T1D Flashcards
What is the difference in insulin processing/signaling in T1D vs T2D?
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
What does “diabetes” and “mellitus” mean?
diabetes = siphon
mellitus = sweet like honey
What is the sex bias of T1D in humans?
male > female
What are the three stages of T1D?
- stage 1: >2 autoAbs
- stage 2: >2 autoAbs + abnormal BG
- stage 3: >2 auto Abs + abnormal BG + clinical manifestations
What is the T1D model mouse? What are the benefits and what are the caveats?
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
Describe the pathogensis of T1D
- the initiation phase (pancreas): Beta cell damage by “natural” apopotosis or after viral infection –> cDCs capture, process and present Beta cell Ags
- 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
- 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
- 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
- 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 can you depelte B cells (i.e what should you target)?
anti-CD20 autoAbs
Which genes confer risk of developing T1D? Which has the strongest effects?
- HLA genes exert the strongest effects
- immune pathway genes
- genes encoding autoAgs (e.g. IDD2 –> encodes insulin)
In MHC molecules, where are the polymorphisms found that impact Ag presentation and thus confers susceptibility or protection to T1D?
polymorphisms are freqeunetly found in the peptide binding groove
What transcription factor allows expression of tissue-restricted Ags in cTECs? What disease happens if this TF is non-functional, what happens?
TF = Aire
Aire-/- –> APECED –> no negative slection of T cells
What are tetramers? Why do we need tetramers for research?
used to indentify certain T cells that recognize specific peptide + MHC allele. Need tetramers because the TCR-MHC interaction is really weak
During T cell selection in the thymus, what kind of binding is required to become a Treg?
intermediate affinity
What suppressive mechanisms do Tregs use?
- 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 are Treg defective in T1D?
low frequency and poor function
Which IDDM2 allele is protective and predisposing of T1D? how does the protective allele work?
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
