Trigger 5: Proposed mechanisms which implicate virus' as B-cell killers

Question 1

proposed mechanisms

Answer 1

• increased expression of PKR
• depletion of Mcl-1 in VP1 expressing cells (B cells)
• dsRNA
• elevated levels of mda5 and dsRNA

Question 2

viral receptor on b cells

Answer 2

(CAR receptors) sector granule proteins which sit on the surface- allows internalisation

Question 3

increased expression of HLA I

Answer 3

1. Virus enters beta cell and gives rise to dsRNA as well as viral antigen
2. The IFN signature in pancreatic β-cells induces the hyperexpression of class I MHC, which presents β-cell and viral antigens to CD8- cytotoxic
3. Activation of immune cells and production of β-cell–specific antibodies and viral-specific antibodies.

Question 4

what can dsRNA do

Answer 4

cause cells to spontaneously apoptose

Question 5

where does dsRNA replicated within the cell

Answer 5

intracellular membranes

Question 6

dsRNA

Answer 6

hijacks one of the intracellular membrane systems and uses as a site of replication

• B cells have a vast amount of intracellular membrane in an unusual place (due to sectors granules of insulin)- looks like they hijack the sector granules membrane

Question 7

to protect virus from taking over

Answer 7

cells switch off protein synthesis

Question 8

why do cells switch off protein synthesis

Answer 8

to prevent virus’ replication using DNA replication machinery (PKR)

Question 9

which proteins primes other cels nearby to resist infection

Answer 9

Mda5 and RIG-1

Question 10

Protein kinase r is a

Answer 10

key viral sensor

Question 11

PKR is

Answer 11

increased in cells that are immune-positive for VP1

- only happens to b cells

Question 12

what does PKR do

Answer 12

works by phosphorylating eif-2a in the protein synthesis pathway.

• phosphorylation of eif-2a inactivates it and halts translation

Question 13

PKR is a mediator of

Answer 13

translational arrest

Question 14

expression fo PKR is enhanced in

Answer 14

VP1 immunpositive islet cells

Question 15

if PKR is active (as when infected y virus)

Answer 15

it should phosphorylate eif-2a

Question 16

phosphorylation of eif-2a

Answer 16

stops protein synthesis

Question 17

effect of PKR stopping protein synthesis by phosphorylation gif-2a

Answer 17

Any proteins that are rapidly turned over, will disappear form the cell- broken down but not replaced

Question 18

labile proteins

Answer 18

broken down quickly)

Question 19

example of labile protein

Answer 19

Mcl-1

Question 20

Mcl-1

Answer 20

anti-apoptotic protein

Question 21

MCL-1 does what

Answer 21

regulates apoptosis

Question 22

MCL-1 is ….. in beta cells

Answer 22

abundant

Question 23

when a virus is present and PKR has caused translation arrest, what happens to MCL-1

Answer 23

is it not produced, therefore it is not present to prevent apoptosis- causes cell death

Question 24

humans are very sensitive to

Answer 24

dsRNA- not human

Question 25

is there dsRNA in islet cells in t1D

Answer 25

only infects insulin producing cells and not alpha cells

Question 26

up regulation of what causes an antiviral response 9by both alpha and beta cels)

Answer 26

Mda5

Question 27

outline the first arm of the viral response (APC)

Answer 27

1) APC phagocytosis Ag
2) presents to Th0 cell which causes differentiation into Th2c ell and Th1 cell
3) Th2 cells secretes cytokines which support B-cell maturation - antibody production
4) Th1 cell releases cytokines which promote cytotoxic killing of infected cells

Question 28

outline the second arm of the viral response (B cell)

Answer 28

1) B cell internalises virus and present it on antibody receptor
2) Th2 cell stimulates it to mature and produce antibodies

Question 29

outline the third arm of the viral response (direct CTL killing)

Answer 29

1) CTL binds to infected cell

2) Th1 cell releases cytokines which stimulate the CTL to cytotoxicly lil the infected cell

Question 30

which cytokines do Th1 cells produced to stimulate CTLs

Answer 30

IL-2, IL-12, IFN-y, TNF-a

Question 31

autoantibodies in those with T1D

Answer 31

• Active against many islet cells

Question 32

autoantibodies are markers for

Answer 32

underlying autoimmunity

Question 33

autoantibodies are not though to

Answer 33

cause T1D0– but cause symptoms of disease

Question 34

CAR

Answer 34

cocksackie and adenovirus receptor (what virus binds to to cause internalisation)