Background
SMPDL3B (short for sphingomyelin phosphodiesterase acid-like 3B) is a protein that sits on the membrane of cells and influences lipids (fatty/waxy substances) within the membrane. Specifically, it tweaks levels of certain lipids called sphingolipids, which are both structural components of the cell membrane and signalling molecules. By regulating these lipids, SMPDL3B can affect how cells communicate and regulate immune responses.
Previous research has explored sphingolipid metabolism in ME/CFS, which may be reduced in the disease and could contribute to symptoms. Furthermore, a recent Open Medicine Foundation study from Canada and Norway investigated SMPDL3B in individuals with ME and found differences in its levels along with changes related to other lipid types beyond sphingolipids. The authors suggest that SMPDL3B is emerging as a potential biomarker and therapeutic target in ME.
The study in more detail
Aim
The researchers were interested in SMPDL3B, an enzyme-like protein that affects sphingolipids, a class of lipids that are attached to the cell membrane. They aimed to explore its role in the underlying disease mechanisms of ME and its clinical relevance.
Methods
The study was a case-control design (an observational study comparing two groups of individuals) involving two independent cohorts from Canada and Norway. The Canadian cohort included 249 ME patients and 63 healthy controls, whilst the Norwegian cohort comprised 141 ME patients. All participants were diagnosed using the Canadian Consensus Criteria for ME/CFS.
To investigate SMPDL3B, using specialised techniques, the researchers measured its levels both in the blood plasma (liquid portion of blood) and on the cell membrane (membrane-bound). They also looked at the gene (segment of DNA) associated with SMPDL3B, as well as PLCXD1, a gene associated with another class of lipids, known as phospholipids. The PLCXD1 gene codes for enzyme, PI-PLC, which the paper seems to suggest has a role in the cleavage, i.e. breaking/cutting, of SMPDL3B. Whilst not stated explicitly, one might assume that SMPDL3B that has been cleaved from the cell membrane ends up in the blood.
The team also conducted in vitro experiments (lab experiments done outside a living body) to examine the effects of oestradiol (a type of oestrogen) and gliptin medications (vildagliptin and saxagliptin) on SMPDL3B, allowing them to study potential therapeutic interventions in addition to molecular mechanisms.
Findings
Key observations in ME patients included:
- Reduced levels of membrane-bound SMPDL3B in monocytes (a type of white blood cell).
- Higher levels of SMPDL3B in the blood plasma, which correlated with symptom severity.
- Increased expression of PLCXD1 and elevated levels of PI-PLC. [Gene expression is the process by which a gene’s DNA instructions are used to make a functional product, usually a protein.]
- Sex-specific differences: Female individuals with ME had higher blood plasma levels of SMPDL3B – an effect the researchers state is influenced by oestrogen. In vitro, oestradiol “upregulated SMPDL3B expression, indicating hormonal regulation.”
- Effect of gliptin medications: Vildagliptin and saxagliptin restored membrane-bound SMPDL3B and reduced its soluble form (i.e. reduced blood plasma levels).
The researchers suggest that immune dysregulation in ME may be linked to enhanced cleavage of membrane-bound SMPDL3B by PI-PLC.
Conclusion
The researchers conclude that SMPDL3B has potential as a biomarker for ME, reflecting disease severity and immune dysregulation. They suggest that its activity is influenced by hormones (such as oestrogen) and by PI-PLC, which can cleave it from the cell membrane.
They also report that gliptin medications (vildagliptin and saxagliptin) were able to preserve SMPDL3B on the cell membrane and reduce the levels in the soluble form i.e. found freely in the blood, thus highlighting a potential therapeutic strategy. The authors recommend further clinical trials to evaluate whether these gliptin medications can mitigate immune dysfunction and reduce symptom burden in ME.
