INTRODUCTION maturation.

Mature cells enter the blood

circulation only after developing into band
- The cellular elements of the blood are
or segmenters.
produced from the progenitor cells, which
undergoes mitotic division. Subsequent Development and Proliferation of Neutrophils,
maturation of progenitor cells produces the Eosinophils, and Basophils
erythrocytes, leukocytes, and thrombocytes,
- Myeloblast forms when CFU-granulocyte-
which are the cellular elements of the
erythrocyte-megakaryocyte (CFU-GEMM)
circulating blood.
cell differentiates into CFU-granulocyte-
- Leukocytes based on function:
macrophage (CFU-GM). The bone marrow’s
o Granulocytic
proliferative compartment or the mitotic
o Monocytic
pool is where the development from
o Lymphoid series
myeloblast (through myelocyte stage) and
THE GRANULOCYTIC SERIES mitosis take place. It includes all cells
capable of DNA synthesis.
Production of Neutrophils, Eosinophils, and
- The myeloblast is the first identifiable cell in
Basophils
the granulocytic series and has short
- Factors that regulate the commitment of a lifespan
human hematopoietic progenitor cell to a -
specific cell line are influenced by: % in bone Hours
o Hematopoietic growth factors marrow cells
o Interleukins – communication Myeloblast About 1% 15 hrs
network between hematopoietic Promyelocyte About 3% 24 hrs
growth factors Myelocyte About 12% 4.3 days
o Microenvironment Metamyelocyte
- Further growth of the cells is dependent on: *here, only 1st
few stages
o Colony-stimulating factor
undergo
o Interleukins
subdivision
*different CSF stimulates specific (sabi ni maam)
differentiation, like development of *once metamyelocyte stage is reached, cells
eosinophils have undergone 4 or 5 divisions and the
*different CSF and interleukins plus proliferative phase comes to an end
the microenvironment of the cell - After proliferative stage, granulocytes enter
favors differential development of maturation-storage compartment, where
either the granulocytic (myeloid) metamyelocytes (45%) and bands (35%)
series or the macrophage-monocytic mature into segmenters (20%).
series - Marrow reserve are the segmenters in the
Sites of Development and Maturation maturation-storage compartment and
- Granulocytic kinetics is the development, constitutes a 4 to 8 day supply of
distribution, and destruction of neutrophils, neutrophils. This combats foreign bodies,
eosinophils, and basophils. These cells thus causing inflammation.
begins as a multipotential cell in the bone - It is estimated that neutrophils remain in the
marrow and stays here throughout maturation-storage phase for 7 to 10 days.
differentiation, multiplication, and
*Bands have longer than wide nucleus than
metamyelocyte
 Eosinophils for about 2.5 days, and basophils NORMAL MATURATIONAL CHARACTERISTICS OF
for the shortest period (approx. 12 hours). NEUTROPHILS, EOSINOPHILS, AND BASOPHILS

Distribution of Neutrophils, Eosinophils, and Myeloblast Read table 14.2 page 237
Basophils
- This is the earliest morphologically
- Some of the factors that influence cellular identifiable granulocytic precursor. The
release include the interleukins. Cellular cytoplasm appears as a small rim of
characteristics include an overall reduction basophilic cytoplasm that lacks granules.
in cell size and a smaller nuclear-cytoplamic Auer rods (aggregates of fused lysosomes)
ratio. may appear as red, needle-like crystalline
- Greater flexibility and mobility of mature cytoplasmic inclusions that may appear
cells enhance the migration of cells into the alone or in groups. These are pathological
peripheral blood pool. inclusions.
- Peripheral blood circulation is divided into 2 - Have myeloperoxidase and scanty cytoplasm
pools of equal size:
Promyelocyte
o Circulating pool
o Marginating pool- helps in defense - Is the second maturational stage seen in
mechanism and contains reserves granulocytes. The outstanding feature of
- The marginating granulocytes adhere to the this cell is the prominent granulation,
endothelium of the blood cells, some in the primarily azurophilic granules, that may
spleen. The movement of granulocytes from obscure the other morphological features of
the circulating pool to the peripheral tissues the cell. These granules are rich in
occurs by a process called diapedesis myeloperoxidase and chloroacetate
(mature dapat in order to move). Once in the esterase
peripheral tissues, granulocytes can now - Larger than the blast. Nuclear chromatin is
phagocytize. more condensed. Cytoplasm is pale grayish
- Average life span of neutrophils is 7 to 10 blue
hours. Once mature cells have migrated to
the tissues, their life span is several days pa Myelocyte
but if merong infection, shorter ang life - 3rd maturational stage. Have specific
span. Eosinophils are in the blood for few cytoplasmic granulation. Neutrophils, eos,
hours and reside in the tissues for several and baso become visibly recognizable in this
days. Basophils circulate for about 8.5 stage.
hours. - Neutrophilic granules are fine and stain a
- If high ang eosinophils, these cells give rise blue-pink color with Wright stain.
to Charcot-Leyden crystals (have Eosinophilic granules are larger than
peroxidase, crystalline granules, and acid neutrophilic granules, round or oval, orange,
phosphatase) found in the body secretions and have a glassy or semiopaque texture.
- If cells are not prematurely destroyed while Basophilic granules have a dark blue-black
defending the body, they are sloughed off color, w/c obscure the nucleus, and have a
with body secretions like urine, saliva, etc. dense appearance, thus nucleus is hard to
- An alternative route for the removal of see.
granulocytes from the circulation is
phagocytosis by the cells of the spleen.
Metamyelocyte o Larger crystalline granules – more
numerous, elliptical, larger than the
- Its characteristic feature is that the nucleus
granules of the neutrophil, and have
begins to assume an indented or kidney
an amorphous matrix (surrounds
bean shape, w/c will continue to become
internal crystalline granules). The
more clumped. It is “i” shaped, mitotic and is
crystals represent the peroxidase
present in the maturational pool.
and the matrix contains acid
Mature Forms phosphatase
- Basophilic granules contain heparin and
- Stages of granulocytes observed in the histamine. Mast cells have granules similar
circulating blood: to blood basophil
o Band form – elongated nucleus
o Segmented form – multilobed THE MONOCYTIC MACROPHAGE SERIES
nucleus, w/c are attached to each
- Mature macrophages are distributed
other by a fine thread-like filament
throughout the body. Macrophages have
that may be hidden.
variety of names:
- Cell forms normally found in the circulating
o Histiocytes – in loose CT
blood: Band form of neutrophils, eos, and
o Kupffer cells – in the sinusoids of
baso, as well as segmenters of neutrophils,
liver
eos, and baso.
o Osteoclasts – in bone
- Mast cells (tissue basophils) are not seen in
o Microglial cells – in the nervous
the blood of a healthy individual. These have
system
an appearance similar to blood basophil.
- Mononuclear phagocyte are macrophage
These cells have round/oval nucleus and
along with reticular cells of the spleen,
granules do not obscure the nucleus like in
thymus, and lymphoid tissues
basophils.
- Segmented neutrophil (predominant
Granulation in Mature Forms phagocytic cell) is confined to the circulating
blood unless it is recruited into the tissues
- All granules are commonly produced by the
RER and transported to the golgi apparatus Production and Development of Monocytes
for packaging, but granules stain differently and Macrophages
because their contents vary
*monocytes have lipase for digestion
- Granules of segmented neutrophils (some
are typical lysosomes) are rich in various - Cells of the macrophage system are formed
antibacterial substances (lysosomal from the progenitor cells in bone marrow.
hydrolases, lysozyme, myeloperoxidase) These cells are derived from CFU-GM and
- Eos. granules differ to neutro. granules in differentiates into either a segmenter or a
that they lack lysozyme monocyte/macrophage.
- Two types of granules:
o Smaller round granules – do not
contain crystalloids and exist in
small quantities in the mature
eosinophil and are rich in acid
phosphatase
- A monocyte is influenced by hematopoietic - Difference in the total leukocyte count do
growth factors to transform into occur between black(lower) and white
macrophage. Both have phagocytosis as persons. Peak level occur in the middle of
their major role, although they also have the night and early morning
regulatory and secretory functions - Eosinophils have a well-documented daily
- In contrast to the granulocytic leukocytes, fluctuation with a diurnal variation in the
promonocyte will undergo 2 or 3 mitotic number of circulating cells. Eosinophils tend
divisions in 2 to 2.5 days. to be highest late at night during sleep,
- Monocytes are released to the circulating decreases during morning and begins to rise
blood w/in 12 to 24 hours after their midafternoon
precursors have completed mitosis. - Variation in person’s eosinophil count is
- Monocytes have no large reserve of cells in a related to the hormone adrenal
maturation-storage pool as do the glucocorticosteroid
granulocytes - Dropping circulating eosinophils at the time
- The ratio of circulating to marginating cells is of ovulation and rising during menstruation.
1:3.5. Monocytes have a half-life of approx. Exercise produces a brief rise in eos whereas
8.5 hours. Cells in noninflammatory areas stress lower eosinophil counts
have been demonstrated to live for months
FUNCTIONAL PROPERTIES OF GRANULOCYTES
to years
AND MONOCYTES
Morphological Characteristics
- One of the major functional properties of
- The monocytic series does have a granulocytes and monocytes is phagocytosis
characteristic nuclear chromatin pattern. for defense against infectious diseases.
The chromatin is clumped and is smaller and - Phagocytosis is the process that enables
more elongated than in neutrophils “lace- particular cells to engulf and disable
like”. Nucleus is round/oval but is particles. Defects in phagocytosis can be
convoluted or twisted fatal (eg. Chronic granulomatous disease, in
- Mature monocytes are the largest mature which there is defective killing of
cells seen in the peripheral blood. Have an phagocytosed microorganism)
irregular cytoplasmic outline. May have - Body defense systems include:
pseudopods and vacuoles. Cytoplasm is o Phagocytic cells
blue-gray in color, with fine granulation o Cells that release inflammatory
resembling ground glass. mediators
o Natural killer cells
Reference Ranges of Granulocytes and
- Neutrophils act quickly in body defense by
Monocytes
recognizing pathogen-associated molecular
- The major function of the granulocytic patterns (PAMPs) through encoded toll-like
leukocytes is phagocytosis receptors.
- Neutrophilic granulocytes are the major - IL-17A and IL-17F are found to indirectly
phagocytic cell of the circulating blood. reduce the recruitment of neutrophils in
Eosinophils and basophils are less effective inflammation
as phagocytes but have additional - Monocytes are heterogenous population of
specialized functions associated with body leukocytes, indisting. by the expression of CD
defense 14 and CD 16 membrane markers.
- Classic monocytes with CD14^+ CD16^- Acute inflammatory response
membrane markers produce lower amounts
- Acute inflammation is of short duration and
of proinflammatory cytokines but contribute
is characterized by vascular and cellular
more effectively to bacterial clearance by
changes.
phagocytosis compared with nonclassical
- In an acute inflammatory response, cells
monocytes. Nonclassical CD14^10 CD16^+
and molecules of the immune system move
monocytes are more potent in presenting
into the affected site. The movement of
antigens in the immune response.
fluids, proteins and leukocytes in the
General Characteristics interstitial tissue is called exudation
- Activation of complement generates C3b,
- Although the major cells associated with
which coats the surface of the pathogen. The
phagocytosis are the neutrophils and
neutrophil chemoattractant and activator
monocytes-macrophages, neutrophils are
C5a together with C3a and C4a, triggers the
the principal leukocytes involved in localized
release of histamine by degranulating mast
inflammatory response. The inflammatory
cells.
exudate (pus) is primarily composed of
- Substances released from a pathogen and
neutrophils and monocytes.
from damaged tissues upregulate the
- Although eosinophils and basophils are
expression of adhesion molecules on the
capable of participating in phagocytosis,
vascular endothelium, alerting passing cells
they possess less phagocytic activity due to
to the presence of infection
small number of these cells in the circulating
- L-selectin (cell surface molecule) recognizes
blood and lack of powerful lytic enzymes.
the carbohydrate structures. As neutrophil
The Role of Macrophages becomes activated, it sheds L-selectin from
its surface and replaces it w/ other cell
- Macrophages participate in the phagocytic surface adhesion molecules (integrins)
process and are particularly important in the - Integrins bind the molecule E-selectin,
processing of antigens as part of the which appears on the blood vessel wall
immune response. under the influence of inflammatory
- Fixed macrophages line the epithelium of mediators
capillaries and the sinuses, the bone marrow - Activated neutrophils move up the
and organs, spleen, and lymph nodes. chemotactic gradient to accumulate at the
Pulmonary alveolar macrophages are the site of infection to phagocytize any
dust phagocytes of the lung and function as C3b-coated microbes
the first line of defense against inhaled
foreign particles and bacteria Sepsis
- Macrophages and their precursor
- WBC can be as high as 100,000
(monocytes) migrate freely into the tissues
- Neutrophils are essential for the killing of
from the blood to replenish and reinforce
pathogens but excessive release of oxidants
the macrophage population.
and proteases by neutrophils is also believed
- When there is tissue damage and
to be responsible for injury to organs
inflammation, cellular activity increases with
- Sepsis is an infection-induced syndrome. It is
the release of substances that attract
the presence of two or more of the ff:
macrophages.
o Fever/hypothermia
o Leukocytosis/leukopenia
 o Tachycardia & tachypnea - Opsonization enhances phagocytosis
o Supranormal minute ventilation through coating of a particle with
- Early biochemical events in sepsis include immunoglobulin or complement thus
cytokines: speeding up ingestion of particles
- *proinflammatory - Phagosome(isolated vacuole) forms when
o Tumor necrosis factor surface tensions are conducive to
o IL-1 engulfment.
o IL-8 - neutrophil chemotaxis.
Digestion
Promotes tissue inflammation
*anti-inflammatory - The vacuole formed during engulfment fuses
o IL-6 with one or more lysosomal granules
o IL-10 - The killing effect of H2O2 is potentiated by
the formation of peroxide-halide. This
Steps in Phagocytosis
reaction requires the enzyme
Movement of cells myeloperoxidase
- Monocytes have lipase, thus effective as
- Damage to tissues and inflammation release
phagocytic cells. Lipase digests the lipid-rich
substances that attract phagocytic cells.
cell wall of bacteria
- Cells are guided to the site of injury by the
concentration gradient of chemotactic Subsequent Phagocytic Activity
substances (Chemotaxis)
- Undigested bacteria produce a secondary
- Extravasation is the movement of
inflammation, where neutrophils and
neutrophils. PMN granule protein induce
macrophages again congregate. Bacteremia
adhesion and emigration of inflammatory
develops if the bacteria escape from
monocytes to the site of inflammation
secondary tissue sites
involving β2-integrins and formyl-peptide
- Leishman-Donovan bodies, which are oblong
receptors
multiply in the phagocytic cells
- Motile segmenters (found in the beginning
- Histoplasma capsulatum can mimic kala-azar
exudate in less than 1 hr) gather at the site
of inflammation quickly but monocytes are
slower to arrive.
- Neutrophils migrate through the vessel wall
to the intestinal tissues. This amoeboid
movement is called diapedesis

Engulfment

- CD18 integrins mediate neutrophil adhesion

during migration and function as phagocytic
receptors for bacterial uptake and killing
- Phagocytosis as an active process that
requires large energy by the cells, which is
provided by anaerobic glycolysis
- Bacteria must be more hydrophobic than the
phagocyte