Damaging Immune activators within the cerebrospinal fluid of progressive MSers

Cristofanilli M, Rosenthal H, Cymring B, Gratch D, Pagano B, Xie B, Sadiq SA. Progressive multiple sclerosis cerebrospinal fluid induces inflammatory demyelination, axonal loss, and astrogliosis in mice. Exp Neurol. 2014 Aug 8. pii: S0014-4886(14)00248-9.

Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination and neurodegeneration throughout the CNS, which lead over time to a condition of irreversible functional decline known as progressive MS. Currently, there are no satisfactory treatments for this condition because the mechanisms that underlie disease progression are not well understood. This is partly due to the lack of a specific animal model that represents progressive MS. We investigated the effects of intracerebroventricular injections of cerebrospinal fluid (CSF) derived from untreated primary progressive (PPMS), secondary progressive (SPMS), and relapsing/remitting (RRMS) MS patients into mice. We found discrete inflammatory demyelinating lesions containing macrophages, B cell and T cell infiltrates in the brains of animals injected with CSF from patients with progressive MS. These lesions were rarely found in animals injected with RRMS-CSF and never in those treated with control-CSF. Animals that developed brain lesions also presented extensive inflammation in their spinal cord. However, discrete spinal cord lesions were rare and only seen in animals injected with PPMS-CSF. Axonal loss and astrogliosis were seen within the lesions following the initial demyelination. In addition, Th17 cell activity was enhanced in the CNS and in lymph nodes of progressive MS-CSF injected animals compared to controls. Furthermore, CSF derived from MS patients who were clinically stable following therapy had greatly diminished capacity to induce CNS lesions in mice. Finally, we provided evidence suggesting that differential expression of pro-inflammatory cytokines present in the progressive MS CSF might be involved in the observed mouse pathology. Our data suggests that the agent(s) responsible for the demyelination and neurodegeneration characteristic of progressive MS is present in patient CSF and is amenable to further characterization in experimental models of the disease.

This study took spinal fluid from MSers and injected it into the brain of mice and they got lesions. This tell us there are things in the CSF that are probably damaging to the brains of progressive MSers. This does not surprise me as others have done the same, often using EAE to get the damaging substances into the brain. This study suggests that cytokines are part of the problem, I also suspect that antibodies are also part of the problem, as we an others have seen problems when transferring antibodies from MSers into brains. 

Here problems were more evident in CSF from progressive MSers than RRMSers and so if progression a problem of the immune system within the brain…so the simple solution would be to get immunomodulators into the brain..it is amazing that most immune modulators used in (RR)MS are largely peripherally active within the blood. Gilenya accumlates in the CNS, but its action, at least in RRMS, is to act in the lymph glands not the brain. 

What are the factors…there is the technology to identify these. 

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  • "…so the simple solution would be to get immunomodulators into the brain..it is amazing that most immune modulators used in (RR)MS are largely peripherally active within the blood" How can this be accomplished without directly injecting into the CNS? It would seem that this invasive approach would not be practical.

  • Are researchers working on getting immunomodulators directly into the brain?
    The invasiveness shouldn't be that much of a barrier. After all, people live with cardiac pacemakers, insulin pumps and continuous ambulatory dialysis

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