❖Why RBC have a specialized membrane ?

because:
▪ provide both character of fluidity & flexibility
• RBC flexibility is provided by specific membrane proteins
attached to an underlying cytoskeleton that is adaptable to
shape change, elongation & deformation)
▪ Provide biconcave shape to increased aria of O2 and CO2 transport
▪ Contains specific proteins that safe there survival for 120 days
▪ Separate the intracellular fluid environment of the cytoplasm of
cell from the extracellular fluid environment around cell
▪ Selectively pass nutrients and ions into and out of cell
▪ Composed of lipids and proteins to form the cytoskeleton of the
cell, which regulate membrane shape and deformability
▪ Keep electrolytes concentration in balancing inside and outside cell
such as potassium, magnesium, and zinc concentrations in red cells
much higher than in the plasma.
❖ Mature RBCs lack enzymes and cellular organelles necessary
to synthesize new lipid or protein, so extensive damage cannot
be repaired and the cell will be culled in the spleen.
❖ RBCs membrane comprises:
I. 40% is a lipid bilayer (semi-permeable) supported by a protein
cytoskeleton (contains both integral and peripheral proteins),
which determine the membrane fluidity.
▪ Gets lipids from circulating LDL
II. 52% is proteins (which is responsible for flexibility) that are
either peripheral or integral penetrating the lipid bilayer
▪ Mature RBC does not synthesize new proteins
III. 8% is carbohydrates that occur only on the external surface.
Metabolism of Mature Erythrocytes RBC Energetics:
❖ RBC contain enzymes of anaerobic glycolytic pathways to
produce energy that is required to:
1. preserve the membrane integrity
2. various enzymatic reactions
3. Maintain reduced proteins as hemoglobin in its reduced state for
proper functioning
4. cell metabolism
5. prevent oxidation of iron atom in heme ring and the sulfhydryl
groups on the globin molecule
• Oxidation of the normal ferrous state (Fe+2) to ferric state
(Fe+3) results in methemoglobin (metHb) which does not
deliver O2
• Normally 1-3% of Fe+2 in Hb is oxidized to methemoglobin
• Oxidation of sulfhydryl groups causes hemoglobin
precipitation on cell membrane (Heinz body formation)
❖ RBCs contain no mitochondria, so there is
▪ no respiratory chain,
▪ no citric acid cycle, and
▪ no oxidation of fatty acids or ketone bodies.
❖ Sources of Energy in the form of ATP is obtained by
glycolysis process only from:
I. The Embden-Meyerhof Pathway (EMP):
• anaerobic process for energy generation from glucose
catabolism to lactate
• 90%-95% of glucose is metabolized by the EMP
II. Pentose phosphate pathway(PPP):
• 1% of glucose used in this pathway
❖ Glucose transport through RBC membrane in order to metabolism:
▪ by a facilitated diffusion using glucose transporters (GLUT-1)
• Glucose transporters (GLUT-1) are independent on insulin i.e.
insulin does not promote glucose transport to RBCS
Catabolism and Destruction of Erythrocytes
❖ At the end of 120 days the erythrocytes are recognized as
abnormal cell that make it susceptible to destruction by
macrophage
❖ Older erythrocyte have decreased and changes in the contents
of the following:
▪ glycolytic enzyme activity
▪ sialic acid and lipids property
which leads to:
▪ loss of deformability and membrane integrity
▪ Increase rigidity and fragility, and
▪ their hemoglobin begins to degenerate
❖ For this reason the erythrocyte is no longer able to move
through the microcirculation and removed by macrophages in
endothelial system (spleen)
Sits and methods of RBCs Fate:
❖ Spleen is the place where RBCs are tested for viability and integrity
❖ Spleen is the most active site for phagocytosis of aged cells by
macrophage. How?
▪ By blood flow through the splenic venous sinusoids, where
erythrocyte flexibility is tested
▪ The aged and abnormal of erythrocyte shape will be remove and
destruction by phagocytic cell found in microvesseles of spleen
and this process is called extravascular destruction
▪ Intact erythrocytes return to the circulation of blood via the small
splenic venous sinusoids
▪ There are tow methods for destruction of aged and abnormal
RBC:
1. extravascular destruction (90% in spleen)
2. intravascular destruction (10% in lumen of blood vessels)
LEUKOPOIESIS
Leukopoiesis/Leucopoiesis
❖ It’s the process formation of whole white blood cells (WBCs) from
pluripotent hematopoietic stem cell (PHSC) in bone marrow
❖ PHSC proliferate and differentiate to form one cell lineage that
will become:
A. The myeloid stem cell (CFU- GEMM) which in progresses to the
progenitor colony-forming unit, granulocyte-erythrocytemonocyte -
megakaryocyte
B. The lymphoid stem cell (CFU-L) which in progresses to the
progenitor colony-forming unit of either mature T cells or B
cells/plasma cells that arise and develop in lymphoid tissues
❖ Leukopoiesis divided to 2 types:
I. Granulopoisesis
II. Agranulopoiesis
Leukopoiesis:
Granulopoiesis And Agranulopoiesis
Granulopoiesis
❖ It’s the process formation of granulocytes cells such as
(neutrophils, Basophils and eosinophils) from immature (blast)
committed progenitor of myeloid stem cells (CFU-GEMM)
❖ CFU- GEMM progress to production of:
▪ CFU-G progress to production of neutrophils
▪ CFU-Eo progress to production of eosinophils
▪ CFU-Ba progress to production of basophils
❖ Requirements and Regulation of Granulopoesis:
▪ Adequate numbers of normal stem cells
▪ Suitable microenvironment provided by a stromal matrix on
which adherent stem cells can proliferate and differentiate
▪ Adequate levels of growth factors such as: HGFs: G-CSF,
GM-CSF and M-CSF
▪ Cytokine such as IL-3, IL-5
▪ Stem cell Factor (SCF)
❖ Hematopoietic growth factors for Granulocyte Maturation
General Changes Occurring During Granulopoiesis:
▪ Size: overall cell generally decreases as the cell matures.
▪ Nucleus: decreases in size and starts to indent at metamyelocyte
stage and segmented into 5 lobes at segmented neutrophilic stage.
• Nuclear the chromatin pattern changes that start with fine in
early stage to coarse in late stage as the cell matures.
• The coarseness indicates mitotic inactivity (no more mitosis).
• Nucleoli disappear by the myelocyte the end stage of mitosis.
• compressed of DNA and are associated with cell division.
▪ N:C ratio decreases from 4:1 to 1:1
▪ Cytoplasm: increases in the amount as a cell matures
• The intensity of blue colour of the cytoplasm indicates the amount
azurophilic granules.
▪ Primary Granules (nonspecific): start to appear at promyelocyte
stage which give cytoplasm blue colour.
▪ Secondary (specific) granules: start to appear at the myelocyte
stage and give cytoplasm pink colour .
▪ Overall cytoplasmic colour goes from blue to neutral or pink
colour (pinkish colour).
▪ In abnormal conditions due to inflammation or other causes,
the cytoplasm of myeloid precursors at all stages of maturation is
more basophilic, and is sometimes vacuolated.
Monopoiesis
Monopoiesis
❖ Stages of Maturation Monocyte/Macrophage:
▪ Monocyte/Macrophages start maturation from immature monoblast
to promonocyte to blood premature monocyte to free and fixed
macrophages as well as final stage of maturation.
▪ Differentiate from CFU-GEMM to precursor CFU-M under stimulation of
HGFs such as: CSF-M, CSF-GM, and IL3
▪ PB monocytes demonstrate morphologic variability
▪ Typically the biggest (largest) cell in the PB
▪ Monocyte series in BM: relatively few in number, very difficult to
distinguish from those of the myeloid series in normal marrow.
• Monoblasts appear similar to myeloblasts, promonocytes and are
similar to metamyelocytes.
▪ Have capability of motility, adherence and phagocytosis
▪ Have aggressive motility and adherence thus may distorted monocytes
during PB smear preparation
▪ Final maturation stage of monocyte is the macrophage in tissues
that called histocyte cell
 LYMPHOPOIESIS

Lymphopoiesis is the process formation of normal mature

lymphocytes cells from immature committed lymphoid
stem cells that finally complete their differentiation and
maturation in other lymph nodes organs
 Lymphocytes
Introduction:
❖ The only human WBCs whose site of development is not just
BM, but also in other tissues referred to as primary and
secondary lymphoid organs that produce immune system cells
are:
I. The primary organs:
▪ bone marrow (Origen) and
▪ thymus (maturation)
• Origen and maturation of lymphocytes
II. The secondary organs include:
▪ the spleen,
▪ Peyer’s patches of the gastrointestinal (GI) tract,
▪ the tonsils,
▪ adenoids and the lymph nodes all this organ used to activation
and maturation.
Requirements of Lymphopoiesis
1. Adequate numbers of normal stem cells (PHSC)
2. Suitable microenvironment provided by a stromal matrix on which
adherent stem cells can proliferate and differentiate
3. Adequate levels of growth factors such as:
▪ Hematopoietic growth factors: CSF-L & Thymosin
▪ Cytokine such as IL-7, IL-6, IL-2 IL-3, IL-5
▪ Stem cell Factor (SCF)
4. Thymosin: in children, prior to maturity: produced by thymus
▪ promote differentiation & maintenance of T cells
5. infections (antigens): In adult:
▪ infections (antigens) play an important role in production of B
& T lymphocytes (increases when antigen appears) is regulated
primarily by exposure to antigens (foreign proteins, cells, or toxins)
Lymphocytes Types Formation
1. B-Lymphocytes formation:
▪ Bone marrow (BM) in adult or liver in the fetal may be the organs
for production and development of B-lymphocytes from
uncommitted lymphoid stem cell.
▪ The maturation ends of B-lymphocytes by migration to other
lymphoid organs (e.g. spleen, gut, liver, tonsils, lymph nodes)
▪ In lymphoid organs, B-lymphocytes differentiate into mature
antibody forming cells called plasma cells (antibody production) and
memory B-cells
• Plasma Cells:
– Have little capacity to undergo mitosis
– Synthesis and secretion of antibodies
(immunoglobulins)
2. T- Lymphocytes formation:
▪ T cell progenitors (Pro-T) originate in BM (~50 million/ day)
and migrates to thymus where complete their maturation
▪ 98% of pro-T never make it to maturity, i.e. only 1 million do
it, so apoptosis hits those because they do not have functional T cell
receptors (TCR) or don’t get selected.
▪ In the thymus the develop to have characteristic surface markers
and genetic/intracellular changes that will be appear after maturation
▪ Differentiation and maturation take place in thymus:
• Pro-T thymocytes differentiate into pre-T thymocytes in the
cortex of thymus
• Pre-T thymocytes loose their antigenic surface molecules and finally
mature into
1. helper/ effector T lymphocytes and
2. suppressor T lymphocytes in medulla of thymus.
▪ The helper and suppressor cells can be differentiated by
presence of specific cell membrane molecules and
receptors
▪ T cell production slows down with increased age human
▪ Mature T cells may differentiate and divide to subtypes
in secondary lymphoid organs
T, B and natural killer (NKC) Lymphocytes:
❖ Secrete cytokines called lymphokines which are:
▪ Regulate proliferation and differentiation of other T cells, B cells,
and macrophages.
▪ Main component of cell mediated immunity.
❖ 60-70% of circulating lymphocytes in PB are T cells
❖ Only 20-35% of circulating lymphocytes are B cells
❖ Lymphocytes have ability to cycle from blood, through
lymphoid tissue and then back to blood via lymphatic fluid
❖Normally, children under the age of 4 years have a higher
proportion of lymphocytes in the PB than adults
❖Lymphocytes are the second most common WBCs of the PB
making up 20-40% of WBCs.
❖Lymphocytes are derived from PHSC in BM.
❖PHSC differentiate to the lymphoid cell (CFU-L) as a result of
factorial and hormonal stimulation according to body
requirements in normal or abnormal conditions
❖CFU-L differentiate and matures in several environments of
BM, thymus and lymphoid organs:
▪ In the first of the CFU-L differentiates in BM to:
I. Pro-B lymphocyte change to pre-B under antigens stimulation
and migrates to place where required and complete their
maturation in lymphoid organs.
• Its dependent on antigenic stimulation
II. Pro-T thymocyte formed under thymosin stimulation and
migrates to thymus gland then change to pre-T in thymus, place
where maturation to T Lymphocytes
• Its dependent or independent on antigenic stimulation
Stages of Lymphocytes Development