Background/Purpose: Murine roseolovirus (MRV) is a recently sequenced beta-herpesvirus that is a natural murine pathogen and is genetically highly related to HHV6 and HHV7. The human roseoloviruses, HHV6 and HHV7, have been associated with autoimmune disease. Demonstrating causality has been difficult due to the ubiquitous and chronic nature of roseolovirus infections. Herein we have demonstrated that neonatal MRV infection induces autoimmune disease and development of autoantibodies in adult mice.
Methods: To evaluate the role of MRV in autoimmune disease, mice were infected within the first 48 hours of life. At 12 weeks post infection (wpi) we performed autoantibody screening as well as histology to identify organ specific tissue inflammation. We utilized flow cytometry and immunofluorescence to characterize the immune response, both systemically and within tissues. Antiviral treatment with ganciclovir was utilized to inhibit viral replication.
Results: Our studies show that autoimmune gastritis occurs in the absence of detectable virus in the gastric mucosa. Neonatal MRV infection results in a transient reduction in thymic and peripheral CD4+Foxp3+ regulatory T cells (Treg). Ganciclovir (GCV), a potent inhibitor of replication of other beta-herpesviruses, inhibits MRV replication as well as MRV-mediated CD4+ T cell and Treg depletion. Treatment with GCV early in life also reduces autoimmune gastritis, suggesting that MRV replication is necessary for altering immunologic tolerance early in life. The inflammatory infiltrate in the gastric mucosa is characterized by an increase in T cells, neutrophils and eosinophils. Furthermore, the CD4+ T cells in the gastric mucosa express IL-17 and IL-4, demonstrating a Th2 and Th17 response. The development of autoimmune gastritis was found to be T cell dependent. Interestingly, neonatal MRV infection results in the production of a wide array of autoantibodies in adult mice, including those associated with rheumatologic disease such as dsDNA, Scl-70, SSA, SSB, Jo-1, Smith, GBM and MPO.
Conclusion: This study shows that neonatal infection with MRV results in the development of autoimmunity later in life, after acute infection has been cleared. Taken together, these findings strongly suggest that infection with a roseolovirus infection early in life results in disruption of immunologic tolerance and development of autoimmune disease.
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