Inhoudsopgave
General information ......................................................................................................................................... 1
LC Theme 2: Innate immune system ................................................................................................................. 4
LC Theme 3: MHC complex structure, and function and antigen processing ..................................................... 5
LC Theme 4: T cell development, and T cell receptor and signaling .................................................................. 7
LC Theme 5: B cell development, B cell receptor and signaling, antibodies .................................................... 11
LC Theme 6: Cellular immunity ....................................................................................................................... 16
LC Theme 7: Humoral immunity ..................................................................................................................... 20
LC Theme 10: Tolerance and autoimmunity ................................................................................................... 25
LC theme 11: Transplantation immunology .................................................................................................... 29
LC Theme 12: Modulation of the immune response ....................................................................................... 31
General information
Humoral innate -> Complement
Cellular innate -> NK cell and macrophage
Humoral adaptive -> B cell
Cellular adaptive -> T cell
Innate immunity
Components of the innate immunity:
- Fagocytose
- Complement
- NK-cellen -> have activating and inhibitory receptors on their surfaces. The balance
between the bound inhibitory and activating receptors determines whether the NK
cell kills its target or not.
Complement system
Classical pathway: Antibody-antigen complex
Lectin pathway: Mannose binding, lectin binds mannose on the
surface of the pathogen
Alternative pathway: The pathogen its self-causes activation
,Classical pathway
Binding of complement factor C1 to the Fc-region of an antibody.
Complement factor C1 is built of 3 proteins:
- C1q -> binds to the Fc region of the antibody.
- C1r and C1s -> protease, activation when C1q is bound to the Fc region.
C1q molecule has 6 identical protein chains that cause the binding to the Fc
region. For optimal activation, all 6 binding places need to be bound. When C1q is
bound, the C1 complex is formed, and it can become active. Because of
activation of the C1-complex, C4 binds a through several steps C3 convertase
is formed.
C3-convertase: complex made from C4b and C2a.
C3-convertase can then split up.
When there is no antibody bound, the acute phase protein C can also
activate the complement system through the classical pathway.
MBL route (lectin pathway)
MBL-> mannose binding lectin
After binding of MBL to the surface of a bacteria, MBL activates a proteolytic enzyme
complex (MASP) (instead of the C1 complex). After that the pathway continues identical to
the classical pathway.
Alternative pathway
In the blood there is always a spontaneous splicing of complement factor C3 into C3b. C3b
can bind to the surface of pathogens. When C3b does not bind, it becomes inactivated
through hydrolysis.
Factor B can bind to C3b. Factor B then gets spliced through factor D. It becomes Factor Bb
what remains linked to C3b. This C3Bb-complex functionates as an alternative C3-convertase
causing more C3 to become spliced. This provides enough C3b to start the terminal pathway.
All 3 routes lead to the same, the formation of C3-convertase. C3-convertase activates
complement factor C3 and splices the C3 protein into C3b and C3a. Binding of C3b to a
pathogen makes the pathogen ready (‘hapklaar’) for phagocytosis -> opsonization. The
pathogen can easily be recognized by the phagocytes and be processed.
Binding of C3b to the pathogen also leads to a cascade of reaction, that eventually leads to
damage of the bacterial cell wall. C3-convertase is converted after binding of C3b into C5-
convertase, where the terminal path starts.
,First 5C-convertse is being spliced which results in
the formation of C5a and C5b. After that the
following factors are bound; C6, C7, C8 and C9
that form the membrane attack complex (MAC).
The C9 polymerizes into a tubular structure, that
forms a pore in the cell membrane. The pathogen
dies because of lysis.
PAMP’s and DAMP’s
There are different kind of pathogens:
- Pathogen associated molecular patterns (PAMPs)
- Damage associated molecular patterns (DAMPs)
To enable recognition, cells are equipped with receptors which can bind to components of
the pathogen. This allows a distinction to be made between self and non-self.
The receptors that can recognize PAMP’s are pattern recognition receptors (PRR).
PRR’s are:
- Toll-like receptors
Binding of PAMP to PRR can induce different cellular processes. It depends on the PRR
where the pathogen interacts with.
- Phagocytosis
- Activation of the immune system
Binding of a ligand to TLR leads to:
- Production of cytokines and chemokines
- Expression of MHC class II
- Expression of Co-stimulators
- Activation of enzymes involved in phagocytosis
- Production of anti-microbial proteins
Interferons
- Stimulate phagocytosis
- Activation of NK cells
Phagocytosis
Under the influence of cytokines and interaction with the pathogen, phagocytes become
activated.
First a phagocyte makes contact with the pathogen and pulls it towards the cell. Then the
plasma membrane folds completely around the pathogen. -> phagosome
, The cytoplasm of the phagocyte contains granula. The granula contains enzymes that can kill
the pathogen. The phagosome merges with the granulas. -> phagolysosome
The enzymes in the granula come in contact with the pathogen, causing it to break down. ->
degranulation
Inhibition T cells
A few days after activation, CTLA-4 comes to the surface of the T cells. CTLA-4 has a very
strong affinity to CD80/CD86, just like CD28. However, the affinity for CTLA-4 is higher than
the affinity for CD28. Because of that the activation is blocked. When T-cells arrive in the
tissue, they also start expressing PD-1. Binding of PD-1 to PD-L1 or PD-L2 leads to inhibition
of the T-cells.
LC Theme 2: Innate immune system
TLR
Signaling pathways and functions of TLRs
TLR recognition of microbial ligands results in the activation of several
signaling pathways and ultimately transcription factors, which induce the
expression of genes whose products are important for inflammatory and
antiviral responses
General information ......................................................................................................................................... 1
LC Theme 2: Innate immune system ................................................................................................................. 4
LC Theme 3: MHC complex structure, and function and antigen processing ..................................................... 5
LC Theme 4: T cell development, and T cell receptor and signaling .................................................................. 7
LC Theme 5: B cell development, B cell receptor and signaling, antibodies .................................................... 11
LC Theme 6: Cellular immunity ....................................................................................................................... 16
LC Theme 7: Humoral immunity ..................................................................................................................... 20
LC Theme 10: Tolerance and autoimmunity ................................................................................................... 25
LC theme 11: Transplantation immunology .................................................................................................... 29
LC Theme 12: Modulation of the immune response ....................................................................................... 31
General information
Humoral innate -> Complement
Cellular innate -> NK cell and macrophage
Humoral adaptive -> B cell
Cellular adaptive -> T cell
Innate immunity
Components of the innate immunity:
- Fagocytose
- Complement
- NK-cellen -> have activating and inhibitory receptors on their surfaces. The balance
between the bound inhibitory and activating receptors determines whether the NK
cell kills its target or not.
Complement system
Classical pathway: Antibody-antigen complex
Lectin pathway: Mannose binding, lectin binds mannose on the
surface of the pathogen
Alternative pathway: The pathogen its self-causes activation
,Classical pathway
Binding of complement factor C1 to the Fc-region of an antibody.
Complement factor C1 is built of 3 proteins:
- C1q -> binds to the Fc region of the antibody.
- C1r and C1s -> protease, activation when C1q is bound to the Fc region.
C1q molecule has 6 identical protein chains that cause the binding to the Fc
region. For optimal activation, all 6 binding places need to be bound. When C1q is
bound, the C1 complex is formed, and it can become active. Because of
activation of the C1-complex, C4 binds a through several steps C3 convertase
is formed.
C3-convertase: complex made from C4b and C2a.
C3-convertase can then split up.
When there is no antibody bound, the acute phase protein C can also
activate the complement system through the classical pathway.
MBL route (lectin pathway)
MBL-> mannose binding lectin
After binding of MBL to the surface of a bacteria, MBL activates a proteolytic enzyme
complex (MASP) (instead of the C1 complex). After that the pathway continues identical to
the classical pathway.
Alternative pathway
In the blood there is always a spontaneous splicing of complement factor C3 into C3b. C3b
can bind to the surface of pathogens. When C3b does not bind, it becomes inactivated
through hydrolysis.
Factor B can bind to C3b. Factor B then gets spliced through factor D. It becomes Factor Bb
what remains linked to C3b. This C3Bb-complex functionates as an alternative C3-convertase
causing more C3 to become spliced. This provides enough C3b to start the terminal pathway.
All 3 routes lead to the same, the formation of C3-convertase. C3-convertase activates
complement factor C3 and splices the C3 protein into C3b and C3a. Binding of C3b to a
pathogen makes the pathogen ready (‘hapklaar’) for phagocytosis -> opsonization. The
pathogen can easily be recognized by the phagocytes and be processed.
Binding of C3b to the pathogen also leads to a cascade of reaction, that eventually leads to
damage of the bacterial cell wall. C3-convertase is converted after binding of C3b into C5-
convertase, where the terminal path starts.
,First 5C-convertse is being spliced which results in
the formation of C5a and C5b. After that the
following factors are bound; C6, C7, C8 and C9
that form the membrane attack complex (MAC).
The C9 polymerizes into a tubular structure, that
forms a pore in the cell membrane. The pathogen
dies because of lysis.
PAMP’s and DAMP’s
There are different kind of pathogens:
- Pathogen associated molecular patterns (PAMPs)
- Damage associated molecular patterns (DAMPs)
To enable recognition, cells are equipped with receptors which can bind to components of
the pathogen. This allows a distinction to be made between self and non-self.
The receptors that can recognize PAMP’s are pattern recognition receptors (PRR).
PRR’s are:
- Toll-like receptors
Binding of PAMP to PRR can induce different cellular processes. It depends on the PRR
where the pathogen interacts with.
- Phagocytosis
- Activation of the immune system
Binding of a ligand to TLR leads to:
- Production of cytokines and chemokines
- Expression of MHC class II
- Expression of Co-stimulators
- Activation of enzymes involved in phagocytosis
- Production of anti-microbial proteins
Interferons
- Stimulate phagocytosis
- Activation of NK cells
Phagocytosis
Under the influence of cytokines and interaction with the pathogen, phagocytes become
activated.
First a phagocyte makes contact with the pathogen and pulls it towards the cell. Then the
plasma membrane folds completely around the pathogen. -> phagosome
, The cytoplasm of the phagocyte contains granula. The granula contains enzymes that can kill
the pathogen. The phagosome merges with the granulas. -> phagolysosome
The enzymes in the granula come in contact with the pathogen, causing it to break down. ->
degranulation
Inhibition T cells
A few days after activation, CTLA-4 comes to the surface of the T cells. CTLA-4 has a very
strong affinity to CD80/CD86, just like CD28. However, the affinity for CTLA-4 is higher than
the affinity for CD28. Because of that the activation is blocked. When T-cells arrive in the
tissue, they also start expressing PD-1. Binding of PD-1 to PD-L1 or PD-L2 leads to inhibition
of the T-cells.
LC Theme 2: Innate immune system
TLR
Signaling pathways and functions of TLRs
TLR recognition of microbial ligands results in the activation of several
signaling pathways and ultimately transcription factors, which induce the
expression of genes whose products are important for inflammatory and
antiviral responses
