3. Blood is considered a fluid connective tissue
Is about four times more viscous than water
1°C higher than measured body temperature;
Total blood volume in the average adult is
about 6 L or 7% to 8 body weight
THE BLOOD
General Composition
Whole blood
Liquid
Cellular components(formed elements)
Plasma(55%)
Erythrocytes(44%)
Leukocytes
Platelets 1%
4.
5. Functions of Blood
Delivery of nutrients and oxygen directly or indirectly to cells,
Transport of wastes and carbon dioxide away from cells,
Delivery of hormones and other regulatory substances to and
from cells and tissues,
Maintenance of homeostasis by acting as a buffer and
participating in coagulation and thermoregulation, and
Transport of humoral agents and cells of the immune system that
protect the body from pathogenic agents, foreign Proteins, and
transformed cells (i.e. cancer cells).
6. The Microscopic Structure Of Erythrocytes
Are anucleate, biconcave discs.
devoid of typical organelles.
They function only within the
bloodstream
The biconcave shape is maximizes
the cell’s surface area (140μm2), an
important attribute in gas exchange
7.8μm in diameter
2.6μm an edge thickness
0.8μm of central thickness
(90%) of them are
phagocytosed by
macrophages in the spleen,
bone marrow, and liver.
The remaining aged
erythrocytes (10%) break
down intravascularly
releasing insignificant
amounts of hemoglobin into
the blood.
7. They are considered as histologic ruler Because their size is relatively consistent in
fixed tissue, they can be used to estimate the size of other cells
The shape of the erythrocyte is maintained by membrane proteins.
The cell membrane of an erythrocyte is composed of a typical lipid bilayer and
contains two functionally significant groups of proteins.
1. Integral membrane proteins
They consist of two major families:
Glycophorins and
Band 3 proteins
The extracellular domains of these proteins are glycosylated and express specific blood
group antigens.
Glycophorin C, a member of the glycophorin family of transmembrane proteins, plays an
important role in attaching the underlying cytoskeletal protein network to the cell
membrane.
Band 3 protein binds hemoglobin and acts as an additional anchoring site for the
cytoskeletal proteins
The Microscopic Structure Of Erythrocytes
8. 2. Peripheral membrane proteins
Reside on the inner surface of the cell
membrane.
They are organized into a two-
dimensional hexagonal lattice
network that laminates the inner layer
of the membrane.
Is composed mainly of cytoskeletal
proteins including
Spectrin tetramers
Actin
Band 4.1 protein
Adducin
Band 4.9protein, and
Tropomyosin that form a network or mesh.
The lattice is anchored to the lipid bilayer by
the globular protein ankyrin, which
interacts with band 4.2 protein as well as with
band 3 integral membrane protein
The Microscopic Structure Of Erythrocytes
9. Erythrocytes contain hemoglobin, a protein specialized for the
transport of oxygen and carbon dioxide.
A high concentration of hemoglobin is present within erythrocytes
and is responsible for their uniform staining
The Microscopic Structure Of Erythrocytes
Hemoglobin
Consists of four polypeptide chains of globin
each complexes to an iron-containing heme group
The structure of the polypeptide chains varies.
Depending on the particular polypeptides present, the following types of
hemoglobin can be distinguished:
Hemoglobin HbA 96% of the total
Hemoglobin HbA2 1.5% to 3% of total hemoglobin in
adults
Hemoglobin HbF less than 1% of total hemoglobin in adults
and principal form of hemoglobin in the fetus.
10. Each hemoglobin molecule is composed
of four subunits.
Each subunit contains a heme, the iron-
containing portion of hemoglobin,
embedded in a hydrophobic cleft of a
globin chain.
The folding of the globin chain places
the heme near the surface of the
molecule, where it is readily accessible
to oxygen.
There are four different types of globin
chains occurring in pairs.
The types of globin chains present in the
molecules determine the type of
hemoglobin.
Hemoglobin
Illustrates hemoglobin A (HbA),
which is composed of two alpha
and two beta chains
11. The Microscopic Structure Of Erythrocytes
Have a life span of about 120 days in humans
When erythrocytes are about 4 months old, they become senescent.
The macrophage system of the spleen, bone marrow, and liver phagocytoses and
degrades the senescent erythrocytes.
The heme and globin dissociate, and the globin is hydrolysed to amino acids,
which enter the metabolic pool for re-use.
The iron on the heme is released, enters the iron-storage pool in the spleen in the
form of hemosiderin or ferritin, and is stored for reuse in hemoglobin synthesis.
The rest of the heme moiety of the hemoglobin molecule is partially degraded
to bilirubin, bound to albumin, released into the bloodstream, and transported
to the liver, where it is conjugated and excreted via the gallbladder as the
bilirubin glucuronide of bile.
13. Major blood grouping systems:
1. ABO blood groups &
2. Rh system (surface antigen D)
14. 1. ABO Blood Grouping
– Based on the presence or absence of two antigens/
agglutinogens (agglutinogen A and agglutinogen B).
– According to ABO blood grouping system blood types of
individuals are classified into four types of blood.
1. When agglutinogen A is present on RBCs, the blood is
type-A
2. When agglutinogen B is present on RBCs, the blood is
type-B
3. When both agglutinogens A & B exist together : type-AB
4. When neither agglutinogen A nor B are present: type-O
15. Agglutinins (Antibodies)
– In the ABO blood grouping, plasma contains agglutinins
(antibodies) against the missing antigen:
1. Anti-A antibodies
2. Anti-B antibodies
existence of agglutinogen and agglutinins:
– When agglutinogen A is present on RBCs, anti-B anitbody in plasma
– When agglutinogen B is present on RBCs, anti-A antibody in plasma
– When agglutinogen A & B exist together, neither anti-A nor anti-B
antibodies present in the serum
– When no both agglutinogens (A and B) on RBCs, both anti-A and
anti-B antibodies are present in the serum (O blood type).
16. Antigen & Antibody coexistence in the ABO Blood groups
Blood
type
Antigen/Agglutinogen
On RBCs
Antibody (agglutinin)
in Blood Plasma
A A anti-B
B B anti-A
AB A & B Neither
O Neither both anti-A & anti-B
17.
18. Agglutination process in transfusion reactions
– when bloods are mismatched so that anti-A or anti-B
plasma agglutinins are mixed with red blood cells that
contain A or B agglutinogens, respectively, the red cells
agglutinate as a result of the agglutinins’ attaching
themselves to the red blood cells
– because the agglutinins have two binding sites (IgG) or 10
binding sites (IgM), a single agglutinin can attach to two or
more red blood cells at the same time, thereby causing the
cells to be bound together by the agglutinin.
– the clumping of RBCs by agglutinins is termed as
agglutination
19.
20.
21. If a person receives mismatched blood, erythrocytes agglutinate
and block small blood vessels
22. Group Antigen on RBC
membrane surface
Antibody Rh Factor
A A B +/-
B B A +/-
AB A and B No Antibody A
and B
+/-
O No A and B
antigen
Both A and B +/-
ABO and Rh BLOOD GROUPS
this is based on the type of membrane protein on RBC
plasma membrane
23. Rh system (surface antigen D)
The Rh blood type is determined by
the presence or absence of the Rh
surface antigen, often called either Rh
factor or surface antigen D
When the Rh factor is present, the
individual is said to be Rh positive
(Rh+) if not (Rh−)
Antibodies to the Rh factor appear in
the blood only when an Rh negative
individual is exposed to Rh positive
blood as a result of an inappropriate
blood transfusion.
24. Rh incompatibility
An Rh incompatibility may result during pregnancy if the mother has
been previously exposed to Rh positive blood (e.g., from a previous
fetus with Rh positive blood).
As a result of the prior exposure to Rh positive blood, the mother has
Rh antibodies that may cross the placenta and destroy the fetal
erythrocytes, resulting in severe illness or death of the fetus.
Giving a pregnant woman special immunoglobulins (e.g., RhoGAM)
prevents her from developing the Rh antibodies during pregnancy.
The ABO and Rh blood types are usually reported together.
For example, types AB and Rh+ together are reported as AB+ and Rh− are
AB−.
25. 2-LEUKOCYTES (WBCs)
– They are colorless because did not contain hemoglobin, however, each cell
has a nucleus. In the bloodstream, they are spherical in shape and mobile.
– According to the type of cytoplasmic granules and the shape of their nuclei,
leukocytes are classified into:-
A-Granular leukocytes:- (which contain specific granules and lobulated
nuclei):
1-Neutrophils 55-70%
2-Eosinophils 2-4%
3-Basophils 0- 1%
B-Agranular leukocytes:- (which do not contain specific granules with non-
lobulated nuclei):
1-Lymphocytes 20-40%
2-Monocytes 3-8%
26. 2-LEUKOCYTES (WBCs)
Total leukocytic count:
• It is the total number of leukocytes per cubic millimeter.
• In normal adult the ‘total leukocytic count’ is between 5,000-
10,000 per cubic mm.
Differential leukocytic count:-
• It is the percentage of each type of leukocytes to the total
number of leukocytes.
Functions of leukocytes:-
1-They protect the body in a number of ways against the infectious
organisms.
2-leukocytes perform their main functions outside the blood
stream after they have entered loose CT. There is a great
correlation between leukocytes and some cells of loose CT
(histiocytes or macrophages, mast cells and plasma cells).
28. Neutrophils
– Are the most numerous leukocytes in peripheral
blood and, as such, account for about 55-70% of
the circulating leukocytes.
– Leave circulation in large numbers in response to
bacterial infection and tissue injury in acute
inflammations.
Size: 10-12 m in diameter
– Their nucleus is multi-lobulated (2-5 lobules) in
appearance, connected to each other by thin
threads of chromatin.
– In females the neutrophils are characterized by a
small separate lobule of the nucleus of
neutrophil looks like ‘‘drumstick’’/ Barr body.
– It is one of the two X chromosomes in an
inactive state.
30. Neutrophils (Polymorphs or polymorphonuclear leukocytes)
The specific fine granules in the cytoplasm stain faintly with neutral
dyes.
They also contain few non specific larger granules termed “azurophilic
granules’’ as they stain with methylene azure dye.
At E.M. level:-
The cytoplasm contains few organelles. It is full of small dark specific
granules which contain alkaline phosphatase and phagocytin (bactericidal
protein) which can destroy bacteria engulfed by neutrophils.
The non specific granules are fewer, course and darker. are the
azurophilic granules which correspond to lysosomes.
31. Neutrophils
The cytoplasmic contents of a neutrophil pseudopod appear as an
expanse of finely granular cytoplasmic matrix with no membranous
organelles.
The finely granular appearance is attributable to the presence of actin
filaments, some microtubules, and glycogen, which are involved in the
extension of the cytoplasm to form the pseudopod and the subsequent
contraction that pulls the cell forward
Once the neutrophil enters the connective tissue, further migration to the
injury site is directed by a process known as chemotaxis
The binding of chemo attractant molecules and extracellular matrix proteins to
specific receptors on the surface of the neutrophil.
33. 1-Specific granules (SMALL): contain lysozyme (bactericidal) e.g.
collagenase, lactoferrin and alkaline phosphatase enzymes.
2- Non specific (azurophilic):
Are larger and less numerous than specific granules.
They arise early in granulopoiesis and occur in all granulocytes, as
well as in monocytes and lymphocytes.
Are primary lysosomes containing hydrolytic enzymes (hydrolases,
myeloperoxidase)
3- Tertiary granules- contain gelatinase, cathepsin & glycoprotein.
The types of granules present in neutrophils and the
functions of each
34. What are the functions of neutrophils?
1. Phagocytosis of bacteria and foreign bodies, & hence
sometimes called microphages. Their number increase
during bacterial infection.
2. Synthesis of group of compounds called leukotriens: that
promotes migration of more neutrophils to the site of
infection and Chemo attractant for eosinophils and
monocytes to the site of infection.
3. Neutrophils release chemical mediators that stimulate
bone marrow to produce neutrophils.
35. Functions of neutrophils:-
– Neutrophils are the first line of defense against invading organisms
especially bacteria.
– Neutrophils (in blood stream) are attracted to bacteria (in CT) by
chemical substance liberated by the organism a process known as
‘‘Chemotaxis’’.
– Neutrophils squeeze their way between endothelial cells of blood
capillaries or venules.
– Once neutrophils are outside the vessel in the CT they move toward
bacteria, which they rapidly phagocytose and destroy.
– Neutrophils are the major constituents of tissue exudates and pus,
and thus they are called pus cells.
– Once the bacteria is engulfed within the cytoplasm of neutrophils,
the two types of granules will act to destroy bacteria.
37. Eosinophils
– Large cell size (10-17 m in diameter)
– Constitute about 2-4% of total leukocytes
– a characteristic bilobed nucleus
– Contain Refractile crystalloid eosinophilic granules
EM: show few organelles
– What are the types of granules present in eosinophils and their
functions?
Specific granules: abundant large, red specific granules (about
200 per cell) that are stained by eosin (acidophilic)
– Contain lysosomal enzymes that inactivate histamine
(histaminase) and also aryl sulftase which neutralize action of
slow reacting substance.
Azurophilic granules: lysosomes containing hydrolytic enzymes
that function in destruction of parasites and hydrolysis of antigen–
antibody complexes internalized by the eosinophil.
40. EOSINOPHIL
TEM (right) of a sectioned eosinophil clearly shows the unique specific
granules, as oval structures with disk-shaped electron-dense crystalline cores
(EG).
These along with lysosomes & a few mitochondria (M) fill the cytoplasm
around the bilobed nucleus (N).
41. Ultrastructurally the eosinophilic specific granules
– Are seen to be oval in shape, with many having a flattened
crystalline core containing major basic protein, an
arginine-rich factor accounting for the granule's intense
acidophilia.
– This protein constitutes 50% of the total granule
protein. The major basic protein, along with
eosinophilic peroxidase, other enzymes and toxins, have
cytotoxic effects on parasites such as helminthic worms
and protozoa.
– Eosinophils also phagocytose antigen-antibody complexes
and modulate inflammatory responses in many ways.
– They are an important source of the factors mediating
allergic reactions and asthma.
42. What is the function of eosinophils?
- Anti-allergic - (phagocytosis of Ag-Ab complex)
- anti-parasitic against helminthic worms and protozoa
What is meant by eosinophilia?
Means increase in number of eosinophils more than 2-4%
of total leukocytes.
It occurs in allergy and parasitic infection
43. Basophils
What is the characteristic feature of basophils?
– Large size cells (9-12 m in diameter)
– S shaped bilobed nucleus
– EM: small Golgi, few mitochondria and many RER.
– are the least numerous of the white cells accounting for less than
1% of the total leukocytes.
– Contains two types of granules
Specific granules:
– Stain metachromatically reddish violet with basic dyes.
– Contain SRS of anaphylaxis, glycosaminoglycans, histamine and
heparin.
Azurophilic granules: small granules containing hydrolytic
enzymes
45. What is the function of basophils?
1. Mediate inflammatory response.
2. They bind immunoglobulin E (IgE) in allergic reaction and
leads to release of their vasoactive substance.
3. Play a role in hypersensitivity (anaphylactic shock) (i.e.
vasodilatation and smooth muscle contraction)
4. Are thought to supplement the function of mast cells in
immediate hypersensitivity rxns.
Basophilia means ……..
– Increase in number of basophils (more than 1%)
– Occurs in allergy and liver cirrhosis
47. LYMPHOCYTES
Are the primary functional cells of the immune system and
also actively involved in autoimmune diseases, inflammatory
responses, allergic reaction, tumor control and transplantation
rejection/graft rejection.
Reveal large, round, almost cell filling condensed nucleus;
cytoplasm forms only a thin rim around the nucleus.
Smallest in size but are the 2nd most numerous (20-30% of
leukocytes in circulation),increased number are commonly
seen during viral infections.
Are the most common agranular leukocytes & are unique in
their ability to return from tissues back to the blood stream
Exist in two morphological forms: large & small
lymphocytes
50. Large lymphocytes:
Are large granular lymphocytes, about 11-15 µm in diameter
Fewer in number, account only about 5% of lymphocytes
They are believed to be NK cells
Small Lymphocytes
– About 5-10 µm in diameter
– Include T and B lymphocytes
T-lymphocytes
Arise in the bone marrow and proliferates in the thymus
Activate B- lymphocytes
B-lymphocytes
Are so named because they were first recognized as a
separate population in bone marrow
are stimulated to become plasma cells and produce
antibodies.
52. B-Lymphocytes T-Lymphocytes
Percentage 15% of the circulating
lymphocytes
80% of the circulating
lymphocytes
Development In the bone marrow
from (CFU-Ly B)
In the bone marrow
from (CFU-Ly T)
Maturation &
Immuno-
competency
In the bone marrow
In the cortex and
medulla of the thymus
Plasma membrane
Have Fc receptors and
antibodies
Have T-cell receptors
Site in Peripheral
Lymphoid Organs Widely distributed in
lymph node, spleen,
In thymus dependent
zone of lymph node,
spleen, tonsil, peyer’s
patch, etc
Life Span 3 months May live for years
Function Humeral immunity Cell mediated immunity
53.
54. Monocytes
– What is the characteristic
feature of monocyte?
– Normal range 3-8% of Total
Leucocyte Count.
– The largest blood cells in
size (12-17 m in diameter)
– Nucleus is large eccentric,
indented and kidney shaped
– Cytoplasm is bluish-grey
and has small number of
azurophilic granules, with
occasional vacuole like
spaces.
57. Monocyte
Monocytosis means ……..
– Increase in number of monocytes (by more than 1%)
– They increases in infectious mononucleosis and chronic
inflammation.
– EM: show glycogen granules, a few
mitochondria, a few ER (RER), free ribosomes
and lysosomes.
– Horse-shoe shaped/kidney shaped nucleus
– Contains more cytoplasm than does the
lymphocyte
What is the function of monocytes?
They are highly phagocytic cells.
They are transformed to macrophages in tissues & at the site of
inflammation.
They concentrate the antigens and present them to the lymphocytes
and other immune cells.
61. PLATELETS
– Small, rounded or oval non
motile fragments of cells
surrounded by a plasma
membrane.
– Small, colorless, non
nucleated cells
– contain granules
– Form platelet plugs
– Releases chemicals
necessary for blood clotting
– Normal values: 200,000-
300,000/mm3
62. Platelets
– They are derived from
megakaryocyte
– Size: 2-3 µm.
– Life span is about 10 days
– Appear as rounded or oval
cell fragments derived singly
or in clumps
With E/M they display
– Peripheral clear region called
hyalomere
– Denser granular center called
the granulomere
– show few mitochondria and
microtubules with actin and
myosin.
63. Platelets contain three types of granules:
a– granules contain fibrinogen and coagulation factors.
d- granules contain ADP, ATP, calcium, serotonin and histamine.
g- granules contain hydrolytic enzymes.
64. Minor trauma to vessels of the microvasculature results in a fibrin
clot, shown here by SEM.
A meshwork of polymeric proteins composed largely of fibrin
traps erythrocytes and more degranulating platelets.
Platelets in various states of degranulation are shown.
Such a clot grows until blood loss from the vasculature stops.
After repair of the vessel wall, fibrin clots are removed by
proteolysis due primarily to locally generated plasmin, a
nonspecific protease.
65. Structurally, platelets may be divided into four zones based on organization and function.
1. The peripheral zone
Consists of the cell membrane
covered by glycocalyx which
consists of glycoproteins,
glycosaminoglycans, and several
coagulation factors adsorbed
from the plasma
2. The structural zone
Comprises microtubules, actin
filaments, myosin, and actin-binding
proteins that form a network
supporting the plasma membrane.
They are circumferentially arranged
and are responsible for maintaining
the platelet’s disc shape
66. .
3. The organelle zone
It consists of mitochondria, peroxisomes, glycogen particles, and at least
three types of granules dispersed within the cytoplasm.
Alpha (α) granules (300 to 500 nm in diameter) that contain mainly
fibrinogen, coagulation factors, plasminogen, plasminogen activator
inhibitor, and platelet-derived growth factor
Delta (σ) granules mainly contain ADP, ATP, serotonin, and histamine,
which facilitate platelet adhesion and vasoconstriction in the area of the injured
vessel.
Gamma (λ) granules are similar to lysosomes found in other cells and contain
several hydrolytic enzymes.
The contents of granules function in clot resorption during the later stages
of vessel repair
4. The membrane zone; consists of two types of membrane channels.
The open canalicular system (OCS)
The dense tubular system (DTS) storage site for calcium ions
Both the OCS and DTS fuse in various areas of the platelet to form membrane
complexes that are important in regulation of the intraplatelet calcium
concentration
68. HEMOPOIESIS OR HEMATOPOIESIS
The process starts with hemopoietic stem cells called
hemocytoblasts
Hemopoiesis occurs in red bone marrow
The process starts with hemopoietic stem cells called
Hemocytoblasts.
IS pluripotent cells, meaning that they can differentiate and develop
into many different kinds of cells.
Hemocytoblasts produce two lines for blood cell development:
The myeloid line forms erythrocytes, megakaryocytes, and all leukocytes
Lymphoid line forms lymphocytes.
69. HEMATOPOIESIS
Includes
Erythropoiesis Is development of red blood cells
Leukopoiesis Is developments of white blood cells
Thrombopoiesis Is development of platelets.
Why blood cells are produced continuously?
Since they have a limited life span which are continuously produced
and destroyed.
To maintain a constant level of the different cell types found in the
peripheral blood
HEMOPOIESIS OR HEMATOPOIESIS
70. Human erythrocyte (life span of 120 days) and the platelet (life span
of 10 days) spend their entire life in the circulating blood.
Leukocytes migrate out of the circulation shortly after entering it
from the bone marrow and spend most of their variable life spans
(and perform all of their functions) in the tissues.
In the adult, erythrocytes, granulocytes, monocytes, and platelets are
formed in the red bone marrow;
Lymphocytes are also formed in the red bone marrow and in the
lymphatic tissues.
HEMOPOIESIS OR HEMATOPOIESIS
71. Stages of hemopoiseis in different developmental stages of the fetus
1. Yolk-sac phase
Begins in 3rd week of gestation and is characterized by the
formation of “blood islands” in the wall of the yolk sac of the
embryo
2. Hepatic phase
Blood cell formation in these sites is largely limited to erythroid
cells although some leukopoiesis occurs in the liver.
The liver is the major blood-forming organ in the fetus during the
second trimester
3. Bone marrow phase
Of fetal hemopoiesis and leukopoiesis involves the bone marrow
and other lymphatic tissues
Begins during the second trimester of pregnancy.
After birth, hemopoiesis takes place only in the red bone marrow
and lymphatic tissues, as in the adult
73. THE MONOPHYLETIC THEORY OF HEMOPOIESIS
All blood cells arise from a common stem cell the hemopoietic stem cell
(HSC) which also known as pluripotential stem cell (PPSC), is capable
not only of differentiating into all the blood cell lineages but also of
self-renewal
HSCs also have the potential to differentiate into multiple non blood
cell lineages and contribute to the cellular regeneration of various
tissues and multiple organ
During embryonic development, HSCs are present in the circulation
and undergo tissue-specific differentiation in different organs
74. Human HSCs have been isolated from umbilical cord blood, fetal
liver, and fetal and adult bone marrow.
In the adult, HSCs have the potential to repair tissues under
pathologic conditions (e.g., ischemic injury, organ failure).
Human HSCs express specific molecular marker proteins such as
CD34 and CD90 and at the same time do not express lineage-
specific markers (Lin– that are found on lymphocytes, granulocytes,
monocytes, megakaryocytes, and erythroid cells.
It is now believed that human HSC can be identified by the Lin,
CD34, CD90, and CD38cell- surface markers.
THE MONOPHYLETIC THEORY OF HEMOPOIESIS
75.
76.
77. A hemopoietic stem cell (HSC) in the bone marrow gives
rise to multiple colonies of progenitor stem cells.
HSC differentiate into two major colonies of multi-
potential progenitor cells:
The common myeloid progenitor (CMP) cells
The Common lymphoid progenitor (CLP) cells
The hemopoietic stem cell (HSC)
78. Megakaryocyte/erythrocyte progenitor (MEP) cells
These bi-potential stem cells give rise to
Monopotent megakaryocyte-committed progenitor cells (MKP
or CFU-Meg) and
Monopotent erythrocyte-committed progenitor cells (ErP or
CFU-E) that give rise to the erythrocyte lineage.
Granulocyte/monocyte progenitor (GMP or CFUGM) cells:
Development of the GMP (CFU-GM) cells requires high-level
expression of PU.1 transcription factor.
The common myeloid progenitor (CMP) cells
79. Granulocyte/monocyte progenitor (GMP or CFUGM) cells give rise to
The neutrophil progenitors
The eosinophil progenitors (EoP or CFU-Eo), cells and
Basophil/mast cell progenitors (BMCP) that give rise either to
basophil progenitor cells (BaP or CFU-Ba) in the bone marrow
MCPs in the gastrointestinal mucosa; and finally monocyte
progenitors (MoP or CFU-M) that develop toward monocyte
lineages.
In addition to the specific lineage progenitors, GMP cells can
give rise to dendritic cells (DCs), which are professional
antigen-presenting cells
80. The common lymphoid progenitor (CLP) cells are capable of
differentiating into
T cells
B cells and
Natural killer (NK) cells.
The NK cells are thought to be the prototype of T cells; they both
possess similar capability to destroy other cells.
Dendritic cells can also developed from CLP cells.
The Common lymphoid progenitor (CLP) cells
81. Colony-stimulating factors (CSFs), or colony forming units (CFUs)
Number of hormones and growth factors influence the maturation and
division of the blood stem cells
Multi-CSF increases the formation of erythrocytes, and all classes of
granulocytes, monocytes, and platelets from myeloid stem cells
GM-CSF FOR all granulocytes and monocytes from their progenitor cells.
G-CSF for granulocytes from myeloblast cells.
M-CSF is for monocytes from monoblasts.
Thrombopoietin Is for both the production of megakaryocytes in the bone marrow
and the subsequent formation of platelets
Erythropoietin (EPO) is a hormone produced by the kidneys to increase the rate of
production and maturation of erythrocyte progenitor and erythroblast cells.
COLONY-STIMULATING FACTORS (CSFS),
82.
83.
84. Development of Erythrocytes (Erythropoiesis)
The first microscopically recognizable precursor cell in erythropoiesis is
called the proerythroblast
PROERYTHROBLAST
12 to 20μm in diameter.
It contains a large spherical nucleus with one or two
visible nucleoli.
The cytoplasm shows mild basophilia because of the
presence of free ribosomes.
Basophilic erythroblast
Is smaller (10 to 16μm in diameter) and progressively
more heterochromatic with repeated mitoses.
The cytoplasm shows strong basophilia because of the
large number of free ribosomes (polyribosomes) that
synthesize hemoglobin
Polychromatophilic erythroblast.
Shows both acidophilic and basophilic staining of
cytoplasm.
85. Orthochromatophilic erythroblast (normoblast)
Is recognized by its increased acidophilic cytoplasm and dense nucleus.
This cell has a small, compact, densely stained nucleus.
The cytoplasm is eosinophilic because of the large amount of hemoglobin
The orthochromatic erythroblast loses its nucleus by extruding it from the cell;it
is then ready to pass into the blood sinusoids of the red bone marrow
Polychromatophilic erythrocytes(reticulocytes)
The new erythrocytes can also be demonstrated with special stains that cause
the polyribosomes to clump and form a reticular network.
Reticulocytes
In normal blood, reticulocytes constitute about 1% to 2% of the total erythrocyte
count.
If increased numbers of erythrocytes enter the bloodstream (as during increased
erythropoiesis to compensate for blood loss), the number of reticulocytes
increases.
Mitoses occur in pro-erythroblasts, basophilic erythroblasts and
polychromatophilic erythroblasts.
It takes about a week for the progeny of a newly formed basophilic erythroblast
to reach the circulation.
Erythrocyte formation and release are regulated by erythropoietin
Erythropoietin acts on the specific receptors expressed on the surface of ErP
86.
87.
88. Development of Thrombocytes (Thrombopoiesis)
Each day bone marrow of a healthy adult produces about 1 *1011
platelets
The thrombocytopoiesis from the bone marrow progenitors is a
complex process of cell divisions and differentiation that requires the
support of
Interleukins
Colony-stimulating factors, and
Hormones.
Platelets are produced in the bone marrow from the same common
myeloid progenitor (CMP) cells
Under the influence of granucolyte-macrophage colony stimulating
factor (GM- CSF) and IL-3, CMP stem cell differentiates into a
bipotent megakaryocyte/erythrocyte progenitor (MEP) cell
megakariocyte- committed progenitor (MKP) cell (or CFU-Meg)
megakaryoblast which is a large cell (about 30μm in diameter) with a
non-lobed nucleus
89. Successive endomitoses occur in the megakaryoblast (i.e.,
chromosomes replicate), but neither karyokinesis nor cytokinesis
occurs.
Under stimulation by thrombopoietin, a 30-kilodalton glycoprotein
hormone produced by liver and kidney, ploidy increases from 8n to
64n before chromosomal replication ceases.
The cell then becomes a platelet-producing megakaryocyte, a cell
measuring 50 to 70μm in diameter with a complex multi-lobed
nucleus and scattered azurophilic granules.
Both the nucleus and the cell increase in size in proportion to the
ploidy of the cell.
With the TEM, multiple centrioles and multiple Golgi apparatuses
are also seen in these cells
Thrombocytopenia (a low blood platelet count) is an important
clinical problem in the management of patients with immune-
system disorders and cancer
Development of Thrombocytes (Thrombopoiesis)
90. Development of Granulocytes (Granulopoiesis)
Granulocytes originate from the multipotential common myeloid
progenitor (CMP) stem cell, which differentiates into
granulocyte/monocyte progenitors (GMPs) under the influence of
cytokines such as
GM-CSF, Granulocyte colony-stimulating factor (G-CSF) and IL-3
GM-CSF is a cytokine secreted by endothelial cells, T cells,
macrophages, mast cells, and fibroblasts.
It stimulates GMP cells to produce granulocytes (neutrophils,
eosinophils, and basophils) and monocytes
91. The neutrophil progenitor (NoP) undergoes six morphologically
identifiable stages in the process of maturation:
Myeloblast promyelocyte myelocyte metamyelocyte
band cell, and mature neutrophil.
Myeloblasts are the first recognizable cells that begin the process of
granulopoiesis.
Eosinophils and basophils undergo a morphologic maturation similar
to that of neutrophils.
GMP cells, when induced by GM-CSF, IL-3, and IL-5, differentiate
to eosinophil progenitors (EoPs), and eventually mature to
eosinophils.
Lack of IL-5 causes the GMP cells to differentiate into basophil
progenitors (BaPs), which produce basophils.
One cannot differentiate eosinophilic or basophilic precursors from
neutrophilic precursors morphologically in the light microscope until
the cells reach the myelocytic stage when the specific granules
appear
92. The myeloblast
It has a large, euchromatic, spherical nucleus with three to five
nucleoli
14 to 20 μm in diameter
Has a large nuclear-to cytoplasmic volume
Promyelocytes
Are the only cells to produce azurophilic granules.
A large spherical nucleus with azurophilic (primary) granules in the
cytoplasm
Do not exhibit subtypes
Myelocytes
First exhibit specific granules.
Specific granules begin to emerge from the convex surface of the
Golgi apparatus, whereas azurophilic granules are seen at the
concave side.
The significance of this separation is unclear.
Myelocytes continue to divide and give rise to metamyelocytes
93. Metamyelocytes
Is the stage at which neutrophil, eosinophil, and basophil lines can be
clearly identified by the presence of numerous specific granules.
The nucleus becomes more heterochromatic, and the indentation
deepens to form a kidney bean-shaped structure
In the neutrophil line, the band (stab) cell precedes development of the
first distinct nuclear lobes.
Theoretically, the metamyelocyte stage in granulopoiesis is followed by
the band stage and then the segmented stage
These stages are obvious in the neutrophil line, they are rarely if ever
observed in the eosinophil and basophil lines in which the next easily
recognized stages of development are the mature eosinophil and mature
basophil, respectively.
94.
95. In neutrophil line, the band (stab) cell precedes development of the
first distinct nuclear lobes.
Nuclear constrictions then develop in the band neutrophil and
become more prominent until two to four nuclear lobes are
recognized;
The cell is then considered a mature neutrophil, also called a
polymorphonuclear neutrophil or segmented neutrophil.
96.
97. Development of Monocytes
The multipotential CMP stem cell also gives rise to the cells that
develop along the monocyte–macrophage pathway.
Monocytes are produced in the bone marrow from a GMP stem cell that
can mature into a monocyte or another of the three granulocytic cell
lines.
In addition, GMP gives rise to dendritic cells.
The proliferation and differentiation of CMP into committed GMP is
controlled by IL-3.
Further progression of monocyte progenitor (MoP) cell lineage depends
on the continued presence of PU.1 and Egr-1 transcription factors and is
stimulated by IL-3 and GM-CSF.
The GMCSF also controls further differentiation into mature cells,
which are then released into circulation.
The transformation of MoPs to monocytes takes about 55 hours, and the
monocytes remain in the circulation for only about 16 hours before
emigrating to the tissues where they differentiate under influence of
both GM-CSF and M-CSF into tissue macrophages.
98. Development of Lymphocytes (Lymphopoiesis)
Development and lineage commitment of CLP cells depend on the
expression of variety of transcription factors
Members of the Ikaros family of transcription factors play major roles
in the differentiation of pluripotent HSCs toward common lymphoid
progenitor (CLP) cells.
Progeny of the CLP cells that express GATA-3 transcription factor are
destined to become T lymphocytes
These cells that express GATA-3 leave the bone marrow as pre–T
lymphocytes and travel to the thymus, where they complete their
differentiation and thymic cell education then enter the circulation as
long-lived, small T lymphocytes
Another transcription factor, Pax5, activates B-cell–specific genes in
CLP cells destined to become B lymphocytes.
In mammals, these cells originate in bone marrow, gut-associated
lymphatic tissue, and spleen
99. The bone marrow is the main NK cell producing organ and also the
lymph nodes or fetal thymus may also contain NK-progenitor cells.
Lymphocytes constitute as much as 30% of all nucleated cells in the
bone marrow
NK cells most likely differentiate under the influence of IL-2 and
IL-15 into immature pre–NK cells, and, after acquisition of NK–cell
effector functions (ability to secrete interferon and cytotoxicity),
become mature NK cells
Development of Lymphocytes (Lymphopoiesis)
