Hematopoiesis

Dr. Usamah Sayed

Chapter 4
Lecture 02

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- Hematopoiesis: is the continuous, regulated process of renewal,
proliferation, differentiation, and maturation of all blood cell lines.
- Mature blood cells have a limited lifespan (e.g., 120 days for red
blood cells [RBCs]) and a cell population capable of self-renewal that
sustains the system.
- A hematopoietic stem cell (HSC) is capable of self-renewal (i.e.,
replenishment) and directed differentiation into all required cell
lineages.
- The hematopoietic system serves as a functional model to study stem
cell biology, proliferation, and maturation and their contribution to
disease and tissue repair.
- Hematopoiesis in the developing human can be characterized as a
select distribution of embryonic cells in specific sites that rapidly
changes during development. 2
- Hematopoiesis in healthy adults is restricted primarily to the bone marrow.
- During fetal development, the restricted, sequential distribution of cells is initiated in the yolk sac and then
progresses in the aorta-gonad-mesonephros (AGM) region (mesoblastic phase), then to the fetal liver
(hepatic phase), and finally resides in the bone marrow (medullary phase).

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I. Mesoblastic phase Hematopoiesis: is considered to begin around the
nineteenth day of embryonic development after fertilization.
- These primitive but transient yolk sac erythroblasts are important in early
embryogenesis to produce hemoglobin (Gower-1, Gower-2, and Portland)
needed for oxygen delivery to rapidly developing embryonic tissues.
- Yolk sac hematopoiesis differs from hematopoiesis which occurs later in the
fetus and adult in that it occurs intravascularly (or within developing blood
vessels).
II. Hepatic phase: The hepatic phase of hematopoiesis begins at 5 to 7
gestational weeks and is characterized by recognizable clusters of developing
erythroblasts, granulocytes, and monocytes colonizing the fetal liver, thymus,
spleen, placenta, and ultimately the bone marrow space in the final medullary
phase.
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- Lymphoid cells begin to appear.
- Hematopoiesis during this phase occurs extravascularly, with the liver remaining the major site of
hematopoiesis during the second trimester of fetal life.
- Hematopoiesis in the AGM region and the yolk sac disappear during this stage.
- Hematopoiesis in the fetal liver reaches its peak by the third month of fetal development, then gradually
declines after the sixth month, retaining minimal activity until 1 to 2 weeks after birth.
- The developing spleen, kidney, thymus, and lymph nodes contribute to the hematopoietic process during this
phase.
- The thymus, the first fully developed organ in the fetus, becomes the major site of T cell production, whereas
the kidney and spleen produce B cells.
- Production of megakaryocytes begins during the hepatic phase.
- The spleen gradually decreases granulocytic production and subsequently contributes solely to lymphopoiesis.
- During the hepatic phase, fetal hemoglobin (Hb F) is the predominant hemoglobin, but detectable levels of
adult hemoglobin (Hb A) may be present
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III. Medullary (myeloid) phase Hematopoiesis in the bone marrow (termed medullary hematopoiesis
because it occurs in the medulla or inner part of the bone cavity).
- Begins between the fourth and fifth month of fetal development.
- During the myeloid phase, HSCs and mesenchymal cells migrate into the core of the bone.
- Mesenchymal cells, a type of embryonic tissue, differentiate into structural elements (e.g., stromal cells
such as endothelial cells and reticular adventitial cells) that support developing hematopoietic elements.
- Hematopoietic activity, especially myeloid activity, is apparent during this stage of development, and the
myeloid-to-erythroid ratio gradually approaches 3: 1 to 4: 1 (normal adult levels).
- By the end of 24 weeks’ gestation, the bone marrow becomes the primary site of hematopoiesis.
- Measurable levels of erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF), granulocyte-
macrophage colony-stimulating factor (GM-CSF), and hemoglobins F and A can be detected.

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 Adult hematopoietic tissue
- In adults, hematopoietic tissue is located in:
1. the bone marrow,
2. lymph nodes,
3. spleen,
4. liver, and
5. thymus.
- The bone marrow contains developing erythroid,
myeloid, megakaryocytic, and lymphoid cells.
- Lymphoid development occurs in both primary and
secondary lymphoid tissue.
- Primary lymphoid tissue consists of the bone marrow and thymus, where T and B lymphocytes are derived.
- Secondary lymphoid tissue is where lymphoid cells respond to foreign antigens, it consists of:
- the spleen, - lymph nodes, and - mucosa-associated lymphoid tissue. 7
 Bone marrow
- One of the largest organs in the body, is located within the cavities of the
cortical bones.
- Projections of calcified bone, called trabeculae, radiate out from the bone
cortex into the central space, forming a three-dimensional matrix resembling a
honeycomb.

- The trabeculae provide structural support for the developing blood cells that
mature within a sea of interposed mature adipocytes.
- Normal bone marrow contains two major components:
- red marrow, hematopoietically active marrow that is composed of developing
blood cells and their progenitors, and
- yellow marrow, hematopoietically inactive marrow composed primarily of
adipocytes (fat cells), with undifferentiated mesenchymal cells and
macrophages.
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- During infancy and early childhood, all the bones in the body contain
primarily red (active) marrow.
- Between 5 and 7 years of age, adipocytes become more abundant and
begin to occupy the spaces in the long bones previously dominated by
active marrow.
- The process of replacing the active marrow with adipocytes (yellow
marrow) during development is called retrogression and eventually results
in the restriction of the active marrow in the adult to the sternum,
vertebrae, scapulae, pelvis, ribs, skull, and proximal portion of the long
bones.
- Yellow marrow is capable of reverting back to active marrow in cases of
increased demand on the bone marrow, such as in excessive blood loss or Adult Skeleton. Darkened areas
depict active red marrow
hemolysis. hematopoiesis
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Fixed and Stained Bone Marrow Biopsy Specimen.
The extravascular tissue consists of blood cell
precursors and various tissue cells with scattered fat Graphic Illustration of the Arrangement of a
tissue. A normal adult bone marrow displays 50% Hematopoietic Cord and Vascular Sinus in Bone
hematopoietic cells and 50% fat. (Hematoxylin and Marrow.
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eosin stain, × 100.)
The bone marrow contains:
1. Hematopoietic cells,
2. Stromal cells, include endothelial cells, adipocytes (fat cells), macrophages and lymphocytes, osteoblasts,
osteoclasts, and reticular adventitial cells (fibroblasts).
3. Blood vessels (arteries, veins, and vascular sinuses).
- Endothelial cells are broad, flat cells that form a single continuous layer along the inner surface of the
arteries, veins, and vascular sinuses. Function to regulate the flow of particles entering and leaving
hematopoietic spaces in the vascular sinuses.
- Reticular adventitial cells form an incomplete layer of cells on the abluminal surface of the vascular sinuses.
They extend long, reticular fibers into the perivascular space that form a supporting lattice for the
developing hematopoietic cells.
- Adipocytes are large cells with a single fat vacuole; they play a role in regulating the volume of the marrow in
which active hematopoiesis occurs.
- Macrophages function in phagocytosis
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- Endothelial cells, reticular adventitial cells, macrophages, adipocytes, and
lymphocytes secrete cytokines or growth factors that positively stimulate
HSC numbers and bone homeostasis.
Red marrow
- It is composed of hematopoietic cells arranged in extravascular cords.
- The cords are separated from the lumen of the vascular sinuses by endothelial
and reticular adventitial cells.
- Hematopoietic cells develop in specific niches within the cords.
- Erythroid precursors or erythroblasts develop in small clusters, and the more
mature forms are located adjacent to the outer surfaces of the vascular
sinuses. Erythroblasts are found surrounding iron-laden macrophages.
- Megakaryocytes are located adjacent to the walls of the vascular sinuses,
which facilitates the release of platelets into the lumen of the sinus.
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- Immature myeloid (granulocytic) cells through the metamyelocyte stage are located deep within the cords.
- As these maturing granulocytes proceed along differentiation, they move closer to the vascular sinuses.

Summary
 The red marrow is composed of hematopoietic cells arranged in extravascular cords.
 Cords are located in spaces between vascular sinuses and are supported by trabeculae of spongy
bone.
 The cords are separated from the lumen of the vascular sinuses by endothelial and reticular
adventitial cells.
 Hematopoietic cells develop in specific niches within the cords.
 Erythroid precursors or erythroblasts develop in small clusters, and the more mature forms are
located adjacent to the outer.

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 Normal Erythrocyte production and destruction
- The erythrocyte has one true function: to carry oxygen from the lung to the tissues.
- The role of the RBC in returning carbon dioxide to the lungs and buffering the pH of the blood is
important but is quite secondary to its oxygen-carrying function.
- RBCs are formally called erythrocytes. Nucleated RBC precursors, normally restricted to the bone
marrow, are called erythroblasts or normoblasts, which refers to developing nucleated RBC precursors
(i.e., blasts) with normal appearance.

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Maturation process

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I. Erythroid progenitors: Erythrocyte precursors develop from two progenitors:
I. burst-forming unit-erythroid (BFU-E) and
II. colony-forming unit-erythroid (CFU-E),
• both committed to the erythroid cell line.
- Estimates of time spent at each stage suggest that it takes about 1 week for the BFU-E to mature to the
CFU-E and another week for the CFU-E to become a pronormoblast
- In the CFU-E stage, the cell completes approximately three to five divisions before maturing further.
II. Erythroid precursors:
- Normoblastic proliferation, is a process encompassing replication to increase cell numbers and
development from immature to mature cell stages.
- The earliest morphologically recognizable erythrocyte precursor is pronormoblast.
- The pronormoblast is able to divide, with each daughter cell maturing to the next stage of development,
the basophilic normoblast. Each of these cells can divide, with each of its daughter cells maturing to the
next stage, the polychromatic normoblast. Each of these cells also can divide and mature.
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- In the erythrocyte cell line, there are typically three divisions with subsequent nuclear and
cytoplasmic maturation of the daughter cells
- From a single pronormoblast, 8 to 32 mature RBCs usually result.
- It takes approximately 6 to 7 days for the precursors to become mature enough to enter circulation
(so approximately 18 to 21 days are required to produce a mature RBC from the BFU-E).
Criteria used in identification of erythroid precursors

1. Morphologic identification of blood cells depends on a well-stained peripheral blood film or bone
marrow smear (a modified Romanowsky stain, such as Wright or Wright-Giemsa, is commonly used).
2. The most important features in the identification of RBCs are the nuclear chromatin pattern (texture,
density, homogeneity), nuclear diameter, nucleus-to-cytoplasm (N: C) ratio, presence or absence of
nucleoli, and cytoplasmic color.
The nucleus-to-cytoplasm (N: C) ratio is a visual estimate of the area of the cell occupied by the nucleus
compared with that of the cytoplasm.
- If the areas of each are approximately equal, the N: C ratio is 1: 1. 17
- If the nucleus takes up less than 50% of the area of the cell, the proportion of the nucleus is lower
and the ratio is lower (e.g., 1: 5 or less than 1).
- If the nucleus takes up more than 50% of the area of the cell, the ratio is higher (e.g., 3: 1 or 3).
- In the red blood cell line, the proportion of the nucleus shrinks as the cell matures and the cytoplasm
increases proportionately, although the overall cell diameter grows smaller. In short, the N: C ratio
decreases.
As erythroid precursors mature, several general trends affect their appearance:
1. Overall diameter of the cell decreases.
2. The diameter of the nucleus decreases more rapidly than does the diameter of the cell. As a result,
the N: C ratio also decreases.
3. Nuclear chromatin pattern becomes coarser, clumped, and condensed.
4. Nucleoli disappear.
5. Cytoplasm changes from blue to gray-blue to salmon pink.
Blueness or basophilia is due to acidic components that attract basic stains, such as methylene blue. 18
- The degree of cytoplasmic basophilia correlates with the amount of ribosomal RNA. The ribosomes
and other organelles decline over the life of the developing erythroid precursor, and the blueness
fades.
- Pinkness, called eosinophilia or acidophilia, is due to the accumulation of more basic components
that attract acid stains, such as eosin. Eosinophilia of erythrocyte cytoplasm correlates with the
accumulation of hemoglobin as the cell matures.
- Thus the cell starts out being active in protein production on the ribosomes that make the cytoplasm
basophilic and transitions through a period in which the red of hemoglobin begins to mix with that
blue.

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1. Pronormoblast (rubriblast)
- Nucleus:
- takes up much of the cell (N: C ratio of 8: 1).
- The nucleus is round to oval, containing one or two nucleoli.
- The purple-red chromatin is open and contains few if any, fine clumps.
- Cytoplasm:
- Dark blue because of the concentration of ribosomes and RNA.
- The Golgi complex may be visible next to the nucleus as a pale, unstained area.
- Division:
- The pronormoblast undergoes mitosis and gives rise to two daughter pronormoblasts.
- More than one division is possible before maturation into basophilic normoblasts.
- Location: (A), Pronormoblast. (Bone marrow,
Wright-Giemsa stain, × 1000.)
- The pronormoblast is present only in the bone marrow in healthy states. ​( B), Electron micrograph of a
pronormoblast
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- Cellular activity:
- The pronormoblast begins to accumulate the components necessary for
hemoglobin production.
- The proteins and enzymes necessary for iron uptake and protoporphyrin
synthesis are produced.
- Globin production begins.
2. Basophilic normoblast (prorubricyte)
- Nucleus:
- The chromatin begins to condense, revealing clumps along the periphery of
the nuclear membrane and a few in the interior.
- As the chromatin condenses, the parachromatin areas become larger and
sharper, and the N:C ratio decreases to about 6: 1.
- The chromatin stains deep purple-red.

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- Cytoplasm:
- When stained, the cytoplasm may be a deeper, richer blue than in the pronormoblast, hence the name
basophilic for this stage.
- Division:
- The basophilic normoblast undergoes mitosis, giving rise to two daughter cells.
- More than one division is possible before the daughter cells mature into polychromatic normoblasts.
- Location:
- The basophilic normoblast is present only in the bone marrow in healthy states.
- Cellular activity:
- Detectable hemoglobin synthesis occurs
- This stage lasts slightly more than 24 hours.

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3. Polychromatic (polychromatophilic) normoblast (rubricyte)
- Nucleus:
- The chromatin pattern varies during this stage of development, showing some
openness early in the stage but becoming condensed by the end.
- The condensation of chromatin reduces the diameter of the nucleus
considerably, so the N: C ratio decreases from 4: 1 to about 1: 1, and no nucleoli
are present.
- Cytoplasm:
- This is the first stage in which the pink color associated with stained hemoglobin
can be seen.
- The color produced is a mixture of pink and blue, resulting in a murky gray-blue.
- The stage’s name refers to this combination of multiple colors, because
polychromatophilic means “many color loving.”
- Division: This is the last stage in which the cell is capable of undergoing mitosis.
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4. Orthochromic normoblast (metarubricyte):
- Nucleus:
- The nucleus is completely condensed (i.e., pyknotic) or nearly so. As a result, the N:C
ratio is low or approximately 1: 2.
- Cytoplasm:
- The increase in the salmon pink color of the cytoplasm reflects nearly complete
hemoglobin production.
- The residual ribosomes and RNA react with the basic component of the stain and
contribute a slightly bluish hue to the cell, but that fades toward the end of the stage
as the RNA and organelles are degraded.
- Division:
- The orthochromic normoblast is not capable of division because of the condensation
of the chromatin.
- Location:
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- The orthochromic normoblast is present only in the bone marrow in healthy states.
- Cellular activity:
- Hemoglobin production continues on the remaining ribosomes using messenger RNA produced earlier.
- Late in this stage, the nucleus is ejected from the cell.
- Also, small fragments of the nucleus are left behind if the projection is pinched off before the entire nucleus
is enveloped. These fragments are called Howell-Jolly bodies when seen in peripheral RBCs and are
typically removed from the cells by the splenic macrophage pitting process once the cell enters circulation.
5. Polychromatic (polychromatophilic) erythrocyte or reticulocyte
- Nucleus:
- Beginning at the polychromatic erythrocyte stage, there is no nucleus.
- When a cell loses its nucleus, regardless of cytoplasmic appearance, it is a polychromatic erythrocyte.
- Cytoplasm:
- The predominant color is that of hemoglobin yet with a bluish tinge due to some residual ribosomes
and RNA.
- It remains larger than a mature cell.
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 - The shape of the cell is not the mature biconcave disc but is irregular in electron
micrographs.
- Division:
- Lacking a nucleus, the polychromatic erythrocyte cannot divide.
- Location:
- The polychromatic erythrocyte resides in the bone marrow for about 1 to 2 days
and then moves into the peripheral blood for about 1 day before reaching maturity.
- During the first several days after exiting the marrow, the polychromatic erythrocyte
is retained in the spleen for pitting of inclusions and membrane polishing by splenic
macrophages, which results in the biconcave discoid mature RBC.
- Cellular activity:
- The polychromatic erythrocyte completes the production of hemoglobin from a
small amount of residual messenger RNA using the remaining ribosomes.
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- The cytoplasmic protein production machinery is simultaneously being dismantled.
- Endoribonuclease, in particular, digests the ribosomes.
- The acidic components that attract the basophilic stain decline during this stage to the point that the
polychromatophilia is only slightly evident in the polychromatic erythrocytes on a peripheral blood film
stained with Wright stain.
- A small amount of residual ribosomal RNA is present, however, can
be visualized with a vital stain such as new methylene blue, so
called because the cells are stained while alive in suspension (i.e.,
vital), before the blood film is made.
- The residual ribosomes appear as a mesh of small blue strands, a
reticulum, or, when more fully digested, merely blue dots.
- When so stained, the polychromatic erythrocyte is called a
reticulocyte. However, the name reticulocyte is often used to refer
to the stage immediately preceding the mature erythrocyte.
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 Cellular Basophilia: Diffuse and Punctate
- The reticulum of a polychromatic erythrocyte is not seen using Wright stain.
- Residual RNA appears as a bluish tinge to the cytoplasm.
- The reticulocyte is called a polychromatic erythrocyte because it lacks a nucleus and
is no longer an erythroblast but still has a bluish tinge.
- When polychromatic erythrocytes are prominent on a peripheral blood film, the
examiner uses the comment polychromasia or polychromatophilia.

- The term polychromasia should be distinguished from red blood cells with punctate
basophilia, in which the blue appears in distinct dots throughout the cytoplasm. More
commonly known as basophilic stippling
- It is indicative of disturbed rather than increased erythropoiesis. It occurs in many blood
diseases: thalassemia, megaloblastic anemias, infections, liver disease, poisoning by lead
and other heavy metals, and unstable hemoglobins. 29
 6. Erythrocyte
- Nucleus: No nucleus is present in mature RBCs.
- Cytoplasm: The mature circulating erythrocyte is a biconcave disc measuring 7 to 8 μm in
diameter, with a thickness of about 1.5 to 2.5 μm.
- On a Wright-stained blood film, it appears as a salmon-pink-stained cell with a
central pale area that corresponds to the concavity.
- The central pallor is about one-third the diameter of the cell.
- Division: The erythrocyte cannot divide.
- Mature RBCs remain active in circulation for approximately 120 days.
- Aging leads to their removal by the spleen
- The mature erythrocyte delivers oxygen to tissues, releases it, and returns to the lung to
be reoxygenated.

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Pronormoblast Basophilic normoblast Polychromatic normoblast Orthochromic normoblast Polychromatic erythrocyte Erythrocyte

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Leukopoiesis

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34
Neutrophils:
- Neutrophil development occurs in the bone marrow. Neutrophils share a common progenitor with monocytes,
known as the Granulocyte-Monocyte Progenitor (GMP).
- The major cytokine responsible for the stimulation of neutrophil production is granulocyte colony-stimulating
factor, or G-CSF.
- There are three pools of developing neutrophils in the bone marrow: the stem cell pool, the proliferation pool,
and the maturation pool.

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 Myeloblasts make up 0% to 3% of the nucleated cells in the
bone marrow. They are frequently subdivided into:
1. Type I: high nucleus-to-cytoplasm (N:C) ratio of 8:1 to 4:1
(the nucleus occupies most of the cell, with very little
cytoplasm), slightly basophilic cytoplasm, fine nuclear
chromatin, and two to four visible nucleoli. blasts have no
visible granules.
2. Type II: presence of dispersed primary (azurophilic) granules
in the cytoplasm; the number of granules does not exceed
20 per Cell.
3. Type III: have a darker chromatin and a more purple
cytoplasm, and they contain more than 20 granules that do
not obscure the nucleus
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 Promyelocytes comprise 1% to 5% of the nucleated cells in the bone marrow.
- They are relatively larger than the myeloblast cells and measure 16 to 25 µm in diameter.
- The nucleus is round to oval and is often eccentric.
- A paranuclear halo or “hof” is usually seen in normal promyelocytes but not in the malignant promyelocytes of
acute promyelocytic leukemia.
- The cytoplasm is evenly basophilic and full of primary (azurophilic) granules.

- These granules are the first in a series of granules to be

produced during neutrophil maturation
- The nucleus is similar to that described earlier for
myeloblasts except that chromatin clumping
(heterochromatin) may be visible, especially around the
edges of the nucleus.
- One to three nucleoli can be seen but may be obscured by
the granules. 37
 Neutrophil myelocytes make up 6% to 17% of the nucleated cells in the
bone marrow and are the final stage in which cell division (mitosis) occurs.
During this stage, the production of primary granules ceases, and the cell
begins to manufacture secondary (specific) neutrophil granules. more
lavender-pink than blue. Nucleoli are difficult to see by light microscopy.
 Neutrophil metamyelocytes constitute 3% to 20% of nucleated marrow
cells. From this stage forward, the cells are no longer capable of division,
and the major morphologic change is in the shape of the nucleus. The
nucleus is indented (kidney bean-shaped or peanut-shaped), and the
chromatin is increasingly clumped.
 Nucleoli are absent. Synthesis of tertiary granules (also known as
gelatinase granules) may begin during this stage. The size of the
metamyelocyte is slightly smaller than that of the myelocyte (14 to 16
µm). The cytoplasm contains very little residual ribonucleic acid (RNA)
and therefore little or no basophilia. 38
 Neutrophil bands make up 9% to 32% of nucleated marrow cells and 0% to 5% of the
nucleated peripheral blood cells. All evidence of RNA (cytoplasmic basophilia) is absent,
and tertiary granules continue to be formed during this stage. Secretory granules (also
known as secretory vesicles) may begin to be formed during this stage. The nucleus is
highly clumped, and the nuclear indentation that began in the metamyelocyte stage now
exceeds one half the diameter of the nucleus, but actual segmentation has not yet
occurred.
 Segmented neutrophils make up 7% to 30% of nucleated cells in the bone marrow.
Secretory granules continue to be formed during this stage. The only morphologic
difference between segmented neutrophils and bands is the presence of between two
and five nuclear lobes connected by threadlike filaments. Segmented neutrophils are
present in the highest numbers in the peripheral blood of adults (50% to 70% of
leukocytes Pediatric values are quite different; relative percentages can be as low as
18% of leukocytes in the first few months of life and do not begin to climb to adult
values until after 4 to 7 years of age. 39
40
Eosinophils
 Eosinophils make up 1% to 3% of nucleated cells in the bone marrow. Slightly more than
a third are mature, a quarter are eosinophilic metamyelocytes, and the remainder are
eosinophilic promyelocytes or eosinophilic myelocytes.
 Eosinophils account for 1% to 3% of peripheral blood leukocytes, with an absolute
number of up to 0.4X109/L in the peripheral blood.
Eosinophil myelocytes
Eosinophil Development
 Eosinophil development is similar to that described earlier for neutrophils, and evidence
indicates that eosinophils arise from the common myeloid progenitor (CMP).
 Eosinophil myelocytes are characterized by the presence of large (resolvable at the light
microscope level), pale, reddish-orange secondary granules, along with azure granules in
blue cytoplasm.
Mature eosinophils
 The nucleus is similar to that described for neutrophil myelocytes.
 Mature eosinophils usually display a bilobed nucleus.
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 Their cytoplasm contains characteristic refractile, orange-red secondary granules.
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 Eosinophil production is increased in infection by parasitic helminths, and in vitro studies have shown that the
eosinophil is capable of destroying tissue-invading helminths through the secretion of major basic protein and
eosinophil cationic protein as well as the production of reactive oxygen species.
 There is also a suggestion that eosinophils play a role in preventing reinfection.
 Finally, eosinophilia is a hallmark of allergic disorders, of which asthma has been the best studied.
 The number of eosinophils in blood and sputum correlates with disease severity.
 This has led to the suggestion that the eosinophil is one of the causes of airway inflammation and mucosal cell
damage.
 Eosinophils have also been implicated in airway remodeling (increase in thickness of the airway wall) through
eosinophil-derived fibrogenic growth factors.
 Eosinophil accumulation in the gastrointestinal tract occurs in allergic disorders such as food allergy, allergic
colitis, and inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis.

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Basophils and mast cells
 These two cells are with morphologic and functional similarities; however,
basophils are true leukocytes because they mature in the bone marrow and
circulate in the blood as mature cells with granules.
 Mast cell precursors leave the bone marrow and use the blood as a transit
system to gain access to the tissues where they mature. they differentiate Immature basophil

under the influence of a number of cytokines including IL-3.

 Along with eosinophils, basophils are involved in the control of helminth
infections.

basophil

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Monocytes
 Macrophage colony-stimulating factor (M-CSF) is the major cytokine responsible for the growth and
differentiation of monocytes.
 The morphologic stages of monocyte development are monoblasts, promonocytes, and monocytes.
 Monoblasts in normal bone marrow are very rare and are difficult to distinguish from myeloblasts based on
morphology.
Promonocytes have a nucleus that is slightly indented or folded.
The chromatin pattern is delicate, and at least one nucleolus is apparent. The
cytoplasm is blue and contains scattered azure granules that are fewer and smaller
than those seen in promyelocytes.

Monocytes are slightly immature cells whose ultimate goal is to enter the tissues
and mature into macrophages, osteoclasts, or dendritic cells. The nucleus may be
round, oval, or kidney-shaped, but more frequently is deeply indented (horseshoe
shaped) or folded on itself. 45
Monocyte/Macrophage Functions (3)
The functions of monocytes/macrophages are numerous and varied.
They can be subdivided into innate immunity, adaptive immunity, and housekeeping functions.
1. Innate immunity: Monocytes/macrophages recognize a wide range of bacterial pathogens by means of
pattern recognition receptors (toll-like receptors) that stimulate inflammatory cytokine production and
phagocytosis.
 Macrophages can synthesize nitric oxide, which is cytotoxic against viruses, bacteria, fungi, protozoa,
helminths, and tumor cells.
 Monocytes and macrophages also have Fc receptors and complement receptors to phagocytize foreign
organisms that have been coated with antibodies or complement components.
2. Adaptive immunity: Both macrophages and dendritic cells degrade antigen and present antigen fragments on
their surfaces (antigen-presenting cells). Because of this, they interact with and activate both T lymphocytes
and B lymphocytes to initiate the adaptive immune response. Dendritic cells are the most efficient and
potent of the antigen-presenting cells.
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3. Housekeeping functions: These include removal of debris and dead cells at
sites of infection or tissue damage, destruction of senescent red blood cells
and maintenance of a storage pool of iron for erythropoiesis, and synthesis of
a wide variety of proteins, including coagulation factors, complement
components, interleukins, growth factors, and enzymes.

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Lymphocytes
Lymphocytes are divided into three major groups: T cells, B cells, and
natural killer (NK) cells.
 T and B cells are major players in adaptive immunity. NK cells
comprise a small percentage of lymphocytes and are part of innate
immunity.

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49
Immature lymphocytes

Plasma cells

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Natural killer cells (NK cells)
 Lymphocyte-like cells.
 Do not express immunoglobulins (antibodies) or TCR.
 Contain abundant cytoplasmic granules.
 Recognize infected or stressed cells and respond by:
A. Killing the cell.
B. Producing IFN-γ which activates the macrophages to kill the
phagocytosed microbes.
 NK cells and macrophages cooperate in eliminating intracellular
microbes.
• Macrophages ingestion of the microbe activates them to
produce several cytokines including IL-12.
• IL-12 activates the NK cells to produce IFN-γ.
• IFN-γ activates the macrophages to destroy the ingested
microbe.
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CD4 T helper cells

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53
CD8- cytotoxic T lymphocyte

Kill by degranulation or
Fas/FasL interaction

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