The present study was undertaken to determine whether germline encoded and polyreactive antibodies might be pathogenic and whether the breach of early tolerance checkpoints in systemic lupus erythematosus (SLE) might lead to a population of B cells expressing germline encoded antibodies that become pathogenic merely by class switching to IgG in a pro-inflammatory milieu. We demonstrate here that IgM, DNA-reactive antibodies obtained from lupus patients that are unmutated and display polyreactivity can bind to isolated glomeruli and exhibit neurotoxic potential. Thus, the IgM polyreactive repertoire in SLE includes antibodies that may acquire pathogenic function merely by undergoing class-switch recombination to become IgG antibodies.