Systemic lupus erythematosus (SLE), the prototypic systemic autoimmune disease, is characterized by
immune system hyperactivation, autoantibody production, and multiorgan inflammation. Although genetic
predisposition is critical for disease expression, the low concordance rate in monozygotic twins (<40%)
suggests the essential contribution of additional factors, mostly provided through environmental exposures.
Indeed, significant epidemiological evidence has linked SLE and other systemic autoimmune disease to
crystalline silica exposure but also to certain viral infections. Considering the critical role of innate immune
activation in systemic autoimmunity, we hypothesized that silica inhalation, virus infection, and genetic
predisposing factors synergize by activating distinct innate immunostimulatory pathways, that together lead to
more efficient break of tolerance, earlier disease onset, and more severe autoimmune manifestations. In
support of this hypothesis, we provide preliminary evidence that silica and virus exposures more effectively
induce autoimmune manifestations in mouse models of lupus when given in combination than when given
individually. Here we will use this experimental system to define the mechanistic basis of the interplay
between virus infection and silica, including the temporal requirements of silica exposure and virus infection,
the contribution of innate inflammatory pathways differentially induced by silica and virus, and roles of these
factors in breaking immunological tolerance.