Physiology Lecture 64

Tanveer Raza MD MS MBBS

razajju2@yahoo.com
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Pluripotential hematopoietic stem cells
CFU-S
CFU-E
Eryhtrocytes
CFU-GM
Granulocytes
Monocytes
CFU-M
Megakaryocytes (Platelets)
LSC
T Lymphocytes
B Lymphocytes
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Genesis of WBC
The different cells of the
myelocyte series are 1,
myeloblast; 2, promyelocyte; 3,
megakaryocyte; 4, neutrophil
myelocyte; 5, young neutrophil
metamyelocyte; 6, "band"
neutrophil metamyelocyte; 7,
polymorphonuclear neutrophil; 8,
eosinophil myelocyte; 9,
eosinophil metamyelocyte; 10,
polymorphonuclear eosinophil;
11, basophil myelocyte; 12,
polymorphonuclear basophil; 13-
16, stages of monocyte formation
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Myelocytic Lineage
Production of Granulocyte and Monocytes
Begins with myeloblast
Formed in bone marrow
Lymphocytic lineage
Production of T and B lymphocytes
Begins with lymphoblast
Produced mainly in various lymphogenous
tissues
Tanveer Raza MD MS MBBS
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White Blood Cells
Lymphogenous tissues
Lymph glands
Spleen
Thymus
Tonsils
Pockets of lymphoid tissue elsewhere in body
Bone marrow
Peyer's patches
Lymphogneous tissue underneath gut
wall epithelium
Tanveer Raza MD MS MBBS
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White Blood Cells
WBC formed in bone marrow are stored
until needed in the circulation
Normally, about three times WBC are stored
in the marrow
a 6-day supply
Lymphocytes are mostly stored in the
various lymphoid tissues
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Megakaryocytes
Formed in the bone marrow
Megakaryocytes fragment in bone marrow
Smaller fragments are known as platelets (or
thrombocytes)
Platelets then pass into the blood
Very important for blood clotting
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Defence Against Infections
Neutrophils and macrophages comprise
the professional phagocytes, are
endowed with a unique capacity to engulf
and thereby eliminate pathogens and cell
debris
Neutrophils attack and destroy bacteria in
circulating blood
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Defence Against Infections
Tissue macrophages
Blood Monocytes
In blood are known as monocytes
Immature cells
Cannot fight infectious agents
When they enter the tissues, begin to swell and
are called macrophages
Tissue Macrophages
Extremely capable of combating
intratissue disease agents
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
a.k.a. White Blood Corpuscles, WBC,
Leukocytes
Normal count 4,000-11,000 cells/L of
blood
Average 7,000 (9,000) cells/L of blood
Life span: Few hours to days

Tanveer Raza MD MS MBBS
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White Blood Cells
Differential Count
Neutrophils 62.0% (50-70%)
Eosinophils 2.3% (1-4%)
Basophils 0.4% (0-0.4%)
Monocytes 5.3% (2-8%)
Lymphocytes 30.0% (20-40%)
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Life Span
Granulocytes
After being released from bone marrow
In blood 4 to 8 hours
In tissues 4 to 5 days where needed
During serious tissue infection, total life
span shortened
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Life Span
Monocytes
In blood 10 to 20 hours
In tissues, they become tissue
Macrophages
Can live for months
Tissue macrophages provide continuing
defense
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Life Span
Lymphocytes
Continual circulation of lymphocytes
Lymphocytes enter circulation with lymph from
the lymph nodes and other lymphoid tissue
After a few hours, they go out of blood and
back into the tissues by diapedesis
Again re-enter lymph and return to blood
Life spans (weeks or months) depends on
the body's need for these cells
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Life Span
Platelets
In the blood are replaced about once every
10 days
About 30,000 platelets are formed each day for
each ml/blood
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Life Span
In bone marrow:
RBC:WBC=1:50
In Circulation:
RBC:WBC=500:1
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells
Types
Granulocytes or Polymorphonuclear
leukocytes
Polymorphonuclear Neutrophils
Polymorphonuclear Basophils
Polymorphonuclear Eosinophils
Agranulocytes or Mononuclear leukocytes
Lymphocytes
Monocytes
Plasma Cells
Tanveer Raza MD MS MBBS
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White Blood Cells
Function
Mobile units of the body's protective system
Phagocytosis
Granulocytes
Monocytes
Immune System
Plasma Cells
Lymphocytes
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells: Diapedesis
Process by which Neutrophils and
Monocytes come out of blood vessel wall
Pores of vessel wall are smaller than cells
Small portion of the cell squeezes through
the pores
Copyright 2006 American Heart Association
Balakrishnan, K. R. et al. Circulation 2006;113:e41-e43
A, Endothelium (EC)-lined neovessel with diapedesis of macrophage
Tanveer Raza MD MS MBBS
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White Blood Cells: Ameboid movement
Special type of movement by which
Neutrophils and Macrophages move
towards damaged tissues
Begins with protrusion of one end of cell
(pseudopodium)
Remainder of cell moves towards
pseudopodium
Tanveer Raza MD MS MBBS
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White Blood Cells: Chemotaxis
Movement towards a chemical substances
Seen in Neutrophil and Macrophages
Chemotactic substances
Bacterial or viral toxins
Degenerative products of the inflamed tissues
Several reaction products of the "complement
complex" activated in inflamed tissues
Several reaction products caused by plasma clotting
in the inflamed area, as well as other substances
Tanveer Raza MD MS MBBS
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White Blood Cells: Phagocytosis
Phagocytosis
Cellular ingestion of offending agent
Phagocytes is selective
Rough surface
Protective protein coating
Opsonin

Tanveer Raza MD MS MBBS
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White Blood Cells: Phagocytosis
Phagocytes is selective
Rough surface
Most natural structures in the tissues have
smooth surfaces, which resist
phagocytosis
Substances to be phagocytosed has a
rough surface
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells: Phagocytosis
Phagocytes is selective
Protective protein coating
Most natural substances of the body have
protective protein coats that repel
phagocytes
Most dead tissues and foreign particles
have no protective coating
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
White Blood Cells: Phagocytosis
Phagocytes is selective
Opsonin
Antibodies adhere to the bacterial
membranes making it more susceptible to
phagocytosis
Tanveer Raza MD MS MBBS
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Phagocytosis by neutrophils. Time-lapse sequence of Fcc receptor-
mediated phagocytosis. Human neutrophils were exposed to IgG-
opsonized latex beads, and differential interference images were acquired
at the indicated times (in minutes). Within several minutes, a neutrophil
extends pseudopodia and engulfs several particles in succession.
Lee at al. 2003
Tanveer Raza MD MS MBBS
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White Blood Cells: Phagocytosis
3 steps
Recognition and attachment
Engulfment
Killing/degradataion
Tanveer Raza MD MS MBBS
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WBC: Neutrophils
Most common WBC
Professional Phagocytes
First to arrive at infection site
Ingests bacteria, virus particles, fungi or
protozoa
Multilobed nuclei
Nuclei may have 2-5 lobes
Granules
Fine, uniformly distributed
Tanveer Raza MD MS MBBS
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Neutrophilic and Eosinophilic Neutrophils, Peripheral blood
smear, Wright-Giemsa stain, 1000x
Tanveer Raza MD MS MBBS
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WBC: Neutrophils
Function
Phagocytosis
After attaching to particle, projects
pseudopodia engulfing particle and forming
a chamber
Chamber is invaginated into cytoplasmic
cavity forming phagocytic vesicle
(phagosome)
Digestion of Ingested particle
Release chemotactic factor for Macrophages
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Neutrophils
Function
Phagocytosis
Digestion of Ingested particle
Lysosomes and other cytoplasmic
granules fuse with phagosome
Dumping many digestive enzymes and
bactericidal agents into the vesicle
Lysosomes contain proteolytic enzymes that
digest bacteria and other foreign protein matter
Release chemotactic factor for Macrophages
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Neutrophils
Function
Neutrophils and Macrophages can Kill
Bacteria
Contains bactericidal agents that kill most
bacteria even when lysosomal enzymes fail
to digest them
Especially important, because some bacteria
have protective coats or other factors that
prevent their destruction by digestive enzymes
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Neutrophils
Function
Bactericidal agents
Powerful oxidizing agents
lethal to most bacteria, even in small quantities
Formed by enzymes in the membrane of the
phagosome or by a special organelle called the
peroxisome
superoxide (O2-)
hydrogen peroxide (H2O2)
hydroxyl ions (-OH-)
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Neutrophils
Function
Bactericidal agents
Lysosomal enzymes
Myeloperoxidase
catalyzes the reaction between H2O2 and
chloride ions to form HOCl, which is
exceedingly bactericidal.
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Neutrophils
Function
Bactericidal agents
Some bacteria, ex. tuberculosis bacillus,
have coats resistant to lysosomal
digestion and secrete substances that
partially resist the killing effects of the
neutrophils and macrophages These
bacteria are responsible for many of the
chronic diseases (tuberculosis)
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Macrophages
Monocytes enter blood from bone marrow
and circulate in blood for about 72 hours
They then enter tissues and become
tissue Macrophages
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
WBC: Macrophages
Phagocytosis by Macrophages
Much more powerful phagocytes than
neutrophils
Can phagocytoze more bacteria
Engulf much larger particles
even whole RBCs, malarial parasites
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
a.k.a.
Monocyte-Macrophage Cell System
Mononuclear Phagocytic System (MPS)
The total combination of monocytes, mobile
macrophages, fixed tissue macrophages, and a
few specialized endothelial cells in the bone
marrow, spleen, and lymph nodes is called the
reticuloendothelial system
All or almost all these cells originate from
monocytic stem cells
Tanveer Raza MD MS MBBS
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Reticuloendothelial System
Tissue Macrophages
Remains attached for months or even years
until called to perform specific local
protective functions
When appropriately stimulated, they become
mobile macrophages
Have similar functions as mobile
macrophages
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Tissue Macrophages
Histiocytes
Tissue Macrophages in the Skin and
Subcutaneous Tissues
Macrophages in the Lymph Nodes
Alveolar Macrophages in the Lungs
Kupffer Cells
Macrophages in the Liver Sinusoids
Macrophages of the Spleen and Bone Marrow
Microglia in brain
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Histiocytes
Tissue macrophages in Skin and
Subcutaneous Tissues
Broken is susceptible to infectious agents
Histiocytes protect against infection in a
subcutaneous tissue and local inflammation
ensues
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Macrophages in the Lymph Nodes
Particles not destroyed in tissues enter
lymph and flow to lymph nodes located
Particles are trapped in these nodes in a
meshwork of sinuses lined by tissue
macrophages
Large numbers of macrophages line lymph
sinuses
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Functional diagram of a lymph node.
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Alveolar Macrophages in the Lungs
Large numbers of tissue macrophages are
present in alveolar walls
Giant Cell
If particle not digestible, macrophages
often form a "giant cell" capsule around
particle until such time-if ever-that it can
be slowly dissolved
Frequently formed around tuberculosis
bacilli, silica dust particles and carbon
particles
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Kupffer Cells
Macrophages (Kupffer Cells) in the Liver
Sinusoids
Bacteria invading through GIT
Portal blood from GIT passes through liver
sinusoids before entering general circulation
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Kupffer cells lining the liver sinusoids, showing
phagocytosis of India ink particles into the cytoplasm of
the Kupffer cells.
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Reticuloendothelial System
Macrophages of Spleen and Bone Marrow
When invading organism enters the general
circulation
Spleen is similar to the lymph nodes
Blood flows instead of lymph
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Functional structures of the spleen.
Tanveer Raza MD MS MBBS
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Inflammatory response
Inflammation
Vascular response to injury
Major local manifestations of acute
inflammation
Vascular dilation and increased blood flow
(causing erythema and warmth)
Extravasation and deposition of plasma
fluid and proteins (edema)
Leukocyte emigration and accumulation in
the site of injury
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response
Some of the many tissue products that cause
these reactions are
Histamine
Bradykinin
Serotonin
Prostaglandins
Several different reaction products of
complement system
Reaction products of blood clotting system
Lymphokines
Substances that are released by sensitized T cells
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response
Several of these substances strongly
activate the macrophage system
Macrophages devour the destroyed tissues.
Sometimes the macrophages further injure
the still-living tissue cells
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response
First Line of Defense Against Infection
Tissue Macrophage
Second Line of Defense
Neutrophil Invasion of the Inflamed Area
Third Line of Defense
Second Macrophage Invasion of Inflamed
Tissue
Fourth Line of Defense
Increased Production of Granulocytes and
Monocytes by the Bone Marrow
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response:
First Line of Defense against infection
Within minutes after inflammation begins,
the macrophages already present in the
tissues, immediately begin their
phagocytic actions
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response:
Second Line of Defense against infection
Neutrophil Invasion of the Inflamed Area
Within the first hour or so after inflammation
begins, large numbers of neutrophils begin to
invade the inflamed area from the blood
Neutrophilia
Acute Increase in Number of Neutrophils in
the Blood
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response:
Third Line of Defense against infection
Second Macrophage Invasion into the
Inflamed Tissue
Along with the invasion of neutrophils,
monocytes from the blood enter the inflamed
tissue and enlarge to become macrophages.
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response:
Fourth Line of Defense against infection
Increased Production of Granulocytes
and Monocytes by the Bone Marrow
It takes 3 to 4 days before newly formed
granulocytes and monocytes reach the stage
of leaving the bone marrow
Tanveer Raza MD MS MBBS
razajju2@yahoo.com
Inflammatory response
Feedback control of Macrophage & Neutrophil responses
Factors which play dominant role
Tumor necrosis factor (TNF)
Interleukin-1 (IL-1)
Granulocyte-monocyte colony-stimulating factor
(GM-CSF)
Granulocyte colony-stimulating factor (G-CSF)
Monocyte colony-stimulating factor (M-CSF)
These factors are formed by activated macrophage
cells in inflamed tissues and alsoin smaller quantities
by other inflamed tissue cells
Thank You