Dr. Zeff Lectures

Question 1

Natural killer cells are especially good at dealing with _______ pathogens

Answer 1

Intracellular

Question 2

What are the 3 types of phagocytic cells?

Answer 2

Macrophages

Dendritic Cells

Neutrophils

Question 3

Which type of phagocyte cannot present MHC?

Answer 3

Neutrophils

Question 4

____ cells are responsible for mediating humoral immunity.

Answer 4

B cells

Question 5

____ cells are responsible for mediating cell-mediated immunity.

Answer 5

T cells

Question 6

Treg cells are generated through negative selection. A small subset of T cells that recognize self-peptide too strongly become Treg cells instead of undergoing apoptosis. Treg cells are only CD____+ cells.

Answer 6

4

Question 7

Define inflammation

Answer 7

Recruitment of circulating blood leukocytes and various plasma proteins to sites of infection where they function to destroy the microbes and repair damged tissue.

Question 8

Describe the process of antigen presentation via MHC II.

Answer 8

Antigen / microbe binds to receptor on surface of APC. Ag is endocytosed. Endosome fuses with lysosome that contains cathepsins, which are proteases. pH decreases in phagosome –> activates cathepsins, which degrade Ag.

Simultaneously, MHC II resides embedded in ER membrane. It is bound by invariant protein, which covers it so that it does’t bind to any peptides in the ER. An endosome from ER buds off and travels to fuse with phagosome. After fusion, proteases in the phagosome remove a small tail portion of invariant chain to produce CLIP. HLA-DM then non-enzymatically removes CLIP so that the Ag peptide (10-30AAs) can bind to MHC II. The phago-edosome then moves to the membrane where it fuses with the membrane and expresses MHC II with bound Ag on its surface.

Question 9

For MHC II, what loci will individuals have in the HLA2 region of their chromosome?

Answer 9

P Q R

They will inherit one allele from mom and one from dad at each location. These genes are co-dominant so if the have P7 (M) and P8 (D) then their APCs can express both a P7 and P8 MHC II protein. These differ slighltly in the peptides they can bind.

Question 10

MHC II is expressed on _____ cells, whereas MHC I is expressed on ______ cells.

Answer 10

APCs

Has the potential to be expressed on all cells

Question 11

Describe the general structure of MHC II.

Answer 11

Question 12

Describe the general structure of MHC I.

Answer 12

Question 13

• For MHC I, what conditions must be present in order for MHC I to be present on a cell’s surface?
• If no foreign peptides are present, what does MHC I load onto its surface?

Answer 13

• It must be bound to peptide and Beta_2_microglobin must be present.
• Self peptide

Question 14

How do cancer cells manipulate MHC I to evade the immune system?

Answer 14

They inactivate beta_2_microglobin so that without a functional Beta_2_microglobin MHC I cannot be presented and the cancer will not be detected inside the cell.

Question 15

• For MHC I, what alleles do we inherit from our parents?
• What does each allele code for?
• How are these alleles inherited?

Answer 15

• B#, C#, A# –> # represents subtype of that allele
• A complete alpha chain
• Co-dominant

Question 16

Describe the process of presentation on MHC I.

Answer 16

Virus binds to receptors on cell surface –> nucleic acid enters cell and virus replicates in the cell producing a lot of viral protein. Viral protein made in excess is recognized by the cell as aberrant and misfolded so it is tagged by Ub for degradation in the proteasome. This produces smaller viral fragments ~ 9AA in length. These fragments then enter the ER via TAP (transporter associated protein) where they are loaded onto MHC I. A vesicle buds off from the ER and fuses with the membrane, expressing MHC I with bound viral peptide on the surface.

Question 17

Does each MHC molecule display only 1 peptide?

Answer 17

Each MHC can display only 1 peptide at a time, but each MHC is capable of displaying many different peptides. There are specific positions within the binding pocket of the MHC peptide binding domain that are called anchor locations, and as long as the peptide has the complementary residues at the anchor locations then it can bind to the MHC.

Question 18

Describe cross-presentation.

Answer 18

A virus infects a cell in a tissue and that cell is not a type of cell that migrates to the lymph nodes. The infected cell presents viral Ag on MHC I. A dendritic cell recognizes the Ag and phagocytizes the infected cell and Ag. Inside the dendritic cell, the viral Ag is transported from the phagosome to the cytosol, where it will be degraded by the proteasome and enter the ER to be loaded on MHC I. Once loaded on MHC I on the surface of the dendritic cell, the dendritic cell can express MHC I + co-stimulator to activate CD8+ cells in lymph nodes.

Question 19

The TCR is similar in structure to the ______ region of Abs.

Answer 19

Variable (FAB)

Question 20

Which Abs contain an extra constant domain (CH4)

Answer 20

IgM and IgE

Question 21

This Ab is the first Ab made by a B cell.

Answer 21

IgM

Question 22

This Ab is a monomeric receptor on B cells. Very little of it will ever be found in the blood.

Answer 22

IgD

Question 23

This Ab is an opsonin, a complement activator, can cross the placenta during the 3rd trimester and mediates Ab dependent cellular cytotoxicity of NK cells.

Answer 23

IgG

Question 24

This Ab exists as a dimer and is released into the GI lumen where it binds to bacteria and antigen to prevent colonization of the gut and damge to gut mucosa.

Answer 24

IgA

Question 25

This Ab mediates hypersensitivity reactions of mast cells, B cells and eosinophils and also responds to extracellular parasites.

Answer 25

IgE

Question 26

The ____ chain in Ab and the ____ chain in TCR are more diverse.

Answer 26

Heavy

Beta

Question 27

Which of the hypervariable regions has the most diveristy and why?

Answer 27

HV3 has the most diveristy because it contains the DJ gene segments which undergo rearrangement so they are subject to high levels of diversity that is not reliant on mutation but rather a programmed mechanism of introducing diversity.

Question 28

The alpha chain of the TCR is homologous to the ____ chain of Ab.

Answer 28

Light

Question 29

The beta chain of the TCR is homologous to the ______ chain of Ab.

Answer 29

Heavy

Question 30

What sources contribute to diversity in the TCR?

Answer 30

1) The # of VDJ gene segments
2) Combinatorial diveristy - total possible combinations based off # of gene segments due to action of VDJ recombinase
3) Combinatorial association - at the protein level, any alpha portion can combine with any beta portion
4) Junctional diversity - action of TDT adding random nucleotides to sites that undergo recombination

Question 31

CD8 binds to ______ on the MHC I molecule.

Answer 31

alpha 3

Question 32

CD4 binds to _________ on the MHC II receptor.

Answer 32

Beta 2

Question 33

What part of the Ab heavy chain gene is unique to the heavy chain?

Answer 33

The d section

Question 34

Heavy Chain

How many V genes are there?

How many D genes are there?

How many J genes are there?

How many mu genes are there?

Answer 34

45

23

6

4

Question 35

Describe the action of VDJ recombinase.

Answer 35

VDJ recombinase is responsible for recombining the heavy chain genes to generate diversity. It consists of RAG1 and RAG2 that are nucleases that cleave dsDNA. Any DNA that is “spliced” out is lost as an episome, so mature lymphocytes actually don’t have an identical genome compared to other cells in the body. The first recombination is between D&J, then between V & DJ. The mRNA that is produced still contains extra V & J genes which are spliced out during post-transcriptional processing of the mRNA to produce the mature mRNA.

Question 36

What part of the heavy chain genome corresponds to the constant regions?

Answer 36

The mu

Question 37

VDJ recombination occurs during the Pro-B cell stage.

True/False.

Answer 37

True

Question 38

What is allelic exclusion and at what point during B cell maturation does it occur?

Answer 38

Allelic exclusion occurs when heavy chain that is produced is bound to surrogate light chain and moves to the membrane of the Pre-B cell. This signals to the B cell to stop making heavy chain and start making light chain.

Question 39

What Ab is expressed on immature B cell?

What about on mature B cell?

Answer 39

IgM

IgM and IgD

Question 40

IgM and IgD are the same isotype.

True/False

Answer 40

False - they are the same idiotype. They bind to the same antigen, but IgM has 4 constant domains whereas IgD only has 3.

Question 41

What 5 elements lead to diversity in B cell Abs?

Answer 41

1) The # of VDJ genes alone
2) Combinatorial diversity: the many ways in which V, D and J can combine as a result of VDJ recombination
3) Combinatorial association: the many combinations of heavy and light chain that can occur
4) Junctional diversity: the action of TDT at splice sites during VDJ recombination that adds random nucleotides to create further diversity
5) Somatic hypermutation: association of CD40 ligand on an activated T cell and CD40 receptor on a mature naive b cell leads to activation of activation induced cytidine deaminase (AID). AID is highly error prone so it results in a high degree of mutation called somatic hypermutation. These mutations occur so frequently that they are likely to eventually result in a mutation that confers a higher degree of affinity for antigen (hyper variable regions). Higher affinity results in better binding and better signaling so B cells that produce Ab with this affinity matured Abs will be selected for further proliferation (memory B cells and plasma cells) while B cells that bind less well will die off.