Sunday, 3 November 2013

Is Kir4.1 a target in MS?

Nerrant E et al. Is anti-KIR4.1 antibody a biomarker for multiple sclerosis? ECTRIMS 2013
Background: Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the central nervous system. Although demyelinating lesions formations are likely related to immune reactions, the identification of a target auto-antigene remained so far largely uncertain. Recently, the ATP-sensitive inward rectifying potassium channel, KIR4.1, was identified as a target of auto-antibodies in 46% of MS patients (Srivastava 2012). The aim of our study was to confirm these findings and to compare clinical characteristics of patients with and without anti-KIR4.1 antibody.
Methods: This prospective study included MS patients fulfilling 2010 McDonald criteria,patients with other neurologic diseases and bone marrow healthy donors as controls. The first step was to develop a specific and sensitive enzyme-linked immunosorbent assay (ELISA) for anti-KIR4.1 antibody evaluation using KIR4.183-120 peptide, as previously described. The threshold positivity was defined as 2 standard deviations (SD) above mean optical density (OD) of the control group. Primate brain and cerebellum sections were used for indirect immunofluorescence analysis. Clinical data were collected independently.
Results: From October 2012 to March 2013, 45 controls, 20 patients with OND and 253 MS patients were consecutively included. Anti-KIR4.1 Ab is found in 2/45 (4.4%) in controls versus 2/20 (10.0%) in patients with OND and 19/253 (7.5%) in MS patients.
Discussion: We confirm the presence of anti-KIR4.1 Ab in 7.5% of MS patients. However, the sensitivity and specificity of
anti-KIR4.1 Ab in MS appear much lower in our study than previously described. Our results suggest that anti-KIR4.1 Ab is not a suitable biomarker for MS. 


Maybe could not duplicate. The original paper indicated over 45% of MSers had this antibody and not in healthly people. 
This currently study suggests a lot less than that and questions the original data. 

Another study needed, which is right?

9 comments:

  1. Yes, the original findings from the group in Germany were verified by a group at Yale University. So, I would say maybe more testing is needed to o confirm. As was shown in CCSVI, the truth will eventually be revealed.

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    1. OK perhaps you could give us reference to the Yale Study, as I have missed it, so we compare the original study (found no activity in healthy individuals, and few in other neurological disease) and this one as you say the truth will be out. If this follows the history of autoantibodies in MS, there are many different specificities that are recognised, they may be pathogenic and invariably they are only detected in a subset of Msers.

      Many MSers do not respond to plasma exchange, in contrast to NMOers where antibodies against a water channel on astrocytes has been implicated as being important Kir4.1 is a potassium channel on astrocytes so interesting.

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    2. From your competitors blog:

      http://www.msdiscovery.org/news/new_findings/5467-evidence-grows-pathogenic-antibody

      "The initial finding of the antibody last year has since been corroborated by Kevin O’Connor, a neuroimmunologist at Yale School of Medicine in New Haven, Connecticut. “We reproduced [Hemmer’s] assay, and we were able to detect antibodies to KIR4.1 in patients with MS,” O’Connor said. He has not yet assayed enough patients to say how many in his sample carry the protein, or whether it will approach the 47% reported by Hemmer. “Different labs working with different populations, even in different countries—you won’t get the same rate,” O’Connor said."

      So it looks like they havent finished the study yet, but they do confirm the results. But it looks like looking for these antibodies are quite difficult and I don't think just any lab can do it accurately:

      "To find new antibodies, MS researchers face a major challenge in developing better screening tools. “Many proteins that are modified by antibodies—including KIR4.1—form three-dimensional structures that are not easy to build in a dish,” Hemmer said. O’Connor agreed. “Many people try to express a protein in a dish and use it [to screen for antibodies] and expect it to work. It’s far, far more complicated than that,” he said. “This assay is very difficult to do.” Through extensive communications with Hemmer’s group, “we figured out all the technical details, and it does work.”"

      I guess this is why you have to send the test for NMO-IgG directly to the Mayo Clinic as other labs do not have the knowledge or capability to conduct the test.

      But as I said, the truth will come forward with time.



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    3. OK ta...will wait for the connor lab to publish their findings it is not clear if they get the high hit rate.

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  2. More is being learned how important this channel is in demyelinating diseases. I think this is a breakthrough and may lead to the true cause of ms:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2885553/?report=classic

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    1. Interesting but this reference is about NMO and not really MS, but let's hope you are right and this is the break though, I will build this into my worldview.

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    2. Whilst http://m.jneurosci.org/content/21/15/5429.full.pdf infers the importanceof Kir 4.1 in oligodendrcytes in the general Kir knockout

      http://www.jneurosci.org/content/27/42/11354.full.pdf implicates the astroglia as a targetand uses conditional knockout in astrocytes

      In the former the mice die from 10 days birth, in the latter they last for 15 days before they die.

      Therefore it is Kir 4.1 is important in neural function, block it with antibodies and it is likely that the out come will not be good.

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  3. So, might it be that MS, NMO and similar diseaes are all "channelpathies" with different channel auto-antigens?

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1112934/

    I think we may be getting close to answering this question.

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