Sunday, 16 November 2014

More Evidence that Kir4.1 is not the causal target for MS

Brill L, Goldberg L, Karni A, Petrou P, Abramsky O, Ovadia H, Ben-Hur T, Karussis D, Vaknin-Dembinsky A.Increased anti-KIR4.1 antibodies in multiple sclerosis: Could it be a marker of disease relapse? Mult Scler. 2014 Nov. pii: 1352458514551779. [Epub ahead of print]

BACKGROUND: Screening of putative autoimmune targets in multiple sclerosis (MS) revealed a proportion of patients carrying antibodies (Abs) against KIR4.1, a potassium channel that shares functional properties with AQP4. Both are localized at the perivascular astrocytic processes.
AIMS:To measure anti-KIR4.1 Abs in the serum of MS and neuromyelitis optica (NMO) patients, and to identify the clinical and laboratory characteristics of patients harboring anti-KIR4.1 Abs.
METHODS:We measured anti-KIR4.1 Abs in serum, using the peptide KIR4.1 (83-120) enzyme-linked immunosorbent assay (ELISA).
RESULTS:Serum levels of anti-KIR4.1 Abs were significantly higher in MS and NMO patients than in healthy controls (HCs); with Abs detected in 21 of 80, 10 of 45, and 2 of 32 individuals, respectively (MS versus HC, p < 0.05). The level of anti-KIR4.1 Abs was significantly higher during MS relapse, versus remission (p = 0.04). The clinical characteristics of our study patients did not vary based on KIR4.1 positivity.
CONCLUSIONS:Anti-KIR4.1 Abs were found in similar proportions of patients with MS and NMO, at a significantly higher level than observed in HCs; consequently, the presence of Abs does not discriminate between these demyelinating diseases. However, anti-KIR4.1 Ab levels differed in MS patients during relapse and remission; as such, they may represent a marker of disease exacerbation.


It had been suggested that 50% of MSers have antibodies but this observation has not been replicated by a number of labs, and this adds one more nail in that coffin. However it was found in about 25% o MSers and NMOers, but was more common than in non MSers and were more common in relapse. Is this a marker of disease exacerbation but do we need a  marker for something that you are sensing..maybe but there is more negative data on the way about the likelihood that that anti-bodies against this potassium channel are highly expressed in MS.

4 comments:

  1. What is KIR5.1 ? , seems like you are on overdrive :). I do not see you header do justice to content of this paper, they do see significant difference between MS and control however they have extended observation in NMO as well which was not in original discovery.I had opportunity to hear talk and look on poster from the group in ISNI meeting.I did find most of KIR4.1 expressed in HEK pretty different than KIR4.1 in human brain.They have in house monoclonal antibody binding to same extracellular epitope and it behave same and do not bind to most of KIR4.1 in HEK. They have have 2-3 blinded cohort study going on from outside center I would wait to have final call.Molecule is too interesting to dump it pretty fast.All of their study is from purified KIR4.1 tetramer which mimic white matter KIR4.1 which I do not see anybody have done yet.

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    1. Yep sorry my mistake it was 4.1 not 5.1 changed. They do indeed see difference between MS and control. I am not saying that this protein is not involved, but this incidence is no where near the 50% originally reported. However the assay was different

      When the researchers you mention from ISNI publish their paper, we can report further and maybe I will be more upbeat then. However at ISNI there were also a few more posters questioning the original observation.

      However if there are antibodies, then they likely to be doing something...We have found pathogenic antibodies in CSF of MSers and suspect that antibodies reacting to potassium channels will not be good news.

      The question for Kir 4.1 is this the cause or the consequence, at present it looks more like the latter. We shall see. Thanks for your post

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  2. I don't believe any antibodies are casual agent in MS and I think no body want to sell that (at least as casual agent) .But if an antibody is the by product of T cell event and just it shows up as an event marker I would guess it would be better for disease management in MSers.I would not mind even as a secondary product as long as it works as marker prior onset of disease phenotype.My gut feeling seeing their poster on T cell response where clone were HLA restricted and responded to full length protein.Antibody could be just transitional event not a casual agent therefore it may vary between 25 to 50 % or even much higher.But who knows ?, time will tell.

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  3. Or Kir4.1 antibodies may be more prevalent during a relapse:

    http://www.ncbi.nlm.nih.gov/pubmed/25392324

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