Transcript Structure and Function of Leukopoietic Tissue

STRUCTURE AND
FUNCTION OF
LEUKOPOIETIC TISSUE
“The WBCs”
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

The basic function of blood leukocytes is as a
defense system against infectious foreign
invaders and non-infectious challenge. This is
divided into two separate, but interconnected
events:

Phagocytosis


Development of a specific immune response


Involves granulocytes and monocytes
Involves monocytes (macrophages) and lymphocytes
The vascular system is only a temporary
residence for leukocytes. The main function of
the vasculature with respect to WBCs is to
transport the leukocytes to body tissues.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

Leukocytes are differentiated from each other by
nuclear and cytoplasmic characteristics:
 Granulocytes (contain granules)
The granules in eosinophils have affinity for the acid
part of the Wright’s stain and they stain orange-pink
 The granules of basophils have affinity for the basic
part of the stain and they stain bluish-black.
 The granules of neutrophils have an affinity for both
acid and basic parts of the stain and they stain
pinkish-blue.

STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

Agranulocytes (lack granules):
Monocytes are usually large with a horseshoe shaped
nucleus
 Lymphocytes may be small (non-reactive) with a large
nuclear to cytoplasmic ratio or large (reactive) with a
smaller nuclear to cytoplasmic ratio. The nucleus is
usually round (small lymphs) or may be slightly
indented (large lymphs).

 Leukocytes
differentiate into mature cells
from the pluripotential stem cell in the
bone marrow.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Normally
only mature cells are released
into the peripheral blood.
 Mature cells may also remain as storage
in the bone marrow.
 At birth the leukocyte count is high: 9-30
x 109/L ; in adults the normal is 4-10.5 x
109/L
 An increase or decrease in WBC count
may be caused by an alteration of all WBC
cell lines, but more commonly results from
an alteration of only one type of WBC.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Therefore,
a differential is important.
From the differential and the WBC count,
the absolute values for each type of WBC
can be calculated (relative differential (%)
x total WBC count).
 Most variations in the leukocyte count are
due to increases or decreases in the
number of neutrophils since by percentage
they are the most numerous:
DIFFERENTIAL
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Neutrophil
matures:

maturation- As the neutrophil
Size decreases
Nucleoli disappear
 Chromatin condenses, indents, and finally
segments
 The cytoplasm goes from an agranular,
basophilic (blue) to a granular, more acidic
(pink) color
 The order of maturation from committed stem
cell to the mature neutrophil (also called a
polymorphonuclear leukocyte or PMN cell) is:

MYELOBLAST

Myeloblast – has a high N:C ration, fine,lacey chromatin,
visible nucleoli, and basophilic cytoplasm:
PROMYELOCYTE

Promyelocyte – basophilic staining primary granules containing
esterase, lysozyme, serprocidins , defensins, bacterial permeability
increasing protein, and myeloperoxidase are formed, nucleoli are
indistinct and chromatin condenses:
MYELOCYTE

Myelocyte –secondary, neutrophilic or specific granules
containing lactoferrin, histaminase, cathelicidins, lysozyme
and collagenase now appear and the concentration of the
primary granules decreases. Secretory vesicles containing
alkaline phosphatase, complement receptor 1, and
cytochrome b are also made:
METAMYELOCYTE

Metamyelocyte – nuclear indentation begins:
BAND

Band – also known as a stab. Has a horseshoe shaped
nucleus. Normal peripheral blood may contain 1-10% bands
(depends upon criteria for calling a cell a band):
VARIOUS STAGES OF
NEUTROPHIL MATURATION

Mature segmented neutrophil – may have 2-5
lobes:
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Neutrophil
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kinetics
The absolute value is 2-7 x 109/L
The absolute count is diurnal, i.e., it is higher
in the evening
Alterations in the peripheral blood
concentration of neutrophils are often the first
indication of an underlying pathology
Neutropenia is when the concentration is < 2 x109/L
and when this occurs it can lead to infections
 Neutrophilia is when the concentration is > 7 x109/L
and this occurs as a response to bacterial infection,
metabolic or drug intoxication, or tissue necrosis.

STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

Only about half of the peripheral neutrophils
are freely circulating in the blood, while the
other half are attached to the vessel walls
(called the marginating pool).
There is a free equilibrium between the circulating
and marginating pool.
 Upon antigenic stimulation, the marginating
neutrophils will move into the tissues (diapedesis).
 The average neutrophil circulates~ 10 hours before
diapedesis.

MOVEMENT OF PMNS TO TISSUES
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

There are two pools of neutrophils in the bone
marrow:
Mitotic and capable of DNA synthesis (myeloblasts up to
myelocytes – takes 3-6 days to mature to this stage)
 Post-mitotic – serve as a storage pool of neutrophils
(metamyelocytes up the mature segmented neutrophils –
takes 5-7 days to mature to this stage).
 These pools in the bone marrow represents 15-20 times the
number of circulating neutrophils!
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STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

Under conditions of stress the normal
marrow transit time can be increased by:
Accelerated maturation
 Skipping cellular divisions
 Releasing cells early from the bone marrow


Normally the input from the bone marrow is
equal to the output to the tissues – this is
achieved by feedback loops.
NEUTROPHIL DISTRIBUTION
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Neutrophil


function –
The characteristic response of the blood
leukocyte count to bacterial infections is
neutrophilia with an increase in the % of
bands and even some metamyelocytes in the
peripheral blood. This is called a shift to the
left.
Neutropenia may be a bad prognostic sign
(only if it is due to depletion of the bone
marrow stores rather than to a transient
increase in marginating neutrophils).
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

Neutrophil morphology may also be
altered during infections
Toxic granulation (cytoplasmic, primary
granules become prominent)
 Dohle bodies may be seen – are large bluish
bodies consisting of aggregated RER
 The cytoplasm may become vacuolated
 May see ingested microorganisms

TOXIC GRANULATION
DOHLE BODIES
NEUTROPHIL RESPONSE TO
INFECTION
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

To participate in an inflammatory reaction,
which is the body’s response to infection,
neutrophils enter the tissues where they are
attracted by chemotactic stimuli released after
tissue injury and during an inflammatory
response. In the tissues, the neutrophils
participate in phagocytosis (opsonization
helps).
 Upon phagocytosis of the microorganism into
a phagocytic vacuole, a plasma membrane
bound oxidase is activated (oxidative or
respiratory burst) resulting in the formation
of oxygen by-products that may be toxic to
microorganisms (superoxide radical,
hydrogen peroxide, etc.)
PMN FUNCTION
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
Next primary and specific granules and
secretory vesicles (collectively called
lysosomes) fuse with the phagocytic vacuole,
releasing their contents (degranulation).
 The enzymes and antimicrobial peptides
such as defensins, serprocidins , and
bacterial permeability increasing protein
(BPI) present in the granules may act to kill
the ingested microorganisms.
 In this process most neutrophils die and are
themselves phagocytosed by macrophages.

PHAGOCYTOSIS
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Eosinophils
Have a maturation similar to that of
neutrophils, but only one type of granule is
formed and it contains acid phosphotase,
peroxidases, ribonuclease, etc.
 Eosinophils function in phagocytosis and
killing of bacteria, but they are more sluggish
and less efficient than neutrophils.
 Their primary function is against helminth
parasites.
 Eosinophilia may occur in allergic conditions
and with parasitic infections, and with chronic
inflammation.

STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Basophils
Basophils also have a similar
maturation process, but their
metachromatic granules contain
histamine and heparin.
 Basophils share a common
hematopoietic stem cell with tissue
mast cells and functionally the two are
similar.


They are mediators of the inflammatory
response, particularly in hypersensitivity
reactions.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

Both have membrane receptors for the Fc region of
IgE. Upon attachment of antigen to the IgE,
degranulation and release of mediators of
hypersensitivity reactions occur. This leads to
vasodilation, increased vascular permeability, smooth
muscle contractions, and increased secretions.
 Monocyte


maturation
Monocytes are derived from a committed
bipotential stem cell capable of maturing into
a monocyte or a neutrophil.
The bipotential stem cell matures into a
monoblast containing an agranular cytoplasm.
It can be differentiated from a myeloblast by
cytochemical stains.
MONOBLAST
PROMONOCYTE
MATURE MONOCYTE
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
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When mature monocytes leave the blood and
enter the tissues, they mature into
macrophages. This is accompanied by
progressive enlargement of the cell. The cells
can live for months in the tissues and are
known collectively as histiocytes.
There is no reserve pool of monocytes in the
bone marrow. All are directly released into the
peripheral circulation where they circulate 1214 hours before diapedesis occurs and they
enter the tissues.
The total vascular pool = the freely circulating
monocytes and the marginating monocytes
which is three times the number of freely
circulating monocytes.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Monocyte
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and macrophage function
They function in phagocytosis of
microorganisms and cellular debris
They secrete substances (cytokines) that affect
the function of other cells, especially
lymphocytes.
They are important in the processing of and
presentation of antigens to lymphocytes for
activation and differentiation.
 Lymphocytes
– their primary function is
to react with antigens and to work with
macrophages in modulating (controlling)
the immune response.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Lymphocyte


maturation
From the pluripotential stem cell comes the
committed lymphoid stem cell which will
eventually differentiate into B and T
lymphocytes.
This lymphopoiesis is divided into two phases

Antigen independent phase – this occurs in the
primary lymphoid tissues (bone marrow, thymus,
fetal liver, and yolk sac) and results in the formation
of immunocompetent B and T cells

In the bone marrow the plupotential stem cell
differentiates into a committed lymphoid stem cell.
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
Those that will become T cells migrate to the thymus for
differentiation and maturation
 Those that will become B cells remain in the bone
marrow for differentiation and maturation
 In those two environments the committed stem cell
matures into a lymphoblast
 The lymphoblast has a high N:C ratio, like the
myeloblast, but it is much smaller.
 The lymphoblast becomes a prolymphocyte
 The prolymphocyte becomes an immunocompetent T
(those that mature in the thymus) or B (those that
mature in the bone marrow) cell.
 Immunocompetent B and T cells have acquired
receptors (antibodies for B cells and T cell receptor for
T cells) that recognize and bind a specific a specific
antigen. One cannot tell the difference between a B or
T cell under the microscope.

AG INDEPENDENT MATURATION LYMPHOBLAST
AG INDEPENDENT MATURATION PROLYMPHOCYTE
AG INDEPENDENT MATURATION –
IMMUNOCOMPETENT LYMPHOCYTE
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE

The mature lymphocyte has extreme size variability
which is primarily dependent upon the amount of
cytoplasm. The majority are small lymphocytes. Large
lymphocytes, which probably represent activated
lymphocytes (see below), are often mistaken for
monocytes. When compared to a monocyte, the
nuclear chromatin of a lymphocyte is more condensed
(clumpy) and the cytoplasm is more clear and nongranular.
The antigen dependent phase of maturation begins
when a specific antigen binds to the antigen receptor
on the surface of an immunocompetent B or T cell.
 Binding triggers a sequence of events called blast
transformation:
 The immunocompetent cell becomes a reactive
lymphocyte (sometimes called Downey cells).

STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
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The reactive lymphocyte becomes an
immunoblast which will undergo clonal
expansion to increase the number of lymphocytes
that can recognize and bind to the antigen that
triggered the whole reaction.
For T cells, these cells may then differentiate
into memory cells or into effector cells that help
to mediate the immune response (T helper, T
supressor, cytotoxic T cells, or delayed
hypersensitivity T cells).
In the case of B cells they may differentiate into
memory cells or plasma cells that will secrete
antibody of the same specificity that was on the
original immunocompetent B cell.
AG DEPENDENT MATURATION –
REACTIVE LYMPHOCYTE
AG DEPENDENT MATURATION IMMUNOBLAST
AG DEPENDENT MATURATION –
PLASMOCYTOID LYMPHOCYTE
AG DEPENDENT MATURATION –
PLASMA CELL
STRUCTURE AND FUNCTION OF
LEUKOPOIETIC TISSUE
 Lymphocyte
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
kinetics
The peripheral blood contains only about 5% of
the total body lymphocytes
Most of the lymphocytes reside in the
lymphoid organs (mainly the spleen and lymph
nodes, but also the thymus, and bone marrow)
LYMPHOCYTE MATURATION