Elliott C et al. Functional identification of pathogenic autoantibody responses in patients with multiple sclerosis. Brain. 2012 May 4. [Epub ahead of print]
Pathological and clinical studies implicate antibody-dependent mechanisms in the immunopathogenesis of multiple sclerosis. We tested this hypothesis directly by investigating the ability of patient-derived immunoglobulins to mediate demyelination and axonal injury in vitro. Using a myelinating culture system, we developed a sensitive and reproducible bioassay to detect and quantify these effects and applied this to investigate the pathogenic potential of immunoglobulin G preparations obtained from people with multiple sclerosis (n = 37), other neurological diseases (n = 10) and healthy control donors (n = 13). This identified complement-dependent demyelinating immunoglobulin G responses in approximately 30% of patients with multiple sclerosis, which in two cases was accompanied by significant complement-dependent antibody mediated axonal loss. No pathogenic immunoglobulin G responses were detected in people with other neurological disease or healthy controls, indicating that the presence of these demyelinating/axopathic autoantibodies is specific for a subset of people with multiple sclerosis. Immunofluorescence microscopy revealed immunoglobulin G preparations with demyelinating activity contained antibodies that specifically decorated the surface of myelinating oligodendrocytes and their contiguous myelin sheaths. No other binding was observed indicating that the response is restricted to autoantigens expressed by terminally differentiated myelinating oligodendrocytes. In conclusion, our study identifies axopathic and/or demyelinating autoantibody responses in a subset of patients with multiple sclerosis. This observation underlines the mechanistic heterogeneity of multiple sclerosis and provides a rational explanation why some patients benefit from antibody depleting treatments.
Green (myelin) Red (Axons) on Right Noode of Ranvier proteins suchas caspr (blue) and in II sodium channels in green also.
If you remember we were recently taking about lesion heterogeneity in MS and some lesions had evidence of antibody binding and complement activation. This combination is a way of damaging and killing the target cell.
There has been much tooing and frowing about whether there is any autoimmunity occuring in MS and we have said that we know that there are undesirable antibodies in the blood because they can cause symptoms when delivered to the brains of animals, this is yet further example of this.
The authors have developed a myelinating culture system whereby they have rat nerves and myelinated them in cell culture. They have added antibodies from the blood of people with MS and about 30% of them had demyelinating antibody. This means that 70% didn't which can mean there is heterogeneity and a different mechanism between MSers.
It could be that there are different levels in the blood dependent on disease activity and could vary over time, although this was not revent in the samples they tested, as we know MRI activity varies, or there are more antibodies in the CNS compared the blood. Alternatively the antibodies may not react with rat proteins used in the asssay, although this is less likely as there is conservation of many myelin proteins.
Whilst this does not say that MS is an autoimmune disease, it clearly show that B cell autoimmunity can be pathogenic . It may suggest that only a subset of MSers would respond B cell inhibitory therapy. They they also showed that plasma exchange could remove the myelin damaging antibodies. This study clearly shows that some form of autoimmunity exsists in at least some MSers