Saturday, 22 April 2017

Potassium Channels as a major autoimmune target in MS, it ain't Kir 4.1

Zhong R1, Liang JTao AWu LYang XXu HHuang QZhuang SLong YGao C.
Anti-KIR4.1 Antibodies in Chinese Patients with Central Nervous System Inflammatory Demyelinating Disorders.

OBJECTIVES: The aim of this study was to explore the frequency of KIR4.1 antibodies in patients with multiple sclerosis (MS) and in control groups using a cell-based assay.
MATERIALS AND METHODS: A transfected HEK-293A cell line expressing KIR4.1 was established to test for the presence of KIR4.1 antibodies in blood serum. We tested 904 subjects, including 188 patients with MS, 264 patients with neuromyelitis optica spectrum disorders (NMOSD), 209 patients with other inflammatory neurologic disease (OIND), 203 patients with other noninflammatory neurological disease (OND), and 40 healthy controls.
RESULTS: KIR4.1 antibodies were present in 23 of the 188 (12.2%) MS patients, 42 of the 264 (15.9%) NMOSD patients, 32 of the 209 (15.3%) OIND patients, 24 of the 203 (11.8%) OND patients, and 2 of the 40 (5%) healthy controls. There were no significant differences among the MS and control groups (p = 0.279).
CONCLUSIONS:Anti-KIR4.1 antibody, as determined by a cell-based assay, is not a specific biomarker for MS


However we also have

Navas-Madroñal M, Valero-Mut A, Martínez-Zapata MJ, Simón-Talero MJ, Figueroa S, Vidal-Fernández N, López-Góngora M, Escartín A, Querol L. Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review. PLoS One. 2017;12(4):e0175538.

INTRODUCTION: Antibodies targeting the inward-rectifying potassium channel KIR4.1 have been associated with multiple sclerosis (MS) but studies using diverse techniques have failed to replicate this association. The detection of these antibodies is challenging; KIR4.1 glycosylation patterns and the use of diverse technical approaches may account for the disparity of results. We aimed to replicate the association using three different approaches to overcome the technical limitations of a single technique. We also performed a systematic review to examine the association of anti-KIR4.1 antibodies with MS.
METHODS:Serum samples from patients with MS (n = 108) and controls (n = 77) were tested for the presence of anti-KIR4.1 antibodies using three methods: 1) by ELISA with the low-glycosylated fraction of recombinant KIR4.1 purified from transfected HEK293 cells according to original protocols; 2) by immunocytochemistry using KIR4.1-transfected HEK293 cells; and 3) by immunocytochemistry using the KIR4.1.-transfected MO3.13 oligodendrocyte cell line. We developed a systematic review and meta-analysis of the association of anti-KIR4.1 antibodies with MS according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
RESULTS: We did not detect anti-KIR4.1 antibodies in the MS patients or in controls using ELISA. Neither did we detect any significant reactivity against the antigen on the cell surface using the KIR4.1-transfected HEK293 cells or the KIR4.1-transfected MO3.13 cells. We included 13 prospective controlled studies in the systematic review. Only three studies showed a positive association between anti-KIR4.1 and MS. Clinical and statistical heterogeneity between studies precluded meta-analysis of their results.
CONCLUSION:We found no association between anti-KIR4.1 antibody positivity and MS. Although this lack of replication may be due to technical limitations, evidence from our study and others is mounting against the role of KIR4.1 as a relevant MS autoantigen.


So one arguably paper in  a high impact factor journal spawned 15+ papers of which the majority (12 show the original claim  was incorrect that the majority of people do not have antibodies to channel. The is a common problem.

                                                                                   source Brain RNAseq

We have previously posted on the the relevance of potassium (K) channels to MS


ATP-sensitive inward rectifier potassium channel 10 is a protein that in humans is encoded by the KCNJ10 gene.

This has as a greater tendency to allow potassium to flow into, rather than out of, a cell. Kir4.1, may form a channel with other potassium channel protein and may be responsible for controlling potassium levels by glial cells in the brain. 

Humans with mutations in the KCNJ10 gene that cause loss of function in related K+ channels can display EpilepsyAtaxia, sensorineural deafness and tubulopathy of the kidney

A channel that is "inwardly-rectifying" is one that passes current (positive charge) more easily in the inward direction (into the cell) than in the outward direction (out of the cell). It is thought that this current may play an important role in regulating neuronal activity, by helping to stabilize the resting membrane potential of the cell.

At membrane potentials negative to potassium's reversal potential/Nernst potential (at the point when there is no ions moving across the membrane) inwardly rectifying K+ channels support the flow of positively charged K+ ions into the cell, pushing the membrane potential back to the resting potential, which is about -70mv. 


However, when the membrane potential is set positive to the channel's resting potential (e.g. +60 mV), these channels pass very little current. Simply put, this channel passes much more current in the inward direction than the outward one, at its operating voltage range. 

These channels are not perfect rectifiers, as they can pass some outward current in the voltage range up to about 30 mV above resting potential, which would occur when marked depolarisation happens.

Kir.4.1 was implicated as a target for autoantibodies antibodies in MS,  but as so often occurs these things are never replicated and indeed these studies, supports other studies and says the original idea that Potassium channels were a major cause of autoimmunity is clearly wrong. As reported previously.


Could antibodies directed to Kir4.1 cause problems? 
Absolutely as they react with astrocytes and oligodendrocytes, and so could block function or kill the cells


Neusch C, Rozengurt N, Jacobs RE, Lester HA, Kofuji P.
Kir4.1 potassium channel subunit is crucial for oligodendrocyte development and in vivo myelination. J Neurosci. 2001 ;21(15):5429-38. Kir4.1 forms the major K(+) conductance of oligodendrocytes and is therefore crucial for myelination. 


Potassium ions may therefore critical in myelination.

Bezine M, Debbabi M, Nury T, Ben-Khalifa R, Samadi M, Cherkaoui-Malki M, Vejux A, Raas Q, de Sèze J, Moreau T, El-Ayeb M, Lizard G. Evidence of K+ homeostasis disruption in cellular dysfunction triggered by 7-ketocholesterol, 24S-hydroxycholesterol, and tetracosanoic acid (C24:0) in 158N murine oligodendrocytes. Chem Phys Lipids. 2017. pii: S0009-3084(17)30011-7.

Imbalance in the homeostasis of K+ ions has been reported to contribute to the pathogenesis of neurodegenerative diseases. 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) (this is oxidised cholesterol=oxysterols), and tetracosanoic acid (C24:0), often found at increased levels in patients with Multiple Sclerosis, are able to trigger numerous nerve cell dysfunctions......They induced [K+]i (potassium ion concentrations within the cell) and changes in lipid content and polarization of the cytoplasmic membrane. These events were associated with increased potassium ion concentrations...(and oligodendrocyte death). Blocking K channels with 4-AP (active ingredient of fampridine) exacerbated oligodenrocyte killing.

So lowering cholesterol should be good. Is this how statins work in progressive MS, by blocking oxysterols?
Too much potassium accumulating in a oligodendrocyte causes it to die. Interestingly 4-AP makes this worse.

Therefore, does fampridine kill off oligodendrocytes and block remyelination?

Bacia A, Wollmann R, Soliven B. K+ channel blockade impairs remyelination in the cuprizone model. Glia. 2004; 48(2):156-65.
We found that treatment with 4-aminopyridine (4-AP), a broad-spectrum K(+) channel antagonist, results in: (1) decreased number of oligodendroglial progenitors (OP) and OLGs; (2) diminished astrogliosis; and (3) decreased remyelination in the corpus callosum based on the immunoreactivity to myelin basic protein (MBP), Rip monoclonal antibody, and by electron microscopy.

However to counter that data in peripheral nerves indicate

Tseng KC, Li H, Clark A, Sundem L, Zuscik M, Noble M, Elfar J. 4-Aminopyridine promotes functional recovery and remyelination in acute peripheral nerve injury. EMBO Mol Med. 2016 ;8(12):1409-1420.


We know Fampridine allows nerves to work harder, improving walking speeds, but is this good news in the long term? 

Maybe it is time, that we saw data on slow release 4-AP improving remyelination in animal models and protecting nerves. 

3 comments:

  1. I didn't understand any of this - should I eat more, or less, bananas?

    ReplyDelete
    Replies
    1. Ha....I think the potassium channel is a new cable tv network.

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  2. From what I understand it's a dysfunction in the potassium channels that causes too much potassium to be concentrated inside the cell, and this ends up interfering with nerve conduction, and cholesterol synthesis, and leads to the death of nerve cells, oligodendrocytes and astrocytes.

    But what would be the cause of this imbalance in the Kr4.1 channel, would it come from mutation in the gene that controls it, or could something else be interfering with this? Can infections lead to this deregulation in the Potassium channels? And would food interfere with something, either positively or negatively, like avoiding foods rich in potassium and saturated fats (because of cholesterol)?

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