Latent gammaherpesvirus exacerbates arthritis through modification of age-associated B cells.

ABSTRACT

Epstein-Barr virus (EBV) infection is associated with rheumatoid arthritis (RA) in adults, though the nature of the relationship remains unknown. Herein, we have examined the contribution of viral infection to the severity of arthritis in mice. We have provided the first evidence that latent gammaherpesvirus infection enhances clinical arthritis, modeling EBV's role in RA. Mice latently infected with a murine analog of EBV, gammaherpesvirus 68 (γHV68), develop more severe collagen-induced arthritis and a Th1-skewed immune profile reminiscent of human disease. We demonstrate that disease enhancement requires viral latency and is not due to active virus stimulation of the immune response. Age-associated B cells (ABCs) are associated with several human autoimmune diseases, including arthritis, though their contribution to disease is not well understood. Using ABC knockout mice, we have provided the first evidence that ABCs are mechanistically required for viral enhancement of disease, thereby establishing that ABCs are impacted by latent gammaherpesvirus infection and provoke arthritis.

Rheumatoid arthritis is one of the most common autoimmune diseases, leaving patients in pain as their immune system mistakenly attacks the lining of their joints. The precise cause is unknown, but research suggests a link to the Epstein-Barr virus, the agent responsible for mononucleosis (also known as glandular fever). After infection and recovery, the virus remains in the body, lying dormant inside immune 'B cells' which are often responsible for autoimmune diseases. Of particular interest are a sub-group known as 'age-associated B-cells', which are mostly cells left over from fighting past infections such as mononucleosis. Yet, the link between Epstein-Barr virus and rheumatoid arthritis remains hard to investigate because of the long gap between the two diseases the virus mostly affects children and young people, while rheumatoid arthritis tends to develop in middle age. To investigate how exactly the two conditions are connected, Mouat et al. created a new animal model they infected young mice with the murine equivalent of the Epstein-Barr virus, and then used a collagen injection to trigger rheumatoid arthritis-like disease once the animals were older. Next, Mouat et al. monitored the paws of the mice, revealing that viral infection early in life worsened arthritis later on. These animals also had more age-associated B cells than normal, and the cells showed signs of participating in inflammation. On the other hand, early viral infection did not make arthritis worse in mice unable to produce age-associated B cells. Taken together, these results suggest that the immune cells are required to enhance the effect of the viral infection on rheumatoid arthritis. This new insight may help to refine current treatments that work by reducing the overall number of B cells. Ultimately, the animal model developed by Mouat et al. could be useful to identify better ways to diagnose, monitor and treat this debilitating disease.