Intrathecal IgG synthesis, persistence of bands of oligoclonal IgG, and memory B‐cell clonal expansion are well‐characterized features of the humoral response in multiple sclerosis (MS). Nevertheless, the target antigen of this response remains enigmatic.

We produced 53 different human IgG1 monoclonal recombinant antibodies (rAbs) by coexpressing paired heavy‐ and light‐chain variable region sequences of 51 plasma cell clones and 2 B‐lymphocyte clones from MS cerebrospinal fluid in human tissue culture cells. Chimeric control rAbs were generated from anti‐myelin hybridomas in which murine variable region sequences were fused to human constant region sequences. Purified rAbs were exhaustively assayed for reactivity against myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein by immunostaining of transfected cells expressing individual myelin proteins, by protein immunoblotting, and by immunostaining of human brain tissue sections.

Whereas humanized control rAbs derived from anti‐myelin hybridomas and anti‐myelin monoclonal antibodies readily detected myelin antigens in multiple immunoassays, none of the rAbs derived from MS cerebrospinal fluid displayed immunoreactivity to the three myelin antigens tested. Immunocytochemical analysis of tissue sections from MS and control brain demonstrated only weak staining with a few rAbs against nuclei or cytoplasmic granules in neurons, glia, and inflammatory cells.

The oligoclonal B‐cell response in MS cerebrospinal fluid is not targeted to the well‐characterized myelin antigens myelin basic protein, proteolipid protein, or myelin oligodendrocyte glycoprotein. Ann Neurol 2009;65:639–649