Intrathecal immunoglobulin G (IgG) synthesis and oligoclonal IgG bands in cerebrospinal fluid (CSF) are hallmarks of multiple sclerosis (MS), but the antigen specificities remain enigmatic. Our study is the first investigating the autoantibody repertoire in paired serum and CSF samples from patients with relapsing-remitting MS (RRMS), primary progressive MS (PPMS) and other neurological diseases by the use of high-density peptide microarrays. Protein sequences of 45 presumed MS autoantigens (e.g., MOG, MBP and MAG) were represented on the microarrays by overlapping 15mer peptides. IgG reactivities were screened against a total of 3991 peptides, including also selected viral epitopes. The measured antibody reactivities were highly individual but correlated for matched serum and CSF samples. We found 54 peptides to be recognized significantly more often by serum or CSF antibodies from MS patients compared to controls (p-values <0.05). The results for RRMS and PPMS clearly overlapped. However, PPMS patients presented a broader peptide-antibody signature. The highest signals were detected for a peptide mapping to a region of the Epstein-Barr virus protein EBNA1 (amino acids 392-411), which is homologous to the N-terminal part of human crystallin alpha-B. Our data confirmed several known MS-associated antigens and epitopes, and they delivered additional potential linear epitopes, which await further validation. The peripheral and intrathecal humoral immune response in MS is polyspecific and includes antibodies that are also found in serum of patients with other diseases. Further studies are required to assess the pathogenic relevance of autoreactive and anti-EBNA1 antibodies as well as their combinatorial value as biomarkers for MS.
Hecker M, Fitzner B, Wendt M, Lorenz P, Flechtner K, Steinbeck F, Schröder I, Thiesen HJ, Zettl UK.High-density peptide microarray analysis of IgG autoantibody reactivities in serum and cerebrospinal fluid of multiple sclerosis patients.Mol Cell Proteomics. 2016. pii: mcp.M115.051664. [Epub ahead of print]
So this is another study hunting for the target specificity of antibodies in MS and lo an behold they find antibodies that react with EBV and alpha B crystallin. Alpha B crystallin is the the dominant antigen that was reported years ago to be the major target for the immune response in MS. In this study they used peptides (a string of amino acids) as the bait and targets were found however it must be said that rather than seeing linear sequences antibodies often see conformational 3D shapes and so many potential targets may be missed.