The T1D BBQ (Big Burning Questions Webinar): Macrophages in type 1 diabetes - Shared screen with speaker view
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It's unexpected but true when all the T1D ImmunoChip/GWAS results are investigated with regard to cell type localisation monocytes/DCs are not colocalised. However, these analyses do not include the T1D HLA variants, the major genetic effect in T1D (antigen presentation and TCR repertoire formation), but suggest aside from HLA class II-islet peptide-TCR as the key _primary_ aetiologic effect of T1D, other pathways are downstream (not genetically inherited and therefore not "primary"). This comment does not mean that inhibiting islet resident macrophages will not treat or prevent T1D. It is surprising (the null genetic-cell colocalization result), but certainly highlighted by unpublished data we have.....the gene FLT3, which has a key function in DC and macrophages, has a variant that is strongest genetic effect in autoimmune thyroid disease, but ZERO effect in T1D.
Is the detection of ATP at all dependent or influenced by the phagocytosis of intact insulin granules?
As a non-expert, I am hoping someone who is can speak about the role macrophages play in sensing disruptions in innervation (M1/M2 shifts) and moreover, what role these cells in tissue remodeling over normal growth and development and how a Th1 skew for example could alter the normal trajectory of resident macrophage function in this process
Based on this model, do you suggest that after capturing signals from the beta cells, the resident macrophages enter the circulation to activate other immune cells?
has anyone looked more at how innervation signals might change macrophage phenotype and function? Gustaf and I had looked into this angle in mice in our paper (Sci Adv) earlier this year - Matthias
ATP also acts at P2Y2 which is integral to inflammasome and releases IL-1 from macs. Has this been looked at in context of islet cell death? A T1D signature from Hessner showed IL-1 to be one of key pathways upregulated in Stage 2 patients developing T1D
If you compare islet-resident macrophages (IRMs) from seperate islets of the same host, are the IRMs more heterogeneous in their responsiveness and function? Or is the heterogeneity seen just between different individuals?
Need to leave the mtg - thanks, John
metabolic reprogramming has been reported following early infections in a number of cell types. Is there any evidence this occurs to macrophages in islets? Do the cells change phenotype transiently or durably following epigenetic alterations?
Are there any differences between mouse and human islet macrophages in context of their activation? Unanue group showed that murine macrophages express mRNA of proinflammatory cytokines in a steady state. Is the same observation true in human macrophages?
Did you look at macrophages in single cell level in diet induced obesity models?
We did also 50mg/kg of STZ for 5 days and saw the same signature
from 3days to 21 days
it peaks at 14 days
Very interesting and complex topic on M1 and M2 macrophages. Can you comment on the role of endothelial cells on macrophage polarization and on the other hand Macrophage populations M1 and M2 affecting vascular permeability ?
Dr. Xiao and Verchere: Are these observations of phenotypes strain -dependent? We know the NOD is hyperinflammatory, but that was before scRNAseq was available
is the macrophage phenotype different in infiltrated versus non-infiltrated human macrophages in T1D ?
would be happy to join that working group. We can bring some restricted access to EADB bio bank samples that has young recent-onset donors. We would be happy to characterise these further in these donors if there are robust markers in FFPE tissue.
I meant in islets…sorry
Thanks ! interesting
are there many studies on inhibiting infiltration pathways ?
Dr. Feduska - we haven’t looked at strain differences but I suspect they are there - it is an interesting question, perhaps looking at Th1 vs Th2 strains
Do islet resident immune cells in general and macrophages as the major cells specifically change phenotype during aging?
I had exactly the same question when Dr. Verchere was talking about heterogeneity. In our mouse studies, we that the number of macs doubles in aged islets. We have not looked at their phenotype in detail.
do IPSC-derived macrophages face the same scrutiny as iPSC-derived beta-cells ?
if there are good antibodies we can try, please email me
I do’t know if there are good abs for IHC?IF but there are for western blotting
While I can't speak for the diabetes field, the infectious disease field is very receptive to iPSC-macrophags
I'm here- yes- Martha
Yes. Here is the reference:
Yes, Bruce there are about 5/70 Medalists that have considerable amyloid plaques.
I really enjoyed this session thanks everyone!
thanks all, very interesting. Happy to join Hubert
Thank you all! email@example.com