DERS KODU:3106 Doç.Dr.

Esin İleri Gürel

DERS TARİHİ: 04/11/2019

FUNCTIONS OF LEUKOCYTES (CONTINUED) AND FUNCTIONS OF PLATELETS

During the inflammation reaction a lot of
cytokines(Cytokines are small secreted proteins
released by cells have a specific effect on the
interactions and communications between cells)
released. Some of them are released from cells of the
immune system and invading microorganism (if
they’re found in the area of injury). Histamine is also
released. We see the vasodilation and increased
permeability of the vessel.

There are some sympthoms/signs of the

inflammation. There are 4 classical signs+1(5th one=
organ injury=at least organ or extremity cannot be
used anymore.)

Local signs:

Redness: Increase in blood flow due to vasodilation.

Heat: Increase in blood flow makes area warmer.
Swelling: Increased permeability of the vessels due to
the histamine causes edema.
Pain: There are 2 stimulations that cause pain

1)Mechanically: Edema changes the localizations

of the cells in tissue.
2)Chemically: Cytokines/chemical substances that
are produced in the inflammmated side. These
chemical substances stimulate free nerve endings.

Which sign is the most important one for the

doctor? PAIN.
Latin Words

Because other signs are more visible, easy to

recognise inflammation.Swelling or redness in your
liver or kidney is nonsense but the pain can be felt by
the internal organs so it is a sign which tells that
something is going wrong with the organ.So for
doctors pain is alarming, important factor.

DONT use any painkillers for abdominal pain if you

dont know the reason of it. Because only sign that
you have is pain so it is critical. You can follow
inflammation whether it is going on or not with the
help of the pain.(Lecturer said that if you dont know
anything about the lecture please know this!)
-Painkiller can be used for menstrual bleeding, kidney
stones (if it is known precisely).
In addition to local signs we also have systemic signs.

Leukocyte counting can be done in order to decide

whether there is an inflamation or not. Leukocyte
count is increased during inflammation.
Also plasma proteins that can act as acute phase
reactants (Fibrinogen, alpha2 macroglobulin etc)
increase in number during inflammation in plasma for
protection. We make ESR test (cheap, simple) in
order to understand whether these proteins increase
in number or not. If they’re increased in number
according to the test results,we can say that there is
inflammation. So one can simply say if sedimentation
rate is higher than normal, then patient might have
an inflammation. Fever is a systemic sign also.
In addition to its generalized innate
immunity, the human body has the
ability to develop extremely powerful
specific immunity against invading
agents which is called acquired or
adaptive immunity.

Acquired immune system uses B and T

lymphocytes.
1)Humoral immunity (B cells)
2)Cell-Mediated immunity (T cells)

So acquired immune system is highly

specific/specialised. Each individual T
or B cell recognizes only one particular
organism.
(On the other hand innate immune
system recognises general structure.)

Cells of the humoral immunity are B

lymphocytes. When B lymphocytes
meet the antigen they get activated
and turn into plasma cells (active form
of B lymphocytes which have huge
capacity to produce antibodies.)

Antibody production is the main

feature of the humoral immunity.
B lymphocytes produced in the bone
marrow.Then they leave as active
and mature cells but when they
expose to antigens they turn into
more mature/active cells.

Here you can see that B lymphocyte

differentiates into plasma cell. Also it
can be seen that the organels of
plasma cells are increased in number.
Also their function is enhanced
especially the ER’s for the secretion
of more proteins that are required for
antibodies.

When B lymphocytes are exposed to

antigens they turn into plasma cells
that produces antibodies ,at the
same time some B lymphocytes turn
into memory cells. Memory cells will
reside in body till you die. If you meet
with the same microorganism or
antigen again these memory cells will
produce antibodies against them in a
shorter time and higher amount in
order not to be sick due to the same
microorganism.
Here you can see the structure of the
antibodies.There are some variable
parts at the top. Also there are
constant parts.These constant regions
are in 5 types. (Only 5 different
structures of this region can be
defined.) So we have 5 different
types of antibodies :IgG/M/D/A/E

Lecturer will NOT ask the differences

btw these antibodies.

But here you see that IgM is

composed of 5 antibodies
(pentamer). It is large.As we learnt
that antibodies produced against A
and B antigens are IgM type(=A and B
antibodies are IgM type)It is because
A and B antibodies are big in size
they cannot pass from the placenta.
But as we learnt before IgG (antibody
of Rh ) is small so it can pass from
placenta and cause problems Rh
mismatch (D antigen mismatch)
Here we see how memory cell response:
After first exposure, lag phase is longer. But in
second it is shorter. Also it can be seen that
IgG response is very quick and higher in
amount.

Question from a student:What happens to the

plasma cells after their function is done?
Lecturer:They die i think but I will check the
information cause dont know it precisely.

T lymphocytes are produced in the bone

marrow. But when they leave the bone
marrow they are NOT mature cells.They are
transported to the thymus. Here, T cells divide
rapidly and exposed thousands of different
antigens. This process continues until there
are thousands of different types of T
lymphocytes with specific reactivities against
different antigens. The thymus also makes
certain that any T cell leaving thymus won’t
react any tissue or protein normally found in
body. After their differentiation and
maturatiıon in thymus they pass into
systematic circulation and they wait in organs
like spleen, lymph nodes etc.

Cytotoxic T cells are important for cell-

mediated immunity and they directly attack
and destroy the cells .
Helper T cells are important both for the
Cytotoxic T cells and B lymphocytes

Here you can see that we meet

an antigen. B lymphocytes turn
into plasma cells then they
begin to produce antibodies.
Cytotoxic T cells directly attack
to the injured, antigen bearing
cells. Helper T lymphocytes
produce cytokines/chemical
substances. These cytokines
activate the B lymphocytes so
that they can turn into plasma
cells. At the same time some
cytokines activate the Cytotoxic
T cells. So the function of
Helper T cell is very critical for
the adaptive immune system.If
you block Helper T cells,system
collapses (Antibodies cannot be
produced anymore,cannot
attack to injured cells that are
affected by viruses,bacteria
etc.) HIV (Human
Immunodeficiency Virus)
attacks only the Helper T-cells.
Previosly we classified the immune system as
innate and acquired.There are also other
classifications:
1)Active Immunity
2)Passive Immunity

Contracting a disease=Having a disease

Serum=Giving antibodies
Activated T lymphocytes=Cytotoxic T
lymphocytes

These two protect body until the own immune

system of the body is activated.

Serum and T lymphocytes have limited time for

protection.

Main difference between active and passive

immunity is memory cells.
But specificity is same.

Because these antibodies or T lymphocytes are

not produced by the own immunity of the body.

Link for the animation of immune system that is

recommended by lecturer to watch.
Platelets:
-Main function: plug the injured vessel
wall.
-are NOT cells. (they are cell fragments)
-are produced in bone marrow from a
giant cell(megakaryocyte)
-are small (diameter) (Lecturer reminded
the diameter of erythrocytes(7-8
micrometer))
-YOU HAVE TO KNOW THIS NORMAL
VALUE!!
-after 10 days they get old and they’re
destroyed especially in the spleen.
--If there is a need for coagulation
,thrombocytes are released from the
spleen into the circulation.
(Additional information: Remember from
last year’s histology labs ,giant cells are
found in spleen.)

You see the megakaryocyte

here.Cytoplasm fragments of this giant
cell called as the platelets.
In order to maintain functions
of platelets they need some
IMPORTANT structures.

Receptors are found on the

plasma membrane.

-This is an organel like ER

-Residue of ER that is seen
megakaryocyte
-stores calcium
-Cyclooxygenase is an enzyme
that is especially found in this
organelle
-Cyclooxygenase is used for
production of thromboxane A2
-Main function of
thromboxane A2 is
vasoconstriction.
Because if there is a vessel
injury, firstly we want to
decrease the loss of blood
-Invagination of the plasma membrane

-Aim of the invagination is to increase

the surface area of the thrombocytes.

-Receptors are very critical to make a

platelet plug.They are the precursors of
clot formation.Firstly they form
platelet plug then this area converted
into clot.

Granules =Vesicles

-Alpha granules contain a lot of

chemical substances but DO NOT
MEMORISE any of them in detail .but
you should know that there are
coagulation proteins,mitogenic
factors,membrane specific proteins etc.
-All of these chemical substances are
necessary for the activation of the
thrombocytes.
Some of the molecules that are
found in alpha granules are
synthesized in megakaryocytes

vWF=von Willebrand factor

PF4=platelet factor 4

But some of them are taken from

the plasma/circulation and stored
in the alpha granules.

DENSE GRANULES:
-Less in number
-Small in size
-Easy to distinguish under
microscope
-its content is limited compare to
the alpha granules.
YOU HAVE TO KNOW
THESE MOLECULES.All of
these molecules are
released from the dense
granules and increase the
activation,adhesion and
aggregation of
thrombocytes.
Question from a student:Can we
consider the secretion of the dense
granules as paracrine or autocrine
secretion bcs they are both
thrombocytes (secretor and the
affected)?
Lecturer:Yes.It can be called as both
of them.
Lecturer said we don’t have to
memorise these weird names for
her lecture but in TUS ,they ask
these particular names.Lecturer said
that she will use general names like
fibrinogen receptor if she asks these
receptors in exam.
Tip from lecturer in order to
memorise:
Ia/b : responsible for the 1st
step(adhesion)
IIb/III a :responsible for the 2nd
step(aggregation)
Collagen receptors and von Willebrand receptors are used for attachment of thrombocytes to the vessel
wall.(THESE TWO ARE FOR THE ADHESION)

And Fibrinogen protein is needed for the attachment of thrombocytes to each other.(THIS ONE IS FOR THE
AGGREGATION)

1)Adhesion: Attachment of two different structures. Ex:adhesion of leukocytes /thrombocytes to the

endothelial/vessel wall. Firstly adhesion occurs then aggregation starts.

2)Aggregation:Attachment of the same cells .Ex:Aggregation of RBC/thrombocytes.Happens after the

adhesion.

Collagen is found in connective tissue/under

endothelial cells/under basal membrane.
If there is no vessel injury,RBC/thrombocytes
cannot meet with the collagen. Exposure can
only happens if there is an injury. So in this
image vessel wall is injured and collagen is
exposed. As a result thrombocyte binds to
collagen fiber via collagen receptor. You will
see that for the binding of thrombocyte
receptor to any molecule sometimes we need
activation of receptor,conformational change
in this molecule.BUT HERE WE DONT NEED
ANY OF THESE (neither activation nor
conformational change).RECEPTOR(IA) IS
ACTIVE AND WHEN IT MEETS WITH
COLLAGEN IT BINDS INSTANTLY. We need this
attachment btw collagen and thrombocyte for
the injury side of the vessel.

-vWF binds to vWR

QUESTION FROM LECTURER:In normal
condition of the circulation do thrombocytes
meet with the vWF? YES because they have
plasma concentration due to the perpetual
secretion of the endothelial cells.(Explained
in the next slide.)So why they dont bind to
each other to make platelet plug/what is the
inhibition mechanism? Normally vWF cannot
bind to its receptor on the thrombocytes
because its structure is NOT suitable. But
when there is a vessel wall injury, when
collagen is exposed, vWF binds to the
collagen.NOW WE SEE A CONFORMATIONAL
CHANGE IN THE vWF. This change in the
structure of this molecule now gives
permission to the binding of thrombocyte
and vWF. Again it is neccessary for the
formation of the platelet plug.(adhesion)
-2nd receptor that we need for the adhesion of
the thrombocytes.
-vWF is found in the plasma and also it is stored
in thrombocytes.So there are 2 sources of the
vWF.
-Endothelial cells produce the vWF ,then they
release it to the plasma (origin of the vWF of the
plasma). Also endothelial cells store vWF in
themselves. These bodies are called as Weibel-
Palade bodies. When there is an injury in the
vessel wall/when the endothelial cells are
injured they release these bodies,as a result
vWF amount is increased in this local
area.Normally/in a routine process endothelial
cells release vWF into the plasma all the time
so we have a concentration of vWF in blood.
Also megakaryocytes can synthesize vWF,and
these are packed in the alpha granules when
thrombocytes tear apart from the plasma of the
megakaryoctes they stay in the
thrombocytes.During the activation of the
thrombocyte,vWF is secreted agaian in order to
increase the local concentration in the injury
side.

Another important function of the vWF :It is

the carrier of Factor 8/FVIII (one of the
important coagulation factor).

vWF has dual function

1)Related to the formation of the platelet
plug(for attachment of thrombocytes to the
vessel wall)
2)Coagulation proteins

Lastly we need the aggregation of the

thrombocytes.(attachment to each other)
Fibrinogen is also found in plasma in normal
condition.(%4 in all plasma proteins)
QUESTION FROM LECTURER:Why these
fibrinogens do not bind to thrombocytes in
normal conditions?Again the activation is
needed.
Different feature from the previos one,NOW
CHANGING COMPONENT IS THE RECEPTOR.
When thrombocytes bind to the vessel wall at
injury side; their plasma membrane, fibrinogen
receptor begin to change.Now it is avaliable for
binding of the fibrinogen.
 SUMMARY Activation Conformational Change
(Additional)

Collagen No Activation No conformatinal change

(Adhesion)

vWF + +( in molecule/vWF)
(Adhesion)

Fibrinogen + +(in receptor on thrombocyte)

(Aggregation)

Answer is E.
vWF receptor allows adhesion btw thrombocytes and vessel wall.
ANSWER İS C: Memory cells are responsible for active
immunity.

İSS
Answer is E: vWF is responsible for adhesion/adherence
during platelet plug formation.