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Samenvatting Immunology
- Instelling
- Vrije Universiteit Amsterdam (VU)
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Voorbeeld 4 van de 38 pagina's
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Voorbeeld van de inhoud
Introduction innate & adaptive immunityOur immune system ensures we stay healthy. It is a diffuse, complex network of interacting cells, cell
products and cell-forming tissues that protects the body:
From pathogens and other foreign substances
Destroys infected and malignant cells
Removes cellular debris
Our immune system needs to discriminate between self and non-self and harmless vs harmful. There is a
delicate balance in immune activation (inflammation) and inhibition (tolerance). A dysbalance in
immunity can cause (severe) diseases:
Non-self/harmful pathogens/infections
Non-self/harmless pets/allergies
Self/harmful cancer
Self/harmless organs/auto-immune disease
Immune related disease can be treated with vaccines or immunotherapy. Before the immune system can
be used for treatment, knowledge is needed on what the right balance is, how this is achieved and what
exactly causes dysbalance.
Innate versus adaptive immunity: components
In our blood, we can find multiple immunological components. The blood consists of red and white blood
cells, plasma and platelets. The white blood cells are also called the leukocytes, which are the immune
cells. These are: neutrophils, eosinophils, basophils, monocytes and lymphocytes. The plasma contains
molecules, such as complement molecules and antibodies. These cells and molecules are subdivided in 2
main immunological categories:
1. Innate immunity “existing in one from birth”
2. Adaptive immunity “able to adapt”
Hematopoiesis is the development of immune cells with 2 important common precursors. Pluripotent
hematopoietic stem cells divide into a common lymphoid cell precursor and a common myeloid cell
precursor. The lymphoid cell precursor develops into the lymphocytes (NK-, B- and T-cells). The myeloid
cell precursor develops into the granulocytes (neutrophils, eosinophils, basophils, dendritic cells, mast
cells and monocytes/macrophages).
,Immunity is subdivided into 3 lines of defence based on the speed of activation upon danger. The skin
(epithelial barrier) is the first line of defence. Then comes the innate immunity and lastly the adaptive
immunity.
However, not only the circulatory system (blood) is important, there is also a lymphatic system. The
lymphatic system is subdivided into primary and secondary lymphoid organs with different functions.
Primary lymphoid tissues are important for the development of the adaptive immune cells. The bone
marrow forms the B-cells and the T-cells are formed in the thymus. The secondary lymphoid tissues are
important for the activation of the adaptive immune cells. These are the lymph nodes, the spleen and Gut
Associated Lymphoid Tissues (GALT). Secondary lymphoid organs are highly structured with specific sites
for T-cell and B-cell activation, such as the T-cell area, B-cell follicle and germinal centre.
Innate versus adaptive immunity: function
The innate and adaptive immune system differ in the speed and specificity of inducing immunity. The
response of the innate immune system against danger is immediate, fast and equal in all of us. However,
the response of the adaptive immune system against danger is adapted, slow and highly specific for each
type of danger. Macrophages and neutrophils are fast responders upon bacterial infection and induce
inflammation. The macrophages make up a great part of the skin and the neutrophils are located in the
blood. When the skin barrier is broken, bacteria infect. This causes a secretion of cytokines by the
activation of macrophages. Vasodilation increases the permeability of the capillary wall and fluid,
proteins and cells leave the blood to enter the tissue. Now, neutrophils can migrate from the blood into
the tissue. They do not just do this, signalling molecules are needed. Cytokines are signalling molecules
for activation and chemokines are signalling molecules for migration. Macrophages recruit neutrophils
from the bone marrow to collaborate and clear the bacterial infection using phagocytosis. This is because
neutrophils can very easily increase in numbers, which takes a lot of time for the macrophages.
Numerous neutrophils are stored in the bone marrow and released on demand to fight infections. They
do this by going to the infected tissue and kill the bacteria. Afterwards, they die and are degraded by
macrophages. While inflammation (macrophages + neutrophils (innate immunity)) is ongoing, dendritic
cells initiate adaptive immunity in secondary lymphoid organs. Dendritic cells take up the pathogen as
well, however they migrate to the lymph nodes. Here, the adaptive immune system will be activated (T-
and B-cells).
, Innate immune cells use pathogen recognition
receptors to distinguish self from non-self, get
activated and ensure the uptake of pathogens. There is
an equal expression of receptors per cell subset, so all
the neutrophils express
the same receptors. They
can differentiate between
major pathogen species
(bacteria and fungi). The
molecular patterns that these receptors recognize are either pathogen-
associated or danger-associated. However, this is not a specific response and in the end, the pathogens
will win. Adaptive immune cells use receptors to specifically detect danger and get activated. B-cell
receptors are expressed on the B-cells (BCR) and the T-cell receptors are expressed on the T-cells (TCR).
These can actually differentiate within major pathogen species. The B-cell can become a plasma cell and
it will secrete its B-cell receptor and become an antibody. These receptors use antigens which are highly
specific for each pathogen and the receptor is highly specific per cell (one for corona, one for HIV, etc.).
An antigen is a molecule or fragment of a pathogen that is recognized by the T- and B-cells of the immune
system. They contain epitopes that are recognized and bound by the receptors of the adaptive immune
system.
After development, every T- and B-cell expresses a receptor which is specific for just one epitope of an
antigen. The T- and B-cells express multiple TCR or BCR, but all with one specificity per cells. Only the
ones with a receptor specific for ongoing infections will be activated in secondary lymphoid organs. These
will proliferate and become a clone of cells, all with the same receptor specific for one epitope. This is
called clonal expansion and takes approximately one week. There is a big difference between BCR’s and
TCR’s. The TCR binds only specific epitopes. They activate other cells which is called the cellular response.
However, the BCR can bind an intact pathogen by recognizing the antigen that is present on the whole
pathogen. These B-cells can differentiate into plasma cells and these produce antibodies. This is called
the humoral response.
, Top panels: a cytotoxic CD8 T cell makes contact with a virus-infected cell, recognizes that it is infected, and kills it. Middle panels: a CD4 helper T cell contacts
a macrophage that is engaged in the phagocytosis of bacteria and secretes cytokines that increase the microbicidal power of the macrophage and its secretion
of inflammatory cytokines. Bottom panels: a CD4 helper T cell contacts a B cell that is binding its specific antigen and secretes cytokines that cause the B cell to
differentiate into an antibody-secreting plasma cell.
Antibodies that are produced during the humoral response have multiple functionalities against
infections. There is a broad range specific for the same pathogen. The antibodies recognize the same
antigen or molecule, but they will bind on a different part of this molecule, because each antibody binds
to one epitope. The functions of the antibodies are neutralization, opsonization and complement
activation. For neutralization, antibodies can bind to viruses or bacterial toxins. After binding, they can no
longer exert their effect. So, they neutralize their function. Opsonization is the binding of an antibody to a
pathogen and this is the red flag that can be detected by other immune cells, which can active
complements. After opsonization, the macrophages can now take up and destroy the pathogen. But, the
opsonized pathogen is not neutralized. The activation of innate cells goes via an antibody-receptor
interaction (Fc-FcR), which enhances phagocytosis and activates granulocytes and NK cells. Neutralization
is really the electricity used for bacterial toxins or corona. As soon as neutralizing antibodies bind, the
virus can no longer enter the host cells. Basically, this is also opsonization, because the macrophages can
still take up the pathogen. Without the neutralizing antibodies, the virus can still infect the host cells.
Inflammation: complement
The complement system complements ongoing inflammation and consist of plasma proteins with
enzymatic activity. The most important factor is C3. C3 is cleaved into active components C3a and C3b,
because C3 by itself is inactive. C3a are, what is called, anaphylatoxins, because they enhance ongoing
inflammation and they induce immune cell recruitments. These are called toxins, because if there is to
much of them in your system, you go into anaphylactic shock. C3b are the ones that are called
complement fixation. So, C3b attaches itself to the surface of the bacteria. It is a complement factor that
fixates on the pathogen, which induces phagocytosis and lysis. Before these active components are
formed, C3 convertase is needed. This is the cutter that activates C3.
The C3a goes into the skin, where the bacteria are residing and multiplying. Here, it activates the
endothelium, so there is even more vasodilatation (widening of vessels). This results in an increase in
fluids of more complement and other plasma proteins. But the C3a can also act as chemokines, because
it can recruit immune cells to the site of infection. C3b leads to the enhancing of the phagocytosis, so the
eating of the pathogens. The first step is opsonization. There are receptors specific for the C3b expressed
by the macrophages, so that they can bind. Now, they can efficiently engulf the pathogens. So, before the
antibodies start coming, there are the complements that make it a bit more efficient for the
macrophages. In the end, the pathogen is destroyed.
Covalently attached C3b fragments coat the pathogen surface, here a bacterium, and bind to complement receptor 1 (CR1) molecules on the phagocyte
surface. This tethers the bacterium to the phagocyte. Intracellular signals generated by CR1 enhance the phagocytosis of the bacterium and fusion of the
phagosome with lysosomes that contain toxic molecules and degradative enzymes. Ultimately, the bacterium is killed.
There are three pathways that lead to the C3 activation. The first one is the alternative pathway, the
second is the lectin pathway and last is the classical pathway. The difference between these three is that
the first one is spontaneously activated. So, there is always some active complement in the system. The
other two need to be induced upon infection. The C3 convertase is build up out of two parts, because the
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