The nonobese diabetic mouse (NOD) is widely used as a model to study human type 1 diabetes (T1D). In the NOD mouse T1D is a T cell-mediated autoimmune disease of complex etiology in which B cells play an essential role. One of the major unresolved issues in T1D is the genetic and/or environmental factors that trigger the autoimmune reaction. In the NOD mouse, as in humans, auto-antibodies to pancreatic islets are present at early ages and are highly correlated to diabetes progression, but their etiological role has long been disputed. NOD auto-antibodies have the characteristics of a natural repertoire, and B1 cells, the main natural antibody producers, exhibit functional differences in this strain that could have consequences for disease determination. Using a genetic approach, we propose to test if the NOD natural auto-antibody repertoire includes innate reactivities that participate in diabetes pathogenesis by promoting insulitis initiation.