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Kuby Immunology chapter 8
Kuby immunology chapter 8
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Biology
Undergraduate 4
04/11/2014
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Term
Every mammal species has a gene cluster //products play a role in seeing self from non-self... intercellular recognition...this chapter is about ____
 Definition
MHC
Term
The MHC is
 Definition
a genetic complex. The products of the MHC genes influence the
ability of an organism to accept or reject transplanted tissue from another
member of the same species.
Term
Proteins encoded by the MHC play an important role in the
 Definition
adaptive
immune responses + the antigens
T H and Tc cells can respond to
Term
MHC gene products affect the response
 Definition
to antigens of infectious
organisms.
MHC gene products have been implicated in the susceptibility of an individual to the development of autoimmunity.
Term
MHC are genes on chromosome __and chromosome 17 in mice.
Human MCH= ____
Mouse MHC = H-2 complex
 Definition
6 in humans
Human MHC = HLA complex
Term
Class I MHC genes encode glycoproteins expressed on ____.
Products of these genes function in presentation of peptide antigen to __ cells.
 Definition
on the surface of nearly all nucleated cells
Tc
Term
Class II MHC genes encode glycoproteins expressed on __such as ____Products of these genes function in presentation of peptide antigen to ___.
 Definition
APCs
as macrophages, dendritic cells, and B cells.
TH cells
Term
Class III MHC genes encode various proteins that have immune functions such as _____
 Definition
some complement proteins
Term
MHC Haplotypes
The genetic loci that make up the MHC are ____. This means that many versions
of each gene exist.
 Definition
polymorphic
Term
Each human inherits one copy of each MHC gene on the chromosome 6
 Definition
one copy from mom and another from dad
Term
The genes of the MHC loci are linked and rarely do recombination.
So you inherit ___.
 Definition
a complete set of alleles on one chromosome 6 ..that all come from Mom
and a complete set on the other chromosome 6 that all come from Dad.
Term
Each set of alleles constitutes a haplotype = receive a maternal haplotype and a paternal haplotype.
All of the alleles of the MHC loci are co-dominant which means ___
 Definition
you will express all of the
gene alleles that you inherit.
Term
________ is encoded by the K and D regions of the H-2 complex in mice and is encoded by the A, B, & C
regions of the HLA complex in humans.
 Definition
Class I MHC
Term
___is encoded by the IA and IE regions of the H-2 complex in mice and the DP, DQ, and DR regions of
the HLA complex in humans.
 Definition
Class II MHC
Term
___ molecules encoded by S region in mice and the C4, C2, and BF regions in humans, are critical for
immune function, but have little structural or functional overlap with the MHC Class I or II molecules.
 Definition
Class III MHC
Term
The genetic loci that make up the MHC are polymorphic. This means ___
 Definition
that many versions
of each gene exist
Term
The genes of the MHC loci are ___ and rarely undergo ____.
 Definition
linked
recombination
Term
most individuals
are outbred, meaning they carry
___ on their two
copies of chromosome 6.
 Definition
different MHC haplotypes
Term
the unit of MHC genes
that makes up a haplotype are typically
inherited _____________
 Definition
as complete set because they
are linked
Term
MHC Class I molecules contain an alpha chain, coded by and MHC Class I gene. The alpha chain is complexed to one copy of beta-two microglobulin, coded by a highly conserved gene on _____
 Definition
another chromosome.
Term
Association of the alpha chain and the beta-2 microglobulin are required for the ______
 Definition
expression of MHC Class I molecules on the cell surface.
Term
Beta-two macroglobulin associates with the alpha 3 domain of the alpha chain via non-covalently interactions.
These two domains share homology ___
 Definition
with
immunoglobulin folds.
Term
The alpha-1 and alpha-2 domains interact to form the peptide binding cleft, which is located
on the ___ molecule and binds a peptide of ____in
length
 Definition
top surface of the MHC Class I
8-10 amino acids
Term
The appropriate assembly of an MHC Class I molecule on the surface of a cell requires the
trimeric interaction between _____
 Definition
an alpha chain, a beta-two microglobulin, and a peptide antigen.
Term
MHC Class II molecules are made of two
different polypeptide chains = ___, both of which are encoded
by MHC Class II genes of different types.
 Definition
alpha chain and the beta chain
Term
Each chain of the MHC Class II molecules are trans-membrane glycoproteins that contain ____ . The
alpha 2 and beta 2 domains share homology with immunoglobulin folds.
 Definition
two extracellular domains (alpha 1/2
and beta 1/2), followed by a transmembrane alpha helix, and a short cytoplasmic tail
Term
The alpha 1 and beta 1 domains associate to
form a _____at the top surface of the
class II molecule.
 Definition
binding cleft
Term
To be expressed an MHC Class II molecule must contain an alpha chain, a beta chain,
and ____
 Definition
a peptide in its binding cleft.
Term
Separate exons within each alpha gene
encode the separate regions of the alpha chain polypeptide of ___.
 Definition
MHC Class I protein
3 alpha domains with B2 next to A 3
Term
Each gene has a leader sequence encoding a signal peptide that facilitates the insertion of the alpha chain into _____.
It is removed by peptidases in the ER
following the completion of alpha
polypeptide translation.
 Definition
the ER
Term
The _____ is followed by gene
sequences for the alpha 1, alpha 2, and
alpha 3 regions as well as the
transmembrane and cytoplasmic regions
 Definition
leader sequence
Term
Separate exons within each alpha gene and beta gene encode the separate regions of the alpha and
beta chain polypeptides of ___
 Definition
MHC Class II proteins.
Term
Each alpha and beta gene has a leader sequence encoding a signal peptide that facilitates the
insertion of the alpha and beta chains into ___ It is removed by peptidases in the ER following the completion of translation of the alpha and beta
polypeptides
 Definition
the ER.
Term
Class II. In the alpha genes, the leader sequence is followed by gene sequences for the alpha 1 and alpha 2
regions as well as the ____
 Definition
transmembrane and cytoplasmic regions.
Term
Class II. In the beta genes, the leader sequence is followed by gene sequences for the ___
regions as well as the transmembrane and
cytoplasmic regions.
 Definition
beta 1 and beta 2
Term
Expressed alpha chains will associate with beta chains and a peptide antigen before ____
 Definition
expression on the cell surface
Term
____ different allelic variants of class I and II MHC molecules have been
identified in humans.
 Definition
Several hundred
Term
Any one person expresses only a small number of these molecules therefore this limited number of class I and II molecules must present an ____
 Definition
enormous array of different antigenic
peptides to T cells.
Term
Peptide binding by MHC Class I and II molecules ____ the fine specificity
characteristic of antigen binding by antibodies and T cell receptors.
 Definition
does not exhibit
Term
Each MHC molecule can ___and therefore exhibit some common
peptide binding features.
 Definition
bind numerous peptides
Term
MHC Class I molecules bind peptides and present them to ____
 Definition
CD8+ T cells
Term
MHC Class II molecules bind peptides and present them to ___
 Definition
CD4+T cells.
Term
Peptides presented by MHC Class I molecules are typically ____peptides
.
 Definition
endogenous
Term
Peptides presented by MHC Class II molecules are typically ____ peptides
 Definition
exogenous
Term
The ability of an individual class I MHC molecule to bind to a diverse spectrum of peptides is due to the presence of ___
 Definition
the same or similar amino acids at several defined positions.
Term
In Class I, amino acids =___because they anchor the peptide to the MHC peptide groove.
 Definition
anchor residues
Term
Anchor residues are typically __ and peptides with the right number and type
of amino acids can bind
the same MHC Class I molecule.
 Definition
hydrophobic
Term
The generation of TCRs and antibodies is
dynamic, changing over the lifetime of the individual due to ___
 Definition
gene rearrangements and
somatic mutation.
Term
The generation of MHC molecules expressed by an individual is fixed over the person’s lifetime because _____
 Definition
the genes themselves do not
change.
Term
The MHC is polygenic— ______
 Definition
contains multiple genes—
A, B, C, DR, DQ, DP.
Term
Diversity of the MHC within a species stems from _____—the presence of multiple alleles at a given genetic locus within a species.
 Definition
polymorphism
Term
Class I and II MHC Molecules Exhibit
Diversity within a Species...The generation of MHC molecules expressed
by an individual
 Definition
is fixed over the person’s
lifetime because the genes themselves do not change.
Term
The generation of TCRs and antibodies is _____ due to gene rearrangements and
somatic mutation
 Definition
dynamic, changing over the lifetime of the
individual
Term
Diversity of the MHC within a species stems from polymorphism—____The MHC complex possesses an
extraordinarily large number of different alleles
at each locus and is one of the most
polymorphic genetic complexes known in
higher vertebrates
 Definition
the presence of multiple alleles at a given genetic locus within a species.
Term
Each HLA haplotype consists of ____and there are 4 x 1019 different
possible combinations of class I and II alleles. This means there are this many different possible haplotypes—assuming completely random combinations of alleles.
 Definition
both Class I and Class II genes
Term
However, certain allelic combinations occur more often in the population than predicted by
random combination = ____. ____ is the difference between the frequency observed for a particular combination of alleles and that expected from the frequencies of individual alleles.
 Definition
linkage disequilibrium
Term
Explanations for linkage disequilibrium:
 Definition
Too few generations...Certain combinations of alleles might produce resistance to certain diseases or might generate harmful effects..Cross-overs may be more frequent incertain DNA sequence
Term
That there is linkage disequilibrium is of what significance of Polymorphism:
 Definition
Sequence variation is greatest in the peptide binding regions of
the different allelic forms of MHC molecules allows these molecules to interact certain peptide antigens, but not others and also allows for them to interact with many different but structurally related antigens. ???
Term
Class I MHC molecules are expressed
on most nucleated cells but ___
 Definition
at varying
levels
Term
____ express the highest level
and liver cells, fibroblasts, muscle cells,
and neural cells express the lowest
levels.
 Definition
Lymphocytes
Term
Any particular MHC molecule can bind
______________
 Definition
many different peptides.
Term
MHC molecules are co-dominantly
expressed and a heterozygous
individual expresses the gene products
coded by ____
 Definition
both alleles at the MHC locus.
Term
Class I molecules will display self
peptides resulting from ___
 Definition
normal turnover
of self proteins
Term
In cells infected by a virus, ____
 Definition
viral peptides also will
be displayed by Class I molecules.
Term
Because of individual allelic differences in the
peptide binding clefts of class I molecules,
different individuals will have the ability to _____
 Definition
bind
different sets of viral peptides.
Term
MHC Class II molecules are expressed
only by antigen presenting cells such as_____—all of which are professional
APCs.
 Definition
macrophages, mature dendritic cells, and B cells but nonprofessional can also have MHC II
Term
______ that make up each Class II molecule can be
expressed off of either the maternal or
paternal chromosomes and the different
maternally and paternally derived alpha
and beta chains can associated to form
functional class II molecules
 Definition
Alpha and beta chain molecules
Term
Regulation of MHC Expression
 Definition
Promoters Positive and Negative Regulatory Elements
CIITA and RFX are transcription factors that regulate the expression of Class II genes.
Term
What are the transcription factors that regulate the expression of Class II genes.
 Definition
C II TA and
RFX
Term
Regulation of MHC Expression
Cytokines Interferons and TNF ____ in part by increasing the
expression of transcription factors that regulate MHC molecule expression.
 Definition
increase expression of class I MHC molecules
Term
Interferons can also upregulate the expression of C II TA which leads to the expression of ___
 Definition
Class II genes.
Term
IL-4 increases the expression of ____
 Definition
class II molecules by resting B cells.
Term
Interferons, prostaglandins, and corticosteroids downregulate the expression of _____.
 Definition
class II
molecules by B cells
Term
Viruses
CMV, Heptatitis B, and adenovirus decrease the expression of MHC molecules.
 Definition
CMV produces a viral protein that binds to beta-2 microglobulin, preventing assembly of MHC
molecules and expression on the cell surface.
Adenovirus decreases the expression of TAP1 and TAP2 proteins, which play a role in peptide loading of MHC Class I molecules. If peptide is not loaded, then MHC Class I molecules do not
make it to the cell surface.
Term
Certain HLA alleles occur at a much higher frequency in people suffering from certain diseases as compared to the general population..what diseases?
 Definition
Autoimmune disorders
Certain viral diseases
Certain complement disorders
Some neurological diseases
Some allergies...Association does not mean that the expression of an HLA allele causes the disease
Term
Inheritance of the HLA-B27 allele makes an individual 90 times more likely to
develop ____________
 Definition
ankylosing spondylitis—
Term
The ability of an animal to mount an immune response as measured by the
production of serum antibodies is determined by ___________
 Definition
the MHC haplotype of the animal.
Term
Control of immune responsiveness maps to the class II MHC genes
because the class II gene products play a central role in _____.
 Definition
in presenting antigen to TH cells which then affect
the development of the B cell response
Term
A great deal of variability in immune responsiveness is observed among differenthaplotypes of individuals. Why? What wild guesses have "they" made?
 Definition
Determiant Selection Model:
Holes-in-the-Repertoire Model:
Term
Determinant Model GUESS is what?
 Definition
Different class II MHC molecules differ in their ability to bind to processed antigen and therefore affect the repertoire of antigens that can be presented to T cells.
Term
Holes-in-the-Repertoire Model:
 Definition
T cells bearing receptors that recognize foreign antigens closely resembling self
antigens may be eliminated during thymic processing.
Term
Since the T cell response to an antigen involves a tri-molecular complex of the TCR,______, both models are likely to explain why certain
haplotypes of individuals respond differently to different antigenic challenges.
 Definition
antigenic, peptide, and MHC molecule
Term
Both CD4+ and CD8+ T cells can recognize antigen only when presented ____ = self MHC restriction.
 Definition
by a self-MHC molecule
Term
Processing of Antigen is a Requirement for _____
 Definition
T cell Activation
Term
Cells that display peptides associated with Class I and present to Tc cells are called ____and cells that display peptides associated with Class II and present to TH cells are called
_____________
 Definition
target cells


antigen presenting cells.
Term
Of the professional APCs, __are the most effective, constitutively expressing high levels of class II molecules as well as costimulatory molecules.
 Definition
dendritic cells
Term
Macrophages must be ___ to undergo phagocytosis before they _____
 Definition
activated
express Class II and costimulatory
molecules.
Term
B cells constitutively express MHC class II but ______
 Definition
must be activated to express costimulatory
molecules.
Term
Role of MHC and Expression Patterns..
5 things. Some of these roles lead to immune activation and some do not.
 Definition
1. Display self class I to demonstrate that the cell healthy.
2. Display foreign peptide in class I to show that the cell is infected and to engage with Tc cells.
3. To display a self peptide in class I and II to test developing T cells for autoreactivity
4. To display a self peptide in class I and II to maintain tolerance to self proteins.
5. To display a foreign peptide in class II to show the body is infected and to activate TH cells
Term
MHC Molecules Present Both
_______________
Antigens
 Definition
Intracellular and Extracellular
Term
Endogenous antigens (generated
within the cell) are processed by the
___and presented in the
context of class I MHC molecules.
 Definition
cytosolic pathway
Term
Exogenous antigens (taken up by
endocytosis) are processed by the
____ and presented in
the context of class II MHC
molecules
 Definition
endocytic pathway
Term
Endogenous Antigens: The Cytosolic
Pathway...Intracellular proteins are tagged with ____and degraded by the ____, which is a
cellular “garbage disposal” located within the cytosol.
 Definition
ubiquitin
proteasome
Term
The immune system uses the ___ pathway to degrade proteins, producing small peptides for presentation with class I MHC molecules.
 Definition
Cytosolic
Pathway
Term
In addition to the regular proteasome, immune cells have an __which can be
induced by interferon and TNF and is found in virally infected cells. It is thought to play a distinct role in processing viral antigens for
class I presentation.
 Definition
immunoproteasome,
Term
Some of the proteins coded by the MHC
contribute to the formation of the
___
 Definition
immunoproteasome.
Term
The immunoproteasome is more efficient at creating
peptides that bind to ____
 Definition
class I MHC molecules.
Term
MHC encoded ____ proteins are transporter proteins associated with antigen processing. They are
transmembrane proteins that have a cytosolic domain
and RER spanning domains as well as an RER luminal domain.
 Definition
TAP1 and TAP 2
Term
The cytosolic domains of TAP1 and 2 contain ATP
binding and peptide binding domains. In an ATP
dependent manner, TAP1 and 2 bind peptides containing
8-16 amino acids and transport the peptides from the
cytosol _____
 Definition
to the RER lumen.
Term
The peptides may be further trimmed by the ____ and then allowed to associate
with MHC Class I molecules.
 Definition
ER aminopeptidase (ERAP)
Term
___ of TAP and LMP genes exist
within the population and can affect the efficiency of
making peptide to present
 Definition
Different allelic forms
Term
Within the RER membrane, a newly synthesized class I alpha chain associates with _____, a molecular
chaperone until beta-2 microglobulin binds to the alpha chain.
 Definition
calnexin
Term
______ releases calnexin and allows binding to the chaperonin
calreticulin and to tapasin, which is associated with the peptide transporter TAP.
 Definition
Subsequent binding to beta-2 microglobulin
Term
ERp57 forms a disulfide bond to ____ and noncovalently associates with calreticulin to stabilize their
interaction and allow for release of the MHC alpha chain and beta-2 microglobulin after acquisition of
peptide.
 Definition
tapasin
Term
_____ promotes peptide capture by the class I molecule before the peptides are exposed to the
luminal environment of the RER. If a peptide is not associated with class I, it will be degraded by ERAP.
 Definition
TAP protein
Term
This association of the antigenic peptide stabilizes the class I molecule allowing the class I molecule—
peptide complex to be ___
 Definition
released from the RER.
Term
antigen from outside the cell...process the antigen by what pathway...
 Definition
Exogenous Antigens: The Endocytic Pathway....APCs internalize antigen by phagocytosis and/or endocytosis.
Term
Peptides are generated from internalized molecules in _____
 Definition
endocytic vesicles.
Term
Internalized exogenous antigen moves through several ____, in which it
is degraded into peptides that ultimately associate with class II MHC molecules
transported in vesicles from the golgi complex.
 Definition
acidic compartments
Term
Within the RER, a newly synthesized class II MHC molecule binds an ______.
 Definition
invariant chain
Term
The bound invariant chain, which has sorting signals in its cytoplasmic tail helps to direct the
class II complex to ____
 Definition
endocytic compartments containing peptides derived from exogenous
antigens.
Term
As the complex moves through the endocytic compartments, the invariant chain is degraded
leaving the _______ bound to the class II molecule,
preventing premature binding of peptides to class II molecules.
 Definition
class II-associated invariant chain peptide (CLIP)
Term
A nonclassical class II MHC molecule, HLA-DM mediates the exchange of CLIP with antigenic peptide. HLA-DM is found ____
 Definition
within the endosomal compartment.
Term
The exchange of __ for peptide that is mediated HLA-DM can be down regulated when
HLA-DO associates with HLA-DM thereby decreasing the exchange rate.
 Definition
CLIP
Term
Cross-Presentation of Exogenous Antigens In some situations APCs will divert exogenously processed antigen to a pathway that
leads to class I MHC loading and peptide presentation to CTLs.
Cross presentation requires that internalized antigens that would normally be
handled by the exogenous pathway leading to class II MHC presentation somehow _____ loading pathway.
Cross-priming—leads to activation of CTL responses
Cross-tolerance—leads to induce of tolerance in the CD8+ T cells.
 Definition
become redirected to a class I peptide
Term
Cross-tolerance—leads to induce of tolerance in the ____.
 Definition
CD8+ T cells
Term
Dendrtic cells internalize and process antigen through the ___ pathway and
present to CD4+ TH cells via MHC class II molecules and costimulatory molecules (CD40).
 Definition
endogenous
Term
The activated TH cells then serve as a bridge to help activate CTL responses by providing ___.
 Definition
local IL-2
Term
The TH cells ___cell to cross-present internalized antigen in MHC class I and to upregulate constimulatory molecules and down regulate
inhibitory molecules.
 Definition
license the dendritic
Term
DC licensing creates a situation for ____
 Definition
antigen-specific CD8+ T cell activation.
Term
Within the RER, a newly synthesized class II MHC molecule binds an ____.
 Definition
invariant chain

((Exogenous Antigens: The Endocytic Pathway of Class II MHC antigen presenting cells))
Term
The _____, which has sorting signals in its cytoplasmic tail helps to direct the
class II complex to endocytic compartments containing peptides derived from exogenous
antigens.
 Definition
bound invariant chain
Term
The bound invariant chain, which has sorting signals in its cytoplasmic tail helps to direct the
class II complex to _____containing peptides derived from exogenous
antigens.
 Definition
endocytic compartments
Term
The bound invariant chain, which has sorting signals in its cytoplasmic tail helps to direct the
class II complex to endocytic compartments containing peptides derived from ___
 Definition
exogenous antigens.
((Exogenous Antigens: The Endocytic Pathway))
Term
Exogenous Antigens: The Endocytic Pathway is about __
 Definition
APCs internalize antigen by phagocytosis and/or endocytosis and presenting ... MHC II
Term
Exogenous Antigens: The Endocytic Pathway Class II MHC
APCs internalize antigen by phagocytosis and/or endocytosis.
Peptides are generated from ___
 Definition
internalized molecules in endocytic vesicles.
Term
Peptides are generated from ______ in endocytic vesicles
 Definition
internalized molecules
Term
Internalized exogenous antigen moves through several acidic compartments, in which it
is degraded into peptides that ultimately associate with class II MHC molecules
transported in vesicles from the ____
 Definition
golgi complex
Term
_____ moves through several acidic compartments, in which it
is degraded into peptides that ultimately associate with class II MHC molecules
transported in vesicles from the golgi complex
 Definition
Internalized exogenous antigen
Term
Exogenous pathway steps of class II MHC
1. Class II MHC α and β bind invariant chains (blocking endogenous antigen.
2 MHC II complex is routed through Golgi to endocytic compartments
 Definition
3 Invarient chain degraded leaving CLIP
4 Exogenous antigen taken up, degraded, routed to endocytic path
5 HLA-DM mediates exchange of CLIP for antigenic peptide 6 Class II MHC-peptice is transported to plasma membrane
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