Background/Purpose: Viral infections have been implicated as major factors in autoimmune disease but demonstrating causality is often challenging. We found that neonatal infection with a roseolovirus (murine roseolovirus, MRV) resulted in transient thymic atrophy, CD4+ T cell depletion, and disruption of central tolerance. Although mice recovered from infection, we observed durable immune dysregulation manifested as autoimmune gastritis and a broad repertoire of autoantibodies. In these studies, we found that additional immune stimulation resulted in systemic autoimmunity.

Methods: We developed a mouse model in which neonatally infected C57BL/6 mice were treated with a toll-like receptor 7 (TLR7) agonist as adults to induce a lupus-like phenotype. Histology, immunofluorescence, ELISA, transcription analysis as well as flow cytometry were used to characterize disease and evaluate immune dysregulation. We used depletion and adoptive transfer experiments to identify the contribution of specific cell types to disease.

Results: We found that MRV replication during the first seven days of life induced a loss of central tolerance and development of autoimmune gastritis and autoantibodies, including those typically associated with autoimmune connective tissue disease. Interestingly, treatment with a TLR7 agonist induced a systemic autoimmune disease with characteristics observed in systemic lupus erythematosus, including splenomegaly, cytopenia, positive ANA, and multi-organ system inflammation in mice. In C57BL/6 mice, this lupus-like disease was only observed after neonatal MRV infection. Although a feature of MRV-induced lupus-like disease was significant thymic disruption, we did not observe MRV reactivation after TLR7 stimulation. We also observed major changes in the phenotype of T and B cells in the blood and spleen, suggesting a shift in the number and activation of different subsets. Moreover, we found that T and B cells play different roles in development of disease.

Conclusion: We have shown that MRV induces autoimmune after neonatal infection in a murine system. Moreover, our data suggest that neonatal MRV infection not only induces mild, organ-specific autoimmunity, but also results in durable immune dysregulation and predisposition to severe systemic autoimmunity after additional immune stimulation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neonatal-roseolovirus-infection-predisposes-to-development-of-lupus-like-disease-after-tlr7-stimulation/