- Types of blood cells -
Human blood is composed of both cellular and
liquid components. It is a specialized connective
tissue in which living blood cells, called the
formed elements, are suspended in a nonliving
fluid matrix called plasma. ● Eosinophils are approximately the size of neutrophils. Their
nucleus usually resembles an old-fashioned telephone
55% of the blood is plasma, which is the
receiver-it has two lobes connected by a broad band of
extracellular matrix.
nuclear material.
- 90% of plasma volume is composed of water
- 8% of plasma volume is composed of plasma proteins, which The granules in the cytoplasm of the eosinophils are
all contribute to osmotic pressure and maintain the water lysosome-like and filled with a unique variety of digestive
balance. enzymes. However, unlike typical lysosomes, they lack
● Albumin: 60% of plasma proteins -> main contributor to enzymes that specifically digest bacteria.
osmotic pressure The most important role of eosinophils is to lead the
● Globulins: 36% of plasma proteins -> Alpha, beta & counterattack against parasitic worms that are too large to be
gamma phagocytized. The eosinophils gather around and release
● Fibrinogen: 4% of plasma proteins -> form fibrin threads enzymes from their cytoplasmic granules onto the parasite’s
of a blood clot surface, digesting it away.
- Rest is composed of organic molecules, such as amino acids,
Eosinophils have complex roles in many other disease
hormones (steroid & thyroid), lipids, ions, nitrogenous waste
including allergies and asthma.
(urea, uric acid, creatine, and ammonium salts), vitamins,
dissolved oxygen & carbon dioxide, and electrolytes (Na+, K, ● Basophils contain large, coarse, histamine&heparin
Ca, H+) -containing granules in their cytoplasm. Heparin is a blood
thinning substance and histamine is an inflammatory
Leukocytes chemical that acts as a vasodilator and attracts other WBCs
Leukocytes, or white blood cells (WBCs), are the only formed elements
to the inflamed site.
that are complete cells, with nuclei and the usual organelles. They are
Basophils are not antigen-specific!
specialized cells that can defend our body from pathogens such as
bacteria, viruses, parasites, toxins, and tumor cells. Agranulocytes (myeloid or lymphoid)
Leukocytes can move against the flow of blood and can slip through Agranulocytes include lymphocytes and monocytes, are WBCs that
the walls of the capillaries and enter our tissue through a process lack visible cytoplasmic granules.
called diapedesis. ● Lymphocytes (lymphoid) typically have a large, dark-purple
nucleus that occupies most of the cell volume. Relatively few
Leukocytes are grouped into two major categories on the basis of
are found in the bloodstream. In fact, lymphocytes are so
structural and chemical characteristics:
called, because most are closely associated with lymphoid
Granulocytes (myeloid)
tissues, where they play a crucial role in immunity.
Granulocytes, which include neutrophils, eosinophils, and
- T lymphocytes (T-cells) function in the immune response
basophils. refer to cells characterized by the presence of granules
by acting directly against virus-infected cells and tumor
in their cytoplasm and by their lobe-shaped nuclei. Functionally, all
cells. They produce cytokines and are cytotoxic.
granulocytes are phagocytes to some degree
- B lymphocytes (B-cells) give rise to plasma cells, which
● Neutrophils are the most numerous WBCs and are about twice produce antibodies (immunoglobulins) that are released
as large as erythrocytes. The cytoplasm contains very fine to the blood. They are antigen-presenting cells (APCs).
granules that are difficult to see. - Natural killer cells, also known as NK cells or large
Neutrophils are chemically attracted to sites of inflammation granular lymphocytes (LGL), are a type of cytotoxic
and are active phagocytes that target bacteria and fungi. lymphocyte critical to the innate immune system. (not
specific, and kill everything they find)
Neutrophils can also make Neutrophil Extracellular Traps
(NETs), which are a platform for platelet adhesion and
coagulation reactions. (puss contains of dead neutrophils
from the NETs). Neutrophils release their DNA (chromatin) to
make the NETs. This occurs by active and passive processes.
These NETs can induce and propagate thrombosis.
,● Monocytes (myeloid) have abundant pale-blue cytoplasm Platelets are essential for the clotting process that occurs in plasma
and a darkly staining purple nucleus, which is distinctively U or when blood vessels are ruptured or their lining is injured. By sticking to
kidney shaped. the damaged site, platelets form a temporary plug that helps seal the
when circulating monocytes leave the bloodstream and enter break. Because they are anucleate, they age quickly and degenerate
the tissues, they differentiate into highly mobile macrophages in about 10 days if they are
with prodigious appetites. Macrophages are actively not involved in clotting.
phagocytic and are crucial in the body’s defense against
viruses, certain intracellular bacterial parasites, and chronic
infections, such as tuberculosis.
Monocytes can also differentiate into dendritic cells. Dendritic
cells are antigen-presenting cells (APCs). Dendritic cells
recognize and capture antigens, then migrate to secondary
lymphoid tissues where they present the antigens to
lymphocytes, which in turn activate them. Dendritic cells can
also be found in the skin as Langerhans cells.
Inflammation
Inflammation is a local response to cellular injury that is marked by
Monocytes are also involved in the production of cytokine
capillary dilatation, leukocytic infiltration, edema, redness, heat, and
protein molecules (such as histamine), which carry signals
pain. It serves as a mechanism initiating the elimination of noxious
between cells.
agents and of damaged tissue.
The leukocytes in order from most abundant to least abundant:
Inflammation vs infection:
Never Let Monkeys Eat Bananas (neutrophils, lymphocytes, 1. inflammation -result of infection.
monocytes, eosinophils, basophils) e.g. handyman cuts finger -> fingertip = red, swollen & warm
2. (Bacterial) infection - due to bacteria or viruses.
(complement activation + pus formation)
e.g. after few days -> swelling = increased, yellow & fluctuates
Characteristics
These characteristics reflect four changes in local blood vessels.
1. The heat and redness during inflammation are the results of an
Erythrocytes increase in vascular diameter. The increase in vascular
Erythrocytes, or red blood cells are small cells, shaped
diameter also results in slower blood flow (less resistance).
like biconcave discs-flattened disc with depressed
2. There is also an increase in vascular permeability. The
centers. They appear lighter in color at their thin centers than at their
endothelial cells that line the blood vessel walls are usually
edged.
packed tightly together, but during inflammation, they have
Erythrocytes lack a nucleus and have essentially no organelles (no gaps between them. This results in fluid from the blood exiting
mitochondria). In fact, they are little more than ‘bags’ of hemoglobin, and accumulating in the local tissues, and this results in edema
the RBC protein that functions in gas transport. Hemoglobin binds and pain. The fluid contains plasma proteins such as
easily and reversible with oxygen. complement proteins and mannose binding lectin, which aid in
defending against pathogens.
Platelets
Platelets, also known as thrombocytes, are not cells in the strict sense.
They are cytoplasmic fragments of extraordinarily large cells called
megakaryocytes. `
During thrombopoiesis, megakaryocytes develop into platelets. This
happens in the bone marrow and is caused by the breakdown of
3. Endothelial cells, which line the walls of blood vessels, are
proplatelets. During the process, almost all membranes, organelles,
‘activated’ during inflammation. That is, endothelial cells
and granules in the cytoplasm are being consumed. Apoptosis plays
express cell-adhesion molecules that promote the binding of
a role in the final stages by letting the proplatelet process to occur
circulating leukocytes.
from the cytoskeleton of actin. Once in circulation, the proplatelets
4. There is clotting in the microvessels at the site of infection,
disintegrate into platelets. A hormone called thrombopoietin regulates
which prevents pathogens from spreading via the blood.
the formation of platelets.
In blood smear, each platelet exhibits a blue-staining outer region
and an inner area containing granules that stain purple. The granules
contain an impressive array of chemicals that act in the clotting
process, including serotonin, calcium, a variety of enzymes, ADP, and
platelet-derived growth factor (PDGF).
,Purpose This is where the first step of leukocyte extravasation starts:
The purpose of the inflammatory response is threefold: Step 1 - rolling adhesion
1. Allows the body to defend itself from invading microorganisms. The initially weak adhesion between leukocytes and the vascular
The increase in vascular diameter, along with the activated endothelium involves selectins. The two important types of selectins
endothelial cells, results in leukocytes being able to attach to the are P-selectin and E-selectin.
endothelium, and then migrate into the tissues where they can These are transmembrane proteins that bind specific carbohydrate
attack pathogens (explained in next learning goal). groups. Selectins are expressed on activated endothelium. They allow
2. Induces local blood clotting. This creates a physical barrier the leukocytes to adhere reversibly to the vessel wall. So they can roll
preventing the infection from spreading into the bloodstream. along the endothelium.
3. Promotes the repair of injured tissue.
P-selectin appears within minutes of inflammation, while E-selectin
Cause appears a few hours later. E-selectin recognizes the sulfated
The state of inflammation is set up when Sialyl-LewisX moiety of certain leukocyte glycoproteins.
tissues are physically damaged, or when Leukocytes have ligands that can bind the selectins:
pathogens are recognized by macrophages - E-selectin ligand 1 (ESL1) binds E-selectin
and later by other leukocytes. - P-selectin glycoprotein ligand-1
(PSGL-1) binds P-selectin
These circumstances induce the release of a variety of inflammatory However, these bindings are very weak.
mediators, which cause the inflammatory response.
Macrophages and neutrophils secrete prostaglandins, leukotrienes,
and platelet-activating factor (PAF), which are lipid mediators of
inflammation. These are produced rapidly because they are made
from degraded membrane phospholipids.
Then, macrophages secrete cytokines1. One kind of cytokine is
chemokines2, which act as chemoattractants. Chemokines cause
Step 2 - tight binding
directed chemotaxis, which is the movement of cells or parts of cells in
The binding between the selectin ligands on the leukocyte and the
a direction corresponding to a gradient of increasing or decreasing
selectins on the endothelial cells is very weak. To stop the rolling
concentration of a substance. In this case of chemokines, they direct
adhesion and for the selectin to bind its ligand tighter, two things have
phagocytes to move towards the source of the chemokines, which is
to happen:
where they are needed.
1. Chemokines increase the affinity of integrins LFA-1 (also known
-Blood cell transportation to the as αLβ2) and VLA-4 on leukocytes (MAC-1 (also known as CR3
or αMβ2) binds fibrin)
site of injury - 2. Cytokines increase the expression of ICAM-1 and VCAM-1 on
Leukocytes perform most of their functions in tissues. To do this, the endothelial cells
leukocytes have to migrate from the vessels to the tissue. ICAM-1 on endothelial cells then binds LFA-1 on leukocytes, and
Leukocyte extravasation, also known as leukocyte adhesion cascade VCAM-1 on endothelial cells then binds VLA-4 on leukocytes.
of diapedesis, is the movement of leukocytes out of the circulatory When these cytokines and chemokines bind to each other, they signal
system and towards the site of tissue damage or infection. the cell to trigger a conformational change in the integrins on the
Usually, leukocytes travel in the center of blood vessels, since this is rolling leukocyte. greatly increasing
where blood flows the fastest. So the first step of leukocyte the adhesive abilities of the leukocyte.
recruitment into infected tissues is dilation of blood vessels, resulting As a result, the leukocyte can attach
in slower blood flow. This allows leukocytes to interact with the firmly to the endothelium, and the
vascular endothelium. rolling stops.
Leukocytes actually need to stick to the vessel walls:
During inflammation, cytokines cause changes in adhesion
molecules on endothelial cells and leukocytes. Step 3 - diapedesis
First, monocytes (which are now macrophages or dendritic cells) In this step the leukocyte extravasates (crosses) the endothelial wall.
release cytokines: TNF-alpha and IL-1. These cytokines act on This again involves the leukocyte integrins as well as further adhesive
endothelial cells to activate P-selectin and E-selectin. interactions involving an immunoglobulin-related molecule called
PECAM (CD31). It is expressed both on the leukocyte
and at the intercellular junctions of endothelial cells
1
Cytokines - substances secreted by cells of the immune system that affect other
(like a stretching spring).
cells
2
Chemokines - type of cytokine that induce direct movement of cells
, Next, the leukocyte ‘crawls’ through the junctions Step 2 - platelet plug formation
between the endothelial cells. The leukocyte follows
This step is also part of the primary hemostasis. In this step,
the concentrations of chemoattractant to the
platelets play a key role in hemostasis by aggregating (sticking
highest concentration (where the microbe is).
together), forming a plug that temporarily seals the break in the
When the leukocyte is at the site of tissue damage,
vessel wall.
it can e.g. phagocyte the microbe.
Intact endothelial cells release nitric oxide and a prostaglandin
called prostacyclin (or PGI2). Both chemicals prevent platelet
aggregation in undamaged tissue and restrict aggregation to the
site of injury. Nitric oxide and prostacyclin are also vasodilators, so
they make sure that vasospasm does not occur.
However, when the endothelium is damaged and the underlying
collagen fibers are exposed, platelets adhere to the collagen fibers.
This is done as follows:
○ Glycoprotein Ib (GPIb) is a platelet receptor with a critical role
in mediating the arrest of platelets at sites of vascular
damage.
Monocytes also use this process in the absence of infection or tissue
○ Glycoprotein IIb/IIIa (Gp2b3a), also known as integrin αIIbβ3, is
damage during their development into macrophages. They do so
an integrin complex found on platelets. It is a receptor for
when they adhere to ICAM-2, which is expressed at low levels by
fibrinogen and von Willebrand factor (vWF) (‘glue’) and aids
unactivated endothelium.
platelet activation (autocrine feedback -> platelets activate themselves).
Blood clot formation Both these receptors bind to the vWF. vWF then also binds to the
collagen, forming a bridge between collagen and the platelets.This
Normally, blood flows smoothly past the intact blood vessel lining
is known as platelet adhesion. When the platelets are activated,
(endothelium). But if a blood vessel wall breaks, a whole series of
they change shape.
reactions are set in motion to accomplish hemostasis, which stops
This is when degranulation begins. The granules inside the platelets
the bleeding. During hemostasis, three steps occur in rapid
get released into the blood. One of these granules is called the
sequence: Vascular spasm - Platelet plug formation - Coagulation
alpha granule. Inside this granule, there are two substances:
(blood clotting). Following hemostasis, the clot retracts. It then
1. Fibrinogen, which is used in secondary hemostasis
dissolves as it is replaced by fibrous tissue that permanently
2. Von Willebrand factor
prevents blood loss.
A smaller granule, called the Dense granule also releases
substances into the blood:
1. Serotonin, which is a constrictor of the smooth muscle cells
and will enhance the vascular spasm.
2. Adenosine diphosphate (ADP) - a potent aggregating agent
Step 1 - vascular spasm that causes more platelets to stick to the area and release
This step is part of the primary hemostasis. In the first step, the their contents.
damaged blood vessels respond to injury by constricting 3. Calcium, which is necessary for several steps of the
(vasoconstriction). Factors that trigger this include: coagulation cascade
➢ direct injury to vascular smooth muscle = myogenic
Think of Dense SAC: Serotonin, Adp, Calcium
mechanism
➢ chemicals (endothelin) released by endothelial cells and Another thing the platelet does, is release thromboxane A2 , which
platelets -> endothelin binds onto receptor on smooth muscle, is the exact opposite of prostacyclin. Thromboxane acts on smooth
which leads to contraction. muscle cells to cause vasoconstriction, it also causes more
➢ Nociceptor activation (reflexes initiated by local pain platelets to activate, and it helps with aggregation.
receptors) The final step of primary hemostasis is platelet aggregation, which
The spasm mechanism becomes more and more efficient as the is mediated primarily through Gp2b3a. The activated platelet
amount of tissue damage increases and is most effective in the causes the 2b3a receptor to change to a shape, that allows it to
smaller blood vessels. bind to fibrinogen. Through fibrinogen binding, many 2b3a
The spasm response is valuable because a strongly constricted receptors from many platelets bind together and create the
artery can significantly reduce blood loss for 20-30 minutes, clumping and the platelet plug.
allowing time for the next As more platelets aggregate, they release more chemicals
two steps to occur. (platelet activation), aggregating more platelets, and so on, in a
positive feedback cycle. Within a minute, a platelet plug is built up,
