Blood physiology by prof.Israa F.Jafar
Physiology of Blood
Components, Characteristics, Functions of Blood
Major Components of Blood
1. Formed elements - the actual cellular components of blood (special connective
tissue)
a.erythrocytes - red blood cells
b.leukocytes - white blood cells
c.platelets - cell fragments for clotting
2. Blood plasma - complex non-cellular fluid surrounding formed elements; protein &
electrolytes.
Separation of Components in a Centrifuge
VOLUME
clear/yellowish PLASMA
55%
thin/whitish buffy coat
<1%
with LEUKOCYTES & PLATELETS
reddish mass - ERYTHROCYTES
45%
LAYER
top
middle
bottom
hematocrit - percentage by VOLUME of erythrocytes when blood is centrifuged (normal =
45%)
Characteristics of Blood
1.
bright red (oxygenated)
2.
dark red/purplish (unoxygenated)
3.
much more dense than pure water
4.
pH range from 7.35 to 7.45 (slightly alkaline)
5.
slightly warmer than body temperature 100.4 F
6.
typical volume in adult male 5-6 liters
7.
typical volume in adult female 4-5 liters
8.
typically 8% of body weight
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Blood physiology by prof.Israa F.Jafar
Major Functions of Blood
1. Distribution & Transport
a.
oxygen from lungs to body cells
b.
carbon dioxide from body cells to lungs
c.
nutrients from GI tract to body cells
d.
nitrogenous wastes from body cells to kidneys
e.
hormones from glands to body cells
2. Regulation (maintenance of homeostasis)
a. maintenance of normal body pH by blood proteins (albumin) &
bicarbonate
b. maintenance of circulatory/interstitial fluid by electrolytes that aid
blood proteins
(albumin)
c. maintenance of temperature (blushed skin)
3. Protection
a.
platelets and proteins "seal" vessel damage
b.
protection from foreign material & infections byleukocytes,
antibodies& complement proteins
Plasma (the liquid part of blood)
A.
General Characteristics
1.
plasma makes up 55% of normal blood by volume
2.
water is 90% of the plasma by volume
3.
many different SOLUTES in the plasma
a.
albumin - pH buffer & osmotic pressure
b.
globulins - binding proteins & antibodies
c.
clotting proteins - prothrombin & fibrinogen
d.
other proteins - enzymes, hormones, others
e.
nutrients - glucose, fatty acids, amino acids, cholesterol, vitamins
f. electrolytes - Na+, K+, Ca++, Mg++, Cl-, phosphate, sulfate, bicarbonate,
others
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Blood physiology by prof.Israa F.Jafar
BONE MARROW
In the adult, red blood cells, many white blood cells, and platelets are formed in the bone
marrow. In the fetus, blood cells are also formed in the liver and spleen, and in adults such
extramedullary hematopoiesis may occur in diseases in which the bone marrow becomes
destroyed or fibrosed. In children, blood cells are actively produced in the marrow cavities of
all the bones. By age 20, the marrow in the cavities of the long bones, except for the upper
humerus and femur, has become inactive . Active cellular marrow is called red marrow;
inactive marrow that is infiltrated with fat is called yellow marrow.
The bone marrow is actually one of the largest organs in the body, approaching the size and
weight of the liver. It is also one of the most active. Normally, 75% of the cells in the marrow
belong to the white blood cell-producing myeloid series and only 25% are maturing red cells,
even though there are over 500 times as many red cells in the circulation as there are white
cells. This difference in the marrow reflects the fact that the average life span of white cells is
short, whereas that of red cells is long.
The bone marrow contains multipotent uncommitted stem cells (pluripotential stem cells)
that differentiate into one or another type of committed stem cells (progenitor cells). These in
turn form the various differentiated types of blood cells. There are separate pools of
progenitor cells for megakaryocytes, lymphocytes, erythrocytes, eosinophils, and basophils,
whereas neutrophils and monocytes arise from a common precursor. The bone marrow stem
cells are also the source of osteoclasts , Kupffer cells . mast cells, dendritic cells, and
Langerhans cells .
The pluripotential cells are few in number but are capable of completely replacing the bone
marrow when injected into a host whose own bone marrow has been completely destroyed.
The best current source for these hematopoietic stem cells is umbilical cord blood.
The pluripotential cells are derived from uncommitted, totipotent stem cells that at least in
theory can be stimulated to form any cell in the body. There are a few of these in adults, but
they are more readily obtained from the blastocysts of embryos. Totipotential cells from
human embryos have now been cultured, and there is immense interest in stem cell research.
However, there are ethical as well as scientific issues involved, and debate on these issues
will undoubtedly continue.
Erythrocytes (red blood ells; RBCs)
Structure
1.
7.5 micron diameter; 2.0 micron thick
2.
biconcave disk shape; ideal for gas exchange;the shape is maintained by
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Blood physiology by prof.Israa F.Jafar
spectrin - elastic protein; allows shape change.
3.
mature cells are anucleate (no nucleus)
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very few organelles; mainly a hemoglobin carrier
i. hemoglobin – 33% of cell mass; carries oxygen
5.
no mitochondria; only anaerobic respiration
6.
ratio erythrocytes:leukocytes = 800:1
7.
red blood cell count: as cells per cubic millimeter
i. normal male count - 5. to 5.8 million
ii. normal female count - 4.3 to 5.2 million
Functions (oxygen & carbon dioxide transport)
Hematopoiesis and Erythropoiesis: hematopoiesis (hemopoiesis) - the maturation,
development and formation of blood cells
a. red bone marrow (myeloid tissue) - location of hematopoiesis; in blood
sinusoids which connect with capillaries; mainly in axial skeleton
and heads of femur & humerus
b. hemocytoblast (stem cell) - the mitotic precursor to blood cells before
differentiation
i. differentiation - maturing cell becomes "committed" to being
certain type blood cell
Erythropoiesis - the maturation, development, and formation of Red Blood Cells
hemocytoblast ->proerythroblast ->early (basophilic) erythroblast ->late
(polychromatophilic) erythroblast ->(hemoglobin) normoblast -> (nucleus
ejected when enough hemoglobin)reticulocyte -> (retaining some endoplasmic
reticulum)
ERYTHROCYTE life span:
hemocytoblast -> reticulocyte
reticulocyte -> ERYTHROCYTE
ERYTHROCYTE lifespan
(primarily destroyed by macrophages in the spleen)
3-5 DAYS
2 DAYS (in blood)
100-120 DAYS
3. Regulation of Erythropoiesis
a.
hormonal controls - erythropoietin is the hormone that stimulates
RBC production
DECREASED oxygen level in blood causes KIDNEYS to increase release of erythropoietin
1.
Less RBCs from bleeding
2.
Less RBCs from excess RBC destruction
3.
Low oxygen levels (high altitude, illness)
4.
Increased oxygen demand (exercise)
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Blood physiology by prof.Israa F.Jafar
Eythropoietin now genetically engineered and synthesized to stimulate erythropoisis
Testosterone can also mildly stimulate production of RBCs in humans
b.
Iron - essential for hemoglobin to carry oxygen
i.
65% of Fe in body is in hemoglobin
ii.
liver and spleen store most excess Fe bound to ferritin and
hemosiderin
iii. Fe in blood bound to transferrin
iv.
daily Fe loss: 0.9 mg men/l.7 mg women
v.
women also lose Fe during menstrual flow
c.
B-complex Vitamins - Vitamin B12 and Folic Acid essential for
DNA synthesis in early mitotic divisions leading to erythrocytes
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Blood physiology by prof.Israa F.Jafar
Hemoglobin
The red, oxygen-carrying pigment in the red blood cells of vertebrates is hemoglobin, a
protein with a molecular weight of 64,450. Hemoglobin is a globular molecule made up of 4
subunits .Each subunit contains a heme moiety conjugated to a polypeptide. Heme is an ironcontaining porphyrin derivative . The polypeptides are referred to collectively as the globin
portion of the hemoglobin molecule.
There are two pairs of polypeptides in each hemoglobin molecule.
1. (hemoglobin A is α2 β2 ) the normal adult human hemoglobin ; the two types of
polypeptide are called the α chains, each of which contains 141 amino acid residues, and
the β chains, each of which contains 146 amino acid residues. Thus, hemoglobin A is
designated α2β2.
2. hemoglobin A2 (α2δ2). this forms about 2.5% of the hemoglobin, in which β chains are
replaced by δ chains (α2δ2). The δ chains also contain 146 amino acid residues, but 10
individual residues differ from those in the β chains.
3.There are small amounts of hemoglobin A derivatives closely associated with hemoglobin
A that represent glycated hemoglobins. One of these, hemoglobin A1c (HbA1c), has a glucose
attached to the terminal valine in each β chain and is of special interest because the quantity
in the blood increases in poorly controlled diabetes mellitus .
4.Hemoglobin in the Fetus
1.The blood of the human fetus normally contains fetal hemoglobin (hemoglobin F
hemoglobin F is( α2 γ2). The γ chains also contain 146 amino acid residues but have 37 that
differ from those in the β chain. Fetal hemoglobin is normally replaced by adult hemoglobin
soon after birth. In certain individuals, it fails to disappear and persists throughout life. In the
body, its O2 content at a given PO2 is greater than that of adult hemoglobin because it binds
2,3-DPG less avidly. This facilitates movement of O2 from the maternal to the fetal
circulation
2. In young embryos there are, in addition, ζ and ε chains, forming Gower 1 hemoglobin
(ζ2ε2) and Gower 2 hemoglobin (α2ε2).
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Blood physiology by prof.Israa F.Jafar
Reactions of Hemoglobin
1.oxygenation:Hemoglobin binds O2 to form oxyhemoglobin, O2 attaching to the Fe2+ in the
heme. The affinity of hemoglobin for O2 is affected by pH, temperature, and the
concentration in the red cells of 2,3-diphosphoglycerate (2,3-DPG). 2,3-DPG and H+
compete with O2 for binding to deoxygenated hemoglobin, decreasing the affinity of
hemoglobin for O2 by shifting the positions of the four peptide chains (quaternary structure).
2.oxidation: When blood is exposed to various drugs and other oxidizing agents in vitro or in
vivo, the ferrous iron (Fe2+) that is normally in the molecule is converted to ferric iron (Fe3+),
forming methemoglobin. Methemoglobin is dark-colored, and when it is present in large
quantities in the circulation, it causes a dusky discoloration of the skin resembling cyanosis .
Some oxidation of hemoglobin to methemoglobin occurs normally, but an enzyme system in
the red cells, the NADH-methemoglobin reductase system, converts methemoglobin back to
hemoglobin. Congenital absence of this system is one cause of hereditary
methemoglobinemia.
3. Carbon monoxide reacts with hemoglobin to form carbon monoxyhemoglobin
(carboxyhemoglobin). The affinity of hemoglobin for O2 is much lower than its affinity for
carbon monoxide, which consequently displaces O2 on hemoglobin, reducing the oxygencarrying capacity of blood .
4. Heme is also part of the structure of myoglobin, an oxygen-binding pigment found in red
(slow) muscles
5.In addition, neuroglobin, an oxygen-binding globin, is found in the brain. It appears to help
supply O2 to neurons. There is heme in the respiratory chain enzyme cytochrome c .
Abnormalities of Hemoglobin Production
The amino acid sequences in the polypeptide chains of hemoglobin are determined by globin
genes.
There are two major types of inherited disorders of hemoglobin in humans: the
hemoglobinopathies, in which abnormal polypeptide chains are produced, and the
thalassemias and related disorders, in which the chains are normal in structure but produced
in decreased amounts or absent because of defects in the regulatory portion of the globin
genes.
The α thalassemias are defined by decreased or absent α polypeptides.
The β thal-assemias are defined by decreased or absent α and β polypeptides.
abnormal hemoglobins Mutant genes that cause the production of abnormal hemoglobins
are widespread, and about 1000 abnormal hemoglobins have been described in humans. They
are usually identified by letter—hemoglobin C, E, I, J, S, etc. In most instances, the abnormal
hemoglobins differ from normal hemoglobin A in the structure of the polypeptide chains.
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Blood physiology by prof.Israa F.Jafar
hemoglobin S, the α chains are normal but the β chains are abnormal, because among
the 146 amino acid residues in each β polypeptide chain, one glutamic acid residue has
been replaced by a valine residue .
When an abnormal gene inherited from one parent dictates formation of an abnormal
hemoglobin—ie, when the individual is heterozygous—half the circulating hemoglobin is
abnormal and half is normal. When identical abnormal genes are inherited from both parents,
the individual is homozygous and all of the hemoglobin is abnormal. It is theoretically
possible to inherit two different abnormal hemoglobins, one from the father and one from the
mother.
Many of the abnormal hemoglobins are harmless. However, some have abnormal O2
equilibriums. Others cause anemia. For example, hemoglobin S polymerizes at low O2
tensions, and this causes the red cells to become sickle-shaped, hemolyze, and form
aggregates that block blood vessels. The result is the severe hemolytic anemia known as
sickle cell anemia. Heterozygous individuals have the sickle cell trait and rarely have severe
symptoms, but homozygous individuals develop the full-blown disease. The sickle cell gene
is an example of a gene that has persisted and spread in the population. It originated in the
black population in Africa, and it confers resistance to one type of malaria. This is an
important benefit in Africa, and in some parts of Africa 40% of the population have the sickle
cell trait. In the United States black population its incidence is about 10%.
Hemoglobin F has the ability to decrease the polymerization of deoxygenated hemoglobin S,
and hydroxyurea causes hemoglobin F to be produced in children and adults. It has proved to
be a very valuable agent for the treatment of sickle cell disease. In patients with severe sickle
cell disease, bone marrow transplantation has been carried out and the patients have generally
done well, though more study is needed.
Synthesis of Hemoglobin
The average normal hemoglobin content of blood is 16 g/dL in men and 14 g/dL in women,
all of it in red cells. In the body of a 70-kg man, there are about 900 g of hemoglobin, and 0.3
g of hemoglobin is destroyed and 0.3 g synthesized every hour . The heme portion of the
hemoglobin molecule is synthesized from glycine and succinyl-CoA.
Catabolism of Hemoglobin
When old red blood cells are destroyed in the tissue macrophage system, the globin portion
of the hemoglobin molecule is split off, and the heme is converted to biliverdin. The enzyme
involved is a subtype of heme oxygenase . and CO is formed in the process. CO may be an
intercellular messenger, like NO .
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Blood physiology by prof.Israa F.Jafar
In humans, most of the biliverdin is converted to bilirubin and excreted in the bile . The iron
from the heme is reused for hemoglobin synthesis.
Exposure of the skin to white light converts bilirubin to lumirubin, which has a shorter halflife than bilirubin. Phototherapy (exposure to light) is of value in treating infants with
jaundice due to hemolysis. Iron is essential for hemoglobin synthesis; if blood is lost from the
body and the iron deficiency is not corrected, iron deficiency anemia results.
Anemias:
I.Defeciency of substrates which are necessary for RBC or Hb production like:
1. Iron deficiency anaemia(increaseloss, or decrease intake)
2.folic acid deficiency anaemia(low intake) folic a. is necessary for DNA formation
and maturation of RBCs.
3 B12 defeciency anaemia. B12 is necessary for DNA formation of RBCs.defeciency
due to low intake as in vegetarians or intrinsic factor deficiency (pernicious anaemia).
II. membrane defects as in hereditary spherocytosis or elliptocytosis.
Haemolytic anaemia eg:autoimmune Haemolytic anaemia,erythroblastosis fetalis.
III.Hemoglobinopathies.Thalassaemiaand sickle cell anaemia.
IV . bone morrow infiltration like aplastic anaemia and different forms of leukaemias.
V. Anaemia of chronic disease.like chronic renal failure.
Effect of anemia on circulation:
1. Decrease the viscosity of blood.
2. increase work load on the heart (PALPITATION & TIREDNESS)
3. In exercise there will be tissue hypoxia that leads to heart failure.
Treatment toward the cause.
Polycythemia:
Increase production of RBCs (count 6-8 milio/mm3)its of 2 types:
1.primarypolycythemia vera(count7-8 milio/mm3)
2.Secondary due to tissue hypoxialike in high altitude or chronic smokers.
Effect of polycythemia on circulation increases the viscisity of blood leads to sluggish
circulation this leads to thrombosis. Blood pressure increases increase work load on the heart
leads to heart failure.
Tretment by venesection
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Blood physiology by prof.Israa F.Jafar
Iron
In adults, the amount of iron lost from the body is relatively small. The losses are generally
unregulated, and total body stores of iron are regulated by changes in the rate at which it is
absorbed from the intestine. Men lose about 0.6 mg/d, largely in the stools. Women have a
variable, larger loss averaging about twice this value because of the additional iron lost in the
blood shed during menstruation.
The average daily iron intake in the United States and Europe is about 20 mg, but the
amount absorbed is equal only to the losses. Thus, the amount of iron absorbed ranges
normally from about 3 to 6% of the amount ingested. Various dietary factors affect the
availability of iron for absorption; for example, the phytic acid found in cereals reacts with
iron to form insoluble compounds in the intestine. So do phosphates and oxalates.
Most of the iron in the diet is in the ferric (Fe 3+) form, whereas it is the ferrous (Fe2+) form
that is absorbed. There is Fe3+ reductase activity associated with the iron transporter in the
brush borders of the enterocytes .
No more than a trace of iron is absorbed in the stomach, but the gastric secretions dissolve
the iron and permit it to form soluble complexes with ascorbic acid and other substances that
aid its reduction to the Fe2+ form. The importance of this function in humans is indicated by
the fact that iron deficiency anemia is a troublesome and relatively frequent complication of
partial gastrectomy.
Almost all iron absorption occurs in the duodenum. Fe2+ is Transported into the enterocytes .
Some is stored in ferritin,
In the plasma, Fe2+ is converted to Fe3+ and bound to the iron transport protein transferrin.
This protein has two iron-binding sites. Normally, transferrin is about 35% saturated with
iron, and the normal plasma iron level is about 130 ug/dL (23 umol/L) in men and 110 ug/dL
(19 umol/L) in women.
70% of the iron in the body is in hemoglobin, 3% in myoglobin, and the rest in ferritin, which
is present not only in enterocytes but also in many other cells. Apoferritin is a globular
protein made up of 24 subunits. Iron forms a micelle of ferric hydroxyphosphate, and in
ferritin, the subunits surround this micelle. The ferritin micelle can contain as many as 4500
atoms of iron.
Ferritin molecules in lysosomal membranes may aggregate in deposits that contain as much
as 50% iron. These deposits are called hemosiderin.
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Blood physiology by prof.Israa F.Jafar
Intestinal absorption of iron is regulated by three factors:
1. Recent dietary intake of iron.
2. The state of the iron stores in the body.
3. The state of erythropoiesis in the bone marrow.
Iron overload causes hemosiderin to accumulate in the tissues, producing hemosiderosis.
Large amounts of hemosiderin can damage tissues, causing hemochromatosis.This syndrome
is characterized by pigmentation of the skin, pancreatic damage with diabetes ("bronze
diabetes"), cirrhosis of the liver, a high incidence of hepatic carcinoma, and gonadal atrophy.
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Blood physiology by prof.Israa F.Jafar
Blood Transfusions and Blood Typing
Transfusion of Blood
1. Whole blood transfusion - all cells and plasma; anticoagulants (citrate and
oxalate salts) used
2. Packed red blood cells - most of the plasma has been removed prior to
transfusion
Human Blood Groups:
1. Agglutinogens - glycoproteins on the surface of blood cells; causes
"agglutination" (clumping)
2. ABO Blood Groups - determined by presence or absence of Type A and Type
B agglutinogen proteins on cell membrane
TYPE
type A
type B
type AB
type O
GENES
A/A, A/O, O/A
B/B, B/O, O/B
A/B or B/A
no A or B
PEOPLE
(30-40%)
(l0-30%)
(3-5%)
(40-50%)
Antibodies
Anti-B
Anti-A
none
Anti-A, Anti-B
Receive Blood from:
A, O
B,O
A, B, AB, O
O only
3. agglutinins - antibodies against either A or B agglutinogen
a. transfusion reaction - patient's antibodies attack the donor blood
i.
A (anti-B) receives A,O (not B)
ii.
B (anti-A) receives B,O (not A)
iii. AB (none) receives A, B, AB, O universal recipient
iv.
O (anti-A,anti-B) receives O universal donor
b. agglutination - when incorrect blood transfused, antibodies will
"clump" new blood after clumping, RBCs may rupture(hemolysis), releasing
hemoglobin this Hb is harming to the kidneys & can lead to renal shutdown .
4. Blood Typing - mixing Donors Blood with Recipient Antibodies (Anti-A,
Anti-B, anti-Rh) in order to identify agglutination
5. Expanding Blood Volume to Avoid Shock by either pure plasma without
antibodies or by plasma expanders - purified human serum albumin, plasminate,
dextran or by isotonic saline - normal electrolyte solution isotonic to blood plasma
(Ringer's Solution)
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Blood physiology by prof.Israa F.Jafar
The Rh Group
The "Rh factor," named for the rhesus monkey because it was first studied using the blood of
this animal, is a system composed primarily of the C, D, and E antigens, although it actually
contains many more. Unlike the ABO antigens, the system has not been detected in tissues
other than red cells. D is by far the most antigenic component, and the term "Rh-positive" as
it is generally used means that the individual has agglutinogen D. The "Rh-negative"
individual has no D antigen and forms the anti-D agglutinin when injected with D-positive
cells. The Rh typing serum used in routine blood typing is anti-D serum. Eighty-five percent
of Caucasians are D-positive and 15% are D-negative; over 99% of Asians are D-positive.
Unlike the antibodies of the ABO system, anti-D antibodies do not develop without exposure
of a D-negative individual to D-positive red cells by transfusion or entrance of fetal blood
into the maternal circulation. However, D-negative individuals who have received a
transfusion of D-positive blood (even years previously) can have appreciable anti-D titers
and thus may develop transfusion reactions when transfused again with D-positive blood.
Hemolytic Disease of the Newborn
Another complication due to "Rh incompatibility" arises when an Rh-negative mother carries
an Rh-positive fetus. Small amounts of fetal blood leak into the maternal circulation at the
time of delivery, and some mothers develop significant titers of anti-Rh agglutinins during
the postpartum period. During the next pregnancy, the mother's agglutinins cross the placenta
to the fetus. In addition, there are some cases of fetal-maternal hemorrhage during pregnancy,
and sensitization can occur during pregnancy. In any case, when anti-Rh agglutinins cross the
placenta to an Rh-positive fetus, they can cause hemolysis and various forms of hemolytic
disease of the newborn (erythroblastosis fetalis). If hemolysis in the fetus is severe, the infant
may die in utero or may develop anemia, severe jaundice, and edema (hydrops fetalis).
Kernicterus, a neurologic syndrome in which unconjugated bilirubin is deposited in the basal
ganglia, may also develop, especially if birth is complicated by a period of hypoxia. Bilirubin
rarely penetrates the brain in adults, but it does in infants with erythroblastosis, possibly in
part because the blood-brain barrier is more permeable in infancy. However, the main
reasons that the concentration of unconjugated bilirubin is very high in this condition are that
production is increased and the bilirubin-conjugating system is not yet mature.
About 50% of Rh-negative individuals are sensitized (develop an anti-Rh titer) by transfusion
of Rh-positive blood. Since sensitization of Rh-negative mothers by carrying an Rh-positive
fetus generally occurs at birth, the first child is usually normal. However, hemolytic disease
occurs in about 17% of the Rh-positive fetuses born to Rh-negative mothers who have
previously been pregnant one or more times with Rh-positive fetuses. Fortunately, it is
usually possible to prevent sensitization from occurring the first time by administering a
single dose of anti-Rh antibodies in the form of Rh immune globulin during the postpartum
period. Such passive immunization does not harm the mother and has been demonstrated to
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Blood physiology by prof.Israa F.Jafar
prevent active antibody formation by the mother. In obstetric clinics, the institution of such
treatment on a routine basis to unsensitized Rh-negative women who have delivered an Rhpositive baby has reduced the overall incidence of hemolytic disease by more than 90%. In
addition, fetal Rh typing with material obtained by amniocentesis or chorionic villus
sampling is now possible, and treatment with a small dose of Rh immune serum will prevent
sensitization during pregnancy.
Platelets (thrombocytes - "clotting")
The platelets are small, granulated bodies that aggregate at sites of vascular injury. They lack
nuclei and are 2-4 um in diameter . There are about 300,000/uL of circulating blood, and they
normally have a half-life of about 4 days. The megakaryocytes, giant cells in the bone
marrow, form platelets by pinching off bits of cytoplasm and extruding them into the
circulation. Between 60% and 75% of the platelets that have been extruded from the bone
marrow are in the circulating blood, and the remainder are mostly in the spleen. Splenectomy
causes an increase in the platelet count (thrombocytosis).
Platelets have a ring of microtubules around their periphery and an extensively invaginated
membrane with an intricate canalicular system in contact with the ECF. Their membranes
contain receptors for collagen, ADP, vessel wall von Willebrand factor . and fibrinogen.
Their cytoplasm contains actin, myosin, glycogen, lysosomes, and two types of granules:
(1) dense granules, which contain the nonprotein substances that are secreted in response to
platelet activation, including serotonin, ADP and other adenine nucleotides,
(2) α-granules, which contain secreted proteins other than the hydrolases in lysosomes.
These proteins include clotting factors and platelet-derived growth factor (PDGF).
PDGF is also produced by macrophages and endothelial cells. PDGF stimulates wound
healing and is a potent mitogen for vascular smooth muscle.
Platelet production is regulated by :
1. colony- stimulating factors that control the production of megakaryocytes.
2. thrombopoietin, a circulating protein factor. This factor, which facilitates megakaryocyte
maturation
Thrombocytopenic purpura
When the platelet count is low, clot retraction is deficient and there is poor constriction
of ruptured vessels. The resulting clinical syndrome (thrombocytopenic purpura) is
characterized by easy bruisability and multiple subcutaneous hemorrhages. Purpura may also
occur when the platelet count is normal, and in some of these cases, the circulating platelets
are abnormal (thrombasthenic purpura). Individuals with thrombocytosis (increased number
of platelets) are predisposed to thrombotic events
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Blood physiology by prof.Israa F.Jafar
Hemostasis (stoppage of blood flow after damage)
Steps of hemostasis:1. Vascular spasms (vasoconstriction at injured site)
2. Platelet plug formation (plugging the hole)
3. Coagulation (blood clotting - complex mechanism)
Vascular Spasms: first response to vascular injury - vasoconstriction is stimulated by: a.
compression of vessel by escaping blood
b.
injury "chemicals" released by injured cells
c.
reflexes from adjacent pain receptors
Formation of a Platelet Plug
1.
damage to endothelium of vessel
2.
platelets become spiky and sticky in response
3.
platelets attach to damaged vessel wall to plug it
4.
platelets produce thromboxane A2 - granule release
5.
serotonin release enhances vascular spasm
6.
ADP - attracts and stimulates platelets at site
7.
prostacylin - inhibits aggregation at other sites
Platelet aggregation: When a blood vessel wall is injured, platelets adhere to the exposed
collagen and von Willebrand factor in the wall via the receptors on the platelet membrane.
Binding produces platelet activations which release the contents of their granules. The
released ADP acts on the ADP receptors in the platelet membranes to produce further
accumulation of more platelets
Coagulation (blood clotting)
General Events in Clotting Is shown in the diagram
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Blood physiology by prof.Israa F.Jafar
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Blood physiology by prof.Israa F.Jafar
Fibrinolysis Blue arrows = stimulation; red arrows = inhibition. tPA is released by
damaged endothelium
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Blood physiology by prof.Israa F.Jafar
summary:
1. anticoagulant - chemical that inhibits clotting
2. procoagulant - chemical that promotes clotting
3. intrinsic pathway - within the damaged vessel
a. more procoagulants needed (I-XIII) toward PF3 and Factor X
b. allows more "scrutiny" before clotting occurs
4.extrinsic pathway - in outer tissues around vessel
a tissue thromboplastin (Tissue Factor) - skips intrinsic steps straight to PF3 and
Fac X
b. allows rapid response to bleeding out of vessel (clot can form in 10 to 15
seconds)
5.
After activation of Factor X, common pathway:
Factor X, PF3 (thromboplastin), Factor V, Ca++ -->
prothrombin activator ->
prothrombin converted -> thrombin (active enzyme)
thrombin stimulates: fibrinogen -> fibrin (meshwork)
Ca++ & thrombin -> Factor XIII (fibrin stabilizer)
Clot Retraction (shrinking of clot)
1.actomyosin - causes contraction of platelets
2.blood serum - plasma WITHOUT clotting Factors
3.platelet-derived growth factor (PDGF) - stimulates fibroblast migration and
endothelial growth
Clot Eradication (Fibrinolysis)
1.healing occurs over 2 - 10 days
2.tissue plasminogen activator (TPA) - causes the activation of plasminogen
3.plasminogen--> plasmin
4.plasmin degrades proteins within the clot
Factors Limiting Growth and Formation of Clots
1. Limiting Normal Clot Growth
a. blood moves too fast to allow procoagulants
b. factors interfere with normal clotting
i.prothrombin III - deactivates thrombin
ii.protein C - inhibits clotting Factors
iii.heparin - inhibits thrombin; prevents adherence of platelets to
injured site
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Blood physiology by prof.Israa F.Jafar
Disorders of Hemostasis
A. Thromboembolytic Disorders (undesirable clotting)
1. Thrombus - blood clot in normal blood vessel
2. Embolus -blood clot/gas bubble floating in blood
a.TPA, streptokinase - can dissolve a clot
b.aspirin - inhibits Thromboxane formation
c.heparin - inhibits thrombin & platelet deposit
d.dicumarol - anticoagulant, blocks Vitamin K
B. Bleeding Disorders
1.thrombocytopenia - reduced platelet count; generally below 50,000 per cubic
millimeter; can cause excessive bleeding from vascular injury
2.impaired liver function - lack of procoagulants (Clotting Factors) that are made in
liver a. vitamin K - essential for liver to make Clotting Factors for coagulation
3.hemophilias - hereditary bleeding disorders that occur almost exclusively in males
a.
hemophilia A - defective Factor VIII (83%)
b.
hemophilia B - defective Factor IX (10%)
c.
now genetically engineered TPA and Factor VIII are produced so
patients do not need transfusions as often.
White Blood Cell Count (WBC) and Differential
White blood cells, or leukocytes, are classified into two main groups: granulocytes and
nongranulocytes (also known as agranulocytes).
General Structure and Function
1. protection from microbes, parasites, toxins, cancer
2. 1% of blood volume; 4-11,000 per cubic mm blood
3 diapedesis - can "slip between" capillary wall
4. amoeboid motion - movement through the body
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Blood physiology by prof.Israa F.Jafar


5. chemotaxis - moving in direction of a chemical
6. leukocytosis - increased "white blood cell count" in response to bacterial/viral
infection
The granulocytes, which include neutrophils, eosinophils, and basophils, have
granules in their cell cytoplasm. Neutrophils, eosinophils, and basophils also have a
multilobed nucleus. As a result they are also called polymorphonuclear leukocytes or
"polys." The nuclei of neutrophils also appear to be segmented, so they may also be
called segmented neutrophils or "segs."
The nongranuloctye white blood cells, lymphocytes and monocytes, do not have
granules and have nonlobular nuclei. They are sometimes referred to as mononuclear
leukocytes.
The lifespan of white blood cells ranges from 13 to 20 days, after which time they are
destroyed in the lymphatic system. When immature WBCs are first released from the bone
marrow into the peripheral blood, they are called "bands" or "stabs." Leukocytes fight
infection through a process known as phagocytosis. During phagocytosis, the leukocytes
surround and destroy foreign organisms. White blood cells also produce, transport, and
distribute antibodies as part of the body's immune response.
1. Neutrophils - destroy and ingest bacteria & fungi (polymorphonuclear leuks.; "polys")
a. most numerous WBC
b. defensins - antibiotic-like proteins (granules)
c. polymorphonuclear - many-lobed nuclei
d. causes lysis of infecting bacteria/fungi
e. HIGH poly count --> likely infection
2. eosinophils - lead attack against parasitic worms
a. only 1-4% of all leukocytes
b. two-lobed, purplish nucleus
c. acidophilic (red) granules with digest enzymes
d. phagocytose antigens & antigen/antibody complex
e. inactivate chemicals released during allergies
3. basophils - releases Histamine which causes inflammation, vasodilation, attraction of
WBCs
a.RAREST of all leukocytes (0.5%)
b.deep purple U or S shaped nucleus
c.basophilic (blue) granules with HISTAMINE
d.related to "mast cells" of connective tissue
e.BOTH release Histamine with "IgE" signal
f.antihistamine - blocks the action of Histamine in response to infection or
allergic antigen
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Blood physiology by prof.Israa F.Jafar
Agranulocytes - WBCs without granules in cytoplasm
1. lymphocytes - two types of lymphocytes
a. T lymphocytes - (thymus) respond against virus infected cells and tumor cells.
b. B lymphocytes - (bone) differentiate into different "plasma cells" which each
produce antibodies against different antigens
c. lymphocytes primarily in lymphoid tissues
d. very large basophilic (purple) nucleus
e. small lymphocytes in blood (5-8 microns)
f. larger lymphocytes in lymph organs (10-17 mic)
2. monocytes - differentiate to become macrophages; serious appetites for infectious
microbes
a.
largest of all leukocytes (18 microns)
b.
dark purple, kidney shaped nucleus
Leukopoiesis and Colony Stimulating Factors (CSFs)
1.
leukopoiesis - the production, differentiation, and development of white
blood cells all cells derived from hemocytoblast
2.
colony stimulating factors (CSF) - hematopoietic hormones that promote
leukopoiesis
a. produced by Macrophages and T lymphocytes
i.
macrophage-monocyte CSF (M-CSF)
ii.
granulocyte CSF (G-CSF)
iii. granulocyte-macrophage CSF (GM-CSF)
iv.
multi CSF (multiple lymphocyte action)
v.
interleukin 3 (IL-3) (general lymphocytes)
Two measurements of white blood cells are commonly done in a CBC:
-the total number of white blood cells in a microliter (1x10 -9 liters) of blood, reported as
an absolute number of "X" thousands of white blood cells, and
-The percentage of each of the five types of white blood cells. This test is known as a
differential and is reported in percentages.
Normal values for total WBC and differential in adult males and females are:

Total WBC: 4,000 - 11,000

Bands or stabs: 3 - 5 %

Granulocytes (or polymorphonuclears)
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Blood physiology by prof.Israa F.Jafar

o
Neutrophils : 50 - 70% relative value (2500-7000 absolute value)
o
Eosinophils: 1 - 3% relative value (100-300 absolute value)
o
Basophils: 0.4% - 1% relative value (40-100 absolute value)
Agranulocytes (or mononuclears)
o
Lymphocytes: 25 - 35% relative value (1700-3500 absolute value)
o
Moncytes: 4 - 6% relative value (200-600 absolute value)
Each differential always adds up to 100%. To make an accurate assessment, consider both
relative and absolute values. For example a relative value of 70% neutrophils may seem
within normal limits; however, if the total WBC is 20,000, the absolute value (70% x 20,000)
would be an abnormally high count of 14,000.
Q (It is important to consider both the relative and absolute values of various types of white
blood cells when interpreting a WBC differential. True, False)
The numbers of leukocytes changes with age and during pregnancy.
 On the day of birth, a newborn has a high white blood cell count, ranging from 9,000
to 30,000 leukocytes. This number falls to adult levels within two weeks.

The percentage of neutrophils is high for the first few weeks after birth, but then
lymphocyte predominance is seen.

Until about 8 years of age, lymphocytes are more predominant than neutrophils.

In the elderly, the total WBC decreases slightly.

Pregnancy results in a leukocytosis, primarily due to an increase in neutrophils with a
slight increase in lymphocytes.
Leukocytosis, a WBC above 10,000, is usually due to an increase in one of the five types of
white blood cells and is given the name of the cell that shows the primary increase.

Neutrophilic leukocytosis = neutrophilia

Lymphocytic leukocytosis = lymphocytosis

Eosinophilic leukocytosis = eosinophilia

Monocytic leukocytosis = monocytosis

Basophilic leukocytosis = basophilia
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Blood physiology by prof.Israa F.Jafar
In response to an acute infection, trauma, or inflammation, white blood cells release a
substance called colony-stimulating factor (CSF). CSF stimulates the bone marrow to
increase white blood cell production. In a person with normally functioning bone marrow, the
numbers of white blood cells can double within hours if needed. An increase in the number
of circulating leukocytes is rarely due to an increase in all five types of leukocytes. When this
occurs, it is most often due to dehydration and hemoconcentration. In some diseases, such as
measles, pertussis and sepsis, the increase in white blood cells is so dramatic that the picture
resembles leukemia. Leukemoid reaction, leukocytosis of a temporary nature, must be
differentiated from leukemia, where the leukocytosis is both permanent and progressive.
Therapy with steroids modifies the leukocytosis response. When corticosteroids are given to
healthy persons, the WBC count rises. However, when corticosteroids are given to a person
with a severe infection, the infection can spread significantly without producing an expected
WBC rise. An important concept to remember is that, leukocytosis as a sign of infection can
be masked in a patient taking corticosteroids.
Q (Corticosteroids can mask infection by suppressing the inflammatory response and
the release of WBCs.
True, False
Leukopenia occurs when the WBC falls below 4,000. Viral infections, overwhelming
bacterial infections, and bone marrow disorders can all cause leukopenia. Patients with severe
leukopenia should be protected from anything that interrupts skin integrity, placing them at
risk for an infection that they do not have enough white blood cells to fight. For example,
leukopenic patients should not have intramuscular injections, rectal temperatures or enemas.

A WBC of less than 500 places the patient at risk for a fatal infection.

A WBC over 30,000 indicates massive infection or a serious disease such as leukemia.
Immune System Innate Immune System
I. Parts of the Immune System
A. Innate or Nonspecific system
1. External body membranes like skin and mucosae
i. prevents physical entry of microorganisms
ii. first line of defense
2. Phagocytes, antimicrobial proteins, inflammation
i. activated by chemical signals when external defenses are penetrated
ii. Second line of defense
B. Adaptive or Specific system
1. Main components are the B and T lymphocytes
i. B-lymphocytes involved in humoral or antibody-mediated immunity
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Blood physiology by prof.Israa F.Jafar
ii. T-lymphocytes involved in cellular or cell-mediated immunity
2. Takes considerable time but is highly specific
i. this is the body’s third line of defense
C. Functional System
1. has organs that are involved in the immune response but involves trillions of
individual immune cells
2. the immune system confers immunity which is resistance to disease
II. Innate defenses
A. Function
1. combat pathogens which are harmful or disease-causing microorganisms
2. in a state of readiness and responds to protect the body from ALL foreign
substances starting within minutes of invasion.
B. Surface Barriers
1. Skin
i. heavily keratinized epithelial membrane is a physical barrier
ii. resistant to most weak acids, weak bases, bacterial enzymes and toxins.
iii. secretions are acidic (pH 3-5) and inhibit bacterial growth
iv. sebum contains chemicals that are toxic to bacteria
2. Mucous membranes
i. line all body cavities that open to the exterior including the digestive,
respiratory, urinary, and reproductive tracts
ii. stomach secretes HCl and protein-digesting enzymes which kill
microorganisms.
iii. Saliva and lacrimal fluid contains lysozyme, an enzyme that destroys
bacteria.
iv. Sticky mucus traps microorganism that enter the digestive and respiratory
passageways.
v. structure modifications such as the tiny mucus-coated hairs and ciliated
mucosa of the respiratory tract which trap and sweep particles away from lower
respiratory passages.
3. When surface barriers are breached by small nicks or cuts then the microorganisms
invade deeper tissues and the internal innate defenses are important
C. Internal Defenses
1. Nonspecific and consists of phagocytes, natural killer cells, antimicrobial proteins,
fever, and the inflammatory response which includes macrophages, mast cells, and
all types of white blood cells.
2. Phagocytes
i. cells that engulf or “eat” pathogens
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Blood physiology by prof.Israa F.Jafar
ii. mainly macrophages
a. derived from monocytes which leave the bloodstream and enter tissue
and enlarge.
b. can roam tissues search for cellular debris or “foreign invaders” like
alveolar macrophages of the lungs or dendritic cells of the epidermis.
c. can be fixed like Kupffer cells in the liver or microglia of the brain
iii. neutrophils
a. most abundant type of white blood cell
b. may become phagocytic upon exposure to infectious material
c. secrete defensins, which are antibiotic-like chemicals
d. can release oxidizing and bleach-like chemicals which can destroy
cells, including themselves
e. prolonged activity may cause normal tissues to become cancerous
iv. eosinophils
a. weak phagocytes but are important against parasitic worms
b. discharges destructive contents of cytoplasmic granules
v. mast cells
a. involved in allergies but have some phagocytic capabilities
3. Mechanism of Phagocytosis
i. Ameoba-like digestion: phagocyte engulfs particle using flowing
cytoplasmic extensions 
the particle is enclosed within a membrane-lined vacuole called a phagosome

a lysosome fuses with the phagosome to form a phagolysosome 
pathogen killed and digested within the phagolysosome 
indigestible waste is removed by exocytosis
ii. requires adherence of the particle to the phagocyte
a. carbohydrate signatures
b. pneumococcus has a capsule which makes adherence difficult
c. opsonization, which is the coating of foreign particles with
complement proteins and antibodies, increases adherence
iii. some pathogens can survive lysosomal enzymes and can multiply within the
vacuole.
a. respiratory burst can be activated by adaptive immune
systemchemicals that produce free radicals, like nitric oxide, which can
kill cells.
4. Natural Killer Cells
i. in the blood and lymph
ii. can kill and lyse cancer cells and virus-infected body cells
iii. belong to the group large granular lymphocytes
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Blood physiology by prof.Israa F.Jafar
iv. recognize surface sugars but are fairly nonspecific
v. not phagocytic, but release cytolytic chemicals called perforins
vi. secrete chemicals that enhance the inflammatory response
5. Inflammation
i. triggered by body tissue injuries like physical trauma, heat, irritating
chemicals, infection by viruses, fungi, and bacteria.
ii. functions to:
a. prevents spread of damaging agents
b. disposes of cell debris and pathogens
c. sets the stage for repair processes
iii. signs of inflammation are redness, heat, swelling, pain, and sometimes
impairment of function.
iv. begins with the release of inflammatory chemicals called inflammatory
mediators into the extracellular fluid
a. can come from injured tissue cells, phagocytes, lymphocytes, mast
cells, and blood proteins
v. main inflammatory mediators are histamine, kinins, prostaglandins,
complement, and cytokines
a. cause vasodilation and hyperemia, which is congestion with blood, that
is responsible for the redness and heat
b. increase permeability of local capillaries
i.fluid containing proteins like clotting factors and
antibodies, called exudates, flows from the bloodstream into tissue spaces
ii. local edema occurs and pain is triggered
vi. edema can be beneficial
a. helps to dilute harmful substances that may be present
b. brings in large quantities of oxygen and nutrients needed for repair.
c. allows entry of clotting proteins which forms a fibrin mesh that
prevents the spread of harmful agents.
vii. increases the production of -defensins, which are antibiotic-like
chemicals.
6. Phagocyte mobilization
i. sequence: mast cells  neutrophils  macrophages
ii. leukocytosis is first and chemicals called leukocytosis-inducing factors are
released from injured cells to promote neutrophil release from red
bone
marrow.
iii. margination is the process of cell adhesion molecules (CAMs) of
neutrophils binding to cell adhesion molecules (CAMs) called selectins of the
endothelial cells of capillary walls causing the neutrophils to cling to the
capillary wall.
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Blood physiology by prof.Israa F.Jafar
iv. diapedesis is the process of neutrophils emigrating through the capillary
walls to the site of inflammation.
v. chemotaxis is the attraction of neutrophils and other white blood cells to the
site of injury due to inflammatory chemicals called chemotactic agents.
vi. monocytes become macrophages about 8-12 hours after entering the
tissues. Macrophages are dominant at sites of chronic inflammation.
7. Pus is a mixture of dead or dying neutrophils, broken-down tissue cells, and living
and dead pathogens.
8. Abscesses are sacs of pus walled off by collagen fibers
9. Infection granulomas are tumorlike growths containing macrophages infected by
pathogens “hiding” within it surrounded by uninfected macrophages and an outer fibrous
capsule.
10. Antimicrobial proteins
i. attack microorganisms directly or inhibit their ability to reproduce
ii. interferon
a. different types like , , and -interferon
b. are small proteins which “interferes” with viral replication.
c. not virus specific
d.  comes from lymphocytes
e.  comes from most other leukocytes
f.  comes from fibroblasts
g. activates macrophages and mobilizes natural killer cells
h. play an anticancer role
i.  is used to treat genital warts and can combat Hep C
11. Complement system
i. group of at least 20 plasma proteins that destroy foreign substances by lysis
when activated.
ii. amplifies the inflammatory process
iii. there is a classical pathway and an alternative pathway that both lead to the
activation of C3, one of the complement proteins, which is then cleaved into two
subunits which can cause inflammation and opsonization.
iv. MAC is the membrane attack complex which inserts into the membrane of
the target cell and inhibits the cell’s ability to eject Ca+2 and causes lysis
12. Fever
i. body temperature is controlled by hypothalamic neurons and is set to about
36.2 C
ii. fever occurs when pyrogens, chemicals secreted by leukocytes and
macrophages exposed to foreign matter, resets the neurons higher.
iii. high fevers can denature enzymes
iv. fevers are helpful because it speeds up the metabolic rate of tissue cells and
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Blood physiology by prof.Israa F.Jafar
cause the liver and spleen to contain iron and zinc, which bacteria require in
large amounts to multiply
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Blood physiology by prof.Israa F.Jafar
Immune System Adaptive Immune System
I.
Adaptive or Specific Immune System
General Characteristics
1.
Specific so that it can eliminate with equal precision almost any type of
pathogen
2.
Functional System
a.
can eliminate specific foreign substances as well as abnormal body
cells
b.
can magnify the inflammatory response
i.
responsible for most complement activation
3.
Must be primed by an initial exposure to a specific foreign substance
called an antigen
a.
takes time
important findings about the adaptive immune response
a.
antigen-specific
b.
systemic
c.
has “memory”
Two branches of adaptive immunity
1.
Humoral immunity or antibody-mediated immunity consists of antibodies
circulating in the fluids of the body
a.
produced by lymphocytes or their offspring
2.
Cellular or cell-mediated immunity – lymphocytes themselves
a.
Targets – virus or parasite-infected tissue cells, cancer cells, foreign
graft cells
b.
can act directly by lysing foreign cells or indirectly by releasing
chemicals that enhance the inflammatory response or activate other
lymphocytes or macrophages.
II.
Antigens
Antigens vs. Haptens:1. Antigens – substances that can mobilize the immune system and
provoke an immune response
a.
most large, complex molecules that are NOT normally present in
the body
b.
help distinguish “self” from “nonself”
2. Complete antigens
formation of specific
b.
a.
they have immunogenicity – the ability to stimulate
lymphocytes and antibody production
have reactivity – the ability to react with the lymphocytes and
antibodies
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Blood physiology by prof.Israa F.Jafar
c.
3.
antigens include nearly all foreign proteins, nucleic acids, lipids,
and many large polysaccharides.
proteins are the strongest antigens
d.
other antigens can be pollen grains or microorganisms
e.
generally small molecules like peptides, nucleotides, and many
hormones are NOT immunogenic
f.
these small particles can link with other substances though and
become immunogenic
allergies
Haptens – small molecules that are reactive but not immunogenic unless
attached to a protein carrier
Cytokines
Cytokines are hormone-like molecules that actto regulate immune responses. They are
secreted not only by lymphocytes and macrophages but by endothelial cells, neurons, glial
cells, and other types of cells. Most of the cytokines are initially named for their actions, eg,
B cell-differentiating factor, B cell-stimulating factor 2. However, there is a convention that
once the amino acid sequence of a factor in humans is known, its name is changed to
interleukin. Thus, for example, the name of B cell- differentiating factor was changed to
interleukin-4(IL4).
The effects of the principal cytokines Some of them have systemic as well as local effects.
For example, IL-1, IL-6, and tumor necrosis factor α cause fever, and IL-1 increases slowwave sleep and reduces appetite.
Another superfamily of cytokines is the chemokine family. Chemokines are substances that
attract neutrophils and other white blood cells to areas of inflammation or immune response.
The Complement System
The cell-killing effects of innate and acquired immunity are mediated in part by a system of
plasma enzymes originally named the complement system because they "complemented" the
effects of antibodies. Nomenclature for the over 30 proteins in the system is confusing
because it is a mixture of letters and numbers: examples include C1q, C3, and C3b. Three
different pathways or enzyme cascades activate the system: the classic pathway, triggered by
immune complexes; the mannose-binding lectin pathway, triggered when this lectin binds
mannose groups in bacteria; and the alternative or properdin pathway, triggered by contact
with various viruses, bacteria, fungi, and tumor cells. The proteins that are produced have
three functions: They help kill invading organisms by opsonization, chemotaxis, and eventual
lysis of the cells; they serve in part as a bridge from innate to acquired immunity by
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Blood physiology by prof.Israa F.Jafar
activating B cells and aiding immune memory; and they help dispose of waste products after
apoptosis. Cell lysis, one of the principal ways the complement system kills cells, is brought
about by inserting proteins called perforins into their cell membranes. The holes produced in
this fashion permit free flow of ions, with disruption of membrane polarity.
Innate Immunity
The cells that mediate innate immunity include neutrophils, macrophages, and natural killer
(NK) cells, large lymphocytes that are not T cells but are cytotoxic. All these cells respond to
lipid and carbohydrate sequences unique to bacterial cell walls and to other substances
characteristic of tumor and transplant cells. They exert their effects by way of the
complement and other systems, with the cells they attack frequently dying by osmotic lysis or
apoptosis. Their cytokines also activate cells of the acquired immune system.
Acquired Immunity
the key to acquired immunity is the ability of lymphocytes to produce antibodies that are
specific for one of the many millions of foreign agents that may invade the body. The
antigens stimulating antibody production are usually proteins and polypeptides, but
antibodies can also be formed against nucleic acids and lipids if these are presented as
nucleoproteins and lipoproteins, and antibodies to smaller molecules can be produced
experimentally when the molecules are bound to protein. Acquired immunity has two
components: humoral immunity and cellular immunity.
Humoral immunity is mediated by circulating immunoglobulin antibodies in the γ-globulin
fraction of the plasma proteins. Immunoglobulins are produced by B lymphocytes, and they
activate the complement system and attack and neutralize antigens. Humoral immunity is a
major defense against bacterial infections.
Cellular immunity is mediated by T lymphocytes. It is responsible for delayed allergic
reactions and rejection of transplants of foreign tissue. Cytotoxic T cells attack and destroy
cells that have the antigen which activated them. They kill by inserting perforins (see above)
and by initiating apoptosis. Cellular immunity constitutes a major defense against infections
due to viruses, fungi, and a few bacteria such as the tubercle bacillus. It also helps defend
against tumors.
Development of the Immune System
During fetal development, lymphocyte precursors come from the bone marrow. Those that
populate the thymus become transformed by the environment in this organ into the
lymphocytes responsible for cellular immunity (T lymphocytes).
humoral immunity (B lymphocytes the transformation to B lymphocytes occurs in bursal
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Blood physiology by prof.Israa F.Jafar
equivalents, ie, the fetal liver and, after birth, the bone marrow. After residence in the thymus
or liver, many of the T and B lymphocytes migrate to the lymph nodes and bone marrow.
Most of the processing occurs during fetal and neonatal life. However, there is also a slow,
continuous production of new lymphocytes from stem cells in adults.
T and B lymphocytes are morphologically indistinguishable but can be identified by markers
on their cell membranes. B cells differentiate into plasma cells and memory B cells. There
are three major types of T cells: cytotoxic T cells, helper T cells, and memory T cells.
There are two subtypes of helper T cells: T helper 1 (TH1) cells secrete IL-2 and γinterferon and are concerned primarily with cellular immunity; T helper 2 (TH2) cells
secrete IL-4 and IL-5 and interact primarily with B cells in relation to humoral immunity.
Cytotoxic T cells destroy transplanted and other foreign cells, with their development aided
and directed by helper T cells. Markers on the surface of lymphocytes are assigned CD
(clusters of differentiation) numbers on the basis of their reactions to a panel of monoclonal
antibodies. Most cytotoxic T cells display the glycoprotein CD8, and helper T cells display
the glycoprotein CD4. These proteins are closely associated with the T cell receptors and
may function as coreceptors.
Natural killer cells are also cytotoxic lymphocytes, though they are not T cells.
Memory B Cells & T Cells
After exposure to a given antigen, a small number of activated B and T cells persist as
memory B and T cells. These cells are readily converted to effector cells by a later encounter
with the same antigen. This ability to produce an accelerated response to a second exposure
to an antigen is a key characteristic of acquired immunity. The ability persists for long
periods of time, and in some instances (eg, immunity to measles) it can be lifelong.
After activation in lymph nodes, lymphocytes disperse widely throughout the body and are
especially plentiful in areas where invading organisms enter the body, eg, the mucosa of the
respiratory and gastrointestinal tracts. This puts memory cells close to sites of reinfection and
may account in part for the rapidity and strength of their response. Chemokines are involved
in guiding activated lymphocytes to these locations.
It had been argued that the long life of memory cells involves their repeated exposure to
small amounts of antigen. However, memory cells persist when infused into mice in which
the ability to process the antigen to which they are sensitive has been abolished by gene
knockout. It may be that they avoid apoptosis by taking up nerve growth factor in the
peripheral tissues.
Antigen Recognition
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Blood physiology by prof.Israa F.Jafar
The number of different antigens recognized by lymphocytes in the body is extremely large.
The recognition ability is innate and develops without exposure to the antigen. Stem cells
differentiate into many million different T and B lymphocytes, each with the ability to
respond to a particular antigen. When the antigen first enters the body, it can bind directly to
the appropriate receptors on B cells. However, a full antibody response requires that the B
cells contact helper T cells. In the case of T cells, the antigen is taken up by an antigenpresenting cell and partially digested. A peptide fragment of it is presented to the appropriate
receptors on T cells. In either case, the cells are stimulated to divide, forming clones of cells
that respond to this antigen (clonal selection).
Antigen Presentation
Antigen-presenting cells (APCs) include specialized cells called dendritic cells in the lymph
nodes and spleen and the Langerhans dendritic cells in the skin. Macrophages and B cells
themselves can also function as APCs. In APCs, polypeptide products of antigen digestion
are coupled to protein products of the major histocompatibility complex (MHC) genes and
presented on the surface of the cell. The products of the MHC genes are called human
leukocyte antigens (HLA).
The class I MHC proteins (MHC-I proteins) are coupled primarily to peptide fragments
generated from proteins synthesized within cells. The peptides to which the host is not
tolerant, eg, those from mutant or viral proteins, are recognized by T cells.
The class II MHC proteins (MHC-II proteins) are concerned primarily with peptide products
of extracellular antigens, such as bacteria, that enter the cell by endocytosis and are digested
in the late endosomes.
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Blood physiology by prof.Israa F.Jafar
n the upper pathway; foreign protein or antigen (1) is taken up by an antigen-presenting cell (2). The antigen
is processed and displayed on an MHC II molecule (3), which interacts with a T helper cell (4). In the lower
pathway; whole foreign proteins are bound by membrane antibodies (5) and presented to B lymphocytes (6),
which process (7) and present antigen on MHC II (8) to a previously activated T helper cell (10), spurring
the production of antigen-specific antibodies (9).
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Blood physiology by prof.Israa F.Jafar
Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.
T Cell Receptors
The MHC protein-peptide complexes on the surface of the antigen-presenting cells bind to
appropriate T cells. Therefore, receptors on the T cells must recognize a very wide variety of
complexes.
CD8 occurs on the surface of cytotoxic T cells that bind MHC-I proteins.
CD4 occurs on the surface of helper T cells that bind MHC-II proteins
The CD8 and CD4 proteins facilitate the binding of the MHC proteins to the T cell receptors.
The activated CD8 cytotoxic T cells kill their targets directly, whereas the activated CD4
helper T cells secrete cytokines that activate other lymphocytes.
B Cells
B cells can bind antigens directly, but they must contact helper T cells to produce full
activation and antibody formation. It is the TH2 subtype that is mainly involved. Helper T
cells are pushed along the TH2 line by the cytokine IL-4 .
On the other hand, IL-12 pushes helper T cells along the TH1 line. IL-2 acts in an autocrine
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Blood physiology by prof.Israa F.Jafar
fashion to cause activated T cells to proliferate.
The activated B cells proliferate and transform into memory B cells (see above) and plasma
cells. The plasma cells secrete large quantities of antibodies into the general circulation. The
antibodies circulate in the globulin fraction of the plasma (see below) and, like antibodies
elsewhere, are called immunoglobulins. The immunoglobulins are actually the secreted form
of antigen-binding receptors on the B cell membrane.
Immunoglobulins
Circulating antibodies protect their host by binding to and neutralizing some protein toxins,
by blocking the attachment of some viruses and bacteria to cells, by opsonizing bacteria and
by activating complement.
Five general types of immunoglobulin antibodies are produced by the lymphocyte-plasma
cell system. The basic component of each is a symmetric unit containing four polypeptide
chains The two long chains are called heavy chains, whereas the two short chains are called
light chains. There are two types of light chains, κ and λ, and eight types of heavy chains.
The chains are joined by disulfide bridges that permit mobility, and there are intrachain
disulfide bridges as well. In addition, the heavy chains are flexible in a region called the
hinge. Each heavy chain has a variable (V) segment in which the amino acid sequence is
highly variable, a diversity (D) segment in which the amino acid segment is also highly
variable, a joining (J) segment in which it is moderately variable, and a constant (C) segment
in which the sequence is constant. Each light chain has a V, a J, and a C segment. The V
segments form part of the antigen-binding sites (Fab portion of the molecule). The Fc portion
of the molecule is the effector portion, which mediates the reactions initiated by antibodies.
Two of the classes of immunoglobulins contain additional polypeptide components :
IgMs, five of the basic immunoglobulin units join around a polypeptide called the J chain to
form a pentamer.
IgAs, the secretory immunoglobulins, the immunoglobulin units form dimers and trimers
around a J chain and a polypeptide that comes from epithelial cells, the secretory component
(SC).
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Blood physiology by prof.Israa F.Jafar
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Blood physiology by prof.Israa F.Jafar
1. IgG - Gamma heavy chains
2. IgM - Mu heavy chains
3. IgA - Alpha heavy chains
4. IgD - Delta heavy chains
5. IgE - Epsilon heavy chains
Recognition of Self
A key question is why T and B cells do not form antibodies against and destroy the cells and
organs of the individual in which they develop. Current evidence indicates that self antigens
are presented along with nonself antigens but are then eliminated during development
(tolerance). Central tolerance occurs in the thymus for T cells and the bone marrow for B
cells. This is supplemented by peripheral tolerance occurring in the lymph nodes and
elsewhere in the body.
Autoimmunity
Sometimes the processes that eliminate antibodies against self antigens fail, and a variety of
different autoimmune diseases are produced. These can be B cell- or T cell-mediated and can
be organ-specific or systemic. They include type 1 diabetes mellitus (antibodies against
pancreatic islet B cells), myasthenia gravis (antibodies against nicotinic cholinergic
receptors), and multiple sclerosis (antibodies against myelin basic protein and several other
components of myelin). In some instances, the antibodies are against receptors and are
capable of activating receptors; for example, antibodies against TSH receptors increase
thyroid activity and cause Graves' disease . Other conditions are due to the production of
antibodies against invading organisms that cross-react with normal body constituents . An
example is rheumatic fever following a streptococcal infection; a portion of cardiac myosin
resembles a portion of the streptococcal M protein, and antibodies induced by the latter attack
the former and damage the heart. Some conditions may be due to bystander effects, in which
inflammation sensitizes T cells in the neighborhood, causing them to become activated when
otherwise they would not respond. However, much is still uncertain about the pathogenesis of
autoimmune disease.
Tissue Transplantation
The T lymphocyte system is responsible for the rejection of transplanted tissue. When tissues
such as skin and kidneys are transplanted from a donor to a recipient of the same species, the
transplants "take" and function for a while but then become necrotic and are "rejected"
because the recipient develops an immune response to the transplanted tissue. This is
generally true even if the donor and recipient are close relatives, and the only transplants that
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Blood physiology by prof.Israa F.Jafar
are never rejected are those from an identical twin.
A number of treatments have been developed to overcome the rejection of transplanted
organs in humans. The goal of treatment is to stop rejection without leaving the patient
vulnerable to massive infections. One approach is to kill T lymphocytes by killing all rapidly
dividing cells with drugs such as azathioprine, a purine antimetabolite, but this makes
patients susceptible to infections and cancer. Another is to administer glucocorticoids, which
inhibit cytotoxic T cell proliferation by inhibiting production of IL-2, but these cause
osteoporosis, mental changes, and the other stigmas of Cushing's syndrome . A third is
treatment with cyclosporine .
Other Clinical Correlates
As knowledge about the immune system has increased, over 50 immunodeficiency
syndromes due to abnormalities in the function of immune cells have been described. These
produce abnormalities ranging from a moderate increase in the incidence of infections to
severe, usually fatal conditions.
Malignant transformation can occur at various stages of lymphocyte development. Most if
not all cases of chronic lymphocytic leukemia are due to uncontrolled proliferation of B
lymphocytes, whereas multiple myeloma is due to malignant proliferation of clones of
mature plasma cells. Some cases of acute lymphocytic leukemia are T lymphocyte cancers.
Acquired immune deficiency syndrome (AIDS), a disease that is currently a major worldwide
problem, is unique in that HIV (human immunodeficiency virus), the retrovirus that causes
many cases of it, binds to CD4 and produces a decrease in the number of CD4 helper T cells.
The loss of helper lymphocytes leads in turn to failure of proliferation of CD8 and B cells,
with eventual loss of immune function and death from infections due to normally
nonpathogenic bacteria or cancer.
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