Micro I-7: Major Histocompatibility Complex

Front 1

Describe the T cell receptor

Back 1

A transmembrane receptor that is obligatorily associated with the CD3 complex. CD3 functions as the signal transducing unit

Front 2

What are the two different types of MHC molecules, and what are they associated with?

Back 2

MHC I, associated with CD8+ & MHC II, associated with CD4+

Front 3

What was the MHC first associated with

Back 3

Rapid rejection of tissue transplants

Front 4

What is another name for the MHC

Back 4

Human leukocyte antigens (HLAs)

Front 5

Which genes are the most polymorphic genes in the genome of mammals

Back 5

MHC genes

Front 6

What are the three MHC I genes

Back 6

HLA-A,B,C

Front 7

What are the three MHC II genes

Back 7

HLA-DR,DP,DQ

Front 8

What is the structure of MHC I

Back 8

a MHC-encoded heavy chain (alpha chain) and a light non-MHC encoded subunit (B2-microglobulin). The alpha chain has a1 and a2 polymorphic domains, and a3 segement that binds CD8

Front 9

What is the structure of MHC II

Back 9

two chains of equivalent mass: alpha chain and Beta chain. a1 and B1 form the peptide binding cleft, and nonpolymorphic B2 binds CD4

Front 10

Which pathway uses MHC I

Back 10

Endogenous, for antigens found in the cytosol. Includes viruses and other intracellular pathogens. Found in all nucleated cells

Front 11

How are cytosolic proteins targeted for degradation

Back 11

Covalent addition of ubiquitin, which leads it to a proteasome

Front 12

Which pathway uses MHC II

Back 12

The exogenous pathway, for antigens outside the cell. Used only by professionals, such as dendritic cells, macrophages, and B cells

Front 13

What stabilizes the MHC II molecules during lysosomal fusion

Back 13

CLIP, which will be replaced by the peptide

Front 14

What do MHC molecules bind?
How is peptide selection determined by the MHC?
What do these pockets specify?

Back 14

- Both foreign and self peptides
- by the size and shape of “pockets” in the
floor of the MHC molecule
- subsets of peptides, which contain specific anchor residues that fit into the pockets

Front 15

What good are polymorphisms?
How?

Back 15

- They increase both the variety of peptides that are recognized and the variety of TCRs that can bind
- polymorphisms cause a change in size and shape of the pockets.

Front 16

What stabilizes the TCR/MHC-peptide interaction

Back 16

CD8 or CD4

Front 17

Why do extensive polymorphisms exist

Back 17

To counter evasive strategies of pathogens

Front 18

Definition of Major Histocompatibility Complex (MHC)?
General Nomenclature of MHC for humans?

Back 18

- an extended genetic locus encoding specialized proteins that were originally
characterized as the primary (“major”) locus influencing skin graft acceptance
or rejection (“histocompatibility”)
- Human Leukocyte Antigens (HLA)

Front 19

What is the function of the MHC?

Back 19

- Cell-associated MHC + antigen stimulates the T cell receptor (TCR)

Front 20

Are NK cell Killer-Inhibitory Receptors (KIRs) antigen-specific?

Back 20

- No they are NOT antigen-specific (peptide is irrelevant)

Front 21

What did Snell’s experiments demonstrate?

Back 21

- That a graft with a differing MHC is the primary locus responsible for graft rejection

Front 22

What role does MHC have in immunity?

Back 22

- w/o MHC, there is no Ab response, and thus no adaptive immunity

Front 23

What chromosome are the MHC genes located?
What are the Class I MHC?
What are the Class II MHC?

Back 23

- Chromosome 6
- HLA-A, -B, -C
- HLA-DR, -DP, -DQ

Front 24

Which cells express Class I MHC?

Back 24

- all nucleated cells (every cell of every organ/tissue; NOT red blood cells)

Front 25

Which cells express Class II MHC?

Back 25

- restricted to “professional” antigen- presenting cells (APCs) = Dendritic cells (most important APC), B cells, Macrophages

Front 26

What is the associated HLA allele of ankylosing spondylitis?

Back 26

B27

Front 27

What is the associated HLA allele of Reactive arthritis (Yersinia, Salmonella, Gonococcus)?

Back 27

B27

Front 28

What is the associated HLA allele of Reiter’s syndrome?

Back 28

B27

Front 29

Ankylosing spondylitis, reactive arthritis, and Reiter’s syndrome all show B27 as the associated HLA allele. What does this show?

Back 29

- shows that MHC gene polymorphism is highly medically relevant

Front 30

What are the two sources of peptides?

Back 30

- Cytosolic (“endogenous”) proteins: e.g., host cell structural proteins, viral pathogen proteins
- Extracellular (“exogenous”) proteins: e.g., host serum proteins, bacterial pathogen proteins

Front 31

What is the MHC association of Cytosolic (“endogenous”) peptides?
What is the MHC association of extracellular (“exogenous”) peptides?

Back 31

- associate with MHC class I
- associate with MHC class II

Front 32

What is the endogenous pathway of MHC class I antigen processing and presentation?
How does the cytosolic ptn transport from the cytosol to ER?

Back 32

- Production of ptns in cytosol -> proteolytic degradation of ptns -> transport of peptides from cytosol to ER -> assembly of peptide-class I MHCcomplexes in ER -> surface expression of peptide-class I complexes
- Two TAP Gene Products Form a Transporter Complex That Moves Peptides From the Cytosol to the ER

Front 33

What is the exogenous pathway of MHC class II antigen processing and presentation?

Back 33

- Uptake of extracellular ptns into vesicular compartments of APC -> processing of internalized ptns in endosomal/lysosomal vesicles -> biosynthesis and transport of class II MHC molecules to endosomes -> association of processed peptides with class II MHC molecules in vesicles -> expression of peptide-MHC complexes on cell surface

Front 34

What is the function of the invariant chain (Ii)?
How does this affect the processing and presentation of extracellular antigen from intracellular antigen?

Back 34

- blocks the peptide binding groove
of MHC II until fusion with low-pH lysosomes/endosomes
- peptide does not get sent to the ER for further processing; instead it goes straight to the surface to be presented. For intracellular peptides, peptides get processed in ER and Golgi, and THEN gets presented on the surface.

Front 35

Intracellular pathogens: viruses, etc are associated with which type of MHC class?
How does evolution explain this?

Back 35

- MHC class I
- All cells are vulnerable to such infections, and all cells must thus have a way of presenting such pathogen peptides to T cells, for recognition and elimination

Front 36

Extracellular pathogens: bacteria, fungi, etc are associated with which type of MHC class?
How does evolution explain this?

Back 36

- MHC class II
- These pathogens can be readily accessed by phagocytosis and other engulfment mechanisms. The evolution of specialized antigen sampling cells is a very efficient way to monitor the entire extracellular space of an organism.

Front 37

What determines the peptide binding specificity of the MHC?
What affects the size and shape of these pockets?

Back 37

- Binding specificity is determined by the size and shape of “pockets” in the peptide-biding groove of the MHC molecule
- Individual MHC genes and alleles have peptide-binding pockets in different sizes, shapes, and locations. Thus, distinct alleles bind different subsets of peptides

Front 38

Where are the MHC polymorphisms located?
What do polymorphisms influence (2)?

Back 38

- Polymorphisms occur in regions of the MHC
that contact the peptide and the TCR
- 1) MHC binding to peptides and 2) MHC recognition by the TCR

Front 39

How does the peptide influence the
binding of the TCR?

Back 39

- Peptide residues which are not buried in the MHC groove
serve as binding sites for the TCR

Front 40

What does CD8 bind to on MHC I?
What does CD4 bind to on MHC II?

Back 40

- Alpha 3 domain
- Beta 2 domain

Front 41

What is a rule about MHC termed MHC restriction?

Back 41

- A given TCR will only recognize a specific MHC molecule in complex with a unique (or a few similar) peptide(s)

Front 42

Why is the knowledge of MHC restriction of T cell responses to antigen important?

Back 42

- b/c it is the basis of functional T cell immunity and transplant rejection

Front 43

Inability of an individual’s MHC to efficiently present peptides from the specific pathogen can cause what?
Then how is this problem solved?

Back 43

- individual may be highly susceptible to infection by a specific pathogen
- within the community or “herd” as a whole, individuals will have many different MHC alleles, of which many will bind the pathogen peptides conferring resistance to pathogen infection = MHC becomes highly polymorphic

Front 44

What is needed for long-term allograft survival after tissue transplant?

Back 44

- good cross-matching btwn donor and recipient and immuno-suppressive drug treatment

Front 45

What is the most useful test in definitive diagnosis of many autoimmune diseases?

Back 45

- HLA typing