Lo et al., page 1 Mapping genes regulating lymphocyte function: correlations with autoimmunity? David Lo, Najla Aftahi, Christina Reilly, Heather Neal, Bee Sim, Nicholas R.J. Gascoigne, Dwight Kono, Adrian Wu, Stacey Schulman, Bernadette Scott Department of Immunology IMM-25, The Scripps Research Institute, La Jolla, CA 92037 USA Introduction Autoimmune diseases such as diabetes are fascinating for what they reveal about the workings of the immune system. While immune responses are the consequence of elaborate interactions between cells and soluble factors, for the most part they manage through the complexity to generate a pretty fair protective mechanism against infectious agents without producing serious “collateral damage” to normal self tissues. When the same apparently normal self tissues become the target of this protective mechanism, we watch the same elaborate interactions dedicated instead to the development of what is considered a pathological inflammatory response. How does this occur? Many investigations of the phenomenon of autoimmunity have tried to focus on a single root cause, or single failure in the mysterious “self/non-self discrimination” function of the immune system. Thus, for example, numerous studies have tried to demonstrate defects in central thymic negative selection of autoreactive T cells in disease susceptible animals. These have uniformly failed to find clear defects in what appears to be an essential process in lymphocyte development. Indeed, it has been pointed out that in normal individuals, autoreactive lymphocytes (both T and B cells) can be readily demonstrated.