Thursday, 18 June 2015

Kir autoantibodies as a cause of MS, more evidence for fiction rather than fact.

Malyavantham K, Weinstock-Guttman B, Suresh L, Zivadinov R, Shanahan T, Badgett D, Ramanathan M.Humoral Responses to Diverse Autoimmune Disease-Associated Antigens in Multiple Sclerosis. PLoS One. 2015;10(6):e0129503.

METHODS:The study analyzed 969 serum samples from 315 HC, 411 relapsing remitting MS (RR-MS), 128 secondary progressive MS (SP-MS), 33 primary progressive MS (PP-MS) and 82 patients with other neurological diseases for autoantibodies against two putative MS antigens CSF114(Glc) and KIR4.1a and KIR4.1b and against 24 key endogenous antigens linked to diseases such as vasculitis, systemic sclerosis, rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, polymyositis, scleroderma, polymyositis, dermatomyositis, mixed connective tissue disease and primary biliary cirrhosis. Associations with disability and MRI measures of lesional injury and neurodegeneration were assessed.
RESULTS:The frequencies of anti-KIR4.1a and anti-KIR4.1b peptide IgG positivity were 9.8% and 11.4% in HC compared to 4.9% and 7.5% in RR-MS, 8.6% for both peptides in SP-MS and 6.1% for both peptides in PP-MS (p = 0.13 for KIR4.1a and p = 0.34 for KIR4.1b), respectively. Antibodies against CSF114(Glc), KIR4.1a and KIR4.1b peptides were not associated with MS compared to HC, or with MS disease progression. HLA DRB1*15:01 positivity and anti-Epstein Barr virus antibodies, which are MS risk factors, were not associated with these putative MS antibodies.
CONCLUSIONS:Antibody responses to KIR4.1a and KIR4.1b peptides are not increased in MS compared to HC nor associated with MS disease progression. The frequencies of the diverse autoreactive antibodies investigated are similar in MS and HC
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Not so long ago we had a study claiming that about 50% of MSers had an antibody against this potassium channel and that was a target for the cause of MS.

Potassium channel KIR4.1 as an immune target in multiple sclerosis.Srivastava R, Aslam M, Kalluri SR, Schirmer L, Buck D, Tackenberg B, Rothhammer V, Chan A, Gold R, Berthele A, Bennett JL, Korn T, Hemmer B. N Engl J Med. 2012;367(2):115-23. 

Three years on and this has not been replicated by anyone, including this new study and where Kir4.1 reactive antibodies are no particularly common in MS.

Nerrant E, Salsac C, Charif M, Ayrignac X, Carra-Dalliere C, Castelnovo G, Goulabchand R, Tisseyre J, Raoul C, Eliaou JF, Labauge P, Vincent T.Lack of confirmation of anti-inward rectifying potassium channel 4.1 antibodies as reliable markers of multiple sclerosis. Mult Scler. 2014;20:1699-703.

Brickshawana A, Hinson SR, Romero MF, Lucchinetti CF, Guo Y, Buttmann M, McKeon A, Pittock SJ, Chang MH, Chen AP, Kryzer TJ, Fryer JP, Jenkins SM, Cabre P, Lennon VA.Investigation of the KIR4.1 potassium channel as a putative antigen in patients with multiple sclerosis: a comparative study. Lancet Neurol. 2014; 13: 795-806

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. 2015; 21:572-9

This quite typical the claims of autoantigens or MS after a big fanfare it seems to turn to keich and so the search for the cause keeps on

10 comments:

  1. MD, it still doesn't answer the question why they are there in the first place, given the role of these channels in physiology, it's potentially not good news.

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    1. Phenytoin act on sodium channels, potassium channels and? Does blocking potassium channels could have a new treatment approach for MS, since some potassium channels act of memory effector T cells? ... It is the neurotoxicinas mechanism produced by some venomous animals ...

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    2. FAMPRIDINE IS A POTASSIUM CHANNEL BLOCKER

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    3. This comment has been removed by the author.

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    4. Excuse me for having MD forgot Frampidine as a blocker potassium ... not remembered her because she is not regarded as a DMT, at least here in Brazil it is not here when it is FrampidinExcuse me for having MD forgot Frampidina as a blocker potassium ... not remembered her because she is not regarded as a DMT, at least here in Brazil it is not here when it is Frampidine recipe only has applicability to improve walking. And here in Brazil to be able to use Fampridine by the Unified Health System is a very bureaucratic process, since it has not yet been incorporated into the class of expensive remedies granted by the SUS, in general only be achieved through legal action ... I think so forget it ...a recipe only has applicability to improve walking. And here in Brazil to be able to use Fampridine by the Unified Health System is a very bureaucratic process, since it has not yet been incorporated into the class of expensive remedies granted by the SUS, in general only be achieved through legal action ... I think so forget it ...

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    5. Afff ... send to ask the cell phone did not work out, having a bad mobile internet, I just see now that sent the same question twice ... I sent another comment explaining why I ended up not remembering phenytoin as a blocker sodium channel ... From now grateful for the attention ...

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    6. There is some data regarding a type of potassium channel blocker affecting the immune system. Yes there are other possibilities for such molecules

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  2. Are all these papers talking about the same antibody? Here is a quote from the PubMed entry for the original paper you linked (Srivastava et al, 2012):
    Analysis of the combined data sets indicated the presence of serum antibodies to KIR4.1 in 186 of 397 persons with multiple sclerosis (46.9%), in 3 of 329 persons with other neurologic diseases (0.9%), and in none of the 59 healthy donors.

    So, the originally found antibodies were NOT present in healthy controls - while more recent papers find them in ca. 10% of healthy individuals (and a smaller fraction of people with MS). It seems to imply that the antibodies are different. Is this due to a different assay? different conformations of the channels (open vs. closed etc.)? different isolation of the channels (which are membrane proteins)? Anything else?
    Has anybody other than original authors looked at the blood samples from the original study? This will tell whether discrepancies are due to the selection of study subjects, or issues with antibody assays.

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    1. You make several valid points, the major issues always with assays is reproducibility of the work, and very few people publish negative findings and I know other groups which have been unable to reproduce the findings - mainly people move onto the next thing. The problem is the technique which is very much dependent on the person performing the test and on the sample sets used. The protein per se is also a problem - you'll be surprised how many companies when you purchase their proteins have not confirmed the protein is what it is by sequencing or via proteomics (I once did this trying to sequence a set of proteins in csf - it took 1 year!).
      Such projects need to be done via large groups with well characterised data sets - one group which has this capability is BioMS.eu, another is standardisation and full disclosure of laboratory findings.

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