MS isn’t caused by antibodies to myelin

Prineas JW, Parratt JDE. Multiple sclerosis: Serum anti-CNS autoantibodies. Mult Scler. 2017:1352458517706037.

BACKGROUND: It is uncertain whether there are autoantibodies detectable by indirect immunofluorescence in the serum of patients with multiple sclerosis (MS).
OBJECTIVE: To determine whether there are anti-central nervous system (CNS) autoantibodies detectable by indirect immunofluorescence in the serum of MS patients.
METHODS:Sera and in some cases cerebrospinal fluid from 106 patients with multiple sclerosis, 156 patients with other neurological diseases, and 70 healthy control subjects were examined by indirect immunofluorescence using cryostat sections of rat cerebrum fixed by perfusion with paraformaldehyde.
RESULTS:Autoantibodies were detected that recognized more than 30 neuronal, glial, and mesodermal structures in 28 of 106 MS cases. Most were also detected in patients with other related and unrelated neurological diseases and several were also found in healthy controls. Novel anti-CNS autoantibodies recognizing particular sets of interneurons were detected in both normal controls and in subjects with CNS diseases.
INTERPRETATION: Serum anti-CNS autoantibodies of diverse specificities are common in MS patients. The same anti-CNS autoantibodies are not uncommon in patients with other neurological diseases. The findings provide no support for the proposition that myelin breakdown in MS is caused by exposure of intact myelin sheaths or oligodendrocytes to a pathogenic serum anti-myelin or anti-oligodendrocyte autoantibody.

The works of Dr Prineus have cast doubt on whether MS is a problem of immune cells entering the CNS to cause damage or whether damage in the CNS cause immune cells to enter. Now they say there is no evidence that exposure of myelin to pathogenic antibodies, so the mechanism must be something else. Maybe implying the damage starts inside the CNS.

It was wondered whether there are antibodies to myelin protein and tissue structures in the blood of pwMS. The answer is simple do some reading the answer is clearly yes…they can be there, and it depends on which study you read to say how people respond.
However, there is disagreement. The suggestion that 50% pwMS have antibodies to the Kir4.1 potassium channel has been disproved,  over and over and over and over again. He’s a new one

Marino M, Frisullo G, Di Sante G, Samengo DM, Provenzano C, Mirabella M, Pani G, Ria F, Bartoccioni E. Low reliability of anti-KIR4.1 83-120 peptide auto-antibodies in multiple sclerosis patients. Mult Scler. 2017 1:1352458517711275

 However, if you read, it is evident that the antibodies detected are often not against myelin. They are often against targets inside the cell. In this study there were thirty structures targeted

The question was are they detectable by immunoflourescence. So you bind antibodies in the serum to a protein in this case in a rat brain and them detect the human antibody by a fluorescent ant-human immunoglobulin = antibody and detect it with an ultraviolet or laser light.  Do they find any…yes they do. 

This is hardly surprising given the many, many claims in the literature. The fact that they are detected by many other methods is irrelevant. 

Most recently people have taken the genes of B cells from MS, including the CNS and have cloned the antibody molecules and they have looked what they are binding to and the answer again is not myelin. 

In this study they find about 30% of pwMS with antibodies that bind to the CNS of a rat. But they found similar things in people who did not have MS. There will likely be more that would bind to the CNS of someone with MS.

First if the antibody targets human proteins they may not react with the rat protein, second the protein may not be exposed on a surface so that it can be bound by the antibody in the tissues seections. Then the fixation method may destroy the target. There are other issues.

Many years ago (1995) a study to see what MS T cells reacted in the MS brain was not myelin, but a protein called alpha B crystallin a cell-stress related (small heat-shock) protein. This would not be present in the rat brain used for screening. This is because there would be no stress in the health rodent brain just as there is no alpha B crystallin in the healthy human brain. 

We did a study many years ago where we sensitized animals to alpha B crystallin and then saw no disease except in one animal and this animals was expressing alpha B crystallin in oligodendrocytes.

However looking in the blood of a mouse a few months after you have induced disease with a known protien, will lead to the detection of antibodies to lots of targets. This is because as damage occurs cell contents are liberated and antibody responses to these are detected. Do this in humans a few years or decades after it all started and it may be unintelligible, just as occurs here and in the many papers on this subject area.

I don’t buy the logic that MS is an autoimmune disease to myelin basic protein,. This current concept is so weak and has more holes in it than a piece of Swiss Cheese. It was made up by short-sighted immunologists who could only make and test water-soluble major myelin proteins. Many people may disagree with me on this one.

My answer is do some reading without blinkers.

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  • I agree with you. I believe in EBV-VD hypothesis. It is for this reasons that I am against current DMT.

  • Little by little it gets clear that MS is not an autoimmune disease to anything, and that CNS damage happens first. Unfortunately, until it gets fully digested, thousand of people will become pwMS.

    • And yet it is obvious that there is immune system involvement, whether MS is a classical autoimmune disease is a moot point and halting inflammatory attacks to the CNS is clearly beneficial but and this is important, we also need effective neuroprotective therapies in addition to DMTs. Combining the two may be a game changer, as we have said here for some time. The pace of work in this area is still too slow.

    • There is disproportionately too much research on drugs that mess with the immune system, than on the origin of MS. No drug of such kind is able to do anything in the long run. Which means that reducing lesions or relapses is the same as turning off the indicator of engine overheating (immune system response on CNS damage): you just make sure that the engine will fail, eventually.

    • And yet all the indications are so far that if you stop relapses early enough, damage to the CNS is halted not only that there can be an improvement, not something you would expect to see if CNS damage was the primary event as this should continue unabated even if relapses were stopped.
      Certainly down the line after many episodes of inflammation in the CNS, nerve loss does happen without further overt relapses, probably as a result of a greatly increased population of activated microglia, which were stimulated by previous inflammation, coupled with a now dystrophic environement and nerves having to work harder to maintain conduction and eventually becoming exhausted and dying. Again pointing to the need for new avenues to be expored, such as neuroprotectants and agents that can turn off damaging activated microglia.

    • Not at all true. "Early enough" means that CNS plasticity overcomes the damage, irrespective of reducing CNS edema (relapse) or not. What you think is progression halt due to drugs is just functional compensation of a virgin brain. Given enough time (16 years, according to natural history) any patient, no matter how early she/he was treated will experience clear progression.

      As for the second paragraph, the neurodegeneration following inflammation as means of MS progression, it is still pure conjecture.

      Ever heard of the ACTION trial?

    • Yes true. Stopping relapses (inflammation as well as oedema) does allow CNS plasticity to occur but also enables damaged nerves to recover and partially remyelinate axons. As you say, go too far down the line and this capacity is exhausted.
      The natural history data for MS is now outdated as data for those pwMS treated with the more effective DMTs is missing.
      Neurodegeneration following inflammation is certainly not conjecture.

      Would that be the Amiloride in optic neuritis trial?

  • More than fifty years ago, it was observed that MS patients had an increased
    level of antibodies in CSF.44 Later on it became clear that this increased
    production of antibodies were oligoclonal in distribution, i e only a limited
    number of plasma cell clones are contributing to the increased levels of
    antibodies.45 A further development was the development of the IgG-index,
    which is an estimate of intrathecal IgG production,46 and today the
    demonstration of intrathecal IgG production is part of the clinical routine in
    establishing a diagnosis of MS. However, the specificity of these antibodies
    has not been established. Most of the oligoclonal antibodies present in the
    CSF are not directed to the major myelin components,47 and some
    controversy exists as to the importance of those that do exist.36 Additionally,
    intrathecal antibody production can be seen in a variety of conditions.48 At
    present it is unclear whether these antibodies are harmful, protective, neither
    or both. It has been demonstrated that patients with RRMS and SPMS have
    antibodies directed towards oligodendrocyte precursor cell lines, but only the
    SPMS patients had antibodies directed towards a neuronal cell line.49 This
    supports the idea that the concept of epitope spreading is important in MS.
    Joachim Burman

    • Hope their ideas are better than their literature searches….it says
      "This observation is the first to demonstrate CCL27 as a potential contributor of brain pathology in MS"

      They forgot to mention their own work "Khaiboullina SF et al. CCL27: Novel Cytokine with Potential Role in Pathogenesis of Multiple Sclerosis. Biomed Res Int. 2015;2015:189638"



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