Antibodies Produced by Clonally Expanded Plasma Cells in Multiple Sclerosis Cerebrospinal Fluid

The cause of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS), is unknown. Competing theories contend that disease is a T-cell–mediated autoimmune response against myelin antigens, infectious, or a virus-triggered immunopathology directed against one or more autoantigens. Clues to the nature of disease may lie in the presence of bands of oligoclonal IgG (OCBs) in MS brain and cerebrospinal fluid (CSF). OCBs are not unique to MS, and among other CNS diseases with intrathecal IgG synthesis and OCBs, all are inflammatory and most are infectious. Importantly, the CSF oligoclonal IgG in these CNS diseases is directed against the causative agent of disease, which provides a rationale for our hypothesis that the OCBs in MS are directed against disease-relevant antigen(s).1 Despite numerous studies, the specificity of oligoclonal IgG in MS CSF remains unknown. Intrathecal IgG synthesis in MS is concomitant with the increased presence of B lymphocytes and antibody-secreting plasma cells in CSF.2,3 Analysis of immunoglobulin oligoclonal heavy (H)- and light (L)-chain variable (V)-region sequences recovered from MS plaques and CSF demonstrate clonal expansion, intraclonal sequence diversity, somatic hypermutation, and VH-gene segment bias, features consistent with a specific and targeted antibody response.4–10 Furthermore, a strong link has been established between expanded IgG V-region sequences (immunoglobulin transcriptome) amplified from cells in MS CSF and V-region peptide sequences (immunoglobulin proteome) generated from purified CSF OCBs indicating that CSF plasma cells are representative of the intrathecal oligoclonal IgG response.11 B-cell clonal expansion is also seen in brain and CSF of patients with subacute sclerosing panencephalitis (SSPE), a persistent measles virus infection of the brain. To validate their use for antigen identification, we prepared recombinant antibodies (rAbs) from expanded plasma cell clones identified in the brain and CSF of SSPE patients. More than half of rAbs prepared from SSPE brain12 and CSF13 recognize measles virus proteins. Because immunization of rabbits, multiple rodent species, and primates with myelin basic protein (MBP), proteolipid protein (PLP), or myelin oligodendrocyte glycoprotein (MOG) produces experimental allergic encephalomyelitis, an autoimmune inflammatory demyelinating disorder of the CNS, we analyzed a panel of rAbs prepared from clonally expanded plasma cells and B lymphocytes in MS CSF for binding to MBP, PLP, and MOG to determine whether these antigens are targeted by the intrathecal antibody response in MS.