An autoantibody signature predictive for multiple sclerosis: evidence at the protein level and association with histopathological lesion types

Recently, an autoantibody signature considered to be predictive of multiple sclerosis (MS) has been reported in an article by Zamecnik et al. published in Nature Medicine, which is characterized by immunoglobulin G (IgG) responses to peptides sharing the amino acid motif P-(SA)-x-(SGA)-R-(SN)-(LRKH). These results are highly important, all the more so as the same motif is present also in two proteins expressed by Epstein-Barr virus (EBV), a pathogen that likely plays a key role in MS pathogenesis. However, clinically relevant autoantibody responses often target conformational epitopes, and peptides often differ from their corresponding proteins in terms of conformation. We were therefore interested in whether these findings can be reproduced at protein level and may thus play a role also in vivo. Here, we report findings from complementary experiments employing a microarray covering nearly 10,000 human full-length proteins and using serum and cerebrospinal fluid samples from patients with a histopathologically confirmed diagnosis of MS. Our data show that prominent IgG responses to full-length proteins bearing the P-(SA)-x-(SGA)-R-(SN)-(LRKH) motif can indeed be found in a substantial proportion of MS patients, although considerable inter-patient variability exists in both the type and number of individual responses. Notably, these IgG responses were more pronounced in patients with histopathologically defined pattern II MS (which is characterized by intralesional IgG and complement deposition) and pattern III MS than in patients with pattern I MS in our study. New motif-bearing candidate antigens identified in this study include RBMY2FP, CHMP2B, SRSF8 (SFRS2B), NUS1 (NgBR, Nogo-B receptor), and RTN2. Further studies investigating the diagnostic, pathophysiological, therapeutic, and prognostic implications of this antibody signature, as well as the potential role of cross-reactivity with EBV-suggested by the presence of the motif of interest in both EBV BRRF2 and EBV envelope glycoprotein M-are warranted and may significantly advance our understanding of MS.