Anti-Sm antibodies are highly specific markers for the diagnosis of systemic lupus erythematosus (SLE). This specificity suggests that the immunoregulation of these autoantibodies would reflect fundamental immune abnormalities in this disorder. As a clue to this immunoregulation, we have investigated the isotype distribution of anti-Sm antibodies by enzyme-linked immunosorbent assays. We have found that the anti-Sm response is markedly restricted to the IgG1 heavy chain isotype. On the other hand, the light chain distribution reflects that in normal serum, while isoelectric focusing analysis fails to show an oligoclonal pattern. The related specificity, anti-ribonucleoprotein, is also restricted to IgG1, while the SLE-specific antibody anti-double-stranded DNA is mostly IgG1 with a lesser contribution by IgG3. These results suggest that antinuclear antibodies that are strongly associated with SLE are produced by a T cell-dependent response, probably driven by antigen. The immunoregulation of the response to several autoantigens may be quite similar.