Gold mining for the cause of MS. Can we improve on the methods? #MSBlog #MSResearch
“The following study looks at an antibody library from MSers and finds that they react to multiple proteins. Interestingly some of them cross-react with viruses and other organisms and putative auto or self antigens. Is this surprising? Not is not, because proteins that are made by humans and micro-organisms are made from a simple set of building blocks so it is not surprising that they cross-react. What is more important is the context in which these cross-reactions will occur. It is reassuring to see that EBV is one of the viruses on the list of organisms. The problem with this paper is that the antibody library was made from cells in the peripheral blood and not the brain and spinal cord. Therefore it could be argued that these antibodies may have little to do with MS.”
“How do you make an antibody library? This is complicated process whereby you take the genes (light chain and heavy chains) that constitute antibodies and you insert them into a virus that makes a part of the antibody and sticks it on its surface. You can then use these surface hemi-antibodies to test how they bind to a panel of proteins. The process of selecting these viruses is called panning; the term is borrowed from the process of panning for gold. The problem with this technique is that it separates the light and heavy chains of the antibodies and selects for them separately. In the human body the light and heavy chains of antibodies work together as a pair. Therefore separating them is not a good idea. What the light or heavy chain bind to may not be what the correct pairing of light and heavy chains bind to. So how can we create a library that expresses both light and heavy chain antibodies together as a matched pair? This is a very difficult job and at present has to be done by cloning antibody genes from single cells. There are some groups doing this and I would think that their results are more likely to biologically meaningful. The problem with their method is that it is very time consuming and instead making trillions of clones they can only make 100s or 1000s.”
“We have some ideas on how to create an industrial scale antibody library that pairs matched light and heavy chain together. This will require someone with green fingers when it comes to molecular biology skills and someone willing to take a high risk developing a new method. It will also take a brave funding agency to fund the research. However, if we did get this method to work it may just be the technology to sort out a lot of unanswered question in relation to MS and other diseases.”
|Panning for gold.
Lomakin et al. Polyreactive monoclonal autoantibodies in multiple sclerosis: functional selection from phage display library and characterization by deep sequencing analysis. Acta Naturae. 2013;5(4):94-104.
Background: MS is a chronic inflammatory demyelinating disease of the central nervous system that primarily affects young and middle-aged people. It is widely accepted that B lymphocyte activation is required for MS progression. Despite the fact that the exact triggering mechanisms of MS remain enigmatic, one may suggest that MS can be induced by viral or bacterial infection in combination with specific genetic and environmental factors.
Methods & Results: Using deep sequencing and functional selection methodologies we characterized clones of poly- and cross-reactive antibodies that are capable of simultaneous recognition of viral proteins and autoantigens. The latter, in turn, possibly may trigger MS progression through molecular mimicry. It was identified that two cross-reactive antigens are probably recognized by light or heavy chains individually.
Conclusions: According to the high structural homology between selected autoantibodies and a number of various antiviral IgGs, we suggest that a wide range of pathogens, instead of a single virus, be regarded as possible triggers of MS.