Mission control-Do we have a problem? Anti-neurofilaments antibodies

M

A lot of faith has been put into measuring neurofilaments, which are structural proteins of nerves as a marker of nerve damage. The idea is that as the nerve gets damaged it releases its contents and you have a marker for progression. However, the reality is that neurofilament light measurent perhaps is a better marker of inflammation induced damage. This floats around the cerebrospinal fluid and it then reaches the blood. The neurofilament can be measured in blood but there could be a problem and this is that neurofilaments are proteins that the immune systems does not normally see and so when it appears outside of nerves, anti-neurofilament antibodies can be made. If they bind to the bits of the neurofilaments that are used to detect them, then the neurofilament level may appear low. So are they a problem? Maybe DrLove, ProfG may want to come back to answer, as it is their work Maybe NDG will make an appearance..

Antibodies to neurofilament light as potential biomarkers in multiple sclerosis.Puentes F, Benkert P, Amor S, Kuhle J, Giovannoni G.BMJ Neurol Open. 2021; 3(2):e000192.

Background and objective: The concentration of neurofilament light (NfL) protein in cerebrospinal fluid (CSF) and blood is widely considered as a quantitative measure of neuro-axonal injury. Immune reactivity to NfL released into extracellular fluids induces specific autoantibody response. We investigated the levels and avidity of antibodies to NfL in patients with multiple sclerosis (MS) treated with disease-modifying therapies (DMTs) and their correlation with disease worsening and NfL protein concentration.

Methods: We conducted a prospective longitudinal study in 246 patients with MS (125 DMT-treated and 121 untreated at baseline). Serum levels of NfL antibodies, antibody avidity and immune complexes were determined by ELISA. NfL protein was measured using the Simoa platform.

Results: Levels of NfL antibodies were higher in progressive MS compared with clinically isolated syndrome (CIS)/relapsing remitting multiple sclerosis (RRMS) (p=0.010). Anti-NfL levels drop with increasing disability score (Expanded Disability Status Scale (EDSS)) (p=0.002), although conversely, were significantly elevated in CIS/RRMS after a recent EDSS increase (p=0.012). Patients receiving DMTs showed decreased levels of anti-NfL (p=0.008), high-avidity antibodies (p=0.017) and immune-complexes compared with untreated CIS/RRMS. Patients with MS switching to natalizumab showed lower levels of anti-NfL but higher immune complexes compared with healthy controls (p=0.0071). A weak association was observed between the levels of NfL protein and NfL antibodies.

Conclusions: These results support the potential usefulness of quantifying antibody response to NfL as potential markers of progression and treatment response in MS and need to be considered when interpreting peripheral blood NfL levels.

However, dont hold your breath. Maybe we could devise a test that avoids these issues but fear not they can detect neurofilament and antibodies in complex

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry, nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.  Please note that Professor Gavin Giovannoni has no responsibility for this blog.

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  • I have just read an article on the BBC website entitled ‘The race to understand ‘immune amnesia’ (https://www.bbc.com/future/columns/immune-response) and it would seem it might offer a way to reset the immune system for those suffering from MS.

    These are extracts from this article:

    Enter “immune amnesia”, a mysterious phenomenon that’s been with us for millennia, though it was only discovered in 2012. Essentially, when you’re infected with measles, your immune system abruptly forgets every pathogen it’s ever encountered before – every cold, every bout of flu, every exposure to bacteria or viruses in the environment, every vaccination. The loss is near-total and permanent. Once the measles infection is over, current evidence suggests that your body has to re-learn what’s good and what’s bad almost from scratch.

    “In a way, infection of the measles virus basically sets the immune system to default mode,” says Mansour Haeryfar, a professor of immunology at Western University, Canada, “as if it has never encountered any microbes in the past”.

    But this was not the end of the story. The team mostly found the receptor measles binds to on a specific kind of immune cell, the memory T cell. Their job is to remain in the body for decades after an infection, quietly looking out for the specific pathogen each one was trained to target. So, measles actively infects the only cells that can remember what the body has encountered before.

    (Unfortunately there’s no evidence this immune reset can be beneficial for those who have malfunctioning immune systems, such as people with autoimmune disorders – and even if it was, Swart points out that measles-based treatments would only work in those who had never encountered measles or the vaccine before.)

      • Probably because most people would get measles before EBV, or at least before they developed an autoimmune disease. Now we we have vaccinations against measles which most people would get before EBV/auto immune disease.
        Measles is a really nasty disease, it indirectly causes loads of childhood deaths in the 2 years or so after infection because of this immune amnesia effect. Measles also has a very rare complication about 6-1.0 years after patient recovers from measles called sun-acute sclerosing panencephalitis that is 100% fatal…. A few things that hard core anti vaxxers don’t realise.
        I wonder if their could be some way of targeting the receptor that measles binds to on memory T-cells that would work in autoimmune diseases.

  • Interesting, maybe there will be a Nfl ab/ag screen lab test in the future that will be an indicator of MS activity somewhat akin to a hepatitis screen and liver damage.

  • Can’t see why this can be useful as it would have as much issues as a simple sNfL measure if not more – 1. delay from CNS to blood; 2. highly variable even for the same individual; 3. requires a longer period of time to make sense when damage has already been done; 4. Results will be biased depending on DMT – I would imagine people on antiCD20s and imods would have a lower antibody count against NfL.

      • If everything else is equivalent which never will..

        So sNfL and anti-NfL antibodies dynamics need to be looked at the same time, and both varies and has its own, different delays?

        Anyway is developing antibody against NfL another autoimmune :D?

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