Antibodies to MOG is this the answer to autoimmunity

Khare P, Challa DK, Devanaboyina SC, Velmurugan R, Hughes S, Greenberg BM, Ober RJ, Ward ES. Myelin oligodendrocyte glycoprotein-specific antibodies from multiple sclerosis patients exacerbate disease in a humanized mouse model. J Autoimmun. 2017. pii: S0896-8411(17)30155-5.

Myelin oligodendrocyte glycoprotein (MOG) is exposed on the outer surface of the myelin sheath, and as such, represents a possible target antigen for antibodies in multiple sclerosis (MS) and other demyelinating diseases. However, despite extensive analyses, whether MOG-specific antibodies contribute to pathogenesis in human MS remains an area of uncertainty. 

In the current study we demonstrate that antibodies derived from adult MS patients exacerbate experimental autoimmune encephalomyelitis (EAE) in ‘humanized’ mice that transgenically express human FcγRs (hFcγRs). 

Importantly, this exacerbation is dependent on MOG recognition by the human-derived antibodies. The use of mice that express hFcγRs has allowed us to also investigate the contribution of these receptors to disease in the absence of confounding effects of cross-species differences. Specifically, by engineering the Fc region of MOG-specific antibodies to modulate FcγR and complement (C1q) binding, we reveal that FcγRs but not complement activation contribute to EAE pathogenesis. Importantly, selective enhancement of the affinities of these antibodies for specific FcγRs reveals that FcγRIIA is more important than FcγRIIIA in mediating disease exacerbation. These studies not only provide definitive evidence for the contribution of MOG-specific antibodies to MS, but also reveal mechanistic insight that could lead to new therapeutic targets.

Does this work change your mind. I have been challenging DrLove to say what causes the oligodendrocyte damage in MS. 

Her response was that it was MOG (myelin oligodendrocyte glycoprotein) specific antibodies and I have said that I don’t buy this. 

There is no question that antibody to MOG can cause damage in rodents. We showed this years ago, but we weren’t the first to do it. It was shown that antibody that could activate complement could kill oligodendrocytes, if it could get in the brain. 

In this study they have used a genetically engineered mouse so that the antibody can more easily interact with the macrophages and other cells that have the Fc receptor that can bind to bottom end of an antibody. They say this is more important than the complement activation and so counteract numerous other studies. 

This contradiction does not worry me as we also showed that the complement fixation element was not an absolute requirement. Also mice can have defective complement systems and even they can have defective Fc receptors like the strain of mouse we work with. They find that antibodies can have greater activity via certain Fc types. This is fine but the question is how common is this activity is this the norm or the isolated case?. 

That the antibodies come from MS, says that this damaging approach can and probably does occur, so yet more evidence that autoimmunity occurs in MS. However a MOG-reactive antibodies are associated with the development of a neuromyelitis optica-like demyelinating syndrome not MS. 

So is this the cause of MS…I’ll be talking with Dr Love, but people have looked for anti-MOG responses in MS and it has not been consistently found, so I may come back and try to convince you that it is the answer.

On thing that animals tell us is that each individual reacts to a different set of antigens.

If we say memory B cells are the issue, again the problem is where does the specificity for the CNS come into the equation? 

What does an EBV infected B cell see or do to trigger relapses. 

Is it alpha B crystallin? 

We know oligodendrocytes express this, 

I dont know but I am pretty convinced it is not the blood vessels…

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  • Correct me if i am wrong but in the past MOG antibodies did´nt correlate with the EAE model in the mouse and MS in humans?


    • MOG antibodies given to any animal if it fixes complement will cause demyelination if it gets in the brain however EAE however you can get EAE with no MOG in the mix. Likewise most humans do not have anti-MOG antibodies

    • In animal models

      Animal models of MS, EAE, have shown that "MOG-specific EAE models (of different animal strains) display/mirror human multiple sclerosis",[8] but basically explains the part involved in the optic neuritis[20] These models with anti-MOG antibodies have been investigated extensively and are considered the only antibodies with demyelinating capacity[8] but again, EAE pathology is closer to NMO and ADEM than to the confluent demyelination observed in MS.

      Anti-MOG mediated demyelination was shown to behave similar to NMO in animal models,[20] and currently it is considered even a biomarker against the MS diagnosis[21][22]

  • MD, do you absolutely reject the possibility that CNS trauma can induce anti-MOG antibodies? These guys leave a window wide open:
    B cells and autoantibodies: complex roles in CNS injury.

    "Emerging data indicate that traumatic injury to the brain or spinal cord activates B lymphocytes, culminating in the production of antibodies specific for antigens found within and outside the central nervous system (CNS)."

    • No, I accept that CNS trauma that liberates myelin and this could allow anti myelin antibodies to be generated and this is probably a route they are generated rather than being a target, this is why most antibodies they clone from CNS B cels react to contents inside a cell.

    • But this study of "trauma," demyelination and MS has a "gap" to be filled: how can one explain why women have more MS than men? Women "hit their heads and back more, I do not know" than men?
      It seems half-nonsense, and this is one of the answers that studies that address the causality of MS has another time to answer, which is the difference of the disease in the genders, and why it affects more women, and when it reaches men tends to be more progressive from the start.

  • "If we say memory B cells are the issue, again the problem is where does the specificity for the CNS come into the equation?"

    Same specificity is why RA is found in the joints.
    More important to have effective therapy than to solve MS rubiks cube

    "Furthermore, 10-fold higher frequencies of EBV-infected B-cells have been observed in RA patients compared to healthy controls [77]. Interestingly, EBV DNA was found in many of the plasma cells producing CCP antibodies localized in synovial tissues of RA patients [78]. These results indicate a widespread lytic EBV infection in RA patients, that also localize in the joints, suggesting a role for EBV-infected cells in the synovial inflammation characteristic for RA patients."

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