The artist Keith Haring once wrote, “Good and evil are not complete opposites… in fact, [they] are often one and the same.” Such dualism is commonplace in the field of cytokine biology, and among the most salient examples of this is interleukin (IL)-27, which was initially classified as proinflammatory but later found to have critical antiinflammatory properties. In this issue, Jones et al. uncover a novel regulatory function of IL-27 that is relevant for the pathogenesis of rheumatoid arthritis (RA).
Using a mouse model of RA, the authors discover that IL-27 is a potent inhibitor of ectopic lymphoid-like structures (ELSs), which tend to occur at sites of chronic inflammation, like arthritic joints, and are associated with severe forms of rheumatic disease. They first demonstrate that both ELS formation and synovial pathology are exaggerated in mice lacking the IL-27 receptor (IL-27R) and then link these phenomena to the well-documented ability of IL-27 to regulate IL-17, a cytokine known to promote ELSs in chronic disease settings. Thus, a model emerges whereby IL-27 limits ELS formation and, in turn, slows RA progression by restricting the ability of infiltrating T cells to produce IL-17, as well as other pro-ELS agents like podoplanin, which was found to be coexpressed with IL-17 and subject to IL-27–mediated inhibition.
The present work also yields potentially valuable insights into the pathogenesis and treatment of RA. Although synovial ELSs are known to correlate with lymphoid infiltrates and disease severity, the cellular factors that control ELS formation have only recently begun to be appreciated. The authors implicate IL-27 by demonstrating an inverse relationship between cytokine production and the appearance of synovial ELS, which, notably, are highly enriched for IL-27R–expressing T cells. Based on loss-of-function studies in mice, they propose a causal link and go one step further to endorse IL-27 as a predictive biomarker for stratifying RA patients into ELS-negative and -positive subtypes. The ability to make this distinction at early stages of disease could provide both a rationale for selective deployment of ELS-targeting drugs and an impetus for development of IL-27–based biologics. Differences between ELS-negative and -positive forms of disease may also explain why IL-27 appears to limit pathology in some, but not all, models of RA. This host-protective quality may become apparent in models with overt ELS involvement, as with the antigen-driven protocol used here, whereas its more damaging, proinflammatory qualities may dominate in settings where ELSs are not prevalent, such as during the onset of disease or in models with more diffuse infiltrates.
The work also raises new questions about other cytokines and cell types that regulate ELS formation and maintenance, whether this pathway is operative in other disease settings that feature ELSs (such as MS), and whether the results form this (or any) mouse model translate to the human disease. But fear not, as Haring said, “[if we] don’t understand anything. That is, I think, the key to understanding everything.”