IMMUNOLOGY
Nanda E.S Sejati
Bismillahirrahmanirrahim
Commensement
Immunology
is study of the immune system, which immune system itself is a mechanism in our
body (not only human basicly) to defense us from threat that can disrupt our
balance system (homeostatis) even can lead to death.
Immune
system consist of some cells correlate together to maintain and protect our
body from invasion of harmful molecules such as virus, microbe, parasite, and etc. The
main actors that role in cell immune system is macrophage, white blood cells,
and lymphocyte (actually lymphocyte is part of white blood cells, hehe). Here i wanna talk a lot about lymphocyte.
Lymphocyte is formed by hemapoietic stem cells in the bone marrow. Lymphocyte
consist of two cell they are B cells and T cells. But to become active T cells and B cells
lymphocyte must through some mechanism. In mammals, after created from hemapoietic
stem cells, lymphocyte flow together with blood into place where they will be
matured. In thymus, lymphocyte will
become lymphocyte T cells, so thymus called as primary lymphoid organ. After
it, lymphocyte T cell will bring to lymph node to become T cell, so lymph node
was called secondary lymphoid organ. B cells has different mechanism of
maturing . In mammals and human, to become B cells, firstly Lymphocyte would
matured in Lymphocyte B cells in bone marrow. But in birds, lymphocyte will
become lymphocyte B cell in Bursa of Fabricius so Bursa of Fabricius called as
primary lymphoid organ in birds. After Being Lymphocyte T and Lymphocyte B,
they will save in lymph node, and become T cells and B cells, T cells was saved
in paracortex and B cells was saved in cortex of lymph node.
So How T cells and B cells circulate in our
body to do their function?
When
lymphocyte B and Lymphocyte T in the blood meet with lymphoid node, they will
get some mechanism to entering them into lymph node. This mechanism depend on
two part, specialized endhotelial cell or “post capilarry high endhotelial
venules” in blood vessel and homing receptor that located in surface of
lymphocyte cell. Lymphocyte contain of protein-adhesion-molecule that construct
the homing receptor, they are two different protein construct the each
receptor, so there are two different type of receptor in lymphocyte B/T cells.
And in specialized endhotelial cells, there are ligand that will bind to the
receptor. First receptor from lymphocyte cell that will bind the ligand is
constructed by E-selectin. This receptor give weak binding force to the ligand,
so it allow the lymphocyte cell to rolling (bergulung-gulung) in endhotelial
cells until rapid change occur because the ligand bind the second receptor that
construct by Integrin, it will give strong power so the lymphocyte cell will
pushed enter the membrane of blood vessel into lymph node. Here, the Lymphocyte
B and Lymphocyte T will matured in different place. Although there are many
blood cell meet with this endhotelial cell, only the lymphocyte cells can enter
because other cell dont have receptor like lymphocyte cell. After lymphocyte
become T cell and B cell, they will circulate in lymph vessel to all part of
the body. T cells and B cells walk out from their maturing place / node through
medullary sinus (Now, i realize that
every building of our body although it has micron or nano size or very simple
form, it has a meaning) and then they will distribute through efferent
lymph vessel, Because there are not only one lymph node, this efferent vessel
from one lymph node will meet together with other efferent lymph vessel and
create larger, and larger lymph vessel until they reach ductus thoracicus, in here, they will spread out from lymph vessel
into blood vessel and from blood vessel into lymph vessel (afferent lymph
vessel) again. So ductus thoracicus acts like a “station” for lymphocyte
traffic.
Clonal Selection Theory
Actually we
have million of different lymphocyte cells. One lymphocyte is only for one
antigen. But, we should know what is antigen first. Antigen is a molecule/agent
that can do a function which influence in our body mechanism and can make a
Lymphocyte response (both of T cell and B cell). Protein, polysaccharide,
virus, microbe, parasite, and drugs can present antigen. Antigen is divided in
two category, they are self-antigen and foreign antigen. Remarkably, Normal
Lymphocyte can recognize which one self-antigen, which one foreign antigen,
although there just only small difference. For instance, antigen that have one
different stucture of amino acid from self-antigen can be categorize as foreign
antigen and will destroyed, or antigen that has same structure with self-antigen
but differ in their orientation (khiral) will recognize as foreign antigen. What be a question is how lymphocyte can be so
specific and how they develope to recognize an antigen. Then there arise theory
that called “clonal selection theory”, why use “clone” term? Yes, because
lymphocyte was divided into clones, each clone is specific for one kind
antigen. Its mean that there are million of lymphocyte clone. This theory also
stated that lymphocyte mainly B cell that secreted antibody, it was created
before invading of antigen. In other word, antibody has prepared their self to
bind an antigen although they never meet with that antigen before, not adapted
their stucture for an specific antigen after they exposed with this antigen. In
simply word, They are “prepared” .
Subhanallah...
How
lymphocyte can differentiate self-antigen and foreign-antigen? There are two
theory that state about how lymphocyte can discriminate foreign antigen and
self-antigen. First theory say that lymphocyte was not code for recognizing
self-antigen, so they never know that in the body also have self-antigen/host
antigen. The second theory say that actually lymphocyte can recognize both of
host-antigen or foreign-antigen, but they learn which should to destroy and
which should not to destroy. This can be proven by some experiment using
skin-graft of two mouse that still in one family. This learning process happen
daily from when the lymphocyte firstly formed until an organism die. If some
host-antigen are taking from this organism, and this organism doesnt have this
host-antigen for several month. When this host-antigen given back to that
organism, it willl recognized as foreign-antigen and will destructed by
lymphocyte (especially antibody that secreted from B cells). So its like a
friendship between Lymphocyte and Host-antigen. In javanese proverb “Jalaran tresno soko kulino” ^.^
Actually
there are lymphocyte that have ability to destroy self-antigen, its call
self-reactive lymphocyte, but in learning process. They are killed (clonal
depletion) or inactivated (clonal anergy). If lymphocyte can not discriminate
the foreign-antigen and self-antigen, it can lead to severe condition like lupus or the worst is die.
Lymphocyte is like neuron, can remember
Lymphocyte
is remarkably cells, not only they can recognize antigen in high specifically,
they also can remember like neuron cells. This characteristic is now used to
immunization program. When lymphocyte firstly created, it call virgin lymphocyte. After they expose by
its antigen, they will through two condition. Some of them can be directly
activated so it wll be activated cells and several of them will be mature cells. Mature cells is not a
lymphocyte cell that will do different mean in response antigen, mature cell is just conditiion, whereas cell
is more ready in responsing the next antigen if they expose again, they will be
active cell quickly. More quick than virgin cell to active cell. Virgin cell
and mature cell can save in the body for a long time ( month to years) but activat
cells have short time period, just several days.
Each Antigen has different antigenic
determinant
Antigenic
determinant is part of antigen that bind to antigen-binding site receptor from
antibody (from B cell) or T cells. Every antigen has distinctive antigen
determinant. Antigene determinant also called Epitope
Lymphocyte consist of T cell and B cells
As we talk
before, lymphocite is consist of T cell and B cell, They are matured in
Secondary lymphoid organ that is lymph node. Actually T cell and B cell has
similar shape when they are not bind with antigen, but they will become
different after bind with antigen. T cell and B cell has different function. T
cell has main function as a mediator in antigen present, they will secrete
mediator signal such lymphokine, interleukine and cytokine. But B cell has
function to secreting antibody for again foreign-antigen molecules. Okay, now
let me to talk first about B cells.
B cells
B cell has a
function to secrete antibody. The simplest antibody is “Y” shape. I dont wanna talk to much about the antibody
structure. They have 2 antigen binding site and tail Between antigen-binding site and tail was
conneted by “Hinge”. Hinge help
antigen-binding-site can move more flexible. Where this antigen binding site is
very variable and polymorphic and tail has function inassociated with complement that will explain later. This
antigen binding site is consist by Light chain and Heavy chain chain. Light
chain and Heavy chain coding by separate exons. There are only two segment gene that code for
antigen-binding-site of light chain, this gene is variable segment (V) and Join
gen (J). And there are three segment that encode for heavy segment, they are
variable gene (V), Diversity gene (D) and join gene (J). There are 5 class
antibody in high vertebrate. They are IgA, IgE, IgG, IgM, and IgD. kind of this immunoglobulin was categorized
by their heavy tail chain type. A for alpha, D for delta, E for Epositon, G for
Gama, and M for Mu. Special for IgG they will divide again into subclass. IgG1,
IgG2, IgG3, igG4, igG5.
How Antibody destruct antigen that enter
the body?
When B cells
expose to antigen, they will secrete clones of antibody that specific antigen.
Actually B cells will co-operate with T cell to recognize antigen ( I will
elaborate it later). Antibody will recruit molecule called complement to incorporate with them in diminishing antigen from the
body. Complement consit of about 20 soluble protein that made by the liver.
Firstly they were inactive form. And they will be activated by antibody-antigen
present or microbe that have polysaccharide envelope. So it has two pathway of
activation, there are classical pathway (antibody-antigen) and alternative
pathway (microbe polysaccharide). When complement active, it become early complement component. early complement component will activate
central complement component (C3). C3
is the axis of other reaction. Early complement and C3 is a pro-enzyme.
Activating C3 and early complement is by cleaving them into several fragment.
The larger fragment of C3 cleavage is C3b. it will bind covalently to target
cell membrane, C3b act not only as the protease but also attract other phagocyte
molecule like macrophage and neutrophil to bind it via receptor-binding. The
smaller fragement of C3, C3a act independently by diffusing into inner part of
target cell and giving inflamatory signal.
C3b induce
some chain reaction by forming themselves into late complement component. C3b will bind with C5, C6, C7, and C8.
And to form membrane-attact-complex. They
will bind to C9. C9 will inserted into target cells membrane. And C9 will bound
other C9 again and again, this reaction happen continously and give a hole in
membrane of target cell. So the target cell will lose their membrane
consitence, and the cell will degrade.
(courtesy of
Molecular biology of the cell)
This picture
is ilustrate the explanation in before paragraph.
T CELL
T cell has
different mechanism in response to antigen, instead of secrete antibody, T cell
dirrectly bind to the targen cell membrane cell surface. T cell consist of two
type, they are Cytotoxic T cell and Helper T cell. Cytotoxic T cell has role in
infected cell’s killing and Helper T cell has role like a mediator for other
cell, it will mark which cell must be destroy. They ( cytotoxic and helper)
have different site of action. Cytotoxic cell mainly act in whole cell, that
vulnerable infected by cell. Otherwise Helper T cell work in extracellular
fluid (plasma, synovial, cerebrospinal) that are not reached by cytotoxic T
cell and also in antigen-presenting cell like macrophage, B cell, Langerhans
cell in skin, and interdigitating dendritic cell
How does Cytotoxic T cell work?
As we talk
in before paragraph, T cell doesnt secrete antibody but they dirrectly bind to
the target cell. Actually both of Cytotoxic
T cell and Helper T cell recognize an antigen in the peptide for. Both
of Cytotoxic T cell and Helper T cell cannot individually to the antigen.
Instead they need other help from molecule called “MHC molecule”. MHC molecule
is Major Histocompabillity complex. This molecule will serve antigen into T
cell (cytotoxic or herper) to recognized. MHC molecule is different between which it
that help cytotoxic T cell and which it that help helper T cell. MHC molecule
which incorporate with Cytotoxic T cell is called class 1 MHC molecule. And MHC
molecule which incorporate with Helper T cell is called class II MHC molecule.
They are have different stucture. But now, i will explain about Class I MHC
molecule incorporate with cytotoxic T cell
a.
Class
I MHC Molecule
The stucture
of class I MHC molecule is constructed by single stranded of alpha chain ( α1,
α2,
and α3).
α3 will associated with β-microglobulin to create
antigen binding site, this stucture is antibody-like antigen binding-site. This
molecule was formed in reticulum endoplasm. They will bind fragment of peptide
foreign antigen, bring them to surface membran for serving to cytotoxic T cell
to recognize. Peptide was met with class I MHC molecule in Endoplasmic
Reticulum. They are entered to the ER by ABC-Transporter protein. Actually the binding force between MHC
molecule and T cell is weak, they will enhance/reinforce by molecule called
Co-receptor. Co-receptor for T cell
consist of two, they are CD8 (for cytotoxic) and CD4 (for helper).
How
Cytotoxic T cell kill the cell that has been infected by antigen? The mechanism
is not really clear. But its consider that Cytotoxic T cell will lead cell to
apoptosis by activating receptor that code for cell death or in other way,
Cytotoxic T cells will release their perforin (core-forming protein) that
homologous to C9. Perforin is saved in vesicle togheter with serin protease
which has role in killing cell by activating C3.
(source
image : Molecular Biology of the cell)
Helper T cell
This T cell
has function as mediator signal of cell that present antigen. In their work,
Helper T cell is helped by Class II MHC molecule and CD4 to reinforce their
Helper-MHC binding. Class II MHC
molecule consist of two strand. α and β, which they will make
stucture simillar to antibody structure. Class II MHC molecule bring
antigen-fragment-peptide in different route and mechanism from Class I MHC
molecule.
Class II MHC
molecule was not created in ER, but they are created in Golgi Apparatus in
transgolgi apparatus network. First their antigen-binding-site is cover by
invariant chain to protect them from binding endogen-antigen-peptide. This
invariant chain will lose after MHC molecule meet with foreign antigen. Then
Class II MHC molecule will bound with foreign antigen in endosome, invariant
chain will send to lysosome for degrading and Class II molecule that have bound
to antigen will move to surface membrane to recognized by Helper T cell
receptor.
Helper T cell need two activation signal to
activate them
Helper T cell also have role in
activate B cell. But before they activate B cell, They activate themselves
first. To activate Helper t cell is not
enough by bound it to class II MHC, it need two signal activation. Signal 1 is
coming from Class II MHC and signal II is coming from its own chemical substance
(IL-1 or B7). Helper T cell after they bind to class II MHC will secrete
interleukin-1 (IL-1). This interleukin then bind to its receptor in the surface
of its own Helper T cell. In other way,
to activate Helper T cell also can use B7 that express in
antigen-presenting-cell plasma-membrane. And then CD28 (co-receptor protein in
the surface of Helper T cell) will recognize it, and Helper T cell become
active. After active Helper T cell will proliferate that control by
interleukine-2 (IL-2)
Helper T cell help in activation of B cell
When Helper
T cell active, they will present a
transmembrane protein called CD40 ligand, this ligand then recognized by B cell
because B cell have CD40 receptor. Class II MHC molecule and CD40 binding ,
will activate B cell to proliferate and mature, they also help B cell to switch
their antibody class.
Summary
Well,
finally i finish my note about immunology, although its so far from complete
and perfect. But at least it has reduce my spare time, haha. Anyone who read
this, if you want for more information about immunology. You can read it in
Molecular Biology of the cell ( im not promoting, but i just want share
knowledge).
Main source
: Molecular biology of the cell and some my opinion ^.^
Wassalamu’alaikum
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