Physiology Lecture 63

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Physiology Lecture 64
Tanveer Raza MD MS MBBS
[email protected]
Tanveer Raza MD MS MBBS
[email protected]
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
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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; 1316, stages of monocyte formation
Tanveer Raza MD MS MBBS
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Tanveer Raza MD MS MBBS
[email protected]
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
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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
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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
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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
[email protected]
Tanveer Raza MD MS MBBS
[email protected]
White Blood Cells
• a.k.a. White Blood Corpuscles, WBC,
Leukocytes
• Normal count 4,000-11,000 cells/µL of
blood
– Average 7,000 (9,000) cells/µL of blood
• Life span: Few hours to days
Tanveer Raza MD MS MBBS
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White Blood Cells
• Differential Count
– Neutrophils
– Eosinophils
– Basophils
– Monocytes
– Lymphocytes
62.0% (50-70%)
2.3% (1-4%)
0.4% (0-0.4%)
5.3% (2-8%)
30.0% (20-40%)
Tanveer Raza MD MS MBBS
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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
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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
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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
[email protected]
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
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White Blood Cells
• Life Span
– In bone marrow:
• RBC:WBC=1:50
– In Circulation:
• RBC:WBC=500:1
Tanveer Raza MD MS MBBS
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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
[email protected]
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
Tanveer Raza MD MS MBBS
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A, Endothelium (EC)-lined neovessel with diapedesis of macrophage
Balakrishnan, K. R. et al. Circulation 2006;113:e41-e43
Copyright ©2006 American Heart Association
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
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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
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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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Lee at al. 2003
Phagocytosis by neutrophils. Time-lapse sequence of Fcc receptormediated phagocytosis. Human neutrophils were exposed to IgGopsonized 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.
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
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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
[email protected]
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
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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
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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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
Reticuloendothelial System
Tanveer Raza MD MS MBBS
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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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
Functional diagram of a lymph node.
Tanveer Raza MD MS MBBS
[email protected]
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
[email protected]
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
[email protected]
Kupffer cells lining the liver sinusoids, showing
phagocytosis of India ink particles into the cytoplasm of
the Kupffer cells.
Tanveer Raza MD MS MBBS
[email protected]
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
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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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
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
[email protected]
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
Tanveer Raza MD MS MBBS
[email protected]
Thank You
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