They found some important phenomena in this study

They found some important phenomena in this study. around the role of Kir4.1 in MS, we consider whether it could be an immune target in this disease. mice [64]. MK-2048 They found some important phenomena in this study. OL-encoded Kir4.1 regulates for OL differentiation and is critical for normal motor and visual function in adult CNS. Furthermore, they observed that OL-encoded Kir4.1 is essential for white MK-2048 matter integrity after chronic focal demyelination lysolecithin is induced. It will be interesting to see how these phenomena are linked to the pathogenicity of the Kir4.1 antibodies. Passive transfer is usually arguably the most important finding required to link a disease to antibody-mediated pathogenic mechanisms [60]. The majority of the Kir4.1 antibodies detected in patient sera belong to the complement-fixing IgG1 and three subclasses, and IgG MK-2048 isotypes capable of activating the match cascade were found. Srivastava et al. reported their findings 24 h after the injection of anti-Kir4.1 antibodies, and as a complement to wild-type mice intracisternally, the authors observed a decreased expression of Kir4.1 and glial fibrillary acidic protein, a protein expressed by astrocytes [14]. They provide data in support of autoantibodies to KIR4.1 as mediators of inflammation and tissue damage in MS [14,65]. While classical features of MS lesion pathology, such as demyelination, axonal loss, and microglial activation, were not observed, the authors reported evidence for cytotoxicity toward astrocytes. More importantly, these data should be considered preliminary, and the immunization with the Kir4.1 protein producing a model disease must be confirmed. Finally, it is important to discuss the relationship between the antibody levels and disease severity. Brill et al. reported that antibody levels were higher during relapse than remission, suggesting that this levels could reflect disease activity and exacerbation [46]. Examples of a reduction in the severity of Kir4.1 antibody-positive MS in response to immunomodulatory treatments that lower the antibody levels, suggested by prospective studies, are required in the future. 6. Conclusions Previous studies exhibited great variability with respect MK-2048 to the prevalence of the Kir4.1 antibodies within the MS population, ranging from 0 to 57.4%. It is necessary to overcome the technical problems in measuring these autoantibodies and establish a novel and reliable method of detection. Alternatively, as we have previously argued, it could be prudent to work internationally to measure the same-coded samples with the various assays established in each country to overcome the variability (especially the ethnic difference) in these results of previous studies. With regard to the pathogenicity of the anti-Kir4.1 antibodies, available evidence has hitherto provided persuasive, if not yet definitive, support for the antibody-mediated pathogenesis in the anti-Kir4.1 antibodies-positive MS. Future studies are required to evaluate the effects of the passive transfer of serum from Kir4.1 antibodies-positive patients, including the patients with MS and OND, and Kir4.1 antibodies-negative patients to recipient animals. From a clinical perspective, it will hereafter be necessary to elucidate how the Kir4.1 antibody levels change over the clinical course of MS, and how they are affected by immunotherapy. Acknowledgments We are grateful to Masaaki Niino, Seiji Kikuchi (NHO Hokkaido Medical Centre), Toshiyuki Fukazawa (Sapporo Neurology Medical center), Toshiyuki Takahashi (NHO Yonezawa Hospital), and Kazuo Fujihara (Tohoku University or college) for useful discussions and collaboration on the previous work. Abbreviations CNScentral nervous systemIgimmunoglobulinCSFcerebrospinal fluidMSmultiple sclerosisVGKCvoltage-gated potassium channelKCacalcium-activated potassiumKirinwardly rectifying potassiumK2Ptandem pore domain name potassiumAQP4aquaporin 4HDHuntingtons diseaseSeSAME/EASTseizures, sensorineural deafness, ataxia, mental retardation and electrolyte imbalance/epilepsy, ataxia, sensorineural deafness and tubulopathyLGI1leucine-rich glioma-inactivated protein 1CASPR2contactin-associated protein like 2ONDother neurological diseasesHChealthy controlELISAenzyme linked immunosorbent assayNMOneuromyelitis opticaLIPSluciferase immunoprecipitation systemsRRMSrelapsing remitting multiple sclerosisSPMSsecondary progressive multiple sclerosisPPMSprimary progressive Fcgr3 multiple sclerosis Author Contributions Conceptualization: M.I. and S.N.; methodology: O.H., H.M., and S.N.; investigation and data curation: M.I., O.H., Y.M., A.M., H.M., and S.N.; writingoriginal draft preparation M.I. and S.N.; writingreview and editing: M.I., O.H., Y.M., A.M., M.U., H.M., and S.N.; visualization: M.I. and S.N.; supervision: S.N.;.

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