T1D Flashcards

1
Q

What is the difference in insulin processing/signaling in T1D vs T2D?

A

T1D: insulin is not produced by beta cells in the pancrease and hence glucose is not removed from the bloodstream, causing diabetes

T2D: prolonged overproduction of insuilin leads to desensitization of the insulin Rs and hence glucose in not removed from the bloodstream, causing diabetes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What does “diabetes” and “mellitus” mean?

A

diabetes = siphon
mellitus = sweet like honey

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is the sex bias of T1D in humans?

A

male > female

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the three stages of T1D?

A
  1. stage 1: >2 autoAbs
  2. stage 2: >2 autoAbs + abnormal BG
  3. stage 3: >2 auto Abs + abnormal BG + clinical manifestations
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What is the T1D model mouse? What are the benefits and what are the caveats?

A

model = non-obese diabetic mouse (NOD)

benefits: develops spontaneous disease mediated by autoreactive T cells beta-cell Ags + have similar genetic susceptibilities

caveats: differences between human and mouse IS + sex bias in NOD mice is oppostie of humans

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Describe the pathogensis of T1D

A
  1. the initiation phase (pancreas): Beta cell damage by “natural” apopotosis or after viral infection –> cDCs capture, process and present Beta cell Ags
  2. in the PLN, pathogenic mechanisms include: activated cDCs prime pathogenic iselt Ag-specific T cells after migration to the draining LN; macrophages promote this activation through IL-12 secretion; B cells present beta cell Ag to diabetogenic T cells and secrete autoAbs
  3. these are counteracted by tolergenic mechanisms: engagement of programmed cell death ligand 1 (PD-L1); iNKT cells can promote the recruitment of tolerogenic cDCs; pDCs that could expand Treg cells through the production of IDO, IL-10, TGFB and ICOSL
  4. in the pancrease, beta cells can be killed by: diabetogenic T cells and Nk cells through the release of IFNg, granzymes, and perforin; macrophages through the production of TNF, IL-1B, and nitric oxide
  5. beta cell damage can be inhibited by: Treg cells that inhibit diabetogenic T cells and innate ICs through IL-10 and TGFB; tolerogenic pDCs stimulated by iNKT cells could also control diabetogenic T cells through IDO production; Beta cells can inhibit diabetogenic T cells by exporessing PDL1
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

How can you depelte B cells (i.e what should you target)?

A

anti-CD20 autoAbs

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Which genes confer risk of developing T1D? Which has the strongest effects?

A
  • HLA genes exert the strongest effects
  • immune pathway genes
  • genes encoding autoAgs (e.g. IDD2 –> encodes insulin)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

In MHC molecules, where are the polymorphisms found that impact Ag presentation and thus confers susceptibility or protection to T1D?

A

polymorphisms are freqeunetly found in the peptide binding groove

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What transcription factor allows expression of tissue-restricted Ags in cTECs? What disease happens if this TF is non-functional, what happens?

A

TF = Aire

Aire-/- –> APECED –> no negative slection of T cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are tetramers? Why do we need tetramers for research?

A

used to indentify certain T cells that recognize specific peptide + MHC allele. Need tetramers because the TCR-MHC interaction is really weak

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

During T cell selection in the thymus, what kind of binding is required to become a Treg?

A

intermediate affinity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What suppressive mechanisms do Tregs use?

A
  • secretion of immunosuppressive cytokines, e.g. IL-10 and TGFB
  • contact dependent mechanisms, such as CTLA-4
  • induction of IDO
  • cytolytic activity
  • consumes IL-2
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How are Treg defective in T1D?

A

low frequency and poor function

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Which IDDM2 allele is protective and predisposing of T1D? how does the protective allele work?

A

VNTRl –> predisposing
VNTRIII –> protective – increase autoAg expression in the thymus which may increase clonal deletion of autoreactive T cells and selection of Tregs in the thymus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What cells do Tregs suppress?

A

B cells and Th cells

17
Q

What environmental factors affect T1D risk?

A
  • infections
  • dietrary factors
  • abnormal microbiome
  • overweight and insulin resistance
  • psychological stress
18
Q

How can viruses cause T1D?

A
  1. direct infection of beta cells –> beta cell death –> shedding of autoAgs; infected beta cells can activate NK cells –> death by Nk cell-mediated cytotoxicity; APCs –> activation of autoreactive T cells
  2. Ag mimicry: microbial infection causes a bystander activation of autoreactive T cells (e.g. rotavirus VP7)
19
Q

Describe the key microbiome and immune changes that happen in the gut to casue T1D

A

key microbiome changes

  • less diversity
  • altered proportions of bacterial composition
  • altered metabolites
  • less mucin

key immune changes

  • more inflammation
  • increased gut permeability
  • fewer Tregs
20
Q

What are three treatments for T1D?

A
  1. insulin
  2. islet transplantation – The Edmonton Protocol
  3. immunotherapies
21
Q

What are some targets of immunotherapies?

A
  1. immune cells: T cells (anti-CD3), B cells (anti-CD20)
  2. inflammatory cytokines
  3. Ag-specific immune responses (e.g. providing autoAg such as insulin peptides in the absernce of danger signals –> tolerance)