Anti-KIR4.1 antibodies do not differentiate multiple sclerosis patients from controls (P5.276)

Background: Reports about preferential detection of autoantibodies against the inward-rectifying potassium channel 4.1 (KIR4.1) have raised the possibility of a major breakthrough in understanding the pathophysiology of multiple sclerosis (MS) and of the existence of a potential biomarker. Anti-KIR4.1 antibodies have been described to be present in 47[percnt] of adult patients with MS or clinically isolated syndrome (CIS) and an even higher number of pediatric patients, but in no healthy controls, using an enzyme-linked immunosorbent assay (ELISA) with either full-length KIR4.1 protein or peptide (amino acids 83-120). Subsequent independent studies using peptide ELISAs or a cell-based approach have failed to replicate these findings. This has been partially attributed to the use of different assays compared to the original report.Methods: We carried out a large, blinded replication study with 141 patients (multiple sclerosis n=59, CIS n=82) and 131 controls (other (non-inflammatory) neurological diseases (OND) n=48, neurodegenerative diseases (ND) n=48, other inflammatory neurological diseases (OIND), n=35) using the same peptide and protein ELISA as originally described.Results: Neither the KIR4.1 recombinant protein ELISA nor the peptide ELISA distinguished patients from controls. Moreover, there was no correlation between the reactivities in the two assays. Comparing serum antibody reactivities against mock transfected and KIR4.1 transfected protein preparation in a subgroup of patients revealed that the reactivity was mainly directed against proteins that were co-purified with KIR4.1. This was corroborated by additional characterization with western blot and mass spectrometry.Conclusion: In our study, using the exact same techniques as originally described, we could not detect differential antibody reactivity to KIR4.1 between patients and controls. This might either be due to the absence of KIR4.1 autoantibodies or due to the non-specificity of the assay. Thus, at this point, we do not consider KIR4.1 to be a valuable biomarker for diagnosing MS. Disclosure: Dr. Proebstel has received personal compensation for activities with Genzyme Corporation and Baxalta. Dr. Kuhle has received research support from Bayer Healthcare, Genzyme, Novartis, Protagen AG, and Roche. Dr. Lecourt has nothing to disclose. Dr. Vock has nothing to disclose. Dr. sanderson has nothing to disclose. Dr. Kappos9s institution (University Hospital Basel) has received royalty payments from Neurostatus Systems GmbH. Dr. Derfuss has received research support from Biogen Idec and Novartis Pharma.