Tag: immune dysregulation

SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis

Abstract:

Background: Sphingomyelin phosphodiesterase acid-like 3B (SMPDL3B) is emerging as a potential biomarker and therapeutic target in myalgic encephalomyelitis (ME), a complex multisystem disorder characterized by immune dysfunction, metabolic disturbances, and persistent fatigue. This study investigates the role of SMPDL3B in ME pathophysiology and explores its clinical relevance.

Methods: A case-control study was conducted in two independent cohorts: a Canadian cohort (249 ME patients, 63 controls) and a Norwegian replication cohort (141 ME patients). Plasma and membrane-bound SMPDL3B levels were quantified using ELISA and flow cytometry. Gene expression of SMPDL3B and PLCXD1, encoding phosphatidylinositol-specific phospholipase C (PI-PLC), was analyzed by qPCR. The effects of dipeptidyl peptidase-4 (DPP-4) inhibitors-vildagliptin, saxagliptin, and linagliptin-on modulation of membrane-bound and soluble SMPDL3B were assessed in vitro by qPCR, flow cytometry and ELISA.

Results: ME patients exhibited significantly elevated plasma SMPDL3B levels, which correlated with symptom severity. Flow cytometry revealed a reduction in membrane-bound SMPDL3B in monocytes, accompanied by increased PLCXD1 expression and elevated plasma levels of PI-PLC and SMPDL3B. These findings suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC. Sex-specific differences were observed, with female ME patients displaying higher plasma SMPDL3B levels, an effect influenced by estrogen. In vitro, estradiol upregulated SMPDL3B expression, indicating hormonal regulation. Vildagliptin and saxagliptin were tested for their potential to inhibit PI-PLC activity independently of their role as DPP-4 inhibitors, and restored membrane-bound SMPDL3B while reduced its soluble form.

Conclusions: SMPDL3B emerges as a key biomarker for ME severity and immune dysregulation, with its activity influenced by hormonal and PI-PLC regulation. The ability of vildagliptin and saxagliptin to preserve membrane-bound SMPDL3B and reduce its soluble form via PI-PLC inhibition suggests a novel therapeutic strategy. These findings warrant clinical trials to evaluate their potential in mitigating immune dysfunction and symptom burden in ME.

Note: See Correction: SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis

Source: Rostami-Afshari B, Elremaly W, Franco A, Elbakry M, Akoume MY, Boufaied I, Moezzi A, Leveau C, Rompré P, Godbout C, Mella O, Fluge Ø, Moreau A. SMPDL3B a novel biomarker and therapeutic target in myalgic encephalomyelitis. J Transl Med. 2025 Jul 7;23(1):748. doi: 10.1186/s12967-025-06829-0. PMID: 40624584; PMCID: PMC12236014. https://pmc.ncbi.nlm.nih.gov/articles/PMC12236014/ (Full text)

How pandemics reshape our brain: Common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration

Highlights:

  • Fatiguing syndromes affect millions of patients in the United States and globally, but are grossly underserved in the clinic and in the contemplative design of basic research.
  • Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem metabolic-immune-inflammatory disorder. Although research on this condition is in its infancy, it appears to involve the immune system and central nervous system malfunction, with cellular oxidative stress as a predominant feature.
  • Approximately half of the cases of long-haul coronavirus disease 2019 meet the diagnostic criteria for ME/CFS, burgeoning the number of affected individuals.
  • Recent strides in neurobiology have yet to transfer the understanding of the neurodegenerative aspects, and potential for neuroprotection, of ME/CFS.
  • ME/CFS may represent a useful paradigm and research model for the study of the impact of sustained oxidative stress on the central nervous system and the body at large.

Archeological findings from the bubonic plague era onward have demonstrated how pandemics can exert selective pressures, as will be highlighted. In particular, the short-term survival advantage during pandemics of individuals with greater immune “plasticity” comes at the cost of increased susceptibility to autoimmunity. Certain viral infections appear to trigger persistent immune system dysregulation, leading to broad autoimmunity and a sequelae of multisystem pathophysiologies with diverse symptoms long after the virus is cleared.

Human coronavirus 2019 (HCoV-19) is the most recent virus that appears to have elevated the incidence of autoimmune diseases in infected individuals. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an autoimmune, multisystem fatiguing syndrome affecting approximately 20 million people globally, representing 1.3% of adults in the United States.1, 2 It involves metabolic, immune, and inflammatory processes, with central nervous system (CNS) dysfunction and cellular oxidative stress being prominent features. Notably, about half of long-haul coronavirus disease 2019 (COVID-19) cases meet the diagnostic criteria for ME/CFS, potentially doubling or tripling its prevalence.

This article highlights ME/CFS, a nascent research area, as a model for neurological pathophysiological outcomes resulting from persistently high oxidative stress levels. Patients with ME/CFS, many who have had this condition for decades, form an underutilized patient population for this study.

A second objective of this Research Highlight is to correct recent reports that have attempted to “retrofit” principles and outcomes from other neurologic diseases to ME/CFS. This has led some neuroscientists to extrapolate erroneously that ME/CFS is not a neurodegenerative disorder. However, substantial evidence indicates that autoimmune ME/CFS is a neurodegenerative disease.

Source: Herman ME. How pandemics reshape our brain: common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration. Neuroprotection. 2025; 1–8. doi:10.1002/nep3.70007 https://onlinelibrary.wiley.com/doi/10.1002/nep3.70007 (Full text)

 

Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC)

Summary:

  • Immune dysregulation is a key aspect of post-acute sequelae of coronavirus disease 2019 (PASC), also known as long COVID, with sustained activation of immune cells, T cell exhaustion, skewed B cell profiles, and disrupted immune communication thereby resulting in autoimmune-related complications.
  • The gut is emerging as a critical link between microbiota, metabolism and overall dysfunction, potentially sharing similarities with other chronic fatigue conditions and PASC.
  • Immunothrombosis and neurological signalling dysfunction emphasise the complex interplay between the immune system, blood clotting, and the central nervous system in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
  • Clear research gaps in the design of PASC studies, especially in the context of longitudinal research, stand out as significant areas of concern.

Source: Adhikari, A., Maddumage, J., Eriksson, E.M., Annesley, S.J., Lawson, V.A., Bryant, V.L. and Gras, S. (2024), Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC). Med J Aust, 221: S40-S48. https://doi.org/10.5694/mja2.52456 https://onlinelibrary.wiley.com/doi/full/10.5694/mja2.52456 (Full text)

An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder characterized by serious physical and cognitive impairments. Recent research underscores the role of immune dysfunction, including the role of autoantibodies, in ME/CFS pathophysiology.

Expanding on previous studies, we analyzed 7542 antibody-antigen interactions in ME/CFS patients using two advanced platforms: a 1134 autoantibody Luminex panel from Oncimmune and Augmenta Bioworks, along with Rapid Extracellular Antigen Profiling (REAP), a validated high-throughput method that measures autoantibody reactivity against 6183 extracellular human proteins and 225 human viral pathogen proteins.

Unlike earlier reports, our analysis of 172 participants revealed no significant differences in autoantibody reactivities between ME/CFS patients and controls, including against GPCRs such as β-adrenergic receptors. However, subtle trends in autoantibody ratios between male and female ME/CFS subgroups, along with patterns of herpesvirus reactivation, suggest the need for broader and more detailed exploration.

Source: Germain A, Jaycox JR, Emig CJ, Ring AM, Hanson MR. An In-Depth Exploration of the Autoantibody Immune Profile in ME/CFS Using Novel Antigen Profiling Techniques. Int J Mol Sci. 2025 Mar 20;26(6):2799. doi: 10.3390/ijms26062799. PMID: 40141440; PMCID: PMC11943395. https://pmc.ncbi.nlm.nih.gov/articles/PMC11943395/ (Full text)