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Rheumatoid arthritis (RA), a painful disease that causes chronic inflammation in the joints, affects about 1% of the population worldwide. Despite treatments, many patients continue to experience flare-ups and joint damage. While it’s long been known that ongoing activation of the immune system plays a key role in RA, exactly what causes this prolonged response by the body’s own immune cells has remained unclear.
A new study from researchers at the Kennedy Institute, University of Oxford performed by KTRR funded DPhil student Anna Marzeda and colleagues within the RACE consortium sheds new light on this problem by exploring how certain immune cells called monocytes "remember" past triggers inside the body and react differently over time. This “immune memory” is usually helpful in fighting infections, but in RA, it may worsen inflammation.
Published in the Annals of the Rheumatic Diseases, the study focused on analysis of inflammatory triggers relevant to the pathogenesis of RA, including the matrix molecule tenascin-C, which is released during joint injury and signals the immune system to respond. Anna Marzeda explained: ‘We discovered that tenascin-C reprograms monocytes in a unique way, causing them to react strongly not only to repeated injury signals but also to other inflammatory triggers found in RA joints. Unlike typical responses to infections, this internal “danger signal” primed monocytes to respond very differently to re-challenge, in particular ramping up inflammatory signals associated with altered metabolism, iron-related cell death and treatment non-response, promoting long-lasting inflammation and tissue damage.’
Further investigation confirmed that monocyte memory is linked to changes in how the cells' genes are regulated at the epigenetic level and revealed again that infectious stimuli and tenascin-C act in distinct ways to reprogramme immune cells. Moreover, RA monocytes had higher levels of proteins that control chromatin accessibility and histone modifications, altering which genes can be turned on or off, and displayed higher levels of tenascin-C activated immune memory signalling. In immune cells isolated from the joints of people with RA, memory pathways driven by tenascin-C were especially high in macrophage subsets known to cause disease flare.
Kim Midwood, Professor of Matrix Biology at the Kennedy Institute, who led the study said: ‘This study provides new insights into pathways underpinning exacerbated inflammation in RA that until now have been poorly explored but which may offer the potential to move towards more focused inhibition of disease relevant immune activation. This could lead to new therapies that specifically calm harmful inflammation in RA without broadly suppressing the immune system, preventing flare, reducing side effects and improving outcomes for patients.’