Antibody-mediated autoimmunity in humans

Is MS an autoimmune disease? I don’t definitively know.

Is there autoimmunity in MS? Absolutely yes.

Why do we know this?

Because if we take autoantibodies found in MS and inject them into the brains of animals with sub clinical disease triggered by T cells,  they cause disease.

Spadaro M, Winklmeier S, Beltrán E, Macrini C, Höftberger R, Schuh E, Thaler FS, Gerdes LA, Laurent S, Gerhards R, Brändle S, Dornmair K, Breithaupt C, Krumbholz M, Moser M, Kirshnamoorthy G, Kamp F, Jenne D, Hohlfeld R, Kümpfel T, Lassmann H, Kawakami N, Meinl E. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein.  Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein.Ann Neurol. 2018 Jul 16. doi: 10.1002/ana.25291. [Epub ahead of print]

Is this new?

No, but it reinforces the view that we have known for years and years:

Puentes F, van der Star BJ, Boomkamp SD, Kipp M, Boon L, Bosca I, Raffel J, Gnanapavan S, van der Valk P, Stephenson J, Barnett SC, Baker D, Amor S. Neurofilament light as an immune target for pathogenic antibodies. Immunology. 2017;152:580-588.

Pathological and regulatory effects of anti-myelin antibodies in experimental allergic encephalomyelitis in mice. Morris-Downes MM, Smith PA, Rundle JL, Piddlesden SJ, Baker D, Pham-Dinh D, Heijmans N, AmorS.J Neuroimmunol. 2002 Apr;125(1-2):114-24.

and years:


Lassmann H, Brunner C, Bradl M, Linington C. Experimental allergic encephalomyelitis: the balance between encephalitogenic T lymphocytes and demyelinating antibodies determines size and structure of demyelinated lesions. Acta Neuropathol. 1988;75(6):566-76.

In this new study, they report:

OBJECTIVE: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) occur in a proportion of patients with inflammatory demyelinating diseases of the CNS. We analyzed their pathogenic activity by affinity-purifying these Abs from patients and transferring them to experimental animals.

METHODS: Patients with Abs to MOG were identified by cell-based assay. We determined the cross-reactivity to rodent MOG and determined the recognized MOG-epitopes. We produced the correctly folded extracellular domain of MOG and affinity-purified MOG-specific Abs from the blood of patients. These purified Abs were used to stain CNS tissue and transferred in two models of experimental autoimmune encephalomyelitis. Animals were analyzed histopathologically.

RESULTS: We identified 17 patients with MOG Abs from our outpatient clinic and selected two with a cross-reactivity to rodent MOG; both had recurrent optic neuritis. Affinity-purified Abs recognized MOG on transfected cells and stained myelin in tissue sections. The Abs from the two patients recognized different epitopes on MOG, the CC’ and the FG loop. In both patients these Abs persisted during our observation period of 2-3 years. The anti-MOG Abs from both patients were pathogenic upon intrathecal injection in two different rat models. Together with cognate MOG-specific T cells, these Abs enhanced T cell infiltration; together with MBP-specific T cells, they induced demyelination associated with deposition of C9neo, resembling a multiple sclerosis type II pathology.

INTERPRETATION: MOG-specific Abs affinity purified from patients with inflammatory demyelinating disease induce pathological changes in vivo upon co-transfer with myelin-reactive T cells, suggesting that these Abs are similarly pathogenic in patients. 

These days virtually all animal models involve disease induction with myelin oligodendrocyte glycoprotein a minor myelin protein.

In this study they report “The vast majority of patients with MS do not have antibodies to MOG, but Abs to MOG are detected in special cases with MS”

The authors suggest that human Abs to MOG are pathogenic but they suggest that “as patients with neuroinflammation may have multiple autoantibodies, which complicates the interpretation of transfer experiments with whole IgG preparations”. 

You know the target and that it binds to native myelin protein and it activates complement, I think you can be pretty sure what it can do and if you put it in a mouse with EAE where it can bind to the same target again I am pretty sure we know it is going to make EAE worse. 

This is exactly what happens but is it really ethical to do these animal experiments, as we already know that anti-MOG antibodies injected into EAE enhances disease activity?

Why do we need two models to report this?

Simple answers are it isn’t ethical and we don’t need two models.  

But a good example of how “sexy science” has gone. Just as you make three dishes out of the same vegetables in fine dining, high-impact factor journal referees expect their science three ways. You get the same answer by doing the same experiment three ways. 

Should we accept this?

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  • “Is MS an autoimmune disease?"

    All the experiments show that autoantibodies to MOG enhance disease but can these autoantibodies induce disease in wild type mice with certain HLA genotype? Once again the which came first question, autoantibodies to MOG, NFL Ags or myelin/neuronal damage and then autoantibody remains unanswered. Prime the immune system and introduce autoantibodies will exacerbate animals with EAE, as you have shown, has been known for decades.

    Will we ever find the initiating antigens? I doubt that autoimmunity and loss of tolerance are the initiating events in MS.

  • "Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury"

    Why should MS differ?

    "Is there autoimmunity in MS?"
    Autoimmunity insinuates immune activation by mistake. There is no proof of that. Why not calling it garbage collection? Immune action in MS has so much in common with Traumatic Brain Injury and Acute Ischmeic Stroke: Debris removal and repair.

    If the above is not enough, here is a cherry on top:

    "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."

    from "Multiple sclerosis: Serum anti-CNS autoantibodies" by John W Prineas and John D.E Parratt

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