When the B-cell response was examined by enumeration of immunoglobulin (Ig)-secreting cells, normal cerebrospinal fluid (CSF)--in contrast to previous beliefs--contained IgG-secreting cells, indeed at an 8-fold higher proportion per 10(4) mononuclear cells (MNC) than blood. As expected, the proportion of IgG-producing cells was greatly increased in MS CSF. Evaluation of antibody (Ab) responses at the cellular level, thereby bypassing draw-backs inherent in determinations of circulating Ab levels, such as Ab binding to target, revealed that in one MS patient group, 57% had, in CSF, cells secreting IgG Ab against myelin basic protein (MBP) and, in another MS group, 55% had, in CSF, cells producing IgG Ab against myelin-associated glycoprotein (MAG); both MBP and MAG are possible targets for immune attack in MS. Anti-MBP and anti-MAG IgG antibody-secreting cells could occur in parallel or independently. They were rarely detected in blood, reflecting strong sequestration in CNS CSF. Their possible role in MS pathogenesis is envisaged in light of recently suggested coupling between polyclonal B-cell hyperresponsiveness and antigen-driven specific responses in autoimmune-prone individuals.