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97 Cards in this Set

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T-cells only recognize processed Ag presented on what?
Only processed Ag presented on MHCs.
Ag presented on an MHC may also be referred to as what?
May be referred to as an HLA complex in humans and H-2 in mice.
In what mammalian species are genes that constitute MHCs present in?
They are present in EVERY mammalian species.
MHCs are implicated in susceptibility to ? and ?.
Implicated in susceptibility to disease and autoimmunity.
MHCs are important for discrimination between what?
Important for discrimination between self and non-self.
When were MHCs discovered?
They were discovered during studies of rejection to transplanted tissue.
MHC encodes how many classes of molecules?
MHC encodes 3 major classes of molecules.
Name the 3 major classes of molecules that are encoded by MHC.
1. Class I MHC genes

2. Class II MHC genes

3. Class III MHC genes
Describe class I MHC genes.
They encode glycoproteins found on the surface of nucleated cells. It present Ags to Cd8/TC cells.
Describe class II MHC genes.
It encodes glycoproteins on APCs to present processed Ags to CD4/Th cells.
Describe Class III MHC genes.
They encode various secreted proteins that have immune functions. (ie, complement and other inflammatory mediators)
In both humans and mice how is MHC organized?
It is organized into regions.
Class I MHC genes and Class II MHC genes have common ? features.
They have common STRUCTURAL features.
Class III MHC genes are flanked by what? What do class II MHC genes encode?
They are flanked by I and II regions. They encode molecules critical to immune function (ie, complement and cytokines)
?, ?, and ? arranges in pairs encoding alpha and beta chains.
DP, DQ, and DR arrange in pairs encoding alpha and beta chains.
MHC gene expression is related to a cluster of genes found where?
A cluster of genes found on CHROMOSOME 6.
Chromosome 6, as it relates to gene expression, could be described as what? Why?
It is polygenic and polymorphic. It has several gene loci. It has many alleles (gene versions)
All alleles are not found with ? ? in humans.
All alleles are not found with equal frequencies in humans.
MHC diversity is a ? ?.
It is a population diversity.
What is a set of MHC genes inherited from each parent called?
It is called a HAPLOTYPE.
What is the probability of siblings inheriting identical haplotypes from both parents?
Sibling have a 1 in 4 probability of inheriting the same haplotypes.
What makes tissue matching between unrelated relative very unlikely?
MHC polymorphism makes this very unlikely.
Why is MHC polymorphism so powerful?
It is powerful because it enable different allelic class I and Class II products to bind an ALMOST infinite array of peptides.
A class I molecule has a ? ?, while class II has a ? ?.
Class I has a deep socket, II has an open pocket.
Class I has an ? chain with ? domains.
Class I has an alpha chain with 3 domains.
In class I which alpha chain is highly conserved and has a sequence of amino acids that interacts with Tc/CD8.
alpha 3
Class I has ? microglobulin.
It has Beta 2 microglobulin.
What is Beta 2 microglobulin required for?
It is required for Class I expression.
Class II is composed of two ?-? chains.
Composed of two non-identical chains.
What are the two non-identical chains of class II composed of?
They are composed of two alpha domains and two beta domains.
It could be said that MHC molecules are what? Explain.
They are promiscuous. They do not exhibit the specificity of Abs and TCRs.
How many allelic variants of MHC are there in humans?
There are several hundred allelic variants in humans.
How many class I and class II molecules are expressed by an individual?
Every individual only expresses up to 6 different class I molecules and up to 12 different class II molecules.
Peptide binding sites are ?.
They are POLYMORPHIC.
What is an anchor residue?
Amino acids that anchor the peptide into the MHC groove. It should be noted that all peptides that binds to Class I molecules contain a carboxyl terminal anchor that are usually hydrophobic (leucine, isoleucine).
The peptide binding domain of Class I molecules?
Alpha 1/ Alpha 2.
The peptide binding domain of class II molecules?
Alpha 1/ Beta 1
The nature of the peptide binding cleft of class I molecules?
It is closed at both ends.
The nature of the peptide binding cleft of class II molecules?
It is open at both ends.
The general size of bound peptides of Class I molecules?
8-10 amino acids.
The general size of bound peptides of Class II molecules?
13-18 amino acids.
The peptide motifs involved in binding to MHC molecule for class I molecules?
Anchor residues at both ends of peptide; generally hydrophobic carboxyl-terminal anchor.
The peptide motifs involved in binding to MHC molecule for class II molecules?
Anchor residues distributed along the length of the peptide.
The nature of the bound peptide for class I molecules?
Extended structure in which both ends interact with MHC cleft but middle arches up away from MHC molecule.
The nature of the bound peptide for class II molecules?
Extended structure that is held at a constant elevation above the floor of MHC cleft.
MHC molecules are ? diverse. Explain.
They are ENORMOUSLY diverse. This diversity is seen within a species and within an individual.
Is MHC diversity for the same reasons that Abs and TCRs are diverse? Explain.
No, it is not the same. Abs and TCR are dynamic and changing. MHCs are fixed in the genes and do not change.
MHC expression is dependent upon ? type.
Dependent upon CELL-TYPE.
Where is MHC I found?
On all NUCLEATED CELLS.
Where is MHC II found?
Found only on APCs.
Where are the highest levels of MHC I found?
The highest levels are found on lymphocytes.
Name 4 cell types that express low levels of MHC I?
1. Neural cells

2. Fibroblasts

3. Muscle cells

4. Hepatocytes
Which cells appear to lack MHC?
Neurons and sperm cells (at certain stages) appear to lack MHC.
MHC II is found only on APCs. What does expression depend upon? Explain.
Expression varies depending on cell differentiation stage. Pre-B-cells lack MHC II. Low levels on monocytes and macrophages until activation by Ag and then level of expression dramatically increases.
Is MHC expression regulated.
Yes, it is regulated.
List 3 things that are involved in the regulation of MHC expression?
1. Transcription Factors

2. Various cytokines

3. Viruses
How are transcription factors involved in the regulation of MHC expression?
MHCs are flanked by 5' promoter sequences. They are mediated both positively and negatively.
How are various cytokines involved in the regulation of MHC expression?
INFs and TNF increase MHC I expression. IL-4 increases the expression of MHC II on resting B-cells.
Name 3 viruses that are involved in the regulation of MHC expression.
1. CMV

2. HPV

3. AD12
Bare lymphocyte syndrome is the result of what?
It is the result of a defect in TRANSCRIPTION.
How many MHCs do BLS patients express?
Bare lymphocyte syndrome patients express little to no MHCs.
BLS patients expression of little to no MHCs leads to an increased susceptibility to what?
They have an increased susceptibility to viral and opportunistic infections.
What are the symptoms seen in BLS patients?
The symptom range from none to SCID (Severe combined immunodeficiency).
A defect in what 2 genes is involved in BLS syndrome? Explain.
A defect in TAP1 and TAP2 genes. These TAP proteins are required for the loading of peptides.
List 5 diseases that compromised MHC leaves you susceptible to?
1. Autoimmune disorders

2. Some viral diseases

3. Complement disorders

4. Neurological disorders

5. Some allergies
Give an example of an autoimmune disorder that a person with compromised MHC expression is susceptible to?
HLA B27 allele (Ankylosing Spondylitis)
Give an example of a neurological disorder that a person with compromised MHC expression is susceptible to?
HLA-DR2 (Narcolepsy)
In the 1970s it was discovered that both ? and ? T-cells could recognize Ag only when couple with a ?-? molecule.
Both CD4 and CD8 T-cells could recognize Ag only when coupled with a self-MHC molecule. This is related to self-MHC restriction.
T-cells require ? Ag.
T-cells require PROCESSED Ag.
The target cells involved in Ag processing and presentation display what?
They are cells that display peptides associated with MHC I to CD8/Tc cells.
APCs associated with Ag processing and presentation display what?
They display peptides associated wtih MHC II to CD4/Th cells. (However, sometimes APCs can present Ag on MHC I).
APCs must express ? ? and deliver a ? signal.
APCs must express MHC II and deliver a co-stimulatory signal.
List 3 professional antigen presenting cells.
1. Dendritic cells (several types)

2. Macrophages

3. B cells
What are the most effective professional antigen presenting cells?
Dendritic cells
What must macrophages be activated by before they become an antigen presenting cell?
They must be activated by phagocytosis.
B-cells constitutively express ? but require activation before they express ? molecules.
They express MHC II but require activation before they express costimulatory molecules.
Dendritic cells express MHC II. What else do they have the ability to use?
They can also use MHC I.
Dendritic cells are ?. Why is this fortunate?
They are NUCLEATED. This is fortunate because most viruses infect cells other than APCs. This relates to "altered self-cells".
Give 3 examples of altered self-cells that can serve as targets for viruses?
Cancer cells, aging body cells or allogenic cells from a graft can serve as targets for dendritic cells that use MHC I.
How are intracellular and extracellular Ags trafficked?
They are trafficked through separate intracellular compartments.
List two intracellular compartments by which intracellular and extracellular Ags may be trafficked through.
1. Cytosolic Pathway

2. Endocytic Pathway
The cytosolic pathway is responsible for processing which Ags? Where is it presented?
Responsible for processing endogenous Ags. (Like viruses replicating within a nuceate host cell). It is presented on membrane with MHC I.
The endocytic pathway is responsible for processing which Ags? Where is it presented?
Processes exogenous Ags. It is presented on the membrane with MHC II.
In eukaryotes, ? levels are regulated.
Protein levels are regulated.
In the cytosolic pathway for endogenous Ags intracellular proteins are degraded into ? ? by ?.
Intracellular proteins are degraded into SHORT PEPTIDES by PROTEOLYSIS (PROTEOSOME).
In the cytosolic pathway for endogenous Ags, the protein targeted for proteolysis has what associated with it?
It has UBIQUITIN associated with it.
List the 5 steps for the pathway of class I MHC-associated antigen presentation.
1. Production of proteins in the cytosol.

2. Proteolytic degradation of cytosolic proteins.

3. Transport of peptides from cytosol to ER.

4. Assembly of peptide-class I complexes in ER.

5. Surface expression of peptide-class I complexes.
What do chaperone molecules help peptides assemble?
They help peptides assemble with MHC-I.
What does MHC I require the presence of for stability?
MHC-I requires the presence of a PEPTIDE for stability.
When peptides are assembled with MHC-I what, at the cell surface, recognizes Ag?
At the cell surface CD8/Tc cells recognize Ag.
Where are the alpha chain and beta2-microglobulin made? What protein are they associated with?
They are made in the RER. They are associated with the ER membrane protein CALNEXIN.
In the endocytic pathway for exogenous Ags what happens to the exogenous Ags? What is involved?
Exogenous Ags are internalized by APCs and are phagocytosed and processed for presentation with MHC-II. This involves endosome action, MHC transport, and MHC-peptide binding.
List the 5 steps of the pathway of class II MHC-associated antigen presentation.
1. Uptake of extracellular proteins into vesicular compartments of APC.

2. Processing of internalized proteins in endosomal/lysosomal vesicles.

3. Biosynthesis and transport of class II MHC molecules to endosomes.

4. Association of processed peptides with class II MHC molecules in vesicles.

5. Expression of peptide-MHC complexes on cell surface.
What is "cross-presentation" necessary for?
It is necessary for immunity against most tumors and viruses that avoided APCs.
What does "cross-presentation" play a role in?
It plays a role in HPV, Influenza, CMV, EBV, Listeria, Salmonella, and E. Coli. Also seen in tumors of the brain, pancreas, melanoma, and leukemia.
Where is the clearest example of "cross-presentation" seen?
The clearest example is found on dendritic cells.
Describe the mechanism of cross-presentation?
The mechanism is not totally clear. It involves transportation by TAP to ER where association with MHC I occurs. The MHC I complex goes to cell surface where it can be detected by CD8/Th cells.