"Viral deja 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 organspecific immune disease without molecular mimicry of self and without breaking self tolerance.

Recognition and Degradation of Myelin Basic Protein Peptides by Serum Autoantibodies: Novel Biomarker for Multiple Sclerosis

“…The expression products of plasmids that contained N-terminal Trx fused through the (SGGGG) 3 S linker to the MBP peptides (MBP epitope library) were used for cleavage and binding analysis. The plasmid encoding Trx with linker (SGGGG) 3 S was designed as a control. The soluble recombinant His-tagged proteins were obtained by Escherichia coli expression and isolated by sorption on a Talon SuperFlow (BD Biosciences) column followed by cation exchange chromatography on a Mono S column (Amersham Biosciences) at pH 5.0 and subsequent size exclusion chromatography on a Superdex 75 GL 10/300 column (Amersham Biosciences) in 150 mM NH 4 HCO 3 buffer.…”

Protracted Course of Lymphocytic Choriomeningitis Virus WE Infection in Early Life: Induction but Limited Expansion of CD8+Effector T Cells and Absence of Memory CD8+T Cells

“…Thus, the massive recruitment of CTLs into effector cells successfully elicited by the infection is followed in infant mice by their functional exhaustion and their peripheral clonal deletion, which purges the T-cell repertoire of LCMV-specific CD8 ϩ T cells. It is tempting to postulate that such permanent changes in the T-cell repertoire could contribute to the long-term influence of the early life environment on the risks and patterns of certain autoimmune diseases (43).…”

Regulation of Immune Response and Inflammatory Reactions against Viral Infection by VCAM-1

“…However, this paradigm is not universal, and several studies have indicated a significant role for antigen-specific T cells in organ pathology. Thus, cellular injury as a consequence of T-cellmediated inflammation and/or the destruction of virus-infected target cells by cytotoxic T cells has been associated with pathology in several experimental models and human diseases, including lethal viral infections of the central nervous system (CNS) (4,6,8,9,19,21,24,44,45,50,58,65). Although the mechanisms by which T cells participate in the control of viral infection without causing collateral damage (such as neurological deficit) remain poorly defined, a consensus is that the development of tissue pathology coincides with a massive extravasation of mononuclear cells to the site of virus replication, a process regulated by the increased expression of adhesion molecules on the nearby vasculature (62,68).…”