A vaccine for T1 diabetes Flashcards
What are the main symptoms of diabetes
- Thirsty
- Tired
- Toilet
- Thin
What can you test to find information relating to the metabolic status and disease progression of patients with T1DM?
- Genetic variants
- autoantibiodies
- c-peptide
- immune cell subsets
- cytokine response
- biomarkers (methylated DNA) possibly
Describe the stages of T1 diabetes
- 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
What has pathology been associated with T1 diabetes
enterovirus infection
Why is it hard to assess the pancreas
relatively inaccessible organ
What are the roles of the pancreas
- major role: make digestive enzymes
- 2% activity: making insulin
What is the hallmark of T1 diabetes
- patients with T1 diabetes have a system destruction of beta cells in islets of langerhans
How does the immune attack in T1 diabetes work
- 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
What is the distribution of immune cells in the inflamed islets
- Macrophages
- Lymphocytes
- CD8
- CD4
- cytotoxic b-cells
Describe the pattern of islet immune cell infiltration
- 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
What is the relationship between enterovirus infection and diabetes
- the tendency to cause diabetes upon infection isn’t genetic but epigenetic
What is an enterovirus
A virus with a single stranded RNA genome
- genome encodes proteins, many of which create the viral capsid in which nucleic acids are kept
Name some proteins which are a part of the viral capsid
- VP1,2, 3,4
What can VP1 be used for
- VP1 is highly immunogenic
- an antibody for VP1 can be used to study presence of the virus
What does the presence of VP1 in pancreatic cells indicate
- that pancreatic beta cells are susceptible to infection
- enterovirus somehow impairs the functioning of beta cells
Name some cellular antiviral responses specific to pancreatic cells
- 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
How has MDA5 been linked to T1 diabetes
has been identified as a critical gene that predisposes T1 diabetes
Which viral sensor has been observed in pancreatic cells with VP1
PKR
How does PKR lead to translational arrest (with diagram)
- 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
What happens to MLCL2 expression during infection by VP1
- switched off when protein translation is off by PKR
- Mlcl2 is an anti-apoptotic protein
What is inulinitis
- invasion of the pancreatic islets of langerhans by lymphocytes which causes an autoimmune or inflammatory response leading to the destruction of beta cells
What is the normal profile of immune cells in T1 diabetes
- 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
Describe how a viral infection becomes persistent in Beta cells
- 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
Describe the infection of beta cells
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
