Nucleic acids represent the main source of autoantigens in systemic lupus erythematosus (SLE). DNA and RNA can exit the cell during cell death and, in the extracellular space, can be immunostimulatory. Also extracellularly, DNA and RNA can be incorporated into microparticles (MPs)-small, membrane-bound vesicles released from dying cells by blebbing. We suggest that MPs display autoantigens, such as RNA and DNA, in a highly immunostimulatory manner, enabling them to function as autoadjuvants. In the bone marrow, nucleic-acid-containing MP autoadjuvants might induce B-cell tolerance, whereas in the periphery, they might stimulate mature B cells that have escaped central tolerance. Indeed, because MP autoadjuvants can trigger several receptors, they could effectively provide apoptotic or activating signals to B cells. We would therefore advance the idea that a model for SLE based on MP autoadjuvants can provide a new paradigm to elucidate the mechanisms by which DNA and RNA affect the immune system and critically influence B-cell fate.