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