Absence of antibodies against KIR4.1 in multiple sclerosis: A three-technique approach and systematic review

Abstract

IntroductionAntibodies 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.MethodsSerum 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.ResultsWe 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.ConclusionWe 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.

Oligoclonal IgG antibodies in multiple sclerosis target patient-specific peptides

“…Despite the high specificity of the intrathecal IgG specific phage peptides, the highly sensitive and specific phage-mediated immuno-PCR technique used here failed to identify common peptide reactivity shared by all MS CSF screened, implying that MS intrathecal IgG antibodies may target patient specific antigens. Our data are consistent with previous studies and support the notion that the disease targets for OCBs in MS have yet to be reproducibly demonstrated [28,29]. Failing to identify MS specific targets for OCBs does not diminish its crucial roles in disease pathogenesis, as the presence of large amount of IgG antibodies are key features of MS lesions [30,31], and have been shown to be associated with increased disease activity and brain atrophy [3,6].…”

Learning from other autoimmunities to understand targeting of B cells to control multiple sclerosis

“…However, analysis of antibody specificity often shows no consistent myelin-directed autoimmunity and evidence has not been reproducible [Srivastava et al 2012;Willis et al 2015;Brändle et al 2016;Navas-Madroñal et al 2017]. These antibodies are often targeted to cytoplasmic proteins [Zhang et al 2005;Willis et al 2015;Brändle et al 2016].…”

“…Whilst many of the above autoimmune conditions have soluble autoantibodies as major effector molecules, this may not be the case in MS. This is in part because a consistent pathogenic autoantibody has been yet to be found in MS [Srivastava et al 2012;Van Haren et al 2013;Navas-Madroñal et al 2017]. However, as the CNS is relatively inaccessible compared to the peripheral tissues, study of B cell targeting in other autoimmune conditions may provide valuable insight into the mechanisms of action of treatments, and possibly disease, as they may be occurring in MS.…”

Dynamics of ion fluxes between neurons, astrocytes and the extracellular space during neurotransmission

“…This has been shown for epilepsy (Xiong and Stringer, 1999), ischemia (Pivonkova et al, 2010) or Rett syndrome, a X-linked neurodevelopmental disorder resulting from mutations in methyl-CpG-binding protein 2 (MeCP2) (Kahanovitch et al, 2018). Antibodies against K ir 4.1 channels have also been suggested as biomarkers for multiple sclerosis and possibly as a cause of the disease via an auto-immune mechanism (Srivastava et al, 2012), although controversies have recently emerged (Filippi et al, 2014;Nerrant et al, 2014;Gu, 2016;Navas-Madronal et al, 2017).…”