 Cells
of the Immune System |
A wide variety of leucocytes (white blood cells) participate in an immune
response. However, only the lymphocytes posses the
attributes of diversity, specificity, memory, and self/nonself recognition.
All of the other cells have
an accessory function: activation of lymphocytes, phagocytosis/antigen
clearance, secretion of cytokines.
MONOCYTES AND MACROPHAGES
also called mononuclear cells
Monocytes circulate
in the blood and lymph (represent 5-8% of WBCs in the blood)
From monocyte ------> macrophage
This transition occurs as the monocytes enter the tissues through the
process of extravastion.
Changes which occur during
this transition:
Cells enlarge [5-10x]
intracellular organelles increase in number and complexity
cells acquire increased phagocytic ability
increased secretion of many soluble factors
Macrophages play the following
important roles:
1) phagocytosis
2) antimicrobial activity
3) secretion of soluble factors
4) antigen presentation
Macrophages are activated
by a variety of stimuli in the course of an immune response.
- One of the earliest activating signals comes from chemokines.
- Phagocyotosis itself is an important activating stimulus.
- Macrophages are further activated by cytokines secreted by T helper
cells [IFN-gamma]
- and by mediators of the inflammatory response
- and by various microbial products (such as LPS)
 PHAGOCYTOSIS
The process of phagocytosis involves:
chemotaxis extension of pseudopodia
formation of a phagosome
fusion with lysosome---->phagolysosome
[lysosomes contain hydrogen peroxide, oxygen free radicals, peroxidase,
lysozyme, and a variety of hydrolytic enzymes]
Waste products are then eliminated
from the macrophage via exocytosis.
ANTIMICROBIAL ACTIVITY
Following phagocytosis, microorganisms are killed by both oxygen dependent
and oxygen independent mechanisms.
Oxygen Dependent
Respiratory burst involves the activation of a membrane-bound oxidase
that catalyzes the reduction of oxygen to superoxide anion
(O2-) which is extremely toxic.
The O2- also generates
other powerful oxidizing agents:
hydroxyl radicals (OH')
singlet oxygen (O2)
hydrogen peroxide (H2O2)
Macrophages activated with
LPS or other microbial products together with IFN-gamma also express
high levels of enzyme= nitric
oxide synthetase. This enzyme oxidizes L-arginine to yield citruline
and nitric oxide (NO).
NO is a very potent toxic agent. When it combines with the superoxide
anion O2- it is even more toxic. Nitric Oxide-mediated killing
may be more important than respiratory burst in the destruction of some
intracellular pathogens.
Oxygen Independent
-Lysozyme
-Other Hydrolytic enzymes
-Defensins [ cysteine-rich cationic peptides - circularize due to the
presence of 3 intramolecular disulfide bonds- Form ion-permeable
channels in bacterial and mammalian cell membranes.
-tumor necrosis factor alpha
SECRETION OF SOLUBLE FACTORS
Secretion of Cytokines
IL-1 - multiple effects (activation
of TH cells, affects vascular endothelial cells thus influencing inflammatory
response, affects the
thermoregulatory center in the hypothalamus leading to fever, induces
the syntesis of acute phase proteins.
TNF-a (Tumor necrosis factor
alpha)
(kills a variety of cells - often by inducing Apoptosis [a
form of programmed cell death )
IL-6
IL-12-(cytokine which functions
during antigen presentation to Th lymphocytes)
plus a large # of cytokines
which play a role in hematopoiesis [IL-6, GM-CSF, G-CSF, M-CSF]
Other soluble factors
several of the complement
proteins
various hydrolytic enzymes
---------------------------------------------
Macrophages possess in their
membrane, receptors for certain classes of antibody (Fc receptors),
receptors for complement
components (CRs). Allowing for opsonization.
---------------------------------------------
GRANULOCYTIC CELLS
(large leucocytes which contain cytoplasmic granules)
Neutrophils, Eosinophils, Basophils, and Mast Cells
NEUTROPHIL-
Represents 50-70% of circulating WBC
If higher numbers, very suggestive of bacterial infection.
Sometimes called PMN (polymorphonuclear) cell because of multi-lobed
nucleus.
The fine granules stain poorly with acidic and basic dyes....thus the
name- neutrophil.
These granules fuse with phagosome to destroy internalized bacteria
Primary granules - electron
dense and contain bactericidal enzymes such as lysozyme and myeloperoxidase;
neutral proteases (i.e.
elastase); and acid hydrolases (B-glucoronidase and cathepsin B).
Secondary granules - not
electron dense, smaller
contain lysozyme, collagenase and lactoferrin
As with macrophages, both
Oxygen dependent and Oxygen independent mechanisms are
used to kill internalized microorganisms.
Neutrophils are more likely
than macrophages to kill ingested microorganisms.
Neutrophils also exhibit a larger respiratory burst than macrophages
and consequently are able to generate more reactive oxygen intermediates.
In addition, neutrophils express higher levels of defensins.
The neutrophil is a phagocytic
cell, particularly important in the phagocytosis of bacteria.
However, these cells DO NOT function as APCs.
As discussed previously,
a number of substances produced during an inflammatory response recruit
neutrophils to a site of inflammation.
Neutrophils are the 1st cells to arrive.
EOSINOPHIL
(represent 1-3% of circulating WBCs)
Possess a bi-lobed nucleus and a heavily granulated cytoplasm.
Granules stain orange/red with the acidic dye Eosin Y.
Somewhat phagocytic but DO NOT act as APCs.
The major role of the eosinophil
is believed to be against parasites, particularly parasitic worms.
Eosinophils kill by ADCC
[antibody dependent cell-mediated cytotoxicity] by binding to parasite
- specific IgE via cell surface
FceRs.
When eosinophils bind to
IgE on the surface of a worm, the cell is triggered to degranulate.
The contents of the granules cause
damage to the worm's tegument. There are many hydrolytic enzymes
present in the granules responsible for the anti-helminthic activity.
One component which is unique to the eosinophils - and highly toxic
to worms - is a substance known as Major Basic Protein (MBP).
BASOPHIL
Only present in the bloodstream, and represent <1% of circulaing
WBC
Lobed nucleus--more variable,
large coarse granules stain blue with basic dye methylene blue.
Basophils are not phagocytic.
They play a major role in the allergic response when they release their
granules (containing histamine, serotonin, heparin, prostaglandin, etc
into the bloodstream following exposure to specific allergens).
Basophils also bear Fc receptors
for IgE (FceRs)
When an individual is exposed to an allergen, allergen specific IgE
is produced. This IgE binds to the surface of basophils [in the sensitization
phase of the allergic response].
Upon re-exposure to the allergen, the allergen binds to IgE on the surface
of basophils resulting in degranulation [effector phase].
MAST CELLS
Mast cells are released from
the bone marrow as undifferentiated precursor cells and do not differentiate
until they enter the tissues
(skin, connective tissue, mucosal epithelium, etc.)
Morphology and function similar
to circulating basophils - but clearly derived from a distinct cell
lineage.
Mast cells bear Fc receptors
for IgE (FceRs) and contain large numbers of cytoplasmic granules
which also play a very important role in the allergic response.
More recently, experimental
evidence has shown that mast cells express class II MHC and are
capable of presenting peptides to Th lymphocytes. They also produce
a variety of cytokines (including the very potent pro-inflammatory cytokine
TNF-a.
In fact, TNF is produced and stored within the cytoplasm of the mast
cell, and it can be released quickly following mast cell activation.
DENDRITIC CELLS
These cells are derived from the monocyte lineage.
They are called dendritic cells due to the fact that they are covered
with a maze of long membrane processes resembling dendrites of nerve
cells. These cells function as "professional" antigen presenting cells.
They constitutively express high levels of Class II MHC molecules. They
capture antigen in the tissues and migrate to various lymphoid organs
where they present the antigen to T helper lymphocytes.
Antigen is internalized through
endocytic or phagocytic processes.
Dendritic cells are termed:
Langerhan cells in skin
Veiled cells in lymph
Interdigitating dendritic cells in T cell areas of secondary lymphoid
tissue and thymic medulla
Interstitial dendritic cells populate most organs (e.g. heart, lungs,
liver, kidney, GI tract)
Follicular dendritic cells-
do not express MHC class II and, therefore, do not present
antigen to Th cells.
They have an exclusive location in lymphoid follicles, which are the
B cell rich areas of lymph node.
These cells express high levels of membrane receptors for antibody and
complement (FcRs and CRs).
Binding of immune complexes to these cells is thought to facilitate
B cell activation.
Complexes are retained for very long periods of time (months and even
years).
An important role in MEMORY B cell development??
 LYMPHOCYTES
Leucocytes which are responsible for the specific immune response.
Represent 20-40% of circulating WBC in blood - 99% of cells in lymph
These cells contain a single, large nucleus.
Lymphocytes circulate in
the blood and lymph but can also extravasate and enter the tissues.
Broadly divided into T lymphocytes and B lymphocytes and null cells.
T and B lymphocytes are small, motile, nonphagocytic cells which cannot
be distinguished from each other morphologically.
B and T lymphocytes which
have not interacted with antigen are said to be resting [virgin or naive]
lymphocytes. These cells have
little visible cytoplasm around their nucleus. Once stimulated with
antigen (and appropriate cytokine/cellular signals) the cell
progresses through the cell cycle and enlarges into a blast cell [Go-->G1-->S-->G2-->M.
Lymphoblasts further differentiate into effector cells or memory cells.
[Plasma cells, Th cells, Tcytotoxic cells]. The memory cells are long-lived
cells that reside in the Go phase of the cell cycle until activated
by a secondary encounter with antigen.
The transition from naive
lymphocyte to lymphoblast involves a transition from a 6µm cell
diameter to a 15µm cell diameter.
Different lineages or different
maturational stages of lymphocytes can be distinguished by their expression
of membrane molecules
recognized by particular monoclonal antibodies. Molecules recognized
are referred to as CD molecules (now well over 100)
Cluster of Differentiation (CD)
B lymphoyctes and T lymphocytes
may be distinguished by the type of cell surface proteins present (including
CD molecules).
A mature T lymphocyte expresses:
Thy-1
TcRs
CD3
CD28
CD45
If it is a Th lymphocyte,
the cell also expresses CD4.
If it is a Tc lymphocyte, the cell also expresses CD8.
A mature B lymphocyte expresses:
Ig (~ 1.5 x 105
per cell)
Class II MHC proteins
CD45 (B220)
CR1 and CR2
FcgRs
B7
CD40
NULL CELLS
A small group of peripheral blood lymphocytes
These cells fail to express membrane Ig or TcR or typical CD molecules.
One functional population of these cells are the NK cells (natural
killer cells).
These cells are large, granular, and represent 5-10% of the peripheral
blood lymphocytes.
NK cells kill tumor cells or virally-infected cells by direct membrane
contact or through antibody-dependent cell-mediated cytotoxicity. NK
cells are activated by the cytokines IFN-a & IFN-b (released by a variety
of different types of cells upon viral infection) and by IL-12 (released
by activated macrophages and dendritic cells).
MEGAKARYOCYTE
Giant polyploid cells.
Nucleus undergoes multiple mitotic divisions with no cytoplasmic divisions.
Megakaryocytes give rise to platelets when fragments or pieces of cytoplasm
break or "bleb" off of the cell body. Platelets are
involved in the blood clotting process.
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