Immunological memory in rheumatic inflammation - a roadblock to tolerance induction

Why do we still have no cure for chronic inflammatory diseases? One reason could be that current therapies are based on the assumption that chronic inflammation is driven by persistent 'acute' immune reactions. Here we discuss a paradigm shift by suggesting that beyond these reactions, chronic inflammation is driven by imprinted, pathogenic 'memory' cells of the immune system. This rationale is based on the observation that in patients with chronic inflammatory rheumatic diseases refractory to conventional immunosuppressive therapies, therapy-free remission can be achieved by resetting the immune system; that is, by ablating immune cells and regenerating the immune system from stem cells. The success of this approach identifies antigen-experienced and imprinted immune cells as essential and sufficient drivers of inflammation. The 'dark side' of immunological memory primarily involves memory plasma cells secreting pathogenic antibodies and memory T lymphocytes secreting pathogenic cytokines and chemokines, but can also involve cells of innate immunity. New therapeutic strategies should address the persistence of these memory cells. Selective targeting of pathogenic immune memory cells could be based on their specificity, which is challenging, or on their lifestyle, which differs from that of protective immune memory cells, in particular for pathogenic T lymphocytes. The adaptations of such pathogenic memory cells to chronic inflammation offers entirely new therapeutic options for their selective ablation and the regeneration of immunological tolerance. Pathogenic, long-lived memory cells of the immune system present a barrier to resolution of chronic inflammatory rheumatic diseases. Approaches to selectively eliminate these cells while sparing protective immune memory cells could restore immunological tolerance and achieve treatment-free remission.

Automated summary

The lack of cure for chronic inflammatory diseases may be due to pathogenic memory cells of the immune system driving the inflammation. Resetting the immune system by ablating immune cells and regenerating it from stem cells has shown success in achieving therapy-free remission. Targeting pathogenic immune memory cells, particularly pathogenic T lymphocytes, offers new therapeutic options for chronic inflammation.