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PowerPoint® Lecture Slides
prepared by
Janice Meeking,
Mount Royal College
CHAPTER
21
The Immune
System:
Innate and
Adaptive Body
Defenses:
Part B
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Humoral Immunity Activity
B-cells
Antibodies
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Antibodies
• Immunoglobulins—gamma globulin portion of
blood
• Proteins secreted by plasma cells
• Capable of binding specifically with antigen
detected by B cells
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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
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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
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Antigen-binding
site
Heavy chain
variable region
Heavy chain
constant region
Light chain
variable region
Light chain
constant region
Disulfide bond
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Hinge
region
Stem
region
(a)
Figure 21.14a
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
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Table 21.3
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
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Classes of Antibodies
• IgE
• Monomer active in some allergies and
parasitic infections
• Causes mast cells and basophils to release
histamine
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Table 21.3
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
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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
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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
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Agglutination
• Antibodies bind the same determinant on
more than one cell-bound antigen
• Cross-linked antigen-antibody complexes
agglutinate
• Example: clumping of mismatched blood cells
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Precipitation
• Soluble molecules are cross-linked
• Complexes precipitate and are subject to
phagocytosis
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Complement Fixation and Activation
• Main antibody defense against cellular
antigens (bacteria and wrong RBCs)
• 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
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Complement Fixation and Activation
• Activated complement functions
• Amplifies the inflammatory response
• Opsonization
• Enlists more and more defensive elements
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Ig E can also attach to parasites causing
Eosinophils to attack
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Adaptive defenses
Humoral immunity
Antigen
Antigen-antibody
complex
Antibody
Inactivates by
Neutralization
(masks dangerous
parts of bacterial
exotoxins; viruses)
Agglutination
(cell-bound antigens)
Enhances
Phagocytosis
Fixes and activates
Precipitation
(soluble antigens)
Enhances
Complement
Leads to
Inflammation
Cell lysis
Chemotaxis
Histamine
release
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Figure 21.15
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
• Diagnose pregnancy (HCG), certain sexually transmitted
diseases like AIDS (ELISA), certain cancers, hepatitis
and rabies
• Treat leukemias and lymphomas – cancers in the blood
stream that are accessible to antibodies
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Cell Mediated Immune Responses
T-cell Activity
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Cell-Mediated Immune Response
• T cells provide defense against intracellular
antigens
• Two types of surface receptors of T cells
• T cell antigen receptors which are CD 3
• Cell differentiation glycoproteins
• CD4 or CD8, CD 10, CD gamma- delta
• Play a role in T cell interactions with other
cells
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All T cells have a T cell receptor – it obtained in the
thymus gland – they slightly differ in the variable
region
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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) CD 10
• T – gamma - delta
• Memory T cells
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Adaptive defenses
Cellular immunity
Immature
lymphocyte
Red bone marrow
T cell
receptor
Class II MHC
protein
T cell
receptor
Maturation
CD4
cell
Thymus
Activation
APC
(dendritic cell)
Activation
Memory
cells
CD4
Class I MHC
protein
CD8
cell
APC
(dendritic cell)
CD8
Lymphoid
tissues and
organs
Helper T cells
(or regulatory T cells)
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Effector
cells
Blood plasma
Cytotoxic T cells
Figure 21.16
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)
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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
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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)
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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
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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)
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8 – 9 endogenously derived Amino acids in MHC I
Cytoplasm of any tissue cell
2 Endogenous antigen
1 Endogenous
peptides enter ER via
antigen is degraded
transport protein.
by protease.
Endogenous antigen—
self-protein or foreign
(viral or cancer) protein
Cisternae of
endoplasmic
reticulum (ER)
3 Endogenous
antigen peptide is
loaded onto class
I MHC protein.
4 Loaded MHC protein
migrates in vesicle to
the plasma membrane,
where it displays the
antigenic peptide.
Transport
protein
(ATPase)
Plasma membrane of a tissue cell
Antigenic peptide
Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.
MHC produced in Endoplasmic Reticulum
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Figure 21.17a
Cytoplasm of any tissue cell
1 Endogenous
antigen is degraded
by protease.
Endogenous antigen—
self-protein or foreign
(viral or cancer) protein
Plasma membrane of a tissue cell
Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.
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Figure 21.17a, step 1
Cytoplasm of any tissue cell
2 Endogenous antigen
1 Endogenous
peptides enter ER via
antigen is degraded
transport protein.
by protease.
Endogenous antigen—
self-protein or foreign
(viral or cancer) protein
Cisternae of
endoplasmic
reticulum (ER)
Transport
protein
(ATPase)
Plasma membrane of a tissue cell
Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.
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Figure 21.17a, step 2
Cytoplasm of any tissue cell
2 Endogenous antigen
1 Endogenous
peptides enter ER via
antigen is degraded
transport protein.
by protease.
Endogenous antigen—
self-protein or foreign
(viral or cancer) protein
Cisternae of
endoplasmic
reticulum (ER)
3 Endogenous
antigen peptide is
loaded onto class
I MHC protein.
Transport
protein
(ATPase)
Plasma membrane of a tissue cell
Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.
Copyright © 2010 Pearson Education, Inc.
Figure 21.17a, step 3
Cytoplasm of any tissue cell
2 Endogenous antigen
1 Endogenous
peptides enter ER via
antigen is degraded
transport protein.
by protease.
Endogenous antigen—
self-protein or foreign
(viral or cancer) protein
Cisternae of
endoplasmic
reticulum (ER)
3 Endogenous
antigen peptide is
loaded onto class
I MHC protein.
4 Loaded MHC protein
migrates in vesicle to
the plasma membrane,
where it displays the
antigenic peptide.
Transport
protein
(ATPase)
Plasma membrane of a tissue cell
Antigenic peptide
Extracellular fluid
(a) Endogenous antigens are processed and displayed on class I MHC of all cells.
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Figure 21.17a, step 4
Only Antigen Presenting Cells have MHC II
• Antigen presenting cells are (1) dendritic cells
(2) macrophages (3) some B-cells
• Antigen presenting cells display both MHC I
and MHC II
• In order to present exogenous antigens on
MHC II – the organism must under
phagocytosis and lysis
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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
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14 – 17 exogenously derived amino acids displayed in MHC II
Cytoplasm of APC
1a
Class II MHC is
synthesized in ER.
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
3
Vesicle fuses with
phagolysosome. Invariant
chain is removed, and
antigen is loaded.
2a
Cisternae of
endoplasmic
Phagosome
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.
Class II MHC
is exported
from ER in a
vesicle.
4
Vesicle with
loaded MHC
migrates to the
plasma
membrane.
2b
Phagosome merges
with lysosome, forming
a phagolysosome;
antigen is degraded.
Extracellular
antigen
Extracellular fluid
Lysosome
Plasma membrane of APC
Antigenic peptide
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b
1a
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
Class II MHC is
synthesized in ER.
Cytoplasm of APC
Cisternae of
endoplasmic
reticulum (ER)
Plasma membrane of APC
Extracellular fluid
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b, step 1a
1a
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
Class II MHC is
synthesized in ER.
Cytoplasm of APC
Cisternae of
endoplasmic
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.
Extracellular
antigen
Extracellular fluid
Plasma membrane of APC
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b, step 1b
1a
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
Class II MHC is
synthesized in ER.
Cytoplasm of APC
2a
Cisternae of
endoplasmic
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.
Extracellular
antigen
Extracellular fluid
Class II MHC
is exported
from ER in a
vesicle.
Plasma membrane of APC
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b, step 2a
Cytoplasm of APC
1a
Class II MHC is
synthesized in ER.
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
2a
Cisternae of
endoplasmic
Phagosome
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.
Class II MHC
is exported
from ER in a
vesicle.
2b
Phagosome merges
with lysosome, forming
a phagolysosome;
antigen is degraded.
Extracellular
antigen
Extracellular fluid
Lysosome
Plasma membrane of APC
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b, step 2b
Cytoplasm of APC
1a
Class II MHC is
synthesized in ER.
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
3
Vesicle fuses with
phagolysosome. Invariant
chain is removed, and
antigen is loaded.
2a
Cisternae of
endoplasmic
Phagosome
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.
Class II MHC
is exported
from ER in a
vesicle.
2b
Phagosome merges
with lysosome, forming
a phagolysosome;
antigen is degraded.
Extracellular
antigen
Extracellular fluid
Lysosome
Plasma membrane of APC
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b, step 3
Cytoplasm of APC
1a
Class II MHC is
synthesized in ER.
Invariant chain
prevents class II
MHC from binding
to peptides in the ER.
3
Vesicle fuses with
phagolysosome. Invariant
chain is removed, and
antigen is loaded.
2a
Cisternae of
endoplasmic
Phagosome
reticulum (ER)
1b Extracellular
antigen (bacterium)
is phagocytized.
Class II MHC
is exported
from ER in a
vesicle.
4
2b
Phagosome merges
with lysosome, forming
a phagolysosome;
antigen is degraded.
Extracellular
antigen
Extracellular fluid
Lysosome
Plasma membrane of APC
Vesicle with
loaded MHC
migrates to the
plasma
membrane.
Antigenic peptide
(b) Exogenous antigens are processed and displayed on class II MHC of
antigen-presenting cells (APCs).
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Figure 21.17b, step 4
Some antigen presenting cells can present
exogenous antigens on their MHC I so as to
be seen by T – cytotoxic cells
• The dendritic cell can either engulf
endogenous antigens from infected cells or
form temporary gap junctions to bring them in
to the cell
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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
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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
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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
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T cell receptor (CD 3)
A T cell receptor (TCR) is similar to surface
antibodies on B-cells but instead of 4 polypeptide
chains – it has two pp chains
The variable portions V alpha and V beta
determine the MHC (I or II) to bind to and the
antigen recognition
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Antibody
T cell receptors for T helper cells have a slightly
different variable region than the T cytotoxic cells and
the other T cells. The T cell receptors for T helper cells
should only recognize MHC II – while the other T cell
receptors should recognize MHC I
T cytotoxic cell membrane
All nucleated cell membranes
Except Antigen Presenting Cell
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T helper cell membrane
Antigen Presenting cell
membrane
If the TCR recognizes the proper MHC and
the self or foreign antigen in the MHCs gripwhat does the CD 4 and CD 8 do?
• The CD 4 and CD 8 act as (1) adhesion
molecules to hold the T cell to the other cell’s
proper MHC and (2) to activate certain kinase
enzymes that phosphorylate cell proteins,
activating some and inactivating others when
antigen binding occurs.
• After this occurs the T-cell is still idling until
the confirmation of co-stimulation occurs
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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)
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Adaptive defenses
Cellular immunity
1 Dendritic cell
Viral antigen
Dendritic
cell
T cell receptor
(TCR)
Clone
formation
Class lI MHC
protein
displaying
processed
viral antigen
CD4 protein
engulfs an
exogenous antigen,
processes it, and
displays its
fragments on class
II MHC protein.
2 Immunocompetent
CD4 cell recognizes
antigen-MHC II
complex. Both TCR
and CD4 protein bind
Immunocom- to antigen-MHC
complex.
petent CD4
T cell
3 CD4 cells are
activated,
proliferate (clone),
and become memory
and effector cells.
Helper T
memory cell
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Activated
helper
T cells
Figure 21.18
Co-stimulation (Confirmation)
• T cells require two signals to become fully activated. A first
signal, which is antigen-specific, is provided through the T cell
receptor which interacts with peptide-MHC molecules on the
membrane of antigen presenting cells (APC). A second signal,
the co-stimulatory signal, is antigen nonspecific and is
provided by the interaction between co-stimulatory
molecules expressed on the membrane of APC and the T
cell.
• One of the best characterized costimulatory molecules
expressed by T cells is CD28, which interacts with CD80 (B7.1)
and CD86 (B7.2) on the membrane of APC. Another
costimulatory receptor expressed by T cells is ICOS ( Inducible
Co-stimulator) , which interacts with ICOS-L.
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T Cell Activation: Co-Stimulation
• T cell co-stimulation is necessary for T cell
proliferation, differentiation and survival.
Without co-stimulation, there is
• T cell inactivity (anergy)
• T-cell deletion
• Immune tolerance to that antigen
• Bottom line without co-stimulation T-cells are
unable to divide and secrete their cytokines
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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
• Secrete appropriate cytokines for their cell
type
• Cytokines (interleukin 1 and 2 from APCs or T
cells) trigger proliferation and differentiation of
activated T cell
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T Cell Activation: Co-Stimulation
• Primary T cell response peaks within a week
(Remember B- cell activity peaks in 10 days)
• 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 – prevention infection driven
hyperplasia and possible cancers
• Memory T cells remain and mediate
secondary responses
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B-cell costimulation
• B cell binds antigens with its BCR (a membrane-bound
antibody), which transfers intracellular signals to the B cell as
well as inducing the B cell to engulf the antigen, process it,
and present it on the MHC II molecules.
• The latter case induces recognition by antigen-specific Th2
cells, leading to activation of the B cell through binding of
TCR to the MHC II-antigen complex.
• It is followed by synthesis and presentation of CD40L
(CD154) on the Th2 cell, which binds to CD40 on the B cell,
thus the Th2 cell can co-stimulate the B cell. Without this costimulation the B cell cannot proliferate further.
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B – cell costimulation
• Co-stimulation for B cells is provided
alternatively by complement receptors.
Microbes may activate the complement
system directly and complement component
C3b binds to microbes.
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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
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Cytokines
• IL-2 is a key growth factor, acting on cells that
release it and other T cells
• Interleukin 2 is used to treat melanoma and
certain kidney cancers
• Encourages activated T cells to divide rapidly
• Used therapeutically to treat melanoma and
kidney cancers
• Other cytokines amplify and regulate innate
and adaptive responses
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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
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Types of T helper cells
• T helper 1 – involved in cell mediated immune
activation – activates inflammation, macrophages
and promote differentiation of cytotoxic T-cells
• T-helper 2 – involved in humoral immunity – B
cell action they mobilize eosinophils and Bcells
• The differentiation into the type depends on the
type of antigen and the site at which it is
encountered as well as the cytokine exposure of
the differentiating T cell.
• IL-12 induces T helper cell type 1 differentiation
whereas IL – 4 drives T helper cell 2
differentiation.
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T- helper 17
• a newly discovered subset of T helper cells
producing interleukin 17 (IL-17). they serve
a very important function in anti-microbial
immunity at epithelial / mucosal barriers.
They produce cytokines (such as
interleukin 22) which stimulates epithelial
cells to produce anti-microbial proteins to
clear out certain types of microbe (such as
Candida and Staphylococcus). Thus, a
severe lack of Th17 cells may leave the
host susceptible to opportunistic infections.
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T – helper 17
• Excessive amounts of this cells activity may play a key
role in autoimmune disease such as multiple sclerosis
(which was previously thought to be caused by Th1 cells),
but also psoriasis, autoimmune uveitis, juvenile diabetes,
rheumatoid arthritis. More specifically, they are thought to
play a role in inflammation and tissue injury in these
conditions
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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 (IL-4)
• 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 (thus B-cell dependent
antigens)
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B – cell independent antigens
• Some antigens are T cell-independent in that they can
deliver both of the signals to the B cell. Mice without a
thymus (nude or athymic mice that do not produce any T
cells) can respond to T independent antigens. Many
bacteria have repeating carbohydrate epitopes that
stimulate B cells, by cross-linking the IgM antigen
receptors in the B cell, responding with IgM synthesis in
the absence of T cell help. There are two types of T cell
independent activation; Type 1 T cell-independent
(polyclonal) activation, and type 2 T cell-independent
activation (in which macrophages present several of the
same antigen in a way that causes cross-linking of
antibodies on the surface of B cells).
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TH cell help in humoral immunity
Activated helper
T cell
1 TH cell binds with the
Helper T cell
CD4 protein
self-nonself complexes of a
B cell that has encountered
its antigen and is displaying
it on MHC II on its surface.
MHC II protein
of B cell displaying
processed antigen
2 TH cell releases
T cell receptor (TCR)
IL- 4 and other
cytokines
interleukins as
co-stimulatory signals to
complete B cell activation.
B cell (being activated)
(a)
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Figure 21.19a
Helper T Cells
• Cause dendritic cells to express costimulatory molecules required for CD8 cell
activation
• two TNFR and 4-1BB, other members of this
family include CD27, CD30, CD40, OX-40,
and Fas
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TH cell help in cell-mediated immunity
CD4 protein
Helper T cell
1 Previously
activated TH cell
binds dendritic cell.
Class II MHC
protein
APC (dendritic cell)
2 TH cell stimulates
IL-2
dendritic cell to express
co-stimulatory
molecules (not shown)
needed to activate CD8
cell.
3 Dendritic cell can
Class I
MHC protein
(b)
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CD8
protein
CD8 T cell
now activate CD8 cell
with the help of
interleukin 2 secreted
by TH cell.
Figure 21.19b
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
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Roles of Cytotoxic T(TC) Cells
• Targets
• Virus-infected cells
• Cells with intracellular bacteria or parasites
• Cancer cells
• Foreign cells (transfusions or transplants)
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Cytotoxic T Cells
• Bind to a self-nonself complex
• Can destroy all infected or abnormal cells
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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
• The Fas receptor (FasR) is a death receptor on the
surface of cells that leads to programmed cell death
(apoptosis). It is one of two apoptosis pathways, the other
being the mitochondrial pathway
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Adaptive defenses
Cytotoxic
T cell (TC)
Cellular immunity
1 TC binds tightly to
the target cell when it
identifies foreign antigen
on MHC I proteins.
granzyme molecules from its
granules by exocytosis.
Granule
Perforin
TC cell
membrane
Target
cell
membrane
Target
cell
2 TC releases perforin and
Perforin
pore
Granzymes
5 The TC detaches and
3 Perforin molecules
insert into the target
cell membrane,
polymerize, and form
transmembrane pores
(cylindrical holes)
similar to those
produced by
complement
activation.
4 Granzymes enter the
target cell via the pores.
Once inside, these
proteases degrade
cellular contents,
stimulating apoptosis.
searches for another prey.
(a) A mechanism of target cell killing by TC cells.
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Figure 21.20a
Natural Killer Cells
• Recognize other signs of abnormality
• Lack of class I MHC
• Antibody coating a target cell
• Different surface marker on stressed cells
(MICA)
• Use the same key mechanisms as Tc cells for
killing their target cells
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Regulatory T (TReg) Cells
• Dampen the immune response by direct contact or by
inhibitory cytokines (IL – 10 and TGF - beta)
• Important in preventing autoimmune reactions
• Transforming growth factor beta (TGF-β) is a protein that
controls proliferation, cellular differentiation, and other
functions in most cells. It plays a role in immunity, cancer,
heart disease, diabetes, and Marfan syndrome. TGF-beta acts
as an antiproliferative factor in normal epithelial cells and at
early stages of oncogenesis
• Some cells secrete TGF-β, and also have receptors for TGFβ. This is known as autocrine signalling. Cancerous cells
increase their production of TGF-β, which also acts on
surrounding cells.
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TGF and cancer (Mutation and role change)
• In normal cells, TGF-β, acting through its signaling
pathway, stops the cell cycle at the G1 stage to stop
proliferation, induce differentiation, or promote apoptosis.
When a cell is transformed into a cancer cell, parts of the
TGF-β signaling pathway are mutated, and TGF-β no
longer controls the cell. These cancer cells proliferate.
The surrounding stromal cells (fibroblasts) also
proliferate. Both cells increase their production of TGF-β.
This TGF-β acts on the surrounding stromal cells,
immune cells, endothelial and smooth-muscle cells. It
causes immunosuppression and angiogenesis, which
makes the cancer more invasive. TGF-β also converts
effector T-cells, which normally attack cancer with an
inflammatory (immune) reaction, into regulatory
(suppressor) T-cells, which turn off the inflammatory
reaction.
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T – Gamma Delta
• The T cell receptor is comprised of a Gamma and Delta
subunit instead of the alpha and beta
• This group of T cells is usually much less common than αβ T
cells, but are found at their highest abundance in the gut
mucosa, within a population of lymphocytes known as
intraepithelial lymphocytes (IELs).
• The antigenic molecules that activate γδ T cells are still
largely unknown. However, γδ T cells are peculiar in that they
do not seem to require antigen processing and MHC
presentation of peptide epitopes although some recognize
MHC class IB molecules. Furthermore, γδ T cells are
believed to have a prominent role in recognition of lipid
antigens
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Cell-mediated
immunity
Antigen (Ag) intruder
Humoral
immunity
Inhibits
Inhibits
Triggers
Adaptive defenses
Innate defenses
Surface Internal
barriers defenses
Ag-infected
body cell engulfed
by dendritic cell
Becomes
Ag-presenting cell
(APC) presents
self-Ag complex
Activates
Free Ags
may directly
activate B cell
Antigenactivated
B cells
Clone and
give rise to
Activates
Naïve
Naïve
CD8
CD4
T cells
T cells
Activated to clone
Activated to clone
and give rise to Induce and give rise to
co-stimulation
Memory
cytotoxic T cells
Activated
cytotoxic
T cells
Memory
helper T cells
Activated
helper
T cells
Memory
B cells
Plasma cells
(effector B cells)
Secrete
Cytokines stimulate
Together the nonspecific killers
and cytotoxic T cells mount a
physical attack on the Ag
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Nonspecific killers
(macrophages and
NK cells of innate
immunity)
Antibodies (Igs)
Circulating lgs along with
complement mount a chemical
attack on the Ag
Figure 21.21
Organ Transplants
• Four varieties
• 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
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Prevention of Rejection
• Depends on the similarity of the tissues
• Patient is treated with immunosuppressive
therapy
1. Corticosteroid drugs to suppress inflammation
2. Antiproliferative drugs (5-FU – pyrimidine analog
that non-competitively inhibits thymidylate
synthetase, Daunomycin – bind G/C in DNA ,
Mitomycin- DNA cross linker –and
Dexamethasone - up regulation of
Transforming Growth Factor - TGG )
3. Immunosuppressant drugs
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Immunosuppressive drugs
• Immunosuppressive drugs can be classified into five groups:
1. Glucocorticoids – inhibit genes that code for the
interleukins s- thus they mainly inhibit cell mediated
immunity but also humoral
2. Cytostatics – inhibit cell division such as the alkylating
agents – like cyclophosphamide, platinum and others
3. Antibodies – targeted monoclonal antibodies
4. Drugs acting on immunophilins – inhibit calcineurin –
inducer of IL- 2 production
5. Other drugs
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(Interferons, TNF binding proteins)
Problems with Transplants
• Approximately 50% have rejection in 10 years
• The immunosuppressive therapy can lead to
overwhelming infections
• Most have to stay on the anti-rejection therapy for
life – but a few are able to stop therapy
• Create a chimera immune system – one method is
to temporarily suppress the recipients bone marrow
and douse it with the bone marrow of the donor –
hoping that this combined immune system will give
tolerance.
• Another method is to try to get T-suppressor cells to
work against rejection
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Chimera
• Typically seen in non-human zoology (but also discovered to
a rare extent in humans), a chimera is an animal that has two
or more different populations of genetically distinct cells that
originated in different zygotes involved with sexual
reproduction; if the different cells emerged from the same
zygote, it is called a mosaicism.
• Chimeras are formed from four parent cells (two fertilized
eggs or early embryos fused together). Each population of
cells keeps its own character and the resulting animal is a
mixture of tissues.
• This condition is either inherited, or it is acquired through the
infusion of allogeneic hematopoietic cells during
transplantation or transfusion
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Immunodeficiencies
• Congenital and acquired conditions that cause
immune cells, phagocytes, or complement to
behave abnormally
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Severe Combined Immunodeficiency (SCID)
Syndrome
• Genetic defect
• Marked deficit in B and T cells
• Abnormalities in interleukin receptors
• Defective adenosine deaminase (ADA)
enzyme – without this enzyme metabolites
lethal to T cells accumulate
• SCID is fatal if untreated; treatment is with
bone marrow transplants and virus vectors to
introduce normal genes
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Hodgkin’s Disease
• An acquired immunodeficiency
• Cancer of the B cells
• Leads to immunodeficiency by depressing
lymph node cells
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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
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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
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Acquired Immune Deficiency Syndrome
(AIDS)
• 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
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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
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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
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Mechanisms of Autoimmune Diseases
1. Foreign antigens may resemble self-antigens
•
Antibodies against the foreign antigen may crossreact with self-antigen – for example Group A
streptoccocal antigens (strep throat) may resemble
isoantigens on some individuals’ heart, joints, skin
and brain. Thus antibodies to Group A streptococcus
infection may interact with those organs. The
symptoms resemble rheumatism thus rheumatic
fever and rheumatic heart disease.
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Mechanisms of Autoimmune Diseases
2. New self-antigens may appear, generated by
•
Gene mutations
•
Changes in self-antigens by hapten attachment or as
a result of infectious damage
3. Release of novel self-antigens by trauma of a
barrier (e.g., the blood-brain barrier)
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Examples of Autoimmune Diseases
• Multiple sclerosis – destruction of myelin of the white matter
of brain and spinal cord
• Myasthenia gravis – impairs communication between
nervous system and skeletal muscles
• Graves’ disease – antibodies that stimulate thyroid gland to
over-secrete
• Type I diabetes mellitus – attack on Beta cells in pancreas
• Systemic lupus erythematosus (SLE)
• Glomerulonephritis – attack on kidney
• Rheumatoid arthritis – attack on joints
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Treatments
• Anti-inflammatory drugs like corticosteroids
• New treatments – for example antibodies against –
TNF (Tumor Necrosis Factor) has helped
rheumatoid arthritis
• Thalidomide also inhibits Tumor Necrosis Factor
• Antibodies against cell adhesion molecules –
preventing lymphocytes from exiting blood vessels in
target cells (helps in Multiple Sclerosis)
• Injecting DNA vaccine that induces tolerance to
myelin antigens (another help to Multiple Sclerosis)
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Tumor Necrosis Factor
• The primary role of TNF is in the regulation of
immune cells. TNF is able to induce apoptotic
cell death, to induce inflammation, and to
inhibit tumorigenesis and viral replication.
Dysregulation of TNF production has been
implicated in a variety of human diseases, as
well as cancer.
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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
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Types of Hypersensitivities
• Type I – Immediate (Acute) Hypersensitivity –IgE – starts
within seconds and lasts approximately 30 minutes (can be
transferred by serum or plasma)
• Types II and III are Intermediate (subacute) starting in 1 – 3
hours and lasting 10 – 15 hours (can be transferred by serum
or plasma)
• Type II –– (Cytotoxic ) mediated by Ig M or G – example is
mismatched blood transfusion
• Type III – (Immune Complex) mediated by Ig M or G –
example is Rheumatoid Arthritis
• Type IV – Delayed Hypersensitivity – starts in 1 – 3 days
Cell mediated immunity – thus cannot be transferred in serum
or plasma – example a contact dermatitis like poison ivy
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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
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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
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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
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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
• Examples: mismatched blood transfusion reaction,
Grave’s disease, Myasthenia Gravis,
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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)- antibodies attack cell’s DNA then
complexes deposit on cells , Rheumatoid
Arthritis (IgM against IgG)
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SLE (heart, joints, skin, lungs, blood vessels, liver, kidney, NS )
• The immune system must have enough genetic diversity to
protect itself against a wide range of possible infectious
organisms; some genetic diversity patterns result in
autoimmunity.
• Some environmental agents (ultraviolet light, drugs, viruses)
can cause the destruction of cells and expose their DNA,
histones, and other proteins, particularly parts of the cell
nucleus.
• Because of genetic variations in different components of the
immune system, in some people the immune system attacks
these nuclear-related proteins and produces antibodies
against them. In the end, these antibody complexes damage
blood vessels in critical areas of the body, such as the
glomeruli of the kidney; these antibody attacks are the cause
of SLE.
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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)
• These chemicals act as haptens, after
diffusing through the skin and attaching to
body proteins.
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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
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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
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