Abstract
Viruses have long been implicated in the pathogenesis of autoimmunity, yet their contribution remains circumstantial partly due to the lack of well-documented information on infections prior to autoimmune disease onset. Here, we used the lymphocytic choriomeningitis virus (LCMV) as a model to mechanistically dissect the impact of viral infection on lupus-like autoimmunity. Virus persistence strongly enhanced disease in mice with otherwise weak genetic predisposition but not in highly predisposed or non-autoimmune mice, indicating a synergistic interplay between genetic susceptibility and virus infection. Moreover, endosomal Toll-like receptors (TLRs) and plasmacytoid dendritic cells (pDCs) were both strictly required for disease acceleration, even though LCMV also induces strong TLR-independent type I interferon (IFN-I) production via RNA helicases and MAVS in conventional DCs. These results suggest that LCMV enhances systemic autoimmunity primarily by providing stimulatory nucleic acids for endosomal TLR engagement, whereas overstimulation of the MAVS-dependent cytosolic pathway in the absence of endosomal TLR signaling is insufficient for disease induction.
Highlights
Systemic lupus erythematosus (SLE) is characterized by hyperactivation of T cells, B cells and DCs, production of autoantibodies to nucleic acid-associated and other self-molecules, and immune complex-mediated inflammatory damage in multiple organs [1]
To study the contribution of virus infections to lupus pathogenesis, we examined disease development in NZB mice persistently infected with two different lymphocytic choriomeningitis virus (LCMV) isolates, Armstrong (ARM) and clone 13 (Cl13)
We report that persistent infection with LCMV exacerbates systemic autoimmunity in lupus-prone NZB mice and even in female BXSB mice with mild spontaneous disease due to the absence of the Y chromosome-associated autoimmunity accelerator
Summary
Systemic lupus erythematosus (SLE) is characterized by hyperactivation of T cells, B cells and DCs, production of autoantibodies to nucleic acid-associated and other self-molecules, and immune complex-mediated inflammatory damage in multiple organs [1]. Mechanistic assessments in both mouse models and humans have highlighted the critical role of innate immune pathways of nucleic acid sensing in lupus pathogenesis, including the engagement of endosomal Toll-like receptors (TLRs) in B cells and plasmacytoid dendritic cells (pDCs), production of type I interferons (IFN-I), and expression of an IFN-I inducible gene signature often correlating with disease activity [2,3,4,5,6]. Multiple environmental factors have been associated with lupus and other autoimmune conditions, with infectious agents receiving prominent attention [19]
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