Download Lesson 11Adaptive Immunity“Specific Immunity”

Lesson 11
Adaptive 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
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 Tdependent B cell requires
cooperation with a T helper
(TH) cell.
T cell
Cytokines activate T
helper (TH) cell.
Cytokines activate
macrophage.
Cytokines
Cytokines
A T cell binds to MHC–
antigen complexes on
the surface of the
infected cell, activating
the T cell (with its
cytokine receptors).
B cell
The B cell, often with stimulation
by cytokines from a TH cell,
differentiates into a plasma cell.
Some B cells become memory
cells.
Cytokines from the TH cell
transform B cells into
antibody-producing plasma
cells.
Cytotoxic T
lymphocyte
Plasma cell
Plasma cells proliferate
and produce antibodies
against the antigen.
Activation of
macrophage (enhanced
phagocytic activity).
TH cell
Memory cell
Some T and B cells differentiate into
memory cells that respond rapidly to
any secondary encounter with an
antigen.
Lysed target cell
The CD8+T cell becomes
a cytotoxic T lymphocyte
(CTL) able to induce
apoptosis of the target
cell.
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
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
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.
2.
3.
Stimulate the production macrophages and other phagocytes
Activate B-cells into becoming plasma cells
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
Figure 17.1 Epitopes (antigenic determinants).
Antibody A
Epitopes (antigenic determinants)
on antigen
Antigens:
components
of cell wall
Binding sites
Bacterial cell
Antibody B
Figure 17.2 Haptens.
Hapten
molecules
Carrier
molecule
Hapten-carrier
conjugate
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.
Antigenbinding
site
Fc (stem) region
Hinge
region
Antibody molecule
Epitope
(antigenic
determinant)
Antigenbinding site
Enlarged antigen-binding site bound to an epitope
Antigen
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
IgD Antibodies
• Monomer
• 0.2% of serum antibodies
• In blood, in lymph, and on B cells
• On B cells, initiate adaptive response
• Half-life = 3 days
IgE 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
Activation of B Cells
• 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
• 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.
Extracellular
antigens
Ag fragment
MHC class II with
Ag fragment
MHC class II
with Ag
fragment
displayed on
surface
Antibodies
B cell
B cell
B cell
Immunoglobulin
receptors
coating
B cell surface
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.
TH cell
Plasma cell
Cytokines
MHC class II–antigenfragment 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 antibodyproducing plasma cells.
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
Stem cells differentiate into mature B cells, each
bearing surface immunoglobulins against a specific
antigen.
Antigen
B cells
I
II
III
IV
B cell III complexes with its
specific antigen and
proliferates.
Memory cells
Some B cells proliferate into long-lived
memory cells, which at a later date can
be stimulated to become antibodyproducing plasma cells. See Figure
17.17.
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
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.
2.
3.
4.
Agglutination
Opsonization
Activation of complement
Antibody-dependent cell-mediated
cytotoxicity
5. Neutralization
Figure 17.7 The results of antigen–antibody binding.
PROCTECTIVE MECHANISM OF
Activation of complement
BINDING ANTIBODIES
(see also Figure 18.5)
(see also Figure 16.9)
TO ANTIGENS
Causes inflammation and
Reduces number of infectious units to
cell lysis
be dealt with
Complement
Agglutination
Bacteria
Bacterium
Lysis
Antibody-dependent
cell-mediated cytotoxicity
Opsonization
(see also Figure 16.9)
(see also Figure 17.16)
Antibodies attached to target cell cause destruction
by macrophages, eosinophils, and NK cells
Coating antigen with antibody
enhances phagocytosis
Phagocyte
Eosinophil
Epitopes
Large target cell (parasite)
Neutralization
(see also Figure 18.9)
Blocks adhesion of
bacteria and viruses to
mucosa
Virus
Bacterium
Blocks attachment
of toxin
Toxin
Perforin and lytic
enzymes
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.
(a) M cell on Peyer’s patch. Note
the tips of the closely packed
microvilli on the surrounding
epithelial cells.
Antigen
M cell
Microvilli on
epithelial 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.
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-gwhich 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
TH1 cells
B cell
TH2 cells
TH17 cells
Recruits neutrophils; provides
protection against extracellular bacteria
and fungi
TH17 cells
Cell-mediated immunity; control
of intracellular pathogens, delayed
hypersensitivity reactions (page 535);
stimulates macrophages.
TH cell
IL-17
IL-4
IFN-g
TH1 cells
TH2 cells
Fungi
Extracellular
bacteria
Neutrophil
Macrophage
Mast cell
Basophil
Eosinophil
Intracellular bacteria
and protozoa
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
Figure 17.10 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)
APC (dendritic cell)
The cytokines cause the TH cell (which
recognizes a dendritic cell that is
producing costimulatory molecules) to
become activated.
T helper cell
Antigen
Microorganism
carrying antigens
Antigen fragment
(short peptides)
Complex of MHC class II
molecule and antigen
fragment
Cytokines
Costimulatory molecule,
(required to activate T cells that
have not previously encountered
antigen)
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
presented with
MHC class I
Processed
antigen
T cell
receptors
Infected
target cell
is lysed
MHC class I
Virus-infected cell (example of
endogenous antigen)
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.
CTL
Virus-infected cell
Cytotoxic T lymphocyte (CTL)
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.
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
Natural Killer (NK) Cells
• Granular leukocytes destroy cells that don’t
express MHC I
• Kill virus-infected and tumor cells
• Attacks parasites
ADCC
• Antibody-dependent cell-mediated cytotoxicity
Figure 17.16a 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.
Figure 17.16b Antibody-dependent cell-mediated cytotoxicity (ADCC).
Eosinophils
Fluke
Eosinophils adhering to the larval stage of a parasitic fluke.
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-g
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
Antibody titer in serum
IgM
Initial
exposure
to antigen
Time (days)
Second
exposure
to antigen
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 (g) globulin: serum fraction containing
Ab