I n healthy individuals the immune system does not react aggressively toward host cells, a phenomenon defined as self tolerance. If self tolerance is broken autoimmune disease can develop, during which autoreactive lymphocytes are directed to a variety of autoantigenic epitopes. However, researchers have yet to determine whether immune responses to multiple autoantigens develop independently of each other or are the result of the response “spreading” from one autoantigen to another. In a study of NOD mice in this issue of the JCI, Krishnamurthy et al. show that the autoreactive T cell response to the autoantigen proinsulin lies upstream of that to islet-specific glucose-6-phosphatase catalytic subunit–related protein, suggesting that the pathogenic autoimmune response to proinsulin subsequently spreads to other antigens (see the related article beginning on page 3258). These data support the current view that this pancreatic β cell hormone is the first autoantigen targeted by the immune response in autoimmune diabetes.