In a previously described case of Waldenstrom's Macroglobulinemia, complicated by polyneuropathy, the IgM/λ monoclonal antibody (mAb) was highly reactive with myelin basic protein (MBP). Given our demonstration that Vλx, a recently described murine λ variable region gene product, can itself bind MBP as well as confer MBP reactivity to an Ab, the possibility of a shared idiotypy between murine Vλx and this human IgM/λ anti-MBP was investigated. We characterized the epitope specificity of the macroglobulinemia patient's MBP-reactive IgM/λ using indirect ELISA procedures with MBP, a citrullinated isomer of MBP termed C8, or peptide fragments of MBP as the coating antigens and monospecific Ab to Vλx as the secondary Ab. The patient's MBP-reactive IgM/λ was recognized by Ab specific for Vλx and, like murine mAb containing Vλx bound human MBP but not MBP-C8 nor other common autoantigens such as DNA, thyroglobulin, or actin. The anti-MBP reactivity was selective for MBP peptide 90-170 and preferentially recognized MBP peptide 84-96. Thus, the patient's macroglobulin and perhaps certain other human Ab with a 'Vλx idiotype' bind to MBP peptide residues 84-96, an immunodominant peptide in multiple sclerosis patients. Such binding may be involved in the pathogenesis of neural damage in patients with neuroimmunologic disorders related to plasma cell dyscrasias or autoimmunity. © 2001 Elsevier Science B.V.