Vedvarende aktivitet i immunforsvaret menes at være den grundlæggende årsag til Myalgisk Encephalomyelitis
En anden artikel afslører ligeledes tegn på påvirkning af antigen præsentation hos ME patienter (2):
Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise
Basisviden: Ekstracellulære veksikler (EV) er små "beholdere" med protein, der udskilles fra forskellige celletyper, f. eks. muskel- og immunceller. Efter motion kan EV indeholde proteiner, der anvendes til ændret metabolisme, inflammations processer og vedligehold af muskler.
Beskrivelse af forsøget
EV blev isoleret fra plasma fra 18 kvinder med ME:
- før motion
- 15 minutter efter motion
- 24 timer efter motion
Resultat
Resultatet fremgår af figur 4 i artiklen. Bemærk "antigen præsentation" har 2. pladsen i listen over påvirkede processer efter motion (2):
Figur 4. Differences in EV protein levels between ME/CFS and controls at each time point (a) and enrichment analysis (b). (a) The y-axis shows the Log2 fold change (ME/CFS vs. Controls) of 10,000 bootstrapped datasets at each time point. A median FC of 0 indicates no difference. Black dots show all proteins significant before FDR correction. Black bars show 95% confidence intervals (CI). Gray bars with caps show the false discovery rate adjusted CIs (with q < 0.1). A protein is significant after FDR correction (DAPs, red dots) if the adjusted CI does not include 0. (b) Bar plot showing—Log10(FDR) of the top 10 significant Reactome pathways (FDR < 0.05) enriched for EV proteins that are significantly different (q < 0.1) between ME/CFS and controls 15 min post-exercise. The number inside the bubble shows the number of EV proteins in each pathway. (Reference 2).
Figur 4. Differences in EV protein levels between ME/CFS and controls at each time point (a) and enrichment analysis (b). (a) The y-axis shows the Log2 fold change (ME/CFS vs. Controls) of 10,000 bootstrapped datasets at each time point. A median FC of 0 indicates no difference. Black dots show all proteins significant before FDR correction. Black bars show 95% confidence intervals (CI). Gray bars with caps show the false discovery rate adjusted CIs (with q < 0.1). A protein is significant after FDR correction (DAPs, red dots) if the adjusted CI does not include 0. (b) Bar plot showing—Log10(FDR) of the top 10 significant Reactome pathways (FDR < 0.05) enriched for EV proteins that are significantly different (q < 0.1) between ME/CFS and controls 15 min post-exercise. The number inside the bubble shows the number of EV proteins in each pathway. (Reference 2).
Fra artiklens afsnit "Dysfunctional immune signalling in EVs in ME/CFS post-exercise" fremgår følgende (2):
"We found increased ANXA2, B2M and ORM1 in ME/CFS versus controls 15 min post-exercise. These three proteins are members of the immune system protein pathways ‘antigen presentation’, ‘cytokine signaling’ and ‘adaptive immune system’ (Figure 4b)."
"Annexin II (ANXA2) is a calcium-dependent phospholipid-binding protein that orchestrates membrane repair, vesicle fusion and cytoskeletal organization during the inflammatory response or tissue injury (Lim & Hajjar, 2021)."
"Beta-2-microglobulin (B2M) is necessary for the cell surface expression and structural stability of the major histocompatibility complex (MHC-I) which plays key roles in antigen presentation and processing, inflammation, the complement cascade, and stress response (Trowsdale & Knight, 2013)."
"In the CNS, B2M can also negatively affect hippocampal neurogenesis and synaptic plasticity and has been linked to clinical depression (Lamers et al., 2016). While B2M dysregulation has not been previously identified in ME/CFS patients, this finding is consistent with dysfunctional adaptive immune cells in ME/CFS (Maya, 2023)."
"Orosomucoid (ORM1) is an acute phase protein associated with fatigue. In our study, ORM1 had a significantly lower 24 h/15 min ratio in ME/CFS patients versus controls, due to opposing trends in controls versus patients (Figure 8, Figure S3). A previous study found that the change in muscle soreness scores in healthy individuals positively correlated with serum ORM1 levels 24 h post-exercise, suggesting that ORM1 is associated with the extent of exercise-induced damage and inflammation (Tékus et al., 2017)."
"This upregulation of serum and CSF ORM at baseline may reflect the body's attempt to mitigate the everyday fatigue that occurs in ME/CFS, while the altered dynamics of ORM1 in EVs post-exercise may indicate disruption of the muscle fatigue—ORM1 feedback loop."
Bemærk også at blodplade (engelsk: platelet) processer har 1. pladsen. Påvisning af blodplade processer hos ME patienter er også beskrevet i ME forskningen (3 og 4):
The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses
"We found increased ANXA2, B2M and ORM1 in ME/CFS versus controls 15 min post-exercise. These three proteins are members of the immune system protein pathways ‘antigen presentation’, ‘cytokine signaling’ and ‘adaptive immune system’ (Figure 4b)."
"Annexin II (ANXA2) is a calcium-dependent phospholipid-binding protein that orchestrates membrane repair, vesicle fusion and cytoskeletal organization during the inflammatory response or tissue injury (Lim & Hajjar, 2021)."
"Beta-2-microglobulin (B2M) is necessary for the cell surface expression and structural stability of the major histocompatibility complex (MHC-I) which plays key roles in antigen presentation and processing, inflammation, the complement cascade, and stress response (Trowsdale & Knight, 2013)."
"In the CNS, B2M can also negatively affect hippocampal neurogenesis and synaptic plasticity and has been linked to clinical depression (Lamers et al., 2016). While B2M dysregulation has not been previously identified in ME/CFS patients, this finding is consistent with dysfunctional adaptive immune cells in ME/CFS (Maya, 2023)."
"Orosomucoid (ORM1) is an acute phase protein associated with fatigue. In our study, ORM1 had a significantly lower 24 h/15 min ratio in ME/CFS patients versus controls, due to opposing trends in controls versus patients (Figure 8, Figure S3). A previous study found that the change in muscle soreness scores in healthy individuals positively correlated with serum ORM1 levels 24 h post-exercise, suggesting that ORM1 is associated with the extent of exercise-induced damage and inflammation (Tékus et al., 2017)."
"This upregulation of serum and CSF ORM at baseline may reflect the body's attempt to mitigate the everyday fatigue that occurs in ME/CFS, while the altered dynamics of ORM1 in EVs post-exercise may indicate disruption of the muscle fatigue—ORM1 feedback loop."
Bemærk også at blodplade (engelsk: platelet) processer har 1. pladsen. Påvisning af blodplade processer hos ME patienter er også beskrevet i ME forskningen (3 og 4):
The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses
Videre analyse af EV proteiner er foretaget og resultatet er vist i figur 7c (2):
Figur 7. Tissue and cell type enrichment analysis. Sankey network diagrams showing 81 and 22 EV proteins contributing to uniquely enriched tissue type terms in controls (a) and in ME/CFS patients (b), respectively. Each line in the Sankey network shows one connection between a protein and an enriched tissue or cell type term. (c) Bubble plot with terms that are commonly enriched in both ME/CFS patients and controls, as well as their significance (-Log10 (FDR)) and the number of proteins overlapping with each reference gene/protein set. (reference 2).
Bemærk, at her dukker motor cortex processer op. I NIH's hypotese (reference 1) var motor cortex problemer sat i relation til vedvarende antigen præsentation.
Så hvis vedvarende antigen præsentation giver motor cortex problemer, der påvirker motion. OG motion inducerer processer vedrørende antigen præsentaion, så lyder det som vi har en ond cirkel. Vi må afvente mere forskning og se hvordan de forklarer alle de sammenhængen, der efterhånden er dukket op.
Referencer:
1) Walitt, B., Singh, K., LaMunion, S.R. et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 15, 907 (2024). https://doi.org/10.1038/s41467-024-45107-3
2) Giloteaux L, Glass KA, Germain A, Franconi CJ, Zhang S, Hanson MR. Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise. J Extracell Vesicles. 2024 Jan;13(1):e12403. doi: 10.1002/jev2.12403. PMID: 38173127; PMCID: PMC10764978.
3) Nunes JM, Kruger A, Proal A, Kell DB, Pretorius E. The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Pharmaceuticals (Basel). 2022 Jul 27;15(8):931. doi: 10.3390/ph15080931. PMID: 36015078; PMCID: PMC9413879.
4) Nunes JM, Kell DB, Pretorius E. Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses. Blood Rev. 2023 Jul;60:101075. doi: 10.1016/j.blre.2023.101075. Epub 2023 Mar 20. PMID: 36963989; PMCID: PMC10027292.
Figur 7. Tissue and cell type enrichment analysis. Sankey network diagrams showing 81 and 22 EV proteins contributing to uniquely enriched tissue type terms in controls (a) and in ME/CFS patients (b), respectively. Each line in the Sankey network shows one connection between a protein and an enriched tissue or cell type term. (c) Bubble plot with terms that are commonly enriched in both ME/CFS patients and controls, as well as their significance (-Log10 (FDR)) and the number of proteins overlapping with each reference gene/protein set. (reference 2).
Bemærk, at her dukker motor cortex processer op. I NIH's hypotese (reference 1) var motor cortex problemer sat i relation til vedvarende antigen præsentation.
Så hvis vedvarende antigen præsentation giver motor cortex problemer, der påvirker motion. OG motion inducerer processer vedrørende antigen præsentaion, så lyder det som vi har en ond cirkel. Vi må afvente mere forskning og se hvordan de forklarer alle de sammenhængen, der efterhånden er dukket op.
Referencer:
1) Walitt, B., Singh, K., LaMunion, S.R. et al. Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome. Nat Commun 15, 907 (2024). https://doi.org/10.1038/s41467-024-45107-3
2) Giloteaux L, Glass KA, Germain A, Franconi CJ, Zhang S, Hanson MR. Dysregulation of extracellular vesicle protein cargo in female myalgic encephalomyelitis/chronic fatigue syndrome cases and sedentary controls in response to maximal exercise. J Extracell Vesicles. 2024 Jan;13(1):e12403. doi: 10.1002/jev2.12403. PMID: 38173127; PMCID: PMC10764978.
3) Nunes JM, Kruger A, Proal A, Kell DB, Pretorius E. The Occurrence of Hyperactivated Platelets and Fibrinaloid Microclots in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Pharmaceuticals (Basel). 2022 Jul 27;15(8):931. doi: 10.3390/ph15080931. PMID: 36015078; PMCID: PMC9413879.
4) Nunes JM, Kell DB, Pretorius E. Cardiovascular and haematological pathology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): A role for viruses. Blood Rev. 2023 Jul;60:101075. doi: 10.1016/j.blre.2023.101075. Epub 2023 Mar 20. PMID: 36963989; PMCID: PMC10027292.
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