Abstract Anti-double-stranded DNA (dsDNA) B cells persist even in non- autoimmune-prone animals. In this review, we summarize data regarding the activation potential of these cells. Provision of cog- nate CD4 T cell help to anti-dsDNA B cells in nonautoimmune mice not only drives their maturation and entry into the B cell follicle, but also leads to secretion of anti-dsDNA autoantibodies. Intrigu- ingly, if T regulatory cells are provided along with T helper cells, the antibody response of anti-dsDNA B cells is diminished. We have also found that T-independent stimulation with CpG oligodeoxy- nucleotides leads to the proliferation and enhanced recovery of anti- dsDNA B cells in vitro. These data suggest that control of anti-dsDNA antibody production may rely on elements from both the innate and adaptive arms of the immune system. Key Words Autoimmunity Tolerance B cell T cell Dendritic cell T-independent T regulation CpG *Jan Erikson, PhD The Wistar Institute Room 276 3601 Spruce Street Philadelphia, PA 19104 E-mail: jan@wistar.upenn.edu 219 © 2003 Humana Press Inc. 0257–277X/03/ 27/2–3:219–233/$20.00 The Regulation and Activation Potential of Autoreactive B Cells Immunologic Research 2003;27/2–3:219–233 Michele L. Fields Su-jean Seo Simone A. Nish Jeff H. Tsai Andrew J. Caton Jan Erikson* The Wistar Institute, Philadelphia, PA Introduction Antibodies (Abs) against self-antigens (Ags) are one of the hallmarks of autoimmunity. In studying how autoAb production is triggered, immunoglobulin (Ig) transgenic (Tg) animals have been used to increase the frequency of B cells with a given specificity (1–7). Early studies used Ig Tgs directed against model self- Ags to demonstrate several outcomes for autoreactive B cells, including deletion, recep- tor editing,and functional inactivation (anergy) (1–4,6,7) . More recently, Tg studies have attempted to define how the autoreactive B cells