Increase in Double-stranded DNA Found in NMOSD Brain Fluid
Higher levels in CSF may trigger inflammation in patients: study
Levels of double-stranded DNA — dubbed dsDNA — are elevated in the fluid around the brain and spinal cord of people with severe neuromyelitis optica spectrum disorder (NMOSD), a small study suggests.
These levels, which indicate cellular damage, may trigger more inflammation in NMOSD patients, potentially contributing to the disease, the researchers noted.
“The dsDNA levels were significantly higher in the [spinal fluid] of patients with NMOSD in the acute phase than in those with [other neurological disorders],” the team wrote.
Examining double-stranded DNA levels in patients
DNA is the molecule that carries the genetic code that provides instructions for making all the molecules and parts of the body. Within human cells, DNA is stored in a double-stranded form, which is what gives the molecule its famous double-helix shape.
Because dsDNA is so important for cellular function, cells carefully regulate how it is stored — most double-stranded DNA is kept in a central compartment called the nucleus, while a bit is kept in mitochondria, the cell’s powerhouses.
If dsDNA is present outside cells, it usually indicates that something is wrong. Typically, it’s a sign of cellular damage and death, or an indication of a viral infection that releases the microbes’ dsDNA.
As such, the immune system has evolved sensors for dsDNA that trigger an inflammatory response when activated.
In NMOSD, the immune system produces antibodies that wrongly attack healthy tissue in the nervous system. Here, a team led by scientists in Japan hypothesized that this autoimmune attack, and the resulting cellular damage, might trigger the release of dsDNA into the cerebrospinal fluid (CSF) — the liquid around the brain and spinal cord.
The scientists postulated that dsDNA in the CSF could trigger more inflammation, further driving the disease.
“To the best of our knowledge, no previous reports have demonstrated the involvement of self-derived dsDNA in the CSF of patients with NMOSD,” the researchers wrote, adding that “the aim of this study was to investigate whether or not dsDNA levels increase in the CSF of patients with NMOSD.”
The scientists analyzed dsDNA levels in the CSF of 23 NMOSD patients experiencing a relapse, and compared them with those of 16 people with other neurological disorders like Parkinson’s disease and amyotrophic lateral sclerosis.
All were admitted to one of two Japanese university hospitals between 2009 and 2021.
The NMOSD patients’ median age was 56, and they had been living with the disease for a median of three months. Most (82.6%) had spinal cord lesions. Each tested positive for antibodies against AQP4, the most common target of NMOSD-causing antibodies.
The median age of the other group of patients was 63 years and their median disease duration was nine months.
Results showed that CSF dsDNA levels were significantly higher in NMOSD patients during relapse than in those with other neurological disorders. This suggests that dsDNA might “play a crucial role in augmenting … immune responses in active NMOSD lesions,” the researchers wrote.
Among NMOSD patients, seven had CSF samples collected after also undergoing inflammation-controlling treatment. Analyses of these samples showed that dsDNA levels tended to decrease after treatment.
However, the difference between before and after treatment did not reach statistical significance, which the researchers said is likely due to the small sample size.
The CSF cell count and antibody levels were significantly higher in the NMOSD group than in the other group, but no significant associations were detected between these factors and dsDNA levels.
“In conclusion, this study showed that dsDNA is released in the CSF to a significantly higher level in acute NMOSD relapse compared to [other neurological disorders],” the team wrote.
“This result suggests that CSF samples from patients with NMOSD may have implications in the disease [mechanisms],” they added.
The researchers stressed that their study is limited by its small size, calling for additional larger studies to investigate the potential role of dsDNA in NMOSD. In addition, the potential association between dsDNA levels and those of anti-AQP4 antibodies “should be analyzed in future studies,” the team concluded.