Journal Club: Friday, January 20, 2012

Peggy Bettin (Tisch MS) presented the following article in Journal Club.

Article title: Intrathecally Synthesized IgG in Multiple Sclerosis Cerebrospinal Fluid Recognizes Identical Epitopes Over Time

Reference: X. Yu, M. Brugoon, M. Green, O. Barmina, K. Dennison, Pointon, M. Davis, and D. Gilden. J. Neuroimmunol. (2011), doi:10.1016/j.jneuroim/2011.10.009

Elevated cerebrospinal fluid (CSF) levels of Oligoclonal Bands (OCBs) of the antibody Immunoglobulin G (IgG) persisting for the lifetime of patients is a recognized hallmark of MS disease, occuring in upwards of 95% of patients. Likewise, OCBs are commonly found in other chronic infectious diseases of the central nervous system, and in each case, have been found to be directed against the causative agents of the disease. Moreover, elevated CSF IgG levels are found more frequently in MS patients experiencing an agressive disease course rather than a benign one. The present paper investigated the specificity of CSF OCBs taken from MS patients to certain antigens, and compared the level and nature of intrathecally synthesized IgG to that found in patients' sera. Using a variety of instruments including Phage-IPCR, IEF Immunoblot, and Western blot, the authors determined that phage peptides bound specifically to IgG in MS CSF collected over time, that these peptides were recognized by OCBs in MS CSF, and that they represented linear epitopes, i.e. natural epitopes (the portion of an antigen recognized by the immune system) of corresponding protein antigens. Furthermore, those phage peptides selected by CSF IgG of MS patients bound approximately tenfold more to CSF IgG than to serum of IgG of the same patient in a dose-dependent manner. Phage peptide database search combined with alanine scan mutagenesis of peptides bound to CSF IgG of MS patients revealed that they are derived from proteins including serine/threonine-protein kinase, protein ZIP2 and MHC Class II. These findings point towards a greater specificity of MS CSF OCBs than has previously been demonstrated experimentally and potentially narrows down the causative agent of MS.