414/514 Immunology Principles
415/515 Immunology Principles and Practice
Cells and Organs of the Immune System
Hematopoiesis
Blood cells (both white and red) are formed from
hematopoietic stem cells (HSC) by a process known as
hematopoiesis
HSCs are first formed in the embryonic yolk
sac, then migrate to the fetal liver and
spleen, which become the major hematopoietic organs
during the third-seventh months of embryogenesis
Bone marrow becomes the
major location of HSC differentiation after the seventh
month of embryogenesis, and continues this role throughout
life
HSC properties
HSC are pluripotent ... they can differentiate into
a number of different blood cell types, including lymphocytes,
granulocytes, monocytes, mast cells, megakaryocytes, and
erythrocytes
HSC are self-renewing ... they can divide to
replenish themselves in their pluripotent (undifferentiated)
state
Process of hematopoiesis
HSC differentiate into either lymphoid or
myeloid progenitor cells under the influence of
growth factors and cytokines produced in
hematopoietic tissues:
Interleukin-3 (IL-3) triggers differentiation of
HSC into lymphoid progenitor cells
Granulocyte-Monocyte Colony Stimulating Factor
(GM-CSF) and IL-3 act in combination to
trigger differentiation of HSC into myeloid progenitor
cells
Progenitor cells subsequently differentiate further
to form a number of more mature cell types, again under the
influence of more growth and differentiation factors
Myeloid differentiation ... is triggered by:
GM-CSF and IL-3, which act in combination to
trigger differentiation of myeloid progenitor cells into:
eosinophil progenitor cells, which then develop into eosinophils ...
under the influence of GM-CSF and IL-5
basoophil progenitor cells, which then develop into:
basophils ... under the influence of GM-CSF and IL-4
mast cells ... under the influence of IL-9
GM-CSF, IL-3 and IL-6, which act in
combination to trigger differentiation of
myeloid progenitor cells into
granulocyte-monocyte progenitor cells, which then
develop into:
Monocytes ... under the influence of
GM-CSF and Monocyte Colony Stimulating
Factor (M-CSF) ... and later (under the influence
of as-yet unknown factors) differentiate into:
macrophages when they enter the tissues
of the body
dendritic cells (the least well-studied
of these cells) may differentiate from
monocytes (in the tissues) or they may have
their own line of differentiation directly from
granulocyte-monocyte progenitor cells ... this has
not been settled yet
Neutrophils ... under the influence of
GM-CSF and Granulocyte Colony Stimulating
Factor (G-CSF)
GM-CSF, IL-3, IL-11 and
Erythropoietin (EPO), which act in
combination to trigger differentiation of
myeloid progenitor cells into
megakaryocytes, which then "disintegrate" to form
platelets (important for triggering blood
clotting) ... under the influence of GM-CSF, EPO
and IL-6
GM-CSF, IL-3 and EPO, which act
in combination to trigger differentiation of
myeloid progenitor cells into erythroid
progenitor cells, which then lose their nucleus as
they differentiate into erythrocytes ... under the
influence of EPO
Lymphocyte
differentiation ... is triggered by:
IL-3 and IL-7, which act in
combination to trigger differentiation of
lymphoid progenitor cells into B progenitor
cells that subsequently develop into B cells
(B lymphocytes) ... under the influence of a combination
of IL-2, IL-4, IL-5 and
IL-6
Unknown factors, which trigger development of
the "default" T progenitor cells that migrate (via
the bloodstream) to the thymus
where they subsequently develop into thymocytes (T
lymphocytes) ... under the influence of a combination of
IL-2, IL-4, IL-5 and IL-6
and, finally, into:
T helper (Th) cells (Th lymphocytes) ...
under the influence of IL-2, IL-4 and
IL-7 followed by positive and negative
selection (more about this later)
T cytotoxic (Tc) cells (Tc lymphocytes) ...
under the influence of IL-2, IL-4 and
IL-7 followed by positive and negative
selection (more about this later)
Unknown factors, which result in development
of natural killer (NK) cells in various tissues of
the body
Apoptosis is used in negative regulation of
hematopoiesis
Inducers of apotosis are many and varied:
Bax, Bcl-Xs
FAS/FAS-ligand binding
Glucocorticosteroids produced by local tissue
cells in the thymus as well as by the adrenal cortex under
stress conditions
Granzymes produced and secreted by cytotoxic
lymphocytes (CTL)
Lack of growth factors, which leads to decreased
intracellular levels of IL-2, NF-kB, etc.
Caspases (cysteine-containing proteolytic enzymes that cleave
after aspartic acid residues) are responsible for carrying out
much of the activity in this programmed cell death
process, and virtually all apoptosis inducers activate caspases
either directly or indirectly
During the Process of apoptosis:
Cells shrink in size, change shape and
their chromatin condenses
Nuclear fragmentation leads to blebbing
which leads to apoptotic body formation
Apoptotic bodies are engulfed and
digested by phagocytes (generally macrophages)
in the area; this is important because it prevents release
of cell contents into the environment ... which would
cause inflammation that might lead to pathology, such as occurs in necrosis
(the
other type of cell death, which is essentially lysis from without and
does lead to release of these inflammatory factors)
Cells of the Immune System
Myeloid Cells
Granulocytes
General Charactistics
comprise 41-81% of blood leukocytes
20-30 µm in diameter
have a multilobed nucleus:
with loosely packed strands of intensely
basophilic chromatin
surrounded by a moderate amount of lightly
basophilic cytoplasm containing large numbers of
granules
Types of Granulocytes
Neutrophils
comprise 40-75% of blood leukocytes
contain small, lightly staining granules
phagocytic effectors of antibody-mediated immunity
and hypersensitivity
Eosinophils
comprise1-5%of blood leukocytes
contain orange-to-red staining granules
help regulate inflammatory responses
active in antibody-mediated cytolysis of immature
forms of intestinal parasites
Basophils
comprise0-1%of blood leukocytes
contain large, blue-black staining histamine-rich
cytoplasmic granules and FcR that bind IgE
molecules
help generate inflammatory responses
mediators of immediate (type I)
hypersensitivity
Mast Cells
tissue cells with histamine-rich cytoplasmic
granules and FcR that bind IgE molecules (~10X more of
each than found in basophils)
help generate inflammatory responses
tissue mediators of immediate (type I)
hypersensitivity
Monocytes
comprise 3-7% of blood leukocytes
20-50 µm in diameter
nucleus is large and indented:
contains loosely packed strands of intensely
basophilic chromatin
surrounded by a large amount of lightly basophilic
cytoplasm
cytoplasm contains numerous granules and occasional
vacuoles
engulf and digest foreign matter
phagocytic effectors of cell-mediated immunity and
hypersensitivity
Macrophages
derived from monocytes after they migrate into tissues
(e.g. histiocytes in connecitve tissue, alveolar macrophages
in lung, microglial cells in CNS, mesangial cells in kidney,
Kupffer cells in liver, osteoclasts in bone, etc.)
nucleus is large and indented:
contains loosely packed strands of intensely
basophilic chromatin
surrounded by a large amount of lightly basophilic
cytoplasm
cytoplasm contains numerous granules and vacuoles,
especially when activated by T lymphocyte cytokines, such as
interferon-gamma
engulf and digest foreign matter
active in antigen processing and presentation
phagocytic effectors of cell-mediated immunity and
hypersensitivity
Dendritic Cells are covered with long membrane
extensions (that make them look like dendrites in nervous
tissues ... hence the name)
Circulating dendritic cells
constitute 0.1% of blood leukocytes and are also
found in lymph ("veiled" cells)
develop into mature tissue dendritic cells (?)
Interdigitating dendritic cells
found in T cell rich regions of secondary lymphoid
tissues
process and present antigen to T cells
Interstitial dendritic cells
found in most organs ... lungs, liver, heart, kidney,
digestive tract, etc.
process and present antigen to T cells
Langerhans cells
found in epidermis of skin
process and present antigen to T cells
Lymphoid Cells
Comprise 20-45% of blood leukocytes
Responsible for immune responses
10-30 µm in diameter
Nucleus is nearly round and contains coarse lumps of
intensely basophilic chromatin
Cytoplasm is lightly basophilic and variable in amount ...
less cytoplasm in "resting" lymphocytes and more in "activity"
lymphocytes
B Lymphocytes develop in bone marrow
differentiate into plasma cells, which synthesize and
secrete antibody molecules
also capable of antigen processing and presentation
T Lymphocytes develop in thymus
T helper cells (Th) can synthesize and
secrete cytokines and function to regulate immune
responses (both antibody and cell-mediated) when
appropriately stimulated during immune responses
T cytotoxic cells (Tc) are mature
precursor cells that, as a result of a cell-mediated immune
response, differentiate into cytotoxic T lymphocytes
(CTL) which mediate cellular immunity vs.
virus-infected cells and tumor cells
Natural Killer (NK) Cells develop in several
lymphoid tissues ... some in thymus, others in bone marrow
not antigen-specific, but can recognize "self"
cells
active in early phases of cell-mediated immune responses
... synthesize and secrete cytokines that promote these
responses
Bone marrow is a loosely-organized grouping of
cells located in central soft tissue portion of bones
(surrounded by the calcified matrix) throughout the body
Reticular cells form a matrix within which the
other bone marrow cells interact
Other cells found here include hematopoietic
stem cells and progenitor cells, as well as immature and
mature forms of all blood cells
Hematopoietic stem
cells (HSC) present in the bone marrow are
responsible for development of all blood cells after about
the seventh month of gestation in humans
B
lymphocytes, granulocytes, monocytes and
erythrocytes all develop to maturity in the bone marrow
before they are released into the bloodstream for transport
to other locations in the body
Pro T
lymphocytes (immature T cells) are released into the
bloodstream before final maturation as a matter of course
... in contrast to granulocytes and erythrocytes, which may
be released into the bloodstream in immature forms in times
of great need
Bilobed organ that
lies within a fat deposit together with the periaortic lymph node
just anterior to the heart in the thoracic cavity
Two types of tissue (with a transitional region
between them) that both contain reticular cells (stromal
cells) and developing T lymphocytes (T cells) are randomly
situated in clusters throughout the thymus:
Cortical (cortex) is an area of intense T
cell developmental activity ... this is the region where pro T
cells develop their antigen-receptors (TCRs)
and their (CD4 and CD 8) co-receptors to become immature
"double-positive" T lymphocytes, then migrate through the corticomedullary
junction, a transitional
region between cortical and medullary tissue areas
where self-responsive T cells are eliminated by
apoptosis following interaction with
antigen-presenting cells (APCs) with self-antigen
fragments associated with their antigen-presenting
cell receptors (ACRs), as they migrate into the ...
Bean-shaped, encapsulated nodules located at
junctions of lymphatics at strategic areas of the
body
Filters particulate and soluble molecules out of
lymph (interstitial tissue fluid picked up by the
lymphatics for transport to the lymph ducts that empty into
the subclavian veins) ... thus capturing immunogens for
immune system stimulation
Three types of tissue (in addition to the
ubiquitous reticular cells that form the tissue matrix along
with trabecular connective tissue) are found in lymph
nodes:
Cortical (cortex) tissue:
Located in the outer region of lymph nodes,
just inside the subcapsular sinus (into which lymph
drains from afferent lymphatics)
B cells are the primary lymphoid cells here
(but there are some T cells and follicular dendritic
cells present as well)
lymphoid follicles (loosely-organized
clusters of lymphoid cells) characterize the
cortical region of lymph nodes
germinal centers develop within lymphoid
follicles as a result of antibody responses that
occur here
Paracortical (paracortex) tissue:
Located in the intermediate region of lymph
nodes and partially surrounding lymphoid follicles (on
the medullary side of the cortex)
T cells are the primary lymphoid cells here
(but there are some macrophages and dendritic cells
present as well) but they migrate in and out of
this tissue:
migrate into lymphoid follicles
following antigenic stimulation by APCs ... to
better "deliver" cytokines to B cells responding to
immunogens present
migrate from lymph into blood and from blood
into lymph (via high endothelial venule cells
in lymph nodes in both cases)
Medullary (medulla) tissue:
Located in the central region of lymph
nodes as a loosely-organized aggregate of
predominantly phagocytic cells
Macrophages and dendritic cells
(both are APCs) are the primary lymphoid cells here
(but there are variable numbers of plasma
cells, especially during active immune
responses)
APCs migrate into the paracortical region
of lymph nodes when they have processed antigen and
are presenting immunogen fragments on their ACRs ...
so they can stimulate T cells to initiate immune
responses
Spleen
Lumpy, rather amorphous encapsulated lymphoid
organ (much larger than a normal lymph node) located
ventral to the stomach in the abdominal cavity
Filters particulate and soluble molecules out of
blood ... thus capturing immunogens for immune system
stimulation
Trabecular connective tissue forms the splenic
matrix, which contains two major types of tissue:
Red pulp consists of a network of
sinusoids containing reticular macrophages
and erythrocytes plus the other elements of blood
being filtered at the time of organ examination
White pulp consists of splenic lymphoid
cells and is organized into two major regions
that form concentric sheaths around each of the
arterioles that deliver the blood into the
sinusoids:
Periarteriolar lymphatic sheath
(PALS) areas surround each of the arterioles
and contain many T cells admixed with
interdigitating dendritic cells
Marginal zone surrounds the PALS and
contains numerous B cells, some of which are
loosely organized to form primary lymphoid
follicles ... these primary follicles develop into
secondary lymphoid follicles with germinal
centers as antibody responses occur in the
spleen
Mucosal-associated lymphoid tissue (MALT)
generally consists of rather loosely-organized lymphoid cells
that are associated with mucosal tissues that line the:
Digestive tract, including:
Tonsils ... lingual, palatine and pharyngeal
(denoids)
Lamina proprial and submucosal lymphoid
follicles of the small intestine ... including Peyer's
patches
Appendix
Respiratory and urogenital tracts contain
other, more loosely-organized lymphoid follicles
Cutaneous-associated lymphoid tissue of the
epidermis contains intraepidermal lymphocytes and
Langerhans (dendritic) cells which can process and
present antigen to T cells ... they even migrate to local lymph
nodes after they have been phagocytized exogenous antigen
(presumably just so they can present their processed antigen to
T cells)
