells and B cells.
Dual Nature of Adaptive Immunity
• Humoral Immunity– Due to antibodies – B cells mature in the bone marrow
• Name derived from chickens: bursa of Fabricius – Bursa is an organ found in chickens that when removed results in
the abrogation in antibody production
Dual Nature of Adaptive Immunity
• Cellular Immunity – Due to T cell activation– T cells mature in the thymus
1. Stimulate the production macrophages and other phagocytes2. Activate B-cells into becoming plasma cells3. Activate Cytotoxic T-Lymphocytes
The Nature of Antigens• Antigen (Ag): a substance that causes the body to
produce specific antibodies or sensitized T cells “foreign molecules”– Microbial cell wall components, proteins, capsules,
flagella, toxins, viral coats– Non-microbial agents such as blood cell surface molecules
can serve as antigens• Organ rejection
– Antibodies (Ab) interact with epitopes, or antigenic determinants which are specific regions on the antigen
– Hapten: antigens that are too small to stimulate a immune response. Require carrier molecules
Binding sites
Epitopes (antigenic determinants) on antigen
Antibody A
Antigens:componentsof cell wall
Antibody B
Bacterial cell
Figure 17.1 Epitopes (antigenic determinants).
Hapten molecules
Carrier molecule
Hapten-carrier conjugate
Figure 17.2 Haptens.
The Nature of Antibodies
• Globular proteins called Immunoglobulins
• Antigen-binding sites (ABS) are parts of the antibody that binds the epitope
• Valence refers to the number of antigen binding sites on an antibody– Two binding sites are bivalent (most common)– One binding site is monovalent
Figure 17.3ab The structure of a typical antibody molecule.
Antigen-binding site
Heavy chainLight chain
Hingeregion
Antibody molecule
Enlarged antigen-binding site bound to an epitope
Fc (stem) region
Epitope(antigenic
determinant)
Antigen
Antigen-binding site
IgG Antibodies
• Monomer• 80% of serum antibodies• Fixes complement• Found in blood, lymph, and
intestine• Cross placenta (passive
immunity)• Enhance phagocytosis;
neutralize toxins and viruses; protect fetus and newborn
• Half-life = 23 days
IgM Antibodies
• Pentamer• 5–10% of serum
antibodies• Fixes 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
IgA Antibodies
• Dimer• 10–15% of serum
antibodies• In secretions• Mucosal protection• Secretory Component
protects Ab from degradation
• Most abundant antibody in the body
• Half-life = 6 days
J-Chain
Secretory Component
• Monomer
• 0.2% of serum antibodies
• In blood, in lymph, and on B cells
• On B cells, initiate adaptive response
• Half-life = 3 days
IgD Antibodies
• Monomer
• 0.002% of serum antibodies
• On mast cells, on basophils, and in blood
• Allergic reactions; lysis of parasitic worms
• Attracts complement and phagocytic cells
• Half-life = 2 days
IgE Antibodies
• B-cells, when activated, become either plasma cells (Ab producers) or memory cells (responsible for enhanced secondary response)
• B-cells are capable of producing multiple Abs (IgM, IgG, IgA) with the same antigenic determinants (class switching)
• Major histocompatibility complex (MHC) expressed on mammalian cells are responsible for antigenic determinants– Molecules containing glycoproteins– Found on Antigen-presenting cells (APC) and lymphocytes– Presents antigen on the surface of the B cell
Activation of B Cells
• T-dependent antigens– Ag presented with (self) MHC to TH cell
• Distinguishes (self) from antigen to prevent antibody production against host cells
– Lupus, Type I diabetes, and rheumatoid arthritis– TH cell produces cytokines that activate the B cell
• T-independent antigens– Antigens stimulate B cells directly to make Abs– Antigens are characterized by repeating subunits that bind multiple B
cell receptors• Polysaccharides• Lipopolysaccharides
Figure 17.4 Activation of B cells to produce antibodies.
Extracellularantigens
Ag fragment MHC class II with Ag fragment
B cell
Immunoglobulin receptorscoatingB cell surface
B cell
B cell
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 ofMHC class II and antigenfragment and is activated—producing cytokines, whichactivate the B cell. The TH cellhas been previously activated byan antigen displayed on adendritic cell (see Figure 17.10).
B cell is activated by cytokines and begins clonal expansion. Some of the progeny become antibody-producing plasma cells.
MHC class II with Ag fragment displayed on surface
TH cell
Cytokines
Plasma cell
Antibodies
Figure 17.6 T-independent antigens.
Polysaccharide(T-independent antigen)
Epitopes
B cell receptors
Figure 17.5 Clonal selection and differentiation of B cells.Stem cell
B cells
Antigen
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 17.17.
Memory cells
B cell III complexes with its specific antigen and proliferates.
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
I II III IV
Stem cells differentiate into mature B cells, each bearing surface immunoglobulins against a specific antigen.
Activation of B Cells
• Clonal Deletion eliminates harmful B cells– MHC molecules that contain self-antigens– Process in which the immune system does not attack
an antigen is called immune tolerance• Gestational immune tolerance protects a baby from the
immune system of the parent– Produces cytokines to inhibit immune system detection
(neurokinin B)– Do not contain receptors that bind cytotoxic Tcells
Antigen-Antibody Binding
• Affinity—is the strength of a bond b/w antigen and antibody– Antibodies recognize the shape of an antigen– Better the fit b/w the antigen’s shape and Ab the
stronger the affinity– Abs are highly specific (discern minor differences
in antigens)
Results of Antigen–Antibody Binding
1. Agglutination2. Opsonization3. Activation of complement4. Antibody-dependent cell-mediated
cytotoxicity5. Neutralization
Figure 17.7 The results of antigen–antibody binding.PROCTECTIVE MECHANISM OF
BINDING ANTIBODIES TO ANTIGENS
Activation of complement(see also Figure 16.9)
Agglutination(see also Figure 18.5)
Opsonization(see also Figure 16.9)
Antibody-dependentcell-mediated cytotoxicity
(see also Figure 17.16)
Neutralization(see also Figure 18.9)
Reduces number of infectious units to be dealt with
Coating antigen with antibody enhances phagocytosis
Phagocyte
Bacteria
Causes inflammation andcell lysis
Bacterium Lysis
Antibodies attached to target cell cause destruction by macrophages, eosinophils, and NK cells
EpitopesEosinophil
Perforin and lytic enzymes
Large target cell (parasite)
Blocks adhesion of bacteria and viruses to mucosa
Bacterium
Virus
Blocks attachment of toxin
Toxin
Complement
T Cells and Cellular Immunity
• T cells are derived from stem cells of bone marrow
• These stem cells migrate to the thymus where they mature into T cells– Thymic selection eliminates many immature T cells
• Similar to clonal deletion of B cells. Weed out cells that would otherwise attack “self”
• Mainly responsible for clearance of intracellular bacteria
Table 17.2 Principal Cells That Function in Cell-Mediated Immunity
T Cells and Cellular Immunity
• T cells require antigen-presenting cells (APCs) to become activated
• T cells respond to Ag by T-cell receptors (TCRs)– Similar to antibodies on the surface of B cells
• Pathogens entering the gastrointestinal or respiratory tracts pass through: – M (microfold) cells over– Peyer’s patches (secondary lymphoid organs), which contain APCs
• T cells are characterized by glycoproteins on surface– CD4—bind to MHC II molecules (found on lymphocytes)– CD8—bind to MHC I molecules (present on all nucleated cells)
Figure 17.9 M cells.
Antigen M cell
Microvilli on epithelial cell
TH cell
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.
M cell on Peyer’s patch. Notethe tips of the closely packedmicrovilli on the surroundingepithelial cells.
(a)
T Cell Classification
• Certain glycoproteins on the surface of T cells help distinguish different classes of T cells– Clusters of Differentiation (CD)– Responsible for the adhesion of T cells to
receptors– Cells containing CD4 are called CD4+ cells and cells
containing CD8 are called CD8+ cells
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
• TFH cells• Memory cells
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
– TFH stimulate B cells to produce plasma cells and are involved in class switching
Figure 17.11 Lineage of effector T helper cell classes and pathogens targeted.
Antibodies
B cell
Recruits neutrophils; provides protection against extracellular bacteria and fungi
Extracellularbacteria
Fungi
TH1 cells
TH2 cells
TH17 cells
IL-17
IL-4
IFN-g
Cell-mediated immunity; controlof intracellular pathogens, delayed hypersensitivity reactions (page 535); stimulates macrophages.
Important in allergic responses, especially by production of IgE
Stimulates activity of eosinophils to control extracellular parasites such as helminths (see ADCC, page 495).
Neutrophil
Mast cellBasophilEosinophil
Macrophage
TH1 cells
TH2 cells
TH17 cells
Intracellular bacteria and protozoa
TH cell
Helminth
Figure 17.10 Activation of CD4+T helper cells.
APC (dendritic cell)
Antigen
Costimulatory molecule, (required to activate T cells that have not previously encountered antigen)
Microorganism carrying antigens
Antigen fragment (short peptides)
TH cell receptor (TCR)
Complex of MHC class II molecule and antigen
fragment
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.
The cytokines cause the TH cell (which recognizes a dendritic cell that is producing costimulatory molecules) to become activated.
Cytokines
T helper cell
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.
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
Figure 17.12 Killing of virus-infected target cell by cytotoxic T lymphocyte.
Processed antigen
MHC class I
Virus-infected cell (example of endogenous antigen) Virus-infected cell Cytotoxic T lymphocyte (CTL)
T cell receptors
Infected target cell is lysed
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.
Processed antigen presented withMHC class I
CTL
Figure 17.13 Apoptosis.
T Regulatory Cells
• Treg cells CD4 and CD25 on surface
• Suppress T cells against self
Antigen-Presenting Cells
• Digest antigen
• Ag fragments on APC surface with MHC– B cells– Dendritic Cells– Activated Macrophages
Figure 17.14 A dendritic cell.
Figure 17.15 Activated macrophages.
Activated macrophages
Resting (inactive)macrophage
• Granular leukocytes destroy cells that don’t express MHC I
• Kill virus-infected and tumor cells
• Attacks parasites
Natural Killer (NK) Cells
ADCC
• Antibody-dependent cell-mediated cytotoxicity
Figure 17.16a Antibody-dependent cell-mediated cytotoxicity (ADCC).
Organisms, such as many parasites, that are too large for ingestion by phagocytic cells must be attacked externally.
Cytotoxic cytokines
Lytic enzymesPerforin enzymes
KEY
Macrophage
Fc region
Large parasite
Eosinophil
Extracellular damage
Epitope
Antibody
(a)
Figure 17.16b Antibody-dependent cell-mediated cytotoxicity (ADCC).
Eosinophils adhering to the larval stage of a parasitic fluke.
Fluke
Eosinophils
Cytokines
• Chemical messengers– Allows for communication between cells
• Overproduction leads to cytokine storm
Cytokines
Cytokine 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
Cytokines
Cytokine 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
Immunological Memory
• Antibody titer is the amount of Ab in serum
• Primary response occurs after initial contact with Ag
• Secondary (memory) response occurs after second exposure
Figure 17.17 The primary and secondary immune responses to an antigen.
IgG
IgM
Initial exposure to antigen
Second exposure to antigen
Time (days)
Antib
ody
titer
in s
erum
Types of Adaptive Immunity
• Naturally acquired active immunity– Resulting from infection
• Naturally acquired passive immunity– Transplacental or via colostrum
• Artificially acquired active immunity– Injection of Ag (vaccination)
• Artificially acquired passive immunity– Injection of Ab
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 • Gamma () globulin: serum fraction containing
Ab
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