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Translational Medical Sciences > A vaccine for T1 diabetes > Flashcards

A vaccine for T1 diabetes Flashcards

1
Q

What are the main symptoms of diabetes

A
  • Thirsty
  • Tired
  • Toilet
  • Thin
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2
Q

What can you test to find information relating to the metabolic status and disease progression of patients with T1DM?

A
  • Genetic variants
  • autoantibiodies
  • c-peptide
  • immune cell subsets
  • cytokine response
  • biomarkers (methylated DNA) possibly
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3
Q

Describe the stages of T1 diabetes

A
  • Individuals have a genetic predisposition to diabetes
  • a precipitating event triggers the onset of overt immunological diabetes
  • progressive loss of insulin release
  • c-peptide detectable
  • no c-peptide detected
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4
Q

What has pathology been associated with T1 diabetes

A

enterovirus infection

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5
Q

Why is it hard to assess the pancreas

A

relatively inaccessible organ

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6
Q

What are the roles of the pancreas

A
  • major role: make digestive enzymes

- 2% activity: making insulin

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7
Q

What is the hallmark of T1 diabetes

A
  • patients with T1 diabetes have a system destruction of beta cells in islets of langerhans
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8
Q

How does the immune attack in T1 diabetes work

A
  • immune cells proceed in a very irregular way
  • presence of immune cell in the pancreas is abnormal
  • immune response is irregular as some beta cells are destroyed while some remain intact
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9
Q

What is the distribution of immune cells in the inflamed islets

A
  • Macrophages
  • Lymphocytes
    • CD8
    • CD4
    • cytotoxic b-cells
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10
Q

Describe the pattern of islet immune cell infiltration

A
  • CD8+ mediated cytotoxic response
  • as beta cells die off, CD8 cells increase in number
  • as CD8 cells increase, insulin decreases
  • B cells also infiltrate and multiply alongside T cells
  • once insulin production ceases, immune cells continue to circulate still
  • destruction of beta cells takes a long time (months-years)
  • early intervention could prevent diabetes
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11
Q

What is the relationship between enterovirus infection and diabetes

A
  • the tendency to cause diabetes upon infection isn’t genetic but epigenetic
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12
Q

What is an enterovirus

A

A virus with a single stranded RNA genome

- genome encodes proteins, many of which create the viral capsid in which nucleic acids are kept

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13
Q

Name some proteins which are a part of the viral capsid

A
  • VP1,2, 3,4
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14
Q

What can VP1 be used for

A
  • VP1 is highly immunogenic

- an antibody for VP1 can be used to study presence of the virus

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15
Q

What does the presence of VP1 in pancreatic cells indicate

A
  • that pancreatic beta cells are susceptible to infection

- enterovirus somehow impairs the functioning of beta cells

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16
Q

Name some cellular antiviral responses specific to pancreatic cells

A
  • protein kinase R (which arrests translation and stops protein synthesis)
  • Mda5 and RIG1 (viral genome sensors) which increase interferon expression and prime surrounding cells
  • TLRs: increase interferon expression
  • Mda5 detects dsRNA and is upregulated in Beta-cells
17
Q

How has MDA5 been linked to T1 diabetes

A

has been identified as a critical gene that predisposes T1 diabetes

18
Q

Which viral sensor has been observed in pancreatic cells with VP1

A

PKR

19
Q

How does PKR lead to translational arrest (with diagram)

A
  • ER stress activates GPR78 in the lumen
  • active GPR78 phosphorylates PERK in the cytosol
  • PERK activates eIF2a to produce proteins
  • PKR prevents eIF2a from synthesising proteins by phosphorylating it
  • proteins aren’t produced anymore but continue to be broken down
20
Q

What happens to MLCL2 expression during infection by VP1

A
  • switched off when protein translation is off by PKR

- Mlcl2 is an anti-apoptotic protein

21
Q

What is inulinitis

A
  • invasion of the pancreatic islets of langerhans by lymphocytes which causes an autoimmune or inflammatory response leading to the destruction of beta cells
22
Q

What is the normal profile of immune cells in T1 diabetes

A
  • lymphocytes and macrophages have been seen in infiltrated islets
  • draw the graph
  • seems to be a CD8 cytotoxic mediated response
  • CD8 and CD20 move into the cell in parallel
  • Both cells are being recruited to islets in parallel and together they mediate the demise of Beta cells
  • Profile is consistent with mechanism that both cells play a role and drive Beta cell destruction
  • Macrophages follow a similar invasion peak but in less in quantity
  • human islets show least amount of CD4 cells
23
Q

Describe how a viral infection becomes persistent in Beta cells

A
  • some virally infected beta cells evade the immune response
  • when virus invades, there a spike in replication of +ve double stranded RNA
  • after a few days, this replication is arrested not by an immune response but the beta cells itself (probably its anti-viral responses)
  • despite clearance, a small percentage of beta cells remain positive for viral DNA but don’t produce capsid proteins
  • therefore, the virus continues to persist in a genomic form (RNA proteins) within the beta cell
24
Q

Describe the infection of beta cells

A 
Direct cytolytic response
- beta cell necrosis
- autoimmune beta cells
Indirect immune response
- viral antigens expressed
- beta cell antigens altered
- expression of cytokines or HLAs
- Autoimmune beta cells
25
Q

List the differences between acute and persistent enteroviral infection in T1D

A

Acute infection
- cytotoxic pathway is activated and leads to cell lysis
- involves CD4 and CD8 cells
- release of free virus, viral and beta cell specific antigens
- expression on HLAs
- single stranded
Persistent infection
- persistence of viral RNA and proteins in beta cells
- upregulation of HLA1
- increased visibility of Beta cells to immune cells
- presence of interferon signature
- enhanced response in genetically at-risk individuals
- Stimulation of resting b cell specific antibody production

26
Q

Describe how you could demonstrate that T1 diabetes is caused by a viral infection

A
  • detection of VP1, dsRNA
  • detection of anti-viral cell strategies
    • PKR
    • Mda5 and RIG1
    • TLRs
    • Mlcl1 (inhibited by PKR)
27
Q

Why is there no commercially available vaccine for enteroviral T1D

A
  • no vaccine has been developed yet that recognises enteroviral serotypes in the pancreas
28
Q

Name a commercially used eneteroviral vaccine

A

Polio (which isn’t involved in the pancreas)

29
Q

What is the latest progress made in enterviral T1D vaccines

A
  • a vaccine for coxsackie virus is being tested (safe for mice but not humans)
30
Q

What can be targeted by an enterovaccine

A
  • a possible genomic approach
  • targeting dsRNA in enterviruses
  • children should be vaccinated soon after birth before encountering risk
  • this way immune system is primed before encounter
  • possibly vaccinate those with a genetic risk
31
Q

How do dsRNA multiply in beta cells

A
  • virus hijack the secretory granule vesicle membranes intended for insulin secretion and use them to multiply
32
Q

What is the proposed genetic basis of T1D

A
  • known that it’s inherited
  • genetic component determines risk level for diabetes
  • no mutations included only polymorphisms
  • polymorphisms are naturally found in the population and aren’t cell type specific but can cause variations in protein expression
  • those with a genetic susceptibility have a greater immune response to viral infection are hence are more likely to get T1D
33
Q

Name some external factors that can contribute to T1D

A
  • entervirus
  • sunlight exposure
  • diet
34
Q

What is the current outlook on T1D

A
  • previously believed that immune cells were the basis
  • now believed that beta cells themselves are the problem
  • Beta cell get inappropriately attracted to the immune system
  • Trigger for this attraction could be external (enterovirus, diet, sunlight exposure) or internal
  • Must be a change in cell that makes it visible to immune system
  • Immune system response results in T1D
35
Q

Name two biomarkers for T1D

A

Markers of autoimmune disease

  • Anti-GAD antibodies
  • IAA (Insulin auto-antibodies)

Translational Medical Sciences (8 decks)

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