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Your Environment. Your Health.

SYNERGISTIC EFFECTS OF SILICA EXPOSURE, VIRUS INFECTION AND GENETIC PREDISPOSITION IN SYSTEMIC AUTOIMMUNITY

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Principal Investigator: Baccala, Roberto G
Institute Receiving Award Scripps Research Institute
Location La Jolla, CA
Grant Number R01ES031082
Funding Organization National Institute of Environmental Health Sciences
Award Funding Period 01 Jul 2020 to 30 Apr 2025
DESCRIPTION (provided by applicant): Project Summary    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.    
Science Code(s)/Area of Science(s) Primary: 53 - Autoimmunity
Secondary: 03 - Carcinogenesis/Cell Transformation
Publications No publications associated with this grant
Program Officer Michael Humble
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