“Viral déjà vu” elicits organ-specific immune disease independent of reactivity to self
Doron Merkler, … , Juan Carlos del la Torre, Daniel D. Pinschewer
Doron Merkler, … , Juan Carlos del la Torre, Daniel D. Pinschewer
Published May 1, 2006
Citation Information: J Clin Invest. 2006;116(5):1254-1263. https://doi.org/10.1172/JCI27372.
View: Text | PDF
Research Article Immunology

“Viral déjà vu” elicits organ-specific immune disease independent of reactivity to self

Abstract

Autoimmune diseases are often precipitated by viral infections. Yet our current understanding fails to explain how viruses trigger organ-specific autoimmunity despite thymic tolerance extending to many nonlymphohematopoietic self antigens. Additionally, a key epidemiological finding needs to be explained: In genetically susceptible individuals, early childhood infections seem to predispose them to multiple sclerosis (MS) or type 1 diabetes years or even decades before clinical onset. In the present work, we show that the innate immune system of neonatal mice was sufficient to eliminate an attenuated lymphocytic choriomeningitis virus (LCMV) from most tissues except for the CNS, where the virus persisted in neurons (predisposing virus). Virus-specific cytotoxic T cells (CTLs) were neither deleted nor sufficiently primed to cause disease, but they were efficiently triggered in adulthood upon WT LCMV infection (precipitating virus). This defined sequence of viral infections caused severe CNS inflammation that was histomorphologically reminiscent of rasmussen encephalitis, a fatal human autoimmune disease. Yet disease in mice was mediated by antiviral CTLs targeting an epitope shared by the precipitating virus and the predisposing virus persisting in neurons (déjà vu). Thus the concept of “viral déjà vu” demonstrates how 2 related but independently encountered viral infections can cause organ-specific immune disease without molecular mimicry of self and without breaking self tolerance.

Authors

Doron Merkler, Edit Horvath, Wolfgang Bruck, Rolf M. Zinkernagel, Juan Carlos del la Torre, Daniel D. Pinschewer

×

Figure 8

Schematic interpretation of the viral déjà vu immunopathogenetic mechanism.

Options: View larger image (or click on image) Download as PowerPoint
Schematic interpretation of the viral déjà vu immunopathogenetic mechani...
(A) Summary of the infection protocol eliciting CNS disease; viral distribution is denoted by color. (B) Mechanistic interpretation. In neonates and in adults, a substantial fraction of the rLCMV/INDG i.c. inoculum reaches the systemic circulation (38). Viral infection of secondary lymphoid organs is abortive due to efficient type I IFN–dependent control, whereas CNS infection is productive. In neonates but not in adults, viral gene expression in secondary lymphoid organs coincides with reduced T cell responsiveness. Hence adult mice mount a protective virus-specific (NP396 and other epitopes) CD8+ T cell response that clears rLCMV/INDG from the CNS, while virus persists in the neonate’s neurons. The antiviral CD8+ T cell response in neonates is inefficient, but ARM infection 50 days later triggers a vigorous response of NP396-specific CTLs (epitope shared by rLCMV/INDG and ARM) that causes CNS disease when reaching persistently rLCMV/INDG-infected neurons. Adult primary rLCMV/INDG infection has been cleared from the CNS, and hence only neonatally rLCMV/INDG-infected mice develop disease.