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The T1D BBQ (Big Burning Questions Webinar): Macrophages in type 1 diabetes - Shared screen with speaker view
John Todd
39:53
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 It is surprising (the null genetic-cell colocalization result), but certainly highlighted by unpublished data we have.....the gene FLT3, which has a key function in DC and macrophages, has a variant that is strongest genetic effect in autoimmune thyroid disease,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.
Jessie Barra
47:26
Is the detection of ATP at all dependent or influenced by the phagocytosis of intact insulin granules?
Todd Brusko
48:49
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
Abhishek Kulkarni
50:17
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?
Matthias’s iPhone
50:47
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
paul dunford
55:23
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
Samuel Blum
56:57
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?
John Todd
57:42
Need to leave the mtg - thanks, John
Todd Brusko
01:01:33
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?
Dominika Nackiewicz
01:03:37
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?
Ibrahim Omar
01:21:29
Did you look at macrophages in single cell level in diet induced obesity models?
Dominika Nackiewicz
01:24:20
We did also 50mg/kg of STZ for 5 days and saw the same signature
Dominika Nackiewicz
01:24:38
from 3days to 21 days
Dominika Nackiewicz
01:24:53
it peaks at 14 days
Nato Teteloshvili
01:28:15
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 ?
Joseph Feduska
01:31:47
Dr. Xiao and Verchere: Are these observations of phenotypes strain -dependent? We know the NOD is hyperinflammatory, but that was before scRNAseq was available
Sasanka Ramanadham
01:33:58
is the macrophage phenotype different in infiltrated versus non-infiltrated human macrophages in T1D ?
Sarah Richardson
01:36:26
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.
Sally Kent
01:39:34
Thanks, Sarah!
Sasanka Ramanadham
01:39:36
I meant in islets…sorry
Nato Teteloshvili
01:39:42
Thanks ! interesting
Sarah Richardson
01:40:01
thanks
Sasanka Ramanadham
01:41:41
are there many studies on inhibiting infiltration pathways ?
Bruce Verchere
01:41:44
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
Joseph Feduska
01:42:25
Thank you
Ibrahim Omar
01:45:33
Do islet resident immune cells in general and macrophages as the major cells specifically change phenotype during aging?
joanaalmaca
01:47:10
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.
Sasanka Ramanadham
01:47:22
do IPSC-derived macrophages face the same scrutiny as iPSC-derived beta-cells ?
Sarah Richardson
01:50:13
if there are good antibodies we can try, please email me
Jared Taylor
01:50:52
Sasanka,
Sally Kent
01:50:59
I do’t know if there are good abs for IHC?IF but there are for western blotting
Sally Kent
01:51:08
IHC/IF
Jared Taylor
01:51:13
While I can't speak for the diabetes field, the infectious disease field is very receptive to iPSC-macrophags
Martha Campbell-Thompson
01:57:53
I'm here- yes- Martha
Irina Kusmartseva
01:58:04
Yes. Here is the reference:
Irina Kusmartseva
01:58:48
https://pubmed.ncbi.nlm.nih.gov/31084520/
Susan Bonner-Weir
01:58:57
Yes, Bruce there are about 5/70 Medalists that have considerable amyloid plaques.
Sally Kent
02:00:37
Hi Martha!
Bruce Verchere
02:13:48
I really enjoyed this session thanks everyone!
Sarah Richardson
02:14:21
thanks all, very interesting. Happy to join Hubert
Hubert Tse
02:15:39
Thank you all! htse@uab.edu