A recent study published in Brain has confirmed that primary progressive multiple sclerosis (PPMS) is an antibody-mediated disease with unique clinical and pathological features distinct from other forms of MS.
The research conducted by the Tisch MS Research Center of New York has confirmed what the scientific community long suspected: PPMS is pathophysiologically distinct from other forms of MS, the researchers noted. The findings have the potential to revolutionize treatment for patients suffering from PPMS, they added.
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MS is characterized by inflammatory demyelination, astrogliosis, microglial activation, and axonal loss in the central nervous system (CNS), ultimately leading to progressive clinical disability.
“The findings from this study are significant because our animal model relies on direct transmission of disease pathology using CSF from MS patients, which arguably mimics pathophysiological mechanisms occurring in patients with greater specificity than any currently existing animal model of MS,” the authors highlighted.
Even though treatments aimed at modifying the immune system have successfully lowered the number of relapses for most people with RRMS, they cannot stop the progression of PPMS, indicating that there are fundamental differences in the underlying causes of the 2 conditions, like relapse remitting MS and PPMS.
The researchers developed the first-ever animal model of PPMS by intrathecal delivery of cerebrospinal fluid (CSF) from patients with PPMS into the cervical spinal cord. They collected CSF samples from 42 patients with MS, of whom 17 had PPMS, 13 RRMS, and 12 SPMS. There were also 2 patients with ALS, 1 patient with HTLV-1, and 4 healthy controls. None of the patients with MS received immunomodulatory treatment for at least 6 months before the sample collection, using either lumbar puncture or aspiration from a previously implanted baclofen pump.
Mice were given anesthetic and preoperative medications, including a ketamine and xylazine cocktail, buprenorphine, baytril, and saline, through subcutaneous injections. The mice underwent 2 surgeries, the first being a C5 laminectomy and the second being the intrathecal delivery of CSF or saline. The motor abilities of the mice were evaluated for the treatment groups through tests of forelimb reaching, gripping, and tail flaccidity, with any deficits being scored on a 3-point scale. The study results were used to investigate the pathogenic component(s) in the CSF and to determine the efficacy of using selective filtration as a therapeutic approach to eliminate them.
Study results showed that mice injected with cerebrospinal fluid (CSF) from patients with RRMS and SPMS did not exhibit significant motor impairments, as their motor deficit scores were similar to those of mice injected with saline or control. Additionally, LFB histology staining revealed that only mice injected with PPMS CSF showed distinct demyelination lesions, while myelin remained intact in all other groups.
The researchers concluded that CSF, in contrast to the fluid from patients with other forms of MS such as RRMS and SPMS, caused motor impairment and hallmark MS-related changes in the spinal cord, including demyelination, impaired remyelination, astroglial reaction, and axonal damage. However, the intrathecal delivery failed to produce these pathological effects, with the exception of mild microglial activation highlighting fundamental differences between PPMS and RR/SPMS.
“Our study suggests that pathogenic antibodies play a unique role in PPMS. Furthermore, selective removal of antibodies from PPMS CSF via filtration or immunodepletion mitigates their pathogenic capacity in our experimental model, providing proof-of-concept to support CSF pheresis as a therapeutic approach for PPMS,“ the authors concluded.
Reference
Jamie KW, Jerry L, Kung N, et al. Cerebrospinal fluid immunoglobulins in primary progressive multiple sclerosis are pathogenic. Brain. Published online February 3, 2023. doi: 10.1093/brain/awad031
