Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in ME/CFS, Almenar-Perez et al. 2020

John Mac

John Mac

Senior Member (Voting Rights)
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Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a debilitating multisystemic disease of unknown etiology, affecting thousands of individuals worldwide. Its diagnosis still relies on ruling out medical problems leading to unexplained fatigue due to a complete lack of disease-specific biomarkers.

Our group and others have explored the potential value of microRNA profiles (miRNomes) as diagnostic tools for this disease. However, heterogeneity of participants, low numbers, the variety of samples assayed, and other pre-analytical variables, have hampered the identification of disease-associated miRNomes.

In this study, our team has evaluated, for the first time, ME/CFS miRNomes in peripheral blood mononuclear cells (PBMCs) and extracellular vesicles (EVs) from severely ill patients recruited at the monographic UK ME biobank to assess, using standard operating procedures (SOPs), blood fractions with optimal diagnostic power for a rapid translation of a miR-based diagnostic method into the clinic.

Our results show that routine creatine kinase (CK) blood values, plasma EVs physical characteristics (including counts, size and zeta-potential), and a limited number of differentially expressed PBMC and EV miRNAs appear significantly associated with severe ME/CFS (p < 0.05).

Gene enrichment analysis points to epigenetic and neuroimmune dysregulated pathways, in agreement with previous reports. Population validation by a cost-effective approach limited to these few potentially discriminating variables is granted.
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https://www.nature.com/articles/s41598-020-58506-5



 
How are these findings related to the cytokine analysis of extracellular vesicles that Maureen Hanson presented at the 3rd OMF symposium last September? She hadn’t found any significant difference in the average size or concentration of total EVs in ME/CFS patients vs healthy controls, but different cytokine associations. I guess my question is, is there any link here? :)

Glad to see new findings about EVs and something that points towards exosomes!

Edit: Maureen Hanson’s presentation: she starts talking about EVs at the 9:50 ish mark.

Edit2: Some EV size and count differences:

As shown in Fig. 1A, the EV yields obtained from equivalent volumes of plasma from ME/CFS samples were higher than those isolated from healthy controls (HCs), although not reaching statistical significance (p > 0.05). Interestingly, isolated EVs showed statistically significant size differences, being on average smaller in the ME/CFS group than in the HC’s (Fig. 1B). To rule out that the observed results could derive from differences in plasma protein content interfering with the isolation method, we proceeded to repeat the procedure, this time including a pre-treatment with proteinase K (an optional step recommended by the vendor when using protein-rich fluids). By introducing this optional treatment, we could confirm that qualitative differences exist, both, in number of vesicles and size, in plasma of ME/CFS patients with respect to HCs (p < 0.05) (Fig. 1C,D).
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I'm interested in their findings; however, I wonder if we would be better focusing on the GWAS study @Simon M has been involved in promoting. From memory a GWAS study may give us clues regarding causes. This study could potentially identify consequence e.g. if the small exosomes (increased in ME) come from a particular tissue --- then that might provide a clue to where to focus research. I suppose both have their place; however, considering these results are not remarkable, then I'd like the results of the GWAS study! E.g. I've been interested in a potential link to thyroid function in ME, a GWAS study might turn up something interesting regarding genes controlling thyroid function.


Some extracts from this paper
"lower levels for alkaline phosphatase and free thyroid hormone T4 levels"
"hormonal glands (mostly thyroid)"
"we find, following a database search formerly described by our group56, that hsa-miR-18a-5p can be upregulated by the anti-psychotic drug desipramine, while hsa-miR-146a-5p and hsa-miR-150-5p expression can be induced by morphine56, raising the possibility that the observed overexpression of these miRNAs derives from patient drug exposure and not from the disease itself. This highlights the enormous importance of detailed medication registry when studying molecular changes in these patients, as recommended by the ME/CFS NINDS CDEs46."
 
Summarising, searchable —

PBMCs
Over-expressed (p<0.05)
  • miR-374a-5p
  • miRNA-4516
  • miR-340–5p
  • miR-140-5p
  • miR-18a-5p
  • miR-146a-5p
  • miR-106a-5p
  • miR-17-5p
  • miR-106b
p<0.1
  • miR-21-5p
Under-expressed (p<0.05)
  • miR-644a
  • miR-451a
  • miR-4454
  • miR-7975
  • miR-549a
  • miR361-3p
  • miR-1253
  • miR-590-5p
EVs
Over-expressed (p<0.05)
  • miR-4454
  • miR-7975
  • miR-150-5p
  • miR-15a-5p
  • let-7d-5p
  • miR-423-5p
  • miR-374a-5p
  • miR-130a-3p
p<0.1
  • miR-21-5p
  • miR-320e
  • miR-185-5p
  • let-7g-5p
  • miR-126-3p
  • miR-223-3p
  • miR-93-5p
Under-expressed (p<0.05)
  • miR-183-3p
  • miR-33a-5p
p<0.1
  • miR-203a-5p
  • miR-607
  • miR-369-3p
Bold are miRs that are differentially expressed in both the PBMCs and EVs. Note that miR-4454 and miR-7975 are over-expressed in EVs but under-expressed in PBMCs. The paper says "At present, the significance of these differences is not understood." (I don't know if one possibility would be that PBMCs are off-loading those particular miRs via EVs.)
 
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