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inflammatory disease and is therefore caused by an inflammatory
response, which is triggered by too much adipose tissue that produces
proinflammatory mediators
o these proinflammatory mediators lead to M1 macrophages, which produce
proinflammatory cytokines and increase inflammation in general
o inflammation will lead to insulin resistance in the adipose tissue → type 2 diabetes is
caused by a lack of regulation of the M1 macrophage
o type 1 diabetes = genetic autoimmune disease, in which the body targets the cells that
should produce insulin

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TESTE DEIN WISSEN


THE IMPORTANCE OF M1 AND M2 MACROPHAGES
- importance in

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- M2 macrophages can cause problems when they are associated with cancer
- many tumors can build a so-called immunosuppressive environment and therefore evade
eradication by the immune system
- immunosuppressive environment is to some extend caused by macrophages in the tumor,
which are called tumor-associated macrophages (TAM) and are M2 macrophages
- these TAM are a target of cancer therapies with the goal to eliminate the immunosuppressive
environment
- on the surface of M2: molecule PD-L1 which interacts with PD1 on the surface of T cells and
inactivates them
- possible to use antibodies to block this interaction and consequently reactivate the T cells

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EPITOPES

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T cell epitopes are always parts of the original protein, because the antigen is
fragmented in order to present it to the T cells
TYPES OF EPITOPES

- epitope (= antigenic determinant) of an antigen is the part of a macromolecule contacted by
antigen receptors
-
the opposite of an epitope is a paratope, which is the antigen binding site of B and T cell
receptors
o typical B cell epitopes are about 6 amino acids long and need to be accessible in the
native antigen
o these are the epitopes that can be recognized by antibodies
o T cell epitopes can be between 8 and 11 amino acids long if they are presented by
MHC1 complexes and 13 to 17 amino acids long when presented by MHC class 2
complexes

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Fc-region

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antibody can be divided into two regions:
o the Fc-region, which includes everything downstream from the hinge
o the Fab-region, which contains everything upstream from the hinge
o together they are called the F(ab)2-regions.

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HAPTENS

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- haptens = a particular class of antigens
- on their own, they do not trigger an immune response, but only when they are coupled to a
protein → in this case antibodies will be made against the hapten as well as against the protein
- example: upon injection of an animal with Ninitrophenol (DNP), which here serves as an
example for haptens, no antibodies will be produced; if injected with bovine serum albumin
(BSA) the animal will produce some, but not many antibodies, since serum albumin can be
found in all chordates, it barely meets the criterium of foreignness → the immune response
will not be very intense
o but if you couple the BSA with the DNP and inject the animal with this fused molecule,
the immune response will be very strong → many antibodies will be produced
o most of the antibodies produced will recognize the hapten and only a few the BSA
protein, because the hapten is much more foreign than the BSA
27

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affinity maturation

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: if an antibody from early in the immune response is compared to one that
was produced late in the immune response, you will find that the late antibody binds the
antigen with a higher affinity than the early one
o during this process the genes which encode for the antibodies are mutagenized and
selected for antibodies with a higher affinity
o effector function of the antibody is not changed during this process → its ability to
activate the complement system and facilitate uptake by phagocytes stays the same
o these functions reside in the constant region of the antibody.

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polyclonal
immune response

monoclonal antibodies

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MONOCLONAL ANTIBODIES
- normal immune response: if a mouse is infected with the protein-antigen X, every lymphocyte
clone, who can bind one of the many epitopes on the antigen X will be activated → all different
activated lymphocytes will start clonal expansion, and, in the end, different types of B cells will
produce different antibodies that bind different epitopes on the antigen X → polyclonal
immune response
-
although antibodies are very specific, they show some cross reactivity: if proteins similar to
their epitope are present in high quantities, the antibody will show some reaction → is
completely irrelevant for natural immune response, but it can become a huge problem when
antibodies are used for technical purposes in the lab, because if each of the different types of
antibodies also show different cross reactivity, the antiserum loses specificity
o avoid this problem by using monoclonal antibodies: these recognize only one epitope
and they also only show one type of cross reactivity

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TESTE DEIN WISSEN


every human has about ?? different MHC proteins

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MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
- MHC protein is encoded in the MHC locus and is a protein on antigen presenting cells (APC)
- MHC locus is responsible for transplant rejection and the quality of an immune response:
o a transplant will be accepted if the locus is in the donor and the recipient the same; if
the locus differs, the transplant will be rejected
o even though many proteins are identical between genetically different individuals, the
MHC proteins of a genetically diverse member of the same species are always
considered foreign → reason is the high polymorphism of the MHC locus (within a
population many different alleles can be found)
o genes can be divided into two classes: MHC class I and MHC class II
▪ perform different functions and are not interchangeable
▪ MHC class I molecules can only bind smaller peptides, while MHC class II
molecules can bind bigger ones
▪ another difference is how they bind their peptide binding cleft
o every human has about 6 different MHC proteins and each of them exists in many
different alleles → chances that two individuals have the same alleles for all 6 MHC
proteins are practically 0
- advantages of the polymorphism of the MHC locus:
o possibility of presenting more types of antigen peptides
o higher diversity increases the likelihood that some individuals fight some pathogens
better than others and therefore survive

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TESTE DEIN WISSEN

IFN-γ


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Interferon-gamma ist ein Glykoprotein aus der Klasse der Zytokine. Es wird vor allem von T-Lymphozyten nach Kontakt mit antigenpräsentierenden Makrophagen gebildet und zeichnet sich durch seine immunstimulierende, vor allem antivirale und antitumorale Wirkung aus. 


expression of MHC is enhanced during an immune response by IFN-γ: IFN-γ not only acts as a
macrophage activating factor, but also increases the abundance of MHC molecules on the
surface of dendritic cells, macrophages and B cells in order to improve their ability to present
antigen during an immune response

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TESTE DEIN WISSEN

IMMUNODOMINANCE

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- MHC molecules cannot bind every existing peptide, it needs to fulfill certain requirements
- some peptides dominate the immune response because a large part of the T cells recognize
the same peptide
- the peptide pool is determined by the proteases that chop of the protein into many pieces;
these proteases require certain amino acid sequences to be active
-
although there are many potential peptides, only some are being generated by the proteases;
additionally, not all generated peptides will be able to interact with MHC molecules
- an immunodominant peptide is a peptide that interacts with many MHC molecules and
thereby a large part of the immune response will be towards this peptide
- immunodominance can be harmful if the concerning peptide is not protective, which makes
the corresponding antibodies useless
-
if a peptide is protective, a large part of the antibodies will be effective against this antigen,
which is beneficial for the host

Lösung ausblenden
TESTE DEIN WISSEN

alloantigen

T CELLS RECOGNITION OF FOREIGN MHC – DIRECT ALLOANTIGEN RECOGNITION

normal situation

two other possibilities

   first

   second

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TESTE DEIN WISSEN

normal situation: MHC that T cell recognizes
o if self-MHC contains a foreign peptide, T cell will recognize → activates T cell
- two other possibilities how foreign MHC could be recognized by T cells via allorecognition:
o first: antigen binding site of allogeneic MHC molecule may make a self-peptide look
like a foreign peptide
▪ foreign peptide has an amino acid residue, that looks like one that comes case
from the binding site of the MHC molecule from the donor
o second: if donor has change in antigen binding site (like possibility above) and has
some other proteins that differ in their amino acid composition, many proteins will
show some degree of genetic polymorphism and this protein is self from the donor,
but because of he polymorphism it looks foreign to the T cell of the recipient → change
in antigen binding site together with change in the self-peptide of the donor makes it
look for the T cell of the recipient like this was a self-MHC with a foreign antigen
-
either way: activated T cell recognizes cells from transplant: cytotoxic T cells can now attack
the cells of the transplant or the helper T cells can lead to antibody production

ir

Lösung ausblenden
TESTE DEIN WISSEN


CLASSICAL AND ALTERNATIVE MACROPHAGE ACTIVATION

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- macrophages are usually activated by interferon γ → M1 macrophages and have enhanced
ability to kill microbes and lead to more inflammation
- macrophages can also be activated by other cytokines: interleukin-13 and interleukin-4 →
alternative activation (M2)
- M2 macrophages are the opposite of M1 macrophages, because M2 has anti-inflammatory
effects
- anti-inflammatory effects are important for the immune system, because too much
inflammation will harm the hosts own cells and tissues
- M2 macrophages produce cytokines like IL-10 and TGF-β (transforming growth factor) that
stop inflammation and try to repair damage that has been caused by inflammation

Lösung ausblenden
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Q:


A:

inflammatory disease and is therefore caused by an inflammatory
response, which is triggered by too much adipose tissue that produces
proinflammatory mediators
o these proinflammatory mediators lead to M1 macrophages, which produce
proinflammatory cytokines and increase inflammation in general
o inflammation will lead to insulin resistance in the adipose tissue → type 2 diabetes is
caused by a lack of regulation of the M1 macrophage
o type 1 diabetes = genetic autoimmune disease, in which the body targets the cells that
should produce insulin

Q:


THE IMPORTANCE OF M1 AND M2 MACROPHAGES
- importance in

A:

- M2 macrophages can cause problems when they are associated with cancer
- many tumors can build a so-called immunosuppressive environment and therefore evade
eradication by the immune system
- immunosuppressive environment is to some extend caused by macrophages in the tumor,
which are called tumor-associated macrophages (TAM) and are M2 macrophages
- these TAM are a target of cancer therapies with the goal to eliminate the immunosuppressive
environment
- on the surface of M2: molecule PD-L1 which interacts with PD1 on the surface of T cells and
inactivates them
- possible to use antibodies to block this interaction and consequently reactivate the T cells

Q:

EPITOPES

A:

T cell epitopes are always parts of the original protein, because the antigen is
fragmented in order to present it to the T cells
TYPES OF EPITOPES

- epitope (= antigenic determinant) of an antigen is the part of a macromolecule contacted by
antigen receptors
-
the opposite of an epitope is a paratope, which is the antigen binding site of B and T cell
receptors
o typical B cell epitopes are about 6 amino acids long and need to be accessible in the
native antigen
o these are the epitopes that can be recognized by antibodies
o T cell epitopes can be between 8 and 11 amino acids long if they are presented by
MHC1 complexes and 13 to 17 amino acids long when presented by MHC class 2
complexes

Q:

Fc-region

A:

antibody can be divided into two regions:
o the Fc-region, which includes everything downstream from the hinge
o the Fab-region, which contains everything upstream from the hinge
o together they are called the F(ab)2-regions.

Q:


HAPTENS

A:

- haptens = a particular class of antigens
- on their own, they do not trigger an immune response, but only when they are coupled to a
protein → in this case antibodies will be made against the hapten as well as against the protein
- example: upon injection of an animal with Ninitrophenol (DNP), which here serves as an
example for haptens, no antibodies will be produced; if injected with bovine serum albumin
(BSA) the animal will produce some, but not many antibodies, since serum albumin can be
found in all chordates, it barely meets the criterium of foreignness → the immune response
will not be very intense
o but if you couple the BSA with the DNP and inject the animal with this fused molecule,
the immune response will be very strong → many antibodies will be produced
o most of the antibodies produced will recognize the hapten and only a few the BSA
protein, because the hapten is much more foreign than the BSA
27

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Q:


affinity maturation

A:

: if an antibody from early in the immune response is compared to one that
was produced late in the immune response, you will find that the late antibody binds the
antigen with a higher affinity than the early one
o during this process the genes which encode for the antibodies are mutagenized and
selected for antibodies with a higher affinity
o effector function of the antibody is not changed during this process → its ability to
activate the complement system and facilitate uptake by phagocytes stays the same
o these functions reside in the constant region of the antibody.

Q:


polyclonal
immune response

monoclonal antibodies

A:


MONOCLONAL ANTIBODIES
- normal immune response: if a mouse is infected with the protein-antigen X, every lymphocyte
clone, who can bind one of the many epitopes on the antigen X will be activated → all different
activated lymphocytes will start clonal expansion, and, in the end, different types of B cells will
produce different antibodies that bind different epitopes on the antigen X → polyclonal
immune response
-
although antibodies are very specific, they show some cross reactivity: if proteins similar to
their epitope are present in high quantities, the antibody will show some reaction → is
completely irrelevant for natural immune response, but it can become a huge problem when
antibodies are used for technical purposes in the lab, because if each of the different types of
antibodies also show different cross reactivity, the antiserum loses specificity
o avoid this problem by using monoclonal antibodies: these recognize only one epitope
and they also only show one type of cross reactivity

Q:


every human has about ?? different MHC proteins

A:

MAJOR HISTOCOMPATIBILITY COMPLEX (MHC)
- MHC protein is encoded in the MHC locus and is a protein on antigen presenting cells (APC)
- MHC locus is responsible for transplant rejection and the quality of an immune response:
o a transplant will be accepted if the locus is in the donor and the recipient the same; if
the locus differs, the transplant will be rejected
o even though many proteins are identical between genetically different individuals, the
MHC proteins of a genetically diverse member of the same species are always
considered foreign → reason is the high polymorphism of the MHC locus (within a
population many different alleles can be found)
o genes can be divided into two classes: MHC class I and MHC class II
▪ perform different functions and are not interchangeable
▪ MHC class I molecules can only bind smaller peptides, while MHC class II
molecules can bind bigger ones
▪ another difference is how they bind their peptide binding cleft
o every human has about 6 different MHC proteins and each of them exists in many
different alleles → chances that two individuals have the same alleles for all 6 MHC
proteins are practically 0
- advantages of the polymorphism of the MHC locus:
o possibility of presenting more types of antigen peptides
o higher diversity increases the likelihood that some individuals fight some pathogens
better than others and therefore survive

Q:

IFN-γ


A:

Interferon-gamma ist ein Glykoprotein aus der Klasse der Zytokine. Es wird vor allem von T-Lymphozyten nach Kontakt mit antigenpräsentierenden Makrophagen gebildet und zeichnet sich durch seine immunstimulierende, vor allem antivirale und antitumorale Wirkung aus. 


expression of MHC is enhanced during an immune response by IFN-γ: IFN-γ not only acts as a
macrophage activating factor, but also increases the abundance of MHC molecules on the
surface of dendritic cells, macrophages and B cells in order to improve their ability to present
antigen during an immune response

Q:

IMMUNODOMINANCE

A:

- MHC molecules cannot bind every existing peptide, it needs to fulfill certain requirements
- some peptides dominate the immune response because a large part of the T cells recognize
the same peptide
- the peptide pool is determined by the proteases that chop of the protein into many pieces;
these proteases require certain amino acid sequences to be active
-
although there are many potential peptides, only some are being generated by the proteases;
additionally, not all generated peptides will be able to interact with MHC molecules
- an immunodominant peptide is a peptide that interacts with many MHC molecules and
thereby a large part of the immune response will be towards this peptide
- immunodominance can be harmful if the concerning peptide is not protective, which makes
the corresponding antibodies useless
-
if a peptide is protective, a large part of the antibodies will be effective against this antigen,
which is beneficial for the host

Q:

alloantigen

T CELLS RECOGNITION OF FOREIGN MHC – DIRECT ALLOANTIGEN RECOGNITION

normal situation

two other possibilities

   first

   second

A:

normal situation: MHC that T cell recognizes
o if self-MHC contains a foreign peptide, T cell will recognize → activates T cell
- two other possibilities how foreign MHC could be recognized by T cells via allorecognition:
o first: antigen binding site of allogeneic MHC molecule may make a self-peptide look
like a foreign peptide
▪ foreign peptide has an amino acid residue, that looks like one that comes case
from the binding site of the MHC molecule from the donor
o second: if donor has change in antigen binding site (like possibility above) and has
some other proteins that differ in their amino acid composition, many proteins will
show some degree of genetic polymorphism and this protein is self from the donor,
but because of he polymorphism it looks foreign to the T cell of the recipient → change
in antigen binding site together with change in the self-peptide of the donor makes it
look for the T cell of the recipient like this was a self-MHC with a foreign antigen
-
either way: activated T cell recognizes cells from transplant: cytotoxic T cells can now attack
the cells of the transplant or the helper T cells can lead to antibody production

ir

Q:


CLASSICAL AND ALTERNATIVE MACROPHAGE ACTIVATION

A:

- macrophages are usually activated by interferon γ → M1 macrophages and have enhanced
ability to kill microbes and lead to more inflammation
- macrophages can also be activated by other cytokines: interleukin-13 and interleukin-4 →
alternative activation (M2)
- M2 macrophages are the opposite of M1 macrophages, because M2 has anti-inflammatory
effects
- anti-inflammatory effects are important for the immune system, because too much
inflammation will harm the hosts own cells and tissues
- M2 macrophages produce cytokines like IL-10 and TGF-β (transforming growth factor) that
stop inflammation and try to repair damage that has been caused by inflammation

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