T1D

Question 1

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

Answer 1

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

Question 2

What does “diabetes” and “mellitus” mean?

Answer 2

diabetes = siphon
mellitus = sweet like honey

Question 3

What is the sex bias of T1D in humans?

Answer 3

male > female

Question 4

What are the three stages of T1D?

Answer 4

1. stage 1: >2 autoAbs
2. stage 2: >2 autoAbs + abnormal BG
3. stage 3: >2 auto Abs + abnormal BG + clinical manifestations

Question 5

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

Answer 5

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

Question 6

Describe the pathogensis of T1D

Answer 6

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

Question 7

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

Answer 7

anti-CD20 autoAbs

Question 8

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

Answer 8

• HLA genes exert the strongest effects
• immune pathway genes
• genes encoding autoAgs (e.g. IDD2 –> encodes insulin)

Question 9

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

Answer 9

polymorphisms are freqeunetly found in the peptide binding groove

Question 10

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

Answer 10

TF = Aire

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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

intermediate affinity

Question 13

What suppressive mechanisms do Tregs use?

Answer 13

• 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

Question 14

How are Treg defective in T1D?

Answer 14

low frequency and poor function

Question 15

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

Answer 15

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

Question 16

What cells do Tregs suppress?

Answer 16

B cells and Th cells

Question 17

What environmental factors affect T1D risk?

Answer 17

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

Question 18

How can viruses cause T1D?

Answer 18

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)

Question 19

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

Answer 19

key microbiome changes

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

key immune changes

• more inflammation
• increased gut permeability
• fewer Tregs

Question 20

What are three treatments for T1D?

Answer 20

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

Question 21

What are some targets of immunotherapies?

Answer 21

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)