“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.
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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

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Figure 4

T cell infiltration in the brains of ARM-challenged rLCMV/INDG carriers.

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T cell infiltration in the brains of ARM-challenged rLCMV/INDG carriers....
(A) Neonatal and adult C57BL/6 mice were infected at day –50 with rLCMV/INDG i.c., resulting in rLCMV/INDG carriers and rLCMV/INDG–immune mice, respectively. On day 0, these animals and a control group of adult mice without rLCMV/INDG infection were challenged with ARM i.v. Brain (top and center panels) and spinal cord sections (bottom panel) were prepared 8 days after ARM challenge and stained for LCMV-NP and CD3+ T cells. Representative images of 7–10 mice per group are shown. Scale bars: 500 μm (top); 100 μm (center); 20 μm (bottom). (B) Brain biopsy of a human patient with RE. A representative neuron surrounded by CD8+ T cells (brown) is shown. Scale bar: 20 μm. (C) C57BL/6 mice were infected with rLCMV/INDG as in A and sacrificed either immediately preceding ARM challenge 50 days later (groups I–III) or 8–12 days after ARM challenge (the peak of disease in rLCMV/INDG carriers; groups IV–VI) to determine the brain inflammatory index. Symbols represent individual mice from a total of 3 independent experiments; horizontal lines indicate means. Neonatally rLCMV/INDG-infected mice after ARM i.v. challenge (Group IV) exhibited dense T cell infiltration in brain, whereas the remaining groups were statistically indistinguishable from each other. Analogous results were also obtained for spinal cord (not shown). **P < 0.001 versus all other groups.