γHV68 infection exacerbates arthritis and requires age-associated B cells

Abstract

Abstract Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA), though the mechanism of contribution remains unknown and there does not exist a sufficient in vivo model to examine the relationship. Here, we utilize and expand in vivo models of EBV and RA to examine mechanisms of immune contribution. We find that infection with latent gamma-herpesvirus 68 (γHV68), a murine analogue of EBV, leads to an enhanced clinical and immunological course of collagen-induced arthritis (CIA). γHV68-infected mice display earlier and more severe CIA clinical symptoms and a Th1-skewed immune profile, compared to uninfected CIA mice. Using a latency-free strain of γHV68 we demonstrate that CIA exacerbation is not due to innate immune stimulation during acute infection but, rather, is dependent upon viral latency. Age-associated B cells (ABCs) are increased in RA patients and during viral infection, though if they act as mediators between the infection and disease remains unknown. We find that ABCs (CD19+CD11c+Tbet+) in γHV68-infected CIA mice are increased and display a proinflammatory phenotype compared to uninfected CIA. Using ABC knockout mice, we demonstrate that ABCs are critical for γHV68-enhancement of CIA, though are dispensable in uninfected CIA. This project establishes that latent γHV68 infection enhances CIA and is a viable model for examining mechanisms of EBV’s contribution to RA. Additionally, we demonstrate that ABCs mediate the viral enhancement of disease.