Brain inflammation in MS, ongoing activity leads to axonal breakdown

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In so far as your immune cells are concerned there is a vast difference between the brain and the rest of the body . In fact, the only resident immune population in your brain are the microglia and the perivascular (surrounding blood vessels) macrophages. These immune sentinels change their baseline identity depending on the disease (see the two figures below).

This segregated state also means that if you don’t study the brain directly you may not get a good idea of what is happening.

See the source image
Figure: Brain microglia (source: sciencemission.com

Add to this, MS is complex in that via the meningeal spaces these resident cells are exposed to also a more diverse immune repertoire from the rest of the body (see Figure below). It is not yet fully appreciated where the problem lies, whether we’re primarily dealing with an ‘inside-out’ response (where autoimmune cells come into the brain) or and ‘outside-in’ (where autoimmunity starts in the brain) one.

See the source image
Figure: Microglial activation (source: Intech Open)

In a study using brain tissue donated for research and matched cerebrospinal fluid sampling, investigators found that the presence of active foamy microglia/macrophages in MS lesions was associated with greatest axonal/neuronal damage (see Figure below based on the occurrence of amyloid precursor protein events).

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Figure: Acute Axonal Damage Most Prevalent in Active Lesions With Foamy Microglia/Macrophages and the Border of Mixed Lesions With Foamy Microglia/Macrophages

Not surprisingly, the CSF NfL levels also correlated with the pathological findings of inflammatory activity; the occurrence of foamy microglia/macrophages followed by the mixed foamy ones.

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Figure: CSF NfL Levels Correlate With Pathological Hallmarks of Inflammatory Lesion Activity

What does this all mean at the end of the day for a person with MS and a jobbing MSologist?

Firstly, brain inflammation may continue unchecked in the CNS compartment despite active control of immune cells in the rest of the body. Secondly, this activity unchecked leads to neuronal damage and likely more progression. Thirdly, there is no easy ways of measuring this aside from using a surrogate measure such as CSF neurofilament light chain (NfL) in MS as traditional MRI techniques may not pick this up. And last but not least, a pure microglial/macrophage targeted strategy may halt this process, but will not prevent reactivation if MS is an ‘outside-in’ phenomenon with secondary stimulation of the existing resident sentinel cells.

If you are following my line of thinking then it’s important to move away from T-cell vs B-cell pathology model and the focal inflammatory MS model and start thinking of MS in terms of Brain Immune Homogenises.

Abstract

Neurol Neuroimmunol Neuroinflamm. 2022 Mar 3;9(3):e1154. doi: 10.1212/NXI.0000000000001154. Print 2022 May.

Neurofilament Light Chain Levels in Multiple Sclerosis Correlate With Lesions Containing Foamy Macrophages and With Acute Axonal Damage

Aletta van den Bosch Nina Fransen Matthew MasonAnnemieke Johanna Rozemuller Charlotte Teunissen Joost Smolders Inge Huitinga 

Background and objectives: To investigate whether white matter lesion activity, acute axonal damage, and axonal density in MS associate with CSF neurofilament light chain (NfL) levels.

Methods: Of 101 brain donors with MS (n = 92 progressive MS, n = 9 relapsing-remitting MS), ventricular CSF was collected, and NfL levels were measured. White matter lesions were classified as active, mixed, inactive, or remyelinated, and microglia/macrophage morphology in active and mixed lesions was classified as ramified, ameboid, or foamy. In addition, axonal density and acute axonal damage were assessed using Bielschowsky and amyloid precursor protein (APP) (immune)histochemistry.

Results: CSF NfL measurements of donors with recent (<1 year) or clinically silent stroke were excluded. CSF NfL levels correlated negatively with disease duration (p = 6.9e-3, r = 0.31). In donors without atrophy, CSF NfL levels correlated positively with the proportion of active and mixed lesions containing foamy microglia/macrophages (p = 9.85e-10 and p = 1.75e-3, respectively), but not with those containing ramified microglia. CSF NfL correlated negatively with proportions of inactive (p = 5.66e-3) and remyelinated lesions (p = 0.03). In the normal appearing pyramid tract, axonal density negatively correlated with CSF NfL levels (Bielschowsky, p = 0.02, r = -0.31), and the presence of acute axonal damage in lesions was related to higher NfL levels (APP, p = 1.17e-6). The amount of acute axonal damage was higher in active lesions with foamy microglia/macrophages and in the rim of mixed lesions with foamy microglia/macrophages when compared with active lesions containing ramified microglia/macrophages (p = 4.6e-3 and p = 0.02, respectively), the center and border of mixed lesions containing ramified microglia/macrophages (center: p = 4.6e-3, border, p = 4.6e-3, and n.s., p = 4.6e-3, respectively), the center of mixed lesions containing foamy microglia/macrophages (p = 4.6e-3 and p = 0.02, respectively), inactive lesions (p = 4.6e-3 and p = 4.6e-3, respectively), and remyelinated lesions (p = 0.03 and p = 0.04, respectively).

Discussion: Our results demonstrated that active and mixed white matter MS lesions with foamy microglia show high acute axonal damage and correlate with elevated CSF NfL levels. Our data support the use of this biomarker to monitor inflammatory demyelinating lesion activity with axonal damage in MS.

About the author

Neuro Doc Gnanapavan

20 comments

  • This seems an important post.
    Does any current DMT follow a microglial/macrophage targeted strategy? What would such a strategy be like?

    Do the current high-efficacy DMTs do the job of controlling MS as an ‘outside-in’ phenomenon?

    • BTK inhibitors are reported to have inhibitory effects on microglia/macrophages, though I suspect this will not be being examined in the first phase of trials.

    • As per MD2 below, but our current treatments may have an indirect effect on microglia/macrophages by taking away the stimulant from other cells that are influencing it.

  • NDG – Excellent description of a topic that at times has been difficult for me to comprehend. The visual depictions (figures) combined with your scientific and non-scientific explanations of brain microglia and microglial activation, was very helpful. I can now at least speak somewhat intelligently about these topics, so thank you.

    Unfortunately, the post seems to suggest there is nothing much we can do with this information, other than there was a correlation between foamy lesions (which current MRIs cannot detect) and NfL levels harvested from the CNS (another lumber puncture, ouch!). Treatments targeting microglia and microglial seem too far off in the future and would require the MS community to determine if the disease is “inside-out” or “outside-in.” The MS community cannot even accept b-cells might be involved in MS. MD1 has been fighting that battle for years.

    I hope a significant amount of money is invested into long COVID, since the symptoms seem very similar to MS, and long COVID has been found to have a relationship with the EBV (similar to MS). Maybe if they solve long COVID, it might give some insights into helping pwms.

    I always say, there is no money is solving MS, so our best hope is some type of ancillary or accidental treatment………..found treating another unrelated disease.

  • Would Alemtuzumab or aHSCT alter these brain immune cells? What about the future BTKi’s?

    It reads devastating that the brain inflammation cannot be fixed.

    • Bone marrow transplant: What is the impact of chemotherapy on the brain?

      In their work, the scientists show that after busulfan chemotherapy, microglial cells completely lose this regenerative capacity, and that many of these cells die by senescence.

      However, this process would not be harmful to the brain, since after transplantation, the disappeared cells are quickly replaced by bone marrow-derived cells (macrophages). The microglial cells eliminated by busulfan chemotherapy leave empty niches in the brain that are soon filled by bone marrow-derived macrophages. These macrophages then adopt the morphology and behavior of normal microglia

      https://medicalxpress.com/news/2022-02-bone-marrow-transplant-impact-chemotherapy.html

  • Great analysis, very clear, thanks. What about spinal MS, most of my lesions are in my spine, I have never been on a DMT, but am quickly heading for a wheelchair, which will mostly go around in circles, as my
    left arm has how given up. Anyway really interested in inflammation as a process, my inflammatory response seems to be off the scale, severe reaction to insect bites, interstitial cystitis, microscopic haematuria, and extremely painful periods back in the day, I mean off the scale, opiate requiring. Any thoughts?

    • Actually, all different types of immune cells have been found in spinal MS including plasma cells and microglial activation. As this study indicates the best surrogate is a CSF NfL measure.

  • NDG,

    Many thanks for this post. This is proper MS research.

    “Firstly, brain inflammation may continue unchecked in the CNS compartment despite active control of immune cells in the rest of the body. Secondly, this activity unchecked leads to neuronal damage and likely more progression.”

    We sought of knew the first bit. Many MSers, even after the most effective DMTs, still progress ie because inflammation / smouldering MS still continues within the CNS. I assume this is why studies such as Sizomus are underway.

    Given what we know now, the focus of pretty much all MS research should be on stopping this unchecked inflammation in the CNS ie in order to stop progression / accruing disability. I’m assuming that trials such as BTK inhibitors and perhaps some anti-virals will provide more insights. For too long MS research has become an ever expanding industry which has been carved up to create lots of research ie genetics, paediatric MS, imaging, tissue bank…… All patients want is to stop accruing disability and to halt their climb up the dreaded EDSS. I can’t believe it’s taken so long to work out that something is happening in the CNS and that relapses is just the peripheral immune system’s response ie it is just a response. Let’s hope work on addressing what’s actually going on in the CNS and how to tackle it can move along at pace.

  • ‘This study points strongly to a key role for activated microglia in initial demyelination in multiple sclerosis……If this is so, therapeutic strategies to inhibit macrophage activity…….may be of greater benefit than efforts to inhibit T cells or other immune reactions’

    ‘The application of multifactorial cluster analysis in the staging of plaques in early multiple sclerosis. Identification and characterisation of the primary demyelinating lesion, Brain(1997), 120,1461-1483.

      • I am wondering if the subsequent report of bacterial toxin and immune complexes associated with the activated microglia, may have been even more ahead of the game?
        ‘Staphylococcal immune complexes and myelinolytic toxin in early acute multiple sclerosis lesions. An immunohistological study supported by multifactorial cluster analysis and antigen-imprint isoelectric focusing’

        MSARD (2013) 2, 213-232.

        Nous verrons.

  • So,I suppose you will advocate serious suppression of the Intrathecal IgG ‘response’, and expect to keep the microglia quiet. OK.
    In the mean time I will continue to explore what antigen(s) induce the continuing IgG (and complement) intrathecal response in the absence of EBV antigens and a convincing ‘autoimmune’ target.
    What a ‘joker’ MS has been!! We will meet some day soon to see where we have got to!

    • The short answer is that there is no direct way of confirming this as the above is an autopsy study. But, you would hope that it has some action in this direction!

  • If anyone is interested, this post prompted me to try to look into whether there is anything available OTC that has been shown to potentially inhibit foamy macrophages in mouse or cell models. That lead me to this paper:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438858/
    > Furthermore, diverse new compounds that influence macrophage and microglial functions are undergoing non-clinical testing. These agents include ethyl pyruvate (Djedović et al., 2017), spermidine (Yang et al., 2016), bryostatin-1 (Kornberg et al., 2018), forskolin (Veremeyko et al., 2018), and lenalidomide (Weng et al., 2018).

    Forskolin is available OTC. The forskolin paper is here:
    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5788911/?report=reader#!po=0.413223

    The graphs in Figure 1 look quite dramatic to me and the dose used (3 mg/kg) is on the same order as doses used in previous human trials of forskolin, even before conversion to a human-equivalent dose. So, I plan to buy a few bottles of forskolin and see whether I notice any changes.

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