Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system and also is regarded as an autoimmune condition. However, the antigenic targets of the autoimmune response in MS have not yet been deciphered. In an effort to mine the autoantibody repertoire within MS, we profiled 2,169 plasma samples from MS cases and population-based controls using bead arrays built with 384 human protein fragments selected from an initial screening with 11,520 antigens. Our data revealed prominently increased autoantibody reactivity against the chloride-channel protein anoctamin 2 (ANO2) in MS cases compared with controls. This finding was corroborated in independent assays with alternative protein constructs and by epitope mapping with peptides covering the identified region of ANO2. Additionally, we found a strong interaction between the presence of ANO2 autoantibodies and the HLA complex MS-associated DRB1*15 allele, reinforcing a potential role for ANO2 autoreactivity in MS etiopathogenesis. Furthermore, immunofluorescence analysis in human MS brain tissue showed ANO2 expression as small cellular aggregates near and inside MS lesions. Thus this study represents one of the largest efforts to characterize the autoantibody repertoire within MS. The findings presented here demonstrate that an ANO2 autoimmune subphenotype may exist in MS and lay the groundwork for further studies focusing on the pathogenic role of ANO2 autoantibodies in MS.
If MS is an autoimmune disease what is the target autoantigen?
This is an age old problem.
The question we first have to ask is it a T cell problem or a B cell problem?
There is a lot of hope placed on B cells at the moment and it is relatively easy to see what B cells are recognising, because this is the target of their B cell receptors, which are the antibody molecules.
Recently we have has a sea of papers reporting on what the antibodies are recognising whether they are proteins or lipids.
There are many ways to do this you can use arrays of proteins and peptides (although antibodies of importance tend to recognise 3D shapes rather than straight short peptides) or you can make the heavy and light chains of the antibody molecule and make them genetically and go fishing for the target.
Both approaches are “fishing expeditions” rather than hypothesis led research. In this trawl they pull out Anoctamin2. The find that people with the gene associated with MS are more likely to make antibodies to this target.
Where is Anoc2 expressed. In the mouse it is in the eye and the olfactory system and if you knock it out there are problems with sensing odour….so does this new one smell fishy.