Anti-rods/rings autoantibody and IMPDH filaments: an update after fifteen years of discovery.

Autoantibodies to unknown subcellular rod and ring-shaped structures were first discovered in sera from hepatitis C patients in 2005. Early studies showed a strong association between these anti-rods/rings antibodies (anti-RR) and the standard of care interferon-α plus ribavirin combination therapy (IFN/RBV), suggesting that anti-RR are drug-induced autoantibodies. In the context of hepatitis C, anti-RR have been linked with relapse from or lack of response to IFN/RBV in some patient cohorts. However, examples of anti-RR in other diseases and healthy individuals have also been reported over the years, although anti-RR remains a rare autoantibody response in general. The advent of new direct-acting antiviral drugs for chronic hepatitis C and studies of anti-RR from different parts of the world are also beginning to change the perception of anti-RR. The nucleotide biosynthetic enzyme inosine monophosphate dehydrogenase (IMPDH) has been identified as the major autoantigen recognized by anti-RR. Coincidentally, the assembly of IMPDH into micron-scale rod and ring-shaped structures was discovered around the same time as anti-RR. Knowledge of the fundamental biological properties and cellular functions of these structures, referred to as "IMPDH filaments" by cell biologists, has advanced in parallel to anti-RR antibodies. Recent studies have revealed that IMPDH filament assembly is a mechanism to prevent feedback inhibition of IMPDH and is therefore important for the increased nucleotide production required in hyperproliferating cells, like activated T cells. Fifteen years later, we review the history and current knowledge in both the anti-RR autoantibody and IMPDH filament fields. TAKE-HOME MESSAGE: Anti-rods/rings are recognized as an example of a drug-induced autoantibody in hepatitis C patients treated with interferon and ribavirin, although new studies suggest anti-rods/rings may be detected in other contexts and may depend on unknown environmental or genetic factors in different populations. Recent data suggest that the assembly of IMPDH into rod and ring structures, the targets of anti-rods/rings autoantibody, is a mechanism for hyperproliferating cells, like activated T cells, to maintain increased guanine nucleotide levels to support rapid cell division.