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Summary Immunology
- Vak
- Immunology
- Instelling
- Vrije Universiteit Amsterdam (VU)
Summary of 34 pages for the course Immunology at VU (Immunology)
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Immuno1 Tuesday, 7 June 2022Immune system elements & Complement response
INTRODUCTION
The immune system is a diffuse, complex network of interacting cells, cell products, and
cell-forming tissues. It protects the body from pathogens and other foreign substances. It
also destroys infected and malignant cells, and removes cellular debris. There is a delicate
balance between inflammation and tolerance. When there is a dysbalance, severe disease
can occur
COMPONENTS OF THE IMMUNE SYSTEM
In our blood we can find multiple
immunological components, which can be
found under white blood cells and plasma. The
white blood cells are the immune cells, also
known as leukocytes. This includes
neutrophils, basophils, eosinophils,
monocytes, and lymphocytes. In the plasma,
complement and antibodies can be found.
The immune cells are divided in the innate and
adaptive immunity
Immune cells develop through hematopoiesis with the common myeloid precursor and the
common lymphoid precursor. These precursors respectively form the cells for the innate
and the adaptive immune system. The only exception are the NK cells, as these arise from
the common lymphoid precursor cells.
Immunity in divided into three lines of defence, based on the speed of activation.
1. Skin/ mucous membranes -> epithelial barrier
2. Phagocytosis, complement, interferon, inflammation, and fever -> innate immunity
3. Lymphocytes and antibodies -> adaptive immunity
Besides the blood circulation, the lymphatic system is also very important for the immune
system. The lymphatic system is divided into primary and secondary lymphoid organs.
These are important for both the development and activation of adaptive immune cells
Primary Lymphoid Organs —> development of adaptive immune cells
- Bone marrow -> B cells
- Thymus -> T cells
Secondary Lymphoid Organs —> activation of adaptive immune cells
- Lymph nodes
- Spleen
- GALT (Gut Associated Lymphoid Tissues)
The secondary lymphoid organs are highly structured with
specific sites for both B- and T- cell activation. The most
important sites of the lymph node are the T cell zone, B
cell follicle, and the germinal centre
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FUNCTION OF IMMUNE COMPONENTS
Your innate and adaptive immune system differ in the speed and specificity of inducing
immunity. The innate immune system in immediate & fast, and is equal in all of us. The
adaptive immune system in adapted & slow, and is highly specific
for each type of danger
Macrophages and neutrophils are the fast responders upon
bacterial infection and induce inflammation. A bacteria infects
the skin, which activates effector cells to secrete cytokines for
immune cell activation. Vasodilation occurs and this increases
the permeability of the capillary wall. This causes fluid, proteins,
and cells to leave the blood and enter tissues via the chemokines
Macrophages recruit neutrophils from the bone marrow to
collaborate and clear the bacterial infection using phagocytosis.
The neutrophils go to the infected tissue and kill bacteria.
Afterward, the neutrophils die and are degraded by
macrophages
While the inflammation in ongoing, dendritic cells intimate the
adaptive immune system in the secondary lymphoid organs. They undergo pathogen
uptake, whereafter the dendritic cells will migrate into the lymphatic tissue to activate the
adaptive system
Innate immune cells use pathogen recognition receptors (PRRs) to distinguish self from
non-self and get activated. The innate immune cell receptors are used for activation and
pathogen uptake & they have equal expression per cell subset. They can differentiate
between major pathogen species (not specific), and they use associated molecular patterns
like PAMPS en DAMPS. Because the innate system is not specific, the pathogens will
eventually win
Adaptive immune cells use receptors to specifically detect danger and get activated. The
adaptive immune cell receptor are used for activation and effector function. The B-cells use
the BCR and the T-cells the TCR. They can differentiate within major pathogen species, and
they use antigens. These receptors are highly specific for each pathogen and per cell. Every
BCR or TCR has one specificity per cell.
Antigens are specific for each pathogen and contain epitopes recognised but he receptors
of the adaptive immune system. An antigen is a molecule or fragment of a pathogen
recognised by the T and B cells. The epitope is the minimal portion of an antigen bound by
antibodies of the BCR, and recognised by the TCR.
After development, every T- and B-cell expresses a receptor which will bind a different
epitope, and therefore have a different specificity. T- and B-cells expresses multiple TCR or
BCR, but with only one specificity per cell. Only the ones with a receptor specific for
ongoing infection will be activated in the secondary lymphoid organs. These will
proliferation and become clone of cells, all with the same receptor specific for one epitope.
This is also known as clonal expansion, and these cells remember infection
The BCR can bind antigens, whereas the TCR only bins processed antigens
Cellular response —> TCR binds processed antigens, and there is activation of
other cells with present epitopes
Humoral response —> BCR binds epitopes on the intact antigens. There is
differentiation into plasma cells and production of antibodies
Antibodies produced during the humoral response have multiple functionalities against
infection. The antibodies have a broad range specificity for the same pathogen. They
recognise different epitopes between antibodies, and they recognise one epitope per
antibody. The antibodies can induce neutralisation (counteract), opsonisation (tagging), and
complement activation. The activation of innate immune cells occurs via antibody-receptor
interaction (Fc-FcR), causing enhanced phagocytosis and activation of granulocytes & NK
cells
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THE COMPLEMENT SYSTEM
The complement system complement ongoing inflammation and consists of plasma
proteins with enzymatic activity. The most important component is factor C3. This can be
cleaned into C3a and C3b via an enzymatic reaction with C3 converts.
C3a -> anaphylatoxins, used for immune cell recruitment. If there is too much of the
activation, an anaphylactic shock is initiated.
C3b -> complement fixation, used for pathogen binding for phagocytosis and lysis.
Anaphylatoxins enhance inflammation within minutes trough activation of endothelial and
immune cell recruitment. Complement and other plasma protein enter the infected tissue,
and the anaphylatoxins increase blood-
vessel permeability. Vasodilation occurs,
allowing leukocytes to enter the infected
tissue and resident macrophages are
activated.
Complement fixation leads to the
enhanced phagocytosis by binding of
complement receptors and phagocytes.
Three pathways lead to complete activation, through are activated sequentially by different
factors
1. Alternative pathway -> spontaneous activation. Soluble C3 convertase is activated
via hydrolysis (H2O). The C3 converts binds to C3 and cleaves it into C3a and C3b
2. Lectin pathway -> induced activation. MBL is bound to the pathogen surface, which
allows factors C4 and C2 to also bind, causing activation of membrane bound C3
convertase. Hereafter, the membrane bound C3 convertase cleaves the C3 into C3a
and C3b
3. Classical pathway -> induced activation. CRP or IgM is bound to the pathogen
surface. C1 then also binds to the surface, and this resembles MBL. CRP/IgM
combined with the C1 can activates C3 convertase . The C3 convertase can again
cleave C3 into C3a and C3b
C3b is also important for the formation of the membrane attack complex (MAC) and
pathogen lysis. C3b can bind C3 invertase on the pathogen surface, cleaving C5. C5b
imitates the formation of the MAC for lysis
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The Induced Response To Infection
MACROPHAGES
Tissue resident macrophages of the innate immune system are the first to respond upon
infection and induce inflammation. Macrophages are the big eaters of the innate immune
system and clear pathogens by phagocytosis. They are present in the tissue and are alert
upon tissue damage and infection. Tissue resident macrophages respond to bacteria using
pathogen recognition receptors.
Macrophages secrete pro-inflammatory cytokine for the induction of inflammation at site of
infection
TNF-⍺ -> Cytokine. Induces blood vessels to be more permeable, enabling cells, fluid,
and soluble effectors to enter the infected tissue
CXCL8 -> Chemokine. Recruits neutrophils from the blood and directs then to the
infected tissue
Macrophages induce the acute phase response, initiating the production of MBL and CRP
by the liver. This allows initiation of the lectin and classical complement pathway
NEUTROPHILS
Neutrophils migrate from the blood into the tissue using
adhesion molecules and chemokines
1. Rolling and adhesion -> selectins, integrins, and
chemokines
2. Diapedesis
3. Migration -> chemokine gradient
Neutrophils express receptors for phagocytosis and toxic granules for killing. They have a
signature multi-lobular nucleus, and are recruited to the infection site.
Neutrophils efficiently kill bacterial following phagocytosis. They die and are cleared by the
macrophages.
1. Phagocytosis -> Neutrophil engulf bacterium
2. Destruction -> pH rises, antimicrobial response is activated and the bacterium is
killed
3. Death -> neutrophil dies by apoptosis and is phagocytosed by the macrophage
RECEPTORS
Innate immune cells distinguish self from non-self using pattern recognition receptors
(PRRs). Different types of PRR are expressed innate immune cells with different functions.
C-type lectin receptors (CLR) -> sensing and phagocytosis & destruction of pathogens.
They recognise carbohydrate structures on the pathogen surface. CLR internalise
pathogens into phagosomes for phagolysosomal destruction
Toll-like receptors (TLR) -> pathogen sensing, signalling, and immune cell activation. It
is expressed by many immune cells (monocytes, dendritic cells, macrophages, NK
cells, B cells, and granulocytes). There is extracellular (membrane) and intracellular
(endosomes) expression for the recognition of many pathogens. TLR knows great
diversity, and the combination of TLR determines the innate response. TLR-induced
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