This week we had the opportunity to read a paper in the New England Journal of Medicine, describing, in my opinion, a breakthrough finding in MS. It’s published by Srivastava and coworkers, from the University of Munich. It describes the presence of antibodies against the KIR4.1 potassium channel in almost 50% of MS patients. Maybe i’m biased because my research is focused in autoantibodies in neuroimmune disorders, but, in my opinion is one of the best papers that has been published in MS in many years for different reasons that i will describe later.
However, the impact in the mainstream scientific media and in the community has not been very big so far. It has had a media coverage that is, for example, far behind a recent study describing some allele variants having a small genetic risk of developing MS, being, in my opinion, much less important from the patient care point of view.
The study is an example of how research should be conducted. From a very good (and old) hypothesis it develops a set of experiments brilliantly designed to achieve, with success, the goal in a completely unbiased approach. The approach is very similar to what Dr Dalmau and co-workers have been doing with autoimmune encephalitis, but it has some key differences that make the study even better if possible. Briefly, the study starts describing a set of patients that react agains glial components of the central nervous system. Then the authors isolate cell membranes from brain tissue (rat and human). They demonstrate reactivity against those membranes and isolate the proteins to which the antibodies are targetted (being that protein KIR4.1). Then they design another set of experiments to confirm the finding. They use ELISA, flow cytometry and immunocytochemistry to define the specificity of the antibodies and their frequency and confirm the results in two different series of cases, testing ¡almost 400 patients!. Then they map the epitope of the protein that is being targetted and design immune competition experiments to further support the specificity of the finding and finally develop in vivo experiments with murine models to confirm that patients’ immunoglobulins bind to that protein and determine loss of the protein and complement fixation (one of the ways how antibodies cause damage). Awesome.
But, why is the discovery of those KIR4.1 antibodies so important? I’ll try to summarize my reasons…
First, for historical reasons. The quest for antibodies in MS has been a research topic for many years. Patients have IgG oligoclonal bands in the CSF and B cells in CSF and brain tissue. And, as we have explained before, a trial with Rituximab, that depletes B cells, the cells producing antibodies, has been very successful in phase II trials. So, as in many other diseases, autoantibodies were thought to play a role. However, animal models, biased towards a T-cell paradigm of MS and a huge body of literature describing antibodies against myelin proteins and other proteins, precluded, in my opinion, an unbiased search for new antibody reactivities. To the point that many researchers thought that there was not a unique antibody but many differnt antibodies depending on the patient. This paper opens a new era in MS research. So, first reason why this paper is important is because it changes a decades-long paradigm and many things in MS research, from animal models to patient classification for trials will have to take those antibodies in account.
The second important reason is because, although not right now, it will have important influence in patient care:
1. Diagnostic criteria will have to incorporate these antibodies and probably set a “seropositive” and “seronegative” category. And this is very important because primary progressive MS patients have antibodies in a similar proportion to RRMS and secondary progressive patients. So maybe we should start classifying patients not depending on clinical features but on serological status.
2. Clinical trials and, thus, treatments, will have to be assaied depending on the presence of these antibodies. Maybe patients with antibodies respond better to Rituximab than those that don’t have them. But, more importantly… we know that patients with primary and secondary progressive MS don’t respond to immune therapies very well (not to say at all). But, what if those with antibodies do respond to antibody-depleting therapies? For example, the OLYMPUS trial, testing Rituximab efficacy in primary progressive MS, failed in finding effectiveness in PPMS patients. But, it detected a subgroup of patients, those with more “active lessions”, in which it could be useful. What if we re-classify patients not by MRI status but by antibody status? Is rituximab then clearly effective?
3.Those antibodies, for sure, will help defining clinical-immunological correlations and prognostic subgroups. I’m mostly thinking about a first neurologic episode, for example. If a patient has an optic neuritis but negative antibodies, has the same risk of developing MS than a patient with positive antibodies? That is applicable to response to therapy subgroups, to severity subgroups and antibody titers, etc.
4. If 50% of patients have KIR4.1 antibodies maybe the other half is “a different thing”…the same way we have myasthenia with anti-AChR, MusK and LRP4 antibodies and they have different clinical features and response to therapies, it can happen the same with MS. Now, having a 50% rate of positivity for KIR4.1 many more scientists will believe that the other half have also autoantibodies against something else and that can help being more accurate in diagnosis and management.
5. Maybe now we can understand some unexplained things in MS…. is KIR 4.1, a potassium channel, responsible for the variation in symptoms depending on temperature (Uhthoff’s phenomenon) in MS? How does fampridine exert its function improving some symptoms in MS if it blocks potassium channels? Is the increased frequency of uveitis intermedia (pars planitis) in MS a general autoimmune association or it derives from the fact that KIR4.1 is expressed in the Müller glia of the retina? And so on…
All these things will have to be addressed in studies designed specifically for solving those dilemmas but, in summary, we will see a lot of changes in MS research and care derived from this study. It’s going to become one of the most cited papers in MS and very likely it will improve a lot what we know of that disease and will rescue B-cell depleting therapies in favor of all patients. Or, at least, in favor of those with antibodies against KIR4.1. Congratulations to Dr Srivastava and co-workers because they have found something very interesting for those like me who like neuroimmunology and, more importantly, something that helps in clarifying MS pathogenesis and, that, in the end, will improve care.